WO2022090699A1

WO2022090699A1 - Pyridone-containing compounds as bromodomain protein inhibitors

Info

Publication number: WO2022090699A1
Application number: PCT/GB2021/052774
Authority: WO
Inventors: Christopher Andrew WOODLAND; Mark Bell
Original assignee: In4Derm Limited
Priority date: 2020-10-26
Filing date: 2021-10-26
Publication date: 2022-05-05
Also published as: GB202016977D0

Abstract

Compounds of formula (I) are described. These compounds can be useful as anti-inflammatory and anti-cancer therapies, in particular for the inhibition of Bromodomain and Extra-Terminal proteins.

Description

COMPOUNDS

FIELD

The present invention concerns a selected range of compounds comprising 2-pyridone or 5-pyridone, and pharmaceutically-acceptable salts and compositions of such compounds. The compounds can be used as anti-inflammatory and anticancer therapies. Therefore, the present invention also concerns compounds comprising 2-pyridone or 5-pyridone for use as medicaments, particularly for the treatment of inflammatory diseases and oncology.

BACKGROUND

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 next to each other toward the N-terminal of the proteins) 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). The BRD is a functional protein domain that contains a defined and predominantly hydrophobic pocket that binds to acetylated lysine residues, typically those found on transcription factors (Shi, J. et al. Cancer Cell 25(2):210-225 (2014)) or on the N-terminal tails of 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 leading to altered expression of genes involved in the cell cycle (Yang et al., Mol. Cell Biol. 28: 967-976 (2008)). BRD2 and BRD3 also regulate growth promoting genes (LeRoy et al., Mol Cell 30:51-60 (2008)). Therefore, BRDs are responsible for transducing the signals carried by acetylated lysine residues into various phenotypes. BETs are considered in the art to be ubiquitously expressed in humans except for BRDT, which is normally expressed in the testes but is also expressed by some cancers (Ekaterina B. F. et al. Cell J. 19(Suppl 1): 1-8 (2017)).

BET proteins have roles in the regulation of biochemical pathways such as MYC, BCL2, F0SL1, P-TEFb, NFkB, Glucocorticoid signalling and others (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 are considered to have potential uses in a range of inflammatory diseases, cancers, infections, metabolic diseases, CNS disorders, fibrotic diseases and cardiac diseases (Deanna A. M. et al. J Exp Med. Oct 21; 210(11): 2181-2190 (2013)), (Rab K. P. et al. Trends Pharmacol. Sci. Mar;33(3):146-53 (2012)), (Anna C. B. et al. J Immunol. Apr 1; 190(7): 3670- 3678 (2013)), (Zuber J. et al. Nature. Aug 3;478(7370):524-8. (2011)), (Montserrat P. S. et al. Epigenetics.; 12(5): 323-339 (2017)), (Qiming D. et al. Sci Transl Med. May 17; 9(390): eaah5084. (2017)), (Kristin M. K et al. J Biol Chem. Aug 11; 292(32): 13284-13295 (2017)), (Ning D. et al. PNAS December 22, 112 (51) 15713-15718 (2015)).

Compounds that can inhibit or affect the function of BET proteins have the potential to modulate gene expression and treat diseases that are at least in part caused 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, W02011054553, W02011054845). Compounds that can selectively inhibit the function of BDII over BDI have the potential to modulate gene expression and treat diseases that are at least in part caused by abnormal regulation of BET protein activity while offering the potential of an improved therapeutic index. Several small molecules have been reported to be effective in selectively inhibiting the function of BET BDII over BDI, including (BY27, RVX-297, ABBV744, GSK046, GSK620, GSK549 (Chen D. et. al. Eur J Med Chem 182, 2019, 111633), (Wells P. S. et. al. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 19754-19759) (Sheppard G. S. et. al. J. Med. Chem. 2020, 63, 10, 5585-5623), (Preston A. et. al. J. Med. Chem. 2020, 63, 17, 9070-9092), (Seal J. T. et. al. J. Med. Chem. 2020, 63, 17, 9093-9126). Improved therapeutic index and pre-clinical safety of BDII selective BET inhibitors verses pan-BET inhibitors have been demonstrated (E. Faivre et al. Nature 578, 306-310 (2020)).

Compounds comprising 6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one moieties, substituted at the 4- and/or 2 -positions are described in patent applications WO 2017177955, WO 2015081280, WO 2014206150, WO 2014206345, WO 2013097601, WO 2013097052 and WO 2018130174 as useful for the inhibition of BET proteins.

The present invention provides alternative BET protein inhibitors that can be used in the treatment or prophylaxis of the conditions described herein.

SUMMARY

It has been found that the selected compounds and compositions of this teaching are surprisingly active and selective in inhibiting all four BET BRDs at binding domain II (BDII) and are less active in inhibiting all four BET BRDs at binding domain I (BDI). The compounds and compositions are surprisingly selective for BDII over BDI offering the potential of an improved therapeutic index and a lower risk of side-effects. The compounds and compositions have surprisingly long half-lives when dosed to rodents, offering potential use as medicaments for oral and/or topical administration.

Improving IV half life

The efficacy of drugs is often driven by a continuous coverage of the minimum efficacious plasma concentration. Half-life must therefore be adapted to achieve a desired pharmacokinetic profile. Often a drugs half-life in mice is often greater than 1 hour. For systemic delivery, in some embodiments the half-life is longer e.g., >1 hour. For topical delivery, in some embodiments the half-life is shorter e.g., <1 hour.

The skilled person is aware that any reference to an aspect of the current disclosure includes every embodiment of that aspect. For example, any reference to the first aspect includes the first aspect and all embodiments of the first aspect.

Viewed from a first aspect, there is provided a compound of formula (I):

or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, and wherein one of the following: (a)

Ri is independently chosen from, or is selected from the group consisting of: (f) CONHC₁-C₄alkyl, (ii) CONH2, (iii) CONHC₁-C₆fluoroalkyl, (iv) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl, (vi) CONHC₁-C₄alkylN(C₁-C₂alkyl)2, (vii) CONHC₀-C₄alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo, (viii) CONHC₃-C₆cycloalkylC₀-C₄alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₂ is C₁-C₆alkyl or C₃-C₆cycloalkyl, wherein in each substituent, optionally one or more carbons is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; R₃, R₄ and R₅ are each independently chosen from, or are selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuteratedC₁-C₂alkyl, and halo; and with the proviso when Q₂ is oxo, R₃, R₄ and R₅ are not simultaneously selected to be methyl, methyl and fluoro respectively; or (b)

Ri is H; R₂ is independently chosen from, or is selected from the group consisting of: (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₁-C₅alkyloxy, (v) C₁-C₅alkylamino, (vi) C₁-C₃alkylCON(C₁-C₄alkyl)2, (vii) C₁-C₆fluoroalkyl, (viii) C₁-C₅fluoroalkyloxy, (ix) C₁-C₅fluoroalkylamino and (X) C₁-C₂alkyl[N, 0 or SO₂]C₁-C₂alkyl; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₃, R₄ and R₅ are each independently chosen from, or are selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuteratedC₁-C₂alkyl, and halo; or (c)

Ri is independently chosen from, or is selected from the group consisting of: (f) CONHC₁-C₄alkyl, (ii) CONH2, (iii) CONHC₁-C₆fluoroalkyl, (iv) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl, (vi) CONHC₁-C₄alkylN(C₁-C₂alkyl)2, (vii) CONHC₀-C₄alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo, (viii) CONHC₃-C₈cycloalkylC₀-C₄alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₂ is independently chosen from, or is selected from the group consisting of; (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₁-C₅alkyloxy, (v) C₁-C₅alkylamino, (vij C₁-C₃alkylCON(C₁-C₄alkyl)2, (viij C₁-C₆fluoroalkyl, (viii) C₁-C₅fluoroalkyloxy, (ix) C₁-C₅fluoroalkylamino, and (X) C₁-C₂alkyl[N, 0 or SO₂]C₁-C₂alkyl; R₃, R₄ and R₅ are each independently chosen from, or are selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuteratedC₁- C₂alkyl, and halo.

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

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.

Suitably, the medicament of the third aspect may be provided for use as a topical or oral medicament.

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, cancers, rheumatic diseases, demyelinating diseases and fibrotic diseases.

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 the inhibition of Bromodomain and Extra-Terminal proteins.

Viewed from a sixth aspect, there is provided a method for the treatment or prophylaxis of inflammatory skin disorders, respiratory diseases, gastrointestinal diseases eye diseases cancers, 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.

Viewed from a seventh aspect, there is provided a method of inhibiting Bromodomain and Extra-Terminal protein activity in a subject, 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.

DETAILED DESCRIPTION

In one or more embodiments, the selective derivatives of 2-pyridone or 5- pyridone disclosed herein have been found to be surprisingly effective in inhibiting all four BET BRDs at binding domain II (BDII). In one or more embodiments, the compounds herein may also have an effect in inhibiting BET BRDs at binding domain I (BDI). In one or more embodiments, the compounds show a greater selectivity for BDII over BDI. In some embodiments the compounds bind effectively to both BDII and BDI. Such compounds may be effective as PAN BET inhibitors.

In one or more embodiments the compounds can have a therapeutic effect systemically. In some embodiments the compounds may be effective therapeutically by administration topically. In some embodiments, e.g., when applied topically systemic penetration is low and below a therapeutic window. In other embodiments, e.g., when applied topically systemic penetration may be sufficient for the compounds to have a systemic therapeutic effect in addition to any topical effect. In some embodiments the administration is designed to be intradermal. In some embodiments the administration is designed to be transdermal. In one or more embodiments systemic delivery may be by any of the known acceptable forms of systemic delivery of the compound or a pharmaceutical composition comprising the compound, including oral, and injection. Topical delivery can be by application of the compound or a pharmaceutical composition comprising the compound to the skin or mucosal surface of a subject, including internal surfaces of body cavities, such as the gastrointestinal tract, vagina, air passageways and lungs. Where compounds have higher selectivity for BDII they may in one or more embodiments be more suited for systemic delivery. Such compounds which also have the property of a longer half-life may in one or more embodiments be more effective systemically. Potential half-life may be indicated by factors like the liver clearance rate and plasma stability. Such compounds which have both the properties of a lower liver clearance rate and a higher plasma stability may in one or more embodiments be more effective systemically. Compounds which have both the reverse properties of a higher liver clearance rate and a lower plasma stability may in one or more embodiments be more effective topically. The potential to be effective against one or more disorders or diseases described herein may in one or more embodiments be illustrated by the ability of the compounds to modulate or reduce biomarkers known or implicated for example in an inflammatory or immune response. A non limiting example would be the reduction in the levels of IL-17 or IL-22.

A non-exhaustive list of methods of administration of the compounds includes, buccally, by inhalation spray, intraperitoneal, intrapulmonary, intradermal, epidural or via an implanted reservoir, nasally, orally, parenterally, rectally, topically, transdermally, sublingually, and vaginally.

The compounds are now described in detail.

In the discussion that follows, reference is made to a number of terms, which have the meanings provided below, unless a context indicates to the contrary. The nomenclature used herein for defining compounds, in particular the compounds according to the invention, is in general based on the rules of the IUPAC organisation for chemical compounds, specifically the "IUPAC Compendium of Chemical Terminology (Gold Book)”. For the avoidance of doubt, if a rule of the IUPAC organisation is contrary to a definition provided herein, the definition herein is to prevail. Furthermore, if a compound structure is contrary to the name provided for the structure, the structure is to prevail.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All ranges disclosed herein include the endpoints. The use of the term "or” shall be construed to mean "and/or” unless the specific context indicates otherwise. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. The term "therapeutic index”, also known as the "therapeutic window” or "safety window” defines the relative safety of a drug. The therapeutic index may be calculated as the ratio of the area under the curve (AUG) in blood, at a concentration of drug that results in no toxicity (No Observed Adverse Effect Level - NOAEL), to the concentration of drug that produces the desired efficacy, typically the dose that has a 50% effect - the Effective dose 50 or ED50. TI = AUC(NOAEL)/AUC(ED50). A drug with a higher therapeutic index is preferable, since administration of the drug is less likely to lead to unwanted side effects, and more drug may be administered to treat a subject more effectively. The desired efficacy of BET inhibitors is driven by their inhibition of the function of BDII, whereas inhibition of the function of BDI leads to unwanted side effects. Thus, drugs that selectively inhibit the function of BDII over BDI have the potential to modulate gene expression and treat diseases that are at least in part caused by abnormal regulation of BET and are less likely to give rise to unwanted side effects with respect to pan inhibitors administered at the same dose. A higher dose of drugs that selectively inhibit BDII over BDI may be safely administered with respect to pan inhibitors, thus such selective drugs may be more efficacious.

The term "cyclic” or variants thereof defines a compound, or a substituent group on the compound, in which one or more series of atoms in the compound or substituent is connected to form a ring. Whereas, the term "acyclic” defines a compound or substituent containing no rings of atoms.

As used herein, the terms "composition(s)” and "formulation(s)” can be used interchangeably depending on the context in which they are used as would be appreciated by a person skilled in the art.

The term "comprising” or variants thereof will be understood to 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.

The term "consisting” or variants thereof will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, and the exclusion of any other element, integer or step or group of elements, integers or steps. As used herein, the terms "disorder(s)” and "disease(s)” can be used interchangeably depending on the context in which they are used as would be appreciated by a person skilled in the art.

The term "alkyl” is well known in the art and defines univalent groups derived from alkanes by removal of a hydrogen atom from any carbon atom, wherein the term "alkane” is intended to define acyclic branched or unbranched hydrocarbons having the general formula C_nH₂n+2, wherein n is an integer ≥1.

The term "cycloalkyl” defines all univalent groups derived from cycloalkanes by removal of a hydrogen atom from a ring carbon atom. The term "cycloalkane” defines saturated monocyclic and polycyclic hydrocarbons.

The term "alkylol” defines a hydroxy derivative of an alkyl radical, i.e. a hydroxy-alkyl.

The term "halo” is well known in the art and defines a halogen radical that, when bonded to a carbon radical makes a fluoride, chloride, bromide or iodide compound.

The term "alkyloxy” is synonymous with "alkoxy” and when used herein defines a univalent group comprising an alkyl singly bonded to an oxygen atom, derived from the corresponding alcohol by removal of the hydrogen atom bonded to the oxygen atom.

The term "alkylamino” is synonymous with "alkamino” and when used herein defines a univalent group comprising an alkyl singly bonded to an amino group, derived from the corresponding amine by removal of a hydrogen atom bonded to the nitrogen atom.

