HK1248697B - Therapeutic compounds and uses thereof - Google Patents

Description

Therapeutic compounds and their uses

Invention priority

This application claims priority to U.S. Provisional Patent Application No. 62/109,522, filed January 29, 2015, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to compounds useful as TAF1 inhibitors.

Background Art

Chromatin is a complex combination of DNA and protein that constitutes chromosomes. It is found in the nucleus of eukaryotic cells and is divided into heterochromatin (condensed) and euchromatin (unfolded) forms. The main components of chromatin are DNA and protein. Histones are the primary protein components of chromatin, which serve as the spool around which DNA is wound. The function of chromatin is to package DNA into smaller volumes to accommodate in cells, enhance DNA to carry out mitosis and meiosis and to serve as a mechanism for controlling expression and DNA replication. Chromatin structure is controlled by a series of post-translational modifications to histones, especially histones H3 and H4, and most commonly in the "histone tails" that extend beyond the core nucleosome structure. Histone tails are easy to participate in protein-protein interactions and are also the parts of histones most susceptible to post-translational modifications. These modifications include acetylation, methylation, phosphorylation, ubiquitination and SUMOylation. These epigenetic marks are written and erased by specific enzymes that place tags on specific residues in the histone tails, thereby forming an epigenetic code that is subsequently interpreted by the cell to effect gene-specific regulation of chromatin structure and thereby transcription.

Among all classes of proteins, histones are the most susceptible to post-translational modifications. Histone modifications are dynamic because they can be added or removed in response to specific stimuli and these modifications cause changes in chromatin structure and gene transcription. Different classes of enzymes, namely histone acetyltransferases (HATs) and histone deacetylases (HDACs), acetylate or deacetylate specific histone lysine residues (Struhl K., Genes Dev., 1989, 12, 5, 599-606).

Bromodomains, which are about 110 amino acids in length, are found in many chromatin-associated proteins and have been identified in about 70 human proteins (usually adjacent 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 for chromatin structural changes and gene regulation. Proteins containing bromodomains are involved in disease processes including cancer, inflammation and viral replication. See, for example, Prinjha et al., Trends Pharm. Sci., 33 (3): 146-153 (2012) and Muller et al., Expert Rev., 13 (29): 1-20 (September 2011).

TBP-associated factor 1 (TAF1) is a subunit of transcription factor IID and contains a HAT domain and a dual bromodomain (Papai et al., Current Opinion in Genetics & Development 21: 219-224 (2011)). Although the function of TAF1 has not been fully elucidated, the molecule is involved in pathways associated with cancer (see, for example, Kloet et al., Molecular and Cellular Biology 32 (16): 3358-3369 (2012)). Therefore, selective inhibition of TAF1 creates various opportunities for developing novel therapeutic agents for the treatment of human disorders, including cancer.

Therefore, there is a need for compounds that inhibit TAF1 to treat diseases such as cancer and for tools to study the pharmacology of TAF1.

SUMMARY OF THE INVENTION

One aspect includes compounds of formula (I) or salts thereof:

in

R ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl or heterocyclyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, cyano, C _1-3 alkoxy and C _3-8 carbocyclyl optionally substituted with one or more groups independently selected from the group consisting of halogen;

R ² is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl or heterocyclyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl and heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halogen, cyano, C _1-3 alkoxy and C _3-8 carbocyclyl optionally substituted with one or more groups independently selected from the group consisting of halogen;

^R3 is H, _C1-6 alkyl, -N( ^Rb ) ₂ , -C(=O) ^Ra , -C(=O) ^ORa , or a 5-6 membered heteroaryl ring, wherein the _C1-6 alkyl and 5-6 membered heteroaryl rings are optionally substituted with one or more groups independently selected from the group consisting of _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, carbocyclyl, heterocyclyl, oxo, halogen, -NO2, -N( ^Rb ) ₂ , -CN, -C(O)-N( ^Rb ) ₂ , -S(O)-N( ^Rb ) ₂ , -S(O) _{2 -} N( ^Rb ) ₂ , ^-ORb , ^-SRb , -OC(O) ^-Rb , -C(O) ^-Rb , -C(O) ^-ORb , -S(O) ^-Rb , -S(O) ₂ - ^Rb 2-R ^b , ^wherein any C 1-6 ^alkyl , C 2-6 alkenyl, ^C 2-6 _alkynyl , carbocyclyl and heterocyclyl are optionally substituted by one or more groups independently selected from the group consisting of R ^f , oxo, _halogen , -NO ₂ , -N(R ^b ) ² , -CN, -C(O ₎ -N( ^{R b} ) ₂ , -S(O)-N(R ^b ) ₂ , -S(O) ₂ -N(R ^b ) ₂ , _-OR b , -SR ^b , _-OC ( ^O ) _-R ^b , -C(O)-R ^b , -C(O ⁾ -OR ^b , -S(O)-R ^{b b} , -S(O) ₂ -R ^b , -N(R ^b )-C(O)-R ^b , -N(R ^b )-S(O)-R ^b , -N(R ^b )-C(O)-N(R ^b ) ₂ and -N(R ^b )-S(O) ₂ -R ^b ;

^Ra is selected from hydrogen, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, carbocyclyl, and heterocyclyl, wherein any of the _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of ^Rd , oxo, halogen, -NO2, -N( ^Rb ) ₂ , -CN, -C(O)-N( ^Rb ) ₂ , -S(O)-N( _{Rb)2 ,} -S(O ⁾ ₂ -N( ^Rb ) ₂ , ^-ORb , ^-SRb , -OC(O) ^-Rb , -C(O) ^-Rb , -C(O) ^-ORb , -S(O) ^-Rb , -S(O) ₂ - ^Rb , -N( ^Rb )-C(O) ^-Rb , -N(R ^b )-S(O)-R ^b , -N(R ^b )-C(O)-N(R ^b ) ₂ and -N(R ^b )-S(O) ₂ -R ^b ;

each ^Rb is independently selected from hydrogen, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, carbocyclyl, and heterocyclyl, wherein each _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Rc, oxo, halogen, -NO2, -N( ^{Rc )} ₂ , -CN, -C(O)-N( ^Rc ) ₂ , -S(O)-N( ^Rc ) ₂ , -S(O) ₂ - _N(Rc)2 ^, _-ORc ^{, -SRc} , -OC(O) ^-Rc , -C(O) ^-Rc , -C(O)-ORc, -S(O) ^-Rc , -S(O) ₂ ^{-Rc ,} -N( ^Rc )-C(O)-R ^c , -N(R ^c )-S(O)-R ^c , -N(R ^c )-C(O)-N(R ^c ) ₂ , and -N(R ^c )-S(O) ₂ -R ^c ; or two R ^b , taken together with the nitrogen to which they are attached, form a heterocyclyl optionally substituted by one or more groups independently selected from the group consisting of oxo, halogen, and C _1-3 alkyl optionally substituted by one or more groups independently selected from the group consisting of oxo and halogen; and

each R ^c is independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl and heterocyclyl, wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, amino, hydroxy, C _1-6 alkoxy, carbocyclyl, heterocyclyl and C ₁ -C ₆ alkyl optionally substituted with one or more groups independently selected from the group consisting of oxo and halogen; or two R ^c together with the nitrogen to which they are attached form a heterocyclyl optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen and C _1-3 alkyl optionally substituted with one or more groups independently selected from the group consisting of oxo and halogen;

each R ^d is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, carbocyclyl and heterocyclyl, wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, carbocyclyl and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of Re, ^oxo , halogen, _-NO2 , -N( ^Re ) ₂ , -CN, -C(O)-N(Re) ₂ , -S( ^O )-N( ^Re ) ₂ , -S(O) ₂ -N( ^Re ) ₂ , ^-ORe , ^-SRe , -OC(O) ^-Re , -C(O) ^-Re , ^-C (O)-ORc, -S(O) ^-Rc , -S(O) ₂ - ^Rc , -N( ^Rc )-C(O)-R ^c , -N(R ^c )-S(O)-R ^c , -N(R ^c )-C(O)-N(R ^c ) ₂ and -N(R ^e )-S(O) ₂ -R ^e ;

each R ^e is independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, carbocyclyl and heterocyclyl, wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1-6 alkoxy, carbocyclyl and heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen, amino, hydroxy, C 1-6} alkoxy, carbocyclyl, heterocyclyl and C ₁ -C ₆ alkyl optionally substituted with one or more groups independently selected from the group consisting of oxo and halogen; or two R ^e together with the nitrogen to which they are attached form a heterocyclyl optionally substituted with one or more groups independently selected from the group consisting of oxo, halogen and _{C 1-3 alkyl} optionally substituted with one or more groups independently selected from the group consisting of oxo and halogen;

each ^Rf is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, carbocyclyl and heterocyclyl, wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, carbocyclyl and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halogen, amino, hydroxy, C _1-6 alkoxy, carbocyclyl, heterocyclyl and C ₁ -C ₆ alkyl optionally substituted with one or more groups independently selected from oxo and halogen;

R ⁴ is absent or is H, hydroxy or C _1-6 alkyl optionally substituted by one or more groups independently selected from halogen;

R ⁵ is H or C _1-6 alkyl optionally substituted by one or more groups independently selected from halogen; and R ⁶ is C _1-6 alkyl, carbocyclyl or heterocyclyl, said C _1-6 alkyl, carbocyclyl and heterocyclyl are optionally substituted by one or more R ^g ; or R ⁵ and R ⁶ together with the carbon to which they are attached form a carbocyclyl or heterocyclyl, said carbocyclyl and heterocyclyl are optionally substituted by one or more R ^g ;

Each ^Rg is independently selected from _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, carbocyclyl and heterocyclyl, ^Rk , halogen, oxo(=O), -NO2, -N( ^Rh ) ₂ , -CN, -C(O)-N( ^Rh ) ₂ , -S(O)-N( ^Rh ) ₂ , -S(O) _{2 -} N( ^Rh ) ₂ , ^-ORh , -SRh, ^-OC (O)-Rh, -C(O) ^-Rh , -C(O) ^-ORh , -S(O) ^-Rh , ^-S (O) ₂ - ^Rh , -N( ^Rh )-C(O) ^-Rh , -N( ^Rh )-S(O)-Rh, -N( ^Rh )-C( ^O )-N( ^Rh ) ₂ , and -N( ^Rh )-S(O) ₂ -R ^h ;

each R ^h is independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, carbocyclyl, and heterocyclyl, wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halogen, amino, hydroxy, C _1-6 alkoxy, carbocyclyl, heterocyclyl, and C ₁ -C ₆ alkyl optionally substituted with one or more groups independently selected from oxo and halogen; or two R ^h, together with the nitrogen to which they are attached, form a heterocyclyl optionally substituted with one or more groups independently selected from oxo, halogen, and C _1-3 alkyl optionally substituted with one or more groups independently selected from oxo and halogen; and

each ^Rk is independently selected from _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein the _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, carbocyclyl, and heterocyclyl are substituted with one or more groups independently selected from the group consisting of halogen, -NO2, -N( ^Rh ) ₂ , -CN, -C(O)-N( ^Rh ) ₂ , -S(O)-N( ^Rh ) ₂ , -S(O) _{2 -N(Rh)2} ^, _-ORh ^{, -SRh} , -OC(O) ^-Rh , -C( ^O )-Rh, -C(O) ^-ORh , -S(O) ^-Rh , -S(O) ₂ - ^Rh , -N( ^Rh )-C(O) ^-Rh , -N( ^Rh )-S(O) ^-Rh , -N(R ^h )-C(O)-N(R ^h ) ₂ and -N(R ^h )-S(O) ₂ -R ^h .

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

Another aspect includes a method for treating a disorder mediated by TAF1 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 use in preventing or treating a disorder mediated by TAF1.

Another aspect includes the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disorder mediated by TAF1 in an animal (eg, a mammal such as a human).

Another aspect includes a method of inhibiting TAF1 in an animal in need thereof, 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 inhibiting TAF1.

Another aspect includes the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting TAF1 in an animal in need thereof.

Another aspect includes a method for treating cancer in an animal comprising administering to the animal an effective amount of a TAF1 inhibitor.

Another aspect includes TAF1 inhibitors for use in medical therapy.

Another aspect includes TAF1 inhibitors for use in preventing or treating cancer.

Another aspect includes the use of a TAF1 inhibitor in the preparation of a medicament for treating cancer in an animal.

Another aspect includes compounds for studying TAF1.

Another aspect includes 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 terminology are described in more detail below.Chemical elements are identified according to Elements, CAS version, Handbook of Chemistry and Physics, 75th edition.

Unless otherwise stated, the compounds of Formula I include enantiomers, diastereomers and geometric (or conformational) isomers of a given structure. For example, the present application includes R and S configurations, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers and enantiomers, diastereomers and geometric (or conformational) isomer mixtures of each asymmetric center. Unless otherwise stated, the present application includes tautomers of all structures described herein. In addition, unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the present application includes compounds of Formula I below, wherein one or more hydrogens are replaced or enriched with deuterium or tritium, one or more carbons are replaced with ¹³ C or ¹⁴ C carbon, one or more nitrogens are replaced with ¹⁵ N nitrogen, one or more sulfurs are replaced with ³³ S, ³⁴ S or ³⁶ S sulfur, or one or more oxygens are replaced or enriched with ¹⁷ O or ¹⁸ O oxygen. The above compounds can be used as, for example, analytical tools, probes or therapeutic agents in biological assays.

When a specific 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 the mixture of enantiomers is made up of a significantly greater proportion of one enantiomer and may be described by enantiomeric excess (ee%). In certain embodiments, the mixture of enantiomers is made up of at least about 90% by weight of a given enantiomer (about 90% ee). In other embodiments, the mixture of enantiomers is made up of at least about 95%, 98%, or 99% by weight of a given enantiomer (about 95%, 98%, or 99% ee). Enantiomers and diastereomers can 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 pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), chiral salt formation and crystallization and then separation by any of the above methods) or prepared by asymmetric synthesis and optionally further enriched. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (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 Resolving Agents and Optical Resolutions, page 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

The term "heteroatom" refers to any atom independently selected from atoms other than carbon or hydrogen, such as one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon and any quaternized form of nitrogen).

As used herein, the terms "halo" and "halogen" refer to an atom selected from the group consisting of fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

The term "oxo" refers to =0 or (=0) ₂ .

As used herein, the term "unsaturated" refers to a group having one or more units of unsaturation.

The term "carbocyclyl" used alone or as part of a larger group refers to a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms. In one embodiment, the carbocyclyl includes 3 to 12 carbon atoms ( _C3 - _C12 ). In another embodiment, the carbocyclyl includes _C3 - _C8 , _C3 - _C10 , or _C5 - _C10 . In another embodiment, the carbocyclyl as a monocyclic ring includes _C3 - _C8 , _C3 - _C6 , or _C5 - _C6 . In another embodiment, the carbocyclyl as a bicyclic ring includes _C7 - _C12 . In another embodiment, the carbocyclyl as a spirocyclic ring system includes _C5 - _C12 . Examples of monocyclic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuterated cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; groups having 7 to 12 ring atoms. The term "carbocyclyl" includes aryl ring systems as defined herein. The term "carbocyclyl" also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocyclic, bicyclic or spirocyclic carbocyclic rings).

As used herein, the term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon group. In one embodiment, the alkyl group has 1 to 18 carbon atoms ( _C1 - _C18 ). In other embodiments, the alkyl group is _C0 - _C6 , _C0 - _C5 , _C0 - _C3 , _C1 - _C12 , _C1 - _C10 , _C1 - _C8 , _C1 - _C6 , _C1 - _C5 , _C1 - _C4 , or _C1 - _C3 . _C0 alkyl refers to a bond. Examples of alkyl _groups include methyl (Me, _-CH3 ), ethyl (Et, _-CH2CH3 ), 1-propyl (n-Pr, _n -propyl, _-CH2CH2CH3 ), 2-propyl (i-Pr, isopropyl, -CH( _CH3 ) ₂ ), 1-butyl ( _n -Bu, n-butyl, _{-CH2CH2CH2CH3} ), ₂ -methyl- ₁ -propyl (i-Bu, isobutyl _{, -CH2CH} ( _CH3 ) ₂ ), 2-butyl (s-Bu, sec _- butyl, -CH( _CH3 ) _CH2CH3 ) _, 2-methyl-2-propyl (t-Bu, tert-butyl, -C( _CH3 ) ₃ ), _{1 -} pentyl ( _n- pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH( _CH3 ) _{CH2CH2CH3 ) , 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 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.

As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl groups include groups having "cis" and "trans" orientations, or "E" and "Z" orientations. In one example, an alkenyl group has 2 to 18 carbon atoms ( _C2 - _C18 ). In other examples, an alkenyl group is _C2 - _C12 , _C2 - _C10 , _C2 - _C8 , _C2 - _C6 , or _C2 - _C3 . Examples include, but are not limited to, vinyl (—CH═CH ₂ ), prop-1-enyl (—CH═CHCH ₃ ), prop-2-enyl (—CH ₂ CH═CH ₂ ), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbut-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

As used herein, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. In one example, the alkynyl group has 2 to 18 carbon atoms ( _C2 - _C18 ). In other examples, the alkynyl group is _C2 - _C12 , _C2 - _C10 , _C2 -C8, C2- _C6 , or _{C2 - C3} . Examples include, but are not limited to, ethynyl (-C≡CH), prop-1-ynyl ( _{-C≡CCH3 )} , prop-2-ynyl (propargyl, _-CH2C≡CH ), but-1-ynyl, but-2-ynyl, and but-3-ynyl.

The term "alkoxy" refers to a linear or branched monovalent group represented by the formula -OR, wherein R is an alkyl, alkenyl, alkynyl or carbocyclic group. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy and cyclopropyloxy.

As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more (eg, 1, 2, 3, or 4) halogens.

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

The term "heteroaryl" used alone or as part of a larger group such as "heteroarylalkyl" or "heteroarylalkoxy" refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 4-6 membered monocyclic aromatic groups in which one or more ring atoms are 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 are independently optionally substituted nitrogen, sulfur, or oxygen. Examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazo[1,5-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, purinyl, benzoxazolyl, benzofuranyl, benzo The term "heteroaryl" also includes groups wherein the heteroaryl group 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, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]1,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic, bicyclic or tricyclic.

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

In one example, the heterocyclic radical includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spirocycle systems, wherein the ring atoms are carbon and 1-5 ring atoms are heteroatoms selected from nitrogen, sulfur or oxygen, which are independently optionally substituted with one or more groups. In one example, the heterocyclic radical includes 1 to 4 heteroatoms. In another example, the heterocyclic radical includes 3 to 7 membered monocycles with one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, the heterocyclic radical includes 4 to 6 membered monocycles with one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, the heterocyclic radical includes 3 membered monocycles. In another example, the heterocyclic radical includes 4 membered monocycles. In another example, the heterocyclic radical includes 5-6 membered monocycles. In one example, the heterocyclic radical includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (eg, NO, SO, SO ₂ ) and any nitrogen heteroatom may optionally be quaternized (eg, [NR ₄ ] ⁺ Cl ⁻ , [NR ₄ ] ⁺ OH ⁻ ). Examples of heterocyclic groups include oxiranyl, aziridinyl, thiirane, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, Oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl 1-Hexyl, 2-Hexyl, 3-Hexyl, 4-Hexyl, 1-Hexyl, 2-Hexyl, 3 ...3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 3-Hexyl, 1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 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]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]decan-2-one, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclic groups containing sulfur or oxygen atoms and 1-3 nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide; thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl; oxazolyl, such as oxazol-2-yl; and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Examples of 5-membered heterocyclic rings containing 2 to 4 nitrogen atoms include imidazolyl, 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. Examples of 5-membered heterocyclic groups fused to benzene are benzoxazol-2-yl, benzothiazol-2-yl, and benzimidazol-2-yl. Examples of 6-membered heterocyclic groups containing 1-3 nitrogen atoms and optionally containing sulfur or oxygen atoms are pyridyl, such as pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; pyrimidinyl, such as pyrimidin-2-yl and pyrimidin-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, specifically pyridazin-3-yl; and pyrazinyl. Pyridine N-oxide and pyridazine N-oxide, and pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazinyl, and 1,3,4-triazin-2-yl are other examples of heterocyclic groups.

