Compounds comprising N-methyl-2-pyridone and pharmaceutically acceptable salts

Abstract

The name of the invention is N-methyl-2-pyridone containing compounds and pharmaceutically acceptable salts thereof. The present invention relates to compounds comprising N-methyl-2-pyridone, as well as pharmaceutically acceptable salts and compositions of such compounds. Such compounds are useful in anti-inflammatory and anti-cancer therapies. The invention therefore also relates to such compounds for use as medicaments, in particular for the treatment of inflammatory diseases and tumors.

Description

[0001] This application is a divisional application of the Chinese national stage patent application with the application number 202080042092.3, which enters the Chinese national stage on December 7, 2021, of the PCT application with the international application number PCT / EP2020 / 061173, the international filing date of April 22, 2020, and the invention title of "Compounds Containing N-Methyl-2-Pyridone and Pharmaceutically Acceptable Salts". Technical Field

[0002] The present invention relates to compounds containing N-methyl-2-pyridone, as well as pharmaceutically acceptable salts and compositions of such compounds. The compounds of the present invention can be used as anti-inflammatory and anti-cancer therapies. Accordingly, the present invention also relates to compounds containing N-methyl-2-pyridone for use as a medicament, in particular for the treatment of inflammatory diseases and tumors. Background Art

[0003] Bromodomain and extra-terminal (BET) proteins are a family of four bromodomain (BRD)-containing proteins (BRD2, BRD3, BRD4, and BRDT). All four members contain two BRDs (positioned adjacent to each other towards the N-terminus of the protein) and an extra-terminal domain (Shi, J. et al. Cancer Cell 25(2):210-225 (2014)). The two BRDs in each BET protein are referred to as binding domain I (BDI) and binding domain II (BDII). The BRD is a functional protein domain that contains a defined and predominantly hydrophobic pocket that binds to acetylated lysine residues, typically those found on transcription factors (Shi, J. et al. Cancer Cell 25(2):210-225 (2014)) or on the N-terminal tails of histones. The BRDs act as epigenetic regulators, i.e., they functionally alter gene activity and expression without changing the DNA sequence. For example, BRD4 recruits the transcription factor P-TEFb to promoters, resulting in altered expression of genes involved in the cell cycle (Yang et al., Mol. Cell Biol. 28:967-976 (2008)). BRD2 and BRD3 also regulate growth-promoting genes (LeRoy et al., Mol Cell 30:51-60 (2008)). Thus, the BRDs are responsible for transducing the signal carried by acetylated lysine residues into various phenotypes. BETs are considered to be ubiquitously expressed in humans in the art, except for BRDT, which is typically expressed in the testis, but some cancers also express BRDT (Ekaterina B.F. et al., Cell J. 19(Suppl 1):1-8 (2017)).

[0004] BET proteins play a role in the regulation of many pathways such as MYC, BCL2, FOSL1, P-TEFb, NFkB, glucocorticoid signaling, etc. (Shi J. et al. Mol Cell. June 5; 54(5):728-36 (2014)), (Hajmirza A. Biomedicines. February 6; 6(1). pii:E16 (2018)), (Shan N. Elife. September 11; 6. pii:e27861. (2017)), (Huang B. Mol Cell Biol. March; 29(5):1375-87 (2009)). Therefore, BET inhibitors are considered to have potential uses in a series of inflammatory diseases, cancers, infections, metabolic diseases, CNS disorders, fibrotic diseases and heart diseases (Deanna A. M et al. J Exp Med. October 21; 210(11):2181–2190 (2013)), (Rab K. P. et al., Trends Pharmacol. Sci. March; 33(3):146-53 (2012)), (Anna C. B. et al., J Immunol. April 1; 190(7):3670–3678 (2013)), (Zuber J. et al., Nature. August 3; 478(7370):524-8. (2011)), (Montserrat P. S. et al., Epigenetics.; 12(5):323–339 (2017)), (Qiming D. et al., Sci Transl Med. May 17; 9(390):eaah5084. (2017)), (Kristin M. K et al., J Biol Chem. August 11; 292(32):13284–13295 (2017)), (Ning D. et al., PNAS December 22, 112(51)15713-15718 (2015)).

[0005] Compounds that can inhibit or affect the function of BET proteins have the potential to regulate gene expression and treat diseases caused at least in part by abnormal regulation of BET protein activity. It has been reported that several small molecules can effectively inhibit BET, and the small molecules include those based on diaza Compounds of 3,5-dimethylisoxazole, thiazol-2-one, diazobenzene, and 4-acylpyrrole (see M. Brand et al., ACS Chem. Biol. 2015, 10, 22-39, WO2011054553, WO2011054845). Compounds that can selectively inhibit BDII but not BDI function have the potential to regulate gene expression and treat diseases caused at least in part by abnormal regulation of BET protein activity, while offering the potential to improve the therapeutic index. Compared with pan-BET inhibitors, BDII-selective BET inhibitors have demonstrated improved therapeutic index and preclinical safety (E. Faivre et al. Nature 578, 306–310 (2020)).

[0006] Compounds containing a 6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one moiety substituted at the 4- and / or 2-position are described in patent applications WO 2017177955, WO 2016077378, WO 2015081280, WO2014206150, WO 2014206345, WO 2013097601, WO 2013097052, and WO 2018130174 as being useful for inhibiting BET proteins.

[0007] The present invention provides alternative BET protein inhibitors that can be used to treat or prevent the conditions described herein. SUMMARY OF THE INVENTION

[0008] It has been found that the compounds and compositions of this teaching have surprising activity in inhibiting all four BET BRDs, with effective potency at nanomolar concentrations. The compounds and compositions are highly soluble in a range of solvents and formulations suitable for topical and / or oral administration. Advantageously, many compounds and compositions of the present invention are stable in human skin and under hydrolysis conditions within a certain pH range. In addition, formulations of the compounds and compositions can deliver viable concentrations of the compounds into the epidermis of the skin, and the compounds are not toxic to skin cells. Some of the compounds and compositions exhibit surprisingly effective liver clearance, thus offering potential use as a drug with a lower risk of side effects. Other compounds and compositions are surprisingly stable, thus offering potential use as an orally administered drug. Some of the compounds have surprising selectivity for BDII rather than BDI, thus offering the potential to improve the therapeutic index and reduce the risk of side effects.

[0009] Those skilled in the art know that any reference to an aspect currently disclosed includes each embodiment of that aspect. For example, any reference to the first aspect includes the first aspect and all embodiments of the first aspect.

[0010] From a first aspect, there is provided a compound of formula (I):

[0011]

[0012] wherein ring structure A is a 5- or 6-membered aromatic or heteroaromatic ring optionally substituted at one or more carbon and / or heteroatoms with a first substituent;

[0013] wherein each first substituent is independently selected from the group consisting of hydroxy, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl alcohol, halo, SO2C1-C4 alkyl, NHSO2C1-C4 alkyl, SO2C3-C6 cycloalkyl, NHSO2C3-C6 cycloalkyl, SO2C1-C4 alkyl alcohol, NHSO2C1-C4 alkyl alcohol, C1-C5 alkoxy, C1-C5 alkylamino, SO2NH2, CONH2, CONHC1-C4 alkyl, NHCOC1-C4 alkyl, NHSO2N(C1-C4 alkyl)2, C1-C6 fluoroalkyl, SO2C1-C4 fluoroalkyl, NHSO2C1-C4 fluoroalkyl, C1-C5 fluoroalkoxy and C1-C5 fluoroalkylamino;

[0014] X is O, CR 2、 NR' or S, wherein R is independently selected from the group consisting of H, C1-C4 alkyl and halo, and R' is selected from the group consisting of C1-C4 alkyl and H;

[0015] Z is a 5- or 6-membered aromatic or heteroaromatic ring optionally substituted at one or more carbon and / or heteroatoms with a second substituent, C1-C6 alkyl, C3-C6 cycloalkyl, CR A R B R C 、C2-C5 oxa-cycloalkyl, C2-C5 aza-cycloalkyl or morpholinyl;

[0016] wherein R A is C3-C5 cycloalkyl, R B is C3-C5 cycloalkyl, methyl or ethyl, and R C is OH; and

[0017] each second substituent is independently selected from the group consisting of hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C5 alkoxy, C1-C5 alkylamino, oxo, cyano, C1-C6 fluoroalkyl, C1-C5 fluoroalkoxy and C1-C5 fluoroalkylamino;

[0018] Ring structure B is optionally present; wherein when ring structure B is present, it is an optionally substituted pyrrole which is bonded such that C is in the 4-position relative to NH; wherein the pyrrole is optionally substituted at position 2 with a third substituent;

[0019] wherein the third substituent is selected from the group consisting of: CONHC1-C4 alkyl optionally substituted with methyl or ethyl at one or more carbon atoms, CONH2, CONHC1-C6 fluoroalkyl, CONHC3-C6 cycloalkyl; CONHC3-C5 cyclofluoroalkyl optionally substituted with methyl or ethyl at one or more carbon atoms, NHCOC1-C4 alkyl and NHCOC1-C4 fluoroalkyl;

[0020] provided that when A is 6-membered, it is substituted with a hydroxy or oxo group at least once.

[0021] In a second aspect, there is provided a pharmaceutical composition comprising any one or combination of the compounds defined in the first aspect in combination with one or more pharmaceutically acceptable excipients.

[0022] In a third aspect, there is provided a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect for use as a medicament.

[0023] In a fourth aspect, there is provided a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect for use in a method of treating or preventing inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases and fibrotic diseases.

[0024] In a fifth aspect, there is provided a compound as defined in the second aspect or a pharmaceutical composition as defined in the second aspect for inhibiting bromodomain and extra-terminal protein.

[0025] In a sixth aspect, there is provided a method of treating or preventing inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases and fibrotic diseases, the method comprising administering to a subject an effective amount of a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect.

[0026] In a seventh aspect, there is provided a method of inhibiting bromodomain and extra-terminal protein activity in a subject, the method comprising administering to a subject an effective amount of a compound as defined in the first aspect or a pharmaceutical composition as defined in the second aspect. Detailed Description

[0027] It has been found that structurally novel derivatives of N-methyl-2-pyridone are surprisingly effective in inhibiting all four BET BRDs, to an extent at least similar to that of inhibitors known in the art. In some cases, the performance of known BET protein inhibitors is superior to that of the compounds described herein. The compounds are now described in detail.

[0028] In the following discussion, many terms with the meanings provided below are referenced, unless the context indicates otherwise. The nomenclature used herein to define compounds, particularly compounds according to the present invention, is generally based on the rules of chemical compounds of the IUPAC organization, specifically the "IUPAC Compendium of Chemical Terminology (Gold Book)". For the avoidance of doubt, if the rules of the IUPAC organization are contrary to the definitions provided herein, then the definitions herein shall prevail. In addition, if the compound structure is contrary to the name provided for said structure, then the said structure shall prevail.

[0029] The term "therapeutic index", also known as the "therapeutic window" or "safety window", defines the relative safety of a drug. The therapeutic index can be calculated as the ratio of the area under the curve (AUC) in the blood at the drug concentration that results in no toxicity (no observed adverse effect level - NOAEL) to the AUC at the drug concentration that achieves the desired efficacy (typically the dose with 50% effect - effective dose 50 or ED50). TI = AUC(NOAEL) / AUC(ED50). Drugs with a higher therapeutic index are preferred because administering such drugs is less likely to cause unwanted side effects and more of the drug can be administered to more effectively treat a subject. The efficacy of BET inhibitors is driven by their inhibition of BDII function, while inhibition of BDI function causes unwanted side effects. Thus, drugs that selectively inhibit the function of BDII rather than BDI have the potential to regulate gene expression and treat diseases caused at least in part by abnormal regulation of BET and are less likely to cause unwanted side effects compared to pan-inhibitors administered at the same dose. A higher dose of a drug that selectively inhibits BDII rather than BDI can be administered compared to a pan-inhibitor, and thus such selective drugs can be more effective.

[0030] The term "aromatic" defines a cyclic conjugated molecular entity whose stability (due to delocalization) is significantly higher than that of a hypothetical localized structure. The Hückel rule is often used in the art to evaluate aromaticity; a monocyclic planar (or near-planar) system of trigonal (or sometimes digonal) hybridized atoms containing (4n + 2) π electrons (where n is a non-negative integer) will exhibit aromaticity. The rule is generally limited to n = 0 to 5.

[0031] The term "heteroaromatic" defines a cyclic conjugated molecular entity that contains heteroatoms and whose stability (due to delocalization) is significantly higher than that of a hypothetical localized structure.

[0032] The term "cyclic" or a variant thereof defines a compound in which one or more series of atoms in the compound are connected to form a ring. The term "acyclic" defines a compound that does not contain an atomic ring.

[0033] The term "conjugated" or a variant thereof defines a molecular entity whose structure can be represented as a system of alternating single and multiple bonds. In such a system, conjugation is the interaction of one p-orbital in such a structure with another p-orbital across an intervening π-bond. In a suitable molecular entity, d-orbitals can be involved. The term also extends to similar interactions involving p-orbitals containing non-bonding electron pairs.

[0034] The term "delocalized" defines π-bonding in a conjugated system where the bonding is not confined between two atoms, but each connection has partial double-bond character or bond order.

[0035] The term "comprising" or a variant thereof will be understood to imply the inclusion of the stated element, integer, or step, or group of elements, integers, or steps, but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps.

[0036] The term "consisting of" or a variant thereof will be understood to imply the inclusion of the stated element, integer, or step, or group of elements, integers, or steps, and the exclusion of any other element, integer, or step, or group of elements, integers, or steps.

[0037] The term "alkyl" is well known in the art and defines a monovalent group derived from an alkane by the removal of a hydrogen atom from any carbon atom, where the term "alkane" is intended to define a cyclic or acyclic branched or unbranched hydrocarbon having the general formula C n H 2n+2 where n is an integer ≥ 1.

[0038] The term "cycloalkyl" defines all monovalent groups derived from cycloalkanes by the removal of a hydrogen atom from a ring carbon atom. The term "cycloalkane" defines saturated monocyclic and polycyclic hydrocarbons.

[0039] The term "alkyl alcohol" defines a hydroxy derivative of an alkyl, i.e., hydroxy-alkyl.

[0040] The term "halo" is well known in the art and defines a halogen group which, when bonded to a carbon group, forms a fluoride, chloride, bromide, or iodide.

[0041] The term "alkyloxy" is synonymous with "alkoxy" and, when used herein, defines a monovalent group containing an alkyl singly bonded to an oxygen atom, which is derived from the corresponding alcohol by the removal of the hydrogen atom bonded to the oxygen atom.

[0042] The term "alkylamino" is synonymous with "alkamino" and, when used herein, defines a monovalent group containing an alkyl moiety singly bonded to an amino group, which is derived from the corresponding amine by removal of the hydrogen atom bonded to the nitrogen atom.

[0043] The term "oxacycloalkyl" defines a monovalent group containing a cycloalkyl moiety in which one of the CH2 moieties is replaced by an oxide. Similarly, the term "aza-cycloalkyl" defines a monovalent group containing a cycloalkyl moiety in which one of the CH2 moieties is replaced by an NH moiety.

[0044] The term "treatment" defines a therapeutic treatment of a human or non-human animal so as to arrest or reduce or halt the rate of progression of a medical condition, or to alleviate or cure the medical condition. Prevention of a medical condition as a result of treatment is also included. Prevention as referred to herein is not intended to require complete prevention of the medical condition: rather, its development is impeded by treatment according to the invention. Typically, treatment is not prophylactic and the compound or composition is administered to a patient suffering from a diagnosed or suspected medical condition. The "effective amount" herein defines the amount of a compound or composition of the invention sufficient to arrest the disease and thus produce the desired therapeutic or inhibitory effect.

[0045] The term "stereoisomers" is used herein to refer to isomers having the same molecular formula and sequence of bonded atoms but differing in the arrangement of their atoms in space.

[0046] The term "enantiomer" defines one of a pair of molecular entities that are mirror images of each other and non-superimposable, i.e., cannot be made to coincide by translation and rigid rotation. Enantiomers are chiral molecules, i.e., distinguishable from their mirror images.

[0047] The term "racemic" is used herein to refer to a racemate. A racemate defines a substantially equimolar mixture of a pair of enantiomers.

[0048] The term "diastereoisomers" (also called diastereomers) defines stereoisomers that are not related as mirror images.

[0049] The term "solvate" is used herein to refer to a complex containing a solute, such as a compound or a salt of the compound, and a solvent. If the solvent is water, the solvate may be called a hydrate, e.g., a monohydrate, dihydrate, trihydrate, etc., depending on the number of water molecules present per molecule of the substrate.

[0050] The term "isotope" is used herein to define variants of a particular chemical element in which the atomic nucleus necessarily has the same atomic number but a different mass number due to having a different number of neutrons.

[0051] The term "prodrug" is used herein to refer to a compound that serves as a drug precursor and is converted, after administration to a subject, by metabolism or other chemical processes to produce a compound of formula (I).

[0052] The term "pharmaceutically acceptable excipient" defines a substance other than the pharmacologically active drug or prodrug, which is included in a pharmaceutical product.

[0053] When used in connection with the compounds or compositions of the present invention, the term "topical" is used to refer to the ability to apply a compound or composition to a body surface (such as the skin or mucosa). Topical compounds or compositions can be applied in the form of creams, foams, gels, lotions or ointments.

[0054] When used in connection with the compounds or compositions of the present invention, the term "oral" is used to refer to the ability to administer a compound or composition by mouth. Typically, orally administered compounds exhibit systemic rather than topical effects, i.e., they affect multiple organ systems rather than a local area.

[0055] When used in connection with signals, the terms "transduce" or "transducing" are synonymous with "transfer" or "transferring", i.e., "signal transduction" is the process of transferring a signal throughout an organism (such as through cells).

[0056] The term "pan" is used herein to refer to "all". For example, pan-inhibition of the BET family means that all members of the BET family (BRD2, BRD3, BRD4, and BRDT) are inhibited.

[0057] The term "T cell" (also known as T lymphocyte) is known in the art to refer to a lymphocyte that has a T cell receptor (a molecule responsible for recognizing antigenic peptide fragments) on its cell surface.[[ID=...]]

[0058] The term "cytokine" is used herein to refer to small proteins (~5 to 20 kDa) that are important in cell signaling (such as autocrine, paracrine, and endocrine signaling) as immunomodulators.

[0059] The term "chemokine" is used herein to refer to a family of cytokines that are capable of inducing directed chemotaxis in responsive cells, i.e., they act as chemotactic agents to guide cell migration.

[0060] The term "intrinsic clearance" is well known in the art and refers to the ability of the liver to remove a drug in the absence of flow limitations and binding to cells or proteins in the blood. Intrinsic clearance is expressed herein as a percentage of hepatic blood flow, i.e.:

[0061]

[0062] The term "soft drug" refers to a compound that is rapidly metabolized after reaching the blood or the liver. Compounds with high clearance are considered to have a clearance > 70% of hepatic blood flow, with the most common clearance being > 75%, moderate clearance being 30% - 70%, most commonly 50% - 75%, and low clearance being < 30%, most commonly < 50%. Soft drugs are typically characterized by their predictable and controllable metabolism in the body to non-toxic products after achieving their therapeutic effect. Soft drugs have low systemic exposure and reduce the risk of side effects.

[0063] Systemic inhibition of drug targets is usually associated with dose-limiting side effects, and there is an unmet need for effective agents that are well tolerated by patients. Compounds that are rapidly cleared after entering the bloodstream have low systemic exposure and reduce the risk of side effects (see Atkinson AJ Jr. and Kushner W., Annu. Rev. Pharmacol. Toxicol., 1979, 19, 105 - 127 and Rowland M. and Tozer T.N., Clinical Pharmacokinetics. Concepts and Applications. Lippincott Williams & Wilkins, 1995, 161 - 167).

[0064] Which groups in the drug structure lead to rapid systemic clearance of the drug is unpredictable. In some cases, it has been observed that phenol groups can be cleared via phase II conjugation clearance mechanisms such as glucuronidation and sulfation (see Pathways of Biotransformation—Phase II Reactions. In: Ionescu C., Caira M.R. (eds) Drug Metabolism. Springer, Dordrecht, 2005).

[0065] As described above, the first aspect provides a compound of formula (I):

[0066]

[0067] wherein ring structure A is a 5 - or 6 - membered aromatic or heteroaromatic ring optionally substituted at one or more carbon and / or heteroatoms with a first substituent;

[0068] Each first substituent is independently selected from the group consisting of: hydroxyl, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl alcohol, halogen, SO2C1-C4 alkyl, NHSO2C1-C4 alkyl, SO2C3-C6 cycloalkyl, NHSO2C3-C6 cycloalkyl, SO2C1-C4 alkyl alcohol, NHSO2C1-C4 alkyl alcohol, C1-C5 alkoxy, C1-C5 alkylamino, SO2NH2, CONH2, CONHC1-C4 alkyl, NHCOC1-C4 alkyl, NHSO2N(C1-C4 alkyl)2, C1-C6 fluoroalkyl, SO2C1-C4 fluoroalkyl, NHSO2C1-C4 fluoroalkyl, C1-C5 fluoroalkoxy and C1-C5 fluoroalkylamino;

[0069] X is O, CR 2、 NR' or S, where R is independently selected from the group consisting of H, C1-C4 alkyl and halogen, and R' is selected from the group consisting of C1-C4 alkyl and H;

[0070] Z is a 5- or 6-membered aromatic or heteroaromatic ring, C1-C6 alkyl, C3-C6 cycloalkyl, CR A R B R C , C2-C5 oxacycloalkyl, C2-C5 azacycloalkyl or morpholinyl;

[0071] where R A is C3-C5 cycloalkyl, R B is C3-C5 cycloalkyl, methyl or ethyl, and R C is OH; and

[0072] Each second substituent is independently selected from the group consisting of: hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, C1-C5 alkoxy, C1-C5 alkylamino, oxo, cyano, C1-C6 fluoroalkyl, C1-C5 fluoroalkoxy and C1-C5 fluoroalkylamino;

[0073] Ring structure B is optionally present; when ring structure B is present, it is an optionally substituted pyrrole which is bonded such that C is in the 4-position relative to NH; wherein the pyrrole is optionally substituted at position 2 with a third substituent;

[0074] wherein the third substituent is selected from the group consisting of: CONHC1-C4 alkyl optionally substituted with methyl or ethyl at one or more carbon atoms, CONH2, CONHC1-C6 fluoroalkyl, CONHC3-C6 cycloalkyl; CONHC3-C5 cyclofluoroalkyl optionally substituted with methyl or ethyl at one or more carbon atoms, NHCOC1-C4 alkyl and NHCOC1-C4 fluoroalkyl;

[0075] provided that when A is 6-membered, it is substituted with a hydroxyl or oxo group at least once.

[0076] B is optionally present. When absent, the carbon atoms at the ortho and meta positions to C are each bonded to H. When present, the ring structure B is an optionally substituted pyrrole; C is at the 4-position relative to NH, thereby forming a 6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one derivative.

[0077] The pyrrole is optionally substituted at the 2-position with a third substituent selected from the group consisting of: CONHC1-C4 alkyl optionally substituted with methyl or ethyl at one or more carbon atoms, CONH2, CONHC1-C6 fluoroalkyl, CONHC3-C6 cycloalkyl; CONHC3-C5 cyclofluoroalkyl optionally substituted with methyl or ethyl at one or more carbon atoms, NHCOC1-C4 alkyl and NHCOC1-C4 fluoroalkyl. The CONHC3-C6 cycloalkyl may be unsubstituted. Generally, the third substituent is selected from the group consisting of: CONHC1-C4 alkyl, CONHC1-C6 fluoroalkyl, CONHC3-C6 cycloalkyl optionally substituted with methyl or ethyl at one or more carbon atoms, and CONHC3-C5 cyclofluoroalkyl optionally substituted with methyl or ethyl at one or more carbon atoms. The third substituent may be selected from the group consisting of: CONHC1-C4 alkyl, CONHC1-C6 fluoroalkyl, CONHC3-C6 cycloalkyl, and CONHC3-C5 cyclofluoroalkyl optionally substituted with methyl or ethyl at one or more carbon atoms. The third substituent may be selected from the group consisting of: CONHC1-C4 alkyl, CONH2, CONHC1-C6 fluoroalkyl, CONHC3-C5 cycloalkyl; CONHC3-C5 cyclofluoroalkyl, NHCOC1-C4 alkyl and NHCOC1-C4 fluoroalkyl. Generally, the third substituent is CONHC1-C4 alkyl, typically CONH ethyl. Typically, the pyrrole is unsubstituted. Most typically, the pyrrole is unsubstituted or substituted with CONH ethyl at the 2-position.

[0078] Typically, B is present and is sometimes a pyrrole optionally substituted at position 2 by a third substituent, which is CONHC1-C4 alkyl. Usually the third substituent is CONH ethyl. Typically, B is present and is an unsubstituted pyrrole. Most typically, B is present and is an unsubstituted pyrrole or a pyrrole substituted at position 2 by CONH ethyl. Thus, the compounds of the invention are typically represented by formula (II) or (III):

[0079]

[0080] wherein A, X and Z are as defined for formula (I), provided that when A is 6-membered, it is substituted at least once by a hydroxyl or oxo group.

[0081] Generally, when A is 6-membered, it is substituted at least once by a hydroxyl or oxo group ortho or meta to X.

[0082] A connects C to X and can be any 5-membered aromatic or heteroaromatic ring, or any 6-membered aromatic or heteroaromatic ring substituted at least once by a hydroxyl or oxo group. 5-membered aromatic or heteroaromatic rings include thiazole, oxazole, imidazole, isoxazole, pyrazole, thiophene, pyrrole, furan and cyclopentadienyl. 5-membered heteroaromatic rings also include triazoles such as 1,2,4-triazole. 6-membered aromatic or heteroaromatic rings include benzene, pyridine, pyridone, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine and 1,3,5-triazine. The 5-membered or 6-membered aromatic or heteroaromatic rings can be substituted at one or more carbon and / or heteroatoms by a first substituent. For example, when A is a pyridine ring, it can be substituted by the first substituent at any one of one, two or three carbon atoms not bonded to C or X and / or at the nitrogen atom.

[0083] When A is 5-membered, it is usually unsubstituted or substituted at one position. Typically, when A is 5-membered, it is unsubstituted.

[0084] Generally, A is selected from the group consisting of benzene, pyridine, thiazole, pyridone, pyrazole, imidazole and triazole optionally substituted at one or more carbon and / or heteroatoms by a first substituent. Typically, A is selected from the group consisting of benzene, pyridine, thiazole and pyridone optionally substituted at one or more carbon and / or heteroatoms by a first substituent. When A is pyridone, it can be 2-, 3- or 4-pyridone. Generally, when A is pyridone, it is 2-pyridone, i.e. A is generally selected from the group consisting of benzene, pyridine, thiazole and 2-pyridone optionally substituted at one or more carbon and / or heteroatoms by a first substituent.

[0085] When A is thiazole, it is generally bonded to C via the thiazole carbon atom at position 5 and to X via the thiazole carbon atom at position 4. The resulting C-A-X moiety is represented by:

[0086]

[0087] Thiazole may be substituted by a first substituent at one or more carbon and / or nitrogen atoms. Typically, thiazole is substituted by a first substituent at position 2.

[0088] When A is 2-pyridone, it typically: either binds to C via the carbon atom at position 4 and binds to X via the carbon atom at position 3, or binds to C via the carbon atom at position 4 and binds to X via the carbon atom at position 5. The resulting C-A-X moiety is represented respectively by:

[0089]

[0090] 2-Pyridone may be substituted by a first substituent at one or more carbon and / or nitrogen atoms. Typically, 2-pyridone is substituted by a C1-C6 alkyl group at one or more carbon atoms and / or nitrogen atoms. Generally, the C1-C6 alkyl group is a C1-C4 alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Typically, the C1-C6 alkyl group is methyl. Typically, 2-pyridone is substituted by methyl at the nitrogen atom.