The term "oxacycloalkyl” defines a univalent group comprising a cycloalkyl, in which one of the CH2 moieties is replaced with an oxide. Similarly, the term "azacycloalkyl” defines a univalent group comprising a cycloalkyl, in which one of the CH2 moieties is replaced with an NH moiety.

The term "treatment" defines the therapeutic treatment of a human or nonhuman animal, in order to impede or reduce or halt the rate of the progress of the condition, or to ameliorate or cure the condition. Prophylaxis of the condition as a result of treatment is also included. References to prophylaxis are intended herein not to require complete prevention of a condition: its development may instead be hindered through treatment in accordance with the invention. Typically, treatment is not prophylactic, and the compound or composition is administered to a patient having a diagnosed or suspected condition. By an "effective amount" herein defines an amount of the compound or composition that is sufficient to impede the noted diseases and thus produces the desired therapeutic or inhibitory effect.

The term "stereoisomer” is used herein to refer to isomers that possess identical molecular formulae and sequence of bonded atoms, but which differ in the arrangement of their atoms in space.

The term "enantiomer” defines one of a pair of molecular entities that are mirror images of each other and non-superimposable, i.e. cannot be brought into coincidence by translation and rigid rotation transformations. Enantiomers are chiral molecules, i.e. are distinguishable from their mirror image.

The term "racemic” is used herein to pertain to a racemate. A racemate defines a substantially equimolar mixture of a pair of enantiomers.

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

The term "solvate” is used herein to refer to a complex comprising a solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, trihydrate etc., depending on the number of water molecules present per molecule of substrate.

The term "isotope” is used herein to define a variant of a particular chemical element, in which the nucleus necessarily has the same atomic number but has a different mass number owing to it possessing a different number of neutrons.

The term "prodrug” is used herein to refer to a compound which acts as a drug precursor and which, upon administration to a subject, undergoes conversion by metabolic or other chemical processes to yield a compound of formula (I).

The term "pharmaceutically acceptable excipient” defines substances other than a pharmacologically active drug or prodrug, which are included in a pharmaceutical product.

The term "topical” when used with respect to compounds or compositions is used to refer to the ability to apply the compound or composition to body surfaces, for example skin or mucous membranes. Topical compounds or compositions may be applied in the form of creams, foams, gels, lotions or ointments.

As used herein, the term "treatment” or "treating” refers to inhibiting, reversing, ameliorating, or reducing the disorder or condition, e.g., arresting its development; relieving the disorder or condition, e.g., causing regression of the disorder or condition or reversing the progression of the disorder or condition; slowing progression, or relieving or reducing one or more symptoms of the disorder or condition. In some embodiments, it can also mean preventing or helping to prevent the disorder or condition or one or more symptoms thereof.

The terms "method(s) of” e.g., "preventing”, "prophylaxis”, or "treating” a disease or a disorder provided throughout the specification is interchangeable with the terms "use of’ or "for use of’.

The term "oral” when used with respect to compounds or compositions is used to refer to the ability to administer the compound or composition through the mouth. Typically, oral compounds exhibit a systemic effect rather than a topical effect, i.e. they affect multiple organ systems, rather than a local area.

The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

As used herein, the term "preventing” or "prophylaxis” refers to avoiding the onset of a disorder or condition from occurring in a subject that has not yet been diagnosed as having the disorder or condition, but who may be susceptible to it.

The terms "transduce” or "transducing”, when used with respect to a signal, are synonymous with "transfer” or "transferring”, i.e. "signal transduction” is the process of transferring a signal throughout an organism, for example through a cell.

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.

The term "T-cell” (also known as a T lymphocyte) is known in the art to refer to a lymphocyte with a T-cell receptor on the cell surface (a molecule that is responsible for recognising fragments of antigen peptides). The term "cytokine” is used herein to refer to a small protein (~5 to 20 kDa) that is important in cell signalling, such as autocrine, paracrine and endocrine signalling, as immunomodulating agents.

The term "chemokine” is used herein to refer to a family of cytokines that are able to induce directed chemotaxis in responsive cells, i.e. they act as a chemoattractant to guide the migration of cells.

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

As alluded to above, the first aspect provides a compound of formula (I) as defined herein.

In some embodiments:

Ri is selected from the group consisting of: (i) CONHC1-C₄alkyl, (ii) CONH₂, (iii) CONHC1-C₆fluoroalkyl, (iv) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl, (vi) CONHC₁-C₄alkylN(C₁-C₂alkyl)2, (vii) CONHC₀-C₄alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo, (viii) CONHC₃-C₆cycloalkylC₀-C₄alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₂ is C₁-C₆alkyl or C₃-C₆cycloalkyl, wherein in each substituent, optionally one or more carbons is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; R₃, R₄ and R₅ are each independently selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuterated C₁- C₂alkyl, and halo; and with the proviso when Q₂ is oxo, R₃, R₄ and R₅ are not simultaneously selected to be methyl, methyl and fluoro respectively.

Alternatively, in some embodiments with the proviso that when Q₂ is oxo, R3 and R4 are not methyl and R₅ is not fluorine.

In some embodiments:

Ri is H; R₂ is selected from the group consisting of: (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₁-C₅alkyloxy, (v) C₁-C₅alkylamino, (vij C₁-C₃alkylCON(C₁-C₄alkyl)2, (vii] C₁-C₆fluoroalkyl, (viii) C₁-C₅fluoroalkyloxy, (ix) C₁-C₅fluoroalkylamino and (X) C₁-C₂alkyl[N, O or SO₂]C₁-C₂alkyl; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₃, R₄ and R₅ are each independently selected from the group consisting

H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuteratedC₁-C₂alkyl, and halo.

In some embodiments:

Ri is selected from the group consisting of: (f) CONHC₁-C₄alkyl, (ii) CONH₂, (iii) CONHC₁-C₆fluoroalkyl, (iv) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl, (vi) CONHC₁-C₄alkylN(C₁-C₂alkyl)2, (vii) CONHC₀-C₄alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo, (viii) CONHC₃-C₈cycloalkylC₀-C₄alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₂ is selected from the group consisting of; (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₁-C₅alkyloxy, (v) C₁-C₅alkylamino, (vij C₁-C₃alkylCON(C₁-C₄alkyl)2, (vii) C₁-C₆fluoroalkyl, (viii) C₁-C₅fluoroalkyloxy, (ix) C₁-C₅fluoroalkylamino, and (X) C₁-C₂alkyl[N, O or SO₂]C₁-C₂alkyl; R₃, R₄ and R₅ are each independently selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuteratedC₁-C₂alkyl, and halo.

In some embodiments, R₃, R₄ and R₅ are each independently selected from the group consisting of H, methyl, CF3, CHF₂, methoxy, CD3 and halo.

Optionally, R₃ and R₄ are methyl and R₅ is F.

Optionally, R₃ and R₄ are methyl and R₅ is H.

The present invention also includes in some embodiments the following compounds:

NA'21 NA'22

Without wishing to be bound by theory, it is considered that selected R₃ and R₄ substituents provide selectivity for BET BDII over BET BDI. BET BDI has an isoleucine 161 (BRD4 numbering) residue which has increased steric bulk compared to the analogous valine 439 (BRD4 BDII numbering) residue in BET BDII (See Uniprot code 060885-1 for BRD4 protein sequence). As such, the selected R₃ and R₄ substituents of the present invention may cause ligands to be displaced from optimum binding with BET BDI proteins by steric clashes with the isoleucine 161 (BRD4 numbering) residue. In addition, the selected R₃ and R₄ substituents of the present invention may give good binding with BET BDII proteins due to the space a valine 439 (BRD4 numbering) reside affords compared to the analogous isoleucine BET BDI residue. These residue combination changes are conserved in all BET BDI and BD2 domains. Symmetrical 2,6-disubstituted phenoxy may be better able to exploit the potential selectivity gains between BET BDI and BDII. A number of the selected compounds defined in the present invention, exemplified by the compounds labeled "NA’17-22” and "NA’44”, and defined herein (but not limited thereto) particularly seek to exploit the benefits of this symmetry to optimize selectivity between BET BDI and BD II.

In some embodiments of the first aspect, the pyridone is a 5-pyridone. Advantageously, it is considered that compounds of the present invention comprising 5-pyridone provide improved binding affinity for BET proteins as well as longer half-life in pharmacokinetic studies.

In some embodiments of the first aspect involving sections (a) or (c) R² is methyl. It is considered that compounds where R² is methyl provide a lower lipophilicity (logD) and molecular weight (MW), which can lead to an improved pharmacokinetic profile, such as a longer drug half-life in animals and humans.

In the selected compounds of the first aspect based on section (a), R1 is a CONH- group. The amine may form hydrogen bond interaction with Asparagine 429 (BRD2 BDII numbering) residue to improve activity which may lead to more efficacious drugs.

As mentioned above, in the selected compounds of the first aspect based on section (a), there is the proviso that when Q₂ is oxo, R₃, R₄ and R₅ are not simultaneously selected to be methyl, methyl and fluoro respectively.

Additionally or alternatively, in the selected compounds of the first aspect based on section (a), there is in some embodiments the proviso that when Q2 is oxo, R3 and R4 are not methyl and R5 is not fluorine;

Additionally or alternatively, in the selected compounds of the first aspect based on section (a), there is the proviso that when Q₁ is oxo, R₃, R₄ and R₅ are not simultaneously selected to be methyl, methyl and fluoro respectively;

Optionally, for compounds of the first aspect involving section (a), Ri is selected from the group consisting: (i) CONHC₁-C₄alkyl, (ii) CONHC₁-C₃fluoroalkyl, (iii) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (iv) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₁-C₂alkylN(Me)2, (vi) CONHC₀-C₂alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with an oxygen or nitrogen, and/or is optionally substituted at one or more carbon atoms or nitrogen atoms if with a methyl, ethyl or halo, and (vii) CONHC₃-C₆cycloalkylC₀-C₂alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo.

Optionally, for compounds of the first aspect involving section (a), Ri is selected from the group consisting: (i) CONHC₂-C₃alkyl, (ii) CONHC₁-C₃fluoroalkyl, (iii) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (iv) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₃-C₆cycloalkylC₀-C₂alkyl optionally substituted at one or more carbon atoms with one or more halos.

Optionally, in the compounds of the first aspect involving section (a), Ri is one of the following: (a) CONH-ethyl; (b) CONH-tert-butyl (c) C ON H -bicyclo [1,1,1] pentan- 1 -yl; (d) CONH-2, 2, 2 -trifluoro ethyl; (e) CONH-isopropyl; (f) CONH-cyclobutyl; (g) CONH-(2 -morpholinoethyl); (h) C ON H - (2 - (dimethylamino) ethyl) ; (i) CONH-(l-methylpiperidin-4-yl); Q) CONH-(l-methylpiperidin-3-yl); (k) CONH- (l-methylazetidin-3-yl); (l) C 0 N H - ( 1 - (tr ifluo ro methyl) cyclop ropyl) ; (m) CONH-4,4-difluorocyclohexyl; (n) CONH-l,l,l-trifluoro-2-methyl-propan-2-yl; and (o) CONH-2,2-difluoro-l-methylcyclopropyl.

See for instance the compounds labelled AA’1-15 herein.

Optionally, for compounds of the first aspect involving section (a), Ri is one of: (a) CONH-ethyl; (b) CONH-isopropyl; (f) CONH-cyclobutyl; (l) C 0 N H - ( 1 - (tr ifluo ro methyl) cyclop ropyl) ; (m) CONH-4,4-difluorocyclohexyl; (n) CONH-l,l,l-trifluoro-2-methyl-propan-2-yl; and (o) CONH-2,2-difluoro-l-methylcyclopropyl.

See for instance the compounds labelled AA’l, AA’5, AA’6, and AA’12-15 herein.

Optionally, for compounds of the first aspect involving section (a), Rl is one of: (a) CONH-ethyl; (f) CONH-cyclobutyl; and (m) CONH-4,4-difluorocyclohexyl.

See for instance the compounds labelled AA’l, AA’6 and AA’13 herein.

Further optionally, R₃ and R₄ are methyl and R₅ is H; the pyridone is a 5- pyridone; and wherein R₂ is methyl.

Further optionally, R₃ and R₄ are methyl and R₅ is H; the pyridone is a 2- pyridone; and wherein R₂ is methyl.

All the above named and listed compounds of the first aspect involving section (a) may also be the equivalent compound where the dimethylphenyl ring has a fluoro group at the para position. It is considered that compounds of the present invention with these selected substituents provide further selected bioavailability, particularly during systemic administration. This may provide a lower required dose or dosage regime, due to increased in vivo stability, including plasma stability, and lower liver metabolism. In particular the Ri groups claimed may reduce (plasma) instability from amide hydrolysis while also lowering liver metabolism rates resulting in longer drug halflife when dosed to animals or humans.

It is further considered that the selection of small alkyl, cycloalkyl and cyclic ether groups in the Ri substituent of the compounds of the present invention, exemplified but not limited to the compounds labelled "AA’1-3,5,6” as described herein may further improve selectivity for BET BDII over BET BDI, by better fitting into the groove made by Histidine 437 and Proline 434 residues in BDII (BRD4 numbering) amino acid residues in this part of all BET BDII protein structures. Histidine 437 and Proline 434 residues in BDII (BRD4 numbering) are changed with Aspartic acid 144 and Lysine 141 residues in BDI (BRD4 numbering). These Aspartic acid 144/Lysine 141 and Histidine 433/Proline 430 residue combination changes are conserved in all BET BDI and BD2 domains.

It is also further considered that the selection of a 'basic’ substituent in the Ri substituent of the compounds of the present invention, exemplified but not limited to the compounds labelled "AA’7-11” as described herein, may increase the ratio of drug levels in body tissues, relative to drug levels in blood (also referred to as the "volume of distribution”), which in turn may increase or improve half-life which may improve duration of action leading to more efficacious compositions.

It is also further considered that the selection of C₃-C₆cyclofluoroalkyl or C₁- C₆fluoroalkyl groups in the Ri substituent of the compounds of the present invention, exemplified but not limited to the compounds labelled "AA’ 4, 12-15” as described herein may increase or improve half-life which may improve duration of action leading to more efficacious compositions.

Optionally, for compounds of the first aspect involving section (b), R₂ is selected from a group consisting: (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₀-C₃alkylCONHC₁-C₄alkyl, (v) C₁-C₆fluoroalkyl, and (vi) C₁- C₂alkyl[N, 0, or SO₂]C₁-C₂alkyl.