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

As used herein, the term "polycyclic" refers to a ring system having two or more (eg, 2, 3, 4, or 5) rings in a fused, bridged, or spiro relationship.

As used herein, the term "inhibitor" refers to a compound that binds to and inhibits the TAF1 bromodomain with measurable affinity and activity. In certain embodiments, the inhibitor has an _IC50 or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 10 nM.

As used herein, the terms "measurable affinity" and "measurably inhibit" refer to a measurable decrease in the activity of the TAF1 bromodomain between (i) a sample comprising a compound of Formula I or a composition thereof and the above-mentioned TAF1 bromodomain and (ii) an equivalent sample comprising the above-mentioned TAF1 bromodomain in the absence of the compound or composition thereof.

"Pharmaceutically acceptable salts" include acid and base addition salts. It should be understood that when a compound or example herein is shown as a specific salt, the application includes the corresponding free base and 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, etc., which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable; and 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, etc.

"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. Specifically, 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, hydroxylamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Specific organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline and caffeine.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization 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 solvents 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.

"Therapeutically effective amount" refers to an amount of a compound of the present invention that (i) treats a specific disease, condition, or disorder; (ii) alleviates, relieves, or eliminates one or more symptoms of a specific disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. For cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down and preferably stop to some extent) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down and preferably stop to some extent) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate one or more symptoms associated with cancer to some extent. For cancer therapy, efficacy can be measured, for example, by assessing time to disease progression (TTP) and/or determining a response rate (RR). For immune disorders, a therapeutically effective amount is an amount sufficient to alleviate or relieve symptoms of allergic disorders, autoimmune and/or inflammatory diseases, or symptoms of acute inflammatory responses (e.g., asthma). In some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein that is sufficient to significantly reduce the activity or number of drug-resistant or persistently drug-resistant cancer cells.

"Treatment" refers to a clinical intervention that attempts to change the natural process of the treated individual or cell and can be used for prevention or implementation in a clinical pathological process. The desired effect of treatment includes one or more of the following: preventing the occurrence or recurrence of the disease, alleviating symptoms, alleviating any direct or indirect pathological consequences of the disease, stabilizing the disease state (i.e., not worsening), preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state, extending the survival period and alleviating or improving prognosis compared to the expected survival period without treatment. In certain embodiments, the compound of Formulas I is used to delay the development of a disease or disorder or to slow down the progress of a disease or disorder. Those individuals in need of treatment include those individuals who have already suffered from a disease or disorder and those individuals who are susceptible to a disease or disorder (e.g., due to genetic mutations or abnormal expression of genes or proteins) or those individuals in which a disease or disorder is to be prevented.

Unless otherwise specifically stated, "a/kind" as used herein refers to one or more. "Another/kind" as used herein refers to at least another/kind or more.

Example values

In one embodiment, R ¹ is C _1-6 alkyl optionally substituted with one or more groups independently selected from halogen, cyano, C _1-3 alkoxy, and C _3-8 carbocyclyl optionally substituted with one or more groups independently selected from halogen.

In one embodiment, R ¹ is methyl.

In one embodiment, R ² is C _1-6 alkyl optionally substituted with one or more groups independently selected from halogen, cyano, C _1-3 alkoxy, and C _3-8 carbocyclyl optionally substituted with one or more groups independently selected from halogen.

In one embodiment, ^R2 is methyl.

In one embodiment, ^R3 is H.

In one embodiment, ^R is _C1-6 alkyl optionally substituted by one or more groups independently selected from the group consisting of carbocyclyl, heterocyclyl, oxo, halogen, -NO2, -N( ^Rb ) ₂ , -CN, -C(O)-N( ^Rb ) ₂ , -S(O)-N( ^Rb ) ₂ , -S(O) _{2 -} N( ^Rb ) ₂ , ^-ORb , ^-SRb , -OC(O)-Rb, -C(O) ^-Rb , -C(O) ^-ORb , -S(O) ^-Rb , ^-S (O) ₂ - ^Rb , -N( ^Rb )-C(O) ^-Rb , -N( ^Rb )-S(O) ^-Rb , -N( ^Rb )-C(O)-N( ^Rb ) ₂ , and -N( ^Rb )-S(O) ₂ - ^Rb. , wherein any carbocyclyl and heterocyclyl groups are optionally substituted by one or more groups independently selected from the group consisting of ^Rf , oxo, halogen, _-NO2 , -N( ^Rb ) ₂ , -CN, -C(O)-N(Rb) ₂ , -S ⁽ O)-N( ^Rb ) ₂ , -S(O) ₂ -N( ^Rb ) ₂ , ^-ORb , ^-SRb , -OC(O) ^-Rb , -C(O) ^-Rb , -C(O) ^-ORb , -S(O) ^-Rb , -S(O) ₂ - ^Rb , -N( ^Rb )-C(O) ^-Rb , -N( ^Rb )-S(O) ^-Rb , -N( ^Rb )-C(O)-N( ^Rb ) ₂ , and -N( ^Rb )-S(O) ₂ - ^Rb .

In one embodiment, R ³ is -N(R ^b ) ₂ .

In one embodiment, R ³ is -C(=O)R ^a .

In one embodiment, R ³ is -C(=O)OR ^a .

In one embodiment, ^R is a 5-6 membered heteroaryl ring optionally substituted by one or more groups independently selected from the group consisting of: _{Ci_6} alkyl, _{C2_6} alkenyl, _{C2_6} alkynyl, carbocyclyl, heterocyclyl, oxo, halogen, -NO2, -N( ^Rb ) ₂ , -CN, -C(O)-N(Rb) ₂ , -S(O)-N( ^{Rb )} ₂ , -S(O) ₂ -N( ^Rb ) ₂ , _-ORb , ^-SRb , -OC(O) ^-Rb , -C(O) ^-Rb , ^-C (O) ^-ORb , -S(O) ^-Rb , -S(O) ₂ - ^Rb , -N( ^Rb )-C(O) ^-Rb , -N( ^Rb )-S(O) ^-Rb , -N( ^Rb )-C(O)-N( ^Rb ) ₂ and -N(R ^b )-S(O) ₂ -R ^b , wherein any C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl and heterocyclyl are optionally substituted by one or more groups independently selected from the group consisting of R ^f , oxo, halogen, -NO ₂ , -N(R ^b ) ₂ , -CN, -C(O)-N(R b ) 2 , -S(O)-N(R ^b ) ₂ , -S(O) ₂ -N(R ^b ) ₂ , -OR b , -SR ^b , -OC( ^O )-R ^b , -C(O)-R ^b , -C(O)-OR b , -S(O)-R ^b , -S(O) ₂ -R ^b , -N(R b )-C(O) _-R ^b , -N(R ^b )-S(O)-R ^b , -N(R ^b )-S(O)-R ^b , -N(R b ) ^{- b} )-C(O)-N(R ^b ) ₂ and -N(R ^b )-S(O) ₂ -R ^b .

In one embodiment, ^R3 is selected from:

In one embodiment, ^R3 is selected from:

In one embodiment, ^R3 is selected from:

In one embodiment, ^R3 is selected from:

In one embodiment, the compound of formula (I) is a compound of formula (Ia) or a salt thereof:

In one embodiment, ^R4 is H.

In one embodiment, ^R4 is hydroxy.

In one embodiment, R ⁴ is C _1-6 alkyl optionally substituted with one or more groups independently selected from halogen.

In one embodiment, ^R5 is H.

In one embodiment, R ⁵ is C _1-6 alkyl optionally substituted with one or more groups independently selected from halogen.

In one embodiment, R ⁶ is C _1-6 alkyl optionally substituted with one or more R ^g .

In one embodiment, R ⁶ is carbocyclyl optionally substituted with one or more R ^g .

In one embodiment, R ⁶ is heterocyclyl optionally substituted with one or more R ^g .

In one embodiment, R ⁶ is C ₁ alkyl substituted with oxo and -N(R ^h ) ₂ to form the group -C(O)-N(R ^h ) ₂ .

In one embodiment, R ⁵ and R ⁶ together with the carbon to which they are attached form a carbocyclyl optionally substituted with one or more R ^g .

In one embodiment, R ⁵ and R ⁶ together with the carbon to which they are attached form a heterocyclyl optionally substituted with one or more R ^g .

In one embodiment, R ⁴ is absent; and R ⁵ and R ⁶ together with the carbon to which they are attached form an aryl ring optionally substituted with one or more R ^g which is attached to the remainder of formula (I) at an atom of the aryl ring.

In one embodiment, R ⁴ is absent; and R ⁵ and R ⁶ together with the carbon to which they are attached form a heterocyclyl optionally substituted with one or more R ^g which is attached to the remainder of formula (I) at an atom of the aromatic ring.

In one embodiment, the group:

Selected from:

In one embodiment, the group:

Selected from:

In one embodiment: R ¹ is C _1-6 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, C _1-3 alkoxy, and C _3-8 carbocyclyl optionally substituted by one or more groups independently selected from the group consisting of halogen;

^R2 is _C1-6 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, _C1-3 alkoxy, and _C3-8 carbocyclyl optionally substituted by one or more groups independently selected from the group consisting of halogen; and

^R3 is _C1-6 alkyl optionally substituted by one or more groups independently selected from the group consisting of carbocyclyl, heterocyclyl, oxo, halogen, -NO2, -N( ^Rb ) ₂ , -CN, -C(O)-N( ^Rb ) ₂ , -S(O)-N( ^Rb ) ₂ , -S(O) ₂ -N( ^Rb ) _{2 ,} ^-ORb , ^-SRb , -OC(O) ^-Rb , -C(O) ^-Rb , -C(O) ^-ORb , -S(O) ^-Rb , -S(O) ₂ - ^Rb , -N( ^Rb )-C(O) ^-Rb , -N( ^Rb )-S(O) ^-Rb , -N( ^Rb )-C(O)-N( ^Rb ) ₂ , and -N( ^Rb )-S(O) ₂ - ^Rb , wherein any carbocyclyl and heterocyclyl groups are optionally substituted by one or more groups independently selected from the group consisting of ^Rf , oxo, halogen, _-NO2 , -N( ^Rb ) ₂ , -CN, -C(O)-N(Rb) ₂ , -S ⁽ O)-N( ^Rb ) ₂ , -S(O) ₂ -N( ^Rb ) ₂ , ^-ORb , ^-SRb , -OC(O) ^-Rb , -C(O) ^-Rb , -C(O) ^-ORb , -S(O) ^-Rb , -S(O) ₂ - ^Rb , -N( ^Rb )-C(O) ^-Rb , -N( ^Rb )-S(O) ^-Rb , -N( ^Rb )-C(O)-N( ^Rb ) ₂ , and -N( ^Rb )-S(O) ₂ - ^Rb .

In one embodiment: R ¹ is C _1-6 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, C _1-3 alkoxy, and C _3-8 carbocyclyl optionally substituted by one or more groups independently selected from the group consisting of halogen;

^R2 is _C1-6 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, _C1-3 alkoxy, and _C3-8 carbocyclyl optionally substituted by one or more groups independently selected from the group consisting of halogen; and

R ³ is -N(R ^b ) ₂ .

In one embodiment: R ¹ is C _1-6 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, C _1-3 alkoxy, and C _3-8 carbocyclyl optionally substituted by one or more groups independently selected from the group consisting of halogen;

^R2 is _C1-6 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, _C1-3 alkoxy, and _C3-8 carbocyclyl optionally substituted by one or more groups independently selected from the group consisting of halogen; and

R ³ is -C(=O)OR ^a .

In one embodiment: R ¹ is C _1-6 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, C _1-3 alkoxy, and C _3-8 carbocyclyl optionally substituted by one or more groups independently selected from the group consisting of halogen;

^R2 is _C1-6 alkyl optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, _C1-3 alkoxy, and _C3-8 carbocyclyl optionally substituted by one or more groups independently selected from the group consisting of halogen; and

^R3 is a 5-6 membered heteroaryl ring optionally substituted by one or more groups independently selected from the group consisting of _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, carbocyclyl, heterocyclyl, oxo, halogen, -NO2, -N( ^Rb ) ₂ , -CN, -C(O)-N( ^Rb ) ₂ , -S(O)-N( ^Rb ) ₂ , -S(O) ₂ - _N(Rb)2 ^, _-ORb , ^-SRb , -OC(O) ^-Rb , -C ⁽ O) ^-Rb , -C(O) ^-ORb , -S(O) ^-Rb , -S(O) ₂ - ^Rb , -N( ^Rb )-C(O) ^-Rb , -N( ^Rb )-S(O) ^-Rb , -N( ^Rb )-C(O)-N( ^Rb ) _2-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl and heterocyclyl are optionally substituted by one or more groups independently selected from the group consisting of R ^f , oxo, halogen, -NO ₂ , -N(R ^b ) ₂ , -CN, ^-C (O)-N(R b ) ₂ , -S(O)-N(R ^b ) ₂ , -S(O) 2-N(R ^b ) ₂ , -OR b , -SR b , _-OC (O)-R ^b , -C(O)-R b , _-C ( ^O ) _-OR ^b , -S(O)-R ^b , -S(O) 2-R ^b , -N(R b )-C(O)-R ^b , ^-N (R b )-S(O)-R ^b , -N( _R b )-S( ^O )-R ^b , -N(R b )-S(O)-R ^b , -N(R ^b )-S(O) ^{-R b} )-C(O)-N(R ^b ) ₂ and -N(R ^b )-S(O) ₂ -R ^b .

In one embodiment, the group:

Selected from:

In one embodiment, the compound is selected from:

and its salts.

One embodiment provides a composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, or vehicle.

One embodiment provides a method for treating a disorder mediated by TAF1 in an animal, the method comprising administering to the animal a compound disclosed herein or a pharmaceutically acceptable salt thereof.

One embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

One embodiment provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in preventing or treating a disorder mediated by TAF1.

One embodiment provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disorder mediated by TAF1 in an animal (eg, a mammal such as a human).

One embodiment provides synthetic intermediates and synthetic methods disclosed herein that can be used to prepare the compounds disclosed herein or salts thereof.

Use, preparation and administration

Pharmaceutical compositions

Another aspect includes a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof. In one embodiment, the composition further comprises a pharmaceutical carrier, adjuvant or vehicle. In another embodiment, the composition further comprises an amount of a compound sufficient to measurably inhibit the TAF1 bromodomain. In certain embodiments, the composition is formulated for administration to a patient in need thereof.

As used herein, the term "patient" or "subject" refers to an animal, such as a mammal, such as a human. In one embodiment, the patient or subject 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 formulated compound. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

The compositions comprising a compound of Formula I or a salt thereof can be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, buccally, sublingually, vaginally, intraperitoneally, intrapulmonary, intradermally, epidurally or by implanted reservoir. 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 or a compound disclosed herein or a pharmaceutically acceptable salt thereof is formulated into 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, or a compound disclosed herein or a pharmaceutically acceptable salt thereof, comprises one or more of the following: (i) an inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate; (ii) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (iii) a binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or acacia; (iv) a humectant, such as glycerol; (v) a disintegrant, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, or sodium carbonate; (vi) a solution retarding 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 adsorbent, 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 buffer. In certain embodiments, the above composition for solid oral dosage form can be formulated as a filler in soft and hard filled gelatin capsules comprising one or more excipients such as lactose, polyethylene glycol, etc.

In certain embodiments, tablets, lozenges, capsules, pills, and granules comprising a compound of Formula I, or a salt thereof, or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, optionally comprise a coating or shell such as an enteric coating. They may optionally comprise an opacifier and may also have a component that releases the active ingredient only or preferentially in a certain portion of the intestinal tract, optionally in a delayed manner. Examples of embedding components include polymers and waxes, which may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

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

In another embodiment, the composition includes a liquid dosage form comprising a compound of Formula I or a salt thereof for oral administration and optionally further includes one or more pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In certain embodiments, the liquid dosage form optionally further includes one or more inert diluents such as water or other solvents, solubilizers, and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, or fatty acid esters of dehydrated sorbitol, and mixtures thereof. In certain embodiments, the liquid oral composition optionally further includes one or more adjuvants such as wetting agents, suspending agents, sweeteners, flavoring agents, and aromatics.

Injectable preparations such as sterile aqueous or oily suspensions for injection can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injections.

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

In order to prolong the effect of the compound of formula (I) or the compound disclosed herein, it is generally desired to slow down the absorption of the compound after subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound thus depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. The injection reservoir form is prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactic acid-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Reservoir-type injection preparations are also prepared by embedding the compound in liposomes or microemulsions 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, or a compound or a salt thereof disclosed herein, with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, such as those that are solid at ambient temperature but liquid at body temperature and thereby melt in the rectum or vaginal cavity and release the compound of Formula (I) or a compound disclosed herein.

Exemplary dosage forms for topical or transdermal administration of a compound of formula (I) or a compound disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The compound of formula (I) or its salt or a compound disclosed herein or its salt is mixed with a pharmaceutical carrier and an optional preservative or buffer under aseptic conditions. Other formulation examples include ophthalmic preparations, ear drops, eye drops, and transdermal patches. Transdermal formulations can be prepared by dissolving or dispersing the compound of formula (I) or its salt in a medium such as ethanol or dimethyl sulfoxide. Absorption enhancers can also be used to increase the flux of the compound through the skin. Rate can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or a gel.

Nasal aerosol or inhalation formulations of a compound of formula (I) or a salt thereof, or a compound or salt thereof disclosed herein, may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizers or dispersants.

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

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

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

An exemplary tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or a salt thereof and further comprises about 5-30 mg of anhydrous lactose, about 5-40 mg of croscarmellose sodium, about 5-30 mg of polyvinyl pyrrolidone (PVP) K30 and about 1-10 mg of magnesium stearate. The process of preparing the tablet comprises mixing the powdered ingredients together and further mixing with a PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared as follows: about 2-500 mg of a compound of formula I or a salt thereof is dissolved in a suitable buffer solution, such as a phosphate buffer, and tonicity agents, such as salts, such as sodium chloride, are added as needed. The solution can be filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.

Uses of compounds and pharmaceutical compositions

Another aspect includes the use of a compound of formula (I) or a salt thereof, or a compound or salt thereof disclosed herein, for inhibiting TAF1 (in vitro or in vivo).

Another embodiment includes a method for treating a condition mediated by TAF1 in an animal, comprising administering to the animal a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a compound disclosed herein or a pharmaceutically acceptable salt thereof. Conditions mediated by TAF1 include, but are not limited to, those described herein.

Another embodiment includes a method of increasing the efficacy of a cancer therapy 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, or a compound disclosed herein 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, or a compound disclosed herein or a pharmaceutically acceptable salt thereof.

Another embodiment includes a method of extending the duration of response to a cancer treatment in an animal, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to an animal receiving cancer treatment, wherein the duration of response to the cancer treatment is extended when the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered beyond the duration of response to the cancer treatment in the absence of the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

Another embodiment includes a method for treating cancer in an individual, the method comprising administering to the individual (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof and (b) a cytotoxic agent. In one embodiment, the cytotoxic agent is selected from antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutics, 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 can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to susceptible individuals (e.g., based on symptom history and/or genetic or other predisposing factors) before the onset of symptoms. Treatment can also continue, for example, to prevent or delay recurrence of symptoms after they have resolved.

TAF1-mediated disorders

A "TAF1-mediated disorder" is characterized by the involvement of TAF1 in the appearance, manifestation, severity, or progression of one or more symptoms or disease markers of the disorder.

Conditions mediated by TAF1 include cancers including, but not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, and chondrosarcoma. disease, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate Prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelioma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin lymphoma), malignant and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NM C), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, 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.