[0091] When A is pyrazole, it generally binds to C via the pyrazole carbon atom at position 5 and binds to X via the nitrogen atom at position 1. The resulting C-A-X moiety is represented by:

[0092]

[0093] Pyrazole may be substituted by a first substituent at one or more carbon and / or nitrogen atoms. Typically, pyrazole is substituted by a first substituent at position 3 or 4.

[0094] When A is imidazole, it generally binds to C via the imidazole carbon atom at position 2 and binds to X via the nitrogen atom at position 1. The resulting C-A-X moiety is represented by:

[0095]

[0096] Imidazole may be substituted by a first substituent at one or more carbon and / or nitrogen atoms. Typically, imidazole is substituted by a first substituent at position 4 or 5.

[0097] When A is triazole, it is typically 1,2,4-triazole. When A is 1,2,4-triazole, it generally binds to C via the imidazole carbon atom at position 5 and binds to X via the nitrogen atom at position 1. The resulting C-A-X moiety is represented by:

[0098]

[0099] 1,2,4-triazole may be substituted by a first substituent at one or more carbon and / or nitrogen atoms. Generally, 1,2,4-triazole is substituted by a first substituent at position 3.

[0100] The first substituent may be hydroxy, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl alcohol, halogen, SO2C1-C4 alkyl, NHSO2C1-C4 alkyl, SO2C3-C6 cycloalkyl, NHSO2C3-C6 cycloalkyl, SO2C1-C4 alkyl alcohol, NHSO2C1-C4 alkyl alcohol, C1-C5 alkoxy, C1-C5 alkylamino, SO2NH2, CONH2, CONHC1-C4 alkyl, NHCOC1-C4 alkyl, NHSO2N(C1-C4 alkyl)2, C1-C6 fluoroalkyl, SO2C1-C4 fluoroalkyl, NHSO2C1-C4 fluoroalkyl, C1-C5 fluoroalkoxy and / or C1-C5 fluoroalkylamino. When the first substituent is selected from SO2C1-C4 alkyl, NHSO2C1-C4 alkyl, SO2C1-C4 fluoroalkyl and NHSO2C1-C4 fluoroalkyl, it is usually SO2CH3, NHSO2CH3, SO2CF3 and / or NHSO2CF3, namely mesyl, mesylamino, trifluoromethanesulfonyl and / or trifluoromethanesulfonamido. When the first substituent is selected from SO2C3-C6 cycloalkyl and NHSO2C3-C6 cycloalkyl, it is usually SO2C3H5, SO2C5H9, SO2C6H 11 、NHSO2C3H5、NHSO2C5H9 and / or NHSO2C6H 11 , namely cyclopropylsulfonyl, cyclopentanesulfonyl, cyclohexanesulfonyl, cyclopropylsulfonamido, cyclopentanesulfonamido and / or cyclohexanesulfonamido. When the first substituent is selected from SO2C1-C4 alkyl alcohol and NHSO2C1-C4 alkyl alcohol, it is usually SO2C(CH3)2OH and / or NHSO2C(CH3)2OH, namely tert-butanolsulfonyl and / or tert-butanolsulfonamido.

[0101] Thus, each first substituent is generally independently selected from the group consisting of: hydroxy, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl alcohol, halogen, SO2CH3, NHSO2CH3, SO2 t Bu, NHSO2 t Bu, SO2C3H5, SO2C5H9, SO2C6H 11 、NHSO2C3H5、NHSO2C5H9、NHSO2C6H 11, C1-C5 alkyloxy, C1-C5 alkylamino, SO2NH2, CONH2, CONHC1-C4 alkyl, NHCOC1-C4 alkyl, NHSO2N(C1-C4 alkyl)2, C1-C6 fluoroalkyl, SO2CF3, NHSO2CF3, C1-C5 fluoroalkyloxy and / or C1-C5 fluoroalkylamino.

[0102] Typically, each first substituent is independently selected from the group consisting of: hydroxy, oxo, C1-C6 alkyl, C1-C6 alkyl alcohol, C3-C6 cycloalkyl, halo, SO2CH3, NHSO2CH3, SO2C3H5, SO2C5H9, SO2C6H 11 , NHSO2C3H5, NHSO2C5H9 and NHSO2C6H 11 . Usually, each first substituent is independently selected from the group consisting of: hydroxy, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, halo, SO2CH3 and NHSO2CH3.

[0103] Generally, each first substituent is independently selected from the group consisting of: hydroxy, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl alcohol and halo. Typically, the C1-C6 alkyl is a C1-C4 alkyl selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and the C3-C6 cycloalkyl is selected from the group consisting of cyclopropyl, cyclopentyl and cyclohexyl. Typically, the C1-C6 alkyl alcohol is hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxyisobutyl and hydroxytert-butyl. Typically, the halo is fluorine or chlorine. Thus, each first substituent generally independently is selected from the group consisting of: hydroxy, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxyisobutyl and hydroxytert-butyl and fluorine and chlorine.

[0104] Most typically, each first substituent is independently selected from the group consisting of: hydroxy, oxo, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxytert-butyl, fluorine and chlorine.

[0105] Usually, each first substituent is independently selected from the group consisting of hydroxy, oxo, methyl and halo.

[0106] When A is benzene or pyridine, it is substituted with a hydroxyl group at least once. Sometimes, it is substituted with a hydroxyl group and another first substituent selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, and chlorine. Typically, it is substituted with a hydroxyl group and another first substituent selected from the group consisting of methyl, fluorine, and chlorine. Usually, at least one hydroxyl group is located at the ortho or meta position of X.

[0107] X is O, CR2, or NR', where R is independently selected from the group consisting of H, C1-C4 alkyl, and halo, and R' is selected from the group consisting of C1-C4 alkyl and H.

[0108] When X is CR 2时 , the halo group is typically chlorine or fluorine. Thus, R is typically independently selected from the group consisting of H, C1-C4 alkyl, fluorine, and chlorine.

[0109] When X is CR2 or NR', the C1-C4 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. Thus, R is typically independently selected from the group consisting of: H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, fluorine, and chlorine, and R' is selected from the group consisting of: H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl and H. Sometimes, R is independently selected from the group consisting of H, methyl, and halo, and R' is selected from the group consisting of methyl and H. Usually, R is independently selected from the group consisting of H, methyl, and fluorine, and R' is methyl.

[0110] Typically, X is O, i.e., A is bonded to Z via an oxide.

[0111] Z is a 5- or 6-membered aromatic or heteroaromatic ring optionally substituted with a second substituent at one or more carbon and / or heteroatoms, C1-C6 alkyl, C3-C6 cycloalkyl, CR A R B R C , C2-C5 oxaalkyl, C2-C5 azaalkyl, or morpholinyl, each independently selected from the group consisting of: hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C5 alkoxy, C1-C5 alkylamino, oxo, cyano, C1-C6 fluoroalkyl, C1-C5 fluoroalkoxy, and C1-C5 fluoroalkylamino;

[0112] where R A is C3-C5 cycloalkyl, R B is C3-C5 cycloalkyl, methyl, or ethyl, and R C is OH.

[0113] Z can be any optionally substituted 5-membered aromatic or heteroaromatic ring. For example, Z can be thiazole, oxazole, imidazole, isoxazole, pyrazole, thiophene, pyrrole, furan or cyclopentadienyl.

[0114] Optionally, Z can be any optionally substituted 6-membered aromatic or heteroaromatic ring. For example, Z can be benzene, pyridine, pyridone, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine or 1,3,5-triazine.

[0115] Otherwise, Z can be an optionally substituted C1-C6 alkyl group, C3-C6 cycloalkyl group, CR A R B R C 、C2-C5 oxaalkyl group, C2-C5 azaalkyl group or morpholinyl group. Typically, the C1-C6 alkyl group is a C1-C4 alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; the C3-C6 cycloalkyl group is selected from the group consisting of cyclopropyl, cyclopentyl and cyclohexyl; R A is cyclopropyl, cyclobutyl or cyclopentyl, and R B is cyclopropyl, cyclobutyl, cyclopentyl, methyl or ethyl; the C2-C5 oxaalkyl group is selected from the group consisting of oxiranyl, oxolanyl and oxanyl; the C2-C5 azaalkyl group is selected from the group consisting of aziridinyl, azolidinyl and azanyl.

[0116] Generally, Z is selected from the group consisting of: benzene, pyridine, thiazole, pyridone, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, oxolanyl, oxanyl, azolidinyl, azanyl and morpholinyl, which are optionally substituted at one or more carbon and / or heteroatoms by a second substituent. Sometimes, Z is selected from the group consisting of: benzene, pyridine, pyridone, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl and cyclohexyl, which are optionally substituted at one or more carbon and / or nitrogen atoms by a second substituent.

[0117] Typically, Z is an optionally substituted 6-membered aromatic or heteroaromatic ring, C1-C6 alkyl group or C3-C6 cycloalkyl group.

[0118] Typically, Z is a phenyl or pyridyl ring, C1-C6 alkyl group or C3-C6 cycloalkyl group, which are optionally substituted at one or more carbon and / or nitrogen atoms by a second substituent.

[0119] Each second substituent is independently selected from the group consisting of: hydroxyl, C1-C6 alkyl group, C3-C6 cycloalkyl group, halogen, C1-C5 alkoxy group, C1-C5 alkylamino group, oxo, cyano, C1-C6 fluoroalkyl group, C1-C5 fluoroalkoxy group and C1-C5 fluoroalkylamino group.

[0120] Typically, each second substituent is independently selected from the group consisting of a hydroxyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, and a halogen group. Typically, the C1-C6 alkyl group is a C1-C4 alkyl group selected from the group consisting of a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group, and the C3-C6 cycloalkyl group is selected from the group consisting of a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group. Typically, the halogen group is fluorine, chlorine, or bromine. Thus, each second substituent is typically independently selected from the group consisting of: a hydroxyl group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, fluorine, chlorine, and bromine. Typically, the halogen group is fluorine or chlorine. Thus, each second substituent is generally independently selected from the group consisting of: a hydroxyl group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, fluorine, and chlorine.

[0121] Sometimes, each second substituent is independently selected from the group consisting of: a hydroxyl group, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, fluorine, chlorine, and bromine. Typically, each second substituent is independently selected from the group consisting of: a hydroxyl group, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, fluorine, and chlorine. Typically, each second substituent is independently selected from the group consisting of a hydroxyl group, a methyl group, fluorine, and chlorine. For example, Z can be a phenyl ring substituted with two methyl groups at the ortho position to X and further substituted with fluorine at the para position to X. Typically, each second substituent is selected from any one or combination of a hydroxyl group, a methyl group, or fluorine. Most typically, each second substituent is a hydroxyl group.

[0122] Z is typically a phenyl ring optionally substituted with a second substituent at one to three carbon atoms, each second substituent being independently selected from the group consisting of: a hydroxyl group, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, fluorine, and chlorine; a pyridyl ring optionally substituted with a hydroxyl group at one carbon atom; a C1-C6 alkyl group; or a C3-C6 cycloalkyl group.

[0123] Sometimes, C-A-X of formula (I) is any one of formula (Ia), (Ib), (Ic), (Id), or (Id'):

[0124]

[0125] wherein A1 is CR 1 or N, A2 is CR 2 or N, A3 is CR 3 or N, A4 is CR 4 , A5 is CR 5 or N, and A6 is CR 5 or N;

[0126] R 1 is H or a hydroxyl group;

[0127] R 2 is H, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, SO2C1-C4 alkyl, NHSO2C1-C4 alkyl, SO2C3-C6 cycloalkyl, NHSO2C3-C6 cycloalkyl, C1-C5 alkoxy or C1-C5 alkylamino;

[0128] R 3 and R 4 are independently selected from the group consisting of: H, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, C1-C5 alkoxy or C1-C5 alkylamino;

[0129] Provided that at least one of R 1 , R 2 , R 3 or R 4 is hydroxy;

[0130] B' is H or hydroxy; and

[0131] R 5 is either H or the first substituent as defined above.

[0132] Sometimes, C-A-X of formula (I) is any one of formula (Ia), (Ib), (Ic) or (Id):

[0133]

[0134] wherein A1 is CR 1 or N, A2 is CR 2 or N, A3 is CR 3 or N, and A4 is CR 4 ;

[0135] R 1 is H or hydroxy;

[0136] R 2 is H, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, SO2C1-C4 alkyl, NHSO2C1-C4 alkyl, SO2C3-C6 cycloalkyl, NHSO2C3-C6 cycloalkyl, C1-C5 alkoxy or C1-C5 alkylamino;

[0137] R 3 and R 4 are independently selected from the group consisting of: H, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, C1-C5 alkoxy or C1-C5 alkylamino;

[0138] Provided that R 1 、R3 or R 4 at least one of which is a hydroxyl group;

[0139] B' is H or a hydroxyl group; and

[0140] R 5 is either H or a first substituent as defined above.

[0141] Typically, R 2 is H, C1-C3 alkyl, halogen, SO2C1-C4 alkyl or NHSO2C1-C4 alkyl; and R 3 and R 4 are independently selected from the group consisting of H, hydroxyl group, C1-C3 alkyl and halogen. Usually, R 2 is H, C1-C3 alkyl, fluorine, chlorine, SO2CH3 or NHSO2CH3; and R 3 and R 4 are independently selected from H, hydroxyl group, C1-C3 alkyl and fluorine or chlorine.

[0142] Typically, R 5 is H.

[0143] Usually, when CAX is represented by formula (Ia), Z is a phenyl ring optionally substituted at one or more carbon atoms with a second substituent; C1-C6 alkyl; or C3-C6 cycloalkyl; and when CAX is represented by any one of formulae (Ib), (Ic) and (Id), Z is a phenyl or pyridyl ring optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent; C1-C6 alkyl; or C3-C6 cycloalkyl.

[0144] Usually, when CAX is represented by formula (Ia), Z is a phenyl ring optionally substituted at one or more carbon atoms with a second substituent; C1-C6 alkyl; or C3-C6 cycloalkyl; and when CAX is represented by any one of formulae (Ib), (Ic), (Id) and (Id’), Z is a phenyl or pyridyl ring optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent; C1-C6 alkyl; or C3-C6 cycloalkyl.

[0145] Typically, when CAX is represented by formula (Ia), Z is an unsubstituted phenyl ring; and when CAX is represented by any one of formulae (Ib), (Ic) and (Id), Z is a phenyl or pyridyl ring optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent, each second substituent being independently selected from the group consisting of hydroxyl group, methyl, fluorine and chlorine.

[0146] Typically, when CAX is represented by formula (Ia), Z is an unsubstituted benzene ring; and when CAX is represented by any one of formulas (Ib), (Ic), (Id) and (Id’), Z is a phenyl or pyridyl ring optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent, each second substituent independently selected from the group consisting of hydroxy, methyl, fluorine and chlorine. Generally, the compound is any one of formulas (Ie) to (IIi):

[0147]

[0148]

[0149] Generally, the compound is any one of formulas (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik). Typically, the compound has formula (Ih) or (IIb).

[0150] The compounds described herein may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" is intended to define pharmaceutically available organic and / or inorganic salts. The compounds of the invention may be isolated from the reaction mixture as pharmaceutically acceptable salts. Alternatively, pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds of the invention by reacting the carboxylic acid-containing moiety with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or a primary, secondary or tertiary amine. Pharmaceutically acceptable salts include cations based on alkali metals or alkaline earth metals such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts as well as non-toxic quaternary ammonium salts; and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine and ethylamine. Other examples of organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

[0151] Pharmaceutically acceptable salts may also be prepared by treating the compounds of the invention with a suitable acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid and ascorbic acid.

[0152] The compounds of the present invention can exist in different stereoisomeric forms. All stereoisomeric forms and their mixtures, including enantiomers and racemic mixtures, are included within the scope of the present invention. Such stereoisomeric forms include enantiomers and diastereoisomers. The individual stereoisomers of the compounds of the present invention are included, i.e., associated with less than 5%, preferably less than 2%, and especially less than 1% of other stereoisomers. Mixtures of stereoisomers in any proportion, such as a racemic mixture containing substantially equal amounts of two enantiomers, are also included within the scope of the present invention.

[0153] Also included are solvates and isotopically labeled compounds of the present invention. Isotopically labeled compounds are identical to those compounds described herein, but in fact one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number predominantly present in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Cl.

[0154] On the other hand, intermediates suitable for producing the compounds of the present invention are included. Specifically, intermediates of formulas (ia) to (ip) are included.

[0155]

[0156] The intermediate can have the formula (ig), (ii), (ij), (ik), or (if). Generally, the intermediate has the formula (ia) to (id), (if), or (ih) to (ip). Typically, the intermediate has the formula (im).

[0157] Prodrugs of the compounds and compositions of the present invention are also within the scope of the present invention. After administration to a subject, the prodrug is converted by metabolism or other chemical processes to produce the compounds of the present invention.

[0158] All amorphous and crystalline forms of the compounds of the present invention are included.

[0159] While it is possible to administer the compounds alone, pharmaceutical compositions are typically used. A second aspect provides a pharmaceutical composition comprising any one or combination of the compounds defined in the first aspect in combination with one or more pharmaceutically acceptable excipients. Excipients can assist in transporting the compound to the site in the body where it is intended to act, for example by increasing the rate at which the compound dissolves into the bloodstream or by increasing the stability of the compound to delay its release in order to enhance its efficiency and prevent damage to delicate tissues. Alternatively, excipients can be used for identification purposes or to make the compound more appealing to the patient, for example by improving its taste, odor, and / or appearance. Typically, excipients make up the bulk of the pharmaceutical composition.

[0160] Excipients include diluents or fillers, binders, disintegrants, lubricants, colorants, and preservatives. Diluents or fillers are inert ingredients that affect the chemical and physical properties of the final composition. If the dose of the compound of the present invention is small, more diluent will be required to produce a composition suitable for practical use. If the dose of the compound of the present invention is high, less diluent will be required.

[0161] Binders increase the cohesiveness of powders to form granules, which can form tablets. The binder must also allow the tablet to disintegrate after ingestion so that the compound of the present invention dissolves. Disintegration of the composition after administration can be facilitated by using a disintegrant.

[0162] A broad overview of pharmaceutically acceptable excipients is described in Handbook of Pharmaceutical Excipients, 6th Edition; edited by R.C. Rowe, P.J. Sheskey, and M.E. Quinn, The Pharmaceutical Press, London, American Pharmacists Association, Washington, 2009. Any suitable pharmaceutically acceptable excipient is within the scope of the present invention.

[0163] Pharmaceutical compositions include those suitable for oral, nasal, topical (including buccal, sublingual, and transdermal), parenteral (including subcutaneous, intravenous, and intramuscular), or rectal administration. In some embodiments, the pharmaceutical composition is suitable for topical or oral administration, i.e., the pharmaceutical composition is a topical or oral formulation.

[0164] The pharmaceutical composition can be compressed into solid dosage units such as tablets, or processed into capsules or suppositories. The pharmaceutical composition can also be injected and can be prepared in the form of a solution, suspension or emulsion for such applications. Alternatively, the pharmaceutical composition can be administered as a spray, including a nasal spray or an oral spray. Otherwise, the pharmaceutical composition can be processed into gels, creams, patches, implants or any other immediate and / or sustained release products. Typically, the pharmaceutical composition is processed into a gel, cream, lotion, foam or ointment for topical administration; or into tablets, capsules or oral sprays for oral administration.

[0165] The third aspect of the present invention provides a compound of the first aspect or a pharmaceutical composition of the second aspect for use as a medicament. Specifically, the compound can be used to treat diseases or conditions associated with the activity of bromodomain and extra-terminal protein. In a fifth aspect, there is provided a compound of the first aspect or a pharmaceutical composition of the second aspect for inhibiting bromodomain and extra-terminal protein. Diseases or conditions associated with the activity of bromodomain and extra-terminal protein include inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, rheumatic diseases, demyelinating diseases and fibrotic diseases. Thus, in a fourth aspect, the present invention provides a compound of the present invention or a pharmaceutical composition of the present invention for use in a method of treating or preventing inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, rheumatic diseases, demyelinating diseases and fibrotic diseases, and in a sixth aspect, the present invention provides a method of treating or preventing skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, rheumatic diseases, demyelinating diseases and fibrotic diseases, the method comprising administering to a subject an effective amount of a compound of the first aspect or a pharmaceutical composition of the second aspect.

[0166] Inflammatory diseases rely on T helper cells Th1, Th2 and Th 17 to mount innate and adaptive immune responses, which affect one or both of the acute or chronic phases of the disease. Many cytokines and chemokines are upregulated in inflammatory diseases, and the ability to reduce the levels of these inflammatory markers is evidence of the ability of a drug to improve the disease. Such cytokines and chemokines include, but are not limited to, granulocyte-macrophage colony-stimulating factor (GM-CSF); interleukins IL-1, IL-2, IL-4, IL-6, IL-8, IL-13, IL-17, IL-22; chemokine (C-C motif) ligand CCL2, CCL27 and CCL20; tumor necrosis factor α (TNF-α); thymic stromal lymphopoietin (TSLP) and chemokine (C-X-C motif) ligand 9 (CXCL9).

[0167] Pan-BET inhibitors may have value in the treatment of inflammatory disorders. These include skin disorders such as alopecia areata, atopic dermatitis, bullous diseases, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, contact dermatitis, psoriasis, rosacea, scleroderma, sicca syndrome, urticaria and chronic idiopathic pruritus and vitiligo; respiratory diseases such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, rhinitis, bronchiolitis, byssinosis, pneumoconiosis, bronchiectasis, hypersensitivity pneumonitis, mesothelioma, sarcoidosis; gastrointestinal diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, retroperitoneal fibrosis, coeliac disease and gastrointestinal cancer; eye diseases such as myasthenia gravis, Sjogren's syndrome( syndrome), conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis and iritis; systemic indications such as Addison's disease, acute gout, ankylosing spondylitis, atherosclerosis, Behcet's disease, giant cell arthritis, glomerulonephritis, hepatitis, hypophysitis, lupus nephritis, Kawasaki disease, multiple sclerosis, myocarditis, myositis, nephritis, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonia, primary biliary cirrhosis, psoriatic arthritis, rheumatoid arthritis, scleroderma (skin or systemic), scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's arteritis, toxic shock, thyroiditis, type 1 diabetes and diabetic complications, uveitis, vasculitis and Wegener's granulomatosis; and other autoimmune diseases and indications requiring immunosuppression, such as organ transplantation.BET inhibitors are also known to affect the growth or survival of a range of cancers, particularly skin and systemic cancers, and can be used to treat acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, granulomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, dysplastic 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, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, 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, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumors, uterine cancer, and Wilms’ tumor.

[0168] BET inhibitors can also be used to treat obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, or diabetic neuropathy.

[0169] A seventh aspect provides a method of inhibiting bromodomain and extra-terminal protein activity in a subject, the method comprising administering to the subject an effective amount of a compound of the first aspect or a pharmaceutical composition of the second aspect.

[0170] An effective amount of the compound can be administered topically, parenterally, or enterally to a subject. The compound can be administered parenterally, sometimes by direct injection, which is typically intramuscular, subcutaneous, or intravenous. However, typically, the compound is administered topically to the skin or mucous membranes via a cream, gel, foam, lotion, or ointment, or enterally via a tablet, capsule, or oral spray.

[0171] The subject can be and typically is a human and can suffer from or be susceptible to inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, and eye diseases. Treatment of the subject can include administering an effective amount of a compound of the present invention. The term "effective amount" refers to an amount of a compound that improves the above-mentioned disease and thus produces the desired therapeutic or inhibitory effect.

[0172] The skilled artisan is aware that the effective amount may vary with the particular compound of the invention, the subject, and the administration procedure used. It is within the means and ability of the skilled artisan to identify the effective amount of the compounds and compositions of the invention through routine work and experimentation.

[0173] Any discussion herein of documents, acts, materials, devices, articles of manufacture or the like should not be construed as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

[0174] It will be appreciated by those skilled in the art that various changes and / or modifications may be made to the invention as described herein without departing from the scope of the invention as described. Therefore, the present embodiments are to be considered for descriptive purposes only and not restrictive, and are not to be limited to the scope described in the embodiments. It will be appreciated by those skilled in the art that the present embodiments may be read individually or in combination, and may be combined with any one or combination of the features described herein.

[0175] The subject matter of each patent and non-patent reference cited herein is hereby incorporated by reference in its entirety.

[0176] Aspects and embodiments of the present disclosure are further described in the following clauses:

[0177] 1. A compound of formula (I):

[0178]

[0179] wherein the ring structure A is a 5- or 6-membered aromatic or heteroaromatic ring optionally substituted at one or more carbon and / or heteroatoms with a first substituent;

[0180] Each first substituent is independently selected from the group consisting of: hydroxy, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl alcohol, halogen, SO2C1-C4 alkyl, NHSO2C1-C4 alkyl, SO2C3-C6 cycloalkyl, NHSO2C3-C6 cycloalkyl, SO2C1-C4 alkyl alcohol, NHSO2C1-C4 alkyl alcohol, C1-C5 alkoxy, C1-C5 alkylamino, SO2NH2, CONH2, CONHC1-C4 alkyl, NHCOC1-C4 alkyl, NHSO2N(C1-C4 alkyl)2, C1-C6 fluoroalkyl, SO2C1-C4 fluoroalkyl, NHSO2C1-C4 fluoroalkyl, C1-C5 fluoroalkoxy and C1-C5 fluoroalkylamino;

[0181] X is O, CR 2、 NR' or S, where R is independently selected from the group consisting of H, C1-C4 alkyl and halogen, and R' is selected from the group consisting of C1-C4 alkyl and H;

[0182] Z is a 5- or 6-membered aromatic or heteroaromatic ring, C1-C6 alkyl, C3-C6 cycloalkyl, CR A R B R C , C2-C5 oxacycloalkyl, C2-C5 azacycloalkyl or morpholinyl;

[0183] where R A is C3-C5 cycloalkyl, R B is C3-C5 cycloalkyl, methyl or ethyl, and R C is OH; and

[0184] Each second substituent is independently selected from the group consisting of: hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, C1-C5 alkoxy, C1-C5 alkylamino, oxo, cyano, C1-C6 fluoroalkyl, C1-C5 fluoroalkoxy and C1-C5 fluoroalkylamino;

[0185] Ring structure B is optionally present; where when ring structure B is present, it is an optionally substituted pyrrole, which is bonded such that C is in the 4-position relative to NH; where the pyrrole is optionally substituted at position 2 with a third substituent;

[0186] wherein the third substituent is selected from the group consisting of: CONHC1-C4 alkyl optionally substituted by methyl or ethyl at one or more carbon atoms, CONH2, CONHC1-C6 fluoroalkyl, CONHC3-C6 cycloalkyl; CONHC3-C5 cyclofluoroalkyl, NHCOC1-C4 alkyl and NHCOC1-C4 fluoroalkyl;

[0187] provided that when A is 6-membered, it is substituted by a hydroxyl or oxo group at least once.

[0188] 2. The compound according to clause 1, wherein the third substituent is selected from the group consisting of: CONHC1-C4 alkyl, CONH2, CONHC1-C6 fluoroalkyl, CONHC3-C5 cycloalkyl; CONHC3-C5 cyclofluoroalkyl, NHCOC1-C4 alkyl and NHCOC1-C4 fluoroalkyl.

[0189] 3. The compound according to clause 1 or clause 2, wherein when A is 6-membered, it is substituted by a hydroxyl or oxo group at the ortho or meta position to X at least once.

[0190] 4. The compound according to any one of the preceding clauses, wherein the third substituent is CONHC1-C4 alkyl.

[0191] 5. The compound according to any one of the preceding clauses, wherein the third substituent is CONH ethyl.

[0192] 6. The compound according to any one of clauses 1 to 3, wherein the compound has the formula (II):

[0193]

[0194] wherein A, X and Z are as defined for formula (I).

[0195] 7. The compound according to any one of the preceding clauses, wherein A is selected from the group consisting of: benzene, pyridine, thiazole, pyridone, pyrazole, imidazole and 1,2,4-triazole optionally substituted by a first substituent at one or more carbon and / or heteroatoms.

[0196] 8. The compound according to clause 7, wherein the pyrazole carbon at position 5 is bonded to C and the pyrazole nitrogen at position 1 is bonded to X.

