Compounds comprising n-methyl-2-pyridone, and pharmaceutically acceptable salts

Abstract

To provide novel BET protein inhibitors useful for the treatment of diseases caused by abnormal regulation of Bromodomain and Extra-Terminal (BET) protein activity (e.g., inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, rheumatic diseases, demyelinating diseases and fibrotic diseases).SOLUTION: For example, pyrrolo[2,3-c]pyridine derivatives having the following structure are disclosed.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to compounds comprising N-methyl-2-pyridone, as well as pharma- ceutically acceptable salts and compositions of such compounds.The compounds of the invention are useful as anti-inflammatory and anti-cancer therapeutic agents.Thus, the present invention also relates to compounds comprising N-methyl-2-pyridone for use as medicaments, particularly for the treatment of inflammatory diseases and tumors. [Background technology]

[0002] Bromodomain and extra-terminal (BET) proteins are a family of four bromodomain-containing (BRD) proteins (BRD2, BRD3, BRD4, and BRDT). All four members contain two BRDs (located adjacent to each other toward 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 designated binding domain I (BDI) and binding domain II (BDII). BRDs are functional protein domains that contain a defined, primarily hydrophobic pocket that binds to acetylated lysine residues, typically found on transcription factors (Shi, J. et al. Cancer Cell 25(2):210-225 (2014)) or the N-terminal tails of histone proteins. BRDs function as epigenetic regulators, i.e., they functionally alter gene activity and expression without altering the DNA sequence. For example, BRD4 recruits the transcription factor P-TEFb to promoters, resulting in changes in the expression of genes involved in the cell cycle (Yang et al., Mol. Cell Biol. 28: 967-976 (2008)). BRD2 and BRD3 also control proliferation-promoting genes (LeRoy et al., Mol Cell 30:51-60 (2008)). Thus, BRDs are involved in transmitting signals conveyed by acetylated lysine residues to various phenotypes. BETs are considered in the art to be ubiquitously expressed in humans, with the exception of BRDT, which is normally expressed in the testis but is also expressed by some cancers (Ekaterina BF et al. Cell J. 19(Suppl 1): 1-8 (2017)).

[0003] BET proteins have roles in the regulation of many pathways such as MYC, BCL2, FOSL1, P-TEFb, NFkB, and glucocorticoid signaling (Shi J. et al. Mol Cell. Jun 5;54(5):728-36 (2014)), (Hajmirza A. Biomedicines. Feb 6;6(1). pii: E16 (2018)), (Shan N. Elife. Sep 11;6. pii: e27861. (2017)), (Huang B. Mol Cell Biol. Mar;29(5):1375-87 (2009)). As such, BET inhibitors may have potential applications in a wide range of inflammatory, cancer, infection, metabolic, CNS, fibrotic and cardiac diseases (Deanna AM et al. J Exp Med. Oct 21; 210(11): 2181-2190 (2013)), (Rab KP et al. Trends Pharmacol. Sci. Mar;33(3):146-53 (2012)), (Anna CB et al. J Immunol. Apr 1; ​​190(7): 3670-3678 (2013)), (Zuber J. et al. Nature. Aug 3;478(7370):524-8. (2011)), (Montserrat PS 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. Aug 11; 292(32): 13284-13295 (2017)), (Ning D. et al. PNAS December 22, 112 (51) 15713-15718 (2015)).

[0004] 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. Several small molecules have been reported to be effective in BET inhibition, including diazepine-, 3,5-dimethylisoxazole-, thiazol-2-one-, diazobenzene-, and 4-acylpyrrole-based compounds (see M. Brand et al, ACS Chem. Biol. 2015, 10, 22-39, WO2011054553, WO2011054845). Compounds that can selectively inhibit the function of BDII over BDI 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 for an improved therapeutic index. Improved therapeutic index and preclinical safety of BDII-selective BET inhibitors compared with pan-BET inhibitors have been demonstrated (E. Faivre et al. Nature 578, 306-310 (2020)).

[0005] 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 have been described as useful for inhibiting BET proteins in patent applications WO2017177955, WO2016077378, WO2015081280, WO2014206150, WO2014206345, WO2013097601, WO2013097052 and WO2018130174.

[0006] The present invention provides further BET protein inhibitors useful in the treatment or prevention of the conditions described herein. Summary of the Invention

[0007] The compounds and compositions of the teachings have surprisingly been found to be active in inhibiting all four BET BRDs and have effective potency at nanomolar concentrations. The compounds and compositions are highly soluble in a wide range of solvents and formulations suitable for topical and / or oral application. Advantageously, many of the compounds and compositions of the present invention are stable in human skin and under hydrolysis conditions at a wide range of pH values. Furthermore, the compound and composition formulations can deliver practical 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 clearance by the liver, offering the potential for use as drugs with lower risk of side effects. Other compounds and compositions are surprisingly stable, offering the potential for use as drugs for oral administration. Some of the compounds are surprisingly selective for BDII over BDI, offering improved therapeutic index and lower risk of side effects.

[0008] Those skilled in the art will appreciate that any reference to an aspect of the present disclosure includes all embodiments of that aspect, for example, any reference to a first aspect includes the first aspect and all embodiments of the first aspect.

[0009] Viewed from a first aspect, there is provided a compound of formula (I): [ka] 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; Each first substituent is selected from the group consisting of hydroxy, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkylol, Halo, SO 2 C 1 -C 4 Alkyl, NHSO 2 C 1 -C 4Alkyl, SO 2 C 3 -C 6 Cycloalkyl, NHSO 2 C 3 -C 6 Cycloalkyl, SO 2 C 1 -C 4 Alkyrol, NHSO 2 C 1 -C 4 Alkyrol, C 1 -C 5 Alkyloxy, C 1 -C 5 Alkylamino, SO 2 NH 2 ,CONH 2 , CONH.C. 1 -C 4 Alkyl, NHCOC 1 -C 4 Alkyl, NHSO 2 N(C 1 -C 4 Alkyl) 2 , C 1 -C 6 Fluoroalkyl, SO 2 C 1 -C 4 Fluoroalkyl, NHSO 2 C 1 -C 4 Fluoroalkyl, C 1 -C 5 Fluoroalkyloxy, and C 1 -C 5 fluoroalkylamino; X is O, CR 2 , NR' or S, R is H, C 1 -C 4 R' is independently selected from the group consisting of alkyl and halo, 1 -C 4 selected from the group consisting of 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; 1 -C 6 Alkyl, C3 -C 6 Cycloalkyl, CR A R B R C , C 2 -C 5 Oxacycloalkyl, C 2 -C 5 azacycloalkyl or morpholinyl; R A is C 3 -C 5 cycloalkyl, R B is C 3 -C 5 cycloalkyl, methyl or ethyl; R C is OH; and Each second substituent is hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, C 1 -C 5 Alkyloxy, C 1 -C 5 Alkylamino, oxo, cyano, C 1 -C 6 Fluoroalkyl, C 1 -C 5 Fluoroalkyloxy, and C 1 -C 5 fluoroalkylamino; Ring structure B is optionally present; when ring structure B is present, it is an optionally substituted pyrrole bonded such that C is in the 4-position relative to NH; the pyrrole is optionally substituted with a third substituent at the 2-position; The third substituent is CONHC 1 -C 4 Alkyl, CONH 2 , CONH.C. 1 -C 6 Fluoroalkyl, CONHC 3 -C 6 Cycloalkyl (optionally substituted at one or more carbon atoms with methyl or ethyl); CONHC 3 -C 5Cyclofluoroalkyl (optionally substituted at one or more carbon atoms with methyl or ethyl), NHCOC 1 -C 4 Alkyl and NHCOC 1 -C 4 fluoroalkyl; With the proviso that when A is six-membered, it is substituted at least once with a hydroxy or oxo group.

[0010] Viewed from a second aspect, there is provided a pharmaceutical composition comprising any one or a combination of compounds as defined in the first aspect, in combination with one or more pharma- ceutically acceptable excipients.

[0011] Viewed from 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.

[0012] Viewed from 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 treatment or prophylaxis of inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases and fibrotic diseases.

[0013] Viewed from 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 use in inhibiting bromodomains and extra-terminal proteins.

[0014] In view of a sixth aspect there is provided a method for the treatment or prophylaxis of inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases and fibrotic diseases, said 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.

[0015] In view of a seventh aspect there is provided a method of inhibiting bromodomain and extra-terminal protein activity in a subject, said method comprising administering to the 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 OF THE PREFERRED EMBODIMENTS

[0016] Structurally novel derivatives of N-methyl-2-pyridone have been found to be surprisingly effective at inhibiting all four BET BRDs at least as effectively as inhibitors known in the art. In some cases, the compounds described herein are superior to known BET protein inhibitors. The compounds are now described in detail.

[0017] In the following discussion, a number of terms are referred to, which have the meanings provided below, 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 the IUPAC organization for chemical compounds, specifically the "IUPAC Chemical Glossary (Gold Book)". To avoid any doubt, if the rules of the IUPAC organization are contrary to the definitions provided herein, the definitions herein shall prevail. Furthermore, if a compound structure is contrary to the name provided for that structure, that structure shall prevail.

[0018] The term "therapeutic index", also known as the "therapeutic window" or "safety margin", defines the relative safety of a drug. The therapeutic index can be calculated as the ratio of the area under the curve (AUC) in blood at the concentration of the drug that results in no toxicity (no observed adverse effect dose - NOAEL) to the concentration of the drug that produces the desired efficacy, typically the 50% effective dose - 50% effective dose or ED50. TI = AUC(NOAEL) / AUC(ED50). Drugs with a higher therapeutic index are preferred because administration of the drug is less likely to cause unwanted side effects, more drug can be administered, and the subject can be treated more effectively. The efficacy of BET inhibitors is driven by their inhibition of the function of BDII, while inhibition of the function of BDI leads to unwanted side effects. Thus, drugs that selectively inhibit the function of BDII over BDI may regulate gene expression and treat diseases caused, at least in part, by aberrant regulation of BET, and are less likely to cause unwanted side effects than pan-inhibitors administered at the same dose. Drugs that selectively inhibit BDII over BDI can be administered at higher doses than pan-inhibitors, and thus such selective drugs may be more effective.

[0019] The term "aromatic" defines a cyclically conjugated molecular entity that has significantly greater stability (due to delocalization) than the assumed localized structure. In the art, the Hückel rule is often used to assess aromaticity; a monocyclic planar (or nearly planar) system of trigonally (or sometimes digonally) hybridized atoms containing (4n+2) π-electrons (where n is a non-negative integer) indicates aromaticity. The rule is generally restricted to n=0-5.

[0020] The term "heteroaromatic" defines a cyclically conjugated molecular entity that contains heteroatoms and has significantly greater stability (due to delocalization) than the assumed localized structure.

[0021] The term "cyclic," or variations thereof, defines a compound in which one or more successions of atoms in the compound are joined to form a ring, while the term "non-cyclic" defines a compound that does not contain a ring of atoms.

[0022] The term "conjugated," or variations 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 with another across the intervening pi bonds in such a structure. In appropriate molecular entities, d orbitals may be involved. The term also extends to analogous interactions involving p orbitals that contain unshared pairs of electrons.

[0023] The term "delocalized" defines a π-bond in a conjugated system where the bond is not localized between two atoms, but instead each link has a partial double bond character, or bond order.

[0024] It will be understood that the term "comprising" or variations thereof imply the inclusion of a 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.

[0025] It will be understood that the term "consisting of" or variations thereof imply the inclusion of the stated elements, integers or steps, or group of elements, integers or steps, and the exclusion of any other elements, integers or steps, or group of elements, integers or steps.

[0026] The term "alkyl" is well known in the art and defines a monovalent group derived from an alkane by removing one hydrogen atom from any carbon atom, and the term "alkane" has the general formula C n H 2n+2 It is intended to define cyclic or acyclic branched or unbranched hydrocarbons having the formula: where n is an integer ≧1.

[0027] The term "cycloalkyl" defines all monovalent groups derived from a cycloalkane by removing a hydrogen atom from a ring carbon atom. The term "cycloalkane" defines saturated monocyclic and polycyclic hydrocarbons.

[0028] The term "alkylol" defines the hydroxy derivative of an alkyl radical, ie, hydroxy-alkyl.

[0029] The term "halo" is well recognized in the art and defines a halogen radical that forms a fluoride, chloride, bromide, or iodide compound when attached to a carbon radical.

[0030] The term "alkyloxy" is synonymous with "alkoxy" and as used herein defines a monovalent group containing an alkyl single-bonded to an oxygen atom derived from the corresponding alcohol by removal of the hydrogen atom bonded to the oxygen atom.

[0031] The term "alkylamino" is synonymous with "alkamino" and, as used herein, defines a monovalent group containing an alkyl single-bonded to an amino group derived from the corresponding amine by removal of the hydrogen atom bonded to the nitrogen atom.

[0032] The term "oxacycloalkyl" defines a monovalent radical containing a cycloalkyl, in this case CH 2 One of the moieties is replaced with an oxide. Similarly, the term "azacycloalkyl" defines a monovalent radical containing a cycloalkyl, in this case CH 2 One of the moieties is replaced with an NH moiety.

[0033] The term "treatment" defines the therapeutic treatment of a human or non-human animal to prevent or reduce or stop the rate of progression of a disease state, or to ameliorate or cure a disease state. Prevention of a disease state as a result of treatment is also included. Reference to prevention is not intended herein to require complete prevention of a disease state: its onset may instead be prevented by treatment with the invention. Typically, treatment is not prophylactic, and a compound or composition is administered to a patient with a diagnosed or suspected disease state. As used herein, an "effective amount" defines the amount of a compound or composition of the invention that is sufficient to prevent the disease, thus producing the desired therapeutic or inhibitory effect.

[0034] The term "stereoisomers" is used herein to refer to isomers that have identical molecular formulas and sequence of bonded atoms, but that differ in the arrangement of their atoms in space.

[0035] The term "enantiomer" defines one of a pair of molecular entities that are mirror images of each other and are non-superimposable, i.e., cannot be matched by translational and / or rigid rotational transformations. Enantiomers are chiral molecules, i.e., distinguishable from their mirror images.

[0036] The term "racemic" is used herein to refer to a racemate, which defines a substantially equimolar mixture of a pair of enantiomers.

[0037] The term "diastereoisomers" (also known as diastereomers) defines stereoisomers that are not related as mirror images.

[0038] The term "solvate" is used herein to refer to a complex that includes a solute, such as a compound or a salt of a compound, and a solvent.When the solvent is water, the solvate can be referred to as a hydrate, such as a monohydrate, a dihydrate, a trihydrate, etc., depending on the number of water molecules present per molecule of substrate.

[0039] The term "isotope" is used herein to define variants of a particular chemical element whose nuclei necessarily have the same atomic number but have different numbers of neutrons and therefore different mass numbers.

[0040] The term "prodrug" is used herein to refer to compounds that act as drug precursors and, upon administration to a subject, are converted by metabolic or other chemical processes to provide a compound of formula (I).

[0041] The term "pharmaceutical acceptable excipient" defines a substance, other than a pharmacologically active drug or prodrug, that is included in a pharmaceutical product.

[0042] The term "topical," when used in reference to a compound or composition of the invention, is used to refer to the compound or composition being applicable to a body surface, such as the skin or mucous membranes. The topical compound or composition may be applied in the form of a cream, foam, gel, lotion, or ointment.

[0043] The term "oral," when used in reference to a compound or composition of the present invention, is used to refer to the ability of the compound or composition to be administered via the mouth. Typically, oral compounds exhibit systemic rather than local effects, i.e., they affect multiple organ systems rather than a localized area.

[0044] The terms "transduce" or "transmitting" when used in reference to a signal are synonymous with "transfer" or "transmitting", i.e., "signal transduction" is the process of transmitting a signal through an organism, e.g., through a cell.

[0045] The term "pan" is used herein to refer to "all." For example, pan-inhibition of the BET family means that all of the members of the BET family (BRD2, BRD3, BRD4, and BRDT) are inhibited.

[0046] 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 on its cell surface (a molecule responsible for recognizing fragments of antigenic peptides).

[0047] The term "cytokine" is used herein to refer to small proteins (approximately 5-20 kDa) that are important in cell signaling, including as immunomodulators, autocrine, paracrine and endocrine signaling.

[0048] The term "chemokine" is used herein to refer to a family of cytokines that can induce directed chemotaxis in responding cells, i.e., they act as chemoattractants to induce cell migration.

[0049] The term "intrinsic clearance" is well known in the art and refers to the ability of the liver to remove a drug without flow restriction and binding to cells or proteins in the blood. Intrinsic clearance is expressed herein as a percentage of hepatic blood flow, i.e.,

number

[0050] The term "soft drugs" refers to compounds that are rapidly metabolized once they reach the blood or liver. Highly cleared compounds are considered to have clearance rates of >70% of the hepatic blood flow, most often >75%, intermediate rates are 30-70%, most often 50-75%, and slow rates are <30%, most often <50%. Soft drugs are often characterized by predictable and controllable in vivo metabolism to non-toxic products after achieving their therapeutic role. Soft drugs may have lower systemic exposure, resulting in a lower risk of side effects.

[0051] Systemic inhibition of drug targets is often associated with doses that limit side effects, and there is an unmet need for effective agonists that are well tolerated in patients. Compounds that are rapidly removed as soon as they enter the bloodstream may have lower systemic exposure and lower risk of side effects (see Atkinson AJ Jr. and Kushner W., Annu. Rev. Pharmacol. Toxicol., 1979, 19, 105-127 and Rowland M. and Tozer TN, Clinical Pharmacokinetics. Concepts and Applications. Lippincott Williams & Wilkins, 1995, 161-167).

[0052] It is not possible to predict which groups in a drug structure will result in rapid systemic clearance of the drug. In some cases, phenolic groups are observed to be removed by Phase II conjugation clearance mechanisms such as glucuronidation and sulfation (see Pathways of Biotransformation - Phase II Reactions in Ionescu C., Caira MR (eds) Drug Metabolism. Springer, Dordrecht, 2005).

[0053] As alluded to above, a first aspect provides a compound of formula (I): [ka] 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; Each first substituent is selected from the group consisting of hydroxy, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkylol, Halo, SO 2C 1 -C 4 Alkyl, NHSO 2 C 1 -C 4 Alkyl, SO 2 C 3 -C 6 Cycloalkyl, NHSO 2 C 3 -C 6 Cycloalkyl, SO 2 C 1 -C 4 Alkyrol, NHSO 2 C 1 -C 4 Alkyrol, C 1 -C 5 Alkyloxy, C 1 -C 5 Alkylamino, SO 2 NH 2 ,CONH 2 , CONH.C. 1 -C 4 Alkyl, NHCOC 1 -C 4 Alkyl, NHSO 2 N(C 1 -C 4 Alkyl) 2 , C 1 -C 6 Fluoroalkyl, SO 2 C 1 -C 4 Fluoroalkyl, NHSO 2 C 1 -C 4 Fluoroalkyl, C 1 -C 5 Fluoroalkyloxy, and C 1 -C 5 fluoroalkylamino; X is O, CR 2 , NR' or S, R is H, C 1 -C 4 R' is independently selected from the group consisting of alkyl and halo, 1 -C 4 selected from the group consisting of 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; 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CR A R B R C , C 2 -C 5 Oxacycloalkyl, C 2 -C 5 azacycloalkyl or morpholinyl; R A is C 3 -C 5 cycloalkyl, R B is C 3 -C 5 cycloalkyl, methyl or ethyl; R C is OH; and Each second substituent is hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, C 1 -C 5 Alkyloxy, C 1 -C 5 Alkylamino, oxo, cyano, C 1 -C 6 Fluoroalkyl, C 1 -C 5 Fluoroalkyloxy, and C 1 -C 5 fluoroalkylamino; Ring structure B is optionally present; when ring structure B is present, it is an optionally substituted pyrrole bonded such that C is in the 4-position relative to NH; the pyrrole is optionally substituted with a third substituent at the 2-position; The third substituent is CONHC 1 -C 4 Alkyl, CONH 2 , CONH.C. 1 -C 6 Fluoroalkyl, CONHC 3 -C6 Cycloalkyl (optionally substituted at one or more carbon atoms with methyl or ethyl); CONHC 3 -C 5 Cyclofluoroalkyl (optionally substituted at one or more carbon atoms with methyl or ethyl), NHCOC 1 -C 4 Alkyl and NHCOC 1 -C 4 fluoroalkyl; With the proviso that when A is six-membered, it is substituted at least once with a hydroxy or oxo group.

[0054] B is optionally present. If not present, the carbon atoms ortho and meta to C are each bonded to H. If present, the ring structure B is an optionally substituted pyrrole; C is in the 4-position to NH, thus forming a 6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one derivative.

[0055] The pyrrole is optionally substituted at the 2-position with a third substituent, which is CONHC. 1 -C 4 Alkyl, CONH 2 , CONH.C. 1 -C 6 Fluoroalkyl, CONHC 3 -C 6 Cycloalkyl (optionally substituted at one or more carbon atoms with methyl or ethyl); CONHC 3 -C 5 Cyclofluoroalkyl (optionally substituted at one or more carbon atoms with methyl or ethyl), NHCOC 1 -C 4 Alkyl and NHCOC 1 -C 4 Fluoroalkyl is selected from the group consisting of CONHC 3 -C 6 Cycloalkyl can be unsubstituted. Often the third substituent is CONHC. 1 -C 4 Alkyl, CONHC1 -C 6 Fluoroalkyl, CONHC 3 -C 6 Cycloalkyl (optionally substituted at one or more carbon atoms with methyl or ethyl), and CONHC 3 -C 5 The third substituent is selected from the group consisting of CONHC. 1 -C 4 Alkyl, CONHC 1 -C 6 Fluoroalkyl, CONHC 3 -C 6 Cycloalkyl and CONHC 3 -C 5 The third substituent may be selected from the group consisting of CONHC, cyclofluoroalkyl, optionally substituted at one or more carbon atoms with methyl or ethyl. 1 -C 4 Alkyl, CONH 2 , CONH.C. 1 -C 6 Fluoroalkyl, CONHC 3 -C 5 Cycloalkyl;CONHC 3 -C 5 Cyclofluoroalkyl, NHCOC 1 -C 4 Alkyl and NHCOC 1 -C 4 The third substituent may be selected from the group consisting of CONHC 1 -C 4 alkyl, typically CONHethyl. Typically, the pyrrole is unsubstituted. Most typically, the pyrrole is unsubstituted or substituted at the 2-position with CONHethyl.

[0056] Typically, B is present, and sometimes optionally at position 2, CONHC 1 -C 4A is a pyrrole substituted with a third substituent which is an alkyl. Often the third substituent is CONHethyl. Typically B is present and is an unsubstituted pyrrole. Most typically B is present and is an unsubstituted pyrrole or a pyrrole substituted at the 2-position with CONHethyl. Thus, the compounds of the invention are typically represented by formula (II) or (III): [ka] [ka] wherein A, X and Z are as defined for formula (I), with the proviso that if A is 6-membered, it is substituted at least once with a hydroxy or oxo group.

[0057] Often when A is six-membered it is substituted at least once with a hydroxy group located ortho or meta to X, or with an oxo group.