Conditions mediated by TAF1 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 diseases, 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, sepsis, systemic lupus erythematosus, Takayasu's arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

Conditions mediated by TAF1 also include AIDS; chronic kidney disease, including but not limited to diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease, and tubulointerstitial nephritis; acute kidney injury or disease or condition, including but not limited to those caused by ischemia-reperfusion, by cardiac surgery and major surgery, by percutaneous coronary intervention, by contrast media, by sepsis, by pneumonia, and by drug toxicity; obesity; dyslipidemia; hypercholesterolemia; Alzheimer's disease; metabolic syndrome; hepatic steatosis; type 2 diabetes; insulin resistance; and diabetic retinopathy.

Co-administration of compounds with other drugs

The compound of formula (I) or its salt or the compound disclosed herein or its pharmaceutically acceptable salt can be used alone or in combination with other drugs for treatment. For example, the second drug in the pharmaceutical combination formulation or dosing regimen may have an activity complementary to that of the compound of formula (I) so that they do not adversely affect each other. The compounds can be administered together or separately in a single pharmaceutical composition. In one embodiment, the compound or its pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

The term "co-administration" refers to the simultaneous administration of a compound of formula (I) or a salt thereof, or a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one or more active pharmaceutical ingredients (including cytotoxic agents and radiotherapy) or their separate sequential administration in any manner. If the administration is not simultaneous, the compounds are administered at times close to each other. In addition, it does not matter whether the compounds are administered in the same dosage form, for example, one compound may be administered topically and the other compound may be administered orally.

In general, any drug active against the disease or condition being treated can be co-administered. Examples of such drugs can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (eds.), 6th ed. (February 15, 2001), Lippincott Williams & Wilkins Publishers. One skilled in the art will be able to discern which drug combinations may be useful based on the specific properties of the drugs and diseases involved.

In one embodiment, the method of treatment includes co-administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent. The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents cell 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 radioisotopes of Lu); chemotherapeutic agents; growth inhibitors; enzymes and fragments thereof, such as nucleic acid hydrolases; 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 can be selected from 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.

"Chemotherapeutic agents" include chemical compounds that can be used to treat cancer. Examples of chemotherapeutic agents include erlotinib (Genentech/OSI Pharm.), bortezomib (Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (AstraZeneca), sunitinib (Pfizer/Sugen), letrozole (Novartis), imatinib mesylate (Novartis), finasunate (Novartis), oxaliplatin (Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (Sirolimus, Wyeth), lapatinib (GSK572016, Glaxo Smith Kline), lonafamib (SCH 66336), sorafenib (Bayer Labs), gefitinib (AstraZeneca), AG1478, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquinone, metodepa, and uredepa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trihydroxymethylmelamine; annonacetic acid lactones (particularly bratacin and bratacinone); camptothecins (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogs adolesine, carzelesin, and biszelesin); cryptophycins (specifically cryptophycin 1 and cryptophycin 8); adrenocortical steroids (including prednisone and prednisolone); cyproterone acetate ; 5α-reductase, including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dolastatin; aldesleukin; talc, duocarmycin (including the synthetic analogs KW-2189 and CB1-TM1); cypermethrin; cypermethrin; cypermethrin; sponge inhibin; nitrogen mustards, such as chlorambucil, naphthiazolin, clofosamide, estramustine, ifosfamide, mechlorethamine, oxazolidinone hydrochloride, melphalan, neomuscarin, phenylephrine, prednimustine, trofosfamide, uracil mustard; nitroureas, such as carmustine, chlorozolin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicins and particularly calicheamicin gamma and omega (Angewandte), Chem. Intl. Ed. Engl. (1994) 33: 183-186); daptomycins, including daptomycin A; bisphosphonates, such as clodronate; esperamicins; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclarubics, actinomycin, anthramycin, azaserine, bleomycin, actinomycin C, carabicin, carminomycin, carmomycin, chromomycin, dactinomycin, daunorubicin, detoximcin, 6-diazo-5-oxo-L-normal Leucine, (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, mexilomycin, mitomycins such as mitomycin C, mycophenolic acid, noramycin, olivomycin, peplomycin, porfiromycin, puromycin, triferon-adriamycin, rhodorubicin, streptozocin, streptozocin, tuberculin, ubenimex, zinstatin, daunorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid Analogs, such as dimethylformamide, methotrexate, tropol, and trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiopurine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens, such as calosterone, drostanolone propionate, cyclothiocarbamate, melastane, and testolactone; antiadrenal agents, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as folinic acid; aceglucuronolactone; and aldehyde phospholipids. Amide glycosides; aminolevulinic acid; eniluracil; aminophenazone; bestrabucil; bisantrene; edatrexate; defosfamide; demeclocycline; diazocine; eflornithine; elliptonium acetate; epothilones; etoglucagon; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansine alkaloids, such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; mopidarol; diamine nitrazepam; pentostatin; methambucil; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizolan; spirogermanamine; tricholomanic acid; triazoline; 2,2′,2″-trichlorotriethylamine; trichothecenes (specifically T-2 toxin, verracurin A, baculocin A, and serpentin); urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; cytarabine (“Ara-C”); cyclophosphamide; thiotepa; taxanes, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), (without Cremophor), and albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceuticals, Inc. Partners, Schaumberg, Ill.) and (docetaxel; Sanofi-Aventis), chlorambucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); vinblastine; teniposide; edatrexate; daunorubicin; aminopterin; capecitabine ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the foregoing.

Chemotherapeutic agents also include (i) antihormonal agents used to modulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, troxifene, keoxifene, LY117018, onapristone, and toremifene citrate; (ii) aromatase inhibitors that inhibit the aromatase enzyme that regulates estrogen production in the adrenal glands, such as 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozole, letrozole, and anastrozole; (iii) antiandrogens, such as flutamide , nilutamide, bicalutamide, leuprorelin and goserelin; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, fenretinide and troxacitabine (1,3-dioxolane nucleoside cytosine analogue); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-α, Ralf and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g., and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as and rIL-2; topoisomerase 1 inhibitors, such as rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above substances.

Chemotherapeutic agents also include antibodies, such as alemtuzumab (Campath), bevacizumab (Genentech); cetuximab (Imclone); panitumumab (Amgen), rituximab (Genentech/Biogen Idec), pertuzumab (2C4, Genentech), trastuzumab (Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate gemtuzumab ozogamicin (Wyeth). Other humanized monoclonal antibodies with therapeutic potential as drugs in combination with the compounds of the invention include apolizumab, aseluzumab, atlizumab, bapinuzumab, bivatuzumab mertansine, cantuzumab, and selezinumab. Mertansine, ciliguzumab, beceretuzumab, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, fevetuzumab, fontuzumab, gemtuzumab ozogamicin, intuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab mab, nunamizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovizumab, rulizumab, sirolizumab, cilizumab, sotuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefeizumab, tocilizumab, tocilizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urovituzumab, ustekinumab, visilizumab, and anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories), which is an exclusively recombinant human sequence, full-length IgG ₁ lambda antibody genetically modified to recognize the interleukin-12p40 protein.

Chemotherapeutic agents also include "EGFR inhibitors", which refer to compounds that bind to EGFR or otherwise directly interact with EGFR and inhibit or reduce its signal transduction activity and may also be referred to as "EGFR antagonists". Examples of the above-mentioned drugs include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb579 (ATCC CRLHB8506), MAb455 (ATCCCRL HB8507), MAb225 (ATCC CRL8508), MAb528 (ATCCCRL8509) (see U.S. Patent No. 4,943,533, Mendelsohn et al.) and variants thereof such as chimeric 225 (C225 or cetuximab;) and reconstructed human 225 (H225) (see WO96/40210, Imclone Systems Inc.); IMC-11F8, which is a fully human EGFR-targeting antibody (Imclone); antibodies that bind to type II mutant EGFR (U.S. Patent 5,212,290); humanized and chimeric antibodies that bind to EGFR, see U.S. Patent 5,891,996; and human antibodies that bind to EGFR, such as ABX-EGF or panitumumab (see WO 98/50433, Abgenix/Amgen); EMD55900 (Stragliotto et al., Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody that is directed against EGFR and competes with EGF and TGF-α for EGFR binding (EMD/Merck); the human EGFR antibody HuMax-EGFR (GenMab); fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3 and described in U.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb806 or humanized mAb806 (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., EP 659,439 A2, Merck Patent GmbH). EGFR antagonists include small molecules such as those described in U.S. Patents 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: WO98/14451, WO98/50038, WO99/09016 and WO99/24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, (Genentech/OSI Pharmaceuticals); PD183805 (CI1033, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-2-acrylamide dihydrochloride, Pfizer Inc.); ZD1839 (gefitinib) (4-(3'-chloro-4'-fluorophenylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, Zeneca); ZM105180 ((6-amino-4-(3-methylphenylamino)-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]- ]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors, such as lapatinib (GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5-[[[2-methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine).

Chemotherapeutic agents also include "tyrosine kinase inhibitors," including the EGFR-targeted drugs described in the preceding paragraphs; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724,714, which is an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), which is an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors, such as those available from ISIS Pharmaceuticals' antisense drug ISIS-5132, which inhibits Raf-1 signaling; non-HER-targeted TK inhibitors, such as imatinib mesylate (available from Glaxo SmithKline); multi-target tyrosine kinase inhibitors, such as sunitinib (available from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular-regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD153035, i.e., 4-(3-chlorophenylamino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP59326, CGP60261, and CGP62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines; Curcumin (diferuloylmethane, 4,5-bis(4-fluorophenylamino)phthalimide); phosphotyrosines containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxalines (U.S. Patent 5,804,396); phosphotyrosines (U.S. Patent 5,804,396); ZD6474 (AstraZeneca). Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS3521; Isis/Lilly); imatinib mesylate PKI166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone); rapamycin (sirolimus); or a chemotherapeutic agent described in any of the following patent publications: U.S. Patent No. 5,804,396, WO1999/09016 (American Cyanamid), WO1998/43960 (American Cyanamid), Cyanamid), WO1997/38983 (Warner Lambert), WO1999/06378 (Warner Lambert), WO1999/06396 (Warner Lambert), WO1996/30347 (Pfizer, Inc), WO1996/33978 (Zeneca), WO1996/3397 (Zeneca) and WO1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprolol, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofabamine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, stem cell transplantation, and cytokine. Interferon alpha-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofituzumab, oprelvekin, palifermin, pamidronate, pegaspargase, pegfilgrastim, pemetrexed disodium, pramycin, porfimer sodium, quinacrine, rasburicase, sarcomastim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronic acid and zoledronic acid and pharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinolone, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, alclometasone dipropionate, betamethasone valerate, betamethasone, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, flucortolone hexanoate, flucortolone pivalate, and flupredniidine acetate; immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (FEG) and its D-isomer (feG) (IMULAN Bio Therapeutics, LLC); antirheumatic drugs drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), becerolizumab (Cimzia), golimumab (Simponi), interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab, interleukin 13 (IL-13) blockers such as rebezumab; interferon alpha (IFN) blockers such as rolizumab; beta7 integrin blockers such as rhuMAb beta7; IgE pathway blockers, such as anti-M1 primers; blockers of the secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1/β2, such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g., At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² , and radioisotopes of Lu); various investigational agents, such as thioplatin, PS-341, phenylbutyrates, ET-18-OCH ₃ or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, proanthocyanidins, betulinic acid and its derivatives; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol); beta-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopoletin, and 9-aminocamptothecin; podophyllotoxin; tegafur and bexarotene; bisphosphonates such as clodronate (e.g., or etidronate NE-580); 95. Zoledronic acid/zoledronic acid, alendronate, pamidronate, tiludronate, or risedronate and epidermal growth factor receptor (EGF-R); vaccines, such as vaccines; perifosine, COX-2 inhibitors (such as celecoxib or etoricoxib), proteasome inhibitors (such as PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors, such as pixantrone sodium; farnesyltransferase inhibitors, such as lanafib (SCH6636, SARASAR ^™ ); and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing; and combinations of two or more of the foregoing, such as CHOP (an abbreviation for cyclophosphamide, doxorubicin, vincristine, and prednisolone combination therapy) and FOLFOX (an abbreviation for oxaliplatin (ELOXATIN ^™ ) combined with 5-FU and folinic acid).

Chemotherapeutic agents also include nonsteroidal anti-inflammatory drugs (NSAIDs) with analgesic, antipyretic, and anti-inflammatory effects. NSAIDs include non-selective inhibitors of cyclooxygenase. Specific examples of NSAIDs include aspirin; propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, and naproxen; acetic acid derivatives such as indomethacin, sulindac, etodolac, and diclofenac; enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, and esoxicam; fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid; and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs are used for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headaches and migraines, postoperative pain, mild to moderate pain due to inflammation and tissue damage, fever, intestinal obstruction, and renal colic.

Chemotherapeutic agents also include treatments for Alzheimer's disease, such as donepezil hydrochloride and rivastigmine; treatments for Parkinson's disease, such as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; drugs used to treat multiple sclerosis (MS), such as beta interferon (e.g., tadalafil and tadalafil), glatiramer acetate, and mitoxantrone; treatments for asthma, such as albuterol and montelukast sodium; drugs used to treat schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's disease agents; drugs for the treatment of cardiovascular disease, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; drugs for the treatment of liver disease, such as corticosteroids, cholestyramine, interferon, and antiviral agents; drugs for the treatment of blood disorders, such as corticosteroids, antileukemia agents, and growth factors; and drugs for the treatment of immunodeficiency disorders, such as gamma globulin.

Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any chemotherapeutic agent described herein, and combinations of two or more thereof.

For the treatment of inflammatory diseases or autoimmune diseases, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with methotrexate, tofacitinib, 6-mercaptopurine, azathioprine, sulfasalazine, mesalazine, olsalazine, chloroquine/hydroxychloroquine, penicillamine, aurothiomalate (intramuscular and oral), azathioprine, colchicine, corticosteroids (oral, inhaled and local injection), β2 adrenergic receptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate/cromolyn, nedocromil, ketotifen, ipratropium and oxtropine, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs (e.g., ibuprofen), corticosteroids (e.g., prednisolone) , phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, 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 converting enzyme inhibitors, T cell signaling inhibitors (e.g., kinase inhibitors), metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurine, angiotensin converting enzyme inhibitors, soluble cytokine receptors (e.g., soluble p55 or p75 TNF receptors and derivatives p75TNFRigG (etanercept) and p55TNFRigG (lenercept), siL-1RI, siL-1RII, siL-6R), anti-inflammatory cytokines (e.g., IL-4, IL-6), -10, IL-11, IL-13, and TGF-β), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, adalimumab, certolizumab pegol, tocilizumab, abatacept, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, sodium aurothiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/acetaminophen, folic acid, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone hydrochloride, hydrocodone bitartrate/acetaminophen, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol hydrochloride, salsalate, sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium, prednisolone, In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with methotrexate or leflunomide. In cases of moderate or severe rheumatoid arthritis, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with cyclosporine and an anti-TNF antibody as described above. The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be co-administered with the following drugs: budesonide; epidermal growth factor; corticosteroids; cyclosporine, sulfasalazine; para-aminosalicylate/ester; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalazine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-1 monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridyl -imidazole compounds; 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); cell surface molecules (e.g., CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, C D69 or CD90 or their ligands); methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs (e.g., ibuprofen); corticosteroids (e.g., prednisolone); phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; complement inhibitors; adrenergic agents; drugs that interfere with signaling through proinflammatory cytokines such as TNF5 or IL-1 (e.g., NIK, IKK, or MAP kinase inhibitors); IL-1 converting enzyme inhibitors; TNF converting enzyme inhibitors; T cell signaling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6-mercaptopurine; angiotensin-converting enzyme inhibitors; soluble cytokine receptors (e.g., soluble p55 or p75 TNF receptor, siL-1RI, siL-1RII, siL-6R), and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, or TGF-β).

For the treatment of Crohn's disease, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with a TNF antagonist (e.g., an anti-TNF antibody), D2E7 (adalimumab), CA2 (infliximab), CDP571, a TNFR-Ig construct (p75TNFRigG (etanercept)), a p55TNFRigG (LENERCEPT ^™ ) inhibitor, or a PDE4 inhibitor.

For the treatment of inflammatory bowel disease, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with the following drugs: corticosteroids (e.g., budesonide or dexamethasone); sulfasalazine, 5-aminosalicylic acid; olsalazine; drugs that interfere with the synthesis or action of proinflammatory cytokines such as IL-1 (e.g., IL-1 converting enzyme inhibitors or IL-1ra); T cell signaling inhibitors (e.g., tyrosine kinase inhibitors); 6-mercaptopurine; IL-11; mesalazine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; dinofenac/atropine sulfate; loperamide hydrochloride; methotrexate Omeprazole; folic acid; ciprofloxacin/dextrose-water; hydrocodone bitartrate/acetaminophen; tetracycline hydrochloride; fluocinolone acetonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; scopolamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone hydrochloride/acetaminophen; promethazine hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide disodium; codeine phosphate/acetaminophen; colesevelam hydrochloride; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab or interferon-gamma.

For the treatment of multiple sclerosis, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with the following drugs: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-1a (Biogen); interferon-1b (Chiron/Berlex); interferon-n3 (Interferon Sciences/Fujimoto), interferon- (Alfa Wassermann/J&J), interferon 1A-IF (Serono/Inhale Therapeutics), pegylated interferon 2b (Enzon/Schering-Plough), copolymer 1 (Cop-1; Teva Pharmaceutical Industries, Inc.); hyperbaric 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 can be co-administered with a cell surface molecule such as an antibody to CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or its ligands. A compound of formula (I) or a pharmaceutically acceptable salt thereof can also be co-administered with methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, an S1P1 agonist, an NSAID (e.g., ibuprofen), a corticosteroid (e.g., prednisolone), a phosphodiesterase inhibitor, an adenosine agonist, an antithrombotic agent, a complement inhibitor, an adrenergic agent, an agent that interferes with signaling through proinflammatory cytokines such as TNF or IL-1 (e.g., NIK, IKK, p38 or MAPKs). AP kinase inhibitors), IL-1 converting enzyme 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 p75 TNF receptor, siL-1RI, siL-1RII, or siL-6R), or anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-13, or TGF-β).

The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be co-administered with the following drugs: for example, alemtuzumab, dronabinol, daclizumab, mitoxantrone, zaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, immune factor NNS03, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (mitoxantrone encapsulated in liposomes), THC.CBD (cannabinoid agonists) , MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone, allotrap1258 (RDP-1258), sTNF-Rl, talampanel, teriflunomide, TGF-β2, tilimotide, VLA-4 antagonist (e.g., TR-14035, VLA4 Ultrahaler, or Antegran-ELAN/Biogen), interferon gamma antagonist, or IL-4 agonist.

For the treatment of ankylosing spondylitis, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocycline, prednisone, anti-TNF antibodies, D2E7CA2 (infliximab), CDP571, TNFR-Ig constructs, p75TNFRigG or p55TNFRigG

For the treatment of asthma, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with the following drugs: 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, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, sodium cromoglycate, fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanate hydrochloride, levofloxacin, guaifenesin, dexamethasone sodium phosphate, moxifloxacin hydrochloride, doxycycline hydrochloride, guaifenesin/d-methorphan, pseudoephedrine/COD/chlorpheniramine, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin, PE/hydrocodone/chlorpheniramine, cetirizine hydrochloride/pseudoephedrine, phenylephrine/COD/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone, anti-IL-13 antibodies, or metaproterenol sulfate.

For the treatment of COPD, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with the following drugs: salbutamol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, salbutamol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levofloxacin hydrochloride ...butamol, salbutamol, salbutamol, salbutamol, salbutamol, salbutamol, salbutamol, salbutamol, salbutamol, salbutamol, salbuta Butamol, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenol sulfate, methylprednisolone, mometasone furoate, pseudoephedrine/COD/chlorpheniramine, pirbuterol acetate, pseudoephedrine/loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast, or roflumilast.