[0197] 9. The compound according to clause 7 or clause 8, wherein the imidazole carbon at position 2 is bonded to C and the nitrogen at position 1 is bonded to X.

[0198] 10. The compound according to any one of clauses 7 to 9, wherein the 1,2,4-triazole carbon at position 5 is bonded to C and the nitrogen at position 1 is bonded to X.

[0199] 11. A compound as described in any one of clauses 1 to 6, wherein A is selected from the group consisting of benzene, pyridine, thiazole, and pyridone, optionally substituted at one or more carbon and / or heteroatoms by a first substituent.

[0200] 12. A compound as described in any one of clauses 7 to 11, wherein the pyridone is 2 - pyridone.

[0201] 13. A compound as described in clause 12, wherein the 2 - pyridone carbon at position 3 is bonded to X and the 2 - pyridone carbon at position 4 is bonded to C; or the 2 - pyridone carbon at position 5 is bonded to X and the 2 - pyridone carbon at position 4 is bonded to C.

[0202] 14. A compound as described in any one of clauses 7 to 13, wherein the thiazole carbon at position 4 is bonded to C and the thiazole carbon at position 5 is bonded to X.

[0203] 15. A compound as described in any one of the preceding clauses, wherein each first substituent is independently selected from the group consisting of hydroxy, oxo, C1 - C6 alkyl, C3 - C6 cycloalkyl, C1 - C6 alkyl alcohol, halo, SO2C1 - C4 alkyl, NHSO2C1 - C4 alkyl, SO2C3 - C6 cycloalkyl, NHSO2C3 - C6 cycloalkyl, SO2C1 - C4 alkyl alcohol, NHSO2C1 - C4 alkyl alcohol, C1 - C5 alkoxy, and C1 - C5 alkylamino.

[0204] 16. A compound as described in any one of the preceding clauses, wherein each first substituent is independently selected from the group consisting of hydroxy, oxo, C1 - C6 alkyl, C3 - C6 cycloalkyl, C1 - C6 alkyl alcohol, and halo.

[0205] 17. A compound as described in any one of the preceding clauses, wherein each first substituent is independently selected from the group consisting of hydroxy, oxo, methyl, and halo.

[0206] 18. A compound as described in any one of the preceding clauses, wherein R is independently selected from the group consisting of H, methyl, and halo, and R' is selected from the group consisting of methyl and H.

[0207] 19. A compound as described in any one of the preceding clauses, wherein the halo is fluorine or chlorine.

[0208] 20. A compound as described in any one of the preceding clauses, wherein R is independently selected from the group consisting of H, methyl, and fluorine, and R' is methyl.

[0209] 21. A compound as described in any one of the preceding clauses, wherein X is O.

[0210] 22. A compound as described in any of the preceding clauses, wherein Z is a 5- or 6-membered aromatic or heteroaromatic ring, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group that is optionally substituted at one or more carbon or heteroatoms with a second substituent.

[0211] 23. A compound as described in any of the preceding clauses, wherein Z is a 6-membered aromatic or heteroaromatic ring, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group that is optionally substituted at one or more carbon or heteroatoms with a second substituent.

[0212] 24. A compound as described in any of the preceding clauses, wherein Z is a 5- or 6-membered aromatic or heteroaromatic ring that is optionally substituted at one or more carbon or heteroatoms with a second substituent

[0213] 25. A compound as described in any of the preceding clauses, wherein Z is a 6-membered aromatic or heteroaromatic ring that is optionally substituted at one or more carbon or heteroatoms with a second substituent

[0214] 26. A compound as described in any of the preceding clauses, wherein Z is a phenyl or pyridyl ring that is optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent.

[0215] 27. A compound as described in any of the preceding clauses, wherein Z is a phenyl ring that is optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent

[0216] 28. A compound as described in any of the preceding clauses, wherein each second substituent is independently selected from the group consisting of: hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C5 alkoxy, C1-C5 alkylamino, oxo, and cyano.

[0217] 29. A compound as described in any of the preceding clauses, wherein each second substituent is independently selected from the group consisting of hydroxy, C1-C4 alkyl, and halo.

[0218] 30. A compound as described in any of the preceding clauses, wherein the second substituent is hydroxy.

[0219] 31. The compound according to clause 27, wherein each second substituent is independently selected from the group consisting of methyl and fluoro.

[0220] 32. The compound according to clause 27, wherein Z is a phenyl ring substituted with two methyl groups ortho to X and one fluoro group para to X.

[0221] 33. A compound as described in any of the preceding clauses, wherein C-A-X of formula (I) is any one of formula (Ia), (Ib), (Ic), (Id), or (Id'):

[0222]

[0223] wherein A1 is CR 1 or N, A2 is CR 2 or N, A3 is CR 3 or N, A4 is CR 4 , A5 is CR 5 or N, and A6 is CR 5 or N;

[0224] R 1 is H or hydroxy;

[0225] R 2 is H, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, SO2C1-C4 alkyl, NHSO2C1-C4 alkyl, SO2C3-C6 cycloalkyl, NHSO2C3-C6 cycloalkyl, C1-C5 alkoxy or C1-C5 alkylamino;

[0226] R 3 and R 4 are independently selected from the group consisting of: H, hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, C1-C5 alkoxy or C1-C5 alkylamino;

[0227] provided that at least one of R 1 , R 2 , R 3 or R 4 is hydroxy;

[0228] B' is H or hydroxy; and

[0229] R 5 is either H or the first substituent as defined above.

[0230] 34. A compound as described in any of the preceding clauses, wherein C-A-X is any one of formula (Ia), (Ib), (Ic) or (Id):

[0231]

[0232] wherein A1 is CR 1 or N, A2 is CR 2 or N, A3 is CR 3 or N, and A4 is CR 4 ;

[0233] R 1 is H or hydroxy;

[0234] R 2is H, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogen group, a SO2C1-C4 alkyl group, an NHSO2C1-C4 alkyl group, a SO2C3-C6 cycloalkyl group, an NHSO2C3-C6 cycloalkyl group, a C1-C5 alkoxy group or a C1-C5 alkylamino group;

[0235] R 3 and R 4 are independently selected from the group consisting of: H, a hydroxyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogen group, a C1-C5 alkoxy group or a C1-C5 alkylamino group;

[0236] provided that R 1 , R 3 or R 4 at least one of which is a hydroxyl group;

[0237] B' is H or a hydroxyl group; and

[0238] R 5 is either H or a first substituent.

[0239] 35. The compound according to clause 33 or 34, wherein R 2 is H, a C1-C3 alkyl group, a halogen group, a SO2C1-C4 alkyl group or an NHSO2C1-C4 alkyl group; and R 3 and R 4 are independently selected from the group consisting of H, a hydroxyl group, a C1-C3 alkyl group and a halogen group.

[0240] 36. The compound according to any one of clauses 33 to 35, wherein when CAX is represented by formula (Ia), Z is a phenyl ring optionally substituted with a second substituent at one or more carbon atoms; and when CAX is represented by any one of formulas (Ib), (Ic), (Id) and (Id'), Z is a phenyl or pyridyl ring optionally substituted with a second substituent at one or more carbon and / or nitrogen atoms.

[0241] 37. The compound according to any one of clauses 33 to 35, wherein when CAX is represented by formula (Ia), Z is an unsubstituted phenyl ring; and when CAX is represented by any one of formulas (Ib), (Ic), (Id) and (Id'), Z is a phenyl or pyridyl ring optionally substituted with a second substituent at one or more carbon and / or nitrogen atoms, and the second substituent is selected from the group consisting of a hydroxyl group, a methyl group, a fluorine atom and a chlorine atom.

[0242] 38. The compound according to any one of clauses 33 to 37, wherein the compound is any one of the following formulas:

[0243] (i) formula (Ia), (Id) or (Id'); or

[0244] (ii) Formula (Ib) or (Ic).

[0245] 39. A compound as described in any one of clauses 33 to 37, wherein the compound is any one of the following formulas:

[0246] (i) Formula (Ia) or (Id); or

[0247] (ii) Formula (Ib) or (Ic).

[0248] 40. A compound as described in clause 1, wherein the compound is any one of Formulas (Ie) to (IIe):

[0249]

[0250]

[0251] 41. A compound as described in clause 40, wherein the compound is any one of Formulas (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik).

[0252] 42. A compound as described in any one of the foregoing clauses, which is in the form of a pharmaceutically acceptable salt.

[0253] 43. A compound of Formula (Ib) or (Ic) as described in any one of clauses 33 to 41, which is in the form of a pharmaceutically acceptable salt.

[0254] 44. A compound of Formula (Ia), (Id) or (Id') as described in any one of clauses 33 to 41, which is in the form of a pharmaceutically acceptable salt.

[0255] 44. A compound of Formula (Ia) or (Id) as described in any one of clauses 33 to 41, which is in the form of a pharmaceutically acceptable salt.

[0256] 45. A pharmaceutical composition comprising any one or combination of the compounds as described in any one of clauses 1 to 41 in combination with one or more pharmaceutically acceptable excipients.

[0257] 46. A pharmaceutical composition as described in clause 45, wherein the pharmaceutical composition is a topical preparation.

[0258] 47. A pharmaceutical composition comprising any one or combination of the compounds of Formula (Ia), (Id) or (Id') as described in any one of clauses 33 to 41 in combination with one or more pharmaceutically acceptable excipients.

[0259] 48. A pharmaceutical composition comprising any one or combination of the compounds of formula (Ia) or (Id) as described in any one of clauses 33 to 41 in combination with one or more pharmaceutically acceptable excipients.

[0260] 49. The pharmaceutical composition according to clause 45, wherein the pharmaceutical composition is an oral preparation.

[0261] 50. A pharmaceutical composition comprising any one or combination of the compounds of formula (Ib) or (Ic) as described in any one of clauses 33 to 41 in combination with one or more pharmaceutically acceptable excipients.

[0262] 51. The compound according to any one of clauses 1 to 44 or the pharmaceutical composition according to any one of clauses 45 to 50, which is used as a drug.

[0263] 52. The compound according to any one of clauses 1 to 44 or the pharmaceutical composition according to any one of clauses 45 to 50, which is used in a method for treating or preventing inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases and fibrotic diseases.

[0264] 53. The compound or composition used as in clause 52, wherein the use is in a method for treating or preventing inflammation or cancer in the intestine, skin or lung.

[0265] 54. The compound according to any one of clauses 1 to 44 or the pharmaceutical composition according to any one of clauses 45 to 50, which is used to inhibit bromodomain and extra terminal protein.

[0266] 55. A method for treating or preventing inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases and fibrotic diseases, the method comprising administering to a subject an effective amount of the compound according to any one of clauses 1 to 44 or the pharmaceutical composition according to any one of clauses 45 to 50.

[0267] 56. The method according to clause 55, wherein the method is used for treating or preventing fibrosis of inflammation or cancer in the intestine, skin or lung.

[0268] 57. A method for inhibiting the activity of bromodomain and extra terminal protein in a subject, the method comprising administering to a subject an effective amount of the compound according to any one of clauses 1 to 44 or the pharmaceutical composition according to any one of clauses 45 to 50.

[0269] The following are presented as non-limiting examples.

[0270] Example

[0271] It has been found that the compounds described herein are surprisingly effective as pan-inhibitors of BET BRD. The examples disclosed herein exhibit nanomolar potency in inhibiting GM-CSF, IL-1α, IL-6, IL-8, CCL2, TNF-α, TSLP, CCL27, CCL20, and CXCL9 from stimulated keratinocytes. They also exhibit surprisingly effective human hepatocyte clearance and solubility in formulations suitable for topical application. Advantageously, for topical administration, the exemplified compounds are stable in human skin S9 fraction and under hydrolysis conditions at a range of pH values. In addition, the exemplified topical formulations deliver a viable concentration of the compound into the skin epidermis, and the exemplified compounds are not toxic to primary keratinocytes.

[0272] Abbreviation

[0273]

[0274]

[0275]

[0276] Equipment

[0277] Reactions using microwave irradiation were carried out in a Biotage Initiator microwave.

[0278] Normal phase TLC was performed on pre-coated silica gel plates (Kieselgel 60F 254 , BDH), visualized via ultraviolet light (UV254 / 365 nm) and / or ninhydrin solution.

[0279] Flash chromatography was performed using a Combiflash Companion Rf (Teledyne ISCO) and pre-packed silica gel columns purchased from Grace Davison Discovery Science or SiliCycle.

[0280] Quality-directed preparative HPLC separations were performed using a Waters HPLC (2545 binary gradient pump, 515 HPLC supplementary pump, 2767 sample manager) connected to a Waters 2998 photodiode array and a Waters 3100 mass detector.

[0281] Preparative HPLC separations were performed using a Gilson HPLC (321 pumps, 819 injection modules, 215 liquid handlers / syringes) connected to a Gilson 155 UV / vis detector. On both instruments, HPLC chromatographic separations were carried out using a Waters XBridge C18 column, 19 x 100 mm, 5 μm particle size; with water containing 0.1% ammonia (solvent A) and acetonitrile (solvent B) as the mobile phase.

[0282] 1 1H NMR and 19 19F NMR spectra were recorded on a Bruker Avance DPX 500 spectrometer (1H at 500.1 MHz, 1 13C at 125 MHz, 13 19F at 470.5 MHz) or a Bruker Avance DPX 300 (1H at 300 MHz). 19 In all cases, chemical shifts (δ) are reported in ppm, using the residual solvent as an internal reference. Signal splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br), or combinations thereof. Coupling constants (J) are cited to the nearest 0.5 Hz. Low-resolution electrospray (ES) mass spectra were recorded on a Bruker MicroTof mass spectrometer operating in the positive mode. High-resolution mass spectrometry (HRMS) was performed using a Bruker MicroTof mass spectrometer. 1 1H)

[0283] LC-MS analysis and chromatographic separations were performed using an Agilent Technologies 1200 series HPLC, connected to an Agilent Technologies 6130 quadrupole LC / MS with an Agilent diode array detector. The column used was a Waters XBridge column (50 mm × 2.1 mm, 3.5 μm particle size), and compounds were eluted with a gradient of 5% to 95% acetonitrile / water + 0.1% formic acid, or using a Shimadzu HPLC, connected to an LCMS-2020 quadrupole LC / MS with a Shimadzu diode array detector. The column used was a Kinetex EVO C18 column (30 mm × 1.8 mm, 5.0 μm particle size), and compounds were eluted with a gradient of 5% to 95% acetonitrile / water + 0.0375% trifluoroacetic acid.

[0284] Reactions were not optimized unless otherwise indicated herein. Solvents and reagents were purchased from commercial suppliers and used without further purification. Dry solvents were purchased in sealed bottles stored over molecular sieves.

[0285] The formulations and compounds have been named using the ChemDraw Professional 15.0 naming application.

[0286] Preparation Process

[0287] The following scheme illustrates the method for synthesizing the compounds of the present invention. Scheme 1 illustrates the general route for preparing the compounds of the present invention by deprotection after Suzuki coupling via intermediates (II) and (VIII). The 6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one boronic acid ester intermediate (II) is prepared as follows:

[0288] 5-Bromo-2-methoxy-4-methyl-3-nitropyridine reacts with DMF-DMA to give intermediate (VII). Iron-catalyzed reduction of the 3-nitro group to the corresponding amine initiates ring closure to give intermediate (VI). Tosyl protection is carried out, followed by acid hydrolysis with HBr to give intermediate (IV). The pyridone group is then N-methylated with methyl iodide and sodium hydride to give intermediate (III). Intermediate (II) is then formed from the 4-bromoaryl compound (III) by treatment with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane in a palladium-catalyzed coupling reaction. Suzuki coupling of (II) and (VIII), followed by deprotection, yields compound (I). Deprotection includes removing the tosyl group of intermediate (II) using, for example, sodium hydroxide. Typically, deprotection also includes converting the methoxy substituents on A and / or Z to hydroxyl groups using, for example, boron tribromide.

[0289] Alternatively, the compound can be functionalized at position 2 of the pyrrole with a third substituent (typically CONH ethyl). This can be carried out by using the alternative synthetic route shown in Scheme 2, where intermediate (III) is reacted with ethyl chloroformate and a strong base such as lithium diisopropylamide (LDA) to form intermediate (III'). Intermediate (II') is then formed from compound (III') via treatment with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane in a palladium-catalyzed coupling reaction. The Suzuki coupling of (II') and (VIII), followed by deprotection, yields compound (I'). Deprotection involves removing the tosyl group using, for example, sodium hydroxide. This also converts the ethoxy substituent of the ethyl formyl group to a hydroxyl group. Finally, the carboxylic acid at position 2 of the pyrrole of intermediate (I') is reacted with a suitable amine to produce the desired third substituent. Oxalyl chloride is typically used to catalyze this reaction step by first converting the carboxylic acid to an acyl chloride, which is more readily nucleophilically substituted by the amine. A person skilled in the art will be able to evaluate which amines and reaction conditions are suitable for functionalizing the carboxylic acid of intermediate (I') to produce compound (I").

[0290]

[0291] Scheme 1: General synthetic route for synthesizing the compounds of the present invention. The definitions of A, X, and Z for compounds (I) and (VIII) are as defined above for the compounds of formula (I). LG for compound (VIII) is a halogen or trifluoromethanesulfonate. Preferably, LG is bromine or iodine.

[0292]

[0293] Scheme 2: General synthetic route for synthesizing the compounds of the present invention. The definitions of A, X, and Z for compounds (I"), (I'), and (VIII) are as defined above for the compounds of formula (I). LG for compound (VIII) is a halogen or trifluoromethanesulfonate. Preferably, LG is bromine or iodine.

[0294] The synthesis of the compounds described herein using Scheme 2 is shown in Scheme 3, where A is 2-pyridone, X is an oxide, and Z is 2,6-dimethyl-4-fluorophenyl, such as in Example 41.

[0295]

[0296] Scheme 3: Example of General Scheme 2, where A is 2-pyridone, X is an oxide, Z is 2,6-dimethyl-4-fluorophenyl, and LG is bromine.

[0297] The synthetic routes applicable for the synthesis of the intermediate of formula (VIII) in Schemes 1 and 2 depend on the identity of A. Suitable routes for synthesizing the intermediate of formula (VIII) are shown in Schemes 4, 5, and 6, wherein: A is a 6-membered aromatic or heteroaromatic ring optionally substituted with a first substituent at one or more carbon and / or heteroatoms and substituted with a hydroxyl or oxo group at at least one carbon atom; A is N-methyl-2-pyridone optionally substituted with a hydroxyl group; and A is thiazole.

[0298] The iodine intermediate (IX) is prepared via the Sandmeyer reaction of the corresponding aniline (X), and the aniline (X) in turn is formed by the iron-catalyzed reduction of the nitro-containing compound (XI). (XI) is formed via the S N Ar reaction of the o-fluoronitroaryl compound (XII).

[0299] The N-methyl-2-pyrone intermediate (XIII) is prepared via the methylation and iron-catalyzed oxidation of the corresponding pyridine (XIV), and the pyridine (XIV) in turn is formed via the reduction of the corresponding oxidized pyridine (XV) using phosphorus tribromide. The bromine intermediate (XV) is prepared via the reaction of the corresponding nitro intermediate (XVI) with acetyl bromide, and the compound (XVI) in turn is produced via the S N Ar reaction of the corresponding oxidized o-fluoronitropyridine compound (XVII).

[0300] The 5-bromothiazole intermediate (XVIII) is prepared via the bromination of the corresponding thiazole intermediate (XIX), and the thiazole intermediate (XIX) in turn is prepared via the copper-catalyzed Ullmann-type reaction of the corresponding bromine compound (XX).

[0301]

[0302] Scheme 4: General synthetic route for synthesizing the compounds of the present invention, wherein A is a 6-membered aromatic or heteroaromatic ring. The definitions of X, Z, A1, A2, A3, and A4 are as defined above for the compounds of formula (I) and (Ia).

[0303]

[0304] Scheme 5: General synthetic route for synthesizing the compounds of the present invention, wherein A is 2-pyridone. The definitions of X, Z, and B' are as defined above for the compounds of formula (I), (Ib), and (Ic).

[0305]

[0306] Scheme 6: General synthetic route for synthesizing the compounds of the present invention, wherein A is thiazole. The definitions of X and Z are as defined above for the compounds of formula (I) and (Id).

[0307] Typically, X is O (oxide). Scheme 7 illustrates suitable reagents and reaction conditions for preparing the compound of Example 1. Those skilled in the art know that the reagents and conditions employed in the chemical transformations of Scheme 7 can be utilized, modified, and / or replaced with alternatives when needed in order to provide various alternative compounds via the general procedures of Schemes 1 and 2.

[0308]

[0309] Scheme 7: Synthetic route for the synthesis of the compound of Example 1.

[0310] Example 1: 4-(3-Hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0311] Preparation 1: (E)-2-(5-Bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethen-1-amine

[0312]

[0313] 5-Bromo-2-methoxy-4-methyl-3-nitropyridine (50 g, 202 mmol) was dissolved in DMF (410 mL) under nitrogen and heated to 80 °C. DMF-DMA (224 mL, 1.686 mol) was added within 20 min. The resulting dark solution was heated at 95 °C. After 5 h, TLC (4:1 heptane / EA) indicated no SM remaining. The mixture was cooled to RT and poured into ice water (1100 mL). The resulting suspension was stirred for 15 min and then filtered. The collected red solid was washed with water and dried under vacuum at 50 °C overnight (56.6 g, 61%). The material was used directly in Preparation 2 without further purification.

[0314] 1 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.02 (d, J = 13.7 Hz, 1H), 4.94 (d, J = 13.7 Hz, 1H), 3.97 (s, 3H), 2.94 (s, 6H).

[0315] Preparation 2: 4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

[0316]

[0317] (E)-2-(5-Bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethen-1-amine (23.3 g, 77.1 mmol) was partially dissolved in methanol (1100 mL) and ammonium chloride (23.3 g, 436 mmol), and then dissolved in water (140 mL). Iron powder (23.3 g, 417 mmol) was added and the mixture was heated to reflux. The reaction mixture was stirred using a overhead stirrer. After 5 hr, another aliquot of iron powder (23.3 g, 417 mmol) was added and heating was continued overnight. The mixture was cooled and solid Na2CO3 was added. The mixture was filtered through a celite pad. The filtrate was filtered and the residue was triturated with 4:1 heptane / ethyl acetate. The mixture was filtered through a silica gel pad. The filtrate was evaporated. The residue was purified on silica gel, eluting with 100:0 to 80:20 heptane / ethyl acetate. Solvent reduction gave an off-white solid (3.7 g, 21%).

[0318] HPLC t R (Agilent, acidic, 3.5 min): 1.46 min, MS: m / z 229.0 [M+2H] + 。

[0319] Preparation 3: 4-Bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

[0320]

[0321] Sodium hydride (60% w / w, 7.90 g, 198 mmol) was suspended in THF (290 mL) under nitrogen and cooled to below 4 °C in an ice bath. 4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (14.0 g, 61.7 mmol) was dissolved in THF (290 mL) and added dropwise over 30 min (gas evolution was observed and an exotherm caused the reaction temperature to rise to 5 °C). The maroon mixture was stirred at RT for 45 min, then cooled to 3 °C. 4-Methylbenzenesulfonyl chloride (15.7 g, 82.1 mmol) was dissolved in THF (290 mL) and added dropwise. The resulting grey suspension was stirred under cooling for 1.5 hr, then at RT for 1 hr. TLC (3:2 heptane / ethyl acetate) indicated no remaining SM. The reaction mixture was quenched by dropwise addition of saturated NH4Cl (300 mL). The mixture was stirred for 5 min, then the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 300 mL). The combined organics were washed (brine), dried (MgSO4), filtered and evaporated to an oil which crystallized on cooling to give a light brown solid (26.2 g, 99%). The material was used directly in the preparation of 4 without further purification.

[0322] HPLC t R (Agilent, acidic, 3.5 min): 1.94 min, m / z = 383.1 [M+2H] + 。

[0323] Preparation 4: 4-Bromo-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0324]

[0325] 4-Bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (26.2 g, 65.3 mmol) was suspended in ethanol (50 mL) and hydrogen bromide (48% w / w, 280 mL) was added in a steady stream. The resulting mixture was heated at 90 °C. After 2 h, TLC (3:2 heptane / ethyl acetate) indicated no remaining SM. The reaction mixture was cooled to RT, then cooled in an ice bath and stirred for 30 min. The mixture was filtered, and the off-white solid was collected and washed with water. The solid was dried in vacuo at 50 °C overnight (22.5 g, 94%). The material was used directly in the preparation of 5 without further purification.

[0326] HPLC t R (Agilent, acidic, 3.5 min): 1.59 min, m / z = 369.0 [M+2H] + 。

[0327] Preparation 5: 4-Bromo-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0328]

[0329] 4-Bromo-1-(tosyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (22.5 g, 61.3 mmol) was dissolved in DMF (225 mL) under nitrogen. The mixture was cooled to 3 °C and sodium hydride (60% w / w, 3.06 g, 76.6 mmol) was added in portions, evolving gas and exotherming to 5 °C. The mixture was stirred for 20 min under cooling. After the evolution of gas ceased, methyl iodide (7.63 mL, 123 mmol) was added dropwise, exotherming and raising the reaction temperature to 10 °C. The mixture was stirred for 15 min under cooling and then for 15 min at RT. After 2 h, LCMS indicated no remaining SM. The reaction mixture was quenched by dropwise addition of water (100 mL, evolving gas and exotherming to 39 °C). The mixture was extracted with ethyl acetate (3 x 300 mL). The combined organics were washed (brine), dried (Na2SO4), filtered and evaporated. The crude product was triturated with TBME and filtered. The collected off-white solid was washed with TBME and dried in vacuo (15 g, 64%).

[0330] HPLC t R (Agilent, basic, 6.0 min): 4.0 min, m / z = 382.9 [M+H] + 。

[0331] Preparation 6: 6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(tosyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0332]

[0333] To a flask containing XPhos (625.22 mg, 1.31 mmol), 4-bromo-6-methyl-1-(tosyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (5 g, 13.1 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.66 g, 26.23 mmol) and potassium acetate (2.83 g, 28.85 mmol) was added 1,4-dioxane (100 mL) and the suspension was degassed for 10 min. Pd2(dba)3 (300 mg, 0.32 mmol) was added and the mixture was degassed for more than 1 min. The reaction was heated at 80 °C overnight. The reaction was diluted with ethyl acetate and washed with 50% brine. The organic matter was dried, filtered and concentrated to a yellow / brown oil. The product was purified by flash chromatography on silica gel (80 g), eluting with an ethyl acetate / heptane gradient (0%-80%). The fractions corresponding to the product were combined and concentrated to give a yellow solid (3.4 g, 55%).

[0334] HPLC t R (Agilent, acidic, 3.5 min): 1.93 min, m / z = 429.2 [M+H] + 。

[0335] Preparation 7: 1-Methoxy-3-nitro-2-phenoxybenzene

[0336]

[0337] Phenol (2.3 g, 24.10 mmol) and potassium tert-butoxide (2.7 g, 24.10 mmol) were dissolved in DMF (40 mL) and stirred at RT for 30 min, then 2-fluoro-1-methoxy-3-nitro-benzene (3.75 g, 21.91 mmol) was added. The reaction mixture was heated to 80 °C and stirred overnight. The reaction mixture was concentrated in vacuo, then redissolved in ethyl acetate and washed with water. The organic phase was dried over MgSO4 and evaporated in vacuo. The crude material was purified by column chromatography (heptane containing 0%-100% ethyl acetate) to give 1-methoxy-3-nitro-2-phenoxy-benzene as a yellow solid (5.4 g, 90%).

[0338] 11H NMR (500 MHz, CDCl3) δ 7.55 (dd, J = 1.4, 8.3 Hz, 1H), 7.35 - 7.30 (m, 3H), 7.24 (dd, J = 1.4, 8.4 Hz, 1H), 7.11 - 7.05 (m, 1H), 6.89 - 6.87 (m, 2H), 3.93 (s, 3H).