Optionally, for compounds of the first aspect involving section (b), R₂ is selected from a group consisting : (i) fluoromethyl, C₂-C₃alkyl, (ii) C₀-C₂alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with an oxygen or nitrogen and/or is optionally substituted at one or more carbon atoms or nitrogen atoms with a methyl, ethyl or halo; (ill) C₁-C₄alkylol, (iv) C₁-C₂alkylCONHC₁-C₂alkyl, (v) C₁-C₄fluoroalkyl, and (vi) C₁-C₂alkyl[N or O]C₁-C₂alkyl.

Further optionally, R₃ and R4 are methyl or chloro, and R₅ is H; and the pyridone is a 5 -pyridone.

Further optionally, R₃ and R4 are methyl or chloro, and R₅ is H; and the pyridone is a 2 -pyridone.

In one or more embodiments there is provided a compound, wherein the compound is selected from the compounds labelled AA’l to AA’15 as illustrated herein. In one or more embodiments there is provided a compound, wherein the compound is selected from labelled AA’l, AA’5, AA’6 AA’12 to AA’15. In one or more embodiments there is provided a compound, wherein the compound is selected from labelled AA’l, AA’6 and AA’13. In one or more embodiments the aforesaid selections are for systemic uses, e.g. by oral delivery. It is considered that compounds of the present invention with these selected substituents provide greater bioavailability, particularly during systemic administration and improved BDII/BDI selectivity. This therefore equates to a lower required dose or dosage regime due to reduced drug metabolism in the liver and/or increased drug binding to blood proteins and/or tissues. Together these improvements lead to a longer half-life of drug when dosed to animals or humans. R₂ groups may also lead to increased selectivity for BDII over BDI activity due to more favorable interactions with the BDII protein.

It is further considered that the selection of 'basic’ substituent in the R₂ substituent of the compounds of the present invention, exemplified but not limited to the compounds labelled "NA’ 3, 5, 10 and 15” (as illustrated herein) as described may increase volume of distribution which in turn may increase half-life which may improve duration of action leading to more efficacious or safer drugs.

It is further considered that the selection of small alkyl, ether, cycloalkyl and cyclic ether groups in the R₂ substituent of the compounds of the present invention, exemplified but not limited to the compounds labelled "NA’ 4, 6, 13 and 16” (as illustrated herein) as described herein may increase lipophilicity, which may increase volume of distribution which in turn may increase half-life which may improve duration of action leading to more efficacious compositions.

It is further considered that the selection of C₃-C₆cyclofluoroalkyl or C₁- C₆fluoroalkyl groups in the R₂ substituent of the compounds of the present invention, exemplified but not limited to the compounds labelled "NA’ 8, 9, 11, 12 and 14” (as illustrated herein) as described herein may increase half-life which may improve duration of action leading to more efficacious compositions. In one or more embodiments there is provided a compound, wherein the compound is NA’12.

Other embodiments of the present compounds include wherein: the pyridone is a 5-pyridone; R₂ is methyl; R₅ is H; and R₃ and R₄ are each independently methyl, CF₃, CHF₂, methoxy, or CD3.

Other embodiments of the present compounds include wherein: the pyridone is a 2 -pyridone; R₂ is methyl; R₅ is H; and R₃ and R₄ are each independently methyl, CF₃, CHF₂, methoxy, or CD3.

The skilled reader can see that combinations of the above selections can also lead to the same improvements discussed, or to additional or even synergistic improvements, and that the present invention can extend to such general and to such specific combinations of selected groups as discussed herein.

Optionally, for compounds of the first aspect involving section (c), Ri is selected from a group consisting: (f) CONHC₁-C₄alkyl, (ii) CONHC₁-C₄fluoroalkyl, (iii) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (iv) CONHC₃-C₆ cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₁-C₂alkylN(Me)2, (vi) CONHC₀-C₂alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with an oxygen or nitrogen, and/or is optionally substituted at one or more carbon atoms or nitrogen atoms if present with a methyl, ethyl or halo, (vii) CONHC₃-C₆cycloalkylC₀-C₂alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H;

R2 is selected from a group consisting of: (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₀-C₃alkylCONHC₁-C₄alkyl, (v) C₁-C₆fluoroalkyl, and (vi) C₁-C₂alkyl[N, 0, or SO₂]C₁-C₂alkyl;

Rs, R₄ and R₅ are each independently selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, methoxy, deuterated C₁-C₄alkyl and halo.

More preferably, for compounds of the first aspect involving section (c), Ri is selected from a group consisting of: (i) fluoromethyl, (ii) C₂-C₃alkyl, (iii) C₀-C₂alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with an oxygen or nitrogen and/or optionally substituted at one or more carbon atoms or nitrogen atoms with a methyl, ethyl or halo; (iv) C₁-C₄alkylol, (v) C₁-C₂alkylCONHC₁-C₂alkyl, (vi) C₁-C₄fluoroalkyl, and (vii) C₁-C₂alkyl[N or O]C₁-C₂alkyl.

In embodiments of the first aspect of the present invention, the compound is first selected from the following labelled compounds AA’1-15, or the equivalent compound where the dimethylphenyl ring has a fluoro group at the para position:

AA'13 AA'14 AA'15

Optionally, in embodiments of the first aspect of the present invention, the compound is first selected from the following:

In embodiments of the first aspect of the present invention, the compound is first selected from the following labelled compounds NA’1-22 and NA’44, or the equivalent compound where the dimethylphenyl ring has a fluoro group at the para position:

Optionally, the compound in some embodiments is the following:

Optionally, the compound in some embodiments is the following:

Other selections are listed herein.

All the compounds described herein above and hereinafter may be in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt” is intended to define organic and/or inorganic salts that are pharmaceutically useful. The compounds may be isolated from reaction mixtures as pharmaceutically acceptable salts. Alternatively, the pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of compounds by reacting a 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 aluminium salts and nontoxic quaternary ammonia and amine cations including 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.

The pharmaceutically acceptable salt may also be prepared by treatment of the compound of the invention with a suitable acid, for example, 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. All the compounds of the invention may exist in different stereoisomeric and atropisomeric forms. All stereoisomeric forms and mixtures thereof, including enantiomers and racemic mixtures, are included within the scope of the invention. Such stereoisomeric forms include enantiomers and diastereoisomers. Individual stereoisomers of compounds of the invention, i.e., associated with less than 5 %, preferably less than 2 % and in particular less than 1 % of the other stereoisomer, are included. Mixtures of stereoisomers in any proportion, for example a racemic mixture comprising substantially equal amounts of two enantiomers are also included within the invention. Also included are solvates and isotopically-labelled compounds of the invention. Isotopically-labelled compounds are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷0, ³⁵S, ¹⁸F, and ³⁶C1, respectively.

In a further aspect, intermediates suitable for production of compounds of the invention are included. Specifically, intermediates of formulae (ia) to (in) are included.

Often, intermediates are of formula (ia), (ib), (im), or (in). Typically, intermediates are of formula (ia) or (ib).

Prodrugs of the compounds and compositions of the invention are also within the scope of the invention. Upon administration to a subject, a prodrug undergoes conversion by metabolic or other chemical processes to yield a compound of the invention.

All amorphous and crystalline forms of the compounds of the invention are included. Whilst it is possible for the compounds to be administered alone, it is typical to use a pharmaceutical composition. The second aspect provides a pharmaceutical composition comprising any one or a combination of the compounds defined in the first aspect and specified herein, in combination with one or more pharmaceutically acceptable excipients. The excipient may aid transport of a compound to the site in the body where it is intended to act, for example by increasing the rate of dissolution of the compound into the blood stream or by increasing the stability of the compound in order to delay its release, in order to increase its efficiency and prevent damage to tender tissues. Alternatively, the excipient may be for identification purposes, or to make the compound more appealing to the patient, for example by improving its taste, smell and/or appearance. Typically, the excipient makes up the bulk of the pharmaceutical composition.

Excipients include diluents or fillers, binders, disintegrants, lubricants, colouring agents and preservatives. Diluents or fillers are inert ingredients that may affect the chemical and physical properties of the final composition. If the dosage of the compound of the invention is small then more diluents will be required to produce a composition suitable for practical use. If the dosage of the compound of the invention is high then fewer diluents will be required.

Binders add cohesiveness to powders in order to form granules, which may form a tablet. 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 may be facilitated through the use of a disintegrant.

An extensive overview of pharmaceutically acceptable excipients is described in the Handbook of Pharmaceutical Excipients, 6^th Edition; Editors R. C. Rowe, P. J. Sheskey and M. E. Quinn, The Pharmaceutical Press, London, American Pharmacists Association, Washington, 2009. Any suitable pharmaceutically acceptable excipient is within the scope of the invention.

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

The pharmaceutical compositions may be compressed into solid dosage units, such as tablets, or be processed into capsules or suppositories. The pharmaceutical compositions may also be injected and may be prepared in the form of a solution, suspension or emulsion for such an application. Alternatively, the pharmaceutical compositions may be administered as a spray, including a nasal or buccal spray. Otherwise, the pharmaceutical compositions may be processed into a gel, cream, patch, implant or any other preparation for immediate and/or sustained release. Typically, the pharmaceutical compositions are processed into a gel, cream, lotion, foam or ointment for topical administration; or a tablet, capsule or buccal spray for oral administration.

The third aspect of the invention provides a compound of the first aspect or as specified, or a pharmaceutical composition of the second aspect, for use as a medicament. Suitably, the medicament may be a medicament for topical or oral use.

Specifically, the compounds can be used in the treatment of diseases or conditions associated with the activity of Bromodomain and Extra-Terminal proteins. In the fifth aspect, there is provided a compound of the first aspect as specified, or a pharmaceutical composition of the second aspect for use, in the inhibition of Bromodomain and Extra-Terminal proteins. Diseases or conditions associated with the activity of Bromodomain and Extra-Terminal proteins include inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, rheumatic diseases, demyelinating diseases and fibrotic diseases. Therefore, in the 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 prophylaxis of inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, rheumatic diseases, demyelinating diseases and fibrotic diseases and in the sixth aspect, the invention provides a method for the treatment or prophylaxis of skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, 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 specified herein, or a pharmaceutical composition of the second aspect.

Inflammatory diseases rely on T helper cells Thi, Th2 and Thi? for innate and adaptive immunity responses which affect either or both of the acute or chronic stages of the disease. Many cytokine and chemokines are upregulated in an inflammatory disease and the ability to reduce the levels of these inflammatory markers is evidence of the ability of a drug to ameliorate a disease. Such cytokine and chemokines include but are not limited to granulocyte-macrophage colonystimulating factor (GM-CSF); interleukins IL-1, IL-2, IL-4, IL-6, IL-8, IL-13, IL-17, IL- 22; chemokine (c-c motif) ligands CCL2, CCL27 and CCL20; tumour necrosis factor alpha (TNF-a); thymic stromal lymphopoietin (TSLP); and chemokine (c-x-c motif) ligand 9 (CXCL9). Unselective BET inhibitors inhibit most markers of inflammation listed above. The selective BET BDII inhibitors described herein affect fewer markers of inflammation including, but are not limited to, interleukins (IL-4, IL-17, IL-33, IL-36); chemokine (c-c motif) ligand 2 (CCL2); and chemokine (c-x-c motif) ligand 10 (CXCL10). These important markers of disease predict efficacy for many inflammatory diseases, while selective BET BDII inhibitors focused profile suggests such compounds have an improved therapeutic index.

Selective BET BDII inhibitors may be of value in the treatment of inflammatory disorders. These include skin disorders such as alopecia areata, Atopic dermatitis, bullous diseases, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, contact dermatitis, psoriasis, rosacea, scleroderma, 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 cancers; eye diseases such as myasthenia gravis, Sjogran’s syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis and iritis; systemic indications like Addison’s disease, acute gout, ankylosing spondylitis, atherosclerosis, Behcet’s disease, giant cell arthritis, glomerulonephritis, hepatitis, hypophysitis, lupus nephritis, Kawasaki disease, multiple sclerosis, myocarditis, myositis, nephritis, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonitis, 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 would be desirable for instance in organ transplantation. BET inhibitors are also known to affect the growth or survival of a range of cancers, specifically skin and systemic cancers, and may be useful for the treatment of acoustic neuroma, acute leukaemia, acute lymphocytic leukaemia, acute myelocytic leukaemia (monocyctic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukaemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukaemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukaemia, chronic myelogenous leukaemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, cutaneous T- cell lymphoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), 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, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukaemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukaemia, lymphoma (Hodgkin’s and non-Hodgkin’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukaemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukaemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, 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 (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumours, uterine cancer, and Wilms’ tumor.

BET inhibitors may also be of use in the treatment of obesity, dyslipidaemia, hypercholesterolemia, Alzheimer’s disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy. The seventh aspect provides a method of inhibiting Bromodomain and ExtraTerminal protein activity in a subject, said method comprising administering to a subject an effective amount of a compound of the first aspect or specified herein, or a pharmaceutical composition of the second aspect.

The inventors have found that certain compounds of the invention may have increased metabolic stability relative to certain prior art compounds. The inventors have also found that certain compounds of the invention may have increased activity against BRD4 BD2 relative to certain prior art compounds. The inventors have also found that certain compounds of the invention may have increased selectivity for BRD4 BD2 over BRD4 BD1 relative to certain prior art compounds.

Thus, the present invention further provides 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 an inflammatory disease or disorder, e.g., inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, rheumatic diseases, demyelinating diseases and fibrotic diseases.

Thus, the present invention further provides a method for the treatment or prophylaxis of an inflammatory disease or disorder, e.g., inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, 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.

Thus, the present invention further provides the use of a compound as defined in the first aspect, or a pharmaceutical composition as defined in the second aspect for the manufacture of a medicament for the treatment or prophylaxis of an inflammatory disease or disorder, e.g. inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, 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.

Thus, the present invention further provides a method of inhibiting Bromodomain and Extra-Terminal protein activity in a subject, 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.

Thus, the present invention further provides a method of treating a disorder associated with Bromodomain and Extra-Terminal protein activity in a subject, 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.

BET inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of value and used in the treatment or amelioration of the following non-limiting examples of disorders and diseases. In one or more embodiments they may be useful where they are selective for one BD domain over another e.g., BDII over BDI or vica versa. In one or more other embodiments they may be useful where they inhibit both BDII and BDI domains. In one or more embodiments they may both inhibit BDII and BDI (PAN BET) and also be selective for BDII.

BET inhibitors including e.g., selective BET BDII inhibitors, and PAN BET inhibitors such as the compounds disclosed herein, may in one or more embodiments, be of value and used in the treatment or amelioration or prophylaxis of one or more of many or multiple disorders or diseases including inflammatory disorders, immune disorders, and autoimmune disorders, which include diseases that have or may have an inflammatory or autoimmune component.