For the treatment of psoriasis, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with the following drugs: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinolone acetonide, betamethasone dipropionate boosted, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emollient, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folic acid, lactic acid, methoxsalen, he/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone, sunscreen, clofloxacin, salicylic acid, anthralin, clocortolone pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone, diazepam, emollients, fluocinolone/emollients, mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874, or ustekinamab.

For the treatment of psoriatic arthritis, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with the following drugs: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone dipropionate boosted, infliximab, methotrexate, folic acid, triamcinolone acetonide, diclofenac, dimethyl Sulfoxides, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinolone acetonide, glucosamine sulfate, sodium aurothiomalate, hydrocodone bitartrate/acetaminophen, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), or efalizumab

For the treatment of lupus, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with an NSAID (e.g., diclofenac, naproxen, ibuprofen, piroxicam, or indomethacin); a COX2 inhibitor (e.g., celecoxib, rofecoxib, or valdecoxib); an antimalarial (e.g., hydroxychloroquine); a steroid (e.g., prednisone, prednisolone, budesonide, or dexamethasone); a cytotoxic agent (e.g., azathioprine, cyclophosphamide, mycophenolate mofetil, or methotrexate); a PDE4 inhibitor or a purine synthesis inhibitor (e.g., sulfasalazine, 5-aminosalicylic acid, olsalazine, a drug that interferes with the synthesis, production, or action of a proinflammatory cytokine (e.g., IL-1) or a caspase inhibitor (e.g., an IL-1 converting enzyme inhibitor or IL-1ra).

The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be co-administered with the following drugs: T cell signaling inhibitors (such as tyrosine kinase inhibitors) or molecules targeting T cell activation (such as CTLA-4-IgG, anti-B7 family antibodies or anti-PD-1 family antibodies).

The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be co-administered with the following drugs: IL-11 antibody, anti-cytokine antibody (such as fonotolizumab (anti-IFNg antibody)) or anti-receptor antibody (such as anti-IL-6 receptor antibody or antibodies against B cell surface molecules).

The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be co-administered with LJP394 (abetimus), drugs that deplete or inactivate B cells (e.g., rituximab (anti-CD20 antibody) or lymphostat-B (anti-BlyS antibody)), TNF antagonists (e.g., anti-TNF antibodies), D2E7 (adalimumab), CA2 (infliximab), CDP571, TNFR-Ig constructs, p75TNFRigG (etanercept), or p55TNFRigG (LENERCEPT ^™ ).

The compound of formula (I) or a pharmaceutically acceptable salt thereof may also be co-administered with one or more drugs used to prevent or treat AIDS: HIV reverse transcriptase inhibitors, HIV protease inhibitors, immunomodulators, or other retroviral drugs. Examples of reverse transcriptase inhibitors include, but are not limited to, abacavir, adefovir, didanosine, delavirdine dipyroxine, efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine, stavudine, tenofovir, zalcitabine, and zidovudine. Examples of protease inhibitors include, but are not limited to, amprenavir, atazanavir, darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranovir. Examples of other retroviral drugs include, but are not limited to, elvitegravir, enfuvirtide, maraviroc, and raltegravir.

For the treatment of type II diabetes, hepatic steatosis, insulin resistance, metabolic syndrome or related conditions, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be co-administered with: insulin or insulin modified to improve the duration of action in vivo; drugs that stimulate insulin secretion, such as acethexamide, chlorpropamide, glibenclamide, glimepiride, glipizide, gliclazide, glyclopyrimide, gliquidone, repaglinide, nateglinide, tolazamide or tolbutamide; as a glucagon-like peptide agonist drugs that inhibit dipeptidyl peptidase IV, such as vildagliptin, sitagliptin, saxagliptin, linagliptin, allografts, or septagliptin; drugs that bind to peroxisome proliferator-activated receptor gamma, such as rosiglitazone or 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 can be co-administered with dopamine, a diuretic (e.g., furosemide), bumetanide, a thiazide, mannitol, calcium gluconate, sodium bicarbonate, albuterol, paricalcitol, doxorcalciferol, cinacalcet, or bardoxolone methyl.

The amount of the compound of formula (I) or its salt or the compound disclosed herein or its salt and other drugs (in those compositions comprising the above-mentioned other therapeutic agents) that can be combined with carrier materials to prepare a single dosage form will vary with the host being treated and the specific mode of administration. In certain embodiments, the compositions of the present invention are formulated into a compound of the present invention that can be administered in a dose of 0.01-100 mg/kg body weight/day.

Other therapeutic agents and compounds of Formula (I) or disclosed herein may act synergistically. Thus, the amount of the other therapeutic agent in the above composition may be less than that required for monotherapy with only that therapeutic agent or, when a lower dose is used, there may be fewer side effects in the patient. In certain embodiments, the other therapeutic agent may be administered in the above composition at a dose of 0.01-1,000 μg/kg body weight/day.

Provided herein are methods of prolonging the duration of response to a cytotoxic agent in an individual having cancer, the methods comprising administering to the individual (a) an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a compound disclosed herein 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 EGFR antagonists, RAF inhibitors, and/or PI3K inhibitors.

In certain embodiments of any method, targeted therapy is an EGFR antagonist. In certain embodiments of any method, 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- base) quinazoline -4-amine di 4- methylbenzenesulfonate or a pharmaceutically acceptable salt thereof (e.g., lapatinib).

In certain embodiments of any method, 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-cyanopropyl-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 method, a compound of formula (I) or a pharmaceutically acceptable salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof is administered simultaneously with a cytotoxic agent (e.g., targeted therapy, chemotherapy, and/or radiotherapy). In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered before and/or in parallel with a cytotoxic agent (e.g., targeted therapy, chemotherapy, and/or radiotherapy).

Example

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

General Scheme A (Examples 1-99a/99b)

Representative compounds of formula (I) were prepared according to the above schemes. Intermediate A (prepared as described below) was alkylated with various R ¹ -halides to provide intermediate B, which was treated with various R ³ -alkynes under Sonagashira conditions in the presence of various bases such as triethylamine or N,N-diisopropylethylamine to provide compounds of formula (I).

General Scheme B (Examples 103-167)

Representative compounds of Formula (Ia) were prepared according to the above schemes. Various N-substituted derivative intermediates B (prepared as in General Scheme A) were treated with 2-(trimethylsilyl)ethoxymethyl chloride under alkaline conditions. Hydrolysis of the ethyl ester exposed the carboxylic acid, which was treated with various ^R2 -halides to provide the corresponding esters. Alternatively, esters were prepared by treating the carboxylic acid chloride with various ^R2 -alcohols, followed by hydrolysis to remove the 2-(trimethylsilyl)ethoxymethyl protecting group. The resulting intermediates were treated with various ^R3 -alkynes under Sonagashira conditions to provide compounds of Formula (Ia).

General Scheme C (Examples 169-172)

Representative compounds of formula (II) were prepared according to the above scheme. Various N-substituted derivative intermediates D (prepared as in general scheme B) were coupled with various amines to provide the corresponding amides, which were then hydrolytically removed from the 2-(trimethylsilyl)ethoxymethyl protecting group. The resulting intermediates were treated with various R ³ -alkynes under Sonagashira conditions to provide compounds of formula (II).

General Scheme D (Examples 172-196)

Representative compounds of formula (III) were prepared according to the above scheme. Intermediate C (prepared as in general scheme B) was treated with hydrazine hydrate to provide a carbohydrazide intermediate, which was then coupled with various carboxylic acids. Cyclization was carried out in the presence of triphenylphosphine, followed by hydrolysis to remove the 2-(trimethylsilyl)ethoxymethyl protecting group. The resulting intermediate was treated with various R ³ -alkynes under Sonagashira conditions to provide compounds of formula (III).

List of abbreviations

General procedure for the preparation of intermediates A, B, C and D

Step 1: Ethyl (Z)-3-((2-methoxypyridin-3-yl)amino)but-2-enoate

A mixture of 2-methoxypyridin-3-amine (100.0 g, 0.80 mol), ethyl 3-oxobutanoate (136.3 g, 1.05 mol), zinc (II) perchlorate hexahydrate (17.9 g, 0.05 mol) and MgSO ₄ (290.0 g, 2.42 mol) in DCM (2.0 L) was stirred at ambient temperature for 15 h. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: EtOAc = 19: 1) to give the title compound (113.3 g, 60% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ )δ7.88-7.87(m,1H),7.32-7.29(m,1H),6.84-6.81(m,1H),4.75(s,1H),4.19-4.12(m,2H),4.00(s,3H),2.04(s,3H),1.27(t,J＝7.2Hz,3H).

Step 2: Ethyl 7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

A mixture of (Z)-ethyl 3-((2-methoxypyridin-3-yl)amino)but-2-enoate (50.0 g, 211.6 mmol), copper(II) acetate (126.8 g, 634.9 mmol), palladium(II) acetate (2.38 g, 10.6 mmol) and K ₂ CO ₃ (67.3 g, 634.9 mmol) in DMF (1.0 L) was heated to 100° C. for 15 h. After cooling to ambient temperature, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (3×1.0 L). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc=3:1) to give the title compound (25.0 g, 51% yield) as a yellow solid. ¹ HNMR (400MHz, DMSO-d ₆ )δ12.35(s,1H),7.74(d,J＝6.0Hz,1H),7.43(d,J＝5.6Hz,1H),4.28-4.23(m,2H),4.01(s,3H),2.63(s,3H),1.33(t,J＝7.2Hz,3H).

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

To a solution of ethyl 7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (10.00 g, 42.69 mmol) in DMF (100 mL) was added palladium (II) acetate (48 mg, 0.21 mmol) and NBS (8.36 g, 46.96 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 15 h and then diluted with water (100 mL). The solution was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc = 3: 1) to give the title compound (10.71 g, 80% yield) as a yellow solid.

Step 4: Ethyl 4-bromo-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of ethyl 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (10.0 g, 31.93 mmol) in EtOH (100 mL) was added hydrogen bromide (40% aqueous solution, 25 mL, 184.16 mmol). The reaction mixture was heated at 80 ° C for 3 h, then cooled to ambient temperature and evaporated under reduced pressure and the residue was diluted with water (100 mL). The resulting precipitate was collected by filtration to give the crude title compound (intermediate A) (8.0 g, 84% yield) as a yellow solid. The crude product was used in the following reaction without further purification.

Step 5: Ethyl 4-bromo-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of ethyl 4-bromo-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (8.0 g, 26.75 mmol) in DMF (100 mL) was added NaH (60% in mineral oil, 1.6 g, 40.13 mmol) in portions at 0°C. The reaction mixture was stirred for 30 min, then methyl iodide (3.8 g, 26.75 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h, then poured into water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc=1:1) to give the title compound (Intermediate B) (7.50 g, 90% yield) as a yellow solid. LCMS M/Z (M+H) 312.8, 314.8.

Step 6: Ethyl 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of ethyl 4-bromo-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (7.50 g, 23.95 mmol) in DMF (100 mL) was added NaH (60% in mineral oil, 1.50 g, 38.32 mmol) at 0°C. The reaction mixture was stirred for 30 min and SEM-Cl (6.69 g, 40.13 mmol) was added. The reaction mixture was stirred at 0°C for 1 h, then poured into water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: EtOAc=4:1) to give the title compound (Intermediate C) (7.30 g, 69% yield) as a yellow solid. ¹ H NMR (400MHz, CD ₃ OD)δ7.51(s,1H),6.06(s,2H),4.39-4.33(m,2H),3.62-3.60(m,2H),3.57( s,3H),2.54(s,3H),1.43-1.37(m,3H),0.84(t,J＝8.0Hz,2H),0.07(s,9H).

Step 7: 4-Bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid

To a solution of ethyl 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (7.00 g, 15.79 mmol) in EtOH (50 mL) was added aqueous NaOH solution (4N, 20 mL, 80.00 mmol). The reaction mixture was heated at 80 ° C for 15 h. After cooling, the mixture was adjusted to pH 4-5 by adding aqueous HCl solution (1N). EtOH was removed under reduced pressure and the aqueous solution was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude title compound (Intermediate D) (6.20 g, 94% yield) as a yellow solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.51 (s, 1H), 6.08 (s, 2H), 3.63-3.58 (m, 2H), 3.58 (s, 3H), 2.58 (s, 3H), 0.85 (t, J = 8.0Hz, 2H), 0.06 (s, 9H).

General procedure for the preparation of intermediates E1-E4

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

To a solution of ethyl 4-bromo-2-methyl-7-oxo-1,6-dihydropyrrolo[2,3-c]pyridine-3-carboxylate (17.00 g, 56.83 mmol) in DMF (250 mL) was added Cs ₂ CO ₃ (27.78 g, 85.25 mmol) and 4-bromobut-1-ene (9.97 g, 73.88 mmol). The reaction mixture was stirred at ambient temperature for 16 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc = 2: 1) to give the title compound (Intermediate E1) (7.00 g, 35% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.69(s,1H),7.57(s,1H),5.85-5.76(m,1H),5.04-4.98(m,2H),4.27- 4.21(m,2H),4.05-4.01(m,2H),2.44-2.39(m,5H),1.30(t,J＝7.2Hz,3H). LCMS M/Z(M+H)355.

The following compounds were prepared in a similar manner to Intermediate E1

Examples 2-4

General procedure for the preparation of intermediate F

Step 1: Ethyl 4-bromo-6-(but-3-en-1-yl)-2-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of ethyl 4-bromo-6-(but-3-ene-1-yl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (Intermediate E1) (1.0 g, 2.83 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 170 mg, 4.25 mmol) at 0 ° C. After stirring for 30 min, SEM-Cl (708 mg, 4.25 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h, then poured into ice water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc = 4: 1) to give the title compound (1.2 g, 88% yield) as a light yellow solid.

Step 2: 4-Bromo-6-(but-3-en-1-yl)-2-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid

To a solution of ethyl 4-bromo-6-(but-3-en-1-yl)-2-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (1.20 g, 2.48 mmol) in EtOH/H ₂ O (10 mL/10 mL) was added NaOH (0.50 g, 12.41 mmol). The reaction mixture was heated at 80 ° C for 16 h. EtOH was evaporated under reduced pressure and the residue was adjusted to pH 5 by adding aqueous HCl (1 N). The solution was extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title compound (Intermediate F) (1.00 g, 88% yield) as a white solid.

General procedure for the preparation of intermediates G1-G2

Step 1: 2-Methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol) in MeOH (1.0 L) was added dropwise over 2 h to a stirred and cooled (0 ° C) solution of NaOMe (250 g, 4.63 mol) in MeOH (850 mL). The reaction mixture was heated to reflux temperature for 23 h. The mixture was partially concentrated under reduced pressure and quenched by adding water (1.5 L). The resulting solid was collected by filtration, washed with water and dried under vacuum to give the title compound (250 g, 100% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.22 (d, J = 5.2 Hz, 1 H), 7.10 (d, J = 5.6 Hz, 1 H), 3.92 (s, 3 H), 2.26 (s, 3 H).

Step 2: 5-Bromo-2-methoxy-4-methyl-3-nitropyridine

At ambient temperature, sodium acetate (365g, 5.37mol) is added to a stirred solution of 2-methoxy-4-methyl-3-nitropyridine (250g, 1.49mol) in acetic acid (1.5L), followed by addition of bromine (639g, 4.00mol) and the reaction mixture is heated at 80°C for 12h. The mixture is then quenched by adding a 10% NaOH aqueous solution (1.5L) and a saturated Na ₂ SO ₃ aqueous solution (1.5L) at 0°C. The resulting solid is collected by filtration and washed with water, dried under vacuum to give the title compound (302g, 82.2% yield) as a light yellow solid. ¹ HNMR (400MHz, DMSO-d ₆ ): δ 8.25 (s, 1H), 3.94 (s, 3H), 2.29 (s, 3H).

Step 3: 2-(5-Bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethyleneamine

N,N-dimethylformamide dimethyl acetal (600 mL) was slowly added to a stirred and heated (80°C) solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol) in DMF (1.1 L). The mixture was heated at 95°C for 5 h. The reaction mixture was cooled to ambient temperature and poured into ice-cold water (3 L). The resulting red solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (167 g, 100% yield) as a slightly reddish solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.24 (s, 1H), 7.05 (d, J = 13.6 Hz, 1H), 7.05 (d, J = 13.6 Hz, 1H), 4.80 (d, J = 13.2 Hz, 1H), 3.88 (s, 3H), 2.90 (s, 6H).

Step 4: 4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

A mixture of 2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethyleneamine (50.0 g, 165 mmol), iron powder (50.0 g, 893 mmol), and NH ₄ Cl (50.0 g, 943 mmol) in MeOH/H ₂ O (1900/250 mL) was heated to reflux for 7 h. The reaction mixture was filtered while hot, and the filter cake was washed with MeOH (3×200 mL). The combined filtrates were concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:EtOAc=5:1) to give the crude product. The crude product was washed with ACN to give the title compound (37.4 g, 99.5% yield) as a light brown solid. LCMSM/Z (M+H) 226.7, 228.7.

Step 5: 4-Bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (34.3 g, 0.15 mol) in THF (700 mL) was added to a stirred and cooled (0°C) solution of NaH (60%, 19.2 g, 0.48 mol) in THF (700 mL). The reaction mixture was stirred at ambient temperature for 1 h, then cooled to 0°C again, and then a solution of p-toluenesulfonyl chloride (38.0 g, 0.20 mol) in THF (700 mL) was added. The reaction mixture was stirred at ambient temperature for 2 h. The mixture was quenched by the addition of saturated aqueous _NH4Cl solution (1.0 L), then extracted with EtOAc (3 × 600 mL). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered, and concentrated. The residue was washed with ACN to give the title compound (51.2 g, 88.9% yield) as a brown solid. The crude product was used in the next step without further purification.

Step 6: 4-Bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Hydrogen bromide (40% aqueous solution, 1.1 L) was added to a solution of 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (102.5 g, 0.27 mol) in EtOH (200 mL). The reaction mixture was heated at 90 ° C for 2 h. The mixture was cooled to 0 ° C and the resulting white solid was collected by filtration. The solid was washed with water and dried to give the title compound (87.5 g, 88.6% yield) as a light brown solid. ¹ H NMR (400MHz, DMSO-d ₆ ): 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).

Step 7: 4-Bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one (6.00 g, 16.34 mmol) in dioxane (120 mL) was added Cs ₂ CO ₃ (10.65 g, 32.68 mmol) and methyl iodide (6.15 g, 43.30 mmol). The reaction mixture was stirred at ambient temperature for 1 h and then quenched by the addition of water (300 mL). The resulting precipitate was collected by filtration, washed with water (100 mL) and dried in vacuo to give the crude title compound (6.00 g, 96% yield) as a white solid. LCMS M/Z(M+H)381.

Step 8: 4-Bromo-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one (6.00 g, 15.74 mmol) in MeOH (120 mL) was added a solution of KOH (4.41 g, 78.69 mmol) in water (24 mL). The mixture was heated at 70 ° C for 30 min and then concentrated under reduced pressure. The residue was diluted with water (60 mL). The resulting precipitate was collected by filtration, washed with water (50 mL) and dried in vacuo to give the crude title compound (3.57 g, 100% yield) as a white solid. LCMSM/Z (M+H) 229.

Step 9: 4-Bromo-6-methyl-3-(2,2,2-trichloroacetyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-6-methyl-1H-pyrrolo[2,3-c]pyridin-7-one (3.57 g, 15.85 mmol) in DCM (200 mL) was added aluminum chloride (12.68 g, 95.12 mmol) in portions. The reaction mixture was stirred at ambient temperature for 10 min and 2,2,2-trichloroacetyl chloride (11.54 g, 63.44 mmol) was added. The reaction mixture was heated at 60 ° C for 8 h and then cooled to ambient temperature. The mixture was slowly added to ice water (100 mL) and the phases were separated. The aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (4.00 g, 68% yield) as an off-white solid.