[0339] Preparation 8: 3-Methoxy-2-phenoxyaniline

[0340]

[0341] A solution of iron (7.37 g, 132.12 mmol) in acetic acid (12 mL) / ethanol (30 mL) was degassed with nitrogen for 5 min. 1-Methoxy-3-nitro-2-phenoxy-benzene (5.4 g, 22.02 mmol) was added and the reaction was heated to 70 °C. After 5 min, the orange solution turned black. After 4 h, the reaction was cooled and the solvent removed. DCM was added and the organic layer was washed with sodium bicarbonate, filtered through a hydrophobic frit and concentrated. The crude product was purified by column chromatography (ethyl acetate / heptane gradient 0% - 100%). The fractions corresponding to the product were combined and concentrated to afford 3-methoxy-2-phenoxyaniline as a brown solid (830 mg, 15%).

[0342] HPLC t R (Agilent, acidic, 3.5 min): 1.53 min, m / z = 216.2 [M + H] + .

[0343] Preparation 9: 1-Iodo-3-methoxy-2-phenoxybenzene

[0344]

[0345] To a solution of 3-methoxy-2-phenoxyaniline (770 mg, 3.57 mmol) in MeCN (21 mL) and water (12 mL) was added p-toluenesulfonic acid monohydrate (2.0 g, 10.72 mmol) and the reaction mixture was stirred vigorously. A solution of potassium iodide (1.48 g, 8.93 mmol) and sodium nitrite (0.49 g, 7.13 mmol) in water (12 mL) was added dropwise over 10 min. The solution turned brown and was stirred for 1 hr. Then saturated sodium bicarbonate solution was added to the solution until pH 8 was reached. Then 1 M sodium thiosulfate solution was added. The product was extracted into DCM and the organic layer was collected via a phase separator and concentrated. The product was purified by flash chromatography on silica gel (12 g), eluting with an ethyl acetate / heptane gradient (0%-40%). The fractions corresponding to the product were combined and concentrated to afford 1-iodo-3-methoxy-2-phenoxybenzene (740 mg, 57%).

[0346] 1 H NMR (500 MHz, CDCl3) δ 7.43 (dd, J = 1.4, 8.3 Hz, 1H), 7.34 - 7.28 (m, 3H), 7.10–7.04 (m, 1H), 6.99 (dd, J = 1.4, 8.4 Hz, 1H), 6.88 - 6.85 (m, 2H), 3.93 (s, 3H).

[0347] Preparation 10: 4-(3-Methoxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0348]

[0349] In a microwave tube, 1-iodo-3-methoxy-2-phenoxybenzene (83.7 mg, 0.25 mmol), sodium carbonate (81.6 mg, 0.77 mmol), and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.25 mmol) in 1,2-dimethoxyethane (2 mL) and water (1 mL) were degassed by bubbling nitrogen for 10 min. Pd(PPh3)4 (14.83 mg, 0.013 mmol) was added, the tube was sealed, and the reaction was heated at 120 °C for 30 min. NaOH (53 mg, 1.25 mmol) was added and the reaction was heated at 120 °C for 1 h. Ethyl acetate (50 mL) was added, and the organic matter was washed successively with 2 x 50 mL of water and 1 x 50 mL of saturated brine solution. The organic matter was then separated and dried (MgSO4), and then concentrated to dryness. The crude product was then purified by flash column chromatography, eluting with an ethyl acetate / heptane gradient (0%-100%). The desired fractions were combined and dried to give 4-(3-methoxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (22 mg, 26%) as a white solid.

[0350] HPLC t R (Agilent, acidic, 3.5 min): 1.62 min, m / z = 347.5 [M+H] + 。

[0351] Preparation 11: 4-(3-Hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0352]

[0353] 4-(3-Methoxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (21 mg, 0.06 mmol) was dissolved in DCM (2 mL) and cooled to -78 °C, then BBr3 (74 mg, 0.29 mmol) was added. The reaction temperature was maintained for 1 hr, then warmed to 0 °C and stirred for an additional 1 hour. The reaction mixture was quenched with water and the pH was adjusted to 8 with saturated aqueous NaHCO3. The reaction mixture was extracted with ethyl acetate. The combined organic layers were separated, passed through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography (0%-50% 20% MeOH / DCM in DCM), followed by purification by reverse phase preparative HPLC (Gilson acidic 60%-90% gradient). The fractions were concentrated overnight on a genevac to afford 4-(3-hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as a white solid (17 mg, 85%).

[0354] HPLC t R (Agilent, acidic, 3.5 min): 1.43 min, m / z = 333.2 [M+H] + 。

[0355] 1 1H NMR (500 MHz, CDCl3) δ 10.36 - 10.30 (m, 1H), 7.26 - 7.20 (m, 2H), 7.15 - 7.06 (m, 4H), 6.89 - 6.85 (m, 2H), 6.68 - 6.64 (m, 2H), 6.39 (dd, J = 2.4, 2.4 Hz, 1H), 6.29 (s, 1H), 3.53 (s, 3H).

[0356] Example 2: 4-(4-Hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0357] Preparation 12: 4-Methoxy-1-nitro-2-phenoxybenzene

[0358]

[0359] Following the procedure in Preparation 7, 2-Fluoro-4-methoxy-1-nitrobenzene (400 mg, 2.34 mmol) was reacted to afford the title compound (541 mg, 85%).

[0360] 11H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 9.2 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.09 - 7.07 (m, 2H), 6.70 (dd, J = 2.7, 9.2 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 3.81 (s, 3H).

[0361] Preparation 13: 4-Methoxy-2-phenoxyaniline

[0362]

[0363] Following the procedure in Preparation 8, 4-methoxy-1-nitro-2-phenoxybenzene (525 mg, 2.14 mmol) was reacted to give the title compound (366 mg, 71%).

[0364] 1 1H NMR (500 MHz, CDCl3) δ 7.35 - 7.31 (m, 2H), 7.08 (t, J = 7.4 Hz, 1H), 7.02 - 7.00 (m, 2H), 6.71 - 6.69 (m, 2H), 6.60 (dd, J = 2.5, 6.9 Hz, 1H), 3.92 (s, 3H), 3.90 (bs, 2H).

[0365] Preparation 14: 1-Iodo-4-methoxy-2-phenoxybenzene

[0366]

[0367] Following the procedure in Preparation 9, 4-methoxy-2-phenoxyaniline (366 mg, 1.70 mmol) was reacted to give the title compound (197 mg, 35%).

[0368] 1 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.34 (m, 2H), 7.29 - 7.23 (m, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 7.7 Hz, 2H), 6.63 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 3.96 (s, 3H).

[0369] Preparation 15: 4-(4-Methoxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0370]

[0371] Following the procedure in Preparation 10, 1-iodo-4-methoxy-2-phenoxybenzene (198 mg, 0.61 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (260 mg, 0.61 mmol) were reacted to give the title compound (182 mg, 86%).

[0372] HPLC t R (Agilent, acidic, 3.5 min): 1.59 min, m / z = 347.2 [M+H] + 。

[0373] Preparation 16: 4-(4-Hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0374]

[0375] Following the procedure in Preparation 11, 4-(4-methoxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (94 mg, 0.27 mmol) was reacted to give the title compound (41 mg, 43%).

[0376] HPLC t R (Agilent, acidic, 3.5 min): 1.48 min, m / z = 333.2 [M+H] + 。

[0377] 1 1H NMR (500 MHz, DMSO-d6) δ 11.82 (s, 1H), 9.89 (bs, 1H), 7.25 (dd, J = 7.4, 8.6 Hz, 2H), 7.18 - 7.12 (m, 2H), 7.00 (s, 2H), 6.84 (d, J = 7.6 Hz, 2H), 6.75 (d, J = 7.8 Hz, 1H), 6.35 (d, J = 8.1 Hz, 1H), 6.00 (d, J = 2.6 Hz, 1H), 3.46 (s, 3H).

[0378] Example 3: 4-(2-Hydroxy-6-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0379] Preparation 17: 1-Fluoro-3-methoxy-2-nitrobenzene

[0380]

[0381] Following the procedure in Preparation 7, 1-fluoro-3-methoxy-2-nitrobenzene (400 mg, 2.34 mmol) was reacted to afford the title compound (565 mg, 89%).

[0382] 1 H NMR (500 MHz, CDCl3) δ 7.41 - 7.37 (m, 2H), 7.30 (dd, J = 7.4, 7.4 Hz, 1H), 7.21 (dd, J = 7.4, 7.4 Hz, 1H), 7.11 - 7.09 (m, 2H), 6.76 (d, J = 7.8 Hz, 1H), 6.53 (d, J = 8.5 Hz, 1H), 3.95 (s, 3H).

[0383] Preparation 18: 2-Methoxy-6-phenoxyaniline

[0384]

[0385] Following the procedure in Preparation 8, 1-methoxy-2-nitro-3-phenoxybenzene (565 mg, 2.30 mmol) was reacted to afford the title compound (350 mg, 64%).

[0386] 1 H NMR (500 MHz, CDCl3) δ 7.36 - 7.32 (m, 2H), 7.09 (dd, J = 7.3, 7.3 Hz, 1H), 7.02 - 7.00 (m, 2H), 6.80 (d, J = 8.7 Hz, 1H), 6.62 (dd, J = 2.7, 8.7 Hz, 1H), 6.52 (d, J = 2.7 Hz, 1H), 3.72 (s, 3H), 3.61 - 3.51 (m, 2H).

[0387] Preparation 19: 2-Iodo-1-methoxy-3-phenoxybenzene

[0388]

[0389] Following the procedure in Preparation 9, 2-methoxy-6-phenoxyaniline (350 mg, 1.63 mmol) was reacted to afford the title compound (324 mg, 55%).

[0390] 1 H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.6 Hz, 1H), 7.29 - 7.25 (m, 2H), 7.05 (dd, J = 7.4, 7.4 Hz, 1H), 6.91 (d, J = 7.6 Hz, 2H) 6.45 - 6.39, (m, 2H), 3.64 (s, 3H).

[0391] Preparation 20: 4-(2-Methoxy-6-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0392]

[0393] Following the procedure in Preparation 10, 2-iodo-1-methoxy-3-phenoxybenzene (320 mg, 0.98 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (420 mg, 0.98 mmol) were reacted to afford the title compound (143 mg, 42%).

[0394] HPLC t R (Agilent, acidic, 3.5 min): 1.65 min, m / z = 347.2 [M+H] + .

[0395] Preparation 21: 4-(2-Hydroxy-6-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0396]

[0397] Following the procedure in Preparation 12, 4-(2-methoxy-6-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (190 mg, 0.55 mmol) was reacted to afford the title compound (32 mg, 16%).

[0398] HPLC t R (Agilent, acidic, 3.5 min): 1.40 min, m / z = 333.2 [M+H] + .

[0399] 1 H NMR (500 MHz, DMSO-d6) δ 11.93 (d, J = 0.9 Hz, 1H), 9.64 (s, 1H), 7.33 - 7.22 (m, 4H), 7.13 (s, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 7.8 Hz, 2H), 6.64 (dd, J = 2.4, 8.3 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.22 - 6.21 (m, 1H), 3.49 (s, 3H).

[0400] Example 4: 6-Methyl-4-(4-phenoxythiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0401] Preparation 22: 4-Phenoxythiazole

[0402]

[0403] CuI (58.0 mg, 0.30 mmol), picolinic acid (75.0 mg, 0.61 mmol), phenol (0.31 mL, 3.66 mmol), and tripotassium phosphate (1.3 g, 6.1 mmol) were added to an oven-dried microwave vial. The tube was then evacuated and backfilled with N2 twice. 4-Bromo-thiazole (500 mg, 3.0 mmol) in DMSO (10 mL) was added and the mixture was heated at 150 °C for 1 h. DMSO was removed using a Genevac EZ-2. Ethyl acetate (50 mL) was added to the residue and the organic layer was washed successively with 2 x 50 mL of water and 1 x 50 mL of saturated brine solution. The organic layer was then separated and dried (MgSO4), and then concentrated to dryness. The crude product was purified by flash chromatography on silica gel, eluting with an ethyl acetate / heptane gradient (0%-100%). The fractions corresponding to the product were combined and concentrated to give the title compound as a yellow solid (93 mg, 17%).

[0404] HPLC t R (Agilent, acidic, 3.5 min): 1.54 min, m / z = 177.9 [M+H] + 。

[0405] Preparation 23: 5-Bromo-4-phenoxythiazole

[0406]

[0407] 4-Phenoxythiazole (60 mg, 0.34 mmol) in MeCN (2 mL) was cooled to 0 °C. 1-Bromopyrrolidine-2,5-dione (72 mg, 0.41 mmol) in MeCN (2 mL) was added dropwise. The reaction was warmed to RT and left for 3 h. Ethyl acetate (50 ml) was added and the organic layer was washed successively with 2 x 50 ml of saturated sodium carbonate and 1 x 50 ml of saturated brine solution. The organic layer was then separated and dried (MgSO4), and then concentrated to dryness to give the title compound (75 mg, 87%). The material was used directly in Preparation 27 without further purification. HPLC t R (Agilent, acidic, 3.5 min): 1.71 min, m / z = 257.7 [M+H] + 。

[0408] Preparation 24: 6-Methyl-4-(4-phenoxythiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0409]

[0410] Following the procedure in Preparation 10, 5-bromo-4-phenoxythiazole (72 mg, 0.28 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.26 mmol) were reacted to afford the title compound (10 mg, 12%).

[0411] HPLC t R (Agilent, acidic, 3.5 min): 1.43 min, m / z = 324.2 [M+H] + .

[0412] 1 H NMR (500 MHz, DMSO-d6) δ 12.20 (bs, 1H), 9.02 (s, 1H), 7.52 (s, 1H), 7.36 - 7.31 (m, 3H), 7.09 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.9 Hz, 2H), 6.44 (s, 1H), 3.53 (s, 3H).

[0413] Example 5: 6-Methyl-4-(1-methyl-2-oxo-3-phenoxypyridin-4-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0414] Preparation 25: 4-Nitro-3-phenoxypyridine 1-oxide

[0415]

[0416] Sodium hydride (278 mg, 6.96 mmol) in DMF (5 mL) was cooled to 0 °C. Phenol (0.58 mL, 6.96 mmol) in DMF (5 mL) was added and the mixture was stirred at this temperature for 10 min, then 1-oxido-3-fluoro-4-nitropyridine (1.0 g, 6.3 mmol) in DMF (5 mL) was added. The reaction was warmed to RT within 30 min. The reaction mixture was stirred with ice water and extracted with DCM. The organic extract was washed with water and saturated sodium chloride solution, dried (MgSO4), filtered and concentrated to give 1-oxido-4-nitro-3-phenoxypyridine as a waxy solid (1.1 g, 74.9%). The material was used directly for the preparation of 29 without further purification.

[0417] HPLC t R (Agilent, acidic, 3.5 min): 1.72 min, m / z = 233.4 [M+H] + 。

[0418] Preparation of 26: 1-oxido-4-bromo-3-phenoxypyridine

[0419]

[0420] 1-Oxido-4-nitro-3-phenoxypyridine (1.1 g, 4.74 mmol) in acetyl bromide (3.51 mL, 47.4 mmol) was refluxed with stirring for 2 h. After cooling to ambient temperature, the mixture was poured onto ice and stirred vigorously. Saturated sodium carbonate was added carefully to bring the solution to pH 10. The organic extract was washed with water and saturated sodium chloride solution, dried (MgSO4), filtered and concentrated. Purification was carried out by silica gel chromatography, eluting with an ethyl acetate / heptane gradient (0%-100%) to give the title product 1-oxido-4-bromo-3-phenoxypyridine (870 mg, 62%).

[0421] HPLC t R (Agilent, acidic, 3.5 min): 1.55 min, m / z = 267.9 [M+H] + 。

[0422] Preparation of 27: 4-bromo-3-phenoxypyridine

[0423]

[0424] Cool 1-bromo-3-phenoxy-4-pyridine N-oxide (715 mg, 2.69 mmol) in chloroform (20 mL) to 0 °C. Add dropwise PBr3 (1.2 g, 3.23 mmol) in chloroform (20 mL), then warm to 50 °C and hold for 1 hr. Concentrate the reaction to dryness and dissolve the residue in ethyl acetate (50 mL). Wash the organic layer successively with 2 x 50 mL water and 1 x 50 mL saturated brine solution. Then separate and dry the organic layer (MgSO4), then concentrate to dryness. Then purify the crude mixture by flash column chromatography, eluting with an ethyl acetate / heptane gradient (0%-100%). Concentrate the desired fractions to dryness in vacuo to afford 4-bromo-3-phenoxy-pyridine (500 mg, 74%).

[0425] HPLC t R (Agilent, acidic, 3.5 min): 1.61 min, m / z = 249.8 [M] + 。

[0426] Preparation 28: 4-Bromo-1-methyl-3-phenoxypyridin-2(1H)-one

[0427]

[0428] In a sealable tube, add dimethyl sulfate (2.0 mL, 21.1 mmol) to 4-bromo-3-phenoxy-pyridine (528 mg, 2.11 mmol) in MeCN (10 mL) and heat the mixture at 80 °C for 30 min. Add additional dimethyl sulfate (7.0 mL, 73.9 mmol) and heat the mixture at 80 °C for 16 hr. Cool the mixture to 0 °C on ice and add potassium ferricyanide (1.74 g, 5.28 mmol) in water (5 mL), then add dropwise potassium hydroxide (948 mg, 16.9 mmol) in water (5 mL) and stir at 80 °C for 16 hr. Add DCM and water and pass through a phase separator. Dry the organic layer and purify the residue by column chromatography, eluting with an ethyl acetate / heptane gradient (0%-100%). Concentrate the desired fractions to dryness in vacuo to afford 4-bromo-1-methyl-5-phenoxypyridin-2(1H)-one (45 mg, 7.6%).

[0429] HPLC t R (Agilent, acidic, 3.5 min): 1.42 min, m / z = 281.0 [M+H] + 。

[0430] Preparation 29: 6-Methyl-4-(1-methyl-2-oxo-3-phenoxy-1,2-dihydropyridin-4-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0431]

[0432] Following the procedure in Preparation 10, 4-bromo-1-methyl-5-phenoxypyridin-2(1H)-one (45 mg, 0.16 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (65 mg, 0.15 mmol) were reacted to afford the title compound (6 mg, 11%).

[0433] HPLC t R (Agilent, acidic, 3.5 min): 1.17 min, m / z = 348.1 [M+H] + 。

[0434] 1 H NMR (500 MHz, DMSO-d6) δ 12.08 (bs, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.18 (dd, J = 7.9, 7.9 Hz, 2H), 6.90 (dd, J = 7.4, 7.4 Hz, 1H), 6.71 (d, J = 7.8 Hz, 2H), 6.41 (d, J = 7.0 Hz, 1H), 6.31 (dd, J = 2.3, 2.3 Hz, 1H), 3.53 (s, 3H), 3.47 (s, 3H).

[0435] Example 6: 4-(5-Hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0436] Preparation 30: 4-Methoxy-2-nitro-1-phenoxybenzene

[0437]

[0438] Following the procedure in Preparation 7, 1-fluoro-4-methoxy-2-nitrobenzene (1.2 g, 7.01 mmol) was reacted to afford the title compound (1.50 mg, 87%).

[0439] HPLC t R (Agilent, acidic, 3.5 min): 1.79 min, m / z = 246.1 [M+H] + 。

[0440] Preparation 31: 5-Methoxy-2-phenoxyaniline

[0441]

[0442] Following the procedure in Preparation 8, 4-Methoxy-2-nitro-1-phenoxybenzene (1.80 g, 5.38 mmol) was reacted to give the title compound (1.23 g, 64%).

[0443] HPLC t R (Agilent, acidic, 3.5 min): 1.64 min, m / z = 216.1 [M+H] + 。

[0444] Preparation 32: 2-Iodo-4-methoxy-1-phenoxybenzene

[0445]

[0446] Following the procedure in Preparation 9, 5-Methoxy-2-phenoxyaniline (1.23 g, 5.71 mmol) was reacted to give the title compound (mg, 10%).

[0447] 1 1H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 2.9 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.10 - 7.03 (m, 1H), 6.96 - 6.91 (m, 4H), 3.83 (s, 3H).

[0448] Preparation 33: 4-(5-Methoxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0449]

[0450] Following the procedure in Preparation 10, 2-Iodo-4-methoxy-1-phenoxybenzene (152 mg, 0.47 mmol) and 6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.47 mmol) were reacted to give the title compound (88 mg, 39%).

[0451] HPLC t R (Agilent, acidic, 3.5 min): 1.65 min, m / z = 347.2 [M+H] + 。

[0452] Preparation 34: 4-(5-Hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0453]

[0454] Following the procedure in Preparation 11, 4-(5-Methoxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (85 mg, 0.25 mmol) was reacted to afford the title compound (50 mg, 58%).

[0455] HPLC t R (Agilent, acidic, 3.5 min): 1.46 min, m / z = 333.2 [M+H] + 。

[0456] 1 1H NMR (^{500}MHz, DMSO-d6) δ 11.97 (s, 1H), 9.47 (s, 1H), 7.26 (dd, J = 2.7, 2.7 Hz, 1H), 7.21 - 7.17 (m, 3H), 6.96 - 6.89 (m, 3H), 6.79 (dd, J = 2.9, 8.7 Hz, 1H), 6.73 (d, J = 7.6 Hz, 2H), 6.25 - 6.23 (m, 1H), 3.46 (s, 3H).

[0457] Example 7: 6-Methyl-4-(1-methyl-2-oxo-5-phenoxy-1,2-dihydropyridin-4-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0458] Preparation 35: 1-Oxo-2-chloro-4-nitro-5-phenoxypyridine

[0459]

[0460] To a solution of 2-chloro-5-fluoro-4-nitropyridine 1-oxide (2.00 g, 10.4 mmol) in THF (100 mL) at 20 °C was added K2CO3 (2.87 g, 20.8 mmol); phenol (1.03 g, 10.9 mmol), and the reaction was stirred at 90 °C for 1 h. The reaction was concentrated in vacuo, and the residue was diluted with saturated NaHCO3 (100 mL). The reaction mixture was extracted with DCM (100 mL × 2), and the combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to afford the title compound as a yellow solid (950 mg, 3.56 mmol, yield = 34.3%).

[0461] HPLC t R (Agilent, acidic, 3.5 min): 1.47 min, m / z = 267.0 [M+H] + 。

[0462] Preparation 36: 2,4-Dibromo-5-phenoxypyridine 1-oxide

[0463]

[0464] Following the procedure in Preparation 26, 2-chloro-4-nitro-5-phenoxypyridine 1-oxide (950 mg, 3.56 mmol) was reacted to afford the title compound (1.2 g, 98%).

[0465] HPLC t R (Agilent, acidic, 3.5 min): 1.49 min, m / z = 345.9 [M+H] + 。

[0466] Preparation 37: 2,4-Dibromo-5-phenoxypyridine

[0467]

[0468] Following the procedure in Preparation 27, 2,4-dibromo-5-phenoxypyridine 1-oxide (1.3 g, 3.77 mmol) was reacted to afford the title compound (1.1 g, 89%).

[0469] HPLC t R (Agilent, acidic, 3.5 min): 1.91 min, m / z = 330.0 [M+H] + 。

[0470] Preparation 38: 4-Bromo-5-phenoxypyridin-2(1H)-one

[0471]

[0472] At 20 °C, KOH (699 mg, 12.5 mmol) was added to a solution of 2,4-dibromo-5-phenoxypyridine (1.28 g, 3.9 mmol) in t-BuOH (30 mL). The reaction mixture was stirred at 90 °C for 12 h. The reaction was concentrated in vacuo. The residue was diluted with H2O (100 mL) and extracted with DCM (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (TFA conditions) to give the title compound as a yellow solid (80 mg, 0.3 mmol, yield = 7.8%).

[0473] HPLC t R (Agilent, acidic, 3.5 min): 1.39 min, m / z = 267.1 [M+H] + 。

[0474] Preparation 39: 4-Bromo-1-methyl-5-phenoxypyridin-2(1H)-one

[0475]

[0476] At 20 °C, MeI (65.1 mg, 0.46 mmol, 2.52 mL) and Cs2CO3 (224.1 mg, 0.69 mmol) were added to a solution of 4-bromo-5-phenoxypyridin-2(1H)-one (61 mg, 0.23 mmol) in DMF (3.0 mL). The reaction was stirred at 20 °C for 1 h. H2O (100 mL) was added to this reaction and it was extracted with DCM (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (TFA conditions) to give 4-bromo-1-methyl-5-phenoxypyridin-2(1H)-one as a yellow solid (63 mg, 0.23 mmol, yield = 98%).

[0477] HPLC t R (Agilent, acidic, 3.5 min): 1.45 min, m / z = 281.0 [M+H] + 。

[0478] Preparation 40: 6-Methyl-4-(1-methyl-2-oxo-5-phenoxy-1,2-dihydropyridin-4-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0479]

[0480] Following the procedure in Preparation 10, 4-bromo-1-methyl-5-phenoxypyridin-2(1H)-one (65 mg, 0.23 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (99 mg, 0.23 mmol) were reacted to afford the title compound (23 mg, 24%).

[0481] HPLC t R (Agilent, acidic, 3.5 min): 1.26 min, m / z = 348.2 [M+H] + 。

[0482] 1 H NMR (500 MHz, DMSO-d6) δ 12.04 (bs, 1H), 7.86 (s, 1H), 7.37 (s, 1H), 7.29 (t, J = 2.8 Hz, 1H), 7.19 - 7.14 (m, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.79 - 6.76 (m, 2H), 6.54 (s, 1H), 6.34 (t, J = 2.4 Hz, 1H), 3.48 (s, 3H), 3.45 (s, 3H).

[0483] Example 8: 5-(5-Hydroxy-2-phenoxyphenyl)-1-methylpyridin-2(1H)-one

[0484] Preparation 41: 5-(5-Methoxy-2-phenoxyphenyl)-1-methylpyridin-2(1H)-one

[0485]

[0486] In a microwave tube, 2-iodo-4-methoxy-1-phenoxybenzene (90 mg, 0.28 mmol), sodium carbonate (81.6 mg, 0.77 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (84 mg, 0.36 mmol) in 1,2-dimethoxyethane (2 mL) and water (1 mL) were degassed by bubbling nitrogen for 10 min. Pd(PPh3)4 (14.83 mg, 0.013 mmol) was added, the tube was sealed, and the reaction was heated at 120 °C for 30 min. Ethyl acetate (50 mL) was added, and the organic matter was washed successively with 2 x 50 mL water and 1 x 50 mL saturated brine solution. Then the organic matter was separated and dried (MgSO4), and then concentrated to dryness. The crude product was then purified by flash column chromatography, eluting with an ethyl acetate / heptane gradient (0%-100%). The desired fractions were combined and dried to give the title compound as a white solid (45 mg, 48%).

[0487] HPLC t R (Agilent, acidic, 3.5 min): 1.58 min, m / z = 308.2 [M+H] + 。

[0488] Preparation 42: 5-(5-Hydroxy-2-phenoxyphenyl)-1-methylpyridin-2(1H)-one

[0489]

[0490] Following the procedure in Preparation 11, 5-(5-methoxy-2-phenoxyphenyl)-1-methylpyridin-2(1H)-one (45 mg, 0.15 mmol) was reacted to give the title compound (26 mg, 55%).

[0491] HPLC t R (Agilent, acidic, 3.5 min): 1.43 min, m / z = 294.2 [M+H] + 。

[0492] 1 1H NMR (500 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.55 - 7.53 (m, 1H), 7.29 - 7.25 (m, 2H), 7.00 - 6.90 (m, 2H), 6.85 - 6.76 (m, 4H), 6.33 (d, J = 9.5 Hz, 1H), 3.42 (s, 3H).

[0493] Example 9: 4-(5-Hydroxy-2-propoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0494] Preparation 43: 1-Fluoro-4-((4-methoxybenzyl)oxy)-2-nitrobenzene

[0495]

[0496] To a solution of 4-fluoro-3-nitrophenol (2.30 g, 14.6 mmol) in DMF (20.0 mL) at 20 °C was added potassium tert-butoxide (1.97 g, 17.6 mmol) and the mixture was stirred for 15 minutes. 1-(Chloromethyl)-4-methoxybenzene (2.7 mL, 19.0 mmol) was added and the reaction was stirred at 20 °C for 1.5 h. The reaction was concentrated in vacuo. The residue was dissolved in EtOAc (2 x 400 mL) and washed with H2O (300 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1-fluoro-4-((4-methoxybenzyl)oxy)-2-nitrobenzene as a yellow solid (2.52 g, 8.64 mmol, yield = 59%).