The disorder or disease may be a skin disorder selected from acne, inflammatory acne, acne fulminans, angiofibroma, nodular papulopustular acne, acne conglobata, acute erysipelas, alopecia, alopecia areata, alopecia totalis, atopic dermatitis, alopecia universalis, autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP), bacterial skin infections, viral skin infections, bullous diseases, cellulitis, cutaneous abscesses, carbuncles, chronic hand eczema, cutaneous mastocytosis, Dercum disease, dermatological pain, dermatological inflammation, contact dermatitis, dermatitis, dermatitis herpetiformis, dermatomyositis, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), neutrophilic dermatoses, such as pyoderma gangrenosum and Sweets syndrome, paronychial infections, pustulosis palmoplantaris edematous, erythema multiforme, erythema nodosum, granuloma annulare, pemphigus, epidermal necrolysis pemphigus, paraneoplastic pemphigus, erythrasma, ecthyma, eczema, folliculitis, furuncles, gustatory sweating, hyperhidrosis, Hailey-Hailey disease, hives, hidradenitis suppurativa, hypertrophic scars, impetigo, ichthyosis, ischemic necrosis, keloids, necrotizing subcutaneous infections, actinic keratosis, keratosis pilaris, miliaria, molluscum contagiosum, lichen planus, netherton syndrome, pityriasis rubra pilaris, psoriasis, pruritus, prurigo nodularis, rashes, rosacea, pediculosis, pityriasis rosea, scleroderma, scalded skin syndrome, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis), trauma or injury to the skin, postoperative or post-surgical skin conditions, wounds, burns (including chemical, electrical fire, friction, radiation, temperature related, thermal and cold), sunburn, scarring, scabies, skin ulcers, urticaria pigmentosa, urticarial and chronic idiopathic pruritus, vitiligo, warts, and xerosis. Skin disorders or diseases when the compound or a pharmaceutical composition comprising the compound is administered topically may benefit in some embodiments from application of a PAN BET. Further advantages may be achieved in some embodiments if the PAN BET has some selectivity for BDII whilst having a higher clearance and or a lower plasma stability.

The disorder or disease may be a respiratory disease selected from asthma, bronchiectasis, bronchiolitis, byssinosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, hypersensitivity pneumonitis, mesothelioma, pneumoconiosis, (idiopathic) pulmonary fibrosis, rhinitis, rhinosinusitis and sarcoidosis.

The disorder or disease may be a gastrointestinal diseases selected from celiac disease, Crohn’s disease, eosinophilic esophagitis, inflammatory bowel disease, retroperitoneal fibrosis, and ulcerative colitis.

The disorder or disease may be an eye disease selected from conjunctivitis, dry eye syndrome, iritis, keratitis, myasthenia gravis, scleritis, Sjogran’s syndrome, and uveitis.

The disorder or disease disorder may be a cardiovascular disease or associated disorder, selected from cerebrovascular disease, aorta disease, arrhythmias, atherosclerosis, aneurysm, angina, stroke, carditis, cardiac hypertrophy, cardiomyopathy, endocarditis, coronary artery disease, deep vein thrombosis, heart attack, heart disease, heart failure, Marfan syndrome, myocarditis, peripheral artery disease, pericarditis, pulmonary embolism, rheumatic heart disease, thrombosis, valvular heart disease, ventricular heart disease, ventricle dysfunction, and vascular diseases.

The disorder or disease may be a systemic indication selected from Addison’s disease, AIDS, ankylosing spondylitis, atherosclerosis, arthritis, Behcet’s disease, cryopyrin-associated periodic syndromes (CAPS), chronic kidney diseases (including, but not limited to nephritis, nephropathy, hypertensive nephropathy, HIV-associated nephropathy, IgA nephropathy, familial Mediterranean fever, focal segmental glomerulosclerosis, Grave’s disease, juvenile arthritis, lymphangitis, lymphadenitis, lupus nephritis, minimal change disease, neurofibromatoses, polycystic kidney disease and tubular interstitial nephritis), acute kidney injury disease or condition (including, but are not limited to ischemia-reperfusion induced, cardiac and major surgery induced, percutaneous coronary intervention induced, radio-contrast agent induced, sepsis induced, pneumonia induced, and drug toxicity induced), giant cell arthritis, glomerulonephritis, gout, hepatitis, hepatitis B, hepatitis C, hypophysitis, Kawasaki disease, liver fibrosis, multiple sclerosis, myositis, osteoarthritis, pancreatitis, pneumonitis, polyarteritis nodosa, primary biliary cirrhosis, prostate disease, prostatitis, benign prostatic hyperplasia (BPH), psoriatic arthritis, rheumatoid arthritis, scleritis, scleroderma (cutaneous or systemic), sclerosing cholangitis, sepsis, systemic lupus erythematosus, systemic mastocytosis, Takayasu’s arteritis, thyroiditis, toxic shock, vasculitis, warm autoimmune hemolytic anemia, and Wegener’s granulomatosis.

The disorder or disease may be an autoimmune disease or indication where immunosuppression would be desirable, for instance, to avoid organ transplant rejection and graft versus host disease (chronic or acute).

BET inhibitors including e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of value and used in the treatment or amelioration of cancers.

The cancer may be a skin or systemic cancer, selected from acoustic neuroma, anal cancer, bladder cancer, Bowen's disease, brain cancer, breast cancer, carcinomas including basal cell carcinoma, bile duct carcinoma, bronchogenic carcinoma, choriocarcinoma, embryonal carcinoma, cystadenocarcinoma, epithelial carcinoma, medullary carcinoma, NUT midline carcinoma (NMC), papillary carcinoma, papillary adenocarcinomas, renal cell carcinoma, sebaceous gland carcinoma, small cell lung carcinoma, squamous cell carcinoma, and sweat gland carcinoma, cervical cancer, chordoma, colon cancer, colorectal cancer, craniopharyngioma, dysproliferative changes (dysplasias and metaplasias), endometrial cancer, ependymoma, esophageal cancer, essential thrombocythemia, estrogen-receptor positive breast cancer, Ewing’s tumour, genital cancer, cancer of the cervix, cancer of the vulva, vulvar intraepithelial neoplasia (VIN), cancer of the vagina, germ cell testicular cancer, gastrointestinal cancers, gastric cancer, glioblastoma, glioma, heavy chain disease, hemangioblastoma, hepatocellular cancer, hepatoma, hormone insensitive prostate cancer, keratinocyte carcinomas, kidney cancer, leukaemias including acute leukaemia, acute lymphocytic leukaemia, acute myeloid leukaemia, acute myelocytic leukaemia (monocyctic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukaemia, chronic leukaemia, chronic lymphocytic leukaemia, chronic myelocytic (granulocytic) leukaemia, chronic myelogenous leukaemia, erythroleukemia, lymphoblastic leukaemia, and myelogenous leukaemia, liver cancer, lung cancer, lymphoid malignancies of T-cell or B-cell origin, lymphomas (Hodgkin’s and non-Hodgkin’s) including cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma, cutaneous (skin) lymphomas, malignancies and hyperproliferative disorders including of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, advanced malignancies, medulloblastoma, melanoma, meningioma, Merkel cell cancer mesothelioma, metastatic cancer, multiple myeloma, myeloma, pancreatic cancer, myelofibrosis, myeloproliferative neoplasms, neuroblastoma, non-small cell lung cancer, head and neck cancer, oligodendroglioma, oral cancer, ovarian cancer, pancreatic cancer, pinealoma, polycythemia vera, prostate cancer, rectal cancer, retinoblastoma, sarcomas including chondrosarcoma, endotheliosarcoma, fibrosarcoma, gliosarcoma, leiomyosarcoma, liposarcoma, lymphagioendotheliosarcoma, lymphangiosarcoma, myxosarcoma, Castleman's disease and Kaposi's sarcoma, osteogenic sarcoma, and rhabdomyosarcoma, seminoma, skin cancer, skin adnexal tumors, and sarcomas, small cell lung cancer, solid tumors, stomach cancer, synovioma, testicular tumours, thyroid cancer, uterine cancer, Waldenstrom’s macroglobulinemia, and Wilms’ tumour.

BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be used to provide male contraception.

BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of use in the treatment or amelioration of obesity, dyslipidaemia, cholesteatoma, hypercholesterolemia, Alzheimer’s disease, metabolic syndrome, hepatic steatosis, type I diabetes, type II diabetes, and complications from diabetes, insulin resistance, and diabetic retinopathy or diabetic neuropathy.

BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of use in the treatment or amelioration of an immune system dysfunction, a viral disease, a bacterial disease, a yeast disease, non-inflammatory acne, an allergic disease, asthma, food allergy, rhinitis, an IL-6 pathway-related disease, an immune response, and a hyperproliferative disorder;

BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of use in the treatment or amelioration of Aicardi-Goutieres syndrome, chilblain lupus, stimulator of interferon genes-Associated Vasculopathy with onset in Infancy (SAVI), Singleton-Merten syndrome, retinal vasculopathy with cerebral leukodystrophy, autoimmune uveitis, lupus, systemic sclerosisan autoimmune thyroid disease, an allograft rejection, a graft-versus-host disease, an allograft rejection reaction, and a graft-versus-host reaction.

BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of use in the treatment or amelioration of disorders caused by a virus, such as Epstein-Barr virus (EBV), HIV, HTLV 1, chickenpox, herpes simplex virus infections, herpes zoster virus (VZVj, and human papillomavirus (HPV) disease. BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of use in the treatment or amelioration of mucopurulent cervicitis (MPC), urethritis, nongonococcal urethritis (NGU), vulvar disorders, vulvodynia, vulvar pain, vulvar dystrophy, pelvic inflammation, endometritis, salpingitis, oophoritis, dyspareunia, anal and rectal disease, anal abscess/fistula, anal fissure, anal warts, hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation, and polyps of the colon and rectum.

BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of use in the restoration of integrity or acceleration of the restoration of the integrity of an area of broken or damaged tissue, skin or mucosa, and in the reduction and amelioration of scar formation or scars. Such restoration of broken or damaged tissue, skin or mucosa, and such the reduction and amelioration of scar formation or scars when the compound or a pharmaceutical composition comprising the compound is administered topically may benefit in some embodiments from application of a PAN BET. Further advantages may be achieved in some embodiments if the PAN BET has some selectivity for BDII whilst having a higher clearance and or a lower plasma stability.

BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of use in the treatment or amelioration of pyoderma gangrenosum (PG), palmar plantar pustulosis (PPP), and generalized pustular psoriasis (GPP). Such skin disorders or diseases when the compound or a pharmaceutical composition comprising the compound is administered topically may benefit in some embodiments from application of a PAN BET. Further advantages may be achieved if the PAN BET has in some embodiments some selectivity for BDII whilst having a higher clearance and or a lower plasma stability.

BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of use in the treatment or amelioration of Crohn’s disease, multiple sclerosis, rheumatoid arthritis, rhinosinusitis, and ulcerative colitis. BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of use in the treatment or amelioration of cryopyrin-associated periodic syndromes (CAPS), cardiovascular disease, cerebrovascular disease, familial Mediterranean fever, Grave’s disease, liver fibrosis, neurofibromatoses, myocardidtis, pericarditis, prostate disease, prostatitis, benign prostatic hyperplasia (BPH), systemic mastocytosis, and warm autoimmune hemolytic anemia.

BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, be of use in the treatment or amelioration of angiofibroma, chronic hand eczema, cutaneous mastocytosis, urticaria pigmentosa, neutrophilic dermatoses such as pyoderma gangrenosum and Sweets syndrome, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), ichthyosis, keloids, scars, hypertrophic scars, netherton syndrome, pruritus, prurigo nodularis, and urticaria pigmentosa. Such skin disorders or diseases when the compound or a pharmaceutical composition comprising the compound is administered topically may benefit in some embodiments from application of a PAN BET. Further advantages may be achieved if the PAN BET has in some embodiments some selectivity for BDII whilst having a higher clearance and or a lower plasma stability.

BET inhibitors including, e.g., selective BET BDII inhibitors, such as the compounds disclosed herein, may in one or more embodiments, also be of value and used in the palliation, diagnosis or prevention of any disease, disorder or condition in humans of one or more of the aforesaid non-limiting examples of disorders and diseases. In one or more embodiments there is provided a method of inhibiting Bromodomain and Extra-Terminal protein activity in a subject comprising administering to a subject an effective amount of any one or a combination of two or more of the compounds described herein or a pharmaceutical composition comprising the compound or compounds in combination with one or more pharmaceutical acceptable excipients. In some embodiments here is provided the said method, wherein the subject has a disease or condition associated with the activity of the Bromodomain and Extra-Terminal protein. In some embodiments there is provided the said method, wherein the compound or pharmaceutical composition comprising the compound is administered systemically e.g., orally. In some embodiments there is provided the said method, wherein the compound or pharmaceutical composition comprising the compound is administered topically, e.g., to the skin or to a mucosa. In some embodiments there is provided the said method, wherein the method comprises administering a pharmaceutical composition comprising any one or a combination of two or more of the described compounds in a therapeutically effective amount in combination with one or more pharmaceutical acceptable excipients, and wherein the disorder or disease is selected from the group consisting of inflammatory disorders, inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, rheumatic diseases, demyelinating diseases, fibrotic diseases, autoimmune diseases, and indications where immunosuppression is desirable.

An effective amount of the compound may be administered to a subject topically, parenterally or enterally. The compound may be administered parenterally, sometimes by direct injection, which is typically intramuscular, subcutaneous or intraveneous. Typically, however, the compound is administered topically to the skin or mucous membranes via a cream, gel, foam, lotion or ointment, or enterally via a tablet, capsule or buccal spray.

The subject may, and typically is, a human, and may be suffering from or liable to suffer from inflammatory disorders such as, but not limited to, inflammatory skin disorders, respiratory diseases, rheumatic diseases, gastrointestinal diseases and eye diseases. Treatment of said subject may comprise administering an effective amount of a compound. The term "effective amount” denotes an amount of the compound that ameliorates the above-noted diseases and thus produces the desired therapeutic or inhibitory effect.

The skilled person is aware that an effective amount is likely to vary with the particular compound, the subject and the administration procedure used. It is within the means and capacity of the skilled person to identify the effective amount of the compounds and compositions.

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

It will be appreciated by those skilled in the art that numerous variations and/or modifications may be made to the invention as described herein without departing from the scope of the invention as described. The present embodiments are therefore to be considered for descriptive purposes and are not restrictive, and are not limited to the extent of that described in the embodiment. The person skilled in the art is to understand that the present embodiments may be read alone, or in combination, and may be combined with any one or a combination of the features described herein.