Step 10a: Ethyl 4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of sodium ethoxide (from 0.18 g of sodium, 8.06 mmol) in EtOH (10 mL) was added 4-bromo-6-methyl-3-(2,2,2-trichloroacetyl)-1H-pyrrolo[2,3-c]pyridin-7-one (1.00 g, 2.69 mmol). The mixture was stirred at ambient temperature for 2 h and then concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude compound as a brown solid.

Step 10b: Ethyl 4-bromo-6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

Crude ethyl 4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate was dissolved in DMF (15 mL) and NaH (60% in mineral oil, 0.19 g, 8.06 mmol) was added. After stirring for 10 min, SEM-Cl (1.34 g, 8.06 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 1 h and then quenched by the addition of water (30 mL). The solution was extracted with EtOAc (3 x 30 mL) and the combined organic layers were dried over _{anhydrous NaSO} , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc = 4: 1) to give 4-bromo-6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester (580 mg, 50% yield (over two steps)) as a light yellow oil.

Step 10c:

4-Bromo-6-methyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester (200 mg, 0.47 mmol) was dissolved in DCM (3 mL) and 2,2,2-trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at ambient temperature for 10 h and then concentrated under reduced pressure. The residue was dissolved in THF (20 mL) and K ₂ CO ₃ (500 mg) was added. The reaction mixture was stirred at ambient temperature for 10 min and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc=4:1) to give the title compound (Intermediate G1) (139 mg, 100% yield) as a brown solid.

Compound G2 was prepared in a similar manner to Intermediate G1 by substituting sodium isobutoxide for sodium ethoxide in step 10.

Example G2

General procedure for the preparation of propargyl alcohol reagents H1-H44

Example H1: 3-Ethynyl-3-hydroxy-1-methylindolin-2-one

To a solution of 1-methylindoline-2,3-dione (1-methylisatin) (0.25 g, 1.54 mmol) in THF (10 mL) was added dropwise a 0.5 M solution of ethynylmagnesium bromide in THF (3.08 mL, 1.54 mmol) at 0°C. The reaction mixture was slowly warmed to ambient temperature and stirred overnight. The reaction mixture was poured into a saturated aqueous solution of _NH4Cl and then extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous _{Na2SO4 ,} filtered, and concentrated under reduced pressure to give the racemic title compound (H1) (213 mg, 74% yield) as an off-white solid. LCMS M/Z (M-OH) 170, (M+Na) 210.

The following compounds were prepared in a similar manner to Example H1:

Examples H2-H24

Example H23: 1,1,1-Trifluoro-2-(pyridin-3-yl)but-3-yn-2-ol

Step 1: 1,1,1-Trifluoro-4-(triisopropylsilyl)but-3-yn-2-one

To a solution of ethynyltriisopropylsilane (4.50 g, 24.67 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 9.9 mL, 24.67 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 1 h, and then ethyl 2,2,2-trifluoroacetate (5.26 g, 37.01 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred for 16 h. The reaction was quenched by adding saturated aqueous NH ₄ Cl solution (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: EtOAc = 20: 1) to give the title compound (5.00 g, 73% yield) as a colorless oil.

Step 2: 1,1,1-Trifluoro-2-(pyridin-3-yl)-4-(triisopropylsilyl)but-3-yn-2-ol

To a solution of 3-bromopyridine (300 mg, 1.90 mmol) in THF (10 mL) was added a solution of n-BuLi in THF (2.5 M, 0.8 mL, 2.00 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 0.5 h, and then a solution of 1,1,1-trifluoro-4-triisopropylsilyl-but-3-yn-2-one (793 mg, 2.85 mmol) in THF (3 mL) was added. The reaction mixture was stirred at ambient temperature for 2 h, and then quenched by the addition of saturated NH ₄ Cl aqueous solution (20 mL). The mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:EtOAc=100:1 to 3:1) to give the title compound (300 mg, 44% yield) as a colorless oil.

Step 3: 1,1,1-Trifluoro-2-(pyridin-3-yl)but-3-yn-2-ol

To a solution of 1,1,1-trifluoro-2-(3-pyridyl)-4-triisopropylsilyl-but-3-yn-2-ol (300 mg, 0.84 mmol) in THF (10 mL) was added tetrabutylammonium fluoride (439 mg, 1.68 mmol). The reaction mixture was stirred at ambient temperature for 2 h and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc=1: 1) to give the title compound (H23) (120 mg, 71% yield) as a yellow oil.

The following compound was prepared in a similar manner to Example H23:

Examples H24-H26

Example H28: 2-(3-(1H-pyrazol-4-yl)phenyl)-1,1,1-trifluorobut-3-yn-2-ol

Step 1: 2-(3-bromophenyl)-1,1,1-trifluorobut-3-yn-2-ol

To a solution of 1-(3-bromophenyl)-2,2,2-trifluoroethanone (1.00 g, 3.95 mmol) in THF (10 mL) was added ethynylmagnesium bromide (0.5 M in THF, 19.7 mL, 9.85 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 16 h and then quenched by the addition of saturated aqueous _NH4Cl solution (20 mL) and water (10 mL). The mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure to give the crude title compound (1.00 g, 91% yield) as a brown oil.

Step 2: 1,1,1-Trifluoro-2-(3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)but-3-yn-2-ol

To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol) in DMF (20 mL) was added K ₂ CO ₃ (1.07 g, 7.73 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (1.03 g, 6.18 mmol). The reaction mixture was stirred at ambient temperature for 16 h and then diluted with water (20 mL). The mixture was extracted with EtOAc (2×30 mL). The combined organic layers were dried over _{anhydrous Na2SO4} and concentrated under reduced pressure to give crude 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.00 g, 60% yield) as a yellow oil.

A mixture of 2-(3-bromophenyl)-1,1,1-trifluorobut-3-yn-2-ol (500 mg, 1.79 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (872 mg, 2.69 mmol), Cs ₂ CO ₃ (1.17 g, 3.58 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (66 mg, 0.09 mmol) in dioxane/H ₂ O (5 mL/1 mL) was heated at 110° C. for 0.5 h under microwave conditions. The solvent was removed and the crude residue was purified by column chromatography (petroleum ether:EtOAc=4:1) to give the title compound (300 mg, 42% yield) as a colorless oil.

Step 3: 2-(3-(1H-pyrazol-4-yl)phenyl)-1,1,1-trifluorobut-3-yn-2-ol

To a solution of 1,1,1-trifluoro-2-(3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)phenyl)but-3-yn-2-ol (300 mg, 0.76 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The reaction mixture was stirred at ambient temperature for 3 h and then concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL) and adjusted to pH 7-8 by addition of solid K ₂ CO _3. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to give the crude title compound (H28) (200 mg, 99% yield) as a white solid.

The following compound was prepared in a similar manner to Example H28:

Example H29

Example H30: (((2-methylbut-3-yn-2-yl)oxy)methyl)benzene

To a solution of 2-methylbut-3-yn-2-ol (2.00 g, 23.78 mmol) in THF (100 mL) was added NaH (60%, 1.05 g, 26.15 mmol) at 0 ° C. The mixture was stirred at ambient temperature for 1 h, and then tetrabutylammonium iodide (0.35 g, 0.95 mmol) and benzyl bromide (4.88 g, 28.53 mmol) were added. The reaction mixture was stirred at ambient temperature for 18 h and quenched by the addition of saturated NH ₄ Cl aqueous solution (10 mL). The solvent was evaporated under reduced pressure and the residue was diluted with EtOAc (100 mL). The solution was washed with water (3 × 100 mL) and brine (100 mL) and dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether: EtOAc = 10: 1) to give the title compound (H30) (2.40 g, 57% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.32 (m, 5H), 4.65 (s, 2H), 2.45 (s, 1H), 1.57 (s, 6H).

Example H31: 3-Ethynyl-3-methyloxetane

Step 1: 3-Methyloxetane-3-carbaldehyde

To a solution of (3-methyloxetane-3-yl)methanol (6.00 g, 58.75 mmol) in ACN (300 mL) was added 2-iodooxybenzoic acid (19.74 g, 70.50 mmol). The reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to ambient temperature, then diluted with ACN (200 mL) and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (5.00 g, 85% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.93 (s, 1H), 4.86 (d, J = 6.4 Hz, 2H), 4.49 (d, J = 6.4 Hz, 2H), 1.46 (s, 3H).

Step 2: 3-Ethynyl-3-methyloxetane

To a solution of 3-methyloxetane-3-carbaldehyde (3.00 g, 29.97 mmol) in MeOH (100 mL) was added K ₂ CO ₃ (20.71 g, 149.83 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (6.04 g, 31.46 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h and filtered. The filtrate was diluted with water (300 mL) and extracted with tert-butyl methyl ether (3×150 mL). The combined organic layers were concentrated under reduced pressure to give the crude title compound (H31) (700 mg, 24% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 4.82 (d, J = 5.2 Hz, 2H), 4.84 (d, J = 5.6 Hz, 2H), 2.37 (s, 1H), 1.62 (s, 3H).

Example H32: N-(2-methylbut-3-yn-2-yl)acetamide

To a solution of 2-methylbut-3-yn-2-amine (500 mg, 6.01 mmol) in DCM (10 mL) was added TEA (910 mg, 9.02 mmol) and acetyl chloride (470 mg, 6.01 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was then diluted with DCM (10 mL) and washed with water (2 × 10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc=3: 1) to give the title compound (H32) (500 mg, 66% yield) as a white solid.

Example H33: 2,2-Dimethylbut-3-ynamide

To a solution of 2,2-dimethylbut-3-ynoic acid (0.80 g, 7.14 mmol) in DCM (10 mL) is added 1,1'-carbonyldiimidazole (1.50 g, 9.28 mmol). The reaction mixture is stirred at ambient temperature for 0.5 h, and then ammoniacal aqueous solution (3 mL) is added. The reaction mixture is stirred for another 3 h and diluted with DCM (15 mL). The organic layer is washed with water (20 mL), dried over _{anhydrous Na2SO4} and concentrated under reduced pressure to give a crude title compound (H33) (0.50 g, 63% yield) as a colorless oil.

The following compound was prepared in a similar manner to Example H33:

Examples H34-H35

Example H36: 1-Ethynylcyclopropanol

Step 1: 1-Ethoxycyclopropanol

A solution of (1-ethoxycyclopropyl)oxy-trimethylsilane (12 mL, 59.60 mmol) in MeOH (10 mL) was stirred at ambient temperature for 21 h. The solvent was evaporated under reduced pressure to give the crude title compound (5.60 g, 92% yield) as a colorless oil.

Step 2: 1-((Trimethylsilyl)ethynyl)cyclopropanol

To a solution of methylmagnesium bromide (48 mmol) in THF (60 mL) was added dropwise a solution of 1-ethoxycyclopropanol (4.90 g, 48 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred for 1 h.

To a solution of (trimethylsilyl)acetylene (5.20 g, 53 mmol) in THF (50 mL) was added n-BuLi (2.5 M, 22 mL, 55 mmol) at -78 ° C. The resulting [(trimethylsilyl)ethynyl]lithium was added to a solution of magnesium bromide 1-ethoxycyclopropanolate at 0 ° C. The reaction mixture was heated at 40 ° C for 17 h, then quenched by the addition of saturated aqueous NH ₄ Cl solution (60 mL) and extracted with EtOAc (2 × 80 mL). The combined organic layers were washed with water (2 × 80 mL), dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure to give the crude title compound (6.00 g, 74% yield) as a colorless oil.

Step 3: 1-Ethynylcyclopropanol

To a solution of ammonium fluoride (2.20 g, 60 mmol) in MeOH/H ₂ O (30 mL/10 mL) was added 1-[(trimethylsilyl)ethynyl]cyclopropanol (4.00 g, 26 mmol). The reaction mixture was stirred at ambient temperature for 36 h, then poured into water (50 mL) and extracted with isopropyl ether (3×30 mL). The combined organic layers were dried over anhydrous MgSO ₄ , filtered, and concentrated to 20 mL to provide a solution of the crude title compound (H36). This solution was used in the next step without further purification.

Example H37: 2-Methyl-1-(phenylamino)but-3-yn-2-ol

Step 1: tert-Butyl (2-methylallyl)(phenyl)carbamate

To a solution of tert-butyl phenylcarbamate (5.20 g, 26.91 mmol) in THF (60 mL) was added NaH (60%, 2.15 g, 53.82 mmol) at 0 ° C. The mixture was stirred for 30 min, and then 3-bromo-2-methylprop-1-ene (11.00 g, 81.48 mmol) was added. The reaction mixture was stirred at ambient temperature for 12 h. The reaction was quenched by adding saturated NH ₄ Cl aqueous solution (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc=3:1) to give the title compound (4.60 g, 69% yield) as a white solid.

Step 2: tert-Butyl (2-oxopropyl)(phenyl)carbamate

To a solution of tert-butyl (2-methylallyl)(phenyl)carbamate (4.50 g, 18.22 mmol) in dioxane/H ₂ O (50 mL/20 mL) was added sodium periodate (15.57 g, 72.78 mmol) and osmium tetroxide (0.19 g, 0.73 mmol). The reaction mixture was stirred at ambient temperature for 12 h and then diluted with water (50 mL). The mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc = 3: 1) to give the title compound (3.80 g, 84% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.34-7.29(m,2H),7.27-7.22(m,2H),7.21-7.16(m,1H),4.34(s,2H),2.17(s,3H),1.43(s,9H).

Step 3: 1-(Phenylamino)propan-2-one

To a solution of tert-butyl (2-oxopropyl)(phenyl)carbamate (3.80 g, 15.26 mmol) in EtOAc (20 mL) was added HCl (4 N in EtOAc, 20 mL) at 0 ° C. The reaction mixture was stirred at ambient temperature for 2 h and then concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO ₃ solution (2 × 30 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude title compound (2.20 g, 95% yield) as a yellow solid. The crude product was used in the next step without further purification.

Step 4: 2-Methyl-1-(phenylamino)but-3-yn-2-ol

To a solution of 1-(phenylamino)propan-2-one (2.20 g, 14.75 mmol) in THF (40 mL) was added ethynylmagnesium bromide (0.5 M, 44 mL, 22.12 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 15 h and then quenched by adding saturated NH ₄ Cl aqueous solution (20 mL). The resulting mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc = 7: 1) to give the title compound (H37) (420 mg, 18% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.26-7.16(m,2H), 6.79-6.72(m,3H), 3.34-3.30(m,2H), 2.50(s,1H), 1.57(s,3H).

Example H38: 4-Ethynylpiperidin-4-ol

Step 1: tert-Butyl 4-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylate

To a solution of ethynyltrimethylsilane (5.42 g, 50.21 mmol) in THF (100 mL) was added n-BuLi (2.5 M, 22.1 mL, 55.25 mmol) at -78 ° C. After stirring at -78 ° C for 1 h, tert-butyl 4-oxopiperidine-1-carboxylate (10.00 g, 50.19 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 h and then quenched by adding saturated NH ₄ Cl aqueous solution (100 mL). The mixture was extracted with EtOAc (3 × 150 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc = 4: 1) to give the title compound (10.00 g, 67% yield) as a white solid. ¹ HNMR (400MHz, CDCl ₃ ) δ3.75-3.69(m,2H),3.25-3.17(m,2H),2.29(s,1H),1.89-1.83(m,2H),1.71-1.63(m,1H),1.46(s,9H),0.17(s,9H).

Step 2: tert-Butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxy-4-(2-trimethylsilylethynyl)piperidine-1-carboxylate (5.00 g, 16.81 mmol) in THF (150 mL) was added TBAF (5.57 g, 17.65 mmol) at 0 ° C. The reaction mixture was stirred at 30 ° C for 16 h and then concentrated under reduced pressure. The residue was dissolved in water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc = 7: 3) to give the title compound (3.00 g, 79% yield) as a white solid.

Step 3: 4-Ethynylpiperidin-4-ol

To a solution of tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (3.00 g, 13.32 mmol) in EtOAc (15 mL) was added 2,2,2-trifluoroacetic acid (1 mL) at 0 ° C. The reaction mixture was stirred at ambient temperature for 3 h and then evaporated under reduced pressure. The residue was dissolved in MeOH (15 mL) and adjusted to pH 7-8 with K ₂ CO ₃ aqueous solution (4 M). The mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude title compound (H38) (1.50 g, 90% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ3.07-3.02(m,2H), 2.89-2.84(m,2H), 2.52(s,1H), 1.96-1.91(m,2H), 1.71-1.66(m,2H).

Example H39: 1-Ethyl-4-ethynylpiperidin-4-ol

To a solution of 4-ethynylpiperidin-4-ol (H38) (322 mg, 2.57 mmol) in DCM (5 mL) was added acetaldehyde (567 mg, 12.86 mmol). The mixture was stirred at 25 ° C for 2 h, and then sodium triacetyl borohydride (1.09 g, 5.15 mmol) was added. The reaction mixture was stirred for 1 h, then quenched by the addition of saturated NH ₄ Cl aqueous solution (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title compound (H39) (200 mg, 51% yield) as a yellow oil.

Example H40: 1-(4-ethynyl-4-hydroxypiperidin-1-yl)ethanone

To a solution of 4-ethynylpiperidin-4-ol (H38) (250 mg, 2.00 mmol) in DCM (10 mL) was added acetic anhydride (306 mg, 3.00 mmol) and TEA (404 mg, 3.99 mmol). The reaction mixture was stirred at ambient temperature for 1 h, then quenched with the addition of water (15 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude title compound (H40) (300 mg, 90% yield) as a yellow oil.

The following compound was prepared in a similar manner to Example H40:

Example H41

Example H42: 1,1,1-Trifluoro-2-(1-methyl-1H-pyrazol-3-yl)but-3-yn-2-ol

Step 1: 2,2,2-Trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanol

To a solution of 1-methyl-1H-pyrazole-3-carbaldehyde (1.00 g, 9.08 mmol) in THF (10 mL) was added trimethyl(trifluoromethyl)silane (2.58 g, 18.16 mmol) and TBAF (238 mg, 0.91 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 3 h, then poured into water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the crude title compound (1.60 g, 98% yield) as a yellow oil.

Step 2: 2,2,2-Trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanone

To a solution of 2,2,2-trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanol (1.60 g, 8.83 mmol) in DMF (20 mL) was added manganese dioxide (2.53 g, 29.15 mmol). The reaction mixture was heated at 100 ° C for 15 h and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc = 9: 1) to give the title compound (800 mg, 51% yield) as a yellow oil.

Step 3: 1,1,1-Trifluoro-2-(1-methyl-1H-pyrazol-3-yl)but-3-yn-2-ol

To a solution of 2,2,2-trifluoro-1-(1-methyl-1H-pyrazol-3-yl)ethanone (600 mg, 3.37 mmol) in THF (10 mL) was added ethynylmagnesium bromide (0.5 M, 8.1 mL, 4.04 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 15 h and then poured into water (10 mL). The solution was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the crude title compound (H42) (500 mg, 73% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39 (d, J=2.4 Hz, 1H), δ 6.44 (s, 1H), δ 4.48 (s, 1H), δ 3.93 (s, 3H), δ 2.70 (s, 1H).

Example H43: 3-Methyl-5-(1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenol

Step 1: 2,2,2-Trifluoro-1-(3-methoxy-5-methylphenyl)ethan-1-one

To a vial was added methyl 3-methoxy-5-methylbenzoate (1.0 g, 5.54 mmol), trimethyl(trifluoromethyl)silane (1.08 mL, 7.3 mmol) and cesium fluoride (8.4 mg, 55 μmol). The reaction mixture was stirred at ambient temperature for 48 h, then poured into THF (20 mL) and treated with 6N HCl (2 mL). The reaction mixture was stirred for an additional 2 h, then neutralized to pH ~7 and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (hexane:EtOAc=8:2) to give the title compound (724 mg, 60% yield) as a colorless oil. LCMS M/Z (M+H) 219.