[0497] 1 1H NMR (400 MHz, CDCl3) δ 7.63 - 7.60 (m, 1H), 7.36 - 7.33 (m, 2H), 7.22 - 7.18 (m, 2H), 6.96 - 6.91 (m, 2H), 5.02 (s, 2H), 3.83 (s, 3H).

[0498] Preparation 44: 4-((4-Methoxybenzyl)oxy)-2-nitro-1-propoxybenzene

[0499]

[0500] To a solution of 1-fluoro-4-((4-methoxybenzyl)oxy)-2-nitrobenzene (750 mg, 2.7 mmol) in DMF (10 mL) at 20 °C was added sodium hydride (194 mg, 8.1 mmol) and the mixture was stirred for 30 minutes. 1-Propanol (0.6 mL, 8.1 mmol) was added and the reaction was stirred at 20 °C for 20 minutes. The reaction was concentrated in vacuo. The residue was dissolved in EtOAc (2 x 100 mL) and washed with H2O (100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 4-((4-methoxybenzyl)oxy)-2-nitro-1-propoxybenzene as a yellow solid (710 mg, 2.13 mmol, yield = 79%).

[0501] 1 1H NMR (500 MHz, CDCl3) δ 7.45 - 7.44 (m, 1H), 7.36 - 7.32 (m, 2H), 7.13 (dd, J = 3.2, 9.2 Hz, 1H), 7.01 - 6.91 (m, 3H), 4.98 (s, 2H), 4.01 (t, J = 6.4 Hz, 2H), 3.83 (s, 3H), 1.84 (tt, J = 8.2, 8.8 Hz, 2H), 1.05 (t, J = 7.6 Hz, 3H).

[0502] Preparation 45: 5 - ((4 - Methoxybenzyl)oxy)-2 - propoxyaniline

[0503]

[0504] Following the procedure in Preparation 8, 4 - ((4 - Methoxybenzyl)oxy)-2 - nitro - 1 - propoxybenzene (710 mg, 2.23 mmol) was reacted to afford the title compound (495 mg, 73%).

[0505] HPLC t R (Agilent, acidic, 3.5 min): 1.73 min, m / z = 288.2 [M + H] + .

[0506] Preparation 46: 2 - Iodo - 4 - ((4 - Methoxybenzyl)oxy)-1 - propoxybenzene

[0507]

[0508] Following the procedure in Preparation 9, 5 - ((4 - Methoxybenzyl)oxy)-2 - propoxyaniline (495 mg, 1.73 mmol) was reacted to afford the title compound (360 mg, 50%).

[0509] 1 1H NMR (500 MHz, DMSO - d6) δ 7.41 (d, J = 2.9 Hz, 1H), 7.34 - 7.31 (m, 2H), 6.92 - 6.87 (m, 3H), 6.72 (d, J = 9.6 Hz, 1H), 4.91 (s, 2H), 3.90 (t, J = 6.4 Hz, 2H), 3.81 (s, 3H), 1.82 (tdt, J = 6.7, 6.7, 6.8 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H).

[0510] Preparation 47: 4-(5-((4-Methoxybenzyl)oxy)-2-propoxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0511]

[0512] Following the procedure in Preparation 40, 2-Iodo-4-((4-methoxybenzyl)oxy)-1-propoxybenzene (107 mg, 0.27 mmol) and 6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (115 mg, 0.27 mmol) were reacted to give the title compound (93 mg, 54%).

[0513] HPLC t R (Agilent, acidic, 3.5 min): 2.07 min, m / z = 573.3 [M+H] + .

[0514] Preparation 48: 4-(5-Hydroxy-2-propoxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0515]

[0516] To a solution of 4-(5-((4-Methoxybenzyl)oxy)-2-propoxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (90 mg, 0.16 mmol) in DCM (2 mL) at 20 °C was added trifluoroacetic acid (0.072 mL, 0.94 mmol) and the mixture was stirred for 4 h. The reaction was concentrated in vacuo. The residue was dissolved in EtOAc (2 x 100 mL) and washed with H2O (100 mL), the combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 4-((4-Methoxybenzyl)oxy)-2-nitro-1-propoxybenzene as a yellow solid (55 mg, 0.12 mmol, yield = 62%).

[0517] HPLC t R (Agilent, acidic, 3.5 min): 1.72 min, m / z = 453.2 [M+H] + .

[0518] Preparation 49: 4-(5-Hydroxy-2-propoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0519]

[0520] To a solution of 4-(5-hydroxy-2-propoxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (55 mg, 0.12 mmol) in THF (1 mL) and methanol (1 mL) was added sodium hydroxide (25.5 mg, 0.61 mmol) and the reaction mixture was heated to 60 °C and stirred for 4 h. The reaction was concentrated in vacuo. The residue was dissolved in EtOAc (2 x 100 mL) and washed with H2O (100 mL), the combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography (0%-50% 20% MeOH / DCM in DCM) followed by purification by reverse phase preparative HPLC (Gilson acidic 60%-90% gradient). The fractions were concentrated overnight on a genevac to afford 4-((4-methoxybenzyl)oxy)-2-nitro-1-propoxybenzene as a yellow solid (55 mg, 0.10 mmol, yield = 62%).

[0521] HPLC t R (Agilent, acidic, 3.5 min): 1.39 min, m / z = 299.2 [M+H] + 。 [[ID=1,5]]

[0522] 1 1H NMR (500 MHz, CDCl3) δ 10.21 (bs, 1H), 7.22 (s, 1H), 7.16 (t, J = 2.8 Hz, 1H), 7.06 (s, 1H), 6.92 - 6.85 (m, 3H), 6.28 (t, J = 2.5 Hz, 1H), 3.80 (t, J = 6.5 Hz, 2H), 3.67 (s, 3H), 1.61 (dt, J = 7.8, 13.9 Hz, 2H), 0.85 (t, J = 7.8 Hz, 3H).

[0523] Example 10: 4-(2-Cyclobutoxy-5-hydroxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0524] Preparation 50: 1-Cyclobutoxy-4-((4-methoxybenzyl)oxy)-2-nitrobenzene

[0525]

[0526] According to the procedure in Preparation 44, 1-fluoro-4-((4-methoxybenzyl)oxy)-2-nitrobenzene (750 mg, 2.70 mmol) and cyclobutanol (0.64 mL, 9.2 mmol) were reacted to obtain the title compound (601 mg, 64%).

[0527] 1 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 3.1 Hz, 1H), 7.34 - 7.31 (m, 2H), 7.09 (dd, J = 3.2, 9.1 Hz, 1H), 6.93 - 6.83 (m, 3H), 4.96 (s, 2H), 4.71 - 4.64 (m, 1H), 3.82 (s, 3H), 2.47 - 2.39 (m, 2H), 2.29 - 2.18 (m, 2H), 1.91 - 1.83 (m, 1H), 1.73 - 1.61 (m, 1H).

[0528] Preparation 51: 2-Cyclobutyloxy-5-((4-methoxybenzyl)oxy)aniline

[0529]

[0530] According to the procedure in Preparation 44, 1-cyclobutyloxy-4-((4-methoxybenzyl)oxy)-2-nitrobenzene (601 mg, 1.82 mmol) was reacted to obtain the title compound (375 mg, 62%).

[0531] HPLC t R (Agilent, acidic, 3.5 min): 1.76 min, m / z = 300.2 [M + H] + .

[0532] Preparation 52: 1-Cyclobutyloxy-2-iodo-4-((4-methoxybenzyl)oxy)benzene

[0533]

[0534] According to the procedure in Preparation 45, 2-cyclobutyloxy-5-((4-methoxybenzyl)oxy)aniline (375 mg, 1.25 mmol) was reacted to obtain the title compound (360 mg, 67%).

[0535] 11H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 3.0 Hz, 1H), 7.32 (d, J = 8.3 Hz, 2H), 6.92 - 6.84 (m, 3H), 6.60 (d, J = 8.3 Hz, 1H), 4.89 (s, 2H), 4.61 - 4.54 (m, 1H), 3.81 (s, 3H), 2.45 - 2.37 (m, 2H), 2.27 - 2.17 (m, 2H), 1.89 - 1.81 (m, 1H), 1.68 - 1.58 (m, 1H).

[0536] Preparation 53: 4-(2-Cyclobutyloxy-5-((4-methoxybenzyl)oxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0537]

[0538] Following the procedure in Preparation 40, 1-cyclobutyloxy-2-iodo-4-((4-methoxybenzyl)oxy)benzene (119 mg, 0.29 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (125 mg, 0.29 mmol) were reacted to give the title compound (130 mg, 72%).

[0539] HPLC t R (Agilent, acidic, 3.5 min): 2.10 min, m / z = 585.2 [M+H] + .

[0540] Preparation 54: 4-(2-Cyclobutyloxy-5-hydroxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0541]

[0542] Following the procedure in Preparation 48, 4-(2-cyclobutyloxy-5-((4-methoxybenzyl)oxy)phenyl)-6-methyl-1-tosyl- 1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (130 mg, 0.22 mmol) was reacted to give the title compound (75 mg, 58%).

[0543] HPLC t R (Agilent, acidic, 3.5 min): 1.71 min, m / z = 465.2 [M+H] + .

[0544] Preparation 55: 4-(2-Cyclobutoxy-5-hydroxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0545]

[0546] Following the procedure in Preparation 49, 4-(2-Cyclobutoxy-5-hydroxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (74 mg, 0.16 mmol) was reacted to afford the title compound (4 mg, 7%).

[0547] HPLC t R (Agilent, acidic, 3.5 min): 1.38 min, m / z = 311.2 [M+H] + 。

[0548] 1 1H NMR (400 MHz, DMSO) δ 11.94 (s, 1H), 8.97 (s, 1H), 7.27 - 7.25 (m, 1H), 7.18 (s, 1H), 6.77 - 6.74 (m, 1H), 6.73 (s, 1H), 6.66 (dd, J = 2.9, 8.7 Hz, 1H), 6.14 - 6.11 (m, 1H), 4.52 - 4.44 (m, 1H), 3.54 (s, 3H), 2.31 - 2.23 (m, 2H), 1.92 - 1.82 (m, 2H), 1.70 - 1.49 (m, 2H).

[0549] Example 11: 4-(2-(Cyclohexyloxy)-5-hydroxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0550] Preparation 56: 1-(Cyclohexyloxy)-4-((4-methoxybenzyl)oxy)-2-nitrobenzene

[0551]

[0552] Following the procedure in Preparation 44, 1-Fluoro-4-((4-methoxybenzyl)oxy)-2-nitrobenzene (750 mg, 2.70 mmol) and cyclohexanol (0.87 mL, 8.2 mmol) were reacted to afford the title compound (843 mg, 82%).

[0553] 11H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 3.4 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.10 (dd, J = 3.1, 9.2 Hz, 1H), 7.02 (d, J = 9.6 Hz, 1H), 6.95 - 6.90 (m, 2H), 4.97 - 4.96 (m, 2H), 4.28 (tt, J = 4.2, 7.9 Hz, 1H), 3.82 (s, 3H), 1.95 - 1.88 (m, 2H), 1.81 (dd, J = 10.2, 10.2 Hz, 2H), 1.68 - 1.50 (m, 3H), 1.38 - 1.26 (m, 3H).

[0554] Preparation 57: 2-(Cyclohexyloxy)-5-((4-methoxybenzyl)oxy)aniline

[0555]

[0556] Following the procedure in Preparation 44, 1-(Cyclohexyloxy)-4-((4-methoxybenzyl)oxy)-2-nitrobenzene (843 mg, 2.35 mmol) was reacted to afford the title compound (469 mg, 55%).

[0557] HPLC t R (Agilent, acidic, 3.5 min): 1.91 min, m / z = 328.2 [M+H] + .

[0558] Preparation 58: 1-(Cyclohexyloxy)-2-iodo-4-((4-methoxybenzyl)oxy)benzene

[0559]

[0560] Following the procedure in Preparation 45, 2-(Cyclohexyloxy)-5-((4-methoxybenzyl)oxy)aniline (469 mg, 1.43 mmol) was reacted to afford the title compound (350 mg, 52%).

[0561] 1 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 2.9 Hz, 1H), 7.34 - 7.31 (m, 2H), 6.92 - 6.86 (m, 3H), 6.77 (d, J = 9.4 Hz, 1H), 4.91 - 4.90 (m, 2H), 4.18 (tt, J = 3.9, 7.7 Hz, 1H), 3.81 (s, 3H), 1.93 - 1.79 (m, 4H), 1.69 - 1.51 (m, 2H), 1.40 - 1.25 (m, 4H).

[0562] Preparation 59: 4-(2-(Cyclohexyloxy)-5-((4-methoxybenzyl)oxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0563]

[0564] Following the procedure in Preparation 40, 1-(Cyclohexyloxy)-2-iodo-4-((4-methoxybenzyl)oxy)benzene (169 mg, 0.39 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (166 mg, 0.39 mmol) were reacted to give the title compound (107 mg, 43%).

[0565] HPLC t R (Agilent, acidic, 3.5 min): 2.21 min, m / z = 613.3 [M+H] + 。

[0566] Preparation 60: 4-(2-(Cyclohexyloxy)-5-hydroxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0567]

[0568] Following the procedure in Preparation 48, 4-(2-(Cyclohexyloxy)-5-((4-methoxybenzyl)oxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (105 mg, 0.17 mmol) was reacted to give the title compound (58 mg, 62%).

[0569] HPLC t R (Agilent, acidic, 3.5 min): 1.86 min, m / z = 493.3 [M+H] + 。

[0570] Preparation 61: 4-(2-(Cyclohexyloxy)-5-hydroxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0571]

[0572] Following the procedure in Preparation 49, 4-(2-(cyclohexyloxy)-5-hydroxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (58 mg, 0.12 mmol) was reacted to give the title compound (12 mg, 29%).

[0573] HPLC t R (Agilent, acidic, 3.5 min): 1.51 min, m / z = 339.2 [M+H] + 。

[0574] 1 H NMR (400 MHz, DMSO) δ 11.95 (s, 1H), 9.01 (s, 1H), 7.27 - 7.22 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 3.0 Hz, 1H), 6.67 (dd, J = 2.9, 8.7 Hz, 1H), 6.18 - 6.16 (m, 1H), 4.00 - 3.94 (m, 1H), 3.54 (s, 3H), 1.66 - 1.65 (m, 2H), 1.52 - 1.49 (m, 2H), 1.37 (s, 1H), 1.28 - 1.25 (m, 3H), 1.19 - 1.14 (m, 2H)

[0575] Example 12: 4-(5-Hydroxy-2-((4-methoxycyclohexyl)oxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0576] Preparation 62: 4-Methoxycyclohexan-1-ol

[0577]

[0578] To a solution of cyclohexane-1,4-diol (4.6 g, 39.6 mmol) in DMF (15 mL) at 20 °C was added sodium hydride (1.74 g, 43.5 mmol, 60% in oil) and the mixture was stirred for 30 minutes. Iodomethane (0.6 mL, 8.1 mmol) was added and the reaction was stirred at 20 °C for 16 hours. The reaction was concentrated in vacuo. The residue was dissolved in EtOAc (2 x 100 mL) and washed with H2O (100 mL), the combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 4-((4-methoxybenzyl)oxy)-2-nitro-1-propoxybenzene as a colorless oil (845 mg, 5.84 mmol, yield = 15%).

[0579] 11H NMR (400 MHz, CDCl3) δ 3.70 - 3.64 (m, 1H), 3.33 (s, 3H), 3.21 - 3.13 (m, 1H), 2.04 - 1.94 (m, 4H), 1.35 - 1.24 (m, 4H).

[0580] Preparation 63: 4 - ((4 - Methoxybenzyl)oxy)-1 - ((4 - methoxycyclohexyl)oxy)-2 - nitrobenzene

[0581]

[0582] Following the procedure in Preparation 44, 1 - fluoro - 4 - ((4 - methoxybenzyl)oxy)-2 - nitrobenzene (600 mg, 2.2 mmol) and 4 - methoxycyclohexan - 1 - ol (845 mg, 6.5 mmol) were reacted to give the title compound (684 mg, 78%).

[0583] 1 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 3.1 Hz, 1H), 7.38 - 7.34 (m, 2H), 7.14 (dd, J = 3.1, 9.2 Hz, 1H), 7.04 (d, J = 9.3 Hz, 1H), 6.96 - 6.93 (m, 2H), 4.99 (s, 2H), 4.43 - 4.36 (m, 1H), 3.85 (s, 3H), 3.40 - 3.33 (m, 4H), 2.07 - 2.01 (m, 4H), 1.72 - 1.63 (m, 2H), 1.57 - 1.47 (m, 2H).

[0584] Preparation 64: 5 - ((4 - Methoxybenzyl)oxy)-2 - ((4 - methoxycyclohexyl)oxy)aniline

[0585]

[0586] Following the procedure in Preparation 44, 4 - ((4 - methoxybenzyl)oxy)-1 - ((4 - methoxycyclohexyl)oxy)-2 - nitrobenzene (684 mg, 1.76 mmol) was reacted to give the title compound (506 mg, 76%).

[0587] HPLC t R (Agilent, acidic, 3.5 min): 1.67 min, m / z = 358.2 [M + H] + .

[0588] Preparation 65: 2 - Iodo - 4 - ((4 - methoxybenzyl)oxy)-1 - ((4 - methoxycyclohexyl)oxy)benzene

[0589]

[0590] Following the procedure in Preparation 45, 5-((4-methoxybenzyl)oxy)-2-((4-methoxycyclohexyl)oxy)aniline (506 mg, 1.41 mmol) was reacted to give the title compound (170 mg, 23%).

[0591] 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 2.9 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 6.95 - 6.89 (m, 3H), 6.80 (d, J = 9.0 Hz, 1H), 4.93 (s, 2H), 4.30 - 4.24 (m, 1H), 3.84 (s, 3H), 3.37 (s, 4H), 2.12 - 2.01 (m, 4H), 1.71 - 1.44 (m, 4H).

[0592] Preparation 66: 4-(5-((4-methoxybenzyl)oxy)-2-((4-methoxycyclohexyl)oxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0593]

[0594] Following the procedure in Preparation 40, 2-iodo-4-((4-methoxybenzyl)oxy)-1-((4-methoxycyclohexyl)oxy)benzene (169 mg, 0.36 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (155 mg, 0.36 mmol) were reacted to give the title compound (185 mg, 72%).

[0595] HPLC t R (Agilent, acidic, 3.5 min): 1.97 min, m / z = 643.3 [M + H] + .

[0596] Preparation 67: 4-(5-hydroxy-2-((4-methoxycyclohexyl)oxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0597]

[0598] Following the procedure in Preparation 48, 4-(5-((4-methoxybenzyl)oxy)-2-((4-methoxycyclohexyl)oxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (185 mg, 0.29 mmol) was reacted to give the title compound (97 mg, 58%).

[0599] HPLC t R (Agilent, acidic, 3.5 min): 1.63 min, m / z = 523.3 [M+H] + 。

[0600] Preparation 68: 4-(5-Hydroxy-2-((4-methoxycyclohexyl)oxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0601]

[0602] Following the procedure in Preparation 49, 4-(5-Hydroxy-2-((4-methoxycyclohexyl)oxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (94 mg, 0.18 mmol) was reacted to give the title compound (21 mg, 30%).

[0603] HPLC t R (Agilent, acidic, 8 min): 2.95 min, m / z = 369.2 [M+H] + 。

[0604] 1 H NMR (400 MHz, DMSO) δ 11.92 (s, 1H), 8.99 (s, 1H), 7.29–7.23 (m, J = 2.7 Hz, 1H), 7.21 (s, 1H), 6.97–6.88 (m, J = 8.7 Hz, 1H), 6.80 (d, J = 3.0 Hz, 1H), 6.68 (dd, J = 8.8, 3.0 Hz, 1H), 6.16 (d, J = 2.2 Hz, 1H), 4.10–3.91 (m, 1H), 3.55 (s, 3H), 3.16 (s, 3H), 3.12–3.02 (m, 1H), 1.87–1.65 (m, 4H), 1.32–1.11 (m, 4H).

[0605] Example 13: 4-(5-Benzyl-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0606] Preparation of 69: 5-Benzyl-2-chloropyridin-4-amine

[0607]

[0608] Under N2, a mixture of 5-bromo-2-chloropyridin-4-amine (4.60 g, 22.17 mmol), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.00 g, 27.51 mmol), K3PO4 (13.8 g, 65.0 mmol, 2.93 equivalents), and cataCXium A Pd-G3 (500 mg, 687 μmol, 0.031 equivalents) in H2O (8 mL) and dioxane (40 mL) was stirred at 75 °C for 12 h. The mixture was poured into water (200 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 - 5:1 - 3:1) (petroleum ether:ethyl acetate = 3:1, Rf = 0.5) to give the title compound as a yellow solid (3.60 g, 16.5 mmol, 74.2% yield). 。

[0609] 1 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.34 - 7.32 (m, 2H), 7.31 - 7.30 (m, 1H), 7.25 - 7.17 (m, 2H), 6.55 (s, 1H), 4.16 - 4.10 (m, 2H), 3.85 (s, 2H)

[0610] Preparation of 70: 5-Benzyl-4-bromo-2-chloropyridine

[0611]

[0612] A mixture of tert-butyl nitrite (2.70 g, 26.2 mmol) and CuBr (4.81 g, 33.5 mmol) in MeCN (10 mL) was stirred at 70 °C for 10 min. A solution of 5-benzyl-2-chloropyridin-4-amine (1.80 g, 8.23 mmol) in MeCN (10 mL) was added dropwise to the reaction mixture at 70 °C, and the mixture was stirred at 70 °C for 1 h. The mixture was poured into water (80 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the title compound as a green oil (2.00 g, 7.08 mmol, 86.0% yield).

[0613] 1 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.29 (m, 2H), 7.29 - 7.23 (m, 2H), 7.17 (d, J = 7.0 Hz, 3H), 4.29 (s, 2H).

[0614] Preparation 71: 5-Benzyl-4-bromo-1-methylpyridin-2(1H)-one

[0615]

[0616] 5-Benzyl-4-bromo-2-chloropyridine (2.00 g, 7.08 mmol) was dissolved in CHCl3 (10 mL), Me2SO4 (5.35 mL, 56.4 mmol) was added and the solution was heated at 70 °C for 12 h. After cooling, a mixture of TEA (15.0 g, 148 mmol), CH3CO2H (13.7 mL, 240 mmol) and EtOH (13.7 mL, 235 mmol) was added and the reaction was heated at 70 °C for another 2 h. The reaction mixture was diluted with H2O (50 mL) and then extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil. The residue was purified by preparative HPLC (HCl conditions; column: Phenomenex luna C18 250x50mmx10um) to give 5-benzyl-4-bromo-1-methylpyridin-2(1H)-one as a yellow solid (859 mg, 3.09 mmol, 43.6% yield).

[0617] 1 1H NMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.33 - 7.26 (m, 2H), 7.23 - 7.17 (m, 3H), 6.77 (s, 1H), 3.81 (s, 2H), 3.41 (s, 3H).

[0618] Preparation 72: 4-(5-Benzyl-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0619]

[0620] Following the procedure in Preparation 10, 5-benzyl-4-bromo-1-methylpyridin-2(1H)-one (71 mg, 0.26 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (100 mg, 0.23 mmol) were reacted to give the title compound (34 mg, 39%).

[0621] HPLC t R (Agilent, acidic, 3.5 min): 1.26 min, m / z = 346.2 [M+H] + 。

[0622] 1 1H NMR (500 MHz, CDCl3) δ 10.61 (bs, 1H), 7.21 (t, J = 2.4 Hz, 1H), 7.13 - 7.07 (m, 3H), 7.01 (s, 1H), 6.77 (d, J = 6.6 Hz, 2H), 6.50 (s, 1H), 6.35 (s, 1H), 6.14 (t, J = 2.4 Hz, 1H), 5.22 (s, 2H), 3.53 (s, 3H), 3.42 (s, 3H).

[0623] Example 14: 4-(1-Benzyl-1H-pyrazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0624] Preparation 73: 4-(5-Benzyl-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0625]

[0626] Following the procedure in Preparation 10, 1-benzyl-5-bromo-1H-pyrazole (61 mg, 0.26 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (100 mg, 0.23 mmol) were reacted to give the title compound (17 mg, 23%).

[0627] HPLC t R (Agilent, acidic, 3.5 min): 1.41 min, m / z = 305.2 [M+H] + 。

[0628] 1 1H NMR (500 MHz, CDCl3) δ 9.61 (bs, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.28 - 7.25 (m, 4H), 7.05 - 7.02 (m, 2H), 6.70 (s, 1H), 6.41 (d, J = 1.8 Hz, 1H), 6.27 (t, J = 2.6 Hz, 1H), 5.34 - 5.33 (m, 2H), 3.55 (s, 3H).

[0629] Example 15: 4-(1-Benzyl-1H-imidazol-2-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0630] Preparation 74: 1-Benzyl-2-bromo-1H-imidazole

[0631]

[0632] To a solution of 2-bromo-1H-imidazole (1.0 g, 7.1 mmol) in TMF (160 mL) at 20 °C was added sodium hydride 60% in oil (286 mg, 7.1 mmol) and the mixture was stirred at 70 °C for 10 minutes. (Bromomethyl)benzene (0.85 mL, 8.1 mmol) was added and the reaction was stirred at 70 °C for 1 hour. The reaction mixture was added to EtOAc (100 mL) and washed with H2O (100 mL), the organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1-benzyl-2-bromo-1H-imidazole (920 mg, 54%).

[0633] HPLC t R (Agilent, acidic, 3.5 min): 1.29 min, m / z = 238.1 [M + H] + .

[0634] Preparation 75: 4-(1-Benzyl-1H-imidazol-2-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0635]

[0636] Following the procedure in Preparation 10, 1-benzyl-2-bromo-1H-imidazole (61 mg, 0.26 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (100 mg, 0.23 mmol) were reacted to give the title compound (18 mg, 24%).

[0637] HPLC t R (Agilent, acidic, 3.5 min): 0.97 min, m / z = 305.2 [M+H] + 。

[0638] 1 H NMR (500 MHz, CDCl3) δ 10.09 (bs, 1H), 7.36 - 7.33 (m, 2H), 7.31 (t, J = 2.9 Hz, 2H), 7.27 (d, J = 1.1 Hz, 1H), 7.12 (s, 1H), 7.06 (t, J = 1.2 Hz, 1H), 7.04 (d, J = 7.4 Hz, 2H), 6.41 (t, J = 2.5 Hz, 1H), 5.18 (s, 2H), 3.62 (s, 3H).

[0639] Example 16: 4-(1-Benzyl-1H-1,2,4-triazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0640] Preparation 76: 4-(1-Benzyl-1H-1,2,4-triazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0641]

[0642] Following the procedure in Preparation 10, 1-benzyl-2-bromo-1H-imidazole (61 mg, 0.26 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (100 mg, 0.23 mmol) were reacted to give the title compound (18 mg, 24%).

[0643] HPLC t R (Agilent, acidic, 3.5 min): 0.97 min, m / z = 305.2 [M+H] + 。

[0644] 1 H NMR (500 MHz, DMSO-d6) δ 12.22 (bs, 1H), 8.12 (s, 1H), 7.48 (s, 1H), 7.36 - 7.26 (m, 4H), 7.09 (d, J = 7.0 Hz, 2H), 6.35 (d, J = 2.4 Hz, 1H), 5.50 (s, 2H), 3.30 (s, 3H).