[0058] A may be any 5-membered aromatic or heteroaromatic ring, or any 6-membered aromatic or heteroaromatic ring, which connects C to X and is substituted at least once with a hydroxy or oxo group. Five-membered aromatic or heteroaromatic rings include thiazole, oxazole, imidazole, isoxazole, pyrazole, thiophene, pyrrole, furan and cyclopentadienyl. Five-membered heteroaromatic rings also include triazoles, such as 1,2,4-triazole. Six-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. Five-membered or 6-membered aromatic or heteroaromatic rings may be substituted with a first substituent at one or more carbon and / or heteroatoms. For example, when A is a pyridine ring, it may be substituted with a first substituent at any of 1, 2 or 3 carbon atoms not bonded to C or X, and / or at a nitrogen atom.

[0059] When A is 5-membered, it is often unsubstituted or substituted at one position. Typically, when A is 5-membered, it is unsubstituted.

[0060] Often, A is selected from the group consisting of benzene, pyridine, thiazole, pyridone, pyrazole, imidazole and triazole, which are optionally substituted with a first substituent at one or more carbon and / or heteroatoms. Typically, A is selected from the group consisting of benzene, pyridine, thiazole and pyridone, which are optionally substituted with a first substituent at one or more carbon and / or heteroatoms. When A is a pyridone, it can be 2-, 3- or 4-pyridone. Generally, when A is a pyridone, it is a 2-pyridone, i.e., A is generally selected from the group consisting of benzene, pyridine, thiazole and 2-pyridone, which are optionally substituted with a first substituent at one or more carbon or heteroatoms.

[0061] When A is a thiazole, it is typically attached to C through the 5-position thiazole carbon atom and to X through the 4-position thiazole carbon. The resulting CAX moiety is represented by: [ka]

[0062] The thiazole may be substituted at one or more carbon and / or nitrogen atoms with a first substituent. Often, the thiazole is substituted at the 2-position with a first substituent.

[0063] When A is a 2-pyridone, it is typically either: bonded to C through the 4-carbon atom and bonded to X through the 3-carbon atom, or bonded to C through the 4-carbon atom and bonded to X through the 5-carbon atom. The resulting CAX moieties are represented, respectively, by: [ka] and [ka]

[0064] The 2-pyridone may be substituted at one or more carbon and / or nitrogen atoms with a first substituent. Often, the 2-pyridone is substituted at one or more carbon and / or nitrogen atoms with a C 1 -C 6 Generally, C 1 -C 6 Alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. 1 -C 4 It is typically C 1 -C 6 Alkyl is methyl. Often the 2-pyridone is substituted at the nitrogen atom with methyl.

[0065] When A is a pyrazole, it is generally attached to C via the pyrazole carbon atom at position 5 and to X by the nitrogen atom at position 1. The resulting CAX moiety is represented by: [ka]

[0066] The pyrazole may be substituted with the first substituent at one or more carbon and / or nitrogen atoms. Often, the pyrazole is substituted with the first substituent at the 3 or 4 position.

[0067] When A is imidazole, it is generally attached to C via the imidazole carbon atom at position 2 and to X by the nitrogen atom at position 1. The resulting CAX moiety is represented by: [ka]

[0068] The imidazole may be substituted with the first substituent at one or more carbon and / or nitrogen atoms. Often, the imidazole is substituted with the first substituent at the 4 or 5 position.

[0069] When A is a triazole, it is typically a 1,2,4-triazole. When A is a 1,2,4-triazole, it is generally bonded to C via the imidazole carbon atom at position 5 and to X by the nitrogen atom at position 1. The resulting CAX moiety is represented by: [ka]

[0070] The 1,2,4-triazole can be substituted with the first substituent at one or more carbon and / or nitrogen atoms. Often, the 1,2,4-triazole is substituted with the first substituent at the 3-position.

[0071] The first substituent is hydroxy, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkylol, Halo, SO 2 C 1 -C 4 Alkyl, NHSO 2 C 1 -C 4 Alkyl, SO 2 C 3 -C 6 Cycloalkyl, NHSO 2 C 3 -C 6 Cycloalkyl, SO 2 C 1 -C 4 Alkyrol, NHSO 2 C 1 -C 4 Alkyrol, C 1 -C 5 Alkyloxy, C 1 -C 5 Alkylamino, SO 2NH 2 ,CONH 2 , CONH.C. 1 -C 4 Alkyl, NHCOC 1 -C 4 Alkyl, NHSO 2 N(C 1 -C 4 Alkyl) 2 , C 1 -C 6 Fluoroalkyl, SO 2 C 1 -C 4 Fluoroalkyl, NHSO 2 C 1 -C 4 Fluoroalkyl, C 1 -C 5 Fluoroalkyloxy, and / or C 1 -C 5 The first substituent may be SO 2 C 1 -C 4 Alkyl, NHSO 2 C 1 -C 4 Alkyl, SO 2 C 1 -C 4 Fluoroalkyl and NHSO 2 C 1 -C 4 When selected from fluoroalkyl, it is often SO 2 CH 3 , N.H.S.O. 2 CH 3 , S.O. 2 CF 3 and / or NHSO 2 CF 3 , i.e., methanesulfonyl, methanesulfonamido, trifluoromethanesulfonyl and / or trifluoromethanesulfonamido. 2 C 3 -C 6 Cycloalkyl and NHSO 2 C 3 -C 6 When selected from cycloalkyl, it is often SO 2 C3 H 5 , S.O. 2 C 5 H 9 , S.O. 2 C 6 H 11 , N.H.S.O. 2 C 3 H 5 , N.H.S.O. 2 C 5 H 9 and / or NHSO 2 C 6 H 11 , i.e., cyclopropanesulfonyl, cyclopentanesulfonyl, cyclohexanesulfonyl, cyclopropanesulfonamido, cyclopentanesulfonamido and / or cyclohexanesulfonamido. 2 C 1 -C 4 Alkyrol and NHSO 2 C 1 -C 4 When selected from alkylols, it is often SO 2 C(CH 3 ) 2 OH and / or NHSO 2 C(CH 3 ) 2 OH, i.e. tert-butanol sulfonyl and / or tert-butanol sulfonamide.

[0072] Thus, each first substituent is often a hydroxy, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkylol, Halo, SO 2 CH 3 , N.H.S.O. 2 CH 3 , S.O. 2 t Bu, NHSO 2 t Bu, S.O. 2 C 3 H 5 , S.O. 2C 5 H 9 , S.O. 2 C 6 H 11 , N.H.S.O. 2 C 3 H 5 , N.H.S.O. 2 C 5 H 9 , N.H.S.O. 2 C 6 H 11 , C 1 -C 5 Alkyloxy, C 1 -C 5 Alkylamino, SO 2 NH 2 ,CONH 2 , CONH.C. 1 -C 4 Alkyl, NHCOC 1 -C 4 Alkyl, NHSO 2 N(C 1 -C 4 Alkyl) 2 , C 1 -C 6 Fluoroalkyl, SO 2 CF 3 , N.H.S.O. 2 CF 3 , C 1 -C 5 Fluoroalkyloxy, and / or C 1 -C 5 fluoroalkylamino.

[0073] Typically, each first substituent is selected from the group consisting of hydroxy, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Alkyrol, C 3 -C 6 Cycloalkyl, halo, SO 2 CH 3 , N.H.S.O. 2 CH 3 , S.O. 2 C 3 H 5 , S.O. 2 C 5 H9 , S.O. 2 C 6 H 11 , N.H.S.O. 2 C 3 H 5 , N.H.S.O. 2 C 5 H 9 and N.H.S.O. 2 C 6 H 11 Often, each first substituent is independently selected from the group consisting of hydroxy, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, SO 2 CH 3 and N.H.S.O. 2 CH 3 are independently selected from the group consisting of:

[0074] Typically, each first substituent is selected from the group consisting of hydroxy, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 alkylol, and halo. Typically, 1 -C 6 Alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl is selected from the group consisting of cyclopropyl, cyclopentyl and cyclohexyl. Typically, 1 -C 6Alkylol is hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-isopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxy-isobutyl and hydroxy-tert-butyl. Typically, halo is fluoro or chloro. Thus, each first substituent is generally independently 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, hydroxy-isopropyl, hydroxy-n-butyl, hydroxy-sec-butyl, hydroxy-isobutyl and hydroxy-tert-butyl, fluoro and chloro.

[0075] Most typically, each first substituent is independently selected from the group consisting of hydroxy, oxo, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, hydroxy-tert-butyl, fluoro and chloro.

[0076] Often, each first substituent is independently selected from the group consisting of hydroxy, oxo, methyl and halo.

[0077] When A is benzene or pyridine, it is substituted at least once with a hydroxy group. Sometimes it is substituted with a hydroxy group and a further first substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, fluoro and chloro. Typically it is substituted with a hydroxy group and a further first substituent selected from the group consisting of methyl, fluoro and chloro. Often, at least one hydroxy group is located ortho or meta to X.

[0078] X is O, CR 2 or NR', where R is H, C 1 -C4 R' is independently selected from the group consisting of alkyl and halo, 1 -C 4 is selected from the group consisting of alkyl and H.

[0079] X is CR 2 When R is H, C, halo is typically chloro or fluoro. 1 -C 4 Each is individually selected from the group consisting of alkyl, fluoro and chloro.

[0080] X is CR 2 or NR', then C 1 -C 4 Alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. Thus, R is typically individually selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, fluoro, and chloro, 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 individually selected from the group consisting of H, methyl, and halo, and R' is selected from the group consisting of methyl and H. Often, R is individually selected from the group consisting of H, methyl, and fluoro, and R' is methyl.

[0081] Typically, X is O, ie A is attached to Z via an oxide.

[0082] Z optionally includes at one or more carbon and / or heteroatoms, respectively, hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, C 1 -C 5 Alkyloxy, C 1 -C 5 Alkylamino, oxo, cyano, C1 -C 6 Fluoroalkyl, C 1 -C 5 Fluoroalkyloxy, and C 1 -C 5 a 5- or 6-membered aromatic or heteroaromatic ring substituted with a second substituent independently selected from the group consisting of fluoroalkylamino; 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CR A R B R C , C 2 -C 5 Oxacycloalkyl, C 2 -C 5 azacycloalkyl or morpholinyl; R A is C 3 -C 5 cycloalkyl, R B is C 3 -C 5 cycloalkyl, methyl or ethyl; R C is OH.

[0083] Z may be any optionally substituted 5-membered aromatic or heteroaromatic ring, for example Z may be thiazole, oxazole, imidazole, isoxazole, pyrazole, thiophene, pyrrole, furan, or cyclopentadienyl.

[0084] Alternatively, Z may be any optionally substituted 6-membered aromatic or heteroaromatic ring, for example Z may be benzene, pyridine, pyridone, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine or 1,3,5-triazine.

[0085] otherwise, Z is an optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CR A RB R C , C 2 -C 5 Oxacycloalkyl, C 2 -C 5 It may be an azacycloalkyl or morpholinyl. Typically, C 1 -C 6 Alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. 1 -C 4 Alkyl; C 3 -C 6 Cycloalkyl is selected from the group consisting of cyclopropyl, cyclopentyl and cyclohexyl; R A is cyclopropyl, cyclobutyl or cyclopentyl; R B is cyclopropyl, cyclobutyl, cyclopentyl, methyl or ethyl; C 2 -C 5 Oxacycloalkyl is selected from the group consisting of oxacyclopropyl, oxacyclopentyl, and oxacyclohexyl; 2 -C 5 Azacycloalkyl is selected from the group consisting of azacyclopropyl, azacyclopentyl, and azacyclohexyl.

[0086] Often, Z is selected from the group consisting of benzene, pyridine, thiazole, pyridone, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, oxacyclopentyl, oxacyclohexyl, azacyclopentyl, azacyclohexyl, and morpholinyl, optionally substituted at one or more carbon and / or heteroatoms with 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, optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent.

[0087] Z is generally an optionally substituted 6-membered aromatic or heteroaromatic ring, C 1 -C 6 Alkyl, or C 3 -C 6 It is cycloalkyl.

[0088] Typically, Z is a phenyl or pyridyl ring, optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent, C 1 -C 6 Alkyl, or C 3 -C 6 It is cycloalkyl.

[0089] Each second substituent is hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, C 1 -C 5 Alkyloxy, C 1 -C 5 Alkylamino, oxo, cyano, C 1 -C 6 Fluoroalkyl, C 1 -C 5 Fluoroalkyloxy, and C 1 -C 5 fluoroalkylamino.

[0090] Often each second substituent is hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 is independently selected from the group consisting of cycloalkyl, cycloalkyl, and halo. Typically, 1 -C 6 Alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. 1 -C 4 Alkyl, C 3 -C 6Cycloalkyl is selected from the group consisting of cyclopropyl, cyclopentyl and cyclohexyl. Often, halo is fluoro, chloro or bromo. Thus, each second substituent is often independently selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, fluoro, chloro and bromo. Typically, halo is fluoro or chloro. Thus, each second substituent is generally independently selected from the group consisting of hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, fluoro and chloro.

[0091] Sometimes, each second substituent is independently selected from the group consisting of hydroxy, methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro and bromo. Often, each second substituent is independently selected from the group consisting of hydroxy, methyl, ethyl, isopropyl, tert-butyl, fluoro and chloro. Typically, each second substituent is independently selected from the group consisting of hydroxy, methyl, fluoro and chloro. For example, Z may be a phenyl ring substituted with two methyl groups located ortho to X and further substituted with a fluoro located para to X. Typically, each second substituent is selected from any one or combination of hydroxy, methyl or fluoro. Most typically, each second substituent is hydroxy.

[0092] Z is often a phenyl ring optionally substituted at 1 to 3 carbon atoms with second substituents, each second substituent being independently selected from the group consisting of hydroxy, methyl, ethyl, isopropyl, tert-butyl, fluoro and chloro; a pyridyl ring optionally substituted at one carbon atom with hydroxy; 1 -C 6 Alkyl; or C 3 -C 6It is cycloalkyl.

[0093] Sometimes, CAX in formula (I) is any one of formulas (Ia), (Ib), (Ic), (Id) or (Id'): [ka] In the formula, A 1 CR 1 or N and A 2 CR 2 or N and A 3 CR 3 or N and A 4 CR 4 And A 5 CR 5 or N and A 6 CR 5 or N; R 1 is H or hydroxy; R 2 is H, hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, SO 2 C 1 -C 4 Alkyl, NHSO 2 C 1 -C 4 Alkyl, SO 2 C 3 -C 6 Cycloalkyl, NHSO 2 C 3 -C 6 Cycloalkyl, C 1 -C 5 Alkyloxy or C 1 -C 5 is alkylamino; R 3 and R 4 is H, hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, C 1 -C 5Alkyloxy or C 1 -C 5 independently selected from the group consisting of alkylamino; However, R 1 , R 2 , R 3 or R 4 provided that at least one of is hydroxy; B' is H or hydroxy; and R 5 is either H or the first substituent, as defined above.

[0094] Sometimes, CAX in formula (I) is any one of formulas (Ia), (Ib), (Ic) or (Id): [ka] In the formula, A 1 CR 1 or N and A 2 CR 2 or N and A 3 CR 3 or N and A 4 CR 4 and; R 1 is H or hydroxy; R 2 , H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, SO 2 C 1 -C 4 Alkyl, NHSO 2 C 1 -C 4 Alkyl, SO 2 C 3 -C 6 Cycloalkyl, NHSO 2 C 3 -C 6 Cycloalkyl, C 1 -C 5 Alkyloxy or C 1 -C 5 is alkylamino; R 3 and R 4 is H, hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, C 1 -C 5 Alkyloxy or C 1 -C 5 independently selected from the group consisting of alkylamino; However, R 1 , R 3 or R 4 provided that at least one of is hydroxy; B' is H or hydroxy; and R 5 is either H or the first substituent, as defined above.

[0095] Typically, R 2 , H, C 1 -C 3 Alkyl, halo, SO 2 C 1 -C 4 Alkyl or NHSO 2 C 1 -C 4 R is alkyl; 3 and R 4 is H, hydroxy, C 1 -C 3 is independently selected from the group consisting of alkyl and halo. 2 , H, C 1 -C 3 Alkyl, fluoro, chloro, SO 2 CH 3 or NHSO 2 CH 3 ;R 3 and R 4 is H, hydroxy, C 1 -C 3 is independently selected from the group consisting of alkyl and fluoro or chloro.

[0096] Typically, R 5is H.

[0097] Often, when CAX is represented by formula (Ia), Z is a phenyl ring, optionally substituted at one or more carbon atoms with a second substituent; C 1 -C 6 Alkyl; or C 3 -C 6 cycloalkyl; when CAX is represented by any one of formulas (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; C 1 -C 6 Alkyl; or C 3 -C 6 It is cycloalkyl.

[0098] Often, when CAX is represented by formula (Ia), Z is a phenyl ring, optionally substituted at one or more carbon atoms with a second substituent; C 1 -C 6 Alkyl; or C 3 -C 6 cycloalkyl; 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; C 1 -C 6 Alkyl; or C 3 -C 6 It is cycloalkyl.

[0099] Typically, when CAX is represented by formula (Ia), Z is an unsubstituted phenyl ring; when CAX is represented by any one of formulas (Ib), (Ic), and (Id), Z is a phenyl or pyridyl ring optionally substituted at one or more carbon and / or nitrogen atoms with second substituents, each second substituent being independently selected from the group consisting of hydroxy, methyl, fluoro, and chloro.

[0100] Typically, when CAX is represented by formula (Ia), Z is an unsubstituted phenyl ring; 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 being independently selected from the group consisting of hydroxy, methyl, fluoro and chloro. Often, the compound is of formula (Ie)-(IIi): [ka] TIFF2025080251000015.tif69162

[0101] Generally, the compound has any one of formulas (Ie), (If), (Ig), (Ih), (Ii) (Ij) or (Ik). Typically, the compound has formula (Ih) or (IIb).

[0102] The compounds described herein may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" is intended to define pharmaceutically useful 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, sodium, potassium, calcium, magnesium and aluminum salts, as well as non-toxic quaternary ammonia and amine cations, such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine and ethylamine. Other examples of organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

[0103] Pharmaceutically acceptable salts may also be prepared by treatment of the compounds of the invention with a suitable acid, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, 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.

[0104] The compounds of the invention may exist in different stereoisomeric forms. All stereoisomeric forms and their mixtures (including enantiomers and racemic mixtures) are included within the scope of the invention. Such stereoisomeric forms include enantiomers and diastereoisomers. Individual stereoisomers of the compounds of the invention are included, i.e., those associated with less than 5%, preferably less than 2%, especially less than 1% of other stereoisomers. Mixtures of stereoisomers in any proportion, such as racemic mixtures containing substantially equal amounts of two enantiomers, are also included within the invention.

[0105] Also included are solvates and isotopically labeled compounds of the invention.Isotopically labeled compounds are identical to those listed herein except for the fact that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those predominantly found in nature.Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, and 36 It is Cl.

[0106] Further aspects include intermediates suitable for producing the compounds of the invention, particularly intermediates of formula (ia)-(ip):

[0107] [ka]

[0108] The intermediate may have formula (ig), (ii), (ij), (ik), or (if). Often the intermediate has formula (ia)-(id), (if), or (ih)-(ip). Typically the intermediate has formula (im).

[0109] Prodrugs of the compounds and compositions of the invention are also within the scope of the invention. When administered to a subject, the prodrugs are converted by metabolic or other chemical processes to provide the compounds of the invention.

[0110] All amorphous and crystalline forms of the compounds of the invention are included.

[0111] Although the compound can be administered alone, it is typical to use a pharmaceutical composition. The 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 pharma- ceutically acceptable excipients. The excipients can help transport the compound to the body site, where they are intended to act to increase its efficiency, for example by increasing the dissolution rate of the compound in the bloodstream, or by increasing the stability of the compound to delay its release, and to prevent damage to soft tissues. Alternatively, the excipients may be for identification purposes or to make the compound more attractive to patients, for example by improving its taste, smell and / or appearance. Typically, the excipients make up the majority of the pharmaceutical composition.

[0112] Excipients include diluents or fillers, binders, disintegrants, lubricants, colorants and preservatives. Diluents or fillers are inert ingredients that can affect the chemical and physical properties of the final composition. When the dosage of the compound of the invention is small, more diluent will be needed to produce a composition suitable for practical use. When the dosage of the compound of the invention is high, less diluent is needed.

[0113] The binder provides adhesive properties to the powder to form granules, which can then be formed into tablets. The binder must also allow the tablet to disintegrate upon ingestion so that the compound of the invention dissolves. Disintegration of the composition after administration can be facilitated by the use of disintegrants.

[0114] An extensive overview of pharma- ceutically acceptable excipients is described in Handbook of Pharmaceutical Excipients, 6th Edition; Editors RC Rowe, PJ Sheskey and ME Quinn, The Pharmaceutical Press, London, American Pharmacists Association, Washington, 2009. Any suitable pharma- ceutically acceptable excipient is within the scope of the invention.

[0115] 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 compositions are suitable for topical or oral administration, i.e., the pharmaceutical compositions are topical or oral formulations.

[0116] The pharmaceutical composition can be compressed into a solid dosage unit, such as a tablet, or processed into a capsule or suppository. The pharmaceutical composition can also be injected and prepared in the form of a solution, suspension or emulsion for such application. Alternatively, the pharmaceutical composition can be administered as a spray, including nasal or buccal spray. Otherwise, the pharmaceutical composition can be processed into a gel, cream, patch, implant or any other preparation for immediate and / or sustained release. Typically, the pharmaceutical composition is processed into a gel, cream, lotion, foam or ointment for topical administration; or into a tablet, capsule or buccal spray for oral administration.

[0117] The third aspect of the invention provides a compound of the first aspect or a pharmaceutical composition of the second aspect for use as a medicament. In particular, the compound is useful in treating a disease or condition associated with the activity of bromodomains and extra-terminal proteins. In the fifth aspect, the compound of the first aspect or the pharmaceutical composition of the second aspect is provided for use in inhibiting bromodomains and extra-terminal proteins. Diseases or conditions associated with the activity of bromodomains and extra-terminal proteins include inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases and fibrotic diseases. Thus, in a fourth aspect the invention provides a compound of the invention or a pharmaceutical composition of the invention for use in a method of treatment or prevention of inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases and fibrotic diseases, and in a sixth aspect the invention provides a method for the treatment or prevention of skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases and fibrotic diseases, said method comprising administering to a subject an effective amount of a compound of the first aspect, or a pharmaceutical composition of the second aspect.

[0118] Inflammatory diseases involve the regulation of the T helper cell (Th) pathway in the innate and adaptive immune responses that affect either or both the acute and chronic phases of the disease. 1 , Th 2 and Th 17 It depends on. Many cytokines and chemokines are upregulated in inflammatory diseases, and the ability to reduce the level of these inflammatory markers is evidence of the ability of a drug to ameliorate 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 (cc motif) ligands CCL2, CCL27 and CCL20; tumor necrosis factor alpha (TNF-α); thymic stromal lymphopoietin (TSLP); and chemokine (cxc motif) ligand 9 (CXCL9).