Step 2: 1,1,1-Trifluoro-2-(3-methoxy-5-methylphenyl)but-3-yn-2-ol

To a solution of 2,2,2-trifluoro-1-(3-methoxy-5-methylphenyl)ethanone (0.724 g, 3.3 mmol) in THF (10 mL) was added ethynylmagnesium bromide (0.5 M in THF, 13.2 mL, 6.62 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 48 h and then quenched with (1:1:1) 1N HCl, water, and brine (120 mL). The mixture was extracted with EtOAc (3 ×) and the combined organic layers were washed with brine, then dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by column chromatography (hexane: EtOAc = 8.5: 1.5) to give the title compound (712 mg, 88% yield) as a light yellow oil. LCMSM/Z (M+H) 245.

Step 3: 3-Methyl-5-(1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenol

To a solution of 1,1,1-trifluoro-2-(3-methoxy-5-methylphenyl)but-3-yn-2-ol (618 mg, 2.5 mmol) in DCM (10 mL) was added boron tribromide (1 M in DCM, 5.56 mL, 5.56 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 1.5 h and quenched with MeOH (10 mL), then concentrated. The residue was dissolved in THF (20 mL) and treated with 1N HCl (20 mL) for 1 h. The solution was adjusted to pH ~ 7 and further diluted with brine and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (hexane: EtOAc = 7.5: 2.5) to give the title compound (H43) (607.3 mg, 104% yield) as a colorless oil. LCMSM/Z(M+H)231.

The following compound was prepared in a similar manner to Example H43:

Example H44

Example 1

2,6-Dimethyl-7-oxo-4-(4,4,4-trifluoro-3-hydroxy-3-(3-pyridinyl)but-1-ynyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester

To a suspension of ethyl 4-bromo-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (intermediate B) (100 mg, 0.32 mmol) in DMF (3 mL) and TEA (1 mL) was added 1,1,1-trifluoro-2-(pyridin-3-yl)but-3-yn _-2- ol (H23) (129 mg, 0.64 mmol), bis(triphenylphosphine)palladium(II) chloride (21 mg, 0.03 mmol) and copper(I) iodide (11 mg, 0.06 mmol). The reaction mixture was purified by N2 for 5 min and then stirred at 110 ° C for 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN 30-60% / 0.2% formic acid in water) to give the title compound (19 mg, 14% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.72(br.s,1H),8.77(br.s,1H),8.21(d,J＝8.4Hz,1H),8.02(s,1H),7.78(s,1H), 7.63-7.48(m,1H),4.20-4.05(m,2H),3.57(s,3H),2.45(s,3H),1.15(t,J＝7.2Hz,3H). LCMS M/Z(M+H)434.

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

Example 2-90

Examples 91a and 91b

2,6-Dimethyl-7-oxo-4-(4,4,4-trifluoro-3-hydroxy-3-phenyl-but-1-ynyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester (91a/91b)

2,6-dimethyl-7-oxo-4-(4,4,4-trifluoro-3-hydroxy-3-phenyl-but-1-ynyl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester was prepared in a manner similar to Example 1. The racemate (50 mg) was separated by supercritical fluid chromatography (SFC) to give the title compound 91a (22 mg, 43% yield) as an off-white solid and compound 91b (21 mg, 42% yield) as an off-white solid. The stereochemistry of the two enantiomers was arbitrarily specified.

SFC conditions: PIC-100, column: Cellulose-3 (21.2 x 150 mm, 5 μm), flow rate: 70 ml/min, mobile phase A: carbon dioxide, mobile phase B: MeOH with 0.1% NH ₄ OH, method: isocratic 20% B, 100 bar, 40°C.

Compound 91a: Chiral HPLC retention time 0.584 min; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.67 (s, 1H), 7.80 (dd, J=7.3, 2.4 Hz, 2H), 7.72 (s, 1H), 7.66 (s, 1H), 7.52-7.36 (m, 3H), 4.14-4.00 (m, 2H), 3.57 (s, 3H), 1.12 (t, J=7.1 Hz, 3H). LCMSM/Z (M+H) 433.

Compound 91b: Chiral HPLC retention time 0.825 min, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.67 (s, 1H), 7.80 (dd, J=7.3, 2.5 Hz, 2H), 7.72 (s, 1H), 7.66 (s, 1H), 7.48-7.39 (m, 3H), 4.06 (t, J=7.0 Hz, 2H), 3.57 (s, 3H), 1.12 (t, J=7.1 Hz, 3H). LCMS M/Z (M+H) 433.

The following compounds were prepared in a similar manner to Example 91a/92b:

Examples 92a/92b-99a/99b

Example 100

2,6-Dimethyl-7-oxo-4-[4,4,4-trifluoro-3-hydroxy-3-[3-(3-pyridyl)phenyl]but-1-ynyl]-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester

Ethyl 4-(3-(3-bromophenyl)-4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate was prepared in a manner similar to Example 1.

To a solution of ethyl 4-(3-(3-bromophenyl)-4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (90 mg, 0.18 mmol) in dioxane (2 mL) and Na ₂ CO ₃ aqueous solution (1 M, 0.44 mL, 0.44 mmol) was added pyridin-3-ylboronic acid (28 mg, 0.23 mmol) and tetrakistriphenylphosphine palladium(0) (10.1 mg, 8 μmol). The reaction mixture was heated at 90 ° C for 12 h and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to give the title compound (20 mg, 22% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.70(s,1H),8.97(br.s.,1H),8.67(d,J＝4.4Hz,1H),8.24(d,J＝8.1Hz,1H),8.17(s,1H),7.92-7.81(m,2 H),7.74(s,1H),7.67-7.59(m,2H),4.05-3.95(m,3H),3.57(s,3H),2.50(br.s.,3H),1.10(t,J＝7.1Hz,3H). LCMS M/Z(M+H)510.

The following compounds were prepared in a similar manner to Example 100:

Examples 101-102

Example 103

Benzyl 4-(3-hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

Step 1: Benzyl 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Intermediate D) (207 mg, 0.50 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 40 mg, 1.00 mmol) at 0 ° C. After stirring for 15 min, benzyl bromide (170 mg, 1.00 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h and then quenched by adding water (20 mL). The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc=4:1) to give the title compound (200 mg, 79% yield) as a yellow solid.

Step 2: Benzyl 4-bromo-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of benzyl 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (200 mg, 0.40 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25 ° C for 2 h and then concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and adjusted to pH 8 by adding K ₂ CO _3. The suspension was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=9:1) to give the title compound (100 mg, 67% yield) as a yellow solid.

Step 3: Benzyl 4-(3-hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a suspension of 4-bromo-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid benzyl ester (100 mg, 0.27 mmol) in DMF (3 mL) and TEA (1 mL) was added 2-methylbut-3-yn-2-ol (109 mg, 1.30 mmol), copper (I) iodide (11 mg, 0.06 mmol) and bis(triphenylphosphine)palladium (II) chloride (21 mg, 0.03 mmol). The reaction mixture was purged with N ₂ for 5 min and then stirred at 110 ° C for 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN43-73% / 0.1% NH ₄ OH in water) to give the title compound (13 mg, 13% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.47(br.s,1H),7.52(s,1H),7.43(d,J＝7.2Hz,2H),7.38-7.35(m,2H),7.31 -7.27(m,1H),5.36(s,2H),5.26(s,1H),3.52(s,3H),2.46(s,3H),1.45(s,6H). LCMS M/Z(M+Na)401.

The following compounds were prepared in a similar manner to Example 103:

Examples 104-133

Example 134

4-(3-Cyclopropyl-3-hydroxy-but-1-ynyl)-2,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (2-cyano-1,1-dimethyl-ethyl) ester

Step 1: 4-Bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbonyl chloride

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Intermediate D) (207 mg, 0.50 mmol) in DCM (10 mL) was added oxalyl chloride (1 mL). The reaction mixture was stirred at ambient temperature for 2 h and then concentrated under reduced pressure to give the crude title compound (217 mg, 100% yield) as a yellow oil.

Step 2: 1-cyano-2-methylpropan-2-yl 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbonyl chloride (217 mg, 0.50 mmol) in toluene (20 mL) was added 3-hydroxy-3-methylbutyronitrile (99 mg, 1.00 mmol). The reaction mixture was heated at 100 ° C for 3 h. After cooling to ambient temperature, the reaction was quenched by adding water (20 mL) and then extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc=4:1) to give the title compound (150 mg, 61% yield) as a yellow solid.

Step 3: 1-cyano-2-methylpropan-2-yl 4-bromo-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid 1-cyano-2-methylprop-2-yl ester (150 mg, 0.30 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The reaction mixture was stirred at ambient temperature for 2 h and then concentrated under reduced pressure. The residue was diluted with MeOH (5 mL) and adjusted to pH 8 by adding K ₂ CO _3. The suspension was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=9:1) to give the title compound (100 mg, 90% yield) as a yellow solid.

Step 4: 4-(3-Cyclopropyl-3-hydroxy-but-1-ynyl)-2,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (2-cyano-1,1-dimethyl-ethyl) ester

To a suspension of 4-bromo-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid 1-cyano-2-methylprop-2-yl ester (100 mg, 0.27 mmol) in DMF (3 mL) and TEA (1 mL) was added 2-cyclopropylbut-3-yn-2-ol (150 mg, 1.37 mmol), copper (I) iodide (11 mg, 0.06 mmol) and bis(triphenylphosphine)palladium (II) chloride (21 mg, 0.03 mmol). The solution was purged with N ₂ for 5 min and then stirred at 110 ° C for 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN 30-60% / 0.1% NH ₄ OH in water) to give the title compound (20 mg, 19% yield) as a white solid. ¹ H NMR (400MHz, CD ₃ OD)δ7.43(s,1H),3.61(s,3H),3.24(s,2H),2.63(s,3H),1.73(s,6H),1.63(s,3 H),1.19-1.15(m,1H),0.72-0.71(m,1H),0.62-0.60(m,1H),0.49-0.46(m,2H). LCMS M/Z(M-OH)378.

The following compounds were prepared in a similar manner to Example 134:

Examples 135-167

Example 168

N-ethyl-4-(3-hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

Step 1: 4-Bromo-N-ethyl-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Intermediate D) (211 mg, 0.51 mmol) in THF (5 mL) was added HOBT (80 mg, 0.56 mmol), ethylamine (2M in THF, 0.28 mL, 0.56 mmol) and EDC (110 mg, 0.56 mmol). The reaction mixture was stirred at ambient temperature for 12 h and then concentrated under reduced pressure. The residue was purified by column chromatography (hexane: EtOAc = 5: 5) to give the title compound (201.4 mg, 88%) as a white solid. LCMS M/Z (M+H) 442, 444.

Step 2: 4-Bromo-N-ethyl-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

To a solution of 4-bromo-N-ethyl-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (201.4 mg, 0.45 mmol) was added 2,2,2-trifluoroacetic acid (4 mL). The reaction mixture was stirred at ambient temperature for 1 h and MeOH (1 mL) was added. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (50% DCM:MeOH: _NH4OH =90:10:1 in DCM) to give the title compound (133.0 mg, 95%) as an off-white solid. LCMS M/Z (M+H) 312, 314.

Step 3: N-ethyl-4-(3-hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

To a solution of 4-bromo-N-ethyl-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (133 mg, 0.43 mmol) in DMF (2 mL) and DIPEA (0.74 mL, 4.26 mmol) was added 2-methylbut-3-yn-2-ol (83 μL, 0.85 mmol), copper (I) iodide (16 mg, 0.09 mmol) and bis(triphenylphosphine)palladium (II) dichloride (15 mg, 0.021 mmol). The reaction mixture was purged with N ₂ for 5 min and then stirred at 100 ° C overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (0-65% DCM:MeOH:NH ₄ OH=90:10:1 in DCM) to give the title compound (84 mg, 63% yield) as an off-white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.14(s,1H),7.82(t,J＝5.4Hz,1H),7.43(s,1H),5.20(s,1H),3.52-3.47 (m,3H),3.31-3.22(m,2H),2.33(s,3H),1.43(s,6H),1.11(t,J=7.2Hz,3H). LCMS M/Z(M+H)316.

The following compounds were prepared in a similar manner to Example 168:

Examples 169-171

Example 172

4-(3-cyclopropyl-3-hydroxy-but-1-ynyl)-3-(5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one

Step 1: 4-Bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbohydrazide

To a solution of ethyl 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (Intermediate C) (500 mg, 1.13 mmol) in ethanedioic acid (15 mL) and EtOH (5 mL) was added hydrazine hydrate (20 mL). The reaction mixture was heated at 100 ° C for 48 h. After cooling to ambient temperature, the solution was diluted with water (30 mL). The resulting precipitate was collected by filtration, washed with water (10 mL) and dried in vacuo to give the crude title compound (300 mg, 62% yield) as a white solid.

Step 2: 4-Bromo-N'-(2-hydroxy-2-methylpropionyl)-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid hydrazide

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid hydrazide (300 mg, 0.70 mmol) in DMF (10 mL) was added EDC (267 mg, 1.40 mmol), HOBT (189 mg, 1.40 mmol) and 2-hydroxy-2-methylpropionic acid (146 mg, 1.40 mmol). The reaction mixture was stirred at ambient temperature for 16 h and then quenched by the addition of water (20 mL). The mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (2 × 20 mL) and brine (2 × 20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude title compound (250 mg, 69% yield) as a yellow solid.

Step 3: 4-Bromo-3-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-N'-(2-hydroxy-2-methylpropanoyl)-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid hydrazide (250mg, 0.49mmol) in DCM (20mL) was added TEA (247mg, 2.45mmol), triphenylphosphine (257mg, 0.98mmol) and carbon tetrachloride (372mg, 2.45mmol). The reaction mixture was heated at 50 DEG C for 16h and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc=1:1) to give the title compound (160mg, 66% yield) as a yellow solid.

Step 4: 4-Bromo-3-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-3-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (160 mg, 0.32 mmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The reaction mixture was stirred at ambient temperature for 2 h and concentrated under reduced pressure. The residue was diluted with MeOH (5 mL) and adjusted to pH 8 by the addition of K ₂ CO _3. The suspension was diluted with water (20 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title compound (100 mg, 85% yield) as a yellow solid.

Step 5: 4-(3-cyclopropyl-3-hydroxy-but-1-ynyl)-3-(5-(1-hydroxy-1-methyl-ethyl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one

To a suspension of 4-bromo-3-(5-(2-hydroxypropan-2-yl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (100 mg, 0.27 mmol) in DMF (3 mL) and TEA (1 mL) was added 2-methylbut-3-yn-2-ol (154 mg, 1.40 mmol), copper (I) iodide (11 mg, 0.06 mmol) and bis(triphenylphosphine)palladium (II) dichloride (21 mg, 0.03 mmol). The reaction mixture was purged with _N2 for 5 min and then stirred at 110 ° C. under microwave conditions for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN 30-60% / 0.1% _NH4OH in water) to give the title compound (20 mg, 18% yield) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.47(s,1H),3.63(s,3H),2.49(s,3H),1.72(s,6H),1.46(s,3H),1.11-1.06(m,1H),0.46-0.36(m,4H). LCMS M/Z(M-OH)379.

The following compounds were prepared in a similar manner to Example 172:

Examples 173-179

Example 180

3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-4-(4,4,4-trifluoro-3-hydroxy-3-phenyl-but-1-ynyl)-1H-pyrrolo[2,3-c]pyridin-7-one

Step 1: 4-Bromo-N'-(cyclopropanecarbonyl)-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid hydrazide

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Intermediate D) (500 mg, 1.20 mmol) in DMF (15 mL) was added TEA (243.63 mg, 2.41 mmol), HATU (549 mg, 1.44 mmol) and cyclopropanecarboxylic acid hydrazide (180 mg, 1.81 mmol). The reaction mixture was stirred at ambient temperature for 16 h and then diluted with water (20 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (500 mg, 84% yield) as a yellow solid.

Step 2: 4-Bromo-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-N'-(cyclopropanecarbonyl)-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid hydrazide (400mg, 0.80mmol) in DCM (20mL) was added TEA (244, 2.41mmol), triphenylphosphine (316mg, 1.21mmol) and carbon tetrachloride (2mL). The reaction mixture was heated at 50 ° C for 6h and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc=1: 1) to give the title compound (280mg, 73% yield) as a yellow solid.

Step 3: 4-Bromo-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (280 mg, 0.58 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The reaction mixture was stirred at ambient temperature for 2 h and then concentrated under reduced pressure. The residue was diluted with MeOH (15 mL) and adjusted to pH 8 by adding K ₂ CO _3. The suspension was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title compound (150 mg, 90% yield) as a yellow solid.

Step 4: 3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-4-(4,4,4-trifluoro-3-hydroxy-3-phenyl-but-1-ynyl)-1H-pyrrolo[2,3-c]pyridin-7-one

To a solution of 4-bromo-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (100 mg, 0.29 mmol) in DMF (2.5 mL) and TEA (290 mg, 2.86 mmol) was added 1,1,1-trifluoro-2-phenyl-but-3-yn-2-ol (115 mg, 0.57 mmol), copper (I) iodide (11 mg, 0.06 mmol), and bis(triphenylphosphine)palladium (II) dichloride (20 mg, 0.03 mmol). The solution was purged with _N2 for 5 min and then stirred at 110 °C under microwave conditions for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN 30-60%/0.1% NH ₄ OH in water) to give the title compound (50 mg, 37% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.87 (br. s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.61-7.58 (m, 2H), 7.41-7.39 (m, 3H), 3.59 (s, 3H), 2.41 (s, 3H), 1.93-1.88 (m, 1H), 0.91-0.75 (m, 4H). LCMS M/Z (M+H) 469.

The following compounds were prepared in a similar manner to Example 180:

Examples 181-196

Example 197

4-[3-(3-Carbamoylphenyl)-4,4,4-trifluoro-3-hydroxy-but-1-ynyl]-2,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester

A mixture of ethyl 4-(3-(3-cyanophenyl)-4,4,4-trifluoro-3-hydroxybut-1-yn-1-yl)-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (Example 40) (60 mg, 0.13 mmol), potassium hydroxide (74 mg, 1.31 mmol), and hydrogen peroxide (30% aqueous solution, 0.2 mL, 6.53 mmol) in DMSO (2 mL) was stirred at ambient temperature for 1 h. The solution was neutralized by adding 2M aqueous HCl and then diluted with water (10 mL). The reaction mixture was extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN 23-53%/0.05% NH ₄ OH in water) to give the title compound (33 mg, 53% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.40 (br. s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.96-7.92 (m, 2H), 7.83 (s, 1H), 7.74 (s, 1H), 7.55-7.51 (m, 1H), 7.47 (s, 1H), 4.04 (q, J = 6.8 Hz, 2H), 3.57 (s, 3H), 2.50 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H). LCM S M/Z (M+H) 476.

Example 198

4-(3-Hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one

Step 1: 5-Bromo-2-methoxy-3-nitropyridine

Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2 mmol) in MeOH (125 mL). The reaction mixture was heated at reflux for 2 h and then concentrated under reduced pressure. The residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 81.5% yield) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.43 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.0 Hz, 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, 55.0mmol) was added dropwise to a stirred solution of 5-bromo-2-methoxy-3-nitropyridine (4.0g, 17.1mmol) in THF (40mL) at -78°C. The reaction mixture was gradually warmed to ambient temperature and stirred for an additional 3h. The reaction mixture was quenched by the addition of 1M _NH4Cl aqueous solution (150mL) and then extracted with EtOAc (3×100mL). The combined organic extracts were dried over anhydrous _{Na2SO4 and} concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc=10:1) to give the title compound (1.65g, 39.9% yield) as a brown oil. LCMS M/Z(M+H)240.1,242.1.

Step 3: 4-Bromo-2-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (1.65 g, 6.8 mmol) in ACN (10 mL) and water (10 mL) was added chlorotrimethylsilane (1.4 g, 13.6 mmol) and potassium iodide (2.5 g, 15.0 mmol). The reaction mixture was heated at 90 ° C for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography (DCM: MeOH = 9: 1) to give the title compound (0.9 g, 59% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.06 (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.