Some of the compounds included herein are a selection from PCT/EP202/061173 filed on 22 April 2020.

The subject-matter of each patent and non-patent literature reference cited herein is hereby incorporated by reference in its entirety. In embodiments of the first aspect of the present invention, the compound is selected from the following, or for compounds with a dimethylphenyl group, the equivalent compound where the dimethylphenyl ring has a fluoro group at the para position:

Other specified compounds of the present invention are set out in the accompanying Figures la-e. The following are presented as non-limiting examples.

EXAMPLES

Abbreviations APCI atmospheric pressure chemical ionisation mass spectrum

BD binding domain

Br broad

C centi

CCL chemokine (C-C motif) ligand

CXCL chemokine (C-X-C motif) ligand δ chemical shift d doublet dd double doublet

DCM dichloromethane

DMF dimethylformamide

DMA dimethylacetamide

DMSO dimethyl sulfoxide

EC effective concentration

ES electrospray

ESI electrospray ionization g Gram

GM-CSF granulocyte-macrophage colony-stimulating factor h Hour

HPLC high performance liquid chromatography

HRMS high resolution mass spectrum

IL Interleukin

J coupling constant

Kd dissociation constant

L litre

LC liquid chromatography

LG leaving group m multiplet m milli m meter

M molar

M+ molecular ion MHz megahertz min minutes mol mole

MS mass spectrometry m/z mass/charge n nano

NMR nuclear magnetic resonance

P para

PTSA p-ToluenesuIfonic acid q quartet

Rf retardation factor rpm revolutions per minute

RT room temperature s singlet

SM starting material

SNAC nucleophilic aromatic substitution (addition- elimination) t triplet

THE tetrahydrofuran

TLC thin layer chromatography

TLR toll-like receptors

TBME methyl tert-butyl ether t_R retention time

TSLP thymic stromal lymphopoietin

INF tumor necrosis factor

XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Ts or Tosyl toluenesulfonyl

DTT dithioreitol

BSA bovine serum albumin

PBS phosphate-buffered saline

MEG monoethylene glycol

NADPH nicotinamide adenine dinucleotide phosphate μ micro UDPGA uridine diphosphate glucuronic acid

UPLC ultra performance liquid chromatography

UV ultraviolet vis visable w/w weigh t by weigh t

°C degree Celsius

% per cent

Equipment

Reactions using microwave irradiation were carried out in a Biotage Initiator microwave or an Antonpaar monowave 300 microwave.

Normal phase TLCs were carried out on pre-coated silica plates (Kieselgel 60 F₂₅₄, BDH) with visualisation via U.V. light (UV254/365 nm) and/or ninhydrin solution.

Flash chromatography was performed using either:Combiflash Companion Rf (Teledyne ISCO) and prepacked silica gel columns purchased from Grace Davison Discovery Science or SiliCycle, Combiflash Companion Rf (Teledyne ISCO) and silica gel purchased from Finar or C-18 silica gel from Exmere Ltd or pre-packed columns purchased from YMC, Buchi Prepchrom (C-700) and silica gel purchased from Finar or C-18 silica gel from Exmere Ltd or pre-packed columns purchased from YMC or Biotage (I solera LS) and silica gel purchased from Finar or C-18 silica gel from Exmere Ltd or pre-packed columns purchased from YMC.

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

Preparative HPLC separations were performed with a Gilson HPLC (321 pumps, 819 injection module, 215 liquid handler/injector) connected to a Gilson 155 UV/vis detector or a Waters HPLC (Delta 600 Quaternary pump) equipped with UV/vis detector Waters 2487 or Shimandzu HPLC (LC-20 AP Binary pump) equipped with Shimandzu SPD-20A UV/vis detector or Waters HPLC (2545 Quaternary pump equipped with UV/vis detector Waters 2489 or Agilent HPLC (Agilent 1260 Infinity II Binary pump) equipped with UV/vis detector Agilent 1260 Infinity along with 1260 Infinity auto sampler. Preparative HPLC separations were also performed using Agilent 1200 series infinity-II with UV Detector. HPLC chromatographic separations were conducted using either Column A) X-bridge Prep, C18, OBD 19 x 250 mm, 5pm, B) viridis prep silica 2-EPD 19 x 250 mm, 5pm, C) YMC-Actus Tri-art Prep C18 (250 X 20) mm, 5pm; using the mobile phase shown. 1H ¹H NMR and ¹⁹F NMR spectra were recorded on a Bruker Avance DPX 500 spectrometer (¹H at 500.1 MHz, ¹³C at 125 MHz ¹⁹F at 470.5 MHz), or a Bruker Avance DPX 300 (¹HH at 300 MHz) or a Bruker Ultra shield 400 spectrometer with i- probe equipped with Avance HI HD console (¹HH at 400.13 MHz, ¹³C at 100 MHz ¹⁹F at 376.12 MHz). Chemical shifts (δ) are expressed in ppm recorded using the residual solvent as the internal reference in all cases. Signal splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br), or a combination thereof. Coupling constants (/) are quoted to the nearest 0.5 Hz. Low resolution electrospray (ES) mass spectra were recorded on a Bruker MicroTof mass spectrometer, run in positive mode. High resolution mass spectroscopy (HRMS) was performed using a Bruker MicroTof mass spectrometer.

LC-MS analysis and chromatographic separation were conducted with an Agilent Technologies 1200 series HPLC connected to an Agilent Technologies 6130 quadrupole LC/MS, connected to an Agilent diode array detector, or a Shimadzu HPLC connected to a LCMS-2020 quadrupole LC/MS, connected to a Shimadzu diode array detector or a Water Acquity UPLC with binary solvent manager with PDA detector and Acquity QDA performance mass detector or a Water Acquity UPLC with quaternary solvent manager with PDA detector and Acquity SQD mass detector or Waters Alliance 2690 and 996 PDA detector with Micromass ZQ or Waters Acquity UPLC with binary solvent manager, PDA detector and SQ detector. LC-MS analysis and chromatographic separation were also conducted with a Waters Acquity Ultra performance LC connected to a Waters QDA Mass detector, connected to Waters diode array detector. The column used was a Waters XBridge column (50 mm x 2.1 mm, 2.5 pm particle size,) and the compounds were eluted with, Mobile Phase A : 0.1 % Formic acid in Milli Q water (pH= 2.70), Mobile Phase B : 0.1%Formic acid in Milli Q water : Acetonitrile (10:90) with a gradient of T = 0 min (97% A, 3% B) flow : 0.8 mL/min; T = 0.75 min (97% A, 3% B) flow : 0.8 mL/min; gradient to T = 2.7 min (2% A, 98% B) flow : 0.8 mL/min; gradient to T = 3 min (0% A, 100% B) flow : 1 mL/min; T = 3.5 min (0% A, 100% B) flow : 1 mL/min; gradient to T= 3.51 min (97% A, 3% B) flow : 0.8 mL/min; end of run at T = 4 min (97% A, 3% B), Flow rate: 0.8 mL/min.

HPLC analysis was conducted with an Agilent 1100 series equipped with PDA UV detector or Agilent 1260 Infinity-II series with PDA and or ELSD (with Agilent-385 ELS-detector) or Waters Alliance e2695 equipped with PDA 2998 Detector. HPLC analysis was also conducted with a Waters alliance e2695 separation Waters 2998 diode array detector. The column used was a Waters XBridge column (150mm x 4.6 mm, 3.5 pm particle size,) and the compounds were eluted with, Mobile Phase A : 0.1 % ammonium hydroxide solution in Milli Q water (pH= 9), Mobile Phase B : Acetonitrile with a gradient of T = 0 min (90% A, 10% B; gradient to T = 7 min (10% A, 90% B); gradient to T = 9 min (0% A, 100% B); T = 14 min (0% A, 100% B); gradient to T = 14.01 min (90% A, 10% B); end of run at T =17 min (90% A, 10% B), Flow rate: 1 mL/min, analysis time 17 min.

Unless otherwise stated herein, reactions have not been optimized. Solvents and reagents were purchased from commercial suppliers and used without further purification. Dry solvents were purchased in sure sealed bottles stored over molecular sieves.

Preparations and compounds have been named using the ChemDraw Professional 19.1 naming application.

Process for Preparation

The following schemes illustrate methods of synthesising analogues of the compounds of the invention which allow the skilled reader to prepare the analogous compounds of the invention. Scheme 1 illustrates a general route for the preparation of compounds herein via Suzuki coupling of intermediates (III) and (IX) followed by deprotection. The 6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one boronic ester intermediate (III) is prepared as follows: 5 -Bromo-2-methoxy-4-methyl-3 -nitropyridine is reacted with DMF-DMA to give intermediate (VIII). An iron catalysed reduction of the 3-nitro group to the corresponding amine initiates ring closure to give intermediate (VII). Tosyl protection followed by acid hydrolysis with HBr gives intermediate (V). The pyridone group is then N-methylated with methyl iodide and sodium hydride to give intermediate (IV). Intermediate (III) is then formed from the 4-bromoaryl compound (IV) via treatment with 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-l,3,2- dioxaborolane in a palladium-catalysed coupling reaction. Suzuki coupling of (III) and (IX), followed by deprotection, produces compound (II). Deprotection involves removal of the tosyl group of intermediate (III) using, for example, sodium hydroxide.

Alternatively, the compound may be functionalised at position 2 of the pyrrole with a third substituent, typically CONHethyl. This may be carried out by using an alternative synthetic pathway, shown in Scheme 2, in which intermediate (IV) is reacted with ethylchloroformate and a strong base, such as lithium diisopropylamide (LDA) to form intermediate (IV’). Intermediate (III') is then formed from compound (IV’) via treatment with 4,4,4',4',5,5,5',5'-Octamethyl-2,2'- bi-l,3,2-dioxaborolane in a palladium-catalysed coupling reaction. Suzuki coupling of (III') and (IX), followed by deprotection, produces compound (II’). Deprotection involves removal of the tosyl group using, for example, sodium hydroxide. This also converts the ethoxy substituent of the ethyl formyl to a hydroxy group. Finally, the carboxylic acid at position 2 of the pyrrole of intermediate (IF) is reacted with a suitable amine to produce the desired third substituent. Oxalyl chloride is typically used to catalyse this reaction step by first converting the carboxylic acid to an acyl chloride, which is more susceptible to nucleophilic substitution with an amine. The skilled person is able to assess which amines and reaction conditions are suitable to functionalise the carboxylic acid of intermediate (IF) to produce compound (II”).

Scheme 1: general synthetic pathway for the synthesis of compounds herein. The definitions of R2, R3, R4 and R5 of compounds (IX) and (II) are as defined above for compounds of formula (I).

Scheme 2: general synthetic pathway for the synthesis of compounds herein. The definitions of Rl, R2, R3, R4 and R5 of compounds (II"), (II) and (IX) are as defined above for formula (I).

The use of Scheme 2 to synthesise compounds described herein wherein Ri is CONHEt, R₂, R₃ and R₄ is methyl and R₅ is fluorine, such as Example 80, is shown in Scheme 3.

Scheme 3: Exemplification of general Scheme 2 wherein Rl is CONHEt, R2, R3 and R4 is methyl and R5 is fluoroine.

Suitable pathways to synthesise intermediates of formula (IX) are shown in Scheme

4, in which (IX) can be a substituted R2 substituted 2-pyridone or substituted R2 substituted 5-pyridone.

Substituted N-methyl-2-pyridone-intermediates (XI) and substituted N- methyl-5-pyridone-intermediates (XI') are prepared via methylation of the corresponding 2-pyridone (XII) or 5-pyridone (XIT) and hydrolysis of the corresponding pyridines (XIII) or (XIII’) using potassium hydroxide. Pyridine intermediates (XIII) or (XIII') are in turn formed via reduction of the corresponding pyridine oxides (XIV) or (XIV’) using phosphorus tribromide. Bromo-intermediates (XIV) or (XIV) are prepared via reaction of the corresponding nitro intermediates (XV) or (XV) with acetyl bromide, and compounds (XV) or (XV) are in turn produced via S_NAr reaction of the corresponding ortho-fluoro nitro pyridine oxide compounds (XVI) or (XVI’). The definitions of Ri, R₂, R₃, R₄ and R₅ for compounds (XI), (XI’), (XII), (XII’), (XIII), (XIII’), (XIV), (XIV), (XV), (XV), (XVI) and (XVI’) are as defined above for formula (I).

Scheme 4: general synthetic pathway for the synthesis of substituted 2-pyridone and substituted 5-pyridone compounds herein. The definitions ofRl, R2, R3, R4 and R5 of compounds (XI), (XI), (XII), (XII), (XIII), (XIII), (XIV), (XIV), (XV), (XV), (XVI) and (XVI) are as defined above for formula (I). The following are a series of illustrative preparations for forming the compounds of the invention

Preparation 1: (E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethen-l- amine

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 (4:1 heptane/EA) after 5 h showed no starting material remaining. The mixture was cooled to RT and poured into ice water (1100 mL). The resulting suspension was stirred for 15 min 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. 1H NHR (400 MHz, CDC1₃) δ 8.14 (s, 1H), 7.02 (d, J=13.7 Hz, 1H), 4.94 (d, J=13.7 Hz, 1H), 3.97 (s, 3H), 2.94 (s, 6H).

Preparation 2: 4-bromo-7-methoxy-lH-pyrrolo[2,3-c]pyridine

(E)-2-(5-Bromo-2-methoxy-3-nitropyridin-4-yl)-/V,/V-dimethylethen-l-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 heated at reflux. The reaction mixture was stirred using an overhead stirrer. After 5 h a further aliquot of iron powder (23.3 g, 417 mmol) was added and heating continued overnight. The mixture was cooled and solid Na₂CO₃ was added. The mixture was filtered through a pad of celite. The filtrate was filtered and the residue triturated with 4:1 heptane/Ethyl acetate. The mixture was filtered through a pad of silica. The filtrate is 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%).

HPLC t_R (Agilent, acidic, 3.5 min): 1.46 min, MS: m/z 229.0 [M+2H]⁺.

Preparation 3: 4-bromo- 7-methoxy-l -tosyl-lH-pyrrolo[2,3-c] pyridine

Sodium hydride (60% w/w, 7.90 g, 198 mmol) was suspended in THF (290 mL) under nitrogen and was cooled to below 4 °C in an ice bath. 4-bromo-7- methoxy-lH-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 (evolution of gas was observed and formation of an exotherm raised the reaction temperature to 5 °C). The maroon mixture was stirred at RT for 45 min before cooling 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 1.5 h with cooling, and then 1 h at RT. TLC (3:2 heptane/ethyl acetate) showed no remaining SM. The reaction mixture was quenched by dropwise addition of sat NH4CI (300 mL). The mixture was stirred 5 min before separating the phases. The aqueous phase was extracted with ethyl acetate (2x300 mL). The combined organics were washed (brine), dried (MgSO₄), filtered and evaporated to an oil that crystallized on cooling to give a light tan solid (26.2 g 99%). The material was used directly in preparation 4 without further purification.