[0119] Pan-BET inhibitors may be useful in the treatment of inflammatory disorders. These include skin disorders such as alopecia areata, atopic dermatitis, bullous dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, contact dermatitis, psoriasis, rosacea, scleroderma, xerosis, urticarial 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, celiac disease and gastrointestinal cancer; eye diseases such as myasthenia gravis, Sjogren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis and iritis; Addison's disease. systemic indications such as inflammatory bowel 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, interstitial pneumonia, primary biliary cirrhosis, psoriatic arthritis, rheumatoid arthritis, scleroderma (cutaneous or systemic), scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's arteritis, toxic shock, thyroiditis, type 1 diabetes and complications from diabetes, uvenitis, vasculitis and Wegener's granulomatosis; as well as other autoimmune diseases and indications where immunosuppression may be desirable, for example, in organ transplantation.BET inhibitors are also known to affect the growth or survival of a range of cancers, particularly skin and systemic cancers, and may be useful in the treatment of: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocyctic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic lung carcinoma, 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, proliferative changes (dysplasia and dysplasia), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, neuroglioma Blastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphoid neoplasms of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, mucinous Sarcoma, Neuroblastoma, NUT midline carcinoma (NMC), Non-small cell lung carcinoma, Oligodendroglioma, Oral carcinoma, 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 carcinoma, Solid tumors (carcinoma and sarcoma), Small cell lung carcinoma, Gastric cancer, Squamous cell carcinoma, Synovium, Sweat gland carcinoma, Thyroid carcinoma, Waldenstrom's macroglobulinemia, Testicular tumor, Uterine cancer, and Wilms' tumor.

[0120] BET inhibitors may also be useful in the treatment of obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, fatty liver, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy.

[0121] A seventh aspect provides a method of inhibiting bromodomain and extra-terminal protein activity in a subject, said method comprising administering to the subject an effective amount of a compound of the first aspect, or a pharmaceutical composition of the second aspect.

[0122] An effective amount of the compound can be administered to a subject topically, parenterally or enterally.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 membrane via cream, gel, foam, lotion or ointment, or enterally via tablet, capsule or buccal spray.

[0123] The subject may be a human, typically a human, and may suffer from or be susceptible to inflammatory skin disorders, respiratory disorders, gastrointestinal disorders, and eye disorders. Treating the subject may include administering an effective amount of a compound of the invention. The term "effective amount" refers to the amount of compound that ameliorates the disorder, thereby producing the desired therapeutic or inhibitory effect.

[0124] Those skilled in the art will recognize 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 capabilities of the skilled artisan to identify effective amounts of the compounds and compositions of the invention through routine practice and experimentation.

[0125] Any description in this specification of documents, acts, materials, devices, articles or the like should not be construed as forming part of the prior art or as being of ordinary general knowledge in the art relevant to the present disclosure, by virtue of the existence of any or all of such matter prior to the priority date of any particular claim of this application.

[0126] Those skilled in the art will recognize that many variations and / or modifications can be made to the invention described herein without departing from the scope of the invention described. Thus, the present embodiment should be considered as illustrative and not intended to be limiting, and should not be limited to the extent described in the embodiment. Those skilled in the art should understand that the present embodiment can be read alone or in combination, and can be combined with any one or combination of the features described herein.

[0127] The subject matter of each patent and non-patent reference cited herein is hereby incorporated by reference in its entirety.

[0128] Aspects and embodiments of the disclosure are further described in the following paragraphs: 1. Compound of formula (I): [ka] 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; Each first substituent is selected from the group consisting of hydroxy, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkylol, Halo, SO 2 C 1 -C 4 Alkyl, NHSO 2 C 1 -C 4 Alkyl, SO 2 C 3-C 6 Cycloalkyl, NHSO 2 C 3 -C 6 Cycloalkyl, SO 2 C 1 -C 4 Alkylol, NHSO 2 C 1 -C 4 Alkylol, C 1 -C 5 Alkyloxy, C 1 -C 5 Alkylamino, SO 2 NH 2 , CONH 2 , CONHC 1 -C 4 Alkyl, NHCOC 1 -C 4 Alkyl, NHSO 2 N(C 1 -C 4 Alkyl) 2 , C 1 -C 6 Fluoroalkyl, SO 2 C 1 -C 4 Fluoroalkyl, NHSO 2 C 1 -C 4 Fluoroalkyl, C 1 -C 5 Fluoroalkyloxy, and C 1 -C 5 independently selected from the group consisting of fluoroalkylamino; X is O, CR 2 , NR’ or S, R is individually selected from the group consisting of H, C 1 -C 4 alkyl and halo, and R’ is selected from the group consisting of C 1 -C 4 alkyl and H; 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, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, CRA R B R C , C 2 -C 5 Oxacycloalkyl, C 2 -C 5 azacycloalkyl or morpholinyl; R A is C 3 -C 5 cycloalkyl, R B is C 3 -C 5 cycloalkyl, methyl or ethyl; R C is OH; and Each second substituent is hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, C 1 -C 5 Alkyloxy, C 1 -C 5 Alkylamino, oxo, cyano, C 1 -C 6 Fluoroalkyl, C 1 -C 5 Fluoroalkyloxy, and C 1 -C 5 fluoroalkylamino; Ring structure B is optionally present; when ring structure B is present, it is an optionally substituted pyrrole bonded such that C is in the 4-position relative to NH; the pyrrole is optionally substituted with a third substituent at the 2-position; The third substituent is CONHC 1 -C 4 Alkyl, CONH 2 , CONH.C. 1 -C 6 Fluoroalkyl, CONHC 3 -C 6 Cycloalkyl (optionally substituted at one or more carbon atoms with methyl or ethyl); CONHC 3 -C 5 Cyclofluoroalkyl (optionally substituted at one or more carbon atoms with methyl or ethyl), NHCOC1 -C 4 alkyl and NHCOC 1 -C 4 selected from the group consisting of fluoroalkyl; provided that when A is 6-membered, it is substituted with a hydroxy or oxo group at least once.

[0129] 2. The third substituent is CONHC 1 -C 4 alkyl, CONH 2 CONHC 1 -C 6 fluoroalkyl, CONHC 3 -C 5 cycloalkyl; CONHC 3 -C 5 cyclofluoroalkyl, NHCOC 1 -C 4 alkyl and NHCOC 1 -C 4 fluoroalkyl, a compound of Closure 1 selected from the group consisting of.

[0130] 3. When A is 6-membered, it is a compound of Closure 1 or 2 substituted with a hydroxy group or an oxo group located ortho or meta to X at least once.

[0131] 4. The third substituent is CONHC 1 -C 4 alkyl, any one of the above-mentioned compounds of Closure.

[0132] 5. The third substituent is CONH ethyl, any one of the above-mentioned compounds of Closure.

[0133] 6. The compound has formula (II):

Chemical formula

[0134] 7. Any of the preceding compounds 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 a first substituent.

[0135] 8. Compound of clause 7 in which the pyrazole carbon at position 5 is bonded to C and the pyrazole nitrogen at position 1 is bonded to X.

[0136] 9. Compounds of clause 7 or 8 in which the imidazole carbon at position 2 is bonded to C and the nitrogen at position 1 is bonded to X.

[0137] 10. The 1,2,4-triazole carbon at position 5 is bonded to C and the nitrogen at position 1 is bonded to X, in any one of clauses 7 to 9.

[0138] 11. A compound according to 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 with a first substituent.

[0139] 12. The pyridone is a 2-pyridone, any one of the compounds of clauses 7 to 11.

[0140] 13. Compounds of 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.

[0141] 14. The compound of 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.

[0142] 15. Each first substituent is selected from the group consisting of hydroxy, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C6 Alkylol, Halo, SO 2 C 1 -C 4 Alkyl, NHSO 2 C 1 -C 4 Alkyl, SO 2 C 3 -C 6 Cycloalkyl, NHSO 2 C 3 -C 6 Cycloalkyl, SO 2 C 1 -C 4 Alkyrol, NHSO 2 C 1 -C 4 Alkyrol, C 1 -C 5 Alkyloxy and C 1 -C 5 Any one of the above compounds is independently selected from the group consisting of alkylamino.

[0143] 16. Each first substituent is selected from the group consisting of hydroxy, oxo, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Compounds of any one of the above clauses independently selected from the group consisting of alkylol and halo.

[0144] 17. A compound of any one of the above clauses, wherein each first substituent is independently selected from the group consisting of hydroxy, oxo, methyl and halo.

[0145] 18. Any one of the above compounds, wherein R is individually selected from the group consisting of H, methyl and halo, and R' is selected from the group consisting of methyl and H.

[0146] 19. Any one of the above compounds wherein halo is fluoro or chloro.

[0147] 20. Any one of the above compounds, wherein R is individually selected from the group consisting of H, methyl and fluoro, and R' is methyl.

[0148] 21. Any one of the above compounds wherein X is O.

[0149] 22. Z is a 5- or 6-membered aromatic or heteroaromatic ring, optionally substituted on one or more carbon or heteroatoms with a second substituent, C 1 -C 6 Alkyl, or C 3 -C 6 A compound of any one of the above clauses, wherein the compound is cycloalkyl.

[0150] 23. Z is a 6-membered aromatic or heteroaromatic ring, optionally substituted on one or more carbon or heteroatoms with a second substituent, C 1 -C 6 Alkyl, or C 3 -C 6 A compound of any one of the above clauses, wherein the compound is cycloalkyl.

[0151] 24. Compounds of any one of the above clauses, wherein Z is a 5- or 6-membered aromatic or heteroaromatic ring optionally substituted on one or more carbon or heteroatoms with a second substituent.

[0152] 25. Compounds of any one of the above clauses, wherein Z is a six-membered aromatic or heteroaromatic ring optionally substituted on one or more carbon or heteroatoms with a second substituent.

[0153] 26. Compounds of any one of the above clauses, wherein Z is a phenyl or pyridyl ring optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent.

[0154] 27. A compound according to any one of the preceding claims, wherein Z is a phenyl ring optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent.

[0155] 28. Each second substituent is hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, C 1 -C 5 Alkyloxy, C 1 -C 5 Any one of the above compounds is independently selected from the group consisting of alkylamino, oxo and cyano.

[0156] 29. Each second substituent is hydroxy, C 1 -C 4 A compound of any one of the above clauses, independently selected from the group consisting of alkyl and halo.

[0157] 30. A compound of any one of the above clauses, wherein the second substituent is hydroxy.

[0158] 31. The compound of clause 27, wherein each second substituent is independently selected from the group consisting of methyl and fluoro.

[0159] 32. A compound of clause 27, in which Z is a phenyl ring substituted with two methyl groups positioned ortho to X and one fluoro positioned para to X.

[0160] 33. CAX in formula (I) is any one of formulas (Ia), (Ib), (Ic), (Id) or (Id'): [ka] In the formula, A 1 CR 1 or N and A 2 CR 2 or N and A 3 CR 3 or N and A 4 CR 4 And A 5 CR 5 or N and A6 CR 5 or N; R 1 is H or hydroxy; R 2 is H, hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, SO 2 C 1 -C 4 Alkyl, NHSO 2 C 1 -C 4 Alkyl, SO 2 C 3 -C 6 Cycloalkyl, NHSO 2 C 3 -C 6 Cycloalkyl, C 1 -C 5 Alkyloxy or C 1 -C 5 is alkylamino; R 3 and R 4 is H, hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, C 1 -C 5 Alkyloxy or C 1 -C 5 independently selected from the group consisting of alkylamino; However, R 1 , R 2 , R 3 or R 4 provided that at least one of is hydroxy; B' is H or hydroxy; and R 5 is H or any of the first substituents defined above; Any one of the above closed compounds.

[0161] 34. CAX is any one of the formulae (Ia), (Ib), (Ic) or (Id): [ka] In the formula, A 1 CR 1 or N and A 2 CR 2 or N and A 3 CR 3 or N and A 4 CR 4 and; R 1 is H or hydroxy; R 2 , H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, SO 2 C 1 -C 4 Alkyl, NHSO 2 C 1 -C 4 Alkyl, SO 2 C 3 -C 6 Cycloalkyl, NHSO 2 C 3 -C 6 Cycloalkyl, C 1 -C 5 Alkyloxy or C 1 -C 5 is alkylamino; R 3 and R 4 is H, hydroxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halo, C 1 -C 5 Alkyloxy or C 1 -C 5 independently selected from the group consisting of alkylamino; However, R 1 , R 3 or R 4 provided that at least one of is hydroxy; B' is H or hydroxy; and R 5 is either H or a first substituent; Any one of the above closed compounds.

[0162] 35.R 2 , H, C 1 -C 3 Alkyl, halo, SO 2 C 1 -C 4 Alkyl or NHSO 2 C 1 -C 4 alkyl; and R 3 and R 4 is H, hydroxy, C 1 -C 3 A compound of clause 33 or 34, independently selected from the group consisting of alkyl and halo.

[0163] 36. The compound of any one of clauses 33 to 35, wherein when CAX is represented by formula (Ia), Z is a phenyl ring optionally substituted at one or more carbon atoms with a second substituent; 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.

[0164] 37. The compound of any one of clauses 33-35, 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 at one or more carbon and / or nitrogen atoms with a second substituent selected from the group consisting of hydroxy, methyl, fluoro and chloro.

[0165] 38. The compound is any one of the compounds of clauses 33 to 37, which is any one of the following: (i) formula (Ia), (Id) or (Id'); or (ii) Formula (Ib) or (Ic).

[0166] 39. The compound is any one of the compounds of clauses 33 to 37, which is any one of the following: (i) formula (Ia) or (Id); or (ii) Formula (Ib) or (Ic).

[0167] 40. The compound of clause 1, which is any one of the compounds of formula (Ie) to (IIe): [ka] TIFF2025080251000022.tif74162

[0168] 41. The compound of clause 40, wherein the compound is any one of formulae (Ie), (If), (Ig), (Ih), (Ii) (Ij) or (Ik).

[0169] 42. Any one of the above compounds in the form of a pharma- ceutically acceptable salt.

[0170] 43. A compound of formula (Ib) or (Ic) as defined in any one of clauses 33 to 41, in the form of a pharma- ceutically acceptable salt.

[0171] 44. A compound of formula (Ia), (Id) or (Id') as defined in any one of clauses 33 to 41, in the form of a pharma- ceutically acceptable salt.

[0172] 44. A compound of formula (Ia) or (Id) as defined in any one of clauses 33 to 41, in the form of a pharma- ceutically acceptable salt.

[0173] 45. A pharmaceutical composition comprising any one or a combination of compounds as defined in any one of clauses 1 to 41 in combination with one or more pharma- ceutically acceptable excipients.

[0174] 46. ​​The pharmaceutical composition of Clause 45, wherein the pharmaceutical composition is a topical formulation.

[0175] 47. A pharmaceutical composition comprising any one or a combination of compounds of formula (Ia), (Id) or (Id') as defined in any one of clauses 33 to 41 in combination with one or more pharma- ceutically acceptable excipients.

[0176] 48. A pharmaceutical composition comprising any one or a combination of compounds of formula (Ia) or (Id) as defined in any one of clauses 33 to 41 in combination with one or more pharma- ceutically acceptable excipients.

[0177] 49. The pharmaceutical composition of Clause 45, wherein the pharmaceutical composition is an oral formulation.

[0178] 50. A pharmaceutical composition comprising any one or a combination of compounds of formula (Ib) or (Ic) as defined in any one of clauses 33 to 41 in combination with one or more pharma- ceutically acceptable excipients.

[0179] 51. A compound as defined in any one of clauses 1 to 44, or a pharmaceutical composition as defined in any one of clauses 45 to 50, for use as a medicament.

[0180] 52. A compound as defined in any one of clauses 1 to 44, or a pharmaceutical composition as defined in any one of clauses 45 to 50, for use in a method for the treatment or prevention of inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancer, rheumatic diseases, demyelinating diseases and fibrotic diseases.

[0181] 53. The compound or composition for use according to clause 52, wherein the use is in a method for the treatment or prevention of intestinal, skin or lung inflammation or cancer.

[0182] 54. A compound as defined in any one of clauses 1 to 44 or a pharmaceutical composition as defined in any one of clauses 45 to 50 for use in inhibiting bromodomains and extra-terminal proteins.

[0183] 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 a compound defined in any one of clauses 1 to 44, or a pharmaceutical composition defined in any one of clauses 45 to 50.

[0184] 56. The method according to Clause 55, wherein the method is for the treatment or prevention of intestinal, skin or lung inflammation or cancer fibrosis.

[0185] 57. A method for inhibiting bromodomain and extra-terminal protein activity in a subject, the method comprising administering to the subject an effective amount of a compound defined in any one of clauses 1 to 44 or a pharmaceutical composition defined in any one of clauses 45 to 50.

[0186] The following are presented as non-limiting examples.

[0187] Working Example The compounds described herein have been found to be surprisingly effective as pan-inhibitors of BET BRD. The examples disclosed herein show nanomolar potency in inhibiting GM-CSF, IL-1a, IL-6, IL-8, CCL2, TNF-a, TSLP, CCL27, CCL20 and CXCL9 from stimulated keratinocytes. They also exhibit surprisingly effective clearance by human hepatocytes 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 wide range of pH. Furthermore, the exemplified topical formulations deliver practical concentrations of the compounds into the skin epidermis, and the exemplified compounds are not toxic to primary keratinocytes.

[0188] [Table 1] TIFF2025080251000024.tif216162

[0189] device Reactions using microwave irradiation were carried out in a Biotage Initiator microwave.

[0190] Normal phase TLC was performed using precoated silica plates (Kieselgel 60 F 254 , BDH) using visualization with UV light (UV254 / 365 nm) and / or ninhydrin solution.

[0191] 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.

[0192] Mass-directed preparative HPLC separations were performed using a Waters HPLC (2545 binary gradient pump, 515 HPLC make-up pump, 2767 sample manager) coupled to a Waters 2998 photodiode array and a Waters 3100 mass detector.

[0193] Preparative HPLC separations were performed using a Gilson HPLC (321 pump, 819 injection module, 215 liquid handler / injector) coupled to a Gilson 155 UV / vis detector. On both instruments, HPLC chromatographic separations were performed using a Waters XBridge C18 column, 19×100 mm, 5 μm particle size; using 0.1% aqueous ammonia (solvent A) and acetonitrile (solvent B) as the mobile phase.

[0194] 1 H NMR and 19 F NMR spectra were recorded on a Bruker Avance DPX 500 spectrometer (500.1 MHz). 1 H, 125MHz 13 C, at 470.5MHz19 F), or Bruker Avance DPX 300 (at 300MHz 1 H). Chemical shifts (δ) are expressed in ppm, reported in all cases using residual solvent as 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 estimated to the nearest 0.5 Hz. Low-resolution electrospray (ES) mass spectra were recorded on a Bruker MicroTof mass spectrometer operated in positive mode. High-resolution mass spectrometry (HRMS) was performed using a Bruker MicroTof mass spectrometer.

[0195] LC-MS analysis and chromatographic separation were performed using an Agilent Technologies 1200 series HPLC coupled to an Agilent Technologies 6130 quadrupole LC / MS coupled to an Agilent diode array detector. The column used was a Waters XBridge column (50 mm x 2.1 mm, 3.5 μm particle size) and compounds were eluted using a gradient of 5-95% acetonitrile / water + 0.1% formic acid or a Shimadzu HPLC coupled to an LCMS-2020 quadrupole LC / MS coupled to a Shimadzu diode array detector. The column used was a Kinetex EVO C18 column (30 mm x 1.8 mm, 5.0 μm particle size) and compounds were eluted using a gradient of 5-95% acetonitrile / water + 0.0375% trifluoroacetic acid.

[0196] Unless otherwise noted herein, reactions have not been optimized. Solvents and reagents were purchased from commercial sources and used without further purification. Dry solvents were purchased in tightly sealed bottles stored over molecular sieves.

[0197] Preparations and compounds were named using the ChemDraw Professional 15.0 naming application.

[0198] Process for preparation The following schemes show methods of synthesizing the compounds of the invention. Scheme 1 shows a general route for the preparation of the compounds of the invention via Suzuki coupling of intermediates (II) and (VIII) followed by deprotection. The 6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one boronic ester intermediate (II) is prepared as follows: 5-Bromo-2-methoxy-4-methyl-3-nitropyridine is reacted 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 followed by acid hydrolysis with HBr gives 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 4-bromoaryl 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. Suzuki coupling of (II) and (VIII) followed by deprotection gives compound (I). Deprotection involves removal of the tosyl group of intermediate (II) using, for example, sodium hydroxide. Often the deprotection also involves conversion of methoxy substituents on A and / or Z to hydroxy groups, for example with boron tribromide.

[0199] Alternatively, the compound can be functionalized at the 2-position of the pyrrole with a third substituent, typically CONH ethyl. This can be accomplished by using another synthetic route as shown in Scheme 2, in which 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. Suzuki coupling of (II') and (VIII), followed by deprotection, produces compound (I'). Deprotection involves removal of the tosyl group, for example, using sodium hydroxide. This also converts the ethoxy substituent of the ethylformyl to a hydroxy group. Finally, the carboxylic acid at the 2-position 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 susceptible to nucleophilic substitution by an amine. One skilled in the art can evaluate which amines and reaction conditions are suitable for functionalizing the carboxylic acid of intermediate (I') to produce compound (I''). [ka] Scheme 1: General synthetic route for the synthesis of the compounds of the invention. The definitions of A, X and Z of compounds (I) and (VIII) are as defined above for the compounds of formula (I). LG of compound (VIII) is halo or triflate. Preferably, LG is bromo or iodo. [ka] Scheme 2: General synthetic route for the synthesis of compounds of the invention. The definitions of A, X and Z of compounds (I″), (I′) and (VIII) are as defined above for compounds of formula (I). LG of compound (VIII) is halo or triflate. Preferably, LG is bromo or iodo.

[0200] Use of Scheme 2 to synthesize compounds described herein, such as Example 41, where A is 2-pyridone, X is oxide, and Z is 2,6-dimethyl-4-fluoro-phenyl, is shown in Scheme 3. [ka] Scheme 3: Illustration of general scheme 2, where A is 2-pyridone, X is oxide, Z is 2,6-dimethyl-4-fluoro-phenyl and LG is bromo.

[0201] Suitable synthetic routes for the synthesis of intermediates of formula (VIII) of Schemes 1 and 2 depend on the identity of A. Suitable routes for the synthesis of intermediates of formula (VIII) are shown in Schemes 4, 5 and 6, where: A is a 6-membered aromatic or heteroaromatic ring optionally substituted at one or more carbon and / or heteroatoms with a first substituent and substituted at at least one carbon atom with a hydroxy or oxo group; A is an N-methyl-2-pyridone optionally substituted with a hydroxy group; and A is a thiazole.

[0202] The iodo-intermediate (IX) is prepared by the Sandmeyer reaction of the corresponding aniline (X), which is in turn formed by iron-catalyzed reduction of the nitro-containing compound (XI). (XI) is the S-substituted ortho-fluoronitroaryl compound (XII). N Formed via Ar reaction.

[0203] The N-methyl-2-pyrone-intermediate (XIII) is prepared via methylation and iron-catalyzed oxidation of the corresponding pyridine (XIV), which in turn is formed via reduction of the corresponding pyridine oxide (XV) using phosphorus tribromide. The bromo-intermediate (XV) is prepared via reaction of the corresponding nitro intermediate (XVI) with acetyl bromide, which in turn is formed via the S reaction of the corresponding ortho-fluoronitropyridine oxide compound (XVII). N It is produced via the Ar reaction.