Step 4: 4-Bromo-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Methyl iodide (112 mg, 0.79 mmol) was added dropwise to a stirred mixture of 4-bromo-2-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (300 mg, 1.32 mmol) and K ₂ CO ₃ (274 mg, 1.98 mmol) in DMF (15 mL) at ambient temperature. The reaction mixture was stirred at 70 ° C for 15 h, then quenched by the addition of water (25 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (82 mg, 26%) as a brown solid. ¹ H NMR (400MHz, CD3OD): δ7.33(s,1H), 6.07(s,1H), 3.58(s,3H), 2.39(s,3H).

Step 5: 4-(3-Hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one

To a solution of 4-bromo-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (100 mg, 0.4 mmol) in ACN (3 mL) and TEA (1 mL) was added 2-methylbut-3-yn-2-ol (70 mg, 0.8 mmol), copper (I) iodide (8 mg, 0.04 mmol) and bis(triphenylphosphine)palladium (II) chloride (30 mg, 0.04 mmol). The reaction mixture was purged with _N2 for 5 min, then the reaction mixture was heated at 90 ° C for 3 h and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN 0-85% / 0.1% _NH4OH in water) to give the title compound (9 mg, 9% yield) as an off-white solid. ¹ H NMR (400MHz, CD ₃ OD) δ 11.87 (s, 1H), 7.39 (s, J = 1.4 Hz, 1H), 6.04 (s, 1H), 5.36 (s, 1H), 3.47 (s, 3H), 2.32 (s, 3H), 1.47 (s, 6H). LCMS M/Z(M+H)245.

Examples 199a and 199b

3-Acetyl-4-(3-hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one (199a) and 3-acetyl-4-(3-hydroxy-3-methyl-but-1-ynyl)-1,2-dimethyl-6H-pyrrolo[2,3-c]pyridin-7-one (199b)

Step 1: 1-(4-Bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethanone

To a solution of 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (1.20 g, 5.00 mmol) in DCM (50 mL) was added acetyl chloride (1.17 g, 15.00 mmol) and aluminum chloride (1.98 g, 15.00 mmol). The reaction mixture was stirred at ambient temperature for 3 h and then slowly quenched by adding water (20 mL). The mixture was extracted with DCM (3 × 30 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc=4: 1) to give the title compound (1.00 g, 71% yield) as a yellow oil.

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

To a solution of 1-(4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethanone (800 mg, 2.84 mmol) in ACN (10 mL) and water (10 mL) was added chlorotrimethylsilane (613 mg, 5.68 mmol) and potassium iodide (943 mg, 5.68 mmol). The reaction mixture was heated at 80 ° C for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography (DCM: MeOH = 9: 1) to give the title compound (450 mg, 59% yield) as a yellow solid.

Step 3: 3-Acetyl-4-bromo-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one and 3-acetyl-4-bromo-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 3-acetyl-4-bromo-2-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (268 mg, 1.00 mmol) in DMF (10 mL) was added K ₂ CO ₃ (414 mg, 3.00 mmol) and methyl iodide (142 mg, 1.00 mmol). The reaction mixture was stirred at ambient temperature for 2 h and then concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=9:1) to give a mixture of the title compounds (70 mg, 25% yield) as a yellow solid.

Step 4: 3-Acetyl-4-(3-hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one (199a) and 3-acetyl-4-(3-hydroxy-3-methyl-but-1-ynyl)-1,2-dimethyl-6H-pyrrolo[2,3-c]pyridin-7-one (199b)

To a suspension of 3-acetyl-4-bromo-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one and 3-acetyl-4-bromo-1,2-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (70 mg, 0.25 mmol) in DMF (3 mL) and TEA (1 mL) was added 2-methylbut-3-yn-2-ol (105 mg, 1.25 mmol), copper(I) iodide (11 mg, 0.06 mmol), and bis(triphenylphosphine)palladium(II) dichloride (21 mg, 0.03 mmol). The reaction mixture was purged with _N₂ for 5 min and then stirred at 110°C under microwave conditions for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN 10-40%/0.1% _NH₄OH in water) to give the title compound.

199a (5.0 mg, 7% yield) was obtained as a white solid: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.53 (s, 1H), 3.64 (s, 3H), 2.71 (s, 3H), 2.53 (s, 3H), 1.57 (s, 6H). LCMS M/Z (M-OH) 269.

199b (6.0 mg, 8% yield) was obtained as a white solid: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.22 (s, 1H), 4.12 (s, 3H), 2.68 (s, 3H), 2.44 (s, 3H), 1.56 (s, 6H). LCMSM/Z (M+Na) 309.

Example 200

4-(3-Hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid

Step 1: 2-(tert-Butoxycarbonyl)amino)benzyl 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (207 mg, 0.50 mmol) in DCM (10 mL) was added tert-butyl (2-(hydroxymethyl)phenyl)carbamate (134 mg, 0.60 mmol), N,N'-dicyclohexylcarbodiimide (205 mg, 1.00 mmol) and DMAP (122 mg, 1.00 mmol). The mixture was heated at 40 °C for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over _{anhydrous Na2SO4} and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc=4:1) to give the title compound (280 mg, 90% yield) as a yellow solid.

Step 2: 2-aminobenzyl 4-bromo-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of 2-((tert-butoxycarbonyl)amino)benzyl 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (300 mg, 0.48 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The reaction mixture was stirred at ambient temperature for 2 h and concentrated under reduced pressure. The residue was diluted with MeOH (5 mL) and adjusted to pH 8 by adding K ₂ CO _3. The suspension was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=9:1) to give the title compound (150 mg, 78% yield) as a yellow solid.

Step 3: 4-(3-Hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid

To a suspension of 2-aminobenzyl 4-bromo-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (150 mg, 0.39 mmol) in DMF (3 mL) and TEA (1 mL) was added 2-methylbut-3-yn-2-ol (168 mg, 2.00 mmol), copper (I) iodide (15 mg, 0.08 mmol) and bis(triphenylphosphine)palladium (II) dichloride (28 mg, 0.04 mmol). The reaction mixture was purged with _N2 for 5 min and then stirred at 110 ° C for 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN 16-46% / 0.1% _NH4OH in water) to give the title compound (by-product, 10 mg, 6.5% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.50 (br.s, 1H), 12.10 (br.s, 1H), 7.47 (s, 1H), 5.12 (s, 1H), 3.51 (s, 3H), 2.48 (s, 3H), 1.44 (s, 6H). LCMS M/Z(M-OH)271.

Example 201

3-(Hydroxymethyl)-4-(3-hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one

Step 1: 4-Bromo-3-(hydroxymethyl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of ethyl 4-bromo-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (Intermediate B) (200 mg, 0.64 mmol) in THF (20 mL) was added diisobutylaluminum hydride (1.0 M, 1.8 mL, 1.80 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 16 h and then quenched by the addition of saturated NH ₄ Cl aqueous solution (10 mL). The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (DCM: MeOH = 9: 1) to give the title compound (160 mg, 92% yield) as a white solid.

Step 2: 3-(Hydroxymethyl)-4-(3-hydroxy-3-methyl-but-1-ynyl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one

To a solution of 4-bromo-3-(hydroxymethyl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (160 mg, 0.59 mmol) in DMF (3 mL) and TEA (1 mL) was added 2-methylbut-3-yn-2-ol (252 mg, 3.00 mmol), copper (I) iodide (23 mg, 0.12 mmol) and bis(triphenylphosphine)palladium (II) dichloride (42 mg, 0.06 mmol). The reaction mixture was purged with _N2 for 5 min and then stirred at 110 ° C for 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN13-29% / 0.1% _NH4OH in water) to give the title compound (5 mg, 3% yield) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ7.35 (s, 1H), 4.95-4.91 (m, 2H), 3.60 (s, 3H), 2.44 (s, 3H), 1.60 (s, 6H). LCMS M/Z(M+H)275.

Example 202

4-(3-Hydroxy-3-methyl-but-1-ynyl)-3-(4-isopropyl-4,5-dihydrooxazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one

Step 1: 4-Bromo-N-(1-hydroxy-3-methylbutan-2-yl)-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Intermediate D) (207 mg, 0.50 mmol) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (129 mg, 1.00 mmol), HATU (380 mg, 1.00 mmol) and 2-amino-3-methylbutan-1-ol (103 mg, 1.00 mmol). The reaction mixture was stirred at ambient temperature for 16 h and then diluted with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with water (20 mL), brine ( ₂₀ mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give the crude title compound (200 mg, 80% yield) as a yellow solid.

Step 2: 4-Bromo-3-(4-isopropyl-4,5-dihydrooxazol-2-yl)-2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-N-(1-hydroxy-3-methylbutan-2-yl)-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (200 mg, 0.40 mmol) in DCM (10 mL) and DMF (10 mL) was added 4-methylbenzene-1-sulfonyl chloride (152 mg, 0.80 mmol) and TEA (124 mg, 1.20 mmol). The reaction mixture was heated at 40 ° C for 6 h and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc=1: 1) to give the title compound (120 mg, 62% yield) as a yellow solid.

Step 3: 4-Bromo-3-(4-isopropyl-4,5-dihydrooxazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-3-(4-isopropyl-4,5-dihydrooxazol-2-yl)-2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (120 mg, 0.25 mmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The reaction mixture was stirred at ambient temperature for 2 h and concentrated under reduced pressure. The residue was diluted with MeOH (5 mL) and adjusted to pH 8 by adding K ₂ CO _3. The suspension was diluted with water (20 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title compound (70 mg, 80% yield) as a yellow solid.

Step 4: 4-(3-Hydroxy-3-methyl-but-1-ynyl)-3-(4-isopropyl-4,5-dihydrooxazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one

To a suspension of 4-bromo-3-(4-isopropyl-4,5-dihydrooxazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (70 mg, 0.20 mmol) in DMF (3 mL) and TEA (1 mL) was added 2-methylbut-3-yn-2-ol (84 mg, 1.00 mmol), copper (I) iodide (8 mg, 0.04 mmol) and bis(triphenylphosphine)palladium (II) dichloride (14 mg, 0.02 mmol). The reaction mixture was purged with _N2 for 5 min and then stirred at 110 ° C. for 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN 23-53% / 0.1% _NH4OH in water) to give the title compound (8 mg, 11% yield) as a white solid. ¹ H NMR (400MHz, CD ₃ OD)δ7.42(s,1H),4.66-4.61(m,1H),4.28-4.24(m,1H),4.16-4.11(m,1H),3.61(s,3H),2 .51(s,3H),1.92-1.86(m,1H),1.57(s,6H),1.06(d,J＝6.8Hz,3H),1.00(d,J＝6.8Hz,3H). LCMS M/Z(M+H)356.

The following compounds were prepared in a similar manner to Example 202:

Example 203

Example 204

4-(3-cyclopropyl-3-hydroxy-but-1-ynyl)-3-(5,5-dimethyl-4H-oxazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one

Step 1: 4-Bromo-N-(2-hydroxy-2-methylpropyl)-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Intermediate D) (207 mg, 0.50 mmol) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (129 mg, 1.00 mmol), HATU (380 mg, 1.00 mmol) and 1-amino-2-methylpropan-2-ol (89 mg, 1.00 mmol). The reaction mixture was stirred at ambient temperature for 16 h and then diluted with water (20 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title compound (200 mg, 82% yield) as a yellow solid.

Step 2: 4-Bromo-3-(5,5-dimethyl-4,5-dihydrooxazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-N-(2-hydroxy-2-methylpropyl)-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxamide (200 mg, 0.41 mmol) in THF (10 mL) was added boron trifluoride etherate (1 N, 2.0 mL, 2.00 mmol). The reaction mixture was heated at 65 ° C for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=9:1) to give the title compound (100 mg, 72% yield) as a yellow solid.

Step 3: 4-(3-cyclopropyl-3-hydroxy-but-1-ynyl)-3-(5,5-dimethyl-4H-oxazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-one

To a suspension of 4-bromo-3-(5,5-dimethyl-4,5-dihydrooxazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (100 mg, 0.30 mmol) in DMF (3 mL) and TEA (1 mL) was added 2-cyclopropylbut-3-yn-2-ol (165 mg, 1.50 mmol), copper (I) iodide (11 mg, 0.06 mmol) and bis(triphenylphosphine)palladium (II) chloride (21 mg, 0.03 mmol). The reaction mixture was purified by _N2 for 5 min and then stirred at 110 ° C for 1 h under microwave conditions. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN 35-65% / 0.1% formic acid in water) to give the title compound (5 mg, 5% yield) as a white solid. ¹ H NMR (400MHz, CD ₃ OD)δ7.39(s,1H),3.82(s,2H),3.61(s,3H),2.49(s,3H),1.59(s,3H),1.54(s,6H),1.18-1.16(m,1H),0.67-0.65(m,1H),0.55-0.47(m,3H). LCMS M/Z(M+H)368.

Example 205

3-(5-(Hydroxymethyl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-4-(4,4,4-trifluoro-3-hydroxy-3-phenyl-but-1-ynyl)-1H-pyrrolo[2,3-c]pyridin-7-one

Step 1: 4-Bromo-N'-(2-methoxyacetyl)-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbohydrazide

To a solution of 4-bromo-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Intermediate D) (414 mg, 1.00 mmol) in DMF (15 mL) was added N-ethyl-N-isopropylpropan-2-amine (258 mg, 2.00 mmol), HATU (570 mg, 1.50 mmol) and 2-methoxyacetohydrazide (208 mg, 2.00 mmol). The reaction mixture was stirred at ambient temperature for 16 h and diluted with water (20 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude title compound (500 mg, 83% yield) as a yellow solid.

Step 2: 4-Bromo-3-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-N'-(2-methoxyacetyl)-2,6-dimethyl-7-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carbohydrazide (500mg, 1.00mmol) in DCM (20mL) and carbon tetrachloride (2mL) was added triphenylphosphine (524mg, 2.00mmol) and TEA (515mg, 5.00mmol). The reaction mixture was heated at 60 ° C for 6h and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: EtOAc=1: 1) to give the title compound (300mg, 62% yield) as a yellow solid.

Step 3: 4-Bromo-3-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of 4-bromo-3-(5-(methoxymethyl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (300 mg, 0.62 mmol) in DCM (20 mL) was added boron tribromide (0.5 mL) at -78 ° C. The reaction mixture was stirred at ambient temperature for 30 min and then quenched by the addition of water (20 mL). The mixture was extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title compound (100 mg, 48% yield) as a yellow solid.

Step 4: 3-(5-(Hydroxymethyl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-4-(4,4,4-trifluoro-3-hydroxy-3-phenyl-but-1-ynyl)-1H-pyrrolo[2,3-c]pyridin-7-one

To a suspension of 4-bromo-3-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one in DMF (3 mL) and TEA (1 mL) were added 1,1,1-trifluoro-2-phenylbut-3-yn-2-ol (96 mg, 0.48 mmol), copper(I) iodide (11 mg, 0.06 mmol), and bis(triphenylphosphine)palladium(II)dichloride (21 mg, 0.03 mmol). The reaction mixture was purged with _N2 for 5 min and then stirred at 110 °C under microwave conditions for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (ACN23-53%/0.1% _NH4OH in water) to give the title compound (40 mg, 37% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.89 (br.s, 1H), 7.87 (s, 1H), 7.60 (d, J = 7.2Hz, 2H), 7.42-7.40 (m, 3H), 4.41-4.28 (m, 2H), 3.59 (s, 3H), 2.45 (s, 3H). LCMS M/Z(M+H)459.

The following compounds were prepared in a similar manner to Example 205:

Example 206

Example 207

2-Cyclopropyl-4-(3-hydroxy-3-methyl-but-1-ynyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester

Step 1: Ethyl 3-cyclopropyl-2-(1-methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-yl)-3-oxopropanoate

To a solution of ethyl 3-cyclopropyl-3-oxopropanoate (2.34 ml, 15.9 mmol) in THF (70 mL) was added NaH (60% in mineral oil, 800 mg, 19.9 mmol) in portions at 0 ° C. The mixture was stirred at 0 ° C for 0.5 h, and then a solution of 4-chloro-1-methyl-3-nitropyridine-2 (1H) -one (2.5 g, 13.3 mmol) in THF (20 mL) was added. The reaction mixture was heated at 50 ° C for 12 h and quenched with 5 mL of 1N HCl, then poured into brine and extracted with EtOAc (3 ×). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (hexane: EtOAc = 3: 7) to give the title compound (3.471 g, 85% yield) as a yellow oil. LCMS M / Z (M + H) 309.

Step 2: Ethyl 2-cyclopropyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of ethyl 3-cyclopropyl-2-(1-methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-yl)-3-oxopropanoate (1.7 g, 5.51 mmol) in MeOH (20 mL) was added Raney nickel (2 mL). The reaction mixture was purified with N ₂ for 15 min and then stirred for 12 h under a hydrogen atmosphere at ambient temperature. The reaction mixture was diluted with DCM (30 mL), filtered through celite and washed with 1: 1 DCM: MeOH and concentrated. The residue was purified by column chromatography (90: 10: 1 DCM: MeOH: 0-40% gradient of NH ₄ OH/DCM) to give the title compound (1.27 g, 84% yield) as a tan solid. LCMS M/Z(M+H)261.

Step 3: Ethyl 4-bromo-2-cyclopropyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate

To a solution of ethyl 2-cyclopropyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (1.27 g, 4.87 mmol) in DMF (13 mL) was added NBS (1.43 g, 8.03 mmol). The reaction mixture was stirred at ambient temperature for 1 h, then poured into water (175 mL) and extracted with EtOAc (3 ×). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (hexane: EtOAc = 4: 6 to 8: 2) to give the title compound (763.4 mg, 46% yield) as a purple solid. LCMS M / Z (M + H) 339 / 341.

Step 4: 2-Cyclopropyl-4-(3-hydroxy-3-methyl-but-1-ynyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester

To a solution of ethyl 4-bromo-2-cyclopropyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (100 mg, 0.29 mmol) in DMF (2 mL) and DIPEA (0.51 mL, 2.9 mmol) was added 2-methylbut-3-yn-2-ol (57 μL, 0.59 mmol), copper (I) iodide (11.1 mg, 59 μmol) and bis(triphenylphosphine)palladium (II) chloride (10.3 mg, 14.7 μmol). The reaction mixture was purged with _N2 for 5 min and then stirred at 100 ° C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (hexane: EtOAc = 30: 70 to 0: 100) to give the title compound (46 mg, 46% yield) as a tan solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ11.97(s,1H),7.49(s,1H),5.24(s,1H),4.31(q,J＝7.1Hz,2H),3.50(s,3H),2.48-2.43(m,1H ), 1.45 (s, 6H), 1.30 (t, J = 7.1Hz, 3H), 1.06 (td, J = 2.8, 5.4Hz, 2H), 0.99 (td, J = 2.9, 8.5Hz, 2H). LCMSM/Z(M+H)343.

Example 208

2,6-Dimethyl-7-oxo-4-[4,4,4-trifluoro-3-hydroxy-3-(3-morpholinophenyl)but-1-ynyl]-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid ethyl ester

To a solution of ethyl 4-(3-(3-bromophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-yn-1-yl)-2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (75 mg, 0.15 mmol) in dioxane (2 mL) was added sodium tert-butoxide (49 mg, 0.51 mmol), ruphos precatalyst G3 (6 mg, 7 μmol) and morpholine (25.4 mL, 0.29 mmol). The reaction mixture was purged with _N2 and then heated at 100 ° C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound (3 mg, 4% yield) as a tan solid. LCMS M/Z(M+H)518.