[0645] Example 17: 4-(4-Benzylthiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0646] Preparation 77: 4-Benzyl-5-bromothiazole

[0647]

[0648] To a solution of 4-benzyl-5-bromothiazol-2-amine (16.2 g, 60.2 mmol) in DMF (160 mL) heated to 55 °C was added dropwise a solution of tert-butyl nitrite (9.3 g, 90.2 mmol) in DMF (50 mL). The reaction mixture was stirred at 70 °C for 1 h. Then it was cooled to RT, water (250 mL) was added, and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent hexane:EtOAc 14:1) to give 4-benzyl-5-bromothiazole (1.1 g, 7.2% yield).

[0649] 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.25 - 7.20 (m, 4H), 7.17 - 7.12 (m, 1H), 4.09 (s, 2H).

[0650] Preparation 78: 4-(4-Benzylthiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0651]

[0652] Following the procedure in Preparation 10, 4-benzyl-5-bromothiazole (65 mg, 0.26 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (100 mg, 0.23 mmol) were reacted to give the title compound (5 mg, 6%).

[0653] HPLC t R (Agilent, acidic, 3.5 min): 1.43 min, m / z = 322.2 [M + H] + .

[0654] 11H NMR (500 MHz, DMSO-d6) δ 11.18 (bs, 1H), 8.86 (s, 1H), 7.34 (t, J = 2.6 Hz, 1H), 7.30 - 7.28 (m, 2H), 7.23 - 7.18 (m, 3H), 6.89 (s, 1H), 6.34 (t, J = 2.5 Hz, 1H), 4.18 - 4.17 (m, 2H), 3.66 - 3.65 (m, 3H).

[0655] Example 18: 1-Methyl-5-(4-phenoxythiazol-5-yl)pyridin-2(1H)-one

[0656] Preparation 79: 4-(4-Benzylthiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0657]

[0658] Following the procedure in Preparation 40, 5-Bromo-4-phenoxythiazole (89 mg, 0.35 mmol) was reacted to give the title compound (48 mg, 48%).

[0659] HPLC t R (Agilent, acidic, 3.5 min): 1.34 min, m / z = 285.0 [M+H] + .

[0660] 1 1H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.06 (s, 1H), 7.70 - 7.66 (m, 1H), 7.37 (t, J = 7.3 Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H), 7.04 - 7.00 (m, 2H), 6.48 - 6.45 (m, 1H), 3.47 (s, 3H).

[0661] Example 19: 4-(4-(2-Hydroxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0662] Preparation 80: 4-(2-Methoxyphenoxy)thiazole

[0663]

[0664] Following the procedure in Preparation 22, 2-Methoxyphenol (1.1 g, 8.65 mmol) was reacted to give the title compound (307 mg, 17%).

[0665] HPLC t R(Agilent, acidic, 3.5 min): 1.47 min, m / z = 208.0 [M+H] + 。

[0666] Preparation 81: 5-Bromo-4-(2-methoxyphenoxy)thiazole

[0667]

[0668] Following the procedure in Preparation 23, 4-(2-methoxyphenoxy)thiazole (155 mg, 0.75 mmol) was reacted to give the title compound (170 mg, 79%).

[0669] HPLC t R (Agilent, acidic, 3.5 min): 1.65 min, m / z = 287.2 [M+H] + 。

[0670] Preparation 82: 4-(4-(2-Methoxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0671]

[0672] Following the procedure in Preparation 10, 5-bromo-4-(2-methoxyphenoxy)thiazole (169 mg, 0.59 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (230 mg, 0.54 mmol) were reacted to give the title compound (43 mg, 23%).

[0673] HPLC t R (Agilent, acidic, 3.5 min): 1.46 min, m / z = 354.2 [M+H] + 。

[0674] Preparation 83: 4-(4-(2-Hydroxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0675]

[0676] Following the procedure in Preparation 11, 4-(4-(2-methoxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (43 mg, 0.12 mmol) was reacted to give the title compound (9 mg, 20%).

[0677] HPLC R (Agilent, acidic, 3.5 min): 1.36 min, m / z = 340.0 [M+H] + .

[0678] 1 H NMR(500MHz,DMSO-d6)δ12.21(bs,1H),9.48(bs,1H),8.88(s,1H),7.69(s,1H),7.36(t, J=2.6Hz,1H),6.98-6.89(m,3H),6.75-6.71(m,1H),6.56(t,J=2.1Hz,1H),3.55(s,3H).

[0679] Example 20: 4-(4-(4-hydroxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0680] Preparation 84: 4-(4-methoxyphenoxy)thiazole

[0681]

[0682] Following the procedure in Preparation 22, 4-methoxyphenol (1.1 g, 8.65 mmol) was reacted to give the title compound (332 mg, 19%).

[0683] HPLC R (Agilent, acidic, 3.5 min): 1.46 min, m / z = 208.0 [M+H] + .

[0684] Preparation 85: 5-Bromo-4-phenoxythiazole

[0685]

[0686] Following the procedure in Preparation 23, 4-(2-methoxyphenoxy)thiazole (280 mg, 1.35 mmol) was reacted to give the title compound (195 mg, 50%).

[0687] HPLC R (Agilent, acidic, 3.5 min): 1.70 min, m / z = 287.2 [M+H] + .

[0688] Preparation 86: 4-(4-(4-methoxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0689]

[0690] Following the procedure in Preparation 10, 5-bromo-4-phenoxythiazole (162 mg, 0.57 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (220 mg, 0.51 mmol) were reacted to afford the title compound (40 mg, 22%).

[0691] HPLC t R (Agilent, acidic, 3.5 min): 1.43 min, m / z = 354.0 [M+H] + 。

[0692] Preparation 87: 4-(4-(4-Hydroxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0693]

[0694] Following the procedure in Preparation 11, 4-(4-(2-Methoxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (40 mg, 0.11 mmol) was reacted to afford the title compound (15 mg, 35%).

[0695] HPLC t R (Agilent, acidic, 3.5 min): 1.30 min, m / z = 340.0 [M+H] + 。

[0696] 1 1H NMR (500 MHz, DMSO-d6) δ 12.19 (bs, 1H), 9.18 (bs, 1H), 8.95 (s, 1H), 7.53 (s, 1H), 7.35 (t, J = 2.7 Hz, 1H), 6.86 - 6.83 (m, 2H), 6.71 - 6.69 (m, 2H), 6.44 (t, J = 2.4 Hz, 1H), 3.54 (s, 3H).

[0697] Example 21: 5-(4-(2-Hydroxyphenoxy)thiazol-5-yl)-1-methylpyridin-2(1H)-one

[0698] Preparation 88: 5-(4-(2-Methoxyphenoxy)thiazol-5-yl)-1-methylpyridin-2(1H)-one

[0699]

[0700] Following the procedure in Preparation 40, 5-bromo-4-(2-methoxyphenoxy)thiazole (167 mg, 0.58 mmol) was reacted to give the title compound (110 mg, 66%).

[0701] HPLC t R (Agilent, acidic, 3.5 min): 1.35 min, m / z = 315.0 [M+H] + 。

[0702] Preparation 89: 5-(4-(2-hydroxyphenoxy)thiazol-5-yl)-1-methylpyridin-2(1H)-one

[0703]

[0704] Following the procedure in Preparation 11, 4-(4-(2-methoxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.35 mmol) was reacted to give the title compound (53 mg, 46%).

[0705] HPLC t R (Agilent, acidic, 3.5 min): 1.26 min, m / z = 301.0 [M+H] + 。

[0706] 1 1H NMR (500 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.79 (s, 1H), 8.12 (s, 1H), 7.83 - 7.81 (d, J = 9.7 Hz, 1H), 6.99 - 6.90 (m, 3H), 6.75 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 10.4 Hz, 1H), 3.48 (s, 3H).

[0707] Example 22: 4-(5-(2-hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0708] Preparation 90: 1-oxido-2-chloro-5-(2-methoxyphenoxy)-4-nitropyridine

[0709]

[0710] Following the procedure in Preparation 35, 2-methoxyphenol (15.5 g, 125 mmol) was reacted to afford the title compound (23.0 g, 75%).

[0711] HPLC t R (Shimadzu, acidic, 1.5 min): 0.92 min, m / z = 297.1 [[ID=(7]]

[0712] [M+H] + 。

[0713] Preparation 91: 2,4-dibromo-5-(2-methoxyphenoxy)pyridine 1-oxide

[0714]

[0715] Following the procedure in Preparation 26, 2-chloro-5-(2-methoxyphenoxy)-4-nitropyridine 1-oxide (6.0 g, 20.2 mmol) was reacted to afford the title compound (7.0 g, 92%).

[0716] HPLC t R (Shimadzu, acidic, 1.5 min): 0.85 min, m / z = 376.0

[0717] [M+H] + 。

[0718] Preparation 92: 2,4-dibromo-5-(2-methoxyphenoxy)pyridine

[0719]

[0720] Following the procedure in Preparation 27, 2,4-dibromo-5-(2-methoxyphenoxy)pyridine 1-oxide (7.0 g, 18.6 mmol) was reacted to afford the title compound (6.7 g, 100%).

[0721] HPLC t R (Shimadzu, acidic, 1.5 min): 0.91 min, m / z = 359.9 [M+H] + 。

[0722] Preparation 93: 4-bromo-5-(2-methoxyphenoxy)pyridin-2(1H)-one

[0723]

[0724] Following the procedure in Preparation 38, 2,4-dibromo-5-(2-methoxyphenoxy)pyridine (6.7 g, 18.6 mmol) was reacted to afford the title compound (4.3 g, 77%).

[0725] HPLC t R (Shimadzu, acidic, 1.5 min): 0.81 min, m / z = 298.0 [M+H] + 。

[0726] Preparation 94: 4-Bromo-5-(2-methoxyphenoxy)-1-methylpyridin-2(1H)-one

[0727]

[0728] Following the procedure in Preparation 39, 4-bromo-5-(2-methoxyphenoxy)pyridin-2(1H)-one (4.2 g, 14.3 mmol) was reacted to give the title compound (50 mg, 1%).

[0729] 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.13 - 7.02 (m, 2H), 6.90 - 6.84 (m, 2H), 6.80 - 6.76 (m, 1H), 3.82 (s, 3H), 3.37 (s, 3H)

[0730] Preparation 95: 4-(5-(2-methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0731]

[0732] Following the procedure in Preparation 10, 4-bromo-5-(2-methoxyphenoxy)-1-methylpyridin-2(1H)-one (36 mg, 0.11 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (50 mg, 0.11 mmol) were reacted to give the title compound (8 mg, 18%).

[0733] HPLC t R (Agilent, acidic, 3.5 min): 1.25 min, m / z = 378.1 [M+H] + 。

[0734] Preparation 96: 4-(5-(2-hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0735]

[0736] Following the procedure in Preparation 11, 4-(5-(2-methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (24 mg, 0.06 mmol) was reacted to afford the title compound (13 mg, 50%).

[0737] HPLC t R (Agilent, acidic, 3.5 min): 1.17 min, m / z = 364.0 [M+H] + 。

[0738] 1 1H NMR (500 MHz, CDCl3) δ 9.56 (bs, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.81 - 6.81 (m, 1H), 6.69 - 6.62 (m, 2H), 6.56 (s, 1H), 6.50 - 6.47 (m, 2H), 6.26 (t, J = 2.5 Hz, 1H), 5.55 (bs, 1H), 3.36 (s, 3H), 3.32 (s, 3H).

[0739] Example 23: 4-(5-(3-methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0740] Preparation 97: 2-Chloro-5-(3-methoxyphenoxy)-4-nitropyridine 1-oxide

[0741]

[0742] Following the procedure in Preparation 35, 3-methoxyphenol (15.5 g, 125 mmol) was reacted to afford the title compound (24.0 g, 78%).

[0743] HPLC t R (Shimadzu, acidic, 1.5 min): 0.94 min, m / z = 297.1 [M+H] + 。

[0744] Preparation 98: 2,4-Dibromo-5-(3-methoxyphenoxy)pyridine 1-oxide

[0745]

[0746] Following the procedure in Preparation 26, 2-chloro-5-(3-methoxyphenoxy)-4-nitropyridine 1-oxide (6.5 g, 21.9 mmol) was reacted to give the title compound (7.0 g, 85%).

[0747] HPLC t R (Shimadzu, acidic, 1.5 min): 0.83 min, m / z = 376.0 [M+H] + 。

[0748] Preparation 99: 2,4-Dibromo-5-(3-methoxyphenoxy)pyridine

[0749]

[0750] Following the procedure in Preparation 27, 2,4-dibromo-5-(3-methoxyphenoxy)pyridine 1-oxide (15 g, 40.0 mmol) was reacted to give the title compound (2.0 g, 14%).

[0751] HPLC t R (Shimadzu, acidic, 1.5 min): 1.00 min, m / z = 359.9 [M+H] + 。

[0752] Preparation 100: 4-Bromo-5-(3-methoxyphenoxy)pyridin-2(1H)-one

[0753]

[0754] Following the procedure in Preparation 38, 2,4-dibromo-5-(3-methoxyphenoxy)pyridine (1.1 g, 3.06 mmol) was reacted to give the title compound (900 mg, 90%).

[0755] HPLC t R (Agilent, acidic, 1.5 min): 0.82 min, m / z = 297.1 [M+H] + 。

[0756] Preparation 101: 4-Bromo-5-(3-methoxyphenoxy)-1-methylpyridin-2(1H)-one

[0757]

[0758] Following the procedure in Preparation 39, 4-bromo-5-(3-methoxyphenoxy)pyridin-2(1H)-one (450 mg, 3.56 mmol) was reacted to give the title compound (0.25 g, 53%).

[0759] HPLC tR (Shimadzu, acidic, 1.5 min): 0.66 min, m / z = 309.8 [M+H] + 。

[0760] Preparation 102: 4-(5-(3-methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0761]

[0762] Following the procedure in Preparation 10, 4-bromo-5-(3-methoxyphenoxy)-1-methylpyridin-2(1H)-one (80 mg, 0.26 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.26 mmol) were reacted to give the title compound (42 mg, 40%).

[0763] HPLC t R (Agilent, acidic, 3.5 min): 1.25 min, m / z = 378.1 [M+H] + 。

[0764] 1 1H NMR (500 MHz, CDCl3) δ 9.63 (bs, 1H), 7.28 - 7.25 (m, 2H), 7.17 - 7.16 (m, 1H), 7.08 (t, J = 8.2 Hz, 1H), 6.86 - 6.86 (m, 1H), 6.55 (t, J = 2.9 Hz, 1H), 6.51 (dd, J = 2.6, 8.4 Hz, 1H), 6.36 (dd, J = 2.1, 8.3 Hz, 1H), 6.32 (t, J = 2.3 Hz, 1H), 3.70 - 3.69 (m, 3H), 3.61 (s, 3H), 3.58 (s, 3H).

[0765] Example 24: 4-(5-(3-hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0766] Preparation 103: 4-(5-(3-hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0767]

[0768] Following the procedure in Preparation 11, 4-(5-(3-methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (37 mg, 0.10 mmol) was reacted to afford the title compound (22 mg, 58%).

[0769] HPLC t R (Agilent, acidic, 3.5 min): 1.13 min, m / z = 364.0 [M+H] + 。

[0770] 1 1H NMR (500 MHz, DMSO) δ 12.05 (bs, 1H), 9.37 (s, 1H), 7.85 (s, 1H), 7.38 (s, 1H), 7.31 (t, J = 2.7 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.55 - 6.54 (m, 1H), 6.34 (t, J = 2.3 Hz, 1H), 6.30 (dd, J = 1.9, 8.0 Hz, 1H), 6.20 (dd, J = 2.2, 8.1 Hz, 1H), 6.17 (d, J = 2.4 Hz, 1H), 3.48 (s, 6H).

[0771] Example 25: 4-(5-(4-methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0772] Preparation 104: 2-chloro-5-(4-methoxyphenoxy)-4-nitropyridine 1-oxide

[0773]

[0774] Following the procedure in Preparation 35, 4-methoxyphenol (4.6 g, 37.4 mmol) was reacted to afford the title compound (6.0 g, 65%).

[0775] 1 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.11 (s, 1H), 7.21 (d, J = 9.2 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H), 3.77 (s, 3H)

[0776] Preparation 105: 2,4-dibromo-5-(4-methoxyphenoxy)pyridine 1-oxide

[0777]

[0778] Following the procedure in Preparation 26, 2-chloro-5-(4-methoxyphenoxy)-4-nitropyridine 1-oxide (6.0 g, 20.2 mmol) was reacted to afford the title compound (7.60 g, 98%).

[0779] HPLC t R (Shimadzu, acidic, 1.5 min): 0.85 min, m / z = 376.0 [M+H] + .

[0780] Preparation 106: 2,4-Dibromo-5-(4-methoxyphenoxy)pyridine

[0781]

[0782] Following the procedure in Preparation 27, 2,4-dibromo-5-(4-methoxyphenoxy)pyridine 1-oxide (7.6 g, 20.3 mmol) was reacted to afford the title compound (7.3 g, 99%).

[0783] HPLC t R (Shimadzu, acidic, 1.5 min): 1.02 min, m / z = 359.9 [M+H] + .

[0784] Preparation 107: 4-Bromo-5-(4-methoxyphenoxy)pyridin-2(1H)-one

[0785]

[0786] Following the procedure in Preparation 38, 2,4-dibromo-5-(4-methoxyphenoxy)pyridine (7.3 g, 20.3 mmol) was reacted to afford the title compound (4.0 g, 59%).

[0787] 1 1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 1H), 6.92 - 6.88 (m, 4H), 6.85 (s, 1H), 3.71 (s, 3H)

[0788] Preparation 108: 4-Bromo-5-(4-methoxyphenoxy)-1-methylpyridin-2(1H)-one

[0789]

[0790] Following the procedure in Preparation 39, 4-bromo-5-(4-methoxyphenoxy)pyridin-2(1H)-one (4.0 g, 13.5 mmol) was reacted to give the title compound (0.7 g, 16%).

[0791] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 6.92 - 6.87 (m, 5H), 3.71 (s, 3H), 3.39 (s, 3H)

[0792] Preparation 109: 4-(5-(4-methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0793] <(

[0794] Following the procedure in Preparation 10, 4-bromo-5-(4-methoxyphenoxy)-1-methylpyridin-2(1H)-one (80 mg, 0.26 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.26 mmol) were reacted to give the title compound (50 mg, 47%).

[0795] HPLC t R (Agilent, acidic, 3.5 min): 1.23 min, m / z = 378.1 [M+H] + .

[0796] 1 H NMR (500 MHz, CDCl3) δ 10.94 (bs, 1H), 7.22 (t, J = 2.7 Hz, 1H), 7.09 (s, 1H), 7.04 (s, 1H), 6.76 (s, 1H), 6.64 (s, 4H), 6.43 (t, J = 2.3 Hz, 1H), 3.64 (s, 3H), 3.53 (s, 3H), 3.49 (s, 3H).

[0797] Example 26: 4-(5-(4-hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0798] Preparation 110: 4-(5-(4-Hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0799]

[0800] Following the procedure in Preparation 11, 4-(5-(4-Methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (46 mg, 0.12 mmol) was reacted to afford the title compound (27 mg, 59%).

[0801] HPLC t R (Agilent, acidic, 3.5 min): 1.13 min, m / z = 364.0 [M+H] + 。

[0802] 1 1H NMR (500 MHz, DMSO) δ 12.03 (bs, 1H), 9.02 (s, 1H), 7.66 (s, 1H), 7.37 - 7.36 (m, 1H), 7.30 (t, J = 2.7 Hz, 1H), 6.65 - 6.62 (m, 2H), 6.58 - 6.55 (m, 2H), 6.49 (d, J = 13.6 Hz, 1H), 6.32 (t, J = 2.3 Hz, 1H), 3.49 (s, 3H), 3.45 (s, 3H).

[0803] Example 27: 5'-(4-Methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0804] Preparation 111: 5'-(4-Methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0805]

[0806] Following the procedure in Preparation 40, 4-Bromo-5-(4-methoxyphenoxy)-1-methylpyridin-2(1H)-one (50 mg, 0.16 mmol) was reacted to afford the title compound (31 mg, 53%).

[0807] HPLC t R (Agilent, acidic, 3.5 min): 1.22 min, m / z = 339.0 [M+H] + 。

[0808] 1 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 2.6 Hz, 1H), 7.56 (dd, J = 2.7, 9.5 Hz, 1H), 7.06 (s, 1H), 6.82 - 6.81 (m, 4H), 6.60 - 6.54 (m, 2H), 3.79 - 3.78 (m, 3H), 3.53 (s, 6H).

[0809] Example 28: 5'-(3-Hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0810] Preparation 112: 5'-(3-Hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0811]

[0812] Following the procedure in Preparation 11, 5'-(4-Methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione (25 mg, 0.07 mmol) was reacted to afford the title compound (12 mg, 49%).

[0813] HPLC t R (Agilent, acidic, 3.5 min): 1.08 min, m / z = 325.0 [M + H] + .

[0814] 1 1H NMR (500 MHz, DMSO-d6) δ 9.10 (bs, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.66 - 7.61 (m, 2H), 6.75 - 6.72 (m, 2H), 6.67 - 6.64 (m, 2H), 6.51 (s, 1H), 6.35 (d, J = 9.5 Hz, 1H), 3.42 (s, 3H), 3.41 (s, 3H).

[0815] Example 29: 5'-(3-Hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0816] Preparation 113: 5'-(3-Methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0817]

[0818] Following the procedure in Preparation 40, 4-bromo-5-(3-methoxyphenoxy)-1-methylpyridin-2(1H)-one (50 mg, 0.16 mmol) was reacted to afford the title compound (29 mg, 48%).

[0819] HPLC t R (Agilent, acidic, 3.5 min): 1.23 min, m / z = 339.0 [M+H] + 。

[0820] Preparation 114: 5'-(3-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0821]

[0822] Following the procedure in Preparation 11, 5'-(4-methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione (23 mg, 0.07 mmol) was reacted to afford the title compound (13 mg, 53%).

[0823] HPLC t R (Agilent, acidic, 3.5 min): 1.08 min, m / z = 325.0 [M+H] + 。

[0824] 1 H NMR (500 MHz, DMSO-d6) δ 9.48 (bs, 1H), 8.06 - 8.05 (m, 1H), 7.83 - 7.82 (m, 1H), 7.62 - 7.59 (m, 1H), 7.04 (t, J = 8.2 Hz, 1H), 6.54 (s, 1H), 6.40 - 6.25 (m, 4H), 3.44 (s, 3H), 3.41 (s, 3H).

[0825] Example 30: 4-(3-(2-methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0826] Preparation 115: 1-oxide 2-chloro-3-(2-methoxyphenoxy)-4-nitropyridine

[0827]

[0828] Following the procedure in Preparation 35, 2-methoxyphenol (6.45 g, 51.9 mmol) and 2-chloro-3-fluoro-4-nitropyridine 1-oxide (10.0 g, 51.9 mmol) were reacted to give the title compound (12.0 g, 78%).

[0829] 1 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H), 7.17 - 7.10 (m, 2H), 6.94 - 6.82 (m, 2H), 3.83 (s, 3H).

[0830] Preparation 116: 2,4-Dibromo-3-(2-methoxyphenoxy)pyridine 1-oxide

[0831]

[0832] Following the procedure in Preparation 26, 2-chloro-3-(2-methoxyphenoxy)-4-nitropyridine 1-oxide (12.0 g, 40.5 mmol) was reacted to give the title compound (11.8 g, 82%).

[0833] HPLC t R (Shimadzu, acidic, 1.5 min): 0.83 min, m / z = 376.1 [M + H] + .

[0834] Preparation 117: 2,4-Dibromo-3-(2-methoxyphenoxy)pyridine

[0835]

[0836] Following the procedure in Preparation 27, 2,4-dibromo-3-(2-methoxyphenoxy)pyridine 1-oxide (18.0 g, 48.0 mmol) was reacted to give the title compound (14.0 g, 68%).

[0837] HPLC t R (Shimadzu, acidic, 1.5 min): 0.94 min, m / z = 360.1 [M + H] + .

[0838] Preparation 118: 4-Bromo-3-(2-methoxyphenoxy)pyridin-2(1H)-one

[0839]

[0840] Following the procedure in Preparation 38, 2,4-dibromo-3-(2-methoxyphenoxy)pyridine (14.0 g, 39.0 mmol) was reacted to give the title compound (2.5 g, 20%).

[0841] 1 H NMR (400 MHz, DMSO-d6) δ 12.1 (brs, 1H), 7.26 (d, J = 6.8 Hz, 1H), 7.06–7.04 (m, 1H), 6.99 - 6.78 (m, 2H), 6.53 - 6.50 (m, 2H), 3.82 (s, 3H).

[0842] Preparation 119: 4-Bromo-3-(2-methoxyphenoxy)-1-methylpyridin-2(1H)-one

[0843]

[0844] Following the procedure in Preparation 39, 4-bromo-3-(2-methoxyphenoxy)pyridin-2(1H)-one (2.4 g, 8.1 mmol) was reacted to give the title compound (1.2 g, 46%).

[0845] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 7.2 Hz, 1H), 7.08 - 7.03 (m, 1H), 7.01 - 6.94 (m, 1H), 6.81 - 6.74 (m, 1H), 6.58 (d, J = 7.2 Hz, 1H), 6.54 - 6.48 (m, 1H), 3.82 (s, 3H), 3.43 (s, 3H).

[0846] Preparation 120: 4-(3-(2-Methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0847]

[0848] Following the procedure in Preparation 10, 4-bromo-3-(2-methoxyphenoxy)-1-methylpyridin-2(1H)-one (30 mg, 0.10 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (41 mg, 0.10 mmol) were reacted to give the title compound (13 mg, 33%).

[0849] HPLC t R(Agilent, acidic, 3.5 min): 1.20 min, m / z = 378.1 [M+H] + 。

[0850] 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (bs, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.41 (s, 1H), 7.29 (t, J = 2.7 Hz, 1H), 6.95 (dd, J = 1.5, 8.1 Hz, 1H), 6.87 - 6.82 (m, 1H), 6.71 - 6.66 (m, 1H), 6.50 - 6.41 (m, 2H), 6.31 (t, J = 2.3 Hz, 1H), 3.76 (s, 3H), 3.51 (s, 3H), 3.45 (s, 3H).

[0851] Example 31: 4-(3-(2-Hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0852] Preparation 121: 4-(3-(2-Hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0853]

[0854] Following the procedure in Preparation 11, 4-(3-(2-Methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (66 mg, 0.18 mmol) was reacted to afford the title compound (17 mg, 26%).

[0855] HPLC t R (Agilent, acidic, 3.5 min): 1.16 min, m / z = 364.1 [M+H] + 。

[0856] 1 H NMR (500 MHz, DMSO-d6) δ 12.17 (bs, 1H), 9.38 (s, 1H), 7.7 (d, J = 7.2 Hz, 1H), 7.64 (s, 1H), 7.32 (t, J = (2.8 Hz, 1H), 6.78 - 6.72 (m, 2H), 6.53 - 6.47 (m, 2H), 6.38 - 6.35 (m, 2H), 3.54 (s, 3H), 3.17 (s, 3H).

[0857] Example 32: 4-(3-(3-Methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0858] Preparation 122: 2-Chloro-3-(3-methoxyphenoxy)-4-nitropyridine 1-oxide

[0859]

[0860] Following the procedure in Preparation 35, 3-Methoxyphenol (6.45 g, 51.9 mmol) and 2-Chloro-3-fluoro-4-nitropyridine 1-oxide (10.0 g, 51.9 mmol) were reacted to afford the title compound (9.0 g, 58%).

[0861] 1 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 7.6 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.27–7.23 (m, 1H), 6.74 - 6.61 (m, 3H), 3.74 (s, 3H).

[0862] Preparation 123: 2,4-Dibromo-3-(3-methoxyphenoxy)pyridine 1-oxide

[0863]

[0864] Following the procedure in Preparation 26, 2-Chloro-3-(3-methoxyphenoxy)-4-nitropyridine 1-oxide (9.0 g, 30.3 mmol) was reacted to afford the title compound (11.0 g, 97%).

[0865] HPLC t R (Shimadzu, acidic, 1.5 min): 0.85 min, m / z = 376.0 [M] + .