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

Preparation 4: 4-bromo- l-tosyl-l,6-dihydro-7H-pyrrolo [2, 3-c]pyridin-7-one

4-Bromo-7-methoxy-l-tosyl-lH-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 (3:2 heptane/ethyl acetate) after 2 h showed no remaining SM. The reaction mixture was cooled to RT and then cooled in an ice bath with stirring for 30 min. The mixture was filtered and the cream coloured 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.

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

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

4-Bromo-l-tosyl-l,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) added in small portions, producing an evolution of gas and exotherm to 5 °C. The mixture was stirred for 20 min with cooling where after the evolution of gas had ceased, iodomethane (7.63 mL, 123 mmol) was added drop wise, producing an exotherm which raised the reaction temperature to 10 °C. The mixture was stirred for 15 min with cooling, then for 15 min at RT. LCMS after 2 h showed no SM remaining. The reaction mixture was quenched by dropwise addition of water (100 mL, evolution of gas and exotherm to 39 °C). The mixture was extracted with ethyl acetate (3x300 mL). The combined organics were washed (brine), dried (Na₂SO₄), filtered and evaporated. The crude product was triturated with TBME and filtered. The collected off-white solid was washed with TBME and dried under vacuum (15 g, 64%).

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

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

To a flask containing XPhos (625.22 mg, 1.31 mmol), 4-bromo-6-methyl-l- tosyl-l,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-l,3,2-dioxaborolan-2-yl)-l,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 is degassed for 10 min. Pd2(dba)s (300 mg, 0.32 mmol) was added and the mixture degassed for 1 min more. 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 ethyl acetate/heptane gradient (0-80%). Fractions corresponding to product were combined and concentrated to give a yellow solid (3.4 g, 55%).

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

Preparation 7: 2-chloro-4-nitro-5-phenoxypyridine 1-oxide

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

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

Preparation 8: 2,4-dibromo-5-phenoxypyridine 1-oxide

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

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

Preparation 9: 2,4-dibromo-5-phenoxypyridine

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

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

Preparation 10: 4-bromo-5-phenoxypyridin-2(1H)-one

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, the reaction mixture was stirred at 90 °C for 12 hours. The reaction was concentrated in vacuum. The residue was diluted with H₂O (100 mL) and extracted with DCM (100 mL x 2), the combined organic phase was washed with brine (100 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep- HPLC (TFA condition) to give the title compound (80 mg, 0.3 mmol, yield = 7.8 %) as a yellow solid.

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

Preparation 11: 4-bromo-l-methyl-5-phenoxypyridin-2(1H)-one

To a solution of 4-bromo-5-phenoxypyridin-2(lH)-one (61 mg, 0.23 mmol) in DMF (3.0 mL) was added Mel (65.1 mg, 0.46 mmol, 2.52 mL); CS2CO3 (224.1 mg, 0.69 mmol) at 20 °C, the reaction was stirred at 20 °C for 1 hours. To this reaction was added H2O (100 mL) and extracted with DCM (100 mL x 2), the combined organic phase was washed with brine (100 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (TFA condition) to give the 4-bromo-l-methyl-5-phenoxypyridin-2(lH)-one (63 mg, 0.23 mmol, yield = 98 %) as a yellow solid.

Comparative Examples:

The following comparative examples provide illustrative general methods for the synthesis of compounds with a similar overall structure of the compounds of the present invention. A person skilled in the art would be well aware of techniques to modify the following methods to synthesise compounds of the present invention. To the extent that any compounds disclosed in these illustrative sections are also disclosed in a prior publication but one or more uses of the compounds in a method of treatment of a disease or disorder disclosed herein or in the manufacture of a pharmaceutical composition or medicament for use in said methods of treatment are not disclosed in the prior publication a selection of such compounds for such methods and for such manufacture of a medicament or pharmaceutical composition is provided herein.

Comparative example 1: 6-methyl-4-(l-methyl-2-oxo-5-phenoxy-l,2- dihydropyridin-4-yl)-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 12: 6-methyl-4-(l-methyl-2-oxo-5-phenoxy-l,2-dihydropyridin-4-yl)-l,6- dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

In a microwave tube, 4-bromo-l-methyl-5-phenoxypyridin-2(lH)-one (70 mg, 0.25 mmol), sodium carbonate (81.6 mg, 0.77 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,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) was degassed by bubbling nitrogen for 10 min. Pd(PPh₃)4 (14.83 mg, 0.013 mmol) was added, the tube sealed and the reaction heated at 120 °C for 30 min. NaOH (53 mg, 1.25 mmol) was added and the reaction heated at 120 °C for lh. Ethyl acetate (50 ml) was added and the organics washed with 2 x 50 ml water then 1 x 50 ml saturated brine solution. The organics were then separated and dried (MgSO₄) before concentration to dryness. The crude was then purified by flash column chromatography eluting with ethyl acetate /heptane gradient (0-100%). The desired fractions were combined and dried to afford 6-methyl-4-(l-methyl-2-oxo-5- phenoxy-l,2-dihydropyridin-4-yl)-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (25mg, 24%) as a white solid.

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

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

Preparation 13: 2-chloro-3-(4-fluoro-2,6-dimethylphenoxy)-4-nitropyridine 1-oxide

Following the procedure in preparation 7, 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) was reacted to give the title compound (11.0 g, 47%).

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

Preparation 14: 2,4-dibromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridine 1-oxide

Following the procedure in preparation 8, 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%).

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

Preparation 15: 2,4-dibromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridine

Following the procedure in preparation 9, 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%).

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

Preparation 16: 4-bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one

Following the procedure in preparation 10, 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%).

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

Preparation 17: 4-bromo-3-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one

Following the procedure in preparation 11, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)pyridin-2(lH)-one (7.5 g, 24.0 mmol) was reacted to give the title compound (1.0 g, 13%).

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

Comparative example 2: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one

Preparation 18: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 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-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) was reacted to give the title compound (50 mg, 40%).

HPLC t_R (Agilent, acidic, 3.5 min): 1.36 min, m/z = 395.1 [M+H]⁺. 1H NMR (500 MHz, DMS0-d6) δ 12.07 (s, 1H), 7.54 (d, J=7.0 Hz, 1H), 7.36 (s, 1H), 7.31 (t, J=2.7 Hz, 1H), 6.69 - 6.66 (m, 2H), 6.32 - 6.26 (m, 2H), 3.55 (s, 3H), 3.44 (s, 3H), 2.01 - 2.00 (m, 6H).

Example 1: 2-(5-(2,6-dimethylphenoxy)-4-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)-2-oxopyridin-l(2H)-yl)-N,N-dimethylacetamide

See for illustration the compound labelled NA’l herein.

Preparation 15: 2-(5-(2,6-dimethylphenoxy)-4-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)-2-oxopyridin-l(2H)-yl)-N,N-dimethylacetamide

Following the procedure in preparation 12, 2-(4-bromo-5-(2,6-dimethylphenoxy)-2- oxopyridin-l(2H)-yl)-N,N-dimethylacetamide (117 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.407min, m/z = 447.17[M+1H] ⁺.

HPLC t_R (Waters Alliance e2695 with 2998 detector, basic, 17.0min): 4.180min 1H ¹H NMR (400 MHz, DMSO) δ12.17 (s, 1H), 7.52 (s, 1H), 7.35 (s,lH), 7.09-7.00 (m, 3H), 6.56 (s, 1H), 6.50 (s, 1H), 6.36 (s, 1H), 4.70 (s, 2H), 3.58 (s, 3H), 2.95 (s, 3H), 2.79 (s, 3H), 2.08 (s, 6H).

Example 2: 4-(5-(2,6-dimethylphenoxy)-l-(oxetan-3-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’2 herein. Preparation 16: 4-(5-(2,6-dimethylphenoxy)-l-(oxetan-3-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6- dimethylphenoxy)-l-(oxetan-3-yl)pyridin-2(lH)-one (109 mg, 0.31 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.461min, m/z = 418.12[M+1H] +.

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.213min

¹H NMR (400 MHz, DMSO) δ12.18 (s, 1H), 7.52 (s, 1H), 7.35 (bs, 1H), 7.14- 7.07 (m, 3H), 6.54 (d, J = 6.4 Hz, 2H), 6.38 (s, 1H), 5.47-5.45 (m, 1H), 4.79 (t, J = 7.6 Hz, 2H), 4.42 (t, J = 6.8 Hz, 2H), 3.50(s, 3H), 2.10 (s, 6H).

Example 3: 4-(5-(2.6-dimethylphenoxy)-l-(l-methylpiperidin-4-yl)-2-oxo-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’3 herein.

Preparation 17: 4-(5-(2,6-dimethylphenoxy)-l-(l-methylpiperidin-4-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6- dimethylphenoxy)-l-(l-methylpiperidin-4-yl)pyridin-2(lH)-one (121 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6- dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.119min, m/z = 459.17 [M+H] ⁺.

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.42min 1H¹H NMR: (400MHz, DMSO) δ 12.17 (s, 1H), 7.52 (s, 1H), 7.34 (s, 1H), 7.16-7.08 (m, 3H), 6.55 (s, 1H), 6.37 (s, 1H), 6.31 (s, 1H), 4.59- 4.57 (m, 1H), 3.57 (s, 3H), 2.76 (d, J = 10.8 Hz, 2H), 2.11 (s, 3H), 2.07 (s, 6H), 1.93 (t, J = 11.6 Hz, 2H), 1.64 (d, J = 10.8 Hz, 2H), 1.37-1.29 (m, 2H).

Example 4: 4-(5-(2,6-dimethylphenoxy)-l-(2-methoxyethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’4 herein.

Preparation 18: 4-(5-(2,6-dimethylphenoxy)-l-(2-methoxyethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dimethylphenoxy)-l-(2- methoxyethyl)pyridin-2(lH)-one (109 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.535min, m/z = 419.18 [M] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Acidic, 17.0min): 6.366min 1H ¹H NMR: (400 MHz, DMSO d₆) δ 12.16 (s, 1H), 7.52 (s, 1H), 7.35 (d, J = 2.6 Hz, 1H), 7.10 (s, 2H), 7.06 - 7.03 (m, 1H), 6.53 (d, J = 8.6 Hz, 1H), 6.51 (s, 1H), 6.36 (s, 1H), 3.93 (d, J = 4.9 Hz, 2H), 3.58 (s, 3H), 3.46 (d, J = 4.9 Hz, 2H), 3.12 (s, 3H), 2.08 (s, 6H).

Example 5: 4-(5-(2,6-dimethylphenoxy)-l-(2-morpholinoethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’5 herein.

Preparation 19: 4-(5-(2,6-dimethylphenoxy)-l-(2-morpholinoethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6- methyl- l,6-dihydro-7H-pyrrolo [2, 3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dimethylphenoxy)-l-(2- morpholinoethyl)pyridin-2(lH)-one (126 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.131min, m/z =475.17 M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.366min 1H ¹H NMR: (400 MHz, DMSO) δ 12.16 (s, 1H), 7.52 (s, 1H), 7.35 (d, J = 2.6 Hz,

1H), 7.10 (m, 3H), 6.62 (s, 1H), 6.49 (s, 1H), 6.35 (s, 1H), 3.93 (d, J = 4.9 Hz, 2H), 3.58 (s, 3H), 3.36 (m, 3H), 2.44 (m, 3H), 2.32 (s, 4H), 2.20 (s, 6H).

Example 6: 4-(5-(2.6-dimethylphenoxy)-l-ethyl-2-oxo-1.2-dihydropyridin-4- yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’6 herein.

Preparation 20: 4-(5-(2,6-dimethylphenoxy)-l-ethyl-2-oxo-l,2-dihydropyridin-4-yl)-6- methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dimethylphenoxy)-l- ethylpyridin-2(lH)-one (100 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.535min, m/z = 390.17 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.366min 1H ¹H NMR: (400 MHz, DMSO) δ 12.16 (s, 1H), 7.49 (s, 1H), 7.34 (d, J = 2.6 Hz, 1H), 7.10 (m, 2H), 7.06 - 7.03 (m, 1H), 6.61 (s, 1H), 6.49 (s, 1H), 6.35 (s, 1H), 3.79 (m, 2H), 3.57 (s, 3H), 2.08 (s, 6H), 1.07 (t, J=7.2Hz, 3H).

Example 7: 4-(5-(2.6-dimethylphenoxy)-l-(2-hydroxy-2-methylpropyl)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

See for illustration the compound labelled NA’7 herein.

Preparation 21: 4-(5-(2,6-dimethylphenoxy)-l-(2-hydroxy-2-methylpropyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dimethylphenoxy)-l-(2- hydroxy-2-methylpropyl)pyridin-2(lH)-one (113 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.48min, m/z = 434.22 [M+H] +.

HPLC t_R (Waters Alliance e2695 with 2998 detector, basic, 17.0min): 5.66min

¹H NMR (400 MHz, DMSO) 12.15 (s, 1H), 7.52 (s, 1H), 7.34 (s, 1H) , 7.09- 7.02 (m, 3H) ,6.71 (s, 1H), 6.52 (s, 1H), 6.36 (s, 1H), 4.68 (s, 1H), 3.76 (s, 2H), 3.58 (s, 3H), 2.07 (s, 6H), 1.00 (s, 6H).

Example 8: 4-(l-(difluoromethyl)-5-(2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’8 herein.

Preparation 22.- 4-(l-(difluoromethyl)-5-(2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(difluoromethyl)-5-(2,6- dimethylphenoxy)pyridin-2(lH)-one (107 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.574min, m/z =412.12 [M+1H] ⁺ HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.213min 1H ¹H NMR (400 MHz, DMSO) δ 12.36 (s, 1H), 7.68 - 7.49 (m, 2H), 7.32 (dd, J = 30.3, 12.5 Hz, 1H), 7.24 - 7.07 (m, 3H), 6.75 (s, 1H), 6.35 (s, 1H), 6.11 (d, J = 2.5 Hz, 1H), 3.54 (s, 3H), 2.16 (d, J = 21.7 Hz, 6H).

Example 9: 4-(l-(3.3-difluorocyclobutyl)-5-(2.6-dimethylphenoxy)-2-oxo-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’9 herein.