[0204] The 5-bromothiazole intermediate (XVIII) is prepared by bromination of the corresponding thiazole intermediate (XIX), which in turn is prepared via a copper catalyzed Ullmann-type reaction of the corresponding bromo compound (XX). [ka] Scheme 4: General synthetic route for the synthesis of compounds of the invention where A is a 6-membered aromatic or heteroaromatic ring. 1 , A 2 , A 3 and A 4 is as defined above for the compounds of formula (I) and (Ia). [ka] Scheme 5: General synthetic route for the synthesis of compounds of the invention where A is a 2-pyridone. The definitions of X, Z and B' are as defined above for compounds of formula (I), (Ib) and (Ic). [ka] Scheme 6: General synthetic route for the synthesis of compounds of the invention where A is a thiazole. The definitions of X and Z are as defined above for compounds of formula (I) and (Id).

[0205] Typically, X is O (oxide). Scheme 7 shows suitable reagents and reaction conditions for the preparation of the compounds of Example 1. Those skilled in the art will recognize that the reagents and conditions employed in the chemical transformations of Scheme 7 can be utilized, modified, and / or substituted as necessary to provide a variety of alternative compounds via the general processes in Schemes 1 and 2. [ka] Scheme 7: Synthetic route for the synthesis of the compound of Example 1.

[0206] Example 1: 4-(3-hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 1: (E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethen-1-amine [ka] 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 over a period of 20 min. The resulting dark solution was heated at 95° C. TLC after 5 h (4:1 heptane / EA) showed 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 overnight under vacuum at 50° C. (56.6 g, 61%). The material was used directly in Preparation 2 without further purification.

[0207] 1 H NMR (400 MHz, CDCl 3 )d8.14(s, 1H), 7.02(d, J=13.7Hz, 1H), 4.94(d, J=13.7Hz, 1H), 3.97(s, 3H), 2.94(s, 6H).

[0208] Preparation 2: 4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine [ka] (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), followed by 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 an overhead stirrer. After 5 hours, a further aliquot of iron powder (23.3 g, 417 mmol) was added and heating was continued overnight. The mixture was cooled and solid Na 2 CO 3 was added. The mixture was filtered through a pad of Celite. The filtrate was filtered and the residue was triturated with 4:1 heptane / ethyl acetate. The mixture was filtered through a pad of silica. The filtrate was evaporated. The residue was purified on silica eluting with 100:0 to 80:20 heptane / ethyl acetate. Solvent reduction gave an off-white solid (3.7 g, 21%).

[0209] HPLC R (Agilent, acidic, 3.5 min): 1.46 min, MS: m / z229.0[M+2H] + .

[0210] Preparation 3: 4-Bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine [ka] Sodium hydride (60% w / w, 7.90 g, 198 mmol) was suspended in THF (290 mL) under nitrogen and cooled in an ice bath to below 4° C. 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 a period of 30 min (gas evolution was observed and the exothermic formation raised the reaction temperature to 5° C.). The maroon mixture was stirred at RT for 45 min and 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 with cooling for 1.5 h and then stirred at RT for 1 h. TLC (3:2 heptane / ethyl acetate) showed no remaining SM. The reaction mixture was diluted with saturated NH 4 The reaction was quenched by the dropwise addition of Cl (300 mL). The mixture was stirred for 5 min before the phases were separated. The aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organics were washed (brine), dried (MgSO 4 ), 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 Preparation 4 without further purification.

[0211] HPLC R (Agilent, acidic, 3.5 min): 1.94 min, m / z=383.1[M+2H] + .

[0212] Preparation 4: 4-Bromo-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] 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. TLC after 2 h (3:2 heptane / ethyl acetate) showed no remaining SM. The reaction mixture was cooled to RT and then cooled with stirring in an ice bath for 30 min. The mixture was filtered and the cream-colored solid was collected and washed with water. The solid was dried overnight under vacuum at 50° C. (22.5 g, 94%). The material was used directly in Preparation 5 without further purification.

[0213] HPLC R (Agilent, acidic, 3.5 min): 1.59 min, m / z=369.0[M+2H] + .

[0214] Preparation 5: 4-Bromo-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] 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 portionwise, causing gas evolution and exotherm to 5° C. The mixture was stirred with cooling for 20 min, and after gas evolution ceased, iodomethane (7.63 mL, 123 mmol) was added dropwise, causing an exotherm which raised the reaction temperature to 10° C. The mixture was stirred with cooling for 15 min, then stirred at RT for 15 min. LCMS after 2 h showed no SM remaining. The reaction mixture was quenched by dropwise addition of water (100 mL, gas evolution and exotherm to 39° C.). The mixture was extracted with ethyl acetate (3×300 mL). The combined organics were washed (brine), dried (Na 2 SO 4), filtered and evaporated. The crude product was triturated with TBME and filtered. The off-white solid collected was washed with TBME and dried under vacuum (15 g, 64%).

[0215] HPLC R (Agilent, basic, 6.0 min): 4.0 min, m / z=382.9[M+H] + .

[0216] 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 [ka] 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. 2 (dba) 3 (300 mg, 0.32 mmol) was added and the mixture was degassed for an additional minute. The reaction was heated at 80° C. overnight. The reaction was diluted with ethyl acetate and washed with 50% brine. The organics were 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%). Fractions corresponding to the product were combined and concentrated to give a yellow solid (3.4 g, 55%).

[0217] HPLC R (Agilent, acidic, 3.5 min): 1.93 min, m / z=429.2[M+H] + .

[0218] Preparation 7: 1-Methoxy-3-nitro-2-phenoxybenzene [ka] 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 for 30 min at RT, after which 2-fluoro-1-methoxy-3-nitro-benzene (3.75 g, 21.91 mmol) was added. The reaction mixture was heated to 80° C. and allowed to stir overnight. The reaction mixture was concentrated under vacuum, then redissolved in ethyl acetate and washed with water. The organic phase was washed with MgSO 4 The mixture was dried over ice and evaporated in vacuo. The crude material was purified by column chromatography (0-100% ethyl acetate in heptane) to give 1-methoxy-3-nitro-2-phenoxy-benzene (5.4 g, 90%) as a yellow solid.

[0219] 1 H NMR (500MHz, CDCl3) d7.55(dd, J=1.4, 8.3Hz, 1H), 7.35-7.30(m, 3H), 7.24(dd, J=1.4, 8.4Hz, 1H), 7.11-7.05(m, 1H), 6.89-6.87(m, 2H), 3.93(s, 3H).

[0220] Preparation 8: 3-Methoxy-2-phenoxyaniline [ka] A solution of iron (7.37 g, 132.12 mmol) in acetic acid (12 mL) / ethanol (30 mL) was degassed with nitrogen for 5 minutes. 1-Methoxy-3-nitro-2-phenoxy-benzene (5.4 g, 22.02 mmol) was added and the reaction was heated to 70° C. The orange solution turned black after 5 minutes. After 4 hours the reaction was allowed to cool and the solvent removed. DCM was added and the organic layer was washed with sodium bicarbonate, passed through a hydrophobic frit and concentrated. The product was purified by column chromatography (ethyl acetate / heptane gradient 0-100%). Fractions corresponding to the product were combined and concentrated to give 3-methoxy-2-phenoxyaniline (830 mg, 15%) as a brown solid.

[0221] HPLC R (Agilent, acidic, 3.5 min): 1.53 min, m / z=216.2[M+H] + .

[0222] Preparation 9: 1-Iodo-3-methoxy-2-phenoxybenzene [ka] 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 h. Saturated sodium bicarbonate solution was then added to the solution until a pH of 8 was achieved. 1 M sodium thiosulfate solution was then added. The product was extracted into DCM and the organics were collected through 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 give 1-iodo-3-methoxy-2-phenoxybenzene (740 mg, 57%).

[0223] 1 H NMR (500 MHz, CDCl 3 )d7.43(dd, J=1.4, 8.3Hz, 1H), 7.34-7.28(m, 3H), 7.10-7.04(m, 1H), 6.99(dd, J=1.4, 8.4Hz, 1H), 6.88-6.85(m, 2H), 3.93(s, 3H).

[0224] Preparation 10: 4-(3-Methoxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] 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 through Pd(PPh) for 10 min. 3 ) 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 organics were washed with 2×50 ml of water followed by 1×50 ml of saturated brine solution. The organics were then separated and dried (MgSO 4 ) 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.

[0225] HPLC R (Agilent, acidic, 3.5 min): 1.62 min, m / z=347.5[M+H] + .

[0226] Preparation 11: 4-(3-hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] 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, followed by addition of BBr 3 (74 mg, 0.29 mmol) was added. The reaction temperature was maintained for 1 h and then allowed to warm to 0° C. and stirred for an additional 1 h. The reaction mixture was quenched with water and the pH was adjusted to 0.5 with saturated NaHCO 3 The acid was adjusted to 8 with aqueous solution. The reaction mixture was extracted with ethyl acetate. The combined organic layers were separated, passed through a phase separator and concentrated under vacuum. The crude material was purified by column chromatography (0-50% 20% MeOH / DCM in DCM) followed by reverse phase preparative HPLC (Gilson, acidic, 60-90% gradient). The fractions were concentrated overnight on a genevac to give 4-(3-hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (17 mg, 85%) as a white solid.

[0227] HPLC R (Agilent, acidic, 3.5 min): 1.43 min, m / z=333.2[M+H] + .

[0228] 1 H NMR (500 MHz, CDCl 3)d10.36-10.30(m, 1H), 7.26-7.20(m, 2H), 7.15-7.06(m, 4H), 6.89-6.85(m, 2 H), 6.68-6.64(m, 2H), 6.39(dd, J=2.4, 2.4Hz, 1H), 6.29(s, 1H), 3.53(s, 3H).

[0229] Example 2: 4-(4-hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 12: 4-Methoxy-1-nitro-2-phenoxybenzene [ka] Following the procedure in Preparation 7, 2-fluoro-4-methoxy-1-nitrobenzene (400 mg, 2.34 mmol) was reacted to give the title compound (541 mg, 85%).

[0230] 1 H NMR (500 MHz, CDCl 3 )d8.10(d, J=9.2Hz, 1H), 7.43-7.39(m, 2H), 7.21(t, J=7.4Hz, 1H), 7.09-7. 07(m, 2H), 6.70(dd, J=2.7, 9.2Hz, 1H), 6.46(d, J=2.6Hz, 1H), 3.81(s, 3H).

[0231] Preparation 13: 4-Methoxy-2-phenoxyaniline [ka] 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%).

[0232] 1 H NMR (500 MHz, CDCl 3)d7.35-7.31(m, 2H), 7.08(t, J=7.4Hz, 1H), 7.02-7.00(m, 2H), 6.71-6.69(m, 2H), 6.60(dd, J=2.5, 6.9Hz, 1H), 3.92(s, 3H), 3.90(bs, 2H).

[0233] Preparation 14: 1-Iodo-4-methoxy-2-phenoxybenzene [ka] 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%).

[0234] 1 H NMR (400 MHz, CDCl 3 )d7.38-7.34(m, 2H), 7.29-7.23(m, 1H), 7.14(t, J=7.4Hz, 1H), 7.01(d, J=7.7Hz, 2H), 6.63(d, J=8.3Hz, 1H), 6.55(d, J=8.3Hz, 1H), 3.96(s, 3H).

[0235] Preparation 15: 4-(4-Methoxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (182 mg, 86%).

[0236] HPLC R (Agilent, acidic, 3.5 min): 1.59 min, m / z=347.2[M+H] + .

[0237] Preparation 16: 4-(4-hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (41 mg, 43%).

[0238] HPLC R (Agilent, acidic, 3.5 min): 1.48 min, m / z=333.2[M+H] + .

[0239] 1 H NMR (500MHz, DMSO-d6)d11.82(s, 1H), 9.89(bs, 1H), 7.25(dd, J=7.4, 8.6Hz, 2H), 7.18-7.12(m, 2H), 7.00(s, 2H), 6.84(d, J=7.6Hz, 2H), 6.75(d, J=7.8Hz, 1H), 6.35(d, J=8.1Hz, 1H), 6.00(d, J=2.6Hz, 1H), 3.46(s, 3H).

[0240] Example 3: 4-(2-hydroxy-6-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 17: 1-Fluoro-3-methoxy-2-nitrobenzene [ka] Following the procedure in Preparation 7, 1-fluoro-3-methoxy-2-nitrobenzene (400 mg, 2.34 mmol) was reacted to give the title compound (565 mg, 89%).

[0241] 1 H NMR (500 MHz, CDCl3 )d7.41-7.37(m, 2H), 7.30(dd, J=7.4, 7.4Hz, 1H), 7.21(dd, J=7.4, 7.4Hz, 1H) , 7.11-7.09(m, 2H), 6.76(d, J=7.8Hz, 1H), 6.53(d, J=8.5Hz, 1H), 3.95(s, 3H).

[0242] Preparation 18: 2-Methoxy-6-phenoxyaniline [ka] Following the procedure in Preparation 8, 1-methoxy-2-nitro-3-phenoxybenzene (565 mg, 2.30 mmol) was reacted to give the title compound (350 mg, 64%).

[0243] 1 H NMR (500 MHz, CDCl 3 )d7.36-7.32(m, 2H), 7.09(dd, J=7.3, 7.3Hz, 1H), 7.02-7.00(m, 2H), 6.80(d, J=8.7Hz, 1H), 6.62(dd, J=2.7, 8.7Hz, 1H), 6.52(d, J=2.7Hz, 1H), 3.72(s, 3H), 3.61-3.51(m, 2H).

[0244] Preparation 19: 2-Iodo-1-methoxy-3-phenoxybenzene [ka] Following the procedure in Preparation 9, 2-methoxy-6-phenoxyaniline (350 mg, 1.63 mmol) was reacted to give the title compound (324 mg, 55%).

[0245] 1 H NMR (400 MHz, CDCl 3 )d7.63(d, J=8.6Hz, 1H), 7.29-7.25(m, 2H), 7.05(dd, J=7.4, 7.4Hz, 1H), 6.91(d, J=7.6Hz, 2H)6.45-6.39, (m, 2H), 3.64(s, 3H).

[0246] Preparation 20: 4-(2-Methoxy-6-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (143 mg, 42%).

[0247] HPLC R (Agilent, acidic, 3.5 min): 1.65 min, m / z=347.2[M+H] + .

[0248] Preparation 21: 4-(2-hydroxy-6-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (32 mg, 16%).

[0249] HPLC R (Agilent, acidic, 3.5 min): 1.40 min, m / z=333.2[M+H] + .

[0250] 1H NMR (500MHz, DMSO-d6)d11.93(d, J=0.9Hz, 1H), 9.64(s, 1H), 7.33-7.22(m, 4H), 7.13(s, 1H), 7.06(t, J=7.4Hz, 1H), 6.93(d, J=7.8Hz, 2H), 6.64(dd, J=2.4, 8.3Hz, 1H), 6.35(d, J=2.4Hz, 1H), 6.22-6.21(m, 1H), 3.49(s, 3H).

[0251] Example 4: 6-Methyl-4-(4-phenoxythiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 22: 4-Phenoxythiazole [ka] To an oven-dried microwave vial was added CuI (58.0 mg, 0.30 mmol), picolinic acid (75.0 mg, 0.61 mmol), phenol (0.31 mL, 3.66 mmol) and potassium phosphate tribasic (1.3 g, 6.1 mmol). The tube was then evacuated and flushed twice with N 2 The mixture was backfilled with 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. To the residue was added ethyl acetate (50 mL) and the organics were washed with 2×50 mL of water and then 1×50 mL of saturated brine solution. The organics were then separated and dried (MgSO 4 ) 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%). Fractions corresponding to the product were combined and concentrated to give the title compound, a yellow solid (93 mg, 17%).

[0252] HPLC R (Agilent, acidic, 3.5 min): 1.54 min, m / z=177.9[M+H] + .

[0253] Preparation 23: 5-Bromo-4-phenoxythiazole [ka] 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 allowed to warm to RT and left for 3 h. Ethyl acetate (50 ml) was added and the organics were washed with 2×50 ml of saturated sodium carbonate, then 1×50 ml of saturated brine solution. The organics were then separated, 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] + .

[0254] Preparation 24: 6-Methyl-4-(4-phenoxythiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (10 mg, 12%).

[0255] HPLC R (Agilent, acidic, 3.5 min): 1.43 min, m / z=324.2[M+H] + .

[0256] 1H NMR (500MHz, DMSO-d6)d12.20(bs, 1H), 9.02(s, 1H), 7.52(s, 1H), 7.36-7.31( m, 3H), 7.09(t, J=7.4Hz, 1H), 7.00(d, J=7.9Hz, 2H), 6.44(s, 1H), 3.53(s, 3H).

[0257] Example 5: 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 Preparation 25: 4-Nitro-3-phenoxypyridine 1-oxide [ka] 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, after which 3-fluoro-4-nitro-pyridine 1-oxide (1.0 g, 6.3 mmol) in DMF (5 mL) was added. The reaction was allowed to warm to RT over 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 (MgSO 4 ), filtered and concentrated to give 4-nitro-3-phenoxy-pyridine 1-oxide (1.1 g, 74.9%) as a waxy solid. The material was used directly in Preparation 29 without further purification.

[0258] HPLC R (Agilent, acidic, 3.5 min): 1.72 min, m / z=233.4[M+H] + .

[0259] Preparation 26: 4-Bromo-3-phenoxypyridine 1-oxide [ka] 4-Nitro-3-phenoxy-pyridine 1-oxide (1.1 g, 4.74 mmol) in acetyl bromide (3.51 mL, 47.4 mmol) was stirred at reflux for 2 h. After cooling to ambient temperature, the mixture was poured onto crushed ice and stirred vigorously. The solution was brought to pH 10 by careful addition of saturated sodium carbonate. The organic extract was washed with water and saturated sodium chloride solution, dried (MgSO 4 ), 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 4-bromo-3-phenoxy-pyridine 1-oxide (870 mg, 62%).

[0260] HPLC R (Agilent, acidic, 3.5 min): 1.55 min, m / z=267.9[M+H] + .

[0261] Preparation 27: 4-Bromo-3-phenoxypyridine [ka] 4-Bromo-3-phenoxy-pyridine 1-oxide (715 mg, 2.69 mmol) in chloroform (20 mL) was cooled to 0° C. 3 (1.2 g, 3.23 mmol) in chloroform (20 mL) was added dropwise and then warmed to 50° C. for 1 h. The reaction was concentrated to dryness and the residue taken up in ethyl acetate (50 mL) and the organics washed with 2×50 mL of water followed by 1×50 ml of saturated brine solution. The organics were then separated and dried (MgSO 4 ) and then concentrated to dryness. The crude mixture was then purified by flash column chromatography eluting with an ethyl acetate / heptane gradient (0-100%). The desired fractions were concentrated to dryness in vacuo to give 4-bromo-3-phenoxy-pyridine (500 mg, 74%).

[0262] HPLC R(Agilent, acidic, 3.5 minutes): 1.61 minutes, m / z=249.8[M] + .

[0263] Preparation 28: 4-Bromo-1-methyl-3-phenoxypyridin-2(1H)-one [ka] To 4-bromo-3-phenoxy-pyridine (528 mg, 2.11 mmol) in MeCN (10 mL) in a sealable tube was added dimethyl sulfate (2.0 mL, 21.1 mmol) and the mixture was heated at 80° C. for 30 min. Additional dimethyl sulfate (7.0 mL, 73.9 mmol) was added and the mixture was heated at 80° C. for 16 h. The mixture was cooled to 0° C. on ice and potassium ferricyanide (1.74 g, 5.28 mmol) in water (5 mL) was added, followed by potassium hydroxide (948 mg, 16.9 mmol) in water (5 mL) dropwise and stirred at 80° C. for 16 h. DCM and water were added and passed through a phase separator. The organic layer was dried and the residue was purified by column chromatography eluting with an ethyl acetate / heptane gradient (0-100%). The desired fractions were concentrated to dryness in vacuo to give 4-bromo-1-methyl-5-phenoxypyridin-2(1H)-one (45 mg, 7.6%).

[0264] HPLC R (Agilent, acidic, 3.5 min): 1.42 min, m / z=281.0[M+H] + .

[0265] 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 [ka] According to 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 obtain the title compound (6 mg, 11%).

[0266] HPLC R (Agilent, acidic, 3.5 min): 1.17 min, m / z=348.1[M+H] + .

[0267] 1 H NMR (500MHz, DMSO-d6) d12.08(bs, 1H), 7.71(d, J=7.0Hz, 1H), 7.36-7.30(m, 2H), 7.18(dd, J=7.9, 7.9Hz, 2H), 6.90(dd, J=7.4, 7.4Hz, 1H), 6.71(d, J=7.8Hz, 2H), 6.41(d, J=7.0Hz, 1H), 6.31(dd, J=2.3, 2.3Hz, 1H), 3.53(s, 3H), 3.47(s, 3H).

[0268] Example 6: 4-(5-hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 30: 4-Methoxy-2-nitro-1-phenoxybenzene [ka] Following the procedure in Preparation 7, 1-fluoro-4-methoxy-2-nitrobenzene (1.2 g, 7.01 mmol) was reacted to give the title compound (1.50 mg, 87%).

[0269] HPLC R (Agilent, acidic, 3.5 min): 1.79 min, m / z=246.1[M+H] + .

[0270] Preparation 31: 5-Methoxy-2-phenoxyaniline [ka] Following the procedure in Preparation 8, 4-methoxy-2-nitro-1-phenoxybenzene (1.80 mg, 5.38 mmol) was reacted to obtain the title compound (1.23 g, 64%).

[0271] HPLC R (Agilent, acidic, 3.5 min): 1.64 min, m / z=216.1[M+H] + .

[0272] Preparation 32: 2-Iodo-4-methoxy-1-phenoxybenzene [ka] Following the procedure in Preparation 9, 5-methoxy-2-phenoxyaniline (1.23 g, 5.71 mmol) was reacted to give the title compound (180 mg, 10%).

[0273] 1 H NMR (500MHz, CDCl3) 7.41 (d, J=2.9Hz, 1H), 7.35-7.31 (m, 2H), 7.10-7.03 (m, 1H), 6.96-6.91 (m, 4H), 3.83 (s, 3H).

[0274] Preparation 33: 4-(5-Methoxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (88 mg, 39%).

[0275] HPLC R (Agilent, acidic, 3.5 min): 1.65 min, m / z=347.2[M+H] + .

[0276] Preparation 34: 4-(5-hydroxy-2-phenoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (50 mg, 58%).

[0277] HPLC R (Agilent, acidic, 3.5 min): 1.46 min, m / z=333.2[M+H] + .

[0278] 1 H NMR (500MHz, DMSO-d6)d11.97(s, 1H), 9.47(s, 1H), 7.26(dd, J=2.7, 2.7Hz, 1H), 7.21-7.17(m, 3H), 6 .96-6.89(m, 3H), 6.79(dd, J=2.9, 8.7Hz, 1H), 6.73(d, J=7.6Hz, 2H), 6.25-6.23(m, 1H), 3.46(s, 3H).