[0866] Preparation 124: 2,4-Dibromo-3-(3-methoxyphenoxy)pyridine

[0867]

[0868] Following the procedure in Preparation 27, 2,4-Dibromo-3-(3-methoxyphenoxy)pyridine 1-oxide (11.0 g, 29.3 mmol) was reacted to afford the title compound (10.1 g, 96%).

[0869] HPLC t R(Agilent, acidic, 1.5 min): 0.97 min, m / z = 359.8 [M+H] + 。

[0870] Preparation 125: 4-Bromo-3-(3-methoxyphenoxy)pyridin-2(1H)-one

[0871]

[0872] Following the procedure in Preparation 38, 2,4-Dibromo-3-(3-methoxyphenoxy)pyridine (10.0 g, 27.9 mmol) was reacted to afford the title compound (1.0 g, 12%).

[0873] 1 H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 5.6 Hz, 1H), 7.13 - 7.09 (m, 1H), 6.52 - 6.21 (m, 4H), 3.70 (s, 3H).

[0874] Preparation 126: 4-Bromo-3-(3-methoxyphenoxy)-1-methylpyridin-2(1H)-one

[0875]

[0876] Following the procedure in Preparation 39, 4-Bromo-3-(3-methoxyphenoxy)pyridin-2(1H)-one (1.0 g, 3.38 mmol) was reacted to afford the title compound (0.7 g, 66%).

[0877] 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 8.4 Hz, 1H), 6.64 - 6.58 (m, 2H), 6.43 (t, J = 2.4 Hz, 1H), 6.38 - 6.34 (m, 1H), 3.72 (s, 3H), 3.45 (s, 3H).

[0878] Preparation 127: 4-(3-(3-Methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0879]

[0880] Following the procedure in Preparation 10, 4-bromo-3-(3-methoxyphenoxy)-1-methylpyridin-2(1H)-one (30 mg, 0.10 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (39 mg, 0.092 mmol) were reacted to give the title compound (12 mg, 30%).

[0881] HPLC R (Agilent, acidic, 3.5 min): 1.19 min, m / z = 378.1 [M+H] + .

[0882] 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),7.71(d,J=7.1Hz,1H),7.36(s,1H),7.32(t,J=2.7Hz,1H),7.06(t,J=8.1Hz, 1H), 6.48 (dd, J=2.0, 7.9Hz, 1H), 6.40 (d, J=7.1Hz, 1H), 6.32-6.25 (m, 3H), 3.64 (s, 3H), 3.52 (s, 3H), 3.47 (s, 3H).

[0883] Example 33: 4-(3-(3-hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0884] Preparation 128: 4-(3-(3-hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0885]

[0886] Following the procedure in Preparation 11, 4-(3-(3-methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (66 mg, 0.18 mmol) was reacted to give the title compound (15 mg, 23%).

[0887] HPLC R (Agilent, acidic, 3.5 min): 1.12 min, m / z = 364.1 [M+H] + .

[0888] 1 1H NMR (500 MHz, DMSO-d6) δ 12.15 (bs, 1H), 9.34 (s, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.37 - 7.31 (m, 2H), 6.93 (t, J = 8.1 Hz, 1H), 6.41 (d, J = 7.0 Hz, 1H), 6.32 - 6.28 (m, 2H), 6.16 - 6.09 (m, 2H), 3.52 (s, 3H), 3.47 (s, 3H).

[0889] Example 34: 4-(3-(4-Methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0890] Preparation 129: 2-Chloro-3-(4-methoxyphenoxy)-4-nitropyridine 1-oxide

[0891]

[0892] Following the procedure in Preparation 35, 4-methoxyphenol (6.5 g, 52.4 mmol) and 2-chloro-3-fluoro-4-nitropyridine 1-oxide (10.0 g, 51.9 mmol) were reacted to afford the title compound (12.0 g, 78%).

[0893] 1 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 7.2 Hz, 1H), 7.05 - 6.99 (m, 2H), 6.92 - 6.87 (m, 2H), 3.73 (s, 3H).

[0894] Preparation 130: 2,4-Dibromo-3-(4-methoxyphenoxy)pyridine 1-oxide

[0895]

[0896] Following the procedure in Preparation 26, 2-chloro-3-(4-methoxyphenoxy)-4-nitropyridine 1-oxide (12.0 g, 40.5 mmol) was reacted to afford the title compound (12.1 g, 79%).

[0897] HPLC t R (Shimadzu, acidic, 1.5 min): 0.85 min, m / z = 375.9 [M+H] + .

[0898] Preparation 131: 2,4-Dibromo-3-(4-methoxyphenoxy)pyridine

[0899]

[0900] Following the procedure in Preparation 27, 2,4-Dibromo-3-(4-methoxyphenoxy)pyridine 1-oxide (18.0 g, 48.0 mmol) was reacted to afford the title compound (14.0 g, 75%).

[0901] HPLC t R (Shimadzu, acidic, 1.5 min): 0.97 min, m / z = 360.1 [M+H] + 。

[0902] Preparation 132: 4-Bromo-3-(4-methoxyphenoxy)pyridin-2(1H)-one

[0903]

[0904] Following the procedure in Preparation 38, 2,4-Dibromo-3-(4-methoxyphenoxy)pyridine (14.0 g, 39.0 mmol) was reacted to afford the title compound (2.0 g, 17%).

[0905] 1 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J = 6.8 Hz, 1H), 6.86 - 6.81 (m, 2H), 6.80 - 6.75 (m, 2H), 6.46 (d, J = 6.8 Hz, 1H), 3.70 (s, 3H).

[0906] Preparation 133: 4-Bromo-3-(4-methoxyphenoxy)-1-methylpyridin-2(1H)-one

[0907]

[0908] Following the procedure in Preparation 39, 4-Bromo-3-(4-methoxyphenoxy)pyridin-2(1H)-one (2.0 g, 6.8 mmol) was reacted to afford the title compound (1.8 g, 82%).

[0909] 1 1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 7.6 Hz, 1H), 6.86 - 6.82 (m, 2H), 6.81 - 6.75 (m, 2H), 6.57 (d, J = 7.2 Hz, 1H), 3.70 (s, 3H), 3.44 (s, 3H)

[0910] Preparation 134: 4-(3-(4-Methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0911]

[0912] Following the procedure in Preparation 10, 4-bromo-3-(4-methoxyphenoxy)-1-methylpyridin-2(1H)-one (30 mg, 0.10 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (39 mg, 0.092 mmol) were reacted to give the title compound (8 mg, 20%).

[0913] HPLC t R (Agilent, acidic, 3.5 min): 1.17 min, m / z = 378.1 [M+H] + 。

[0914] 1 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H),   7.68 (d, J = 7.2 Hz, 1H), 7.36 - 7.30 (m, 2H), 6.75 - 6.62 (m, 4H), 6.39 (d, J = 7.1 Hz, 1H), 6.30 (t, J = 2.3 Hz, 1H), 3.64 (s, 3H), 3.51 (s, 3H), 3.48 (s, 3H).

[0915] Example 35: 4-(3-(4-Hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0916] Preparation 135: 4-(3-(4-Hydroxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0917]

[0918] Following the procedure in Preparation 11, 4-(3-(4-methoxyphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (63 mg, 0.17 mmol) was reacted to give the title compound (17 mg, 27%).

[0919] HPLC R (Agilent, acidic, 3.5 min): 1.06 min, m / z = 364.0 [M+H] + .

[0920] 1 H NMR (500MHz, DMSO-d6) δ12.12(bs,1H),8.93(s,1H),7.68(d,J=7.2Hz,1H),7.35(s,1H),7.32(t,J=2 .7Hz,1H),6.54-6.52(m,4H),6.38(d,J=7.0Hz,1H),6.29(t,J=2.2Hz,1H),3.51(s,3H),3.47(s,3H).

[0921] Example 36: 3'-(2-Hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0922] Preparation 136: 3'-(2-methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridyl]-2',6(1H,1'H)-dione

[0923]

[0924] Following the procedure in Preparation 40, 4-bromo-3-(2-methoxyphenoxy)-1-methylpyridin-2(1H)-one (100 mg, 0.32 mmol) was reacted to give the title compound (37 mg, 34%).

[0925] HPLC R (Agilent, acidic, 3.5 min): 1.15 min, m / z = 339.0 [M+H] + .

[0926] Preparation 137: 5'-(2-Hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridyl]-2',6(1H,1'H)-dione

[0927]

[0928] Following the procedure in Preparation 11, 3'-(2-methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione (37 mg, 0.11 mmol) was reacted to give the title compound (21 mg, 53%).

[0929] HPLC R(Agilent, acidic, 3.5 min): 1.10 min, m / z = 325.0 [M+H] + 。

[0930] 1 H NMR (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 2.6, 10.0 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 6.84 - 6.77 (m, 2H), 6.60 - 6.56 (m, 1H), 6.46 (d, J = 6.9 Hz, 1H), 6.42 - 6.37 (m, 2H), 3.50 (s, 3H), 3.46 (s, 3H).

[0931] Example 37: 3'-(3-Hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0932] Preparation 138: 3'-(3-Methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0933]

[0934] Following the procedure in Preparation 40, 4-Bromo-3-(3-methoxyphenoxy)-1-methylpyridin-2(1H)-one (100 mg, 0.32 mmol) was reacted to give the title compound (58 mg, 53%).

[0935] HPLC t R (Agilent, acidic, 3.5 min): 1.17 min, m / z = 339.0 [M+H] + 。

[0936] Preparation 139: 5'-(3-Hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0937]

[0938] Following the procedure in Preparation 11, 3'-(3-Methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione (58 mg, 0.17 mmol) was reacted to give the title compound (23 mg, 40%).

[0939] HPLC t R(Agilent, acidic, 3.5 min): 1.05 min, m / z = 325.0 [M+H] + 。

[0940] 1 H NMR (500 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.10 (d, J = 2.6 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.63 (dd, J = 2.7, 9.5 Hz, 1H), 7.02 (t, J = 8.2 Hz, 1H), 6.43 (d, J = 7.2 Hz, 1H), 6.40 - 6.37 (m, 2H), 6.24 (dd, J = 2.3, 8.1 Hz, 1H), 6.17 (t, J = 2.2 Hz, 1H), 3.48 (s, 3H), 3.45 (s, 3H).

[0941] Example 38: 3'-(4-Hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0942] Preparation 140: 3'-(4-Methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0943]

[0944] Following the procedure in Preparation 40, 4-Bromo-3-(4-methoxyphenoxy)-1-methylpyridin-2(1H)-one (100 mg, 0.32 mmol) was reacted to afford the title compound (50 mg, 46%).

[0945] HPLC t R (Agilent, acidic, 3.5 min): 1.15 min, m / z = 339.0 [M+H] + 。

[0946] Preparation 141: 5'-(4-Hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0947]

[0948] Following the procedure in Preparation 11, 3'-(4-Methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione (50 mg, 0.15 mmol) was reacted to afford the title compound (18 mg, 34%).

[0949] HPLC t R(Agilent, acidic, 3.5 min): 1.00 min, m / z = 325.0 [M+H] + 。

[0950] 1 H NMR (500 MHz, DMSO-d6) δ 9.02 (m, 1H), 8.08 (d, J = 2.6 Hz, 1H), 7.69 - 7.62 (m, 2H), 6.62 - 6.61 (m, 4H), 6.39 (dd, J = 8.4, 10.9 Hz, 2H), 3.46 (s, 3H), 3.45 (s, 3H).

[0951] Example 39: 3'-(4-Fluoro-2,6-dimethylphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0952] Preparation 142: 1-Oxo-2-chloro-3-(4-fluoro-2,6-dimethylphenoxy)-4-nitropyridine

[0953]

[0954] Following the procedure in Preparation 35, 4-Fluoro-2,6-dimethylphenol (14.0 g, 99.9 mmol) and 1-oxo-2-chloro-3-fluoro-4-nitropyridine (10.0 g, 51.9 mmol) were reacted to afford the title compound (11.0 g, 47%).

[0955] HPLC t R (Shimadzu, acidic, 1.5 min): 0.94 min, m / z = 313.2 [M+H] + 。

[0956] Preparation 143: 1-Oxo-2,4-dibromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridine

[0957]

[0958] Following the procedure in Preparation 26, 1-Oxo-2-chloro-3-(4-fluoro-2,6-dimethylphenoxy)-4-nitropyridine (10.0 g, 31.9 mmol) was reacted to afford the title compound (11.6 g, 93%).

[0959] HPLC t R (Shimadzu, acidic, 1.5 min): 0.92 min, m / z = 392.0 [M+H] + 。

[0960] Preparation 144: 2,4-Dibromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridine

[0961]

[0962] Following the procedure in Preparation 27, 2,4-Dibromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridine 1-oxide (15.0 mg, 38.4 mmol) was reacted to give the title compound (12.2 g, 85%).

[0963] HPLC t R (Shimadzu, acidic, 1.5 min): 1.15 min, m / z = 376.1 [M+H] + 。

[0964] Preparation 145: 4-Bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one

[0965]

[0966] Following the procedure in Preparation 38, 2,4-Dibromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridine (11.6 g, 30.9 mmol) was reacted to give the title compound (8.0 g, 83%).

[0967] HPLC t R (Shimadzu, acidic, 1.5 min): 0.88 min, m / z = 313.8 [M+H] + 。

[0968] Preparation 146: 4-Bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one

[0969]

[0970] Following the procedure in Preparation 39, 4-Bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one (7.5 g, 24.0 mmol) was reacted to give the title compound (1.0 g, 13%).

[0971] 1 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 9.2 Hz, 2H), 6.55 (d, J = 7.2 Hz, 1H), 3.35 (s, 3H), 2.09 (s, 6H)

[0972] Preparation 147: 3'-(4-Fluoro-2,6-dimethylphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione

[0973]

[0974] Following the procedure in Preparation 40, 4-bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one (100 mg, 0.31 mmol) was reacted to afford the title compound (73 mg, 60%).

[0975] HPLC t R (Agilent, acidic, 3.5 min): 1.34 min, m / z = 355.0 [M+H] + 。

[0976] 1 1H NMR (500 MHz, DMSO-d6) δ 8.11 - 8.09 (m, 1H), 7.80 (dd, J = 2.7, 9.5 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 6.78 - 6.75 (m, 2H), 6.45 (d, J = 9.5 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 3.51 - 3.50 (m, 3H), 3.40 (s, 3H), 2.04 - 2.03 (m, 6H).

[0977] Example 40: 4-(3-(4-Fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0978] Preparation 148: 4-(3-(4-Fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0979]

[0980] Following the procedure in Preparation 10, 4-bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one (100 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) were reacted to afford the title compound (50 mg, 40%).

[0981] HPLC t R (Agilent, acidic, 3.5 min): 1.36 min, m / z = 395.1 [M+H] + 。

[0982] 1 H NMR (500 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.54 (d, J = 7.0 Hz, 1H), 7.36 (s, 1H), 7.31 (t, J = 2.7 Hz, 1H), 6.69 - 6.66 (m, 2H), 6.32 - 6.26 (m, 2H), 3.55 (s, 3H), 3.44 (s, 3H), 2.01 - 2.00 (m, 6H).

[0983] Example 41: N-Ethyl-4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0984] Preparation 149: Ethyl 4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0985]

[0986] 4-Bromo-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (1.3 g, 3.4 mmol) in THF (100 mL) was cooled to -78 °C. LDA (2.03 mL, 4.06 mmol) was added dropwise and the resulting solution was stirred at this temperature for 30 minutes. Ethyl chloroformate (0.39 mL, 4.06 mmol) was added and the reaction was stirred at -78 °C for 1 hour. Ethyl acetate (500 ml) was added and the organic matter was washed successively with 2 x 500 ml of water and 1 x 500 ml of saturated brine solution. Then the organic matter was separated and dried (MgSO4), and then concentrated to dryness. Then the crude product was purified by flash column chromatography, eluting with an ethyl acetate / heptane gradient (0% - 100%). The desired fractions were combined and dried to afford the reaction to give the title compound (770 mg, 50%).

[0987] HPLC t R (Agilent, acidic, 3.5 min): 1.85 min, m / z = 454.8 [M+H] + 。

[0988] Preparation 150: ethyl 6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

[0989]

[0990] Following the procedure in Preparation 6, ethyl 4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (710 mg, 1.6 mmol) was reacted to give the title compound (437 mg, 56%).

[0991] HPLC R (Agilent, acidic, 3.5 min): 2.10 min, m / z = 501.1 [M+H] + .

[0992] Preparation 151: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid

[0993]

[0994] Following the procedure in Preparation 10, 4-bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one (285 mg, 0.87 mmol) and 6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (436 mg, 0.87 mmol) were reacted to give the title compound (112 mg, 29%).

[0995] HPLC R (Agilent, acidic, 3.5 min): 1.17 min, m / z = 378.1 [M+H] + .

[0996] Preparation 152: N-ethyl-4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[0997]

[0998] To a solution of 4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (25 mg, 0.06 mmol) in DCM (1 mL) was added oxalyl chloride (0.1 mL, 0.11 mmol) and DMF (0.01 mL). The reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and THF (1 mL) was added. 30% Ethylamine solution in THF (0.11 mL, 0.23 mmol) was added and the resulting solution was stirred at room temperature for 2 h. Ethyl acetate (50 mL) was added and the organic matter was washed successively with 2 x 50 mL water and 1 x 50 mL saturated brine solution. The organic matter was then separated and dried (MgSO4), and then concentrated to dryness. The crude product was then purified by flash column chromatography, eluting with an ethyl acetate / heptane gradient (0%-100%). The desired fractions were combined and dried to afford the reaction to give the title compound (12 mg, 42%).

[0999] HPLC t R (Agilent, acidic, 3.5 min): 1.52 min, m / z = 465.2 [M+H] + 。

[1000] 1 H NMR (500 MHz, DMSO-d6) δ 12.25 (bs, 1H), 8.34 (t, J = 5.3 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.41 (s, 1H), 6.90 (s, 1H), 6.70 - 6.67 (m, 2H), 6.33 - 6.31 (m, 1H), 3.56 (s, 3H), 3.45 (s, 3H), 3.28 - 3.30 (m, 2H), 2.00 (s, 6H), 1.14 (t, J = 7.2 Hz, 3H).

[1001] Example 42: N-(tert-Butyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[1002] Preparation 153: N-(tert-Butyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[1003]

[1004] Following the procedure in Preparation 152, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (15.6 mg, 0.04 mmol) was reacted with 2-amino-2-methylpropane (0.015 mL, 0.14 mmol) to afford the title compound (3 mg, 16%).

[1005] HPLC t R (Agilent, acidic, 3.5 min): 1.54 min, m / z = 493.2 [M+H] + 。

[1006] 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (bs, 1H), 7.84 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.43 (s, 1H), 6.89 (d, J = 1.1 Hz, 1H), 6.71 - 6.67 (m, 2H), 6.33 (d, J = 7.0 Hz, 1H), 3.57 (s, 3H), 3.45 (s, 3H), 2.01 - 2.00 (m, 6H), 1.39 (s, 9H).

[1007] Example 43: N-(tert-Butyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[1008] Preparation 154: N-(tert-Butyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[1009]

[1010] Following the procedure in Preparation 152, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (15.6 mg, 0.04 mmol) was reacted with 1,1,1-trifluoro-2-methylpropan-2-amine (18.3 mg, 0.14 mmol) to afford the title compound (5 mg, 23%).

[1011] HPLC t R (Agilent, acidic, 3.5 min): 1.60 min, m / z = 547.1 [M+H] + 。

[1012] 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (bs, 1H), 8.06 (s, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.44 (s, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.70 - 6.67 (m, 2H), 6.33 (d, J = 7.1 Hz, 1H), 3.57 (s, 3H), 3.45 (s, 3H), 2.01 (s, 6H), 1.63 (s, 6H).

[1013] Example 44: N-(2,2-Difluoro-1-methylcyclopropyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[1014] Preparation 155: N-(2,2-Difluoro-1-methylcyclopropyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

[1015]

[1016] Following the procedure in Preparation 152, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (15.6 mg, 0.04 mmol) was reacted with 2,2-difluoro-1-methylcyclopropan-1-amine hydrochloride (20.5 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) to afford the title compound (3 mg, 14%).

[1017] HPLC t R (Agilent, acidic, 3.5 min): 1.49 min, m / z = 527.2 [M+H] + 。

[1018] 11H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.79 (s, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.43 (s, 1H), 6.96 (d, J = 2.2 Hz, 1H), 6.70 - 6.66 (m, 2H), 6.33 (d, J = 7.1 Hz, 1H), 3.55 (s, 3H), 3.45 (s, 3H), 2.00 (s, 6H), 1.71 - 1.62 (m, 2H), 1.48 (s, 3H).

[1019] Example 45: 4-(4-Cyclobutoxythiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1020] Preparation 156: 4-Cyclobutoxythiazole

[1021]

[1022] At room temperature, NaH (183 mg, 4.5 mmol) was added to cyclobutanol (1.29 mL, 16.5 mmol), and the resulting solution was then heated to 60 °C for 1 hour. 4-Bromo-thiazole (300 mg, 1.83 mmol) was added and the resulting solution was heated to 150 °C for 1 hour. Ethyl acetate (50 ml) was added, and the organic matter was washed successively with 2 x 50 ml of water and 1 x 50 ml of saturated brine solution. Then the organic matter was separated and dried (MgSO4), and then concentrated to dryness. The crude product was then purified by flash column chromatography, eluting with an ethyl acetate / heptane gradient (0% - 100%). The desired fractions were combined and dried to afford the reaction to give the title compound (124 mg, 44%).

[1023] 1 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 6.04 (s, 1H), 4.80 - 4.73 (m, 1H), 2.47 - 2.16 (m, 4H), 1.90 - 1.81 (m, 1H), 1.70 - 1.61 (m, 1H).

[1024] Preparation 157: 5-Bromo-4-cyclobutoxythiazole

[1025]

[1026] Following the procedure in Preparation 23, 4-cyclobutoxythiazole (485 mg, 3.1 mmol) was reacted to give the title compound (453 mg, 62%).

[1027] 11H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 5.03 - 4.90 (m, 1H), 2.37 - 2.27 (m, 2H) 2.15 - 2.05 (m, 2H), 1.79 - 1.67 (m, 1H), 1.58 - 1.45 (m, 1H).

[1028] Preparation 158: 4-(4-Cyclobutoxythiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1029]

[1030] Following the procedure in Preparation 10, 5-bromo-4-cyclobutoxythiazole (66 mg, 0.28 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (110 mg, 0.026 mmol) were reacted to afford the title compound (7 mg, 8%).

[1031] HPLC t R (Agilent, acidic, 3.5 min): 1.51 min, m / z = 302.1 [M+H] + .

[1032] 1 1H NMR (400 MHz, DMSO-d6) δ 12.17 (bs, 1H), 8.85 (s, 1H), 7.56 (s, 1H), 7.36 (t, J = 2.8 Hz, 1H), 6.44 (t, J = 2.4 Hz, 1H), 5.12 - 5.05 (m, 1H), 3.58 (s, 3H), 2.40 - 2.32 (m, 2H), 2.15 - 2.05 (m, 2H), 1.81 - 1.72 (m, 1H), 1.66 - 1.56 (m, 1H).

[1033] Example 46: 6-Methyl-4-(4-propoxythiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1034] Preparation 159: 4-Propoxythiazole

[1035]

[1036] Following the procedure in Preparation 156, 1-propanol (3.6 mL, 54.9 mmol) was reacted to afford the title compound (150 mg, 28%).

[1037] 1 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J = 2.1 Hz, 1H), 6.14 (d, J = 2.3 Hz, 1H), 4.13 - 4.09 (m, 2H), 1.89 - 1.82 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H).

[1038] Preparation 160: 5-Bromo-4-propoxythiazole

[1039]

[1040] Following the procedure in Preparation 23, 4-propoxythiazole (610 mg, 4.3 mmol) was reacted to give the title compound (592 mg, 62%).

[1041] 1 1H NMR (500 MHz, CDCl3) δ 8.53 (s, 1H), 4.33 - 4.29 (m, 2H), 1.82 - 1.74 (m, 2H), 1.04 - 1.00 (m, 3H).

[1042] Preparation 161: 6-Methyl-4-(4-propoxythiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1043]

[1044] Following the procedure in Preparation 10, 5-bromo-4-propoxythiazole (57 mg, 0.26 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (100 mg, 0.023 mmol) were reacted to give the title compound (17 mg, 23%).

[1045] HPLC t R (Agilent, acidic, 3.5 min): 1.52 min, m / z = 290.1 [M + H] + .

[1046] 1 [[ID=

[1047] Example 47: 4-(3-(4-Fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1048] Preparation 162: 2-Chloro-5-(4-fluoro-2,6-dimethylphenoxy)-4-nitropyridine 1-oxide

[1049]

[1050] Following the procedure in Preparation 35, 4-Fluoro-2,6-dimethylphenol (15.0 g, 77.9 mmol) was reacted to give the title compound (16.0 g, 64%).

[1051] 1 H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.69 (s, 1H), 6.88 (d, J = 8.4 Hz, 2H), 2.183 (s, 6H).

[1052] Preparation 163: 2,4-Dibromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridine 1-oxide

[1053]

[1054] Following the procedure in Preparation 26, 2-Chloro-5-(4-fluoro-2,6-dimethylphenoxy)-4-nitropyridine 1-oxide (11.0 g, 35.1 mmol) was reacted to give the title compound (11.9 g, 78%).

[1055] HPLC t R (Shimadzu, acidic, 1.5 min): 0.93 min, m / z = 391.8 [M+H] + .

[1056] Preparation 164: 2,4-Dibromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridine

[1057]

[1058] Following the procedure in Preparation 27, 2,4-Dibromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridine 1-oxide (17.7 g, 42.5 mmol) was reacted to give the title compound (16.5 g, 65%).

[1059] HPLC t R(Shimadzu, acidic, 1.5 min): 1.08 min, m / z = 375.8 [M+H] + 。

[1060] Preparation 165: 4-Bromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one

[1061]

[1062] Following the procedure in Preparation 38, 2,4-Dibromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridine (7.5 g, 20.0 mmol) was reacted to give the title compound (6.2 g, 99%).

[1063] HPLC t R (Shimadzu, acidic, 1.5 min): 0.90 min, m / z = 312.0 [M+H] + 。

[1064] Preparation 166: 4-Bromo-5-(4-fluoro-2,6-dimethylphenoxy)-1-methylpyridin-2(1H)-one

[1065]

[1066] Following the procedure in Preparation 39, 4-Bromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one (6.24 g, 20.0 mmol) was reacted to give the title compound (1.42 g, 22%).

[1067] 1 1H NMR (500 MHz, DMSO-d6) δ 7.04 (d, J = 8.8 Hz, 2H), 6.92 (s, 1H), 6.82 (s, 1H), 3.27 (s, 3H), 2.12 (s, 6H)

[1068] Preparation 167: 4-(3-(4-Fluoro-2,6-dimethylphenoxy)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1069]

[1070] Following the procedure in Preparation 10, 4-bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one (152 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.47 mmol) were reacted to afford the title compound (77 mg, 42%).

[1071] HPLC t R (Agilent, acidic, 3.5 min): 1.36 min, m / z = 394.1 [M+H] + 。

[1072] 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (bs, 1H), 7.46 (s, 1H), 7.36 - 7.33 (m, 1H), 7.00 - 6.96 (m, 2H), 6.72 (s, 1H), 6.51 - 6.50 (m, 1H), 6.34 (t, J = 2.3 Hz, 1H), 3.58 (s, 3H), 3.34 (s, 3H), 2.09 (s, 6H).

[1073] Main Activity

[1074] The dissociation constants (K d)。 BRD4 is a representative example of the BET family as there are no highly isotype-selective compounds to date. The dissociation constants were determined as described below and are shown in Table 1.