Preparation 23: 4-(l-(3,3-difluorocyclobutyl)-5-(2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(3,3-difluorocyclobutyl]-5- (2,6-dimethylphenoxy)pyridin-2(lH)-one (119 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) reacts to give the title compound.

Example 10: 4-(5-(2.6-dimethylphenoxy)-l-(l-methylazetidin-3-yl)-2-oxo-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’10 herein.

Preparation 24: 4-(5-(2,6-dimethylphenoxy)-l-(l-methylazetidin-3-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dimethylphenoxy)-l-(l- methylazetidin-3-yl)pyridin-2(lH)-one (113 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.135min, m/z =431.17 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 5.643min 1H ¹H NMR: (400 MHz, DMSO) δ 12.15 (s, 1H), 7.51 (s, 1H), 7.35-7.34 (d, J = 2.8 Hz, 1H), 7.15-7.13 (d, J = 7.2 Hz, 2H), 7.090-7.073 (d, J = 6.8 Hz, 1H), 6.78 (s, 1H), 6.505 (s, 1H), 6.38-6.37 (d, J = 2.4 Hz, 1H), 5.03-4.98 (m, 1H), 3.58 (s, 3H), 3.55-3.51 (t, J = 7.6 Hz, 2H), 2.89-2.86 (t, J = 6.6 Hz, 2H), 2.12-2.11 (d, J = 4.0 Hz, 9H).

Example 11: 4-(5-(2,6-dimethylphenoxy)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’ll herein.

Preparation 25: 4-(5-(2,6-dimethylphenoxyJ-2-oxo-l-(2,2,2-trifluoroethylJ-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dimethylphenoxy)-l- (2,2,2-trifluoroethyl)pyridin-2(lH)-one (117 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.739min, m/z =444.07 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 7.173min 1H ¹H NMR: (400 MHz, DMSO) δ 12.19 (s, 1H), 7.57 (s, 1H), 7.36-7.34 (t, J = 2.6

Hz, 1H), 7.13-7.11 (d, J = 7.2 Hz, 2H), 7.08-7.04 (m, 1H), 6.67 (s, 1H), 6.61 (s, 1H), 6.37 (s, 1H), 4.83-4.76 (m, 2H), 3.57 (s, 3H), 2.07 (s, 6H).

Example 12: 4-(5-(2,6-dimethylphenoxy)-l-(3-fluoropropyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one See for illustration the compound labelled NA’12 herein.

Preparation 26: 4-(5-(2,6-dimethylphenoxy)-l-(3-fluoropropyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dimethylphenoxy)-l-(3- fluoropropyl)pyridin-2(lH)-one (110 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.598min, m/z =422.17 [M+1H] +

HPLC t_R (Waters Alliance e2695 with 2998 detector, basic, 17.0min): 6.052min

¹H NMR (400 MHz, DMSO) δ12.10 (s, 1H), 7.49 (s, 1H), 7.35-7.34 (m, 1H), 7.11-7.02 (m, 3H) ,6.59 (s, 1H), 6.51 (s, 1H), 6.36 (s, 1H), 4.47-4.32 (t, J = 5.6 Hz, 1H), 4.35-4.32 (t, J = 5.6 Hz, 1H), 3.88-3.84 (t, J = 7.2 Hz, 2H), 3.57 (s, 3H), 2.07 (s, 6H), 1.95-1.85 (m, 2H).

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

See for illustration the compound labelled NA’13 herein.

Preparation 27: 4-(5-(2,6-dimethylphenoxy)-l-isopropyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dimethylphenoxy)-l- isopropylpyridin-2(lH)-one (104 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.702min, m/z = 403.19 [M+1H] ⁺ HPLC t_R (Waters Alliance e2695 with 2998 detector, Acidic, 17.0min): 6.965min 1H ¹H NMR: (400 MHz, DMSO d₆) δ 12.18 (s, 1H), 7.53 (s, 1H), 7.36 (s, 1H), 7.13 (d, J = 15.6 Hz, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.54 (s, 1H), 6.38 (d, J = 5.1 Hz, 2H), 5.02 - 4.92 (m, 1H), 3.59 (s, 3H), 2.09 (s, 6H), 1.09 (d, J = 6.7 Hz, 6H).

Example 14: 4-(5-(2.6-dimethylphenoxy)-2-oxo-l-(3.3.3-trifluoropropyl)-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’14 herein.

Preparation 28: 4-(5-(2,6-dimethylphenoxy)-2-oxo-l-(3,3,3-trifluoropropyl)-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6- dimethylphenoxy)-l-(3,3,3-trifluoropropyl)pyridin-2(lH)-one (121 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro- 7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.757min, m/z =458.2 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.366min 1H ¹H NMR: (400 MHz, DMSO) δ 12.16 (s, 1H), 7.52 (s, 1H), 7.35 (t, J = 2.6 Hz, 1H), 7.10 (d, J = 6.8 Hz, 2H), 7.06 - 7.03 (m, 1H), 6.68(s, 1H), 6.53 (s, 1H), 6.33 (s, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.58 (s, 3H), 2.66 (m, 2H), 2.06 (s, 6H). Example 15: 4-(l-(2-(dimethylamino)ethyl)-5-f2.6-dimethylphenoxy)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

See for illustration the compound labelled NA’15 herein.

Preparation 29: 4-(l-(2-(dimethylamino)ethyl)-5-(2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(2-(dimethylamino)ethyl)-5- (2,6-dimethylphenoxy)pyridin-2(lH)-one (113 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.145min, m/z = 433.22 [M+H] ⁺.

HPLC t_R (Waters Alliance e2695 with 2998 detector, basic, 17.0min):

6.719min 1H ¹H NMR: (400 MHz, DMSO) δ 12.16 (s, 1H), 7.51 (s, 1H), 7.34 (bs, 1H), 7.11- 7.04 (m, 3H), 6.55 (s, 1H), 6.47 (s, 1H), 6.35 (br s, 1H), 3.83 (t, J = 4.8 Hz, 2H), 3.57 (s, 3H) 2.34 (t, J = 5.6 Hz, 2H), 2.07 (s, 6H), 2.00 (s, 6H).

Example 16: 4-(l-cyclopropyl-5-(2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’16 herein. Preparation 30: 4-(l-cyclopropyl-5-(2,6-dimethylphenoxy)-2-oxo-l,2-dihydropyridin-

4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-cyclopropyl-5-(2,6- dimethylphenoxy)pyridin-2(lH)-one (103 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): m/z= 402.17, RT=1.578 min.

HPLC t_R (Waters Alliance e2695 with 2998 detector, basic, 17.0min): 6.693min 1H ¹H NMR: (400 MHz, DMSO) δ 12.16 (s, 1H), 7.48 (s, 1H), 7.34 (t, / = 2.4 Hz, 1H), 7.14-7.04 (m, 3H), 6.49 (s, 1H), 6.359 (bs,lH), 6.23 (s, 1H), 3.57 (s, 3H), 3.18- 3.13 (m, 1H), 2.07 (s, 6H), 0.92 -0.83 (m, 2H), 0.58-0.54 (q, J = 6.4 Hz, 6.8 Hz, 2H).

Example 17: 2-(5-(4-fluoro-2,6-dimethylphenoxy)-4-(6-methyl-7-oxo-6,7- dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-2-oxopyridin-l(2H)-yl)-N,N- dimethylacetamide

See for illustration the compound labelled NA’23 herein.

Preparation 31: 2-(5-(4-fluoro-2,6-dimethylphenoxy)-4-(6-methyl-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridin-4-yl)-2-oxopyridin-l(2H)-yl)-N,N-dimethylacetamide

Following the procedure in preparation 12, 2-(4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-2-oxopyridin-l(2H)-yl)-N,N-dimethylacetamide (123 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6- dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 18: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-(oxetan-3-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one See for illustration the compound labelled NA’24 herein.

Preparation 32: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-(oxetan-3-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-l-(oxetan-3-yl)pyridin-2(lH)-one (114 mg, 0.31 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 19: 4-(5-(4-fluoro-2.6-dimethylphenoxy)-l-(l-methylpiperidin-4-yl)- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

See for illustration the compound labelled NA’25 herein.

Preparation 33: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-(l-methylpiperidin-4-yl)-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-l-(l-methylpiperidin-4-yl)pyridin-2(lH)-one (127 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6- dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 20: 4-(5-(4-fluoro-2.6-dimethylphenoxy)-l-(2-methoxyethyl)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

See for illustration the compound labelled NA’26 herein.

Preparation 34: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-(2-methoxyethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-l-(2-methoxyethyl)pyridin-2(lH)-one (115 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 21: 4-(5-(4-fluoro-2.6-dimethylphenoxy)-l-(2-morpholinoethyl)-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one See for illustration the compound labelled NA’27 herein.

Preparation 35: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-(2-morpholinoethyl)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-l-(2-morpholinoethyl)pyridin-2(lH)-one (132 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro- 7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 22: 4-(l-ethyl-5-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’28 herein. Preparation 36: 4-(l-ethyl-5-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-ethyl-5-(4-fluoro-2,6- dimethylphenoxy)pyridin-2(lH)-one (105 mg, 0.31 mmol) and 6-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 23: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-(2-hydroxy-2- methylpropyl)-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’29 herein.

Preparation 37: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-(2-hydroxy-2-methylpropyl)-

2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-l-(2-hydroxy-2-methylpropyl)pyridin-2(lH)-one (119 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6- dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 24: 4-(l-(difluoromethyl)-5-(4-fluoro-2.6-dimethylphenoxy)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

See for illustration the compound labelled NA’30 herein.

Preparation 38: 4-(l-(difluoromethyl)-5-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(difluoromethyl)-5-(4- fluoro-2,6-dimethylphenoxy)pyridin-2(lH)-one (112 mg, 0.31 mmol) and 6-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 25: 4-(l-(3.3-difluorocyclobutyl)-5-(4-fluoro-2.6-dimethylphenoxy)- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

See for illustration the compound labelled NA’31 herein.

Preparation 39: 4-(l-(3,3-difluorocyclobutyl)-5-(4-fluoro-2,6-dimethylphenoxy)-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(3,3-difluorocyclobutyl]-5- (4-fluoro-2,6-dimethylphenoxy)pyridin-2(lH)-one (125 mg, 0.31 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 26: 4-(5-(4-fluoro-2.6-dimethylphenoxy)-l-(l-methylazetidin-3-yl)- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one See for illustration the compound labelled NA’32 herein.

Preparation 40: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-(l-methylazetidin-3-yl)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-l-(l-methylazetidin-3-yl)pyridin-2(lH)-one (118 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6- dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 27: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l-(2,2,2- trifluoroethyl)-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’33 herein.

Preparation 41: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l-(2,2,2-trifluoroethyl)- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-l-(2,2,2-trifluoroethyl)pyridin-2(lH)-one (122 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro- 7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 28: 4-(5-(4-fluoro-2.6-dimethylphenoxy)-l-(3-fluoropropyl)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

See for illustration the compound labelled NA’34 herein.

Preparation 42: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-(3-fluoropropyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-l-(3-fluoropropyl)pyridin-2(lH)-one (115 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 29: 4-(5-(4-fluoro-2.6-dimethylphenoxy)-l-isopropyl-2-oxo-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’35 herein. Preparation 43: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-isopropyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-l-isopropylpyridin-2(lH)-one (110 mg, 0.31 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 30: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l-(3,3,3- trifluoropropyl)-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’36 herein. Preparation 44: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l-(3,3,3-trifluoropropyl)- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)-l-(3,3,3-trifluoropropyl)pyridin-2(lH)-one (126 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro- 7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 31: 4-(l-(2-(dimethylamino)ethyl)-5-(4-fluoro-2,6- dimethylphenoxy)-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’37 herein.

Preparation 45: 4-(l-(2-(dimethylamino)ethyl)-5-(4-fluoro-2,6-dimethylphenoxy)-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(2-(dimethylamino)ethyl)-5- (4-fluoro-2,6-dimethylphenoxy)pyridin-2(lH)-one (119 mg, 0.31 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 32: 4-(l-(2-(dimethylamino)ethyl)-5-(4-fluoro-2,6- dimethylphenoxy)-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’38 herein. Preparation 46: 4-(l-cyclopropyl-5-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-cyclopropyl-5-(4-fluoro-2,6- dimethylphenoxy)pyridin-2(lH)-one (109 mg, 0.31 mmol) and 6-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 33: 2-(3-(2.6-dimethylphenoxy)-4-(6-methyl-7-oxo-6.7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)-2-oxopyridin-l(2H)-yl)-N,N-dimethylacetamide See for illustration the compound labelled NA1 herein.

Preparation 47: 2-(3-(2,6-dimethylphenoxy)-4-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)-2-oxopyridin-l(2H)-yl)-N,N-dimethylacetamide

Following the procedure in preparation 12, 2-(4-bromo-3-(2,6-dimethylphenoxy)-2- oxopyridin-l(2H)-yl)-N,N-dimethylacetamide (117 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 34: 4-(3-(2,6-dimethylphenoxy)-l-(oxetan-3-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA2 herein.

Preparation 48: 4-(3-(2,6-dimethylphenoxy)-l-(oxetan-3-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l- (oxetan-3-yl)pyridin-2(lH)-one (109 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound. Example 35: 4-(3-(2.6-dimethylphenoxy)-l-(l-methylpiperidin-4-yl)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one See for illustration the compound labelled NA3 herein.

Preparation 48: 4-(3-(2,6-dimethylphenoxy)-l-(l-methylpiperidin-4-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l-(l- methylpiperidin-4-yl)pyridin-2(lH)-one (121 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 36: 4-(3-(2,6-dimethylphenoxy)-l-(2-methoxyethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA4 herein.

Preparation 49: 4-(3-(2,6-dimethylphenoxy)-l-(2-methoxyethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l-(2- methoxyethyl)pyridin-2(lH)-one (109 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 37: 4-(3-(2.6-dimethylphenoxy)-l-(2-morpholinoethyl)-2-oxo-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA5 herein. Preparation 50: 4-(3-(2,6-dimethylphenoxy)-l-(2-morpholinoethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l-(2- morpholinoethyl)pyridin-2(lH)-one (126 mg, 0.31 mmol) and 6-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound. Example 38: 4-(3-(2.6-dimethylphenoxy)-l-ethyl-2-oxo-1.2-dihydropyridin-4- yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA6 herein.

Preparation 51: 4-(3-(2,6-dimethylphenoxy)-l-ethyl-2-oxo-l,2-dihydropyridin-4-yl)-6- methyI-l,6-dihydro-7H-pyrroIo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l- ethylpyridin-2(lH)-one (100 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 39: 4-(3-(2,6-dimethylphenoxy)-l-(2-hydroxy-2-methylpropyl)-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one See for illustration the compound labelled NA7 herein.