[0279] 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 Preparation 35: 2-Chloro-4-nitro-5-phenoxypyridine 1-oxide [ka] A solution of 2-chloro-5-fluoro-4-nitropyridine 1-oxide (2.00 g, 10.4 mmol) in THF (100 mL) was treated with K 2 CO 3 (2.87 g, 20.8 mmol); phenol (1.03 g, 10.9 mmol) was added at 20 °C and the reaction was stirred at 90 °C for 1 h. The reaction was concentrated in vacuo and the residue was diluted with saturated NaHCO 3 (100 mL), and the reaction mixture was extracted with DCM (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 and filtered, then concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound as a yellow solid (950 mg, 3.56 mmol, yield = 34.3%).

[0280] HPLC t R (Agilent, acidic, 3.5 min): 1.47 min, m / z = 267.0 [M+H] + .

[0281] Preparation 36: 2,4-Dibromo-5-phenoxypyridine 1-oxide

Chem.

[0282] HPLC t R (Agilent, acidic, 3.5 min): 1.49 min, m / z = 345.9 [M+H] + .

[0283] Preparation 37: 2,4-Dibromo-5-phenoxypyridine

Chem.

[0284] HPLC R (Agilent, acidic, 3.5 min): 1.91 min, m / z=330.0[M+H] + .

[0285] Preparation 38: 4-Bromo-5-phenoxypyridin-2(1H)-one [ka] To a solution of 2,4-dibromo-5-phenoxypyridine (1.28 g, 3.9 mmol) in t-BuOH (30 mL) was added KOH (699 mg, 12.5 mmol) at 20° C. and the reaction mixture was stirred at 90° C. for 12 h. The reaction was concentrated in vacuo. The residue was purified by H 2 The mixture was diluted with 2×DCM (100 mL) and extracted with DCM (2×100 mL). The combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 The mixture was dried over hexanes, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition) to give the title compound as a yellow solid (80 mg, 0.3 mmol, yield=7.8%).

[0286] HPLC R (Agilent, acidic, 3.5 min): 1.39 min, m / z=267.1[M+H] + .

[0287] Preparation 39: 4-Bromo-1-methyl-5-phenoxypyridin-2(1H)-one [ka] To a solution of 4-bromo-5-phenoxypyridin-2(1H)-one (61 mg, 0.23 mmol) in DMF (3.0 mL), add MeI (65.1 mg, 0.46 mmol, 2.52 mL); Cs 2 CO3 (224.1 mg, 0.69 mmol) was added at 20° C. and the reaction was stirred at 20° C. for 1 h. 2 O (100 mL) was added and extracted with DCM (100 mL x 2), the combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 The mixture was dried with hexane, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (TFA condition) to give 4-bromo-1-methyl-5-phenoxypyridin-2(1H)-one as a yellow solid (63 mg, 0.23 mmol, yield=98%).

[0288] HPLC R (Agilent, acidic, 3.5 min): 1.45 min, m / z=281.0[M+H] + .

[0289] 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 [ka] According to 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 obtain the title compound (23 mg, 24%).

[0290] HPLC R (Agilent, acidic, 3.5 min): 1.26 min, m / z=348.2[M+H] + .

[0291] 1H NMR (500MHz, DMSO-d6)d12.04(bs, 1H), 7.86(s, 1H), 7.37(s, 1H), 7.29(t, J=2.8Hz, 1H), 7.19-7.14(m, 2H) ), 6.89(t, J=7.4Hz, 1H), 6.79-6.76(m, 2H), 6.54(s, 1H), 6.34(t, J=2.4Hz, 1H), 3.48(s, 3H), 3.45(s, 3H).

[0292] Example 8: 5-(5-hydroxy-2-phenoxyphenyl)-1-methylpyridin-2(1H)-one Preparation 41: 5-(5-methoxy-2-phenoxyphenyl)-1-methylpyridin-2(1H)-one [ka] 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 through Pd(PPh) for 10 min. 3 ) 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 organics were washed with 2×50 ml of water followed by 1×50 ml of saturated brine solution. The organics were then separated and dried (MgSO 4 ) 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%).

[0293] HPLC R (Agilent, acidic, 3.5 min): 1.58 min, m / z=308.2[M+H] + .

[0294] Preparation 42: 5-(5-hydroxy-2-phenoxyphenyl)-1-methylpyridin-2(1H)-one [ka] 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%).

[0295] HPLC R (Agilent, acidic, 3.5 min): 1.43 min, m / z=294.2[M+H] + .

[0296] 1 H NMR (500MHz, DMSO-d6)d9.50(s, 1H), 7.85(d, J=2.4Hz, 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=9.5Hz, 1H), 3.42(s, 3H).

[0297] Example 9: 4-(5-hydroxy-2-propoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 43: 1-Fluoro-4-((4-methoxybenzyl)oxy)-2-nitrobenzene [ka] To a solution of 4-fluoro-3-nitrophenol (2.30 g, 14.6 mmol) in DMF (20.0 mL) was added potassium tert-butoxide (1.97 g, 17.6 mmol) at 20° C. and stirred for 15 min. 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 under vacuum. The residue was dissolved in EtOAc (2×400 mL) and diluted with H 2O (300 mL), and the combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 Drying with hexanes, filtration and concentration in vacuo afforded 1-fluoro-4-((4-methoxybenzyl)oxy)-2-nitrobenzene as a yellow solid (2.52 g, 8.64 mmol, yield=59%).

[0298] 1 H NMR (400MHz, CDCl3)d7.63-7.60(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).

[0299] Preparation 44: 4-((4-methoxybenzyl)oxy)-2-nitro-1-propoxybenzene [ka] To a solution of 1-fluoro-4-((4-methoxybenzyl)oxy)-2-nitrobenzene (750 mg, 2.7 mmol) in DMF (10 mL) was added sodium hydride (194 mg, 8.1 mmol) at 20° C. and stirred for 30 min. 1-propanol (0.6 mL, 8.1 mmol) was added and the reaction was stirred at 20° C. for 20 min. The reaction was concentrated under vacuum. The residue was dissolved in EtOAc (2×100 mL) and diluted with H 2 O (100 mL), and the combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 Drying with hexanes, filtration and concentration in vacuo afforded 4-((4-methoxybenzyl)oxy)-2-nitro-1-propoxybenzene as a yellow solid (710 mg, 2.13 mmol, yield=79%).

[0300] 11H 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).

[0301] Preparation 45: 5 - ((4 - Methoxybenzyl)oxy)-2 - propoxyaniline [Chemical formula] Following the procedure in Preparation 8, 4 - ((4 - Methoxybenzyl)oxy)-2 - nitro - 1 - propoxybenzene (710 mg, 2.23 mmol) was reacted to obtain the title compound (495 mg, 73%).

[0302] HPLC t R (Agilent, acidic, 3.5 minutes): 1.73 minutes, m / z = 288.2 [M + H] + .

[0303] Preparation 46: 2 - Iodo - 4 - ((4 - Methoxybenzyl)oxy)-1 - propoxybenzene [Chemical formula] Following the procedure in Preparation 9, 5 - ((4 - Methoxybenzyl)oxy)-2 - propoxyaniline (495 mg, 1.73 mmol) was reacted to obtain the title compound (360 mg, 50%).

[0304] 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).

[0305] Preparation 47: 4-(5-((4-methoxybenzyl)oxy)-2-propoxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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%).

[0306] HPLC R (Agilent, acidic, 3.5 min): 2.07 min, m / z=573.3[M+H] + .

[0307] Preparation 48: 4-(5-hydroxy-2-propoxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] 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) was added trifluoroacetic acid (0.072 mL, 0.94 mmol) at 20° C. and stirred for 4 h. The reaction was concentrated under vacuum. The residue was dissolved in EtOAc (2×100 mL) and diluted with H 2 O (100 mL), and the combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4Drying with hexanes, filtration and concentration in vacuo afforded 4-((4-methoxybenzyl)oxy)-2-nitro-1-propoxybenzene as a yellow solid (55 mg, 0.12 mmol, yield=62%).

[0308] HPLC R (Agilent, acidic, 3.5 min): 1.72 min, m / z=453.2[M+H] + .

[0309] Preparation 49: 4-(5-hydroxy-2-propoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] 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 under vacuum. The residue was dissolved in EtOAc (2×100 mL) and diluted with H 2 O (100 mL), and the combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 The crude material was purified by column chromatography (0-50% 20% MeOH / DCM in DCM) followed by reverse phase preparative HPLC (Gilson, acidic, 60-90% gradient). The fractions were concentrated overnight on a genevac to give 4-((4-methoxybenzyl)oxy)-2-nitro-1-propoxybenzene as a yellow solid (55 mg, 0.10 mmol, yield=62%).

[0310] HPLC R (Agilent, acidic, 3.5 min): 1.39 min, m / z=299.2[M+H] + .

[0311] 1 H NMR (500MHz, CDCl3) δ10.21(bs, 1H), 7.22(s, 1H), 7.16(t, J=2.8Hz, 1H), 7.06(s, 1H), 6.92-6.85(m, 3H), 6. 28(t, J=2.5Hz, 1H), 3.80(t, J=6.5Hz, 2H), 3.67(s, 3H), 1.61(dt, J=7.8, 13.9Hz, 2H), 0.85(t, J=7.8Hz, 3H).

[0312] Example 10: 4-(2-cyclobutoxy-5-hydroxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 50: 1-Cyclobutoxy-4-((4-methoxybenzyl)oxy)-2-nitrobenzene [ka] Following 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 give the title compound (601 mg, 64%).

[0313] 1 H NMR (400MHz, CDCl3) d7.44(d, J=3.1Hz, 1H), 7.34-7.31(m, 2H), 7.09(dd, J=3.2, 9.1Hz, 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).

[0314] Preparation 51: 2-Cyclobutoxy-5-((4-methoxybenzyl)oxy)aniline [ka] Following the procedure in Preparation 44, 1-cyclobutoxy-4-((4-methoxybenzyl)oxy)-2-nitrobenzene (601 mg, 1.82 mmol) was reacted to give the title compound (375 mg, 62%).

[0315] HPLC R (Agilent, acidic, 3.5 min): 1.76 min, m / z=300.2[M+H] + .

[0316] Preparation 52: 1-Cyclobutoxy-2-iodo-4-((4-methoxybenzyl)oxy)benzene [ka] Following the procedure in Preparation 45, 2-cyclobutoxy-5-((4-methoxybenzyl)oxy)aniline (375 mg, 1.25 mmol) was reacted to give the title compound (360 mg, 67%).

[0317] 1 H NMR (400MHz, CDCl3) d7.40(d, J=3.0Hz, 1H), 7.32(d, J=8.3Hz, 2H), 6.92-6.84(m, 3H), 6.60(d, J=8.3Hz, 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).

[0318] Preparation 53: 4-(2-cyclobutoxy-5-((4-methoxybenzyl)oxy)phenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to the procedure in Preparation 40, 1-cyclobutoxy-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%).

[0319] HPLC R (Agilent, acidic, 3.5 min): 2.10 min, m / z=585.2[M+H] + .

[0320] Preparation 54: 4-(2-cyclobutoxy-5-hydroxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to the procedure in Preparation 48, 4-(2-cyclobutoxy-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 obtain the title compound (75 mg, 58%).

[0321] HPLC R (Agilent, acidic, 3.5 min): 1.71 min, m / z=465.2[M+H] + .

[0322] Preparation 55: 4-(2-cyclobutoxy-5-hydroxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (4 mg, 7%).

[0323] HPLC R (Agilent, acidic, 3.5 min): 1.38 min, m / z=311.2[M+H] + .

[0324] 1 H NMR (400MHz, DMSO) d11.94(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, 8.7Hz, 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).

[0325] Example 11: 4-(2-(cyclohexyloxy)-5-hydroxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 56: 1-(cyclohexyloxy)-4-((4-methoxybenzyl)oxy)-2-nitrobenzene [ka] 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 give the title compound (843 mg, 82%).

[0326] 1H NMR (400MHz, CDCl3) d7.40(d, J=3.4Hz, 1H), 7.35-7.31(m, 2H), 7.10(dd, J=3.1, 9.2Hz, 1H), 7.02(d, J=9.6Hz, 1H), 6.95-6.90(m, 2H), 4.97-4 .96(m, 2H), 4.28(tt, J=4.2, 7.9Hz, 1H), 3.82(s, 3H), 1.95-1.88(m, 2H) ), 1.81(dd, J=10.2, 10.2Hz, 2H), 1.68-1.50(m, 3H), 1.38-1.26(m, 3H).

[0327] Preparation 57: 2-(cyclohexyloxy)-5-((4-methoxybenzyl)oxy)aniline [ka] Following the procedure in Preparation 44, 1-(cyclohexyloxy)-4-((4-methoxybenzyl)oxy)-2-nitrobenzene (843 mg, 2.35 mmol) was reacted to give the title compound (469 mg, 55%).

[0328] HPLC R (Agilent, acidic, 3.5 min): 1.91 min, m / z=328.2[M+H] + .

[0329] Preparation 58: 1-(cyclohexyloxy)-2-iodo-4-((4-methoxybenzyl)oxy)benzene [ka] Following the procedure in Preparation 45, 2-(cyclohexyloxy)-5-((4-methoxybenzyl)oxy)aniline (469 mg, 1.43 mmol) was reacted to give the title compound (350 mg, 52%).

[0330] 1H NMR (400MHz, CDCl3) d7.40(d, J=2.9Hz, 1H), 7.34-7.31(m, 2H), 6.92-6.86(m, 3H), 6.77(d, J=9.4Hz, 1H), 4.91- 4.90(m, 2H), 4.18(tt, J=3.9, 7.7Hz, 1H), 3.81(s, 3H), 1.93-1.79(m, 4H), 1.69-1.51(m, 2H), 1.40-1.25(m, 4H).

[0331] 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 [ka] According to 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%).

[0332] HPLC R (Agilent, acidic, 3.5 min): 2.21 min, m / z=613.3[M+H] + .

[0333] Preparation 60: 4-(2-(cyclohexyloxy)-5-hydroxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (58 mg, 62%).

[0334] HPLC R (Agilent, acidic, 3.5 min): 1.86 min, m / z=493.3[M+H] + .

[0335] Preparation 61: 4-(2-(cyclohexyloxy)-5-hydroxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (12 mg, 29%).

[0336] HPLC R (Agilent, acidic, 3.5 min): 1.51 min, m / z=339.2[M+H] + .

[0337] 1 H NMR (400MHz, DMSO)d11.95(s, 1H), 9.01(s, 1H), 7.27-7.22(m, 2H), 6.91(d, J=8.7Hz, 1H), 6.79(d, J=3.0Hz, 1H), 6.67(dd, J=2.9, 8.7Hz, 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)

[0338] Example 12: 4-(5-hydroxy-2-((4-methoxycyclohexyl)oxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 62: 4-Methoxycyclohexan-1-ol [ka] To a solution of cyclohexane-1,4-diol (4.6 g, 39.6 mmol) in DMF (15 mL) was added sodium hydride, 60% in oil (1.74 g, 43.5 mmol) at 20° C. and stirred for 30 min. Iodomethane (0.6 mL, 8.1 mmol) was added and the reaction was stirred at 20° C. for 16 h. The reaction was concentrated under vacuum. The residue was dissolved in EtOAc (2×100 mL) and diluted with H 2 O (100 mL), and the combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 The mixture was dried over hexanes, 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%).

[0339] 1 H NMR (400MHz, CDCl3)d3.70-3.64(m, 1H), 3.33(s, 3H), 3.21-3.13(m, 1H), 2.04-1.94(m, 4H), 1.35-1.24(m, 4H).

[0340] Preparation 63: 4-((4-methoxybenzyl)oxy)-1-((4-methoxycyclohexyl)oxy)-2-nitrobenzene [ka] 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%).

[0341] 1 H NMR (400MHz, CDCl3) d7.44(d, J=3.1Hz, 1H), 7.38-7.34(m, 2H), 7.14(dd, J=3.1, 9.2Hz, 1H), 7.04(d, J=9.3Hz, 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).

[0342] Preparation 64: 5-((4-methoxybenzyl)oxy)-2-((4-methoxycyclohexyl)oxy)aniline [ka] 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%).

[0343] HPLC R (Agilent, acidic, 3.5 min): 1.67 min, m / z=358.2[M+H] + .

[0344] Preparation 65: 2-Iodo-4-((4-methoxybenzyl)oxy)-1-((4-methoxycyclohexyl)oxy)benzene [ka] 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%).

[0345] 1H NMR (400MHz, CDCl3) d7.42(d, J=2.9Hz, 1H), 7.35(d, J=8.6Hz, 2H), 6.95-6.89(m, 3H), 6.80(d, J=9.0Hz , 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).

[0346] 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 [ka] According to 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%).

[0347] HPLC R (Agilent, acidic, 3.5 min): 1.97 min, m / z=643.3[M+H] + .

[0348] 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 [ka] According to 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 obtain the title compound (97 mg, 58%).

[0349] HPLC R (Agilent, acidic, 3.5 min): 1.63 min, m / z=523.3[M+H] + .

[0350] Preparation 68: 4-(5-hydroxy-2-((4-methoxycyclohexyl)oxy)phenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (21 mg, 30%).

[0351] HPLC R (Agilent, acidic, 8 minutes): 2.95 minutes, m / z=369.2[M+H] + .

[0352] 1 H NMR (400MHz, DMSO) δ11.92(s, 1H), 8.99(s, 1H), 7.29-7.23(m, J=2.7Hz, 1H), 7.21(s, 1H), 6.97-6.88(m, J=8.7Hz, 1H), 6.80(d, J=3.0Hz, 1H), 6.68( dd, J=8.8, 3.0Hz, 1H), 6.16(d, J=2.2Hz, 1H), 4.10-3.91(m, 1H), 3.55(s, 3 H), 3.16(s, 3H), 3.12-3.02(m, 1H), 1.87-1.65(m, 4H), 1.32-1.11(m, 4H).

[0353] 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 Preparation 69: 5-Benzyl-2-chloropyridin-4-amine [ka] H 2 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), K 3 PO 4 (13.8 g, 65.0 mmol, 2.93 eq) and cataCXium A Pd-G3 (500 mg, 687 μmol, 0.031 eq) were incubated at 75 °C for 12 h with N 2 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) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , 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).

[0354] 1 H NMR (400MHz, CDCl3) δ8.09(s, 1H), 7.34-7.32(m, 2H), 7.31-7.30(m, 1H), 7.25-717(m, 2H), 6.55(s, 1H), 4.16-4.10(m, 2H), 3.85(s, 2H)

[0355] Preparation 70: 5-Benzyl-4-bromo-2-chloropyridine [ka] A mixture of tert-butyl nitrite (2.70 g, 26.2 mmol) and CuBr (4.81 g, 33.5 mmol) was stirred in MeCN (10 mL) 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) and concentrated with Na 2 SO 4 It was dried over water, filtered and concentrated to give the title compound as a green oil (2.00 g, 7.08 mmol, 86.0% yield).

[0356] 1 H NMR (400MHz, CDCl3) δ7.37-7.29(m, 2H), 7.29-7.23(m, 2H), 7.17(d, J=7.0Hz, 3H), 4.29(s, 2H).

[0357] Preparation 71: 5-Benzyl-4-bromo-1-methylpyridin-2(1H)-one [ka] 5-Benzyl-4-bromo-2-chloropyridine (2.00 g, 7.08 mmol) was dissolved in CHCl 3 (10 mL) and dissolved in Me 2 SO 4 (5.35 mL, 56.4 mmol) was added and the solution was heated at 70 °C for 12 h. Upon cooling, TEA (15.0 g, 148 mmol), CH 3 CO 2 A mixture of H (13.7 mL, 240 mmol) and EtOH (13.7 mL, 235 mmol) was added and the reaction was heated at 70° C. for an additional 2 h. 2 The mixture was diluted with 200 mL of ethyl acetate (50 mL) and then extracted with 200 mL of ethyl acetate. The combined organic layers were washed with brine (50 mL) and diluted with Na 2 SO 4The mixture was dried over water, filtered and concentrated under reduced pressure to obtain an oil. The residue was purified by prep-HPLC (HCl condition; column: Phenomenex luna C18 250×50 mm×10 μm) to obtain 5-benzyl-4-bromo-1-methylpyridin-2(1H)-one as a yellow solid (859 mg, 3.09 mmol, 43.6% yield).

[0358] 1 H NMR (400MHz, DMSO-d6) δ7.80(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).

[0359] 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 [ka] According to 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 obtain the title compound (34 mg, 39%).

[0360] HPLC R (Agilent, acidic, 3.5 min): 1.26 min, m / z=346.2[M+H] + .

[0361] 1H NMR (500MHz, CDCl3)d10.61(bs, 1H), 7.21(t, J=2.4Hz, 1H), 7.13-7.07(m, 3H), 7.01(s, 1H), 6.77(d, J =6.6Hz, 2H), 6.50(s, 1H), 6.35(s, 1H), 6.14(t, J=2.4Hz, 1H), 5.22(s, 2H), 3.53(s, 3H), 3.42(s, 3H).

[0362] Example 14: 4-(1-benzyl-1H-pyrazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one 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 [ka] According to 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 obtain the title compound (17 mg, 23%).

[0363] HPLC R (Agilent, acidic, 3.5 min): 1.41 min, m / z=305.2[M+H] + .

[0364] 1 H NMR (500MHz, CDCl3) d9.61 (bs, 1H), 7.68 (d, J=1.8Hz, 1H), 7.28-7.25 (m, 4H), 7.05-7.02 (m, 2 H), 6.70(s, 1H), 6.41(d, J=1.8Hz, 1H), 6.27(t, J=2.6Hz, 1H), 5.34-5.33(m, 2H), 3.55(s, 3H).

[0365] Example 15: 4-(1-benzyl-1H-imidazol-2-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 74: 1-Benzyl-2-bromo-1H-imidazole [ka] To a solution of 2-bromo-1H-imidazole (1.0 g, 7.1 mmol) in TMF (160 mL) was added sodium hydride, 60% in oil (286 mg, 7.1 mmol) at 20° C. and stirred for 10 min at 70° C. (Bromomethyl)benzene (0.85 mL, 8.1 mmol) was added and the reaction was stirred at 70° C. for 1 h. The reaction mixture was added to EtOAc (100 mL) and diluted with H 2 O (100 mL), and the organic phase was washed with brine (100 mL), and then with anhydrous Na 2 SO 4 It was dried over hexanes, filtered and concentrated in vacuo to give 1-benzyl-2-bromo-1H-imidazole (920 mg, 54%).

[0366] HPLC R (Agilent, acidic, 3.5 min): 1.29 min, m / z=238.1[M+H] + .

[0367] Preparation 75: 4-(1-benzyl-1H-imidazol-2-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (18 mg, 24%).

[0368] HPLCR (Agilent, acidic, 3.5 min): 0.97 min, m / z=305.2[M+H] + .

[0369] 1 H NMR(500MHz, CDCl3)d10.09(bs, 1H), 7.36-7.33(m, 2H), 7.31(t, J=2.9Hz, 2H), 7.27(d, J=1.1Hz, 1H), 7. 12(s, 1H), 7.06(t, J=1.2Hz, 1H), 7.04(d, J=7.4Hz, 2H), 6.41(t, J=2.5Hz, 1H), 5.18(s, 2H), 3.62(s, 3H).

[0370] 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 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 [ka] According to 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 obtain the title compound (18 mg, 24%).