[1075] Bromodomain Assay Procedure

[1076] T7 phage strains displaying bromodomains were grown in parallel in 24-well blocks in an Escherichia coli host derived from the BL21 strain. The E. coli was grown to the logarithmic phase and infected with T7 phage from a frozen stock (multiplicity of infection = 0.4) and incubated with shaking at 32 °C until lysis (90 - 150 min). The lysate was centrifuged (5,000 x g) and filtered (0.2 μm) to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecules or acetylated peptide ligands for 30 min at RT to generate affinity resin for bromodomain assays. The conjugated beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and reduce non-specific phage binding. Binding reactions were assembled by combining bromodomains, conjugated affinity beads, and test compounds in 1x binding buffer (16% SeaBlock, 0.32x PBS, 0.02% BSA, 0.04% Tween 20, 0.004% sodium azide, 7.9 mM DTT). Test compounds were prepared as 1000X stock solutions in 100% DMSO and subsequently diluted 1:25 in MEG. The compounds were then diluted directly into the assay such that the final concentrations of DMSO and MEG were 0.1% and 2.4%, respectively. All reactions were carried out in polypropylene 384-well plates with a final volume of 0.02 ml. The assay plates were incubated with shaking at RT for 1 hr, and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated with shaking at RT for 30 min. The concentration of bromodomains in the eluate was measured by quantitative polymerase chain reaction (qPCR).

[1077] An 11-point 3-fold serial dilution of each test compound was prepared at a final test concentration of 1000x in 100% DMSO. All compounds were dispensed in 100% DMSO by acoustic transfer (non-contact dispensing). The compounds were then diluted directly into the assay such that the final concentration of DMSO was 0.09%. Most dissociation constants were determined using a compound highest concentration = 10,000 nM. If the initial dissociation constant measured < 0.169 nM (the lowest concentration tested), then measurements were repeated with serial dilutions starting from a lower highest concentration.

[1078] Table 1: Dissociation constants of exemplary compounds from BRD4 BD1 and BD2

[1079]

[1080]

[1081] Note

[1082] +Kd > 1 μM

[1083] ++Kd > 0.1 μM and ≤ 1 μM

[1084] +++Kd > 0.01 μM and ≤ 0.1 μM ++++Kd ≤ 0.01 μM

[1085] Preferably, the BET protein inhibitor exhibits a K of < 0.1 μM for BRD4 BD2 or BD1 and BD2 d . A K with selectivity for BRD4 BD2 d < 0.1 μM BET protein inhibitor is a promising oral candidate, while a K with selectivity for BRD4 BD1 and BD2 d < 0.1 μM BET protein inhibitor is a promising topical candidate.

[1086] BET Selectivity

[1087] Examples 1 and 41 of the present invention were assayed for selectivity against BRD2, 3, 4, and T BD1 and BD2 as described below and are shown in Table 2.

[1088] Bromodomain Assay Procedure

[1089] Using the same bromodomain assay procedure as above. Screening exemplary compounds at 30 times its K d , and the results of the primary screening binding interaction are reported as '% control', where the smaller the number, the stronger the hit in the matrix.

[1090]

[1091] Test compound = Compound of formula (I), such as Example 1

[1092] Negative control = DMSO (100% control)

[1093] Positive control = Control compound (0% control)

[1094] Table 2: Single-point concentration binding interaction of exemplary compounds

[1095]

[1096] Preferably, the BET protein inhibitor exhibits < 10% control for BRD2, 3, 4 and TBD2 or TBD1 and BD2. BET protein inhibitors with < 10% control for BRD2, 3, 4 and TBD2 are promising oral candidate drugs, while BET protein inhibitors with < 10% control for BRD2, 3, 4 and TBD1 and BD2 are promising topical candidate drugs. The data in Table 2 indicate that Example 41 is a promising oral candidate drug, while Example 1 is a promising topical candidate drug.

[1097] BET Selectivity Dose Response

[1098] The dissociation constant (K d ) of Example 41 of the present invention from BRD2, 3, 4 and TBD1 and BD2 was determined as described below and is listed in Table 3.

[1099] Bromodomain Assay Procedure

[1100] The same bromodomain assay procedure as described above was used.

[1101] Table 3: Dose-response binding interactions of exemplary compounds

[1102]

[1103] For BRD2, 3, 4 and optionally TBD2 K d < 10 nM BET protein inhibitors are promising oral candidate drugs. Example 41 exhibits a K d < 10 nM for BRD4(2), and a K d > 3000 nM for BRD4(1). Therefore, Example 41 is a promising oral candidate drug.

[1104] Cell Activity – Multiple Indicators

[1105] The EC50 values of Example compounds 1 and 3 of the present invention in reducing the levels of GM-CSF, IL-1a, IL-6, IL-8, CCL2, TNF-a, TSLP, CCL27, CCL20 and CXCL9 were determined in primary keratinocytes stimulated with polyinosinic acid: polycytidylic acid. The EC50 was determined as described below and is shown in Table 4.

[1106] Assay procedure

[1107] 1. Primary human keratinocytes (PHK) were seeded at 9000 cells / well in a flat-bottom 96-well plate.

[1108] 2. Prior to treatment, the cells must reach 90%-100% confluence, and then the medium is replaced with fresh medium without hydrocortisone.

[1109] 3. Incubate the cells for 24 hr prior to TLR ligand stimulation (polyinosinic acid: polycytidylic acid).

[1110] 4. Treat the cells with 20 μg / mL polyinosinic acid: polycytidylic acid in 180 μL medium for 48 hours and treat with different compounds or controls.

[1111] 5. Collect the supernatant and perform chemokine and cytokine analysis by Magpix-Luminex.

[1112] Immunoassay procedure

[1113] Day 1

[1114] 1. Add 200 μL assay buffer to each well. Oscillate for 10 min, RT. Decant.

[1115] 2. Add 25 μL of standards or controls to the appropriate wells.

[1116] 3. Add 25 μL assay buffer to the background wells and sample wells.

[1117] 4. Add 25 μL cell culture medium to the background wells, standard wells, and control wells.

[1118] 5. Add 25 μL of pure sample to the sample wells.

[1119] 6. Add 25 μL beads to each well.

[1120] 7. Incubate overnight (16-18 hr) at 4°C.

[1121] Day 2

[1122] 8. Remove the well contents and wash twice with 200 μL wash buffer.

[1123] 9. Add 25 μL detection antibodies to each well.

[1124] 10. Incubate for 1 hour at RT (20°C-25°C).

[1125] 11. Add 25 μL streptavidin-phycoerythrin to each well (do not aspirate).

[1126] 12. Incubate for 30 min at RT.

[1127] 13. Remove the well contents and wash twice with 200 μL of wash buffer.

[1128] 14. Add 150 μL of wash buffer to each well. Resuspend the beads on a plate shaker for 5 min.

[1129] 15. Read on a Luminex (50 beads per bead set).

[1130] Table 4: EC50 values of the exemplary compounds of the present invention. The measured drug response was a decrease in the levels of GM-CSF, IL-1a, IL-6, IL-8, CCL2, TNF-α, TSLP, CCL27, CCL20, and CXCL9 in primary keratinocytes stimulated with polyinosinic acid:polycytidylic acid.

[1131] Example GM-CSF IL-6 IL-8 1 ++++ +++ ++++ 3 ++++ +++ ++++

[1132] Example TSLP IL-1a TNF-a 1 +++ ++++ ++++ 3 ++++ ++++ ++++

[1133] Example CCL2 CCL20 CCL27 1 +++ +++ +++ 3 ++++ ++++ +++

[1134] Example CXCL9 1 ++++ 3 ++++

[1135] Note

[1136] + EC50 > 1 μM

[1137] ++ EC50 > 0.1 μM and ≤ 1 μM

[1138] +++ EC50 > 0.01 μM and ≤ 0.1 μM

[1139] ++++ EC50 ≤ 0.01 μM

[1140] Preferably, the BET protein inhibitor exhibits a cellular EC50 value of < 0.1 μM for one or more disease-related markers in stimulated human primary keratinocytes. Examples 1 and 3 exhibit a cellular EC50 value of < 0.1 μM in stimulated human primary keratinocytes.

[1141] Cell Activity – IL-4

[1142] The EC50 values of the compounds of the specific embodiments of the present invention in reducing the level of IL-4 produced by CD4+ T cells activated by CD2, CD3, and CD28 antibodies were determined as described below and are listed in Table 5.

[1143] Assay procedure

[1144] 1. Use EasySep TMA kit (product catalog number 17952, Stemcell Technologies) was used to isolate CD4 + T cells from cryopreserved human peripheral blood mononuclear cells (PBMCs).

[1145] 2. Beads coated with CD2, CD3, and CD28 antibodies from a T cell activation / expansion kit (product catalog number 130 - 091 - 441, Miltenyi Biotec) were added to the CD4 + T cells at a bead - to - cell ratio of 1:2.

[1146] 3. The CD4 + T cells together with the beads were seeded at 2x10 5 cells / well in a round - bottom 96 - well plate and treated with different compounds and controls, with a total volume of 200 μl.

[1147] 4. The cells were cultured at 37 °C and 5% CO2 for 48 hr.

[1148] 5. The supernatant was collected and IL - 4 was analyzed by ELISA.

[1149] Table 5: EC50 values of the exemplary compounds of the present invention. The measured drug response was the reduction in IL - 4 levels in CD4+ T cells stimulated with CD2, CD3, and CD28 antibody - coated beads

[1150] Example IL-4 1 ++++ 3 +++ 4 +++ 5 ++++ 6 +++ 7 +++ 8 ++ 10 +++ 18 + 20 +++ 24 ++ 39 + 40 ++ 41 +++ 42 ++ 43 ++ 44 ++ 46 +++ 47 ++

[1151] Note

[1152] + EC50 > 1 μM

[1153] ++ EC50 > 0.1 μM and ≤ 1 μM

[1154] +++ EC50 > 0.01 μM and ≤ 0.1 μM

[1155] ++++ EC50 ≤ 0.01 μM

[1156] Preferably, the BET protein inhibitor exhibits a cellular EC50 value of < 0.1 μM for reducing IL - 4 levels. Examples 1, 3, 4, 5, 6, 7, 10, 20, 41, and 46 exhibit cellular EC50 values of < 0.1 μM in CD4+ T cells stimulated with CD2, CD3, and CD28 antibody - coated beads from a T cell activation / expansion kit.

[1157] Human Tissue Data - Stimulation of Th2 and Th17 on Human Skin Explants

[1158] The % reduction of the compounds of the examples listed below of the present invention at 2.5 μM on IL-4 or IL-17A mRNA was determined in healthy human skin stimulated with Th2- or Th17-biased mixtures and is listed in Table 6.

[1159] Assay procedure

[1160] 1. Healthy human skin tissue freshly excised from abdominoplasty was defatted, cleaned and cut into 7 mm biopsies.

[1161] 2. The biopsies were placed in inserts with the epidermal tip exposed to air and the dermis immersed in the medium in the basal chamber.

[1162] 3. The biopsies were pre-treated overnight at 37 °C, 5% CO2 with different compounds and controls added to the medium in the basal chamber.

[1163] 4. The next day, the contents of the basal chamber were replaced with fresh medium containing the test compound and a stimulating mixture for Th2 inflammation (proprietary Medpharm mixture) or Th17 inflammation (mixture of antibodies against CD3, CD28, IL-4, IFNγ and recombinant IL-1β, IL-6, IL-21, TGF-β).

[1164] 5. The biopsies were incubated for another 24 hours at 37 °C, 5% CO2.

[1165] 6. After harvesting, the biopsies were cut in half and one half was homogenized and used for RNA extraction by standard methods. IL-4 or IL-17A was evaluated by RT-qPCR.

[1166] Table 6: % reduction of IL-4 and IL-17A mRNA by compounds 1 and 41 of the present invention at 2.5 μM. The measured drug response is the reduction of IL-4 or IL-17A mRNA levels in healthy human skin stimulated with Th-2 or Th17-biased mixtures.

[1167] Example IL-17 IL-4 1 +++ +++ 41 +++ ++

[1168] Note

[1169] + > 25% reduction

[1170] ++ > 50% reduction

[1171] +++ > 75% reduction

[1172] Preferably, the BET protein inhibitor exhibits a >50% decrease in IL-4 or IL-17 levels, and Examples 1 and 41 exhibit a >50% decrease in healthy human skin stimulated with a Th2 or Th17-biased mixture.

[1173] Intrinsic Clearance of Human Hepatocytes

[1174] BET protein inhibitors with rapid clearance rates in human hepatocytes are promising topical candidates. Some of the exemplary compounds of the present invention have rapid clearance in human hepatocytes, and the rate is expressed as a percentage of hepatic blood flow. Experimental methods and results are provided below (Table 7).

[1175] Assay Procedure

[1176] Thaw vial human cryopreserved hepatocytes provided by Life Technologies according to the manufacturer's instructions, and resuspend the cells in Williams Medium E (WME) containing a cell maintenance supplement pack (CM4000, Life Technologies). Incubate the hepatocytes in a 48-well non-collagen-coated cell culture plate (500,000 cells / mL) at 37 °C, 5% CO2 for 10 min. After adding an equal volume of supplemented WME containing 1 μM test compound, transfer an aliquot of the incubation solution to acetonitrile containing an internal standard (final concentration of 0.5 μM test compound, and cell density of 250,000 cells / mL). Similarly, take aliquots at 3, 6, 9, 15, 30, 45, 60, 90, and 120 min. Add 100 μL of 80:20 water:acetonitrile to all samples, and centrifuge the assay plate at RT for 10 min before injection and analysis of the samples by UPLC-MS / MS. Plot the reaction (area ratio of test compound to internal standard) against time using an exponential decay model, from which the disappearance rate is calculated.

[1177] Table 7: Intrinsic Clearance Rates (%) of Exemplary Compounds 1 to 3 in Human Hepatocytes.

[1178] Example % Hepatic Blood Flow 1 83 2 88 3 86 4 80 5 <34 6 94 7 <34 8 95 9 95 10 93 11 97 12 82 13 34 18 69 22 <34 23 38 24 45 25 38 26 <34 27 <34 28 <34 29 <34 30 <34 31 <34 32 <34 33 <34 34 <34 40 <34 41 <34 42 <34 43 38 44 34 45 86 46 89

[1179] Preferably, the BET protein inhibitor used as a topical drug exhibits an intrinsic clearance rate >75% in human hepatocytes. Exemplary compounds 1 to 4, 6, 8 to 12, 45, and 46 exhibit an intrinsic clearance rate >75%.

[1180] Solubility in Topical Formulations

[1181] Examples 1 to 3 and 6 of the present invention have shown desirable solubility in a series of simple topical formulations. Solubility is expressed in mg / mL. Experimental methods and results are provided below.

[1182] Determination procedure

[1183] After equilibration, the solubility of the solid exemplary compounds was determined in the selected solvents and solvent combinations (Transcutol, 50:50 Transcutol:water, Labrasol, propylene glycol, and 1:5:4 ethanol:propylene glycol:water). An appropriate volume of each combination was added to a manually weighed amount of the solid compound to provide a concentration of 20 mg / mL. The resulting suspension was shaken at 1000 rpm for 5 hr at 32 °C and then centrifuged at 13,000 x g for 10 min to precipitate any solids. The supernatant was removed and inserted into an HPLC vial and quantified by HPLC-UV against a calibration of the compound at known concentrations in DMSO.

[1184] Table 8: Solubility of exemplary compounds of the invention in various solvents and solvent combinations. TC is Transcutol; LB is Labrasol; PG is propylene glycol; EtOH is ethanol.

[1185] Example TC TC: Water 1:1 LB 1 +++ ++ ++ 2 +++ ++ ++ 3 +++ +++ +++ 6 +++ ++ +++

[1186]

[1187] Note

[1188] + > 0.1 mg / mL and ≤ 1 mg / mL

[1189] ++ > 1 mg / mL and ≤ 10 mg / mL

[1190] +++ > 10 mg / mL

[1191] Preferably, the BET protein inhibitors for topical formulations exhibit a solubility of the formulation > 1 mg / mL. Exemplary compounds 1 to 3 and 6 exhibit a solubility of the formulation > 1 mg / mL and in some cases > 10 mg / mL.

[1192] Stability in Human Skin S9 Fraction

[1193] Exemplary compounds 1 to 3 and 6 have desirable stability in human skin S9 fractions. Such fractions mimic human skin and the stability is expressed as the time required for the compound concentration to decrease by half (half-life). The experimental method and some results (Table 9) are provided below.

[1194] Determination procedure

[1195] Prepare an incubation mixture containing 50 mM potassium phosphate buffer (pH 7.4), 0.3 mg / mL human skin S9 (Sekisui Xenotech), NADPH (final concentration 0.8 mg / mL), and UDPGA (final concentration 0.16 mg / mL) and warm it to 37 °C for 5 min. Start the reaction after adding the test compound (final concentration 0.5 μM). Immediately, at time zero, then at 3, 6, 15, 30, 60, 120, and 180 min, take an aliquot (50 μL) of the incubation mixture and mix it with acetonitrile (100 μL) to terminate the reaction. Add the internal standard to all samples, centrifuge the samples to deposit the precipitated protein, then seal the plate, and subsequently perform UPLC-MS / MS analysis using a Quattro Premier XE (Waters corporation, USA).

[1196] Grafit (Erithacus Ltd) was used to calculate the exponential decay, and thus the rate constant (k) was calculated from the ratio of the peak area of the test compound to the internal standard at each time point. The half-life (T 1 / 2 ) of each test compound was determined using the following equation:

[1197] T 1 / 2 = 0.693 / k

[1198] Table 9: T of exemplary compounds in human skin S9 fraction 1 / 2 .

[1199] Example <![CDATA[T 1 / 2 (min)]]> 1 >120 2 >120 3 >120 6 >120

[1200] Preferably, the BET protein inhibitor for topical formulations exhibits a T 1 / 2 value > 120 minutes in human skin. Exemplary compounds 1 to 3 and 6 exhibit a T 1 / 2 value > 120 min in human skin S9 fraction.

[1201] Hydrolytic Stability at a Series of pH Values

[1202] Exemplary compounds 1 to 3 of the present invention are stable under conditions designed to promote hydrolytic degradation. The stability is expressed as % decrease after 6 days. The experimental methods and results are provided below (Table 10).

[1203] Assay Procedure

[1204] To test the hydrolytic stability, a 1 mg / mL solution of the test material was prepared in DMSO (0.1% solution). To 300 μL of each solution in an HPLC vial, add 1200 μL of one of the following:

[1205] pH 4.0 buffer – Held at 60 °C for 5 days. Samples taken at t = 0 hr and 6 days

[1206] pH 5.5 buffer – Held at 60 °C for 5 days. Samples taken at t = 0 hr and 6 days

[1207] pH 7.4 buffer – Held at 60 °C for 5 days. Samples taken at t = 0 hr and 6 days

[1208] At each time point, 100 μL aliquots were taken and added to 900 μL DMSO. This sample was used to determine % degradation.

[1209] % Degradation was measured using a Bruker MicrOTOF II Focus ESI mass spectrometer in parallel with a Dionex Ultimate 3000 RSLC system with a diode array detector.

[1210] Table 10: Hydrolytic stability of exemplary compounds of the invention under conditions designed to promote hydrolytic degradation, measured at specific pH values and given as % degradation.

[1211]

[1212] Preferably, the BET protein inhibitor exhibits < 5% degradation under conditions designed to promote hydrolytic cleavage. When tested at a pH of 7.4, exemplary compounds 1 to 3 exhibit < 5% degradation. Compounds 1 and 3 exhibit < 5% degradation at all tested pH values.

[1213] Skin Permeation (Franz Cell)

[1214] Example 1 of the invention has desirable skin penetration properties in human skin. Epidermal skin concentrations were determined as described below; experimental methods and some results are provided below (Table 11).

[1215] Determination procedure

[1216] Administration solutions were prepared at saturated concentration for each test compound in a suitable formulation mixture. The positive control, caffeine (final concentration 10 mg / mL), was prepared in 50:50 transcutol / water. Warm, degassed phosphate buffered saline (PBS) was applied to the receiving chamber (1 cm, containing a magnetic stir bar) of each jacketed Franz cell. Porcine / human skin was removed from -80 °C storage and cut to a certain size (~2 cm) using a scalpel. 2)。Then thaw the skin at RT and then place it in warm PBS for 10 min. Then dry each skin piece and then place it on the orifice of the Franz cell, removing any air bubbles that appear. Place the donor chamber on the skin and clamp it in place. Then place 10 μL of the dosing solution on the skin and place a sealing film on the donor chamber to provide occlusion. Using a 1 mL syringe, transfer 200 μL of the receiving solution to a 96 deep well plate via the sampling arm, which is the first time point (T0). Add 200 μL of fresh warm buffer to replace the removed volume. Remove another 200 μL at the defined time points within 24 hr as described above. Then transfer 100 μL of each sample to 100 μL of acetonitrile containing the internal standard (IS, Donepezil, 4 ng / mL).

[1217] After completion, wipe the skin surface with a cotton swab to remove any remaining compound. Then dip the cotton swab tip into DMSO for compound extraction. Remove the skin from the Franz cell and apply 30 strips of tape to remove the stratum corneum and place it in a vial containing a known volume of DMSO. Then place the skin surface down on a heating block at 70 °C for 1 minute and then gradually pick the epidermis from the dermis using a scalpel. Cut the remaining dermis from the compressed tissue such that exposed tissue is left, weigh the two pieces of tissue and then place them in separate glass vials and add a known volume of DMSO.

[1218] Place all skin extraction and wash samples on an oscillator at RT for 24 hours and then transfer the samples to Eppendorfs (where applicable) and centrifuge. Remove the supernatant and dilute appropriately (e.g., 1:10, 100, 500, and 1000).

[1219] Prepare calibration lines in PBS (5000 ng / mL – 0.2 ng / mL). Add 100 μL of each sample to 100 μL of acetonitrile containing the IS. All samples are quantified using UPLC-MS / MS (Waters Xevo TQ-S).

[1220] The concentration of the compound present at each time point is corrected for the addition of fresh buffer. By plotting the compound concentration versus time, the J flux and T lag can be calculated (the values for caffeine should be approximately J flux: 0.9 - 1.1 μg / cm / hr, T 滞后 : 244 - 257 min, ~20% of the dose is present in the receiving chamber after 24 hours, mass balance 70% - 90%).

[1221] Skin extraction samples are corrected for the dilution factor and the volume of the extraction solution. The amount of the dose measured in the skin layer and time point samples is used to measure the mass balance of the experiment.

[1222] The exemplary compound did not penetrate the skin (thus no J flux and T hysteresis values are given). In contrast, the exemplary compound was present in high concentrations in the skin (see Table 11). The mass balance was calculated to be 94%.

[1223] Table 11: Concentrations of exemplary compounds of the invention in pig / human skin epidermis 24 hours after skin surface exposure to the corresponding compounds.

[1224] Example Epidermal Concentration (μM) 1 27

[1225] Primary Keratinocyte Viability

[1226] The EC50s of exemplary compounds 1 and 3 of the present invention were determined in human primary keratinocytes stimulated with polyinosinic:polycytidylic acid. The EC50s were determined as described below and are shown in Table 12, where the compound numbers correspond to those in the Examples.

[1227] Determination procedure

[1228] 1. Primary human keratinocytes (PHK) were seeded at 9000 cells / well in a flat-bottom 96-well plate.

[1229] 2. Before treatment, cells must reach 90%-100% cell confluence, and then the culture medium is replaced with fresh culture medium without hydrocortisone.

[1230] 3. The cells were cultured for 24 hours before TLR ligand stimulation (polyinosinic:polycytidylic acid).

[1231] 4. Cells were treated with 20 μg / ml polyinosinic:polycytidylic acid in 180 μl of culture medium for 48 hours and treated with different compounds or controls.

[1232] 6. Add 20 μL of Cell Titer Blue reagent along with 100 μL of fresh culture medium directly to each well and incubate at 37°C (cell culture incubator) until the blue color turns to light pink (usually 1 hr).

[1233] 7. Fluorescence was measured using a Citation 3 instrument. Excitation: 560 nm. Emission: 590 nm.

[1234] Table 12: EC50 values of exemplary compounds of the invention in human primary keratinocytes.

[1235] Example Viability (EC50 μM) 1 >10 3 >10

[1236] Preferably, the BET protein inhibitor exhibits a cell viability (EC50 value) > 1 μM. Exemplary compounds 1 and 3 exhibit a cell viability (EC50 value) > 1 μM in human primary keratinocytes.

Claims

1. A compound of formula (I): wherein ring structure A is a 5- or 6-membered aromatic or heteroaromatic ring optionally substituted at one or more carbon and / or heteroatoms with a first substituent; wherein each first substituent is independently selected from the group consisting of hydroxy, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl alcohol, halo, SO2C1-C4 alkyl, NHSO2C1-C4 alkyl, SO2C3-C6 cycloalkyl, NHSO2C3-C6 cycloalkyl, SO2C1-C4 alkyl alcohol, NHSO2C1-C4 alkyl alcohol, C1-C5 alkoxy, C1-C5 alkylamino, SO2NH2, CONH2, CONHC1-C4 alkyl, NHCOC1-C4 alkyl, NHSO2N(C1-C4 alkyl)2, C1-C6 fluoroalkyl, SO2C1-C4 fluoroalkyl, NHSO2C1-C4 fluoroalkyl, C1-C5 fluoroalkoxy and C1-C5 fluoroalkylamino; X is O, CR2, NR' or S, where R is independently selected from the group consisting of H, C1-C4 alkyl and halo, and R' is selected from the group consisting of C1-C4 alkyl and H; Z is a 5- or 6-membered aromatic or heteroaromatic ring optionally substituted at one or more carbon and / or heteroatoms with a second substituent, C1-C6 alkyl, C3-C6 cycloalkyl, CR A R B R C , C2-C5 oxacycloalkyl, C2-C5 azacycloalkyl or morpholinyl; wherein R A is a C3-C5 cycloalkyl group, R B is a C3-C5 cycloalkyl group, methyl or ethyl, and R C is OH; and each second substituent is independently selected from the group consisting of hydroxy, C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C5 alkoxy, C1-C5 alkylamino, oxo, cyano, C1-C6 fluoroalkyl, C1-C5 fluoroalkoxy and C1-C5 fluoroalkylamino; ring structure B is optionally present; wherein when ring structure B is present, it is an optionally substituted pyrrole bonded such that C is in the 4-position relative to NH; wherein the pyrrole is optionally substituted at position 2 with a third substituent; wherein the third substituent is selected from the group consisting of CONHC1-C4 alkyl, CONH2, CONHC1-C6 fluoroalkyl, CONHC3-C6 cycloalkyl optionally substituted at one or more carbon atoms with methyl or ethyl; CONHC3-C5 cycloalkylfluoro optionally substituted at one or more carbon atoms with methyl or ethyl, NHCOC1-C4 alkyl and NHCOC1-C4 fluoroalkyl; provided that when A is 6-membered, it is substituted with a hydroxy or oxo group at least once.

2. The compound according to claim 1, wherein the compound has the formula (II): wherein A, X and Z are as defined for formula (I).

3. The compound according to claim 1 or claim 2, wherein A is selected from the group consisting of benzene, pyridine, thiazole, pyridone, pyrazole, imidazole and 1,2,4-triazole optionally substituted at one or more carbon and / or heteroatoms with the first substituent.

4. The compound according to claim 3, wherein the pyridone is 2-pyridone.

5. The compound according to claim 4, wherein the 2-pyridone carbon at position 3 is bonded to X and the 2-pyridone carbon at position 4 is bonded to C; or the 2-pyridone carbon at position 5 is bonded to X and the 2-pyridone carbon at position 4 is bonded to C.

6. The compound according to any one of claims 3 to 5, wherein the thiazole carbon at position 4 is bonded to C and the thiazole carbon at position 5 is bonded to X.

7. The compound according to any one of claims 3 to 6, wherein the pyrazole carbon at position 5 is bonded to C and the pyrazole nitrogen at position 1 is bonded to X.

8. The compound according to any one of claims 3 to 7, wherein the imidazole carbon at position 2 is bonded to C and the nitrogen at position 1 is bonded to X.

9. The compound according to any one of claims 3 to 8, wherein the 1,2,4-triazole carbon at position 5 is bonded to C and the nitrogen at position 1 is bonded to X.

10. The compound according to any one of the preceding claims, wherein each first substituent is independently selected from the group consisting of hydroxy, oxo, methyl, and halo.

Images