Example 209

Biological assays

Measuring the _IC50 of inhibitors using the TAF1-BD2TR-FRET binding assay

TAF1-BD2 _1504-1635 tagged with His/Flag epitope was cloned, expressed and purified to homogeneity. TAF1-BD2 binding and inhibition were assessed as follows: the engagement of biotinylated small molecule compound 1000 with the target was monitored using TR-FRET assay technology (Perkin-Elmer). Specifically, TAF1-BD2 (final 0.012 μM) in 50 mM HEPES (pH 7.5; final), 50 mM NaCl (final), 1 mM TCEP (final), 0.1 mg/mL BSA (final) and 0.069 mM Brij-35 (final) was added to a 384-well ProxiPlate in the presence of DMSO (final 0.2% DMSO) or a serial dilution of the compound in DMSO. After incubation at room temperature for 10 minutes, biotin-ligand (final 0.04 μM) was added. After incubation at room temperature for 10 minutes, a mixture of Eu-W1024 anti-6×His antibody (PerkinElmer AD0110) and SureLight ^™ streptavidin-allophycocyanin (SA-APC, Perkin Elmer CR130-100) was added to a final concentration of 0.2 nM for antibody and 0.025 μM for SA-APC, respectively. After equilibration at room temperature for 40 minutes, the plate was read on the Envision instrument and the IC ₅₀ was calculated using a four-parameter logistic model (XLFIT). Compound 1000 and the above-described TAF1-BD2TR-FRET binding assay represent additional embodiments of the present invention.

Measuring the _IC50 of inhibitors using the TAF1-BD1TR-FRET binding assay

TAF1-BD1 _1381-1497 tagged with His/Flag epitope was cloned, expressed and purified to homogeneity. TAF1-BD1 binding and inhibition were assessed as follows: the engagement of biotinylated small molecule compound 1000 with the target was monitored using TR-FRET assay technology (Perkin-Elmer). Specifically, TAF1-BD1 (final 0.08 μM) in 50 mM HEPES (pH 7.5; final), 50 mM NaCl (final), 1 mM TCEP (final), 0.1 mg/mL BSA (final) and 0.069 mM Brij-35 (final) was added to a 384-well ProxiPlate in the presence of DMSO (final 0.2% DMSO) or a serial dilution of the compound in DMSO. After incubation at room temperature for 10 minutes, biotin-ligand (final 0.08 μM) was added. After incubation at room temperature for 10 minutes, a mixture of Eu-W1024 anti-6×His antibody (Perkin Elmer AD0110) and SureLight ^™ streptavidin-allophycocyanin (SA-APC, Perkin Elmer CR130-100) was added to a final concentration of 0.2 nM antibody and 0.05 μM SA-APC, respectively. After equilibration at room temperature for 40 minutes, the plate was read on the Envision instrument and the IC ₅₀ was calculated using a four-parameter logistic model (XLFIT). The above-described TAF1-BD1 TR-FRET binding assay represents an additional embodiment of the present invention.

Example 210

Synthesis of Compound 1000

Step 1: 2-Methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol) in methanol (1.0 L) was added dropwise (2 h) to a stirred and cooled (0 ° C) solution of sodium methoxide (250 g, 4.63 mol) in methanol (850 mL). After addition, the mixture was heated to reflux for 23 h, at which time TLC indicated that the reaction was complete. The mixture was concentrated under reduced pressure to a volume of approximately 900 mL and quenched by adding water (1.5 L). The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (250 g, 100% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J = 5.2 Hz, 1H), 7.10 (d, J = 5.6 Hz, 1H), 3.92 (s, 3H), 2.26 (s, 3H).

Step 2: 5-Bromo-2-methoxy-4-methyl-3-nitropyridine

At ambient temperature, sodium acetate (365g, 5.37mol) is added to a stirred solution of 2-methoxy-4-methyl-3-nitropyridine (250g, 1.49mol) in acetic acid (1.5L), and then Br ₂ (639g, 4.00mol) is added dropwise (30min). After addition, the mixture is heated at 80°C for 12h, at which time TLC indicates that the reaction is complete. The mixture is cooled (0°C) and quenched by the addition of 10% Na ₂ SO ₃ aqueous solution (1.5L) and saturated Na ₂ SO ₃ aqueous solution (1.5L). The resulting solid is collected by filtration, washed with water and dried under reduced pressure to obtain the title compound (302g, 82.2% yield) as a light yellow solid. ¹ H NMR (400MHz, DMSO-d6): δ 8.25 (s, 1H), 3.94 (s, 3H), 2.29 (s, 3H).

Step 3: (E)-2-(5-Bromo-2-methoxy-3-nitro-4-pyridinyl)-N,N-dimethyl-ethyleneamine

DMF-DMA (600 mL) was slowly added to a stirred and heated (80°C) solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol) in DMF (1.1 L). After addition, the mixture was heated at 95°C for 5 h, at which point TLC indicated the reaction was complete. The mixture was cooled to room temperature and poured into ice-cold water (3 L). The resulting red solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (167 g, 100% yield) as a red solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 7.05 (d, J = 13.6 Hz, 1H), 7.05 (d, J = 13.6 Hz, 1H), 4.80 (d, J = 13.2 Hz, 1H), 3.88 (s, 3H), 2.90 (s, 6H).

Step 4: 4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

A mixture of 2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethyleneamine (50.0 g, 165 mmol), Fe (50.0 g, 893 mmol), and NH ₄ Cl (50.0 g, 943 mmol) in methanol/H ₂ O (1900/250 mL) was heated at reflux for 7 h, at which point 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 the crude product. This crude product 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.

Step 5: 4-Bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine

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

Step 6: 4-Bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one

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

Step 7: 4-Bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one

Methyl iodide (24.5 g, 172.8 mmol) was added dropwise to a stirred suspension of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (intermediate A) (16.7 g, 45.5 mmol) and cesium carbonate (17.8 g, 54.6 mmol) in dioxane (250 mL). After addition, the reaction mixture was stirred at room temperature for 18 h, at which point LCMS indicated that the reaction was complete. The solvent was evaporated under reduced pressure and the residue was 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 (14.0 g, 81.4% yield) as a brown solid. ^1H 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).

Step 8:

A 50 mL vial was charged with a magnetic stir bar, 4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (0.281 g, 0.737 mmol), 1,4-dioxane (3.69 ml, 0.737 mmol), water (0.5 ml, 27.8 mmol), K ₂ CO ₃ (0.306 g, 2.211 mmol), 4-(tert-butoxycarbonylamino)phenylboronic acid (0.227 g, 0.958 mmol), and Pd(PPh ₃ ) ₄ (0.085 g, 0.074 mmol). The vial was purged, placed under a nitrogen atmosphere, and heated to 95° C. and stirred for 12 h, 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. The substance was suspended in methanol (～5 mL) and treated with KOH (200 mg). After 2 h, MeOH was removed in vacuo and the crude product was suspended in water (～20 mL) and the resulting solid was collected using a Buchner funnel by vacuum filtration. The solid was washed with additional water, collected and dried in vacuo to give tert-butyl 4- (6- methyl -7- oxo -6,7- dihydro -1H- pyrrolo [2,3-c] pyridin-4-yl) phenylcarbamate (362 mg, 0.907 mmol) as a light yellow solid. LCMS M/Z (M+H) 494.

Step 9:

A 50mL round-bottom flask was charged with a magnetic stirring bar, tert-butyl 4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbamate (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 and then diluted with dioxane (25mL). A precipitate was formed, which was collected using a Buchner funnel by vacuum filtration, 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:

A 25 mL vial was charged with a magnetic stir bar, 4-(4-aminophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (0.038 g, 0.159 mmol), anhydrous DMF (0.794 ml, 0.159 mmol), DIPEA (0.139 ml, 0.794 mmol), 17-oxo-21-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10,13-tetraoxa-16-azaheneicosane-1-oic acid (0.078 g, 0.159 mmol), and HATU (0.075 g, 0.199 mmol). 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,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoylamino)-3,6,9,12-tetraoxopentadecane-15-carboxamide (31 mg, 0.041 mmol, 26.0% yield). LCMSM/Z (M+2H)/2 357.

While various embodiments have been described, these examples can be altered to provide other embodiments utilizing the compounds and methods described herein. Accordingly, the scope of the invention is to be defined by the appended claims rather than by the specific embodiments presented as examples.

Claims (59)

1. Compounds of formula (I) or their salts: in ^R1 is a _C1-6 alkyl or _C2-6 alkenyl group, wherein the _C1-6 alkyl or _C2-6 alkenyl group is optionally substituted by one or more groups independently selected from _C3-8 carbocyclic groups; ^R2 is a _C1-6 alkyl or carbocyclic group; ^R3 is H, _C1-6 alkyl, -N( ^Rb ) ₂ , -C(=O) ^Ra , -C(=O) ^ORa , or a 5-6 membered heteroaryl ring, wherein the _C1-6 alkyl and 5-6 membered heteroaryl rings are optionally substituted by one or more groups independently selected from the following: _C1-6 alkyl, carbocyclic, heterocyclic, oxo, halogen, -N( ^Rb ) ₂ , and ^-ORb , wherein any _C1-6 alkyl, carbocyclic, and heterocyclic group is optionally substituted by one or more groups independently selected from the following: -N( ^Rb ) ₂ , -N( ^Rb )-C(O) ^-Rb , and ^-ORb ; ^Ra is selected from hydrogen, _C1-10 alkyl and carbocyclic groups, wherein any _C1-10 alkyl group is optionally substituted by one or more groups independently selected from the following: ^Rd , -N( ^Rb ) ₂ , -CN and -N( ^Rb )-C(O) ^-Rb ; Each ^Rb is independently selected from hydrogen and _C1-6 alkyl groups; Each R ^d is independently selected from carbocyclic and heterocyclic groups, wherein each carbocyclic and heterocyclic group is optionally substituted by one or more groups independently selected from the following groups: ^Re , oxo, halogen, -CN, ^-ORe and -C(O) ^-Re ; Each ^Re is a _C1-6 alkyl group, wherein each _C1-6 alkyl group is optionally substituted by one or more groups independently selected from the group consisting of halogens and hydroxyl groups; ^R4 is absent or is H, hydroxyl, or _C1-6 alkyl; ^R5 is a _C1-6 alkyl group, H, or optionally substituted with one or more groups independently selected from halogens _; and ^R6 is a _C1-6 alkyl, carbocyclic, or heterocyclic group, which is optionally substituted with one or more Rg ^groups ; or ^R5 and ^R6 together with the carbons attached to them form a carbocyclic or heterocyclic group, which is optionally substituted with one or more ^Rg groups. Each ^Rg is independently selected from _C1-6 alkyl, carbocyclic, heterocyclic, ^Rk , halogen, oxo (=O), -N( ^Rh ) ₂ , -CN, -C(O)-N( ^Rh ) ₂ , ^-ORh and -C(O) ^-Rh ; Each ^Rh is independently selected from hydrogen, _C1-6 alkyl, and carbocyclic groups, wherein each _C1-6 alkyl and carbocyclic group is optionally substituted with one or more halogens; and Each ^Rk is independently selected from _C1-6 alkyl and carbocyclic groups, wherein the _C1-6 alkyl and carbocyclic groups are substituted by one or more -ORh ^groups ; and The carbocyclic group is a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms; and Heterocyclic groups are carbocyclic groups in which one, two, three, or four carbon atoms are replaced by heteroatoms independently selected from O, N, and S. 2. The compound of claim 1 or a salt thereof, wherein ^R1 is a _C1-6 alkyl group optionally substituted with one or more groups independently selected from _C3-8 carbon cyclic groups. 3. The compound of claim 1 or a salt thereof, wherein ^R1 is a methyl group. 4. The compound of any one of claims 1-3 or a salt thereof, wherein ^R2 is a _C1-6 alkyl group. 5. The compound of any one of claims 1-3 or a salt thereof, wherein ^R2 is a methyl group. 6. The compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is H. 7. The compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is a _C1-6 alkyl group optionally substituted with one or more groups independently selected from the group consisting of: carbocyclic, heterocyclic, oxo, halogen, -N( ^Rb ) ₂ and ^-ORb , wherein any carbocyclic and heterocyclic group is optionally substituted with one or more groups independently selected from the group consisting of: -N( ^Rb ) ₂ and ^-ORb . 8. The compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is -N( ^Rb ) ₂ . 9. The compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is -C(=O) ^Ra . 10. The compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is -C(=O)OR ^a . 11. The compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is a 5-6 membered heteroaryl ring optionally substituted with one or more groups independently selected from the group consisting of: _C1-6 alkyl, carbocyclic, heterocyclic, oxo, halogen, -N( ^Rb ) ₂ and ^-ORb , wherein any _C1-6 alkyl, carbocyclic and heterocyclic group is optionally substituted with one or more groups independently selected from the group consisting of: -N( ^Rb ) ₂ , -N( ^Rb )-C(O) ^-Rb and ^-ORb . 12. The compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is selected from: 13. The compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is selected from: 14. The compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is selected from: 15. The compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is selected from: 16. A compound or a salt thereof according to any one of claims 1-3, wherein the compound is a compound of formula (Ia): 17. The compound of any one of claims 1-3 or a salt thereof, wherein ^R4 is H. 18. The compound of any one of claims 1-3 or a salt thereof, wherein ^R4 is a hydroxyl group. 19. The compound of any one of claims 1-3 or a salt thereof, wherein ^R4 is a _C1-6 alkyl group. 20. The compound of any one of claims 1-3 or a salt thereof, wherein ^R5 is H. 21. A compound of any one of claims 1-3 or a salt thereof, wherein ^R5 is a _C1-6 alkyl group optionally substituted with one or more groups independently selected from halogens. 22. The compound of any one of claims 1-3 or a salt thereof, wherein ^R6 is a _C1-6 alkyl group optionally substituted with one or more ^Rg . 23. The compound of any one of claims 1-3 or a salt thereof, wherein ^R6 is a carbocyclic group optionally substituted with one or more Rg ^groups . 24. The compound of any one of claims 1-3 or a salt thereof, wherein ^R6 is a heterocyclic group optionally substituted with one or more Rg ^groups . 25. The compound of any one of claims 1-3 or a salt thereof, wherein ^R6 is a _C1 alkyl group substituted with oxo and -N( ^Rh ) ₂ to form the group -C(O)-N( ^Rh ) ₂ . 26. A compound of any one of claims 1-3 or a salt thereof, wherein ^R5 and ^R6 together with the carbons to which they are attached form a carbocyclic group optionally substituted by one or more Rg ^groups . 27. A compound of any one of claims 1-3 or a salt thereof, wherein ^R5 and ^R6 together with the carbons to which they are attached form a heterocyclic group optionally substituted with one or more Rg ^groups . 28. A compound of any one of claims 1-3 or a salt thereof, wherein ^R4 is absent; and ^R5 and ^R6 together with the carbons to which they are attached form an aryl ring optionally substituted with one or more ^Rgs , which are attached at atoms of the aryl ring to the remainder of formula (I). 29. A compound of any one of claims 1-3 or a salt thereof, wherein ^R4 is absent; and ^R5 and ^R6 together with the carbons to which they are attached form a heterocyclic group optionally substituted with one or more ^Rgs , which is attached to the remainder of formula (I) at an atom of the aromatic ring. 30. The compound of claim 1 or a salt thereof, wherein the groups are: Selected from: 31. The compound of claim 1 or a salt thereof, wherein the groups are: Selected from: 32. The compound of claim 1 or a salt thereof, wherein ^R1 is a _C1-6 alkyl group optionally substituted with one or more _C3-8 carbon cyclogroups; ^R2 is a _C1-6 alkyl group; and ^R3 is a _C1-6 alkyl group optionally substituted with one or more groups independently selected from the following: carbocyclic, heterocyclic, oxo, halogen, -N( ^Rb ) ₂ and ^-ORb , wherein any carbocyclic and heterocyclic group is optionally substituted with one or more groups independently selected from the following: -N( ^Rb ) ₂ and ^-ORb . 33. The compound of claim 1 or a salt thereof, wherein ^R1 is a _C1-6 alkyl group optionally substituted with one or more _C3-8 carbon cyclogroups; ^R2 is a _C1-6 alkyl group; and R ³ is -N(R ^b ) ₂ . 34. The compound of claim 1 or a salt thereof, wherein ^R1 is a _C1-6 alkyl group optionally substituted with one or more _C3-8 carbon cyclogroups; ^R2 is a _C1-6 alkyl group; and R ³ is -C(＝O)OR ^a . 35. The compound of claim 1 or a salt thereof, wherein ^R1 is a _C1-6 alkyl group optionally substituted with one or more _C3-8 carbon cyclogroups; ^R2 is a _C1-6 alkyl group; and ^R3 is a 5-6 membered heteroaryl ring optionally substituted with one or more groups independently selected from the following: _C1-6 alkyl, carbocyclic, heterocyclic, oxo, halogen, -N( ^Rb ) ₂ and ^-ORb , wherein any _C1-6 alkyl, carbocyclic and heterocyclic group is optionally substituted with one or more groups independently selected from the following: -N( ^Rb ) ₂ and ^-ORb . 36. The compound or a salt thereof of any one of claims 32-35, wherein the groups are: Selected from: 37. A compound of any one of claims 1-3 or a salt thereof, wherein ^R3 is H, a _C1-6 alkyl, -C(=O) ^Ra , -C(=O) ^ORa or a 5-6 membered heteroaryl ring, wherein the _C1-6 alkyl and the 5-6 membered heteroaryl ring are optionally substituted by one or more groups independently selected from the group consisting of: _C1-6 alkyl, carbocyclic, heterocyclic, oxo, halogen, -N( ^Rb ) ₂ and ^-ORb , wherein any _C1-6 alkyl, carbocyclic and heterocyclic group are optionally substituted by one or more groups independently selected from the group consisting of: -N( ^Rb ) ₂ , -N( ^Rb )-C(O) ^-Rb and ^-ORb . 38. A compound or a salt thereof, said compound being selected from: 39. A composition comprising the compound of any one of claims 1-38 or a pharmaceutical salt thereof and pharmaceutical excipients, carriers or mediators. 40. The composition of claim 39, further comprising other therapeutic agents. 41. The composition of claim 40, wherein the other therapeutic agent is a chemotherapeutic agent. 42. Use of any compound of claims 1-38 or a pharmaceutical salt thereof in the preparation of a medicament for treating TAF1-mediated conditions in animals. 43. The use of claim 42, wherein the condition is cancer. 44. The use of claim 43, wherein the cancer is selected from acoustic neuroma, acute lymphoblastic leukemia, acute myeloid leukemia, acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, aberrant proliferative changes, embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, angioblastoma, etc. Liver cancer, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lymphangiocarcinoma, lymphoblastic leukemia, T-cell or B-cell-derived lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, midline NUT carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovoma, sweat gland carcinoma, thyroid cancer, Waldenström macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor. 45. The use of claim 43, wherein the cancer is selected from solid tumors. 46. The use of claim 43, wherein the cancer is selected from carcinomas and sarcomas. 47. The use of claim 43, wherein the cancer is selected from leukemia. 48. The use of claim 43, wherein the cancer is selected from acute leukemia and chronic leukemia. 49. The use of claim 43, wherein the cancer is selected from hepatocellular carcinoma. 50. The use of claim 43, wherein the cancer is selected from lymphangiosarcoma. 51. The use of claim 43, wherein the cancer is selected from lymphoma. 52. The use of claim 43, wherein the cancer is selected from lung cancer. 53. The use of claim 43, wherein the disease is cancer and the cancer is selected from lung cancer, breast cancer, pancreatic cancer, colorectal cancer and melanoma. 54. Use of any compound of claims 1-38 or a pharmaceutical salt thereof in the preparation of a medicament for medical treatment. 55. Use of any compound of claims 1-38 or a pharmaceutical salt thereof in the preparation of a medicament for the prevention or treatment of TAF1-mediated conditions. 56. Use of any compound of claims 1-38 or a pharmaceutical salt thereof in the preparation of a medicament for treating TAF1-mediated conditions in humans. 57. Use of any compound of claims 1-38 or a pharmaceutical salt thereof in the preparation of a medicament for inhibiting TAF1 in animals in which such an effect is desired. 58. Use of any compound of claims 1-38 or a pharmaceutical salt thereof in the preparation of a medicament for inhibiting TAF1. 59. Use of any compound of claims 1-38 or a pharmaceutical salt thereof in the preparation of a medicament for inhibiting TAF1 in humans in need of it.