[0371] HPLC R (Agilent, acidic, 3.5 min): 0.97 min, m / z=305.2[M+H] + .

[0372] 1H NMR (500MHz, DMSO-d6)d12.22(bs, 1H), 8.12(s, 1H), 7.48(s, 1H), 7.36-7.26( m, 4H), 7.09 (d, J=7.0Hz, 2H), 6.35 (d, J=2.4Hz, 1H), 5.50 (s, 2H), 3.30 (s, 3H).

[0373] Example 17: 4-(4-benzylthiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 77: 4-Benzyl-5-bromothiazole [ka] To a solution of 4-benzyl-5-bromothiazol-2-amine (16.2 g, 60.2 mmol) in DMF (160 mL) heated to 55° C., a solution of tert-butyl nitrite (9.3 g, 90.2 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at 70° C. for 1 h. After that, it was cooled to RT, water (250 mL) was added, and the aqueous layer was then extracted with EtOAc (3×100 mL). The combined organics were washed with Na 2 SO 4 It was dried over 100 ml 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).

[0374] 1 H NMR (400MHz, CDCl3)d8.68(s, 1H), 7.25-7.20(m, 4H), 7.17-7.12(m, 1H), 4.09(s, 2H).

[0375] Preparation 78: 4-(4-benzylthiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (5 mg, 6%).

[0376] HPLC R (Agilent, acidic, 3.5 min): 1.43 min, m / z=322.2[M+H] + .

[0377] 1 H NMR (500MHz, DMSO-d6)d11.18(bs, 1H), 8.86(s, 1H), 7.34(t, J=2.6Hz, 1H), 7.30-7.28(m, 2H) , 7.23-7.18(m, 3H), 6.89(s, 1H), 6.34(t, J=2.5Hz, 1H), 4.18-4.17(m, 2H), 3.66-3.65(m, 3H).

[0378] Example 18: 1-Methyl-5-(4-phenoxythiazol-5-yl)pyridin-2(1H)-one Preparation 79: 4-(4-benzylthiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] 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%).

[0379] HPLC R (Agilent, acidic, 3.5 min): 1.34 min, m / z=285.0[M+H] + .

[0380] 1H NMR (500MHz, DMSO-d6)d8.93(s, 1H), 8.06(s, 1H), 7.70-7.66(m, 1H), 7.37(t, J=7. 3Hz, 2H), 7.12(t, J=7.4Hz, 1H), 7.04-7.00(m, 2H), 6.48-6.45(m, 1H), 3.47(s, 3H).

[0381] Example 19: 4-(4-(2-hydroxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 80: 4-(2-Methoxyphenoxy)thiazole [ka] Following the procedure in Preparation 22, 2-methoxyphenol (1.1 g, 8.65 mmol) was reacted to give the title compound (307 mg, 17%).

[0382] HPLC R (Agilent, acidic, 3.5 min): 1.47 min, m / z=208.0[M+H] + .

[0383] Preparation 81: 5-Bromo-4-(2-methoxyphenoxy)thiazole [ka] 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%).

[0384] HPLC R (Agilent, acidic, 3.5 min): 1.65 min, m / z=287.2[M+H] + .

[0385] Preparation 82: 4-(4-(2-methoxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (43 mg, 23%).

[0386] HPLC R (Agilent, acidic, 3.5 min): 1.46 min, m / z=354.2[M+H] + .

[0387] Preparation 83: 4-(4-(2-hydroxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (9 mg, 20%).

[0388] HPLC R (Agilent, acidic, 3.5 min): 1.36 min, m / z=340.0[M+H] + .

[0389] 1 H NMR (500MHz, DMSO-d6)d12.21(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).

[0390] Example 20: 4-(4-(4-hydroxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 84: 4-(4-Methoxyphenoxy)thiazole [ka] Following the procedure in Preparation 22, 4-methoxyphenol (1.1 g, 8.65 mmol) was reacted to give the title compound (332 mg, 19%).

[0391] HPLC R (Agilent, acidic, 3.5 min): 1.46 min, m / z=208.0[M+H] + .

[0392] Preparation 85: 5-Bromo-4-phenoxythiazole [ka] 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%).

[0393] HPLC R (Agilent, acidic, 3.5 min): 1.70 min, m / z=287.2[M+H] + .

[0394] Preparation 86: 4-(4-(4-methoxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (40 mg, 22%).

[0395] HPLC R (Agilent, acidic, 3.5 min): 1.43 min, m / z=354.0[M+H] + .

[0396] Preparation 87: 4-(4-(4-hydroxyphenoxy)thiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (15 mg, 35%).

[0397] HPLC R (Agilent, acidic, 3.5 min): 1.30 min, m / z=340.0[M+H] + .

[0398] 1 H NMR (500MHz, DMSO-d6)d12.19(bs, 1H), 9.18(bs, 1H), 8.95(s, 1H), 7.53(s, 1H), 7.35(t, J=2.7Hz, 1H), 6.86-6.83(m, 2H), 6.71-6.69(m, 2H), 6.44(t, J=2.4Hz, 1H), 3.54(s, 3H).

[0399] Example 21: 5-(4-(2-hydroxyphenoxy)thiazol-5-yl)-1-methylpyridin-2(1H)-one Preparation 88: 5-(4-(2-methoxyphenoxy)thiazol-5-yl)-1-methylpyridin-2(1H)-one [ka] 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%).

[0400] HPLC R (Agilent, acidic, 3.5 min): 1.35 min, m / z=315.0[M+H] + .

[0401] Preparation 89: 5-(4-(2-hydroxyphenoxy)thiazol-5-yl)-1-methylpyridin-2(1H)-one [ka] According to 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 obtain the title compound (53 mg, 46%).

[0402] HPLC R (Agilent, acidic, 3.5 min): 1.26 min, m / z=301.0[M+H] + .

[0403] 1 H NMR (500MHz, DMSO-d6) d9.54(s, 1H), 8.79(s, 1H), 8.12(s, 1H), 7.83-7.81(d, J=9.7H z, 1H), 6.99-6.90(m, 3H), 6.75(t, J=7.6Hz, 1H), 6.48(d, J=10.4Hz, 1H), 3.48(s, 3H).

[0404] 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 Preparation 90: 2-Chloro-5-(2-methoxyphenoxy)-4-nitropyridine 1-oxide [ka] Following the procedure in Preparation 35, 2-methoxyphenol (15.5 g, 125 mmol) was reacted to give the title compound (23.0 g, 75%).

[0405] HPLC R (Shimadzu, acidic, 1.5 min): 0.92 min, m / z=297.1[M+H] + .

[0406] Preparation 91: 2,4-Dibromo-5-(2-methoxyphenoxy)pyridine 1-oxide [ka] Following the procedure in Preparation 26, 2-chloro-5-(2-methoxyphenoxy)-4-nitropyridine 1-oxide (6.0 g, 20.2 mmol) was reacted to give the title compound (7.0 g, 92%).

[0407] HPLC R (Shimadzu, acidic, 1.5 min): 0.85 min, m / z=376.0[M+H] + .

[0408] Preparation 92: 2,4-Dibromo-5-(2-methoxyphenoxy)pyridine [ka] Following the procedure in Preparation 27, 2,4-dibromo-5-(2-methoxyphenoxy)pyridine 1-oxide (7.0 g, 18.6 mmol) was reacted to give the title compound (6.7 g, 100%).

[0409] HPLC R (Shimadzu, acidic, 1.5 min): 0.91 min, m / z=359.9[M+H] + .

[0410] Preparation 93: 4-Bromo-5-(2-methoxyphenoxy)pyridin-2(1H)-one [ka] Following the procedure in Preparation 38, 2,4-dibromo-5-(2-methoxyphenoxy)pyridine (6.7 g, 18.6 mmol) was reacted to give the title compound (4.3 g, 77%).

[0411] HPLC R (Shimadzu, acidic, 1.5 min): 0.81 min, m / z=298.0[M+H] + .

[0412] Preparation 94: 4-Bromo-5-(2-methoxyphenoxy)-1-methylpyridin-2(1H)-one [ka] 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%).

[0413] 1 H NMR (400MHz, DMSO-d6) d7.78(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)

[0414] 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 [ka] According to 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 obtain the title compound (8 mg, 18%).

[0415] HPLC R (Agilent, acidic, 3.5 min): 1.25 min, m / z=378.1[M+H] + .

[0416] 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 [ka] According to 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 obtain the title compound (13 mg, 50%).

[0417] HPLC R (Agilent, acidic, 3.5 min): 1.17 min, m / z=364.0[M+H] + .

[0418] 1 H NMR (500MHz, CDCl3) d9.56(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=2.5Hz, 1H), 5.55(bs, 1H), 3.36(s, 3H), 3.32(s, 3H).

[0419] 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 Preparation 97: 2-Chloro-5-(3-methoxyphenoxy)-4-nitropyridine 1-oxide [ka] Following the procedure in Preparation 35, 3-methoxyphenol (15.5 g, 125 mmol) was reacted to give the title compound (24.0 g, 78%).

[0420] HPLC R (Shimadzu, acidic, 1.5 min): 0.94 min, m / z=297.1[M+H] + .

[0421] Preparation 98: 2,4-Dibromo-5-(3-methoxyphenoxy)pyridine 1-oxide [ka] 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%).

[0422] HPLC R (Shimadzu, acidic, 1.5 min): 0.83 min, m / z=376.0[M+H] + .

[0423] Preparation 99: 2,4-Dibromo-5-(3-methoxyphenoxy)pyridine [ka] 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%).

[0424] HPLC R (Shimadzu, acidic, 1.5 min): 1.00 min, m / z=359.9[M+H] + .

[0425] Preparation 100: 4-Bromo-5-(3-methoxyphenoxy)pyridin-2(1H)-one [ka] 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%).

[0426] HPLC R (Agilent, acidic, 1.5 min): 0.82 min, m / z=297.1[M+H] + .

[0427] Preparation 101: 4-Bromo-5-(3-methoxyphenoxy)-1-methylpyridin-2(1H)-one [ka] 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%).

[0428] HPLC R (Shimadzu, acidic, 1.5 min): 0.66 min, m / z=309.8[M+H] + .

[0429] 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 [ka] According to 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 obtain the title compound (42 mg, 40%).

[0430] HPLC R (Agilent, acidic, 3.5 min): 1.25 min, m / z=378.1[M+H] + .

[0431] 1 H NMR(500MHz, CDCl3)d9.63(bs, 1H), 7.28-7.25(m, 2H), 7.17-7.16(m, 1H), 7.08(t, J=8.2Hz, 1H), 6.86-6.86(m, 1H), 6.55(t, J=2.9H) z, 1H), 6.51(dd, J=2.6, 8.4Hz, 1H), 6.36(dd, J=2.1, 8.3Hz, 1H), 6.32(t, J=2.3Hz, 1H), 3.70-3.69(m, 3H), 3.61(s, 3H), 3.58(s, 3H).

[0432] 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 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 [ka] According to 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 obtain the title compound (22 mg, 58%).

[0433] HPLC R (Agilent, acidic, 3.5 min): 1.13 min, m / z=364.0[M+H] + .

[0434] 1 H NMR (500MHz, DMSO) d12.05(bs, 1H), 9.37(s, 1H), 7.85(s, 1H), 7.38(s, 1H), 7.31(t, J=2.7Hz, 1H), 6.94(t, J=8.0Hz, 1H), 6.55-6 .54(m, 1H), 6.34(t, J=2.3Hz, 1H), 6.30(dd, J=1.9, 8.0Hz, 1H), 6.20(dd, J=2.2, 8.1Hz, 1H), 6.17(d, J=2.4Hz, 1H), 3.48(s, 6H).

[0435] 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 Preparation 104: 2-Chloro-5-(4-methoxyphenoxy)-4-nitropyridine 1-oxide [ka] Following the procedure in Preparation 35, 4-methoxyphenol (4.6 g, 37.4 mmol) was reacted to give the title compound (6.0 g, 65%).

[0436] 1 H NMR (400MHz, DMSO-d6) d8.69(s, 1H), 8.11(s, 1H), 7.21(d, J=9.2Hz, 2H), 7.01(d, J=9.2Hz, 2H), 3.77(s, 3H)

[0437] Preparation 105: 2,4-Dibromo-5-(4-methoxyphenoxy)pyridine 1-oxide [ka] Following the procedure in Preparation 26, 2-chloro-5-(4-methoxyphenoxy)-4-nitropyridine 1-oxide (6.0 g, 20.2 mmol) was reacted to give the title compound (7.60 g, 98%).

[0438] HPLC R (Shimadzu, acidic, 1.5 min): 0.85 min, m / z=376.0[M+H] + .

[0439] Preparation 106: 2,4-Dibromo-5-(4-methoxyphenoxy)pyridine [ka] Following the procedure in Preparation 27, 2,4-dibromo-5-(4-methoxyphenoxy)pyridine 1-oxide (7.6 g, 20.3 mmol) was reacted to give the title compound (7.3 g, 99%).

[0440] HPLC R (Shimadzu, acidic, 1.5 min): 1.02 min, m / z=359.9[M+H] + .

[0441] Preparation 107: 4-Bromo-5-(4-methoxyphenoxy)pyridin-2(1H)-one [ka] Following the procedure in Preparation 38, 2,4-dibromo-5-(4-methoxyphenoxy)pyridine (7.3 g, 20.3 mmol) was reacted to give the title compound (4.0 g, 59%).

[0442] 1H NMR (400MHz, DMSO-d6) d7.49(s, 1H), 6.92-6.88(m, 4H), 6.85(s, 1H), 3.71(s, 3H)

[0443] Preparation 108: 4-Bromo-5-(4-methoxyphenoxy)-1-methylpyridin-2(1H)-one [ka] 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%).

[0444] 1 H NMR (400MHz, DMSO-d6)d7.90(s, 1H), 6.92-6.87(m, 5H), 3.71(s, 3H), 3.39(s, 3H)

[0445] 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 [ka] According to 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 obtain the title compound (50 mg, 47%).

[0446] HPLC R (Agilent, acidic, 3.5 min): 1.23 min, m / z=378.1[M+H] + .

[0447] 1H NMR (500MHz, CDCl3)d10.94(bs, 1H), 7.22(t, J=2.7Hz, 1H), 7.09(s, 1H), 7.04(s, 1H), 6 .76(s, 1H), 6.64(s, 4H), 6.43(t, J=2.3Hz, 1H), 3.64(s, 3H), 3.53(s, 3H), 3.49(s, 3H).

[0448] 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 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 [ka] According to 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 obtain the title compound (27 mg, 59%).

[0449] HPLC R (Agilent, acidic, 3.5 min): 1.13 min, m / z=364.0[M+H] + .

[0450] 1 H NMR (500MHz, DMSO) d12.03(bs, 1H), 9.02(s, 1H), 7.66(s, 1H), 7.37-7.36(m, 1H), 7.30(t, J=2.7Hz, 1H), 6.6 5-6.62(m, 2H), 6.58-6.55(m, 2H), 6.49(d, J=13.6Hz, 1H), 6.32(t, J=2.3Hz, 1H), 3.49(s, 3H), 3.45(s, 3H).

[0451] Example 27: 5'-(4-Methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione Preparation 111: 5'-(4-methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] Following the procedure in Preparation 40, 4-bromo-5-(4-methoxyphenoxy)-1-methylpyridin-2(1H)-one (50 mg, 0.16 mmol) was reacted to give the title compound (31 mg, 53%).

[0452] HPLC R (Agilent, acidic, 3.5 min): 1.22 min, m / z=339.0[M+H] + .

[0453] 1 H NMR (400MHz, CDCl3) d7.67 (d, J=2.6Hz, 1H), 7.56 (dd, J=2.7, 9.5Hz, 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).

[0454] Example 28: 5'-(3-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione Preparation 112: 5'-(3-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] According to 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 obtain the title compound (12 mg, 49%).

[0455] HPLCR (Agilent, acidic, 3.5 min): 1.08 min, m / z=325.0[M+H] + .

[0456] 1 H NMR (500MHz, DMSO-d6) d9.10 (bs, 1H), 8.04 (d, J=2.6Hz, 1H), 7.66-7.61 (m, 2H), 6.75-6.7 2(m, 2H), 6.67-6.64(m, 2H), 6.51(s, 1H), 6.35(d, J=9.5Hz, 1H), 3.42(s, 3H), 3.41(s, 3H).

[0457] Example 29: 5'-(3-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione Preparation 113: 5'-(3-methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] Following the procedure in Preparation 40, 4-bromo-5-(3-methoxyphenoxy)-1-methylpyridin-2(1H)-one (50 mg, 0.16 mmol) was reacted to give the title compound (29 mg, 48%).

[0458] HPLC R (Agilent, acidic, 3.5 min): 1.23 min, m / z=339.0[M+H] + .

[0459] Preparation 114: 5'-(3-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] According to 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 obtain the title compound (13 mg, 53%).

[0460] HPLC R (Agilent, acidic, 3.5 min): 1.08 min, m / z=325.0[M+H] + .

[0461] 1 H NMR (500MHz, DMSO-d6)d9.48(bs, 1H), 8.06-8.05(m, 1H), 7.83-7.82(m, 1H), 7.62-7.59( m, 1H), 7.04(t, J=8.2Hz, 1H), 6.54(s, 1H), 6.40-6.25(m, 4H), 3.44(s, 3H), 3.41(s, 3H).

[0462] 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 Preparation 115: 2-Chloro-3-(2-methoxyphenoxy)-4-nitropyridine 1-oxide [ka] 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%).

[0463] 1 H NMR (400MHz, DMSO-d6) d8.59(d, J=7.6Hz, 1H), 8.20(d, J=7.6Hz, 1H), 7.17-7.10(m, 2H), 6.94-6.82(m, 2H), 3.83(s, 3H).

[0464] Preparation 116: 2,4-Dibromo-3-(2-methoxyphenoxy)pyridine 1-oxide [ka] 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%).

[0465] HPLC R (Shimadzu, acidic, 1.5 min): 0.83 min, m / z=376.1[M+H] + .

[0466] Preparation 117: 2,4-Dibromo-3-(2-methoxyphenoxy)pyridine [ka] 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%).

[0467] HPLC R (Shimadzu, acidic, 1.5 min): 0.94 min, m / z=360.1[M+H] + .

[0468] Preparation 118: 4-Bromo-3-(2-methoxyphenoxy)pyridin-2(1H)-one [ka] 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%).

[0469] 1 H NMR (400MHz, DMSO-d6) d12.1(brs, 1H), 7.26(d, J=6.8Hz, 1H), 7.06-7.04(m, 1H), 6.99-6.78(m, 2H), 6.53-6.50(m, 2H), 3.82(s, 3H).

[0470] Preparation 119: 4-Bromo-3-(2-methoxyphenoxy)-1-methylpyridin-2(1H)-one [ka] 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%).

[0471] 1 H NMR (400MHz, DMSO-d6) d7.62(d, J=7.2Hz, 1H), 7.08-7.03(m, 1H), 7.01-6.94(m, 1H), 6 .81-6.74(m, 1H), 6.58(d, J=7.2Hz, 1H), 6.54-6.48(m, 1H), 3.82(s, 3H), 3.43(s, 3H).

[0472] 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 [ka] According to 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 obtain the title compound (13 mg, 33%).

[0473] HPLC R (Agilent, acidic, 3.5 min): 1.20 min, m / z=378.1[M+H] + .

[0474] 1H NMR (400MHz, DMSO-d6) d12.08(bs, 1H), 7.68(d, J=7.2Hz, 1H), 7.41(s, 1H), 7.29(t, J=2.7Hz, 1H), 6.95(dd, J=1.5, 8.1Hz, 1 H), 6.87-6.82(m, 1H), 6.71-6.66(m, 1H), 6.50-6.41(m, 2H), 6.31(t, J=2.3Hz, 1H), 3.76(s, 3H), 3.51(s, 3H), 3.45(s, 3H).

[0475] 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 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 [ka] According to 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 obtain the title compound (17 mg, 26%).

[0476] HPLC R (Agilent, acidic, 3.5 min): 1.16 min, m / z=364.1[M+H] + .

[0477] 1 H NMR (500MHz, DMSO-d6) d12.17(bs, 1H), 9.38(s, 1H), 7.72(d, J=7.2Hz, 1H), 7.64(s, 1H), 7.32(t, J=2.8Hz, 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).

[0478] 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 Preparation 122: 2-Chloro-3-(3-methoxyphenoxy)-4-nitropyridine 1-oxide [ka] 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 give the title compound (9.0 g, 58%).

[0479] 1 H NMR (400MHz, DMSO-d6) d8.61(d, J=7.6Hz, 1H), 8.22(d, J=7.2Hz, 1H), 7.27-7.23(m, 1H), 6.74-6.61(m, 3H), 3.74(s, 3H).

[0480] Preparation 123: 2,4-Dibromo-3-(3-methoxyphenoxy)pyridine 1-oxide [ka] Following the procedure in Preparation 26, 2-chloro-3-(3-methoxyphenoxy)-4-nitropyridine 1-oxide (9.0 g, 30.3 mmol) was reacted to give the title compound (11.0 g, 97%).

[0481] HPLC R (Shimadzu, acidic, 1.5 minutes): 0.85 minutes, m / z=376.0[M] + .

[0482] Preparation 124: 2,4-Dibromo-3-(3-methoxyphenoxy)pyridine [ka] Following the procedure in Preparation 27, 2,4-dibromo-3-(3-methoxyphenoxy)pyridine 1-oxide (11.0 g, 29.3 mmol) was reacted to give the title compound (10.1 g, 96%).

[0483] HPLC R (Agilent, acidic, 1.5 min): 0.97 min, m / z=359.8[M+H] + .

[0484] Preparation 125: 4-Bromo-3-(3-methoxyphenoxy)pyridin-2(1H)-one [ka] Following the procedure in Preparation 38, 2,4-dibromo-3-(3-methoxyphenoxy)pyridine (10.0 g, 27.9 mmol) was reacted to give the title compound (1.0 g, 12%).

[0485] 1 H NMR (400MHz, DMSO-d6) d7.34(d, J=5.6Hz, 1H), 7.13-7.09(m, 1H), 6.52-6.21(m, 4H), 3.70(s, 3H).

[0486] Preparation 126: 4-Bromo-3-(3-methoxyphenoxy)-1-methylpyridin-2(1H)-one [ka] Following the procedure in Preparation 39, 4-bromo-3-(3-methoxyphenoxy)pyridin-2(1H)-one (1.0 g, 3.38 mmol) was reacted to give the title compound (0.7 g, 66%).

[0487] 1 H NMR (400MHz, DMSO-d6)d7.65(d, J=7.2Hz, 1H), 7.17(t, J=8.4Hz, 1H), 6.64-6. 58(m, 2H), 6.43(t, J=2.4Hz, 1H), 6.38-6.34(m, 1H), 3.72(s, 3H), 3.45(s, 3H).

[0488] 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 [ka] According to 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 obtain the title compound (12 mg, 30%).

[0489] HPLC R (Agilent, acidic, 3.5 min): 1.19 min, m / z=378.1[M+H] + .

[0490] 1 H NMR (400MHz, DMSO-d6) d12.07(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).

[0491] 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 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 [ka] According to 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 obtain the title compound (15 mg, 23%).

[0492] HPLC R (Agilent, acidic, 3.5 min): 1.12 min, m / z=364.1[M+H] + .

[0493] 1 H NMR (500MHz, DMSO-d6) d12.15(bs, 1H), 9.34(s, 1H), 7.71(d, J=7.0Hz, 1H), 7.37-7.31(m, 2H), 6.93(t , J=8.1Hz, 1H), 6.41(d, J=7.0Hz, 1H), 6.32-6.28(m, 2H), 6.16-6.09(m, 2H), 3.52(s, 3H), 3.47(s, 3H).

[0494] 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 Preparation 129: 2-Chloro-3-(4-methoxyphenoxy)-4-nitropyridine 1-oxide [ka] 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 give the title compound (12.0 g, 78%).

[0495] 1H NMR (400MHz, DMSO-d6) d8.60(d, J=7.6Hz, 1H), 8.20(d, J=7.2Hz, 1H), 7.05-6.99(m, 2H), 6.92-6.87(m, 2H), 3.73(s, 3H).

[0496] Preparation 130: 2,4-Dibromo-3-(4-methoxyphenoxy)pyridine 1-oxide [ka] Following the procedure in Preparation 26, 2-chloro-3-(4-methoxyphenoxy)-4-nitropyridine 1-oxide (12.0 g, 40.5 mmol) was reacted to give the title compound (12.1 g, 79%).

[0497] HPLC R (Shimadzu, acidic, 1.5 min): 0.85 min, m / z=375.9[M+H] + .

[0498] Preparation 131: 2,4-Dibromo-3-(4-methoxyphenoxy)pyridine [ka] Following the procedure in Preparation 27, 2,4-dibromo-3-(4-methoxyphenoxy)pyridine 1-oxide (18.0 g, 48.0 mmol) was reacted to give the title compound (14.0 g, 75%).

[0499] HPLC R (Shimadzu, acidic, 1.5 min): 0.97 min, m / z=360.1[M+H] + .

[0500] Preparation 132: 4-Bromo-3-(4-methoxyphenoxy)pyridin-2(1H)-one [ka] Following the procedure in Preparation 38, 2,4-dibromo-3-(4-methoxyphenoxy)pyridine (14.0 g, 39.0 mmol) was reacted to give the title compound (2.0 g, 17%).

[0501] 1 H NMR (400MHz, DMSO-d6) d7.28(d, J=6.8Hz, 1H), 6.86-6.81(m, 2H), 6.80-6.75(m, 2H), 6.46(d, J=6.8Hz, 1H), 3.70(s, 3H).

[0502] Preparation 133: 4-Bromo-3-(4-methoxyphenoxy)-1-methylpyridin-2(1H)-one [ka] Following the procedure in Preparation 39, 4-bromo-3-(4-methoxyphenoxy)pyridin-2(1H)-one (2.0 g, 6.8 mmol) was reacted to give the title compound (1.8 g, 82%).

[0503] 1 H NMR (400MHz, DMSO-d6) d7.62(d, J=7.6Hz, 1H), 6.86-6.82(m, 2H), 6.81-6.75(m, 2H), 6.57(d, J=7.2Hz, 1H), 3.70(s, 3H), 3.44(s, 3H)

[0504] 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 [ka] According to 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 obtain the title compound (8 mg, 20%).

[0505] HPLC R (Agilent, acidic, 3.5 min): 1.17 min, m / z=378.1[M+H] + .

[0506] 1 H NMR (400MHz, DMSO-d6)d12.08(s, 1H), 7.68(d, J=7.2Hz, 1H), 7.36-7.30(m, 2H), 6.75-6.62( m, 4H), 6.39(d, J=7.1Hz, 1H), 6.30(t, J=2.3Hz, 1H), 3.64(s, 3H), 3.51(s, 3H), 3.48(s, 3H).

[0507] 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 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 [ka] According to 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 obtain the title compound (17 mg, 27%).

[0508] HPLC R (Agilent, acidic, 3.5 min): 1.06 min, m / z=364.0[M+H] + .

[0509] 1 H NMR (500MHz, DMSO-d6) d12.12(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).

[0510] Example 36: 3'-(2-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione Preparation 136: 3'-(2-methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] 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%).

[0511] HPLC R (Agilent, acidic, 3.5 min): 1.15 min, m / z=339.0[M+H] + .

[0512] Preparation 137: 5'-(2-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] According to 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 obtain the title compound (21 mg, 53%).

[0513] HPLC R (Agilent, acidic, 3.5 min): 1.10 min, m / z=325.0[M+H] + .

[0514] 1 H NMR (500MHz, DMSO-d6) d9.38(s, 1H), 8.24(d, J=2.4Hz, 1H), 7.76(dd, J=2.6, 10.0Hz, 1H), 7.71(d, J=7.2Hz, 1 H), 6.84-6.77(m, 2H), 6.60-6.56(m, 1H), 6.46(d, J=6.9Hz, 1H), 6.42-6.37(m, 2H), 3.50(s, 3H), 3.46(s, 3H).

[0515] Example 37: 3'-(3-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione Preparation 138: 3'-(3-methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] 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%).

[0516] HPLC R (Agilent, acidic, 3.5 min): 1.17 min, m / z=339.0[M+H] + .

[0517] Preparation 139: 5'-(3-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] According to 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 obtain the title compound (23 mg, 40%).

[0518] HPLC R (Agilent, acidic, 3.5 min): 1.05 min, m / z=325.0[M+H] + .

[0519] 1 H NMR (500MHz, DMSO-d6) d9.43(s, 1H), 8.10(d, J=2.6Hz, 1H), 7.71(d, J=7.2Hz, 1H), 7.63(dd, J=2.7, 9.5Hz, 1H), 7.02(t, J=8.2H) z, 1H), 6.43(d, J=7.2Hz, 1H), 6.40-6.37(m, 2H), 6.24(dd, J=2.3, 8.1Hz, 1H), 6.17(t, J=2.2Hz, 1H), 3.48(s, 3H), 3.45(s, 3H).

[0520] Example 38: 3'-(4-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione Preparation 140: 3'-(4-methoxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] Following the procedure in Preparation 40, 4-bromo-3-(4-methoxyphenoxy)-1-methylpyridin-2(1H)-one (100 mg, 0.32 mmol) was reacted to give the title compound (50 mg, 46%).

[0521] HPLC R (Agilent, acidic, 3.5 min): 1.15 min, m / z=339.0[M+H] + .

[0522] Preparation 141: 5'-(4-hydroxyphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] According to 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 obtain the title compound (18 mg, 34%).

[0523] HPLC R (Agilent, acidic, 3.5 min): 1.00 min, m / z=325.0[M+H] + .

[0524] 1 H NMR (500MHz, DMSO-d6)d9.02(m, 1H), 8.08(d, J=2.6Hz, 1H), 7.69-7.62(m, 2H ), 6.62-6.61(m, 4H), 6.39(dd, J=8.4, 10.9Hz, 2H), 3.46(s, 3H), 3.45(s, 3H).

[0525] Example 39: 3'-(4-fluoro-2,6-dimethylphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione Preparation 142: 2-Chloro-3-(4-fluoro-2,6-dimethylphenoxy)-4-nitropyridine 1-oxide [ka] Following the procedure in Preparation 35, 4-fluoro-2,6-dimethylphenol (14.0 g, 99.9 mmol) and 2-chloro-3-fluoro-4-nitropyridine 1-oxide (10.0 g, 51.9 mmol) were reacted to give the title compound (11.0 g, 47%).

[0526] HPLC R (Shimadzu, acidic, 1.5 min): 0.94 min, m / z=313.2[M+H] + .

[0527] Preparation 143: 2,4-Dibromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridine 1-oxide [ka] Following the procedure in Preparation 26, 2-chloro-3-(4-fluoro-2,6-dimethylphenoxy)-4-nitropyridine 1-oxide (10.0 g, 31.9 mmol) was reacted to give the title compound (11.6 g, 93%).

[0528] HPLC R (Shimadzu, acidic, 1.5 min): 0.92 min, m / z=392.0[M+H] + .

[0529] Preparation 144: 2,4-Dibromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridine [ka] 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%).

[0530] HPLC R (Shimadzu, acidic, 1.5 min): 1.15 min, m / z=376.1[M+H] + .

[0531] Preparation 145: 4-Bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one [ka] 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%).

[0532] HPLC R (Shimadzu, acidic, 1.5 min): 0.88 min, m / z=313.8[M+H] + .

[0533] Preparation 146: 4-Bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one [ka] 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%).

[0534] 1 H NMR (400MHz, DMSO-d6) d7.46(d, J=7.2Hz, 1H), 6.83(d, J=9.2Hz, 2H), 6.55(d, J=7.2Hz, 1H), 3.35(s, 3H), 2.09(s, 6H)

[0535] Preparation 147: 3'-(4-fluoro-2,6-dimethylphenoxy)-1,1'-dimethyl-[3,4'-bipyridine]-2',6(1H,1'H)-dione [ka] 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 give the title compound (73 mg, 60%).

[0536] HPLC R (Agilent, acidic, 3.5 min): 1.34 min, m / z=355.0[M+H] + .

[0537] 1 H NMR (500MHz, DMSO-d6) d8.11-8.09(m, 1H), 7.80(dd, J=2.7, 9.5Hz, 1H), 7.53(d, J=7.2Hz, 1H), 6.78-6.75 (m, 2H), 6.45(d, J=9.5Hz, 1H), 6.36(d, J=7.2Hz, 1H), 3.51-3.50(m, 3H), 3.40(s, 3H), 2.04-2.03(m, 6H).

[0538] 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 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 [ka] According to 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 obtain the title compound (50 mg, 40%).

[0539] HPLC R (Agilent, acidic, 3.5 min): 1.36 min, m / z=395.1[M+H] + .

[0540] 1 H NMR (500MHz, DMSO-d6) d12.07(s, 1H), 7.54(d, J=7.0Hz, 1H), 7.36(s, 1H), 7.31(t, J=2.7H) z, 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).

[0541] 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 Preparation 149: Ethyl 4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate [ka] 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 min. Ethyl carbonochloridate (0.39 mL, 4.06 mmol) was added and the reaction was stirred at -78 °C for 1 h. Ethyl acetate (500 ml) was added and the organics were washed with 2 x 500 ml water and then 1 x 500 ml saturated brine solution. The organics were then separated and dried (MgSO 4 ) 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 (770 mg, 50%).

[0542] HPLC R (Agilent, acidic, 3.5 min): 1.85 min, m / z=454.8[M+H] + .

[0543] Preparation 150: 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-carboxylate ethyl [ka] According to the procedure in Preparation 6, 4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate ethyl (710 mg, 1.6 mmol) was reacted to obtain the title compound (437 mg, 56%).

[0544] HPLC R (Agilent, acidic, 3.5 min): 2.10 min, m / z=501.1[M+H] + .

[0545] 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 [ka] According to 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-carboxylate ethyl (436 mg, 0.87 mmol) were reacted to obtain the title compound (112 mg, 29%).

[0546] HPLC R (Agilent, acidic, 3.5 min): 1.17 min, m / z=378.1[M+H] + .

[0547] 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 [ka] 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 for 1 h at room temperature. The solvent was removed under reduced pressure and THF (1 mL) was added. A 30% solution of ethylamine in THF (0.11 mL, 0.23 mmol) was added and the resulting solution was stirred for 2 h at room temperature. Ethyl acetate (50 ml) was added and the organics were washed with 2×50 ml of water followed by 1×50 ml of saturated brine solution. The organics were then separated and dried (MgSO 4 ) 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 (12 mg, 42%).

[0548] HPLC R (Agilent, acidic, 3.5 min): 1.52 min, m / z=465.2[M+H] + .

[0549] 1H NMR (500MHz, DMSO-d6)d12.25(bs, 1H), 8.34(t, J=5.3Hz, 1H), 7.57(d, J=7.2Hz, 1H), 7.41(s, 1H), 6.90(s, 1H), 6.7 0-6.67(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=7.2Hz, 3H).

[0550] 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 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 [ka] According to 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) and 2-amino-2-methylpropane (0.015 mL, 0.14 mmol) were reacted to give the title compound (3 mg, 16%).

[0551] HPLC R (Agilent, acidic, 3.5 min): 1.54 min, m / z=493.2[M+H] + .

[0552] 1H NMR (400MHz, DMSO-d6) d12.36(bs, 1H), 7.84(s, 1H), 7.56(d, J=7.2Hz, 1H), 7.43(s, 1H), 6.89(d, J=1.1Hz , 1H), 6.71-6.67(m, 2H), 6.33(d, J=7.0Hz, 1H), 3.57(s, 3H), 3.45(s, 3H), 2.01-2.00(m, 6H), 1.39(s, 9H).

[0553] 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 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 [ka] According to 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) and 1,1,1-trifluoro-2-methylpropan-2-amine (18.3 mg, 0.14 mmol) were reacted to give the title compound (5 mg, 23%).

[0554] HPLC R (Agilent, acidic, 3.5 min): 1.60 min, m / z=547.1[M+H] + .

[0555] 1H NMR (400MHz, DMSO-d6) d12.49(bs, 1H), 8.06(s, 1H), 7.57(d, J=7.1Hz, 1H), 7.44(s, 1H), 7.00(d, J=2.2 Hz, 1H), 6.70-6.67(m, 2H), 6.33(d, J=7.1Hz, 1H), 3.57(s, 3H), 3.45(s, 3H), 2.01(s, 6H), 1.63(s, 6H).

[0556] 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 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 [ka] According to 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) and 2,2-difluoro-1-methylcyclopropan-1-amine hydrochloride (20.5 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) were reacted to give the title compound (3 mg, 14%).

[0557] HPLC R (Agilent, acidic, 3.5 min): 1.49 min, m / z=527.2[M+H] + .

[0558] 1H NMR (400MHz, DMSO-d6)d12.35(s, 1H), 8.79(s, 1H), 7.57(d, J=7.1Hz, 1H), 7.43(s, 1H), 6.96(d, J=2.2Hz, 1H), 6 .70-6.66(m, 2H), 6.33(d, J=7.1Hz, 1H), 3.55(s, 3H), 3.45(s, 3H), 2.00(s, 6H), 1.71-1.62(m, 2H), 1.48(s, 3H).

[0559] Example 45: 4-(4-cyclobutoxythiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 156: 4-Cyclobutoxythiazole [ka] NaH (183 mg, 4.5 mmol) was added to cyclobutanol (1.29 mL, 16.5 mmol) at room temperature and the resulting solution was then heated to 60° C. for 1 h. 4-Bromo-thiazole (300 mg, 1.83 mmol) was added and the resulting solution was heated to 150° C. for 1 h. Ethyl acetate (50 ml) was added and the organics were washed with 2×50 ml of water and then 1×50 ml of saturated brine solution. The organics were then separated and dried (MgSO 4 ) 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 (124 mg, 44%).

[0560] 1 H NMR (500MHz, DMSO-d6) d8.52(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).

[0561] Preparation 157: 5-Bromo-4-cyclobutoxythiazole [ka] Following the procedure in Preparation 23, 4-cyclobutoxythiazole (485 mg, 3.1 mmol) was reacted to give the title compound (453 mg, 62%).

[0562] 1 H NMR (400MHz, DMSO-d6) d8.42(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).

[0563] Preparation 158: 4-(4-cyclobutoxythiazol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (7 mg, 8%).

[0564] HPLC R (Agilent, acidic, 3.5 min): 1.51 min, m / z=302.1[M+H] + .

[0565] 1 H NMR (400MHz, DMSO-d6)d12.17(bs, 1H), 8.85(s, 1H), 7.56(s, 1H), 7.36(t, J=2.8Hz, 1H), 6.44(t, J=2.4Hz, 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).

[0566] Example 46: 6-Methyl-4-(4-propoxythiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 159: 4-Propoxythiazole [ka] Following the procedure in Preparation 156, 1-propanol (3.6 mL, 54.9 mmol) was reacted to give the title compound (150 mg, 28%).

[0567] 1 H NMR (500MHz, CDCl3) d8.56(d, J=2.1Hz, 1H), 6.14(d, J=2.3Hz, 1H), 4.13-4.09(m, 2H), 1.89-1.82(m, 2H), 1.07(t, J=7.5Hz, 3H).

[0568] Preparation 160: 5-Bromo-4-propoxythiazole [ka] Following the procedure in Preparation 23, 4-propoxythiazole (610 mg, 4.3 mmol) was reacted to give the title compound (592 mg, 62%).

[0569] 1 H NMR (500MHz, CDCl3)d8.53(s, 1H), 4.33-4.29(m, 2H), 1.82-1.74(m, 2H), 1.04-1.00(m, 3H).

[0570] Preparation 161: 6-Methyl-4-(4-propoxythiazol-5-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one [ka] According to 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 obtain the title compound (17 mg, 23%).

[0571] HPLC R (Agilent, acidic, 3.5 min): 1.52 min, m / z=290.1[M+H] + .

[0572] 1 H NMR (400MHz, DMSO-d6)d12.19(bs, 1H), 8.87(s, 1H), 7.56(s, 1H), 7.35(t, J=2.8Hz, 1H), 6.44( t, J=2.4Hz, 1H), 4.31(t, J=6.5Hz, 2H), 3.29(s, 3H), 1.76-1.69(m, 2H), 0.96(t, J=7.4Hz, 3H).

[0573] 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 Preparation 162: 2-Chloro-5-(4-fluoro-2,6-dimethylphenoxy)-4-nitropyridine 1-oxide [ka] 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%).

[0574] 1 H NMR (400MHz, CDCl3) d8.25(s, 1H), 7.69(s, 1H), 6.88(d, J=8.4Hz, 2H), 2.183(s, 6H).

[0575] Preparation 163: 2,4-Dibromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridine 1-oxide [ka] 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%).

[0576] HPLC R (Shimadzu, acidic, 1.5 min): 0.93 min, m / z=391.8[M+H] + .

[0577] Preparation 164: 2,4-Dibromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridine [ka] 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%).

[0578] HPLC R (Shimadzu, acidic, 1.5 min): 1.08 min, m / z=375.8[M+H] + .

[0579] Preparation 165: 4-Bromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one [ka] 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%).

[0580] HPLCR (Shimadzu, acidic, 1.5 min): 0.90 min, m / z=312.0[M+H] + .

[0581] Preparation 166: 4-Bromo-5-(4-fluoro-2,6-dimethylphenoxy)-1-methylpyridin-2(1H)-one [ka] According to 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 obtain the title compound (1.42 g, 22%).

[0582] 1 H NMR (500MHz, DMSO-d6) d7.04(d, J=8.8Hz, 2H), 6.92(s, 1H), 6.82(s, 1H), 3.27(s, 3H), 2.12(s, 6H)

[0583] 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 [ka] According to 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 obtain the title compound (77 mg, 42%).

[0584] HPLC R (Agilent, acidic, 3.5 min): 1.36 min, m / z=394.1[M+H] + .

[0585] 1 H NMR (400MHz, DMSO-d6)d12.17(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=2.3Hz, 1H), 3.58(s, 3H), 3.34(s, 3H), 2.09(s, 6H).

[0586] primary activity The dissociation constants (K d ) was determined because BRD4 is a representative of the BET family and to date there are no highly isoform-selective compounds. The dissociation constants were determined as described below and are shown in Table 1.

[0587] Bromodomain assay procedure T7 phage strains exhibiting bromodomains were grown in parallel in E. coli hosts derived from the BL21 strain in 24-well blocks. E. coli were grown to log phase, infected with T7 phage from frozen stocks (multiplicity of infection = 0.4), and incubated with shaking at 32 °C until lysis (90-150 min). Lysates were centrifuged (5,000 × g) and filtered (0.2 μm) to remove cell debris. Streptavidin-coated magnetic beads were treated with biotinylated small molecule or acetylated peptide ligands for 30 min at RT to generate affinity resins for bromodomain assays. Ligated 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 ligand and reduce nonspecific phage binding. Binding reactions were assembled by combining bromodomains, ligated affinity beads, and test compounds in 1× binding buffer (16% SeaBlock, 0.32× PBS, 0.02% BSA, 0.04% Tween20, 0.004% sodium azide, 7.9 mM DTT). Test compounds were prepared as 1000× stocks in 100% DMSO and then diluted 1:25 in MEG. Compounds were then diluted directly into the assay so that the final concentrations of DMSO and MEG were 0.1% and 2.4%, respectively. All reactions were performed in a final volume of 0.02 ml in polypropylene 384-well plates. Assay plates were incubated for 1 h with shaking at RT and affinity beads were washed with wash buffer (1× PBS, 0.05% Tween20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 2μM non-biotinylated affinity ligand) and incubated for 30 min with shaking at RT. Bromodomain concentrations in the eluates were measured by quantitative polymerase chain reaction (qPCR).

[0588] An 11-point 3-fold serial dilution of each test compound was prepared in 100% DMSO at 1000x the final test concentration. All compounds were dispensed by acoustic transfer (non-contact dispensing) in 100% DMSO. Compounds were then diluted directly into the assay so that the final concentration of DMSO was 0.09%. Most dissociation constants were determined using a compound top concentration = 10,000 nM. If the initial dissociation constant determined was < 0.169 nM (the lowest concentration tested), measurements were repeated using a serial dilution starting with a lower top concentration. [Table 2] TIFF2025080251000200.tif65162 Key +Kd>1μM ++Kd>0.1μM and ≦1μM +++Kd > 0.01 μM and ≤ 0.1 μM ++++Kd≦0.01μM

[0589] Preferably, the BET protein inhibitor has a K of <0.1 μM for BRD4 BD2 or BD1 and BD2. d Selective for BRD4 BD2 with a K of <0.1 μM d BET protein inhibitors with K of <0.1 μM selective for BRD4 BD1 and BD2 are promising oral drug candidates. d BET protein inhibitors with

[0590] BET selectivity The selectivity of Examples 1 and 41 of the current invention for BRD2, 3, 4 and T BD1 and BD2 was determined as described below and is shown in Table 2.

[0591] Bromodomain assay procedure The same bromodomain assay procedure as outlined above was used. Example compounds were assayed according to their K dThe results for the primary screen binding interactions are reported as "% Ctrl," where lower numbers indicate stronger hits in the matrix.

number

[0592] Preferably, the BET protein inhibitors show a %Ctrl of <10 for BRD2, 3, 4 and T BD2 or T BD1 and BD2. BET protein inhibitors with a %Ctrl of <10 for BRD2, 3, 4 and T BD2 are promising oral drug candidates, while BET protein inhibitors with a %Ctrl of <10 for BRD2, 3, 4 and T BD1 and BD2 are promising topical drug candidates. The data in Table 2 show that Example 41 is a promising oral drug candidate, while Example 1 is a promising topical drug candidate.

[0593] BET Selectivity Dose Response The dissociation constants (K d ) were determined as described below and tabulated in Table 3.

[0594] Bromodomain assay procedure The same bromodomain assay procedure was used as outlined above. [Table 4]

[0595] K<10 nM for TBD2, 3, 4 and selectively for TBD2 dBET protein inhibitors with a K of <10 nM for BRD4(2) are promising oral drug candidates. d , and a K of >3000 nM for BRD4(1) d Thus, Example 41 is a promising oral drug candidate.

[0596] Cellular Activity - Broad Panel The EC50 values ​​of inventive example compounds 1 and 3 in reducing GM-CSF, IL-1a, IL-6, IL-8, CCL2, TNF-a, TSLP, CCL27, CCL20 and CXCL9 levels in primary keratinocytes stimulated with polyinosinic:polycytidylic acid were determined. The EC50s were determined as described below and are shown in Table 4.

[0597] Assay procedure 1. Primary human keratinocyte cells (PHK) are seeded at 9000 cells / well in flat-bottom 96-well plates. 2. Before treatment, cells must reach 90-100% confluence and then the medium is replaced with fresh medium without hydrocortisone. 3. Cells are cultured for 24 hours before TLR ligand stimulation (polyinosinic:polycytidylic acid). 4. Cells are treated with 20 μg / mL polyinosinic:polycytidylic acid for 48 hours in 180 μL of media and treated with different compounds or controls. 5. Supernatants are collected and chemokine and cytokine analysis is performed by Magpix-Luminex.

[0598] Immunoassay procedure Day 1 1. Add 200 μL Assay Buffer per well. Shake for 10 minutes at RT. Decant. Add 2.25 μL of standards or controls to appropriate wells. 3.25 μL of Assay Buffer is added to background and sample wells. 4.25 μL of cell culture medium is added to background, standard and control wells. 5. Add 25 μL of the appropriate sample to the sample well. 6.25 μL of beads are added to each well. Incubate at 7.4°C overnight (16-18 hours).

[0599] Day 2 8. Remove well contents and wash twice with 200 μL of Wash Buffer. 9. Add 25 μL of detection antibody per well. 10. Incubate at RT (20-25°C) for 1 hour. 11. Add (do not aspirate) 25 μL of Streptavidin-Phycoerythrin per well. 12.Incubate at RT for 30 min. 13. Remove well contents and wash twice with 200 μL of Wash Buffer. 14. Add 150 μL of Wash Buffer per well. Resuspend beads on plate shaker for 5 minutes. 15. Read 100 μl on Luminex (50 beads / bead set). [Table 5] key +EC50>1μM ++EC50>0.1μM and ≦1μM +++EC50>0.01μM and ≦0.1μM ++++EC50≦0.01μM

[0600] Preferably, the BET protein inhibitors exhibit cellular EC50 values ​​of <0.1 μM for one or more disease-associated markers in stimulated human primary keratinocytes. Examples 1 and 3 exhibit cellular EC50 values ​​of <0.1 μM in stimulated human primary keratinocytes.

[0601] Cellular activity-IL-4 The EC50 values ​​of certain example compounds of the invention in reducing IL-4 levels produced by CD4+ T cells activated with CD2, CD3 and CD28 antibodies were determined as described below and are tabulated in Table 5.

[0602] Assay procedure 1. CD4 + T cells are isolated from cryopreserved human peripheral blood mononuclear cells (PBMCs) using the EasySep™ kit (Cat. No. 17952, Stemcell Technologies). 2. CD2, CD3 and CD28 antibody-coated beads from the T cell activation / proliferation kit (Cat. No. 130-091-441, Miltenyi Biotec) were used at a bead-to-cell ratio of 1:2 to CD4 + Add to T cells. 3. CD4 with Beads + T cells were cultured at 2 × 10 in a round-bottom 96-well plate. 5 Cells / well are seeded and treated with different compounds and controls in a total volume of 200 μl. 4. Incubate the cells at 37 °C and 5% CO 2 Incubate for 48 hours at RT. 5. Supernatants are collected and IL-4 is analyzed by ELISA. [Table 6] key +EC50>1μM ++EC50>0.1μM and ≦1μM +++EC50>0.01μM and ≦0.1μM ++++EC50≦0.01μM

[0603] Preferably, the BET protein inhibitors exhibit cellular EC50 values ​​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 the T cell activation / proliferation kit.

[0604] Human tissue data – Th2 and Th17 stimulation of human skin explants The % reduction of example compounds listed under the invention at 2.5 μM in IL-4 or IL-17A mRNA in healthy human skin stimulated with Th2 or Th17 biased cocktails was determined as described below and tabulated in Table 6.

[0605] Assay procedure 1. Healthy human skin tissue freshly excised from an abdominoplasty is degreased, cleaned, and sectioned into 7 mm biopsies. 2. The biopsy is placed in a Transwell® insert with the epidermis apical and exposed to air, and the dermis submerged in medium in the basal chamber. 3. Biopsies were incubated overnight at 37°C, 5% CO with different compounds and controls added to the medium in the basal chamber. 2 Pretreat with. 4. The following day, the contents of the basal chamber are replaced with fresh medium containing the test compound and a stimulatory cocktail for either Th2 inflammation (proprietary Medpharm cocktail) or Th17 inflammation (a mixture of antibodies against CD3, CD28, IL-4, IFNγ and recombinant IL-1β, IL-6, IL-21, TGF-β). 5. Incubate the biopsy at 37 °C and 5% CO for an additional 24 h. 2 Incubate at 37 °C for 2 h. 6. After collection, the biopsies are cut in half and one half is homogenized and used for RNA extraction by standard methods. IL-4 or IL-17A are assessed by RT-qPCR. [Table 7] key +>25% reduction ++>50% reduction +++>75% reduction

[0606] Preferably, BET protein inhibitors show a >50% reduction in IL-4 or IL-17 levels, with examples 1 and 41 showing a >50% reduction in healthy human skin stimulated with a Th2 or Th17 biased cocktail.

[0607] Intrinsic clearance in human liver hepatocytes BET protein inhibitors with rapid clearance rates in human liver hepatocytes are promising local drug candidates. Some of the exemplary compounds of the current invention have rapid clearance rates in human liver hepatocytes, with the rates expressed as % of hepatic blood flow. The experimental methods and results (Table 7) are provided below.

[0608] Assay procedure A vial of human cryopreserved hepatocytes supplied by Life Technologies was thawed according to the manufacturer's instructions and the cells were resuspended in Williams Medium E (WME) with cell maintenance supplement pack (CM4000, Life Technologies). Hepatocytes were incubated in suspension (0.5 million cells / mL) in 48-well non-collagen-coated cell culture plates for 10 min at 37°C, 5% CO. 2 Upon addition of an equal volume of supplemented WME containing 1 μM test compound, an aliquot of the incubation solution was removed into acetonitrile containing internal standard (final concentration 0.5 μM test compound and cell density of 250,000 cells / mL). Similarly, aliquots were removed at 3, 9, 15, 30, 45, 60, 90 and 120 min. 100 μL of 80:20 water:acetonitrile was added to all samples and the analysis plate was centrifuged for 10 min at RT, after which the samples were injected and analyzed by UPLC-MS / MS. The response (area ratio of test compound to internal standard) was plotted against time using an exponential decay model, from which the disappearance rate was calculated. [Table 8]

[0609] Preferably, BET protein inhibitors for use as localized drugs exhibit an intrinsic clearance rate >75% in human liver hepatocytes. Exemplary compounds 1-4, 6, 8-12, 45 and 46 exhibit intrinsic clearance rates of >75%.

[0610] Solubility in topical formulations Examples 1-3 and 6 of the current invention have been shown to have desirable solubility in a wide range of simple topical formulations. Solubility is expressed in mg / mL. Experimental methods and results are provided below.

[0611] Assay procedure The solubility of exemplary solid compounds was determined in a selection of solvents and solvent combinations (Transcutol, 50:50 Transcutol:water, Labrasol, propylene glycol, and 1:5:4 ethanol:propylene glycol:water) after equilibration. An appropriate volume of each combination was added to a manually weighed amount of solid compound to obtain a 20 mg / mL concentration. The resulting suspension was shaken at 1000 rpm for 5 hours at 32°C, and then centrifuged at 13,000 x g for 10 minutes to pellet any precipitate. The supernatant solution was removed, inserted into an HPLC vial, and quantified by HPLC-UV against a calibration of known concentration of compound in DMSO. [Table 9] key +>0.1mg / mL and ≤1mg / mL ++>1 mg / mL and ≤ 10 mg / mL +++>10mg / mL

[0612] Preferably, BET protein inhibitors for use in topical formulations exhibit a formulation solubility of >1 mg / mL. Exemplary compounds 1-3 and 6 exhibit a formulation solubility of >1 mg / mL, and in some cases >10 mg / mL.

[0613] Stability in human skin S9 fraction Exemplary compounds 1-3 and 6 have desirable stability in human skin S9 fraction. Such fractions model human skin and stability is expressed as the time it takes for the concentration of the compound to decrease by half (half-life). The experimental method and some results (Table 9) are provided below.

[0614] Assay procedure The incubation mixture was prepared 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), UDPGA (final concentration 0.16 mg / mL) and warmed to 37°C for 5 min. Test compound (final concentration 0.5 μM) was added to initiate the reaction. Immediately at zero time, then at 3, 6, 15, 30, 60, 120 and 180 min, one aliquot (50 μL) of the incubation mixture was removed and mixed with acetonitrile (100 μL) to stop the reaction. Internal standards were added to all samples, and the samples were centrifuged to sediment precipitated proteins, then the plates were sealed and subsequently analyzed by UPLC-MS / MS using Quattro Premier XE (Waters corporation, USA).

[0615] Grafit (Erithacus Ltd) was used to calculate the exponential decay and, consequently, the rate constant (k) was calculated from the ratio of the peak areas of the test compound to the internal standard at each time point. The half-life (T 1 / 2 ) was determined using the following formula: T 1 / 2 =0.693 / k [Table 10]

[0616] Preferably, the BET protein inhibitor for use in a topical formulation has a T of >120 min in human skin. 1 / 2 Exemplary compounds 1-3 and 6 have T values ​​of >120 min in human skin S9 fraction. 1 / 2 Indicates the value.

[0617] Hydrolytic stability over a wide pH range Exemplary compounds of the invention, 1-3, are stable under conditions designed to promote hydrolysis. Stability is expressed as % loss after 6 days. Experimental methods and results (Table 8) are provided below.

[0618] Assay procedure To test hydrolytic stability, 1 mg / mL solutions of test materials were made in DMSO (0.1% solution). To 300 μL of each solution in an HPLC vial, 1200 μL of one of the following was added: pH 4.0 buffer, left at -60°C for 5 days. Samples were taken at t=0 and t=6. pH 5.5 buffer, left at -60°C for 5 days. Samples were taken at t=0 and 6 days. pH 7.4 buffer, left at -60°C for 5 days. Samples were taken at t=0 and 6 days.

[0619] A 100 μL aliquot was taken at each time point and added to 900 μL of DMSO. This sample was used to determine % degradation.

[0620] The % degradation was measured using a Bruker MicroTof II focused ESI mass spectrometer connected in parallel to a Dionex Ultimate 3000 RSLC system with a diode array detector. [Table 11]

[0621] Preferably, the BET protein inhibitors exhibit <5% decomposition in conditions designed to promote hydrolytic cleavage. Exemplary compounds 1-3 exhibit <5% decomposition when tested at a pH value of 7.4. Compounds 1 and 3 exhibit <5% decomposition at all pH values ​​tested.

[0622] Skin penetration (Franz cell) Inventive Example 1 has desirable skin penetration properties in human skin. Epidermal skin concentrations were determined as described below; the experimental method and some results (Table 9) are provided below.

[0623] Assay procedure Dosing solutions were prepared for each test compound at saturating concentrations in the appropriate 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 of each jacketed Franz cell (1 cm with magnetic stir bar). Pig / human skin was removed from -80°C storage and cut to size (approximately 2 cm) using a scalpel. 2 ) was cut. The skin was then allowed to thaw at RT and then placed in warm PBS for 10 min. Each piece of skin was then dried and then placed over the orifice of a Franz cell and any bubbles that may have formed were removed. A donor chamber was placed on the skin and clamped in place. 10 μL of dosing solution was then placed on the skin and parafilm was placed over the donor chamber to occlude. Using a 1 mL syringe, 200 μL of receiver solution was drawn through the sampling arm into a 96 deep well plate, which was used to sample the first time point (T 0 ) 200 μL of fresh warmed buffer was added to replace the volume removed. An additional 200 μL was removed over a 24 hour period at defined time points as described. 100 μL of each sample was then removed into 100 μL of acetonitrile containing an internal standard (IS, donepezil, 4 ng / mL).

[0624] After completion, the skin surface was wiped with a cotton swab to remove remaining compound. The cotton swab tip was then dipped into DMSO for compound extraction. The skin was removed from the Franz cell, and 30 tape strips were applied to remove the stratum corneum, which were then placed into a vial containing a known amount of DMSO. The skin was then placed face down on a heater block at 70°C for 1 minute, after which the epidermis was slowly torn away from the dermis using a scalpel. The remaining dermis was cut from the compressed tissue so that only exposed tissue remained, and both pieces of tissue were weighed and then placed into individual glass vials, and a known volume of DMSO was added.

[0625] All skin extracts and wash samples were placed on a shaker for 24 hours at RT, after which the samples were removed and centrifuged in an Eppendorf (if applicable). The supernatant was removed and appropriately diluted (e.g., 1:10, 100, 500 and 1:1000).

[0626] Calibration lines were prepared in PBS (5000ng / mL-0.2ng / mL). 100μL of each was added to 100μL of acetonitrile containing IS. All samples were quantified using UPLC-MS / MS (Waters Xevo TQ-S).

[0627] The concentration of compound present at each time point was corrected for the addition of fresh buffer. By plotting the concentration of compound versus time, J flux and T lag could be calculated (values ​​for caffeine were approximately: J Flux: 0.9-1.1 μg / cm / hr, T lag : 244-257 min, approximately 20% of dose present in the receiving chamber after 24 h, mass balance 70-90%).

[0628] Skin extraction samples were corrected for dilution factor and volume of extraction solution. The doses measured in the skin layer and time point samples were used to determine the mass balance of the experiment.

[0629] The exemplary compounds did not penetrate the skin (so J flux and T lag values ​​are not given). Rather, the exemplary compounds were present in high concentrations in the skin (see Table 9). The mass balance was calculated to be 94%. [Table 12]

[0630] Primary keratinocyte cell viability The EC50 of exemplary compounds 1 and 3 of the invention in human primary keratinocytes stimulated with polyinosinic:polycytidylic acid was determined. The EC50 was determined as described below and is shown in Table 10, where the compound number corresponds to the number in the examples.

[0631] Assay procedure 1. Primary human keratinocyte cells (PHK) are seeded at 9000 cells / well in flat-bottom 96-well plates. 2. Before treatment, cells must reach 90-100% confluence and then the medium is replaced with fresh medium without hydrocortisone. 3. Cells are cultured for 24 hours before TLR ligand stimulation (polyinosinic:polycytidylic acid). 4. Cells are treated with 20 μg / ml polyinosinic:polycytidylic acid for 48 hours in 180 μl of medium and treated with different compounds or controls. 6. Add 20 μL of Cell titre blue reagent along with 100 μL of fresh medium directly to each well and incubate at 37° C. (cell incubator) until the blue color changes to a slight pink color (usually 1 hour). 7. Fluorescence is measured using a Citation3 instrument. Excitation: 560 nm. Emission: 590 nm. [Table 13]

[0632] Preferably, BET protein inhibitors exhibit cell viability, EC50 values ​​of >1 μM. Exemplary compounds 1 and 3 exhibit cell viability, EC50 values ​​of >1 μM in human primary keratinocytes.

Claims

1. A compound of formula (I): 【Chemistry 1】 During the ceremony, 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; Each first substituent is selected from the group consisting of hydroxy, oxo, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkylol, Halo, SO ２ C １ -C ４ Alkyl, NHSO ２ C １ -C ４ Alkyl, SO ２ C ３ -C ６ Cycloalkyl, NHSO ２ C ３ -C ６ Cycloalkyl, SO ２ C １ -C ４ Alkyrol, NHSO ２ C １ -C ４ Alkyrol, C １ -C ５ Alkyloxy, C １ -C ５ Alkylamino, SO ２ N.H. ２ , C.O.N.H. ２ , CONHC １ -C ４ Alkyl, NHCOC １ -C ４ Alkyl, NHSO ２ N (C １ -C ４ Alkyl) ２ , C １ -C ６ Fluoroalkyl, SO ２ C １ -C ４ Fluoroalkyl, NHSO ２ C １ -C ４ Fluoroalkyl, C １ -C ５ Fluoroalkyloxy, and C １ -C ５ independently selected from the group consisting of fluoroalkylamino; X is O, CR ２ , NR′ or S, where R is H, C １ -C ４ R' is independently selected from the group consisting of alkyl and halo, １ -C ４ selected from the group consisting of 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; １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, CR Ａ R Ｂ R Ｃ , C ２ -C ５ Oxacycloalkyl, C ２ -C ５ azacycloalkyl or morpholinyl; R Ａ is C ３ -C ５ cycloalkyl, R Ｂ is C ３ -C ５ cycloalkyl, methyl or ethyl, and R Ｃ is OH; and Each second substituent is hydroxy, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, halo, C １ -C ５ Alkyloxy, C １ -C ５ Alkylamino, oxo, cyano, C １ -C ６ Fluoroalkyl, C １ -C ５ Fluoroalkyloxy, and C １ -C ５ independently selected from the group consisting of fluoroalkylamino; Ring structure B is optionally present; when ring structure B is present, it is an optionally substituted pyrrole bonded such that C is in the 4-position relative to NH; the pyrrole is optionally substituted at the 2-position with a third substituent; The third substituent is CONHC １ -C ４ Alkyl, CONH ２ , CONHC １ -C ６ CONHC optionally substituted at one or more carbon atoms with fluoroalkyl, methyl or ethyl ３ -C ６ Cycloalkyl; CONHC optionally substituted at one or more carbon atoms with methyl or ethyl ３ -C ５ Cyclofluoroalkyl, NHCOC １ -C ４ Alkyl and NHCOC １ -C ４ fluoroalkyl; with the proviso that when A is 6-membered it is substituted at least once with a hydroxy or oxo group. compound.

2. The compound has the formula (II): 【Chemistry 2】 2. The compound of claim 1, wherein A, X and Z are as defined for formula (I).

3. 3. The compound of claim 1 or 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 a first substituent.

4. The compound of claim 3, wherein the pyridone is a 2-pyridone.

5. 5. The compound of 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. 6. The compound of claim 3, wherein the 4-position thiazole carbon is bonded to C and the 5-position thiazole carbon is bonded to X.

7. 7. The compound of any one of claims 3 to 6, wherein the 5-position pyrazole carbon is bonded to C and the 1-position pyrazole nitrogen is bonded to X.

8. 8. The compound of claim 3, wherein the imidazole carbon at position 2 is bonded to C and the nitrogen at position 1 is bonded to X.

9. 9. The compound of 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. 4. The compound of claim 1, wherein each first substituent is independently selected from the group consisting of hydroxy, oxo, methyl and halo.

11. The compound of any preceding claim, wherein R is individually selected from the group consisting of H, methyl and fluoro, and R' is methyl.

12. 4. The compound according to any preceding claim, wherein X is O.

13. Z is a 5- or 6-membered aromatic or heteroaromatic ring, optionally substituted on one or more carbon or heteroatoms with a second substituent; １ -C ６ Alkyl, or C ３ -C ６ 3. The compound according to any preceding claim, which is cycloalkyl.

14. Z is a 6-membered aromatic or heteroaromatic ring, optionally substituted on one or more carbon or heteroatoms with a second substituent; １ -C ６ Alkyl, or C ３ -C ６ 3. The compound according to any preceding claim, which is cycloalkyl.

15. 4. The compound of any preceding claim, wherein Z is a phenyl or pyridyl ring optionally substituted at one or more carbon and / or nitrogen atoms with a second substituent.

16. Each second substituent is hydroxy, C １ -C ４ The compound of any preceding claim, wherein each is independently selected from the group consisting of alkyl and halo.

17. 4. The compound of claim 1, wherein each second substituent is any one or combination of hydroxy, methyl and fluoro.

18. C-A-X in formula (I) is any one of formulas (Ia), (Ib), (Ic), (Id) or (Id'): 【Chemistry 3】 In the formula, A １ is CR １ or N, and A ２ is CR ２ or N, and A ３ is CR ３ or N, and A ４ is CR ４ And A ５ is CR ５ or N and A ６ is CR ５ or N; R １ is H or hydroxy; R ２ is H, hydroxy, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, halo, SO ２ C １ -C ４ Alkyl, NHSO ２ C １ -C ４ Alkyl, SO ２ C ３ -C ６ Cycloalkyl, NHSO ２ C ３ -C ６ Cycloalkyl, C １ -C ５ Alkyloxy or C １ -C ５ alkylamino; R ３ and R ４ is H, hydroxy, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, halo, C １ -C ５ Alkyloxy or C １ -C ５ independently selected from the group consisting of alkylamino; However, R １ , R ２ , R ３ Or R ４ is hydroxy; B' is H or hydroxy; and R ５ is H or any of the first substituents defined above; A compound according to any one of the preceding claims.

19. R ２ is H, C １ -C ３ Alkyl, halo, SO ２ C １ -C ４ Alkyl or NHSO ２ C １ -C ４ alkyl; and R ３ and R ４ is H, hydroxy, C １ -C ３ 20. The compound of claim 18, wherein each is independently selected from the group consisting of alkyl and halo.

20. 20. The compound of claim 18 or 19, wherein when CAX is represented by formula (Ia), Z is a phenyl ring optionally substituted at one or more carbon atoms with a second substituent; 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.

21. 3. The compound of any preceding claim, wherein halo is fluoro or chloro.

22. 20. The compound of claim 18 or 19, 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 at one or more carbon and / or nitrogen atoms with a second substituent selected from the group consisting of hydroxy, methyl, fluoro and chloro.

23. The compound of claim 1, wherein the compound is any one of formulas (Ie) to (IIe): 【Chemistry 4】 【change】

24. A compound according to any one of claims 1 to 23 in the form of a pharma- ceutically acceptable salt.

25. A pharmaceutical composition comprising any one or a combination of compounds as defined in any one of claims 1 to 24 in combination with one or more pharma- ceutically acceptable excipients.

26. A compound as defined in any one of claims 1 to 24, or a pharmaceutical composition as defined in claim 25, for use as a medicament.

27. A compound as defined in any one of claims 1 to 24, or a pharmaceutical composition as defined in claim 25, for use in a method for the treatment or prevention of inflammatory skin disorders, respiratory disorders, gastrointestinal disorders, eye disorders, cancer, rheumatic disorders, demyelinating disorders and fibrotic disorders.

28. 28. A compound or composition for use according to claim 27, wherein said use is in a method for the treatment or prevention of intestinal, skin or lung inflammation or cancer.

29. A compound as defined in any one of claims 1 to 24, or a pharmaceutical composition as defined in claim 25, for use in the inhibition of bromodomains and extra-terminal proteins.

30. A method for the treatment or prevention of inflammatory skin disorders, respiratory disorders, gastrointestinal disorders, eye disorders, cancer, rheumatic disorders, demyelinating disorders and fibrotic disorders, comprising administering to a subject an effective amount of a compound as defined in any one of claims 1 to 24, or a pharmaceutical composition as defined in claim 25.

31. 31. The method of claim 30 for the treatment or prevention of intestinal, skin or lung inflammation or cancer fibrosis.

32. A method for inhibiting bromodomain and extra-terminal protein activity in a subject, comprising administering to the subject an effective amount of a compound as defined in any one of claims 1 to 24, or a pharmaceutical composition as defined in claim 25.

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