Preparation 52: 4-(3-(2,6-dimethylphenoxy)-l-(2-hydroxy-2-methylpropyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l-(2- hydroxy-2-methylpropyl)pyridin-2(lH)-one (113 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

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

See for illustration the compound labelled NA8 herein.

Preparation 53: 4-(l-(difluoromethyl)-3-(2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(difluoromethyl]-3-(2,6- dimethylphenoxy)pyridin-2(lH)-one (107 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 41: 4-(l-(3,3-difluorocyclobutyl)-3-(2,6-dimethylphenoxy)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

See for illustration the compound labelled NA9 herein.

Preparation 54: 4-(l-(3,3-difluorocyclobutyl)-3-(2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(3,3-difluorocyclobutyl]-3- (2,6-dimethylphenoxy)pyridin-2(lH)-one (119 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 42: 4-(3-(2.6-dimethylphenoxy)-l-(l-methylazetidin-3-yl)-2-oxo-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA10 herein. Preparation 55: 4-(3-(2,6-dimethylphenoxy)-l-(l-methylazetidin-3-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l-(l- methylazetidin-3-yl)pyridin-2(lH)-one (113 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 43: 4-(3-(2.6-dimethylphenoxy)-2-oxo-l-(2.2.2-trifluoroethyl)-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA11 herein.

Preparation 56: 4-(3-(2,6-dimethylphenoxy)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l- (2,2,2-trifluoroethyl)pyridin-2(lH)-one (117 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 44: 4-(3-(2,6-dimethylphenoxy)-l-(3-fhioropropyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA12 herein. Preparation 57: 4-(3-(2,6-dimethylphenoxy)-l-(3-fluoropropyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l-(3- fluoropropyl)pyridin-2(lH)-one (110 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 45: 4-(3-(2,6-dimethylphenoxy)-l-isopropyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one See for illustration the compound labelled NA13 herein.

Preparation 58: 4-(3-(2,6-dimethylphenoxy)-l-isopropyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l- isopropylpyridin-2(lH)-one (104 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 46: 4-(3-(2.6-dimethylphenoxy)-2-oxo-l-(3.3.3-trifluoropropyl)-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA14 herein.

Preparation 59: 4-(3-(2,6-dimethylphenoxy)-2-oxo-l-(3,3,3-trifluoropropyl)-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l- (3,3,3-trifluoropropyl)pyridin-2(lH)-one (121 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 47: 4-(l-(2-(dimethylamino)ethyl)-3-(2.6-dimethylphenoxy)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one See for illustration the compound labelled NA15 herein.

Preparation 60: 4-(l-(2-(dimethylamino)ethyl)-3-(2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(2-(dimethylamino)ethyl)-3- (2,6-dimethylphenoxy)pyridin-2(lH)-one (113 mg, 0.31 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 48: 4-(l-cyclopropyl-3-(2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA16 herein.

Preparation 61: 4-(l-cyclopropyl-3-(2,6-dimethylphenoxy)-2-oxo-l,2-dihydropyridin- 4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-cyclopropyl-3-(2,6- dimethylphenoxy)pyridin-2(lH)-one (103 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 49: 2-(3-(4-fluoro-2,6-dimethylphenoxy)-4-(6-methyl-7-oxo-6,7- dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-2-oxopyridin-l(2H)-yl)-N,N- dimethylacetamide See for illustration the compound labelled NA23 herein.

Preparation 62: 2-(3-(4-fluoro-2,6-dimethylphenoxy)-4-(6-methyl-7-oxo-6, 7-dihydro- lH-pyrrolo[2,3-c]pyridin-4-yl)-2-oxopyridin-l(2H)-yl)-N,N-dimethylacetamide

Following the procedure in preparation 12, 2-(4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-2-oxopyridin-l(2H)-yl)-N,N-dimethylacetamide (123 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6- dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 50: 4-(3-(4-fluoro-2.6-dimethylphenoxy)-l-(oxetan-3-yl)-2-oxo-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA24 herein.

Preparation 63: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-(oxetan-3-yl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-l-(oxetan-3-yl)pyridin-2(lH)-one (114 mg, 0.31 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 51: 4-(3-(4-fluoro-2.6-dimethylphenoxy)-l-(l-methylpiperidin-4-yl)- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

See for illustration the compound labelled NA25 herein.

Preparation 64: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-(l-methylpiperidin-4-yl)-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-l-(l-methylpiperidin-4-yl)pyridin-2(lH)-one (127 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6- dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 52: 4-(3-(4-fluoro-2.6-dimethylphenoxy)-l-(2-methoxyethyl)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

See for illustration the compound labelled NA26 herein.

Preparation 65: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-(2-methoxyethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-l-(2-methoxyethyl)pyridin-2(lH)-one (115 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 53: 4-(3-(4-fluoro-2.6-dimethylphenoxy)-l-(2-morpholinoethyl)-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one See for illustration the compound labelled NA27 herein.

Preparation 66: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-(2-morpholinoethyl)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-l-(2-morpholinoethyl)pyridin-2(lH)-one (132 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro- 7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 54: 4-(l-ethyl-3-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA28 herein.

Preparation 67: 4-(l-ethyl-3-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-ethyl-3-(4-fluoro-2,6- dimethylphenoxy)pyridin-2(lH)-one (105 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 55: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-(2-hydroxy-2- methylpropyl)-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one See for illustration the compound labelled NA29 herein.

Preparation 68: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-(2-hydroxy-2-methylpropylJ-

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-l-(2-hydroxy-2-methylpropyl)pyridin-2(lH)-one (119 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6- dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 56: 4-(l-(difluoromethyl)-3-(4-fluoro-2.6-dimethylphenoxy)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

See for illustration the compound labelled NA30 herein. Preparation 69: 4-(l-(difluoromethyl)-3-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(difluoromethyl]-3-(4- fluoro-2,6-dimethylphenoxy)pyridin-2(lH)-one (112 mg, 0.31 mmol) and 6-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 57: 4-(l-(3.3-difluorocyclobutyl)-3-(4-fluoro-2.6-dimethylphenoxy)-

2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

See for illustration the compound labelled NA31 herein.

Preparation 70: 4-(l-(3,3-difluorocyclobutyl)-3-(4-fluoro-2,6-dimethylphenoxy)-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(3,3-difluorocyclobutyl]-3- (4-fluoro-2,6-dimethylphenoxy)pyridin-2(lH)-one (125 mg, 0.31 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 58: 4-(3-(4-fluoro-2.6-dimethylphenoxy)-l-(l-methylazetidin-3-yl)- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one See for illustration the compound labelled NA32 herein.

Preparation 71/ 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-(l-methylazetidin-3-yl)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-l-(l-methylazetidin-3-yl)pyridin-2(lH)-one (118 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6- dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 59: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l-(2,2,2- trifluoroethyl)-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA33 herein.

Preparation 72: 4-(3-(4-fluoro-2,6-dimethylphenoxyJ-2-oxo-l-(2,2,2-trfluoroethylJ- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-l-(2,2,2-trifluoroethyl)pyridin-2(lH)-one (122 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro- 7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 60: 4-(3-(4-fluoro-2.6-dimethylphenoxy)-l-(3-fluoropropyl)-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

See for illustration the compound labelled NA34 herein.

Preparation 73: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-(3-fluoropropyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-l-(3-fluoropropyl)pyridin-2(lH)-one (115 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 61: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-isopropyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA35 herein. Preparation 74: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-isopropyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-l-isopropylpyridin-2(lH)-one (110 mg, 0.31 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound. Example 62: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l-(3,3,3- trifluoropropyl)-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA36 herein. Preparation 75: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l-(3,3,3-trifluoropropyl)- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)-l-(3,3,3-trifluoropropyl)pyridin-2(lH)-one (126 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro- 7H-pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 63: 4-(l-(2-(dimethylamino)ethyl)-3-(4-fluoro-2,6- dimethylphenoxy)-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA37 herein.

Preparation 76: 4-(l-(2-(dimethylamino)ethyl)-3-(4-fluoro-2,6-dimethylphenoxy)-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-(2-(dimethylamino)ethyl)-3- (4-fluoro-2,6-dimethylphenoxy)pyridin-2(lH)-one (119 mg, 0.31 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) react to give the title compound.

Example 64: 4-(l-cyclopropyl-3-(4-fluoro-2.6-dimethylphenoxy)-2-oxo-1.2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA38 herein. Preparation 77: 4-(l-cyclopropyl-3-(4-fluoro-2,6-dimethylphenoxy)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-l-cyclopropyl-3-(4-fluoro-2,6- dimethylphenoxy)pyridin-2(lH)-one (109 mg, 0.31 mmol) and 6-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (124 mg, 0.29 mmol) react to give the title compound. Process Example 1: N-ethyl-4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Preparation 78: ethyl 4-bromo-6-methyl-7-oxo-l-tosyl-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxylate

4-Bromo-6-methyl-l-tosyl-l,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 drop wise and the resulting solution stirred at this temperature for 30 minutes. Ethyl carbonochloridate (0.39 mL, 4.06 mmol) was added and the reaction stirred for 1 hour at -78 °C. Ethyl acetate (500 ml) was added and the organics washed with 2 x 500 ml water then 1 x 500 ml saturated brine solution. The organics were then separated and dried (MgSO₄) before concentration to dryness. The crude was then purified by flash column chromatography eluting with ethyl acetate/heptane gradient (0-100%). The desired fractions were combined and dried to afford the title compound (770 mg, 50%).

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

Preparation 79: ethyl 6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- l-tosyl-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxylate

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

HPLC t_R (Agilent, acidic, 3.5 min): 2.10 min, m/z = 501.1 [M+H]⁺. Preparation 80: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxylic acid

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)pyridin-2(lH)-one (285 mg, 0.87 mmol) and ethyl 6-methyl-7- oxo-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylate (436 mg, 0.87 mmol) was reacted to give the title compound (112 mg, 29%).

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

Preparation 81: N-ethyl-4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

To a solution of 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-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). Reaction was stirred for lh at room temperature. Solvent removed under reduced pressure and THF (1 mL) added. 30% ethylamine solution (0.11 mL, 0.23 mmol) in THF was added and the resulting solution stirred for 2h at room temperature. Ethyl acetate (50 ml) was added and the organics washed with 2 x 50 ml water then 1 x 50 ml saturated brine solution. The organics were then separated and dried (MgSCH) before concentration to dryness. The crude was then purified by flash column chromatography eluting with ethyl acetate /heptane gradient (0-100%). The desired fractions were combined and dried to afford the title compound (12 mg, 42%).

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

12.25 (bs, 1H), 8.34 (t, J=5.3 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.41 (s, 1H), 6.90 (s, 1H), 6.70 - 6.67 (m, 2H), 6.33 - 6.31 (m, 1H), 3.56 (s, 3H), 3.45 (s, 3H), 3.28 - 3.30 (m, 2H), 2.00 (s, 6H), 1.14 (t, J=7.2 Hz, 3H).

Process example 2: N-(tert-butyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Preparation 82: N-(tert-butyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6- dimethylpheno xy)-l-methyl-2 -oxo-1, 2 -dihydropyridin-4-yl)-6-methyl-7-oxo-6, 7- dihydro-lH-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) was reacted to give the title compound (3 mg, 16%).

HPLC t_R (Agilent, acidic, 3.5 min): 1.54 min, m/z = 493.2 [M+H]⁺. ¹H ¹H NMR (400 MHz, DMSO-d6) δ 12.36 (bs, 1H), 7.84 (s, 1H), 7.56 (d, J=7.2 Hz, 1H), 7.43 (s, 1H), 6.89 (d, J=l.l Hz, 1H), 6.71 - 6.67 (m, 2H), 6.33 (d, J=7.0 Hz, 1H), 3.57 (s, 3H), 3.45 (s, 3H), 2.01 - 2.00 (m, 6H), 1.39 (s, 9H). Process example 3: N-(tert-butyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Preparation 83: N-(tert-butyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7- dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid (15.6 mg, 0.04 mmol) and l,l,l-trifluoro-2-methylpropan-2 -amine (18.3 mg, 0.14 mmol) was reacted to give the title compound (5 mg, 23%).

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

¹H NMR (400 MHz, DMSO-d6) δ 12.49 (bs, 1H), 8.06 (s, 1H), 7.57 (d, J=7.1 Hz, 1H), 7.44 (s, 1H), 7.00 (d, J=2.2 Hz, 1H), 6.70 - 6.67 (m, 2H), 6.33 (d, J=7.1 Hz, 1H), 3.57 (s, 3H), 3.45 (s, 3H), 2.01 (s, 6H), 1.63 (s, 6H).

Process example 4: N-(2,2-difluoro-l-methylcyclopropyl)-4-(3-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

Preparation 84: N-(2,2-difluoro-l-methylcyclopropyl)-4-(3-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7- dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7- dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid (15.6 mg, 0.04 mmol) and 2,2- difluoro-l-methylcyclopropan-l-amine hydrochloride (20.5 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) was reacted to give the title compound (3 mg, 14%).

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

¹H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.79 (s, 1H), 7.57 (d, J=7.1 Hz, 1H), 7.43 (s, 1H), 6.96 (d, J=2.2 Hz, 1H), 6.70 - 6.66 (m, 2H), 6.33 (d, J=7.1 Hz, 1H), 3.55 (s, 3H), 3.45 (s, 3H), 2.00 (s, 6H), 1.71 - 1.62 (m, 2H), 1.48 (s, 3H).

Example 65: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-

4-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

See for illustration the compound labelled AA’l herein.

Preparation 85: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-

N-ethyl-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6- methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c] pyridine-2 -carboxylic acid (0.1g, 0.238mmol) was dissolved in THF(4.0mL) under nitrogen. Triethylamine (0.12mL, 1.19mmoL) was added to the reaction mixture and the resulting suspension was allowed to stir at 0 °C for 30 min. Propylphosphonic anhydride (0.758mL, 1.15mmoL) was added to the reaction mixture at 0 °C and allowed to stir for 30 min. Ethylamine hydrochloride (0.053 g, 1.19mmoL) was added to the reaction mixture and heated 100 °C for 16 h. TLC (9.5:0.5:0.1 DCM: MeOH: NH3) showed no starting material remaining. The reaction mixture was cooled at RT and neutralized by NaHCO₃ solution (50mL). The mixture was stirred for 5 min before separating the phases. The aqueous phase was extracted with ethyl acetate (3 x 50mL). The combined organics were washed (brine), dried (Na₂SO₄), filtered and evaporated. The residue was purified on silica, eluting with 54:46 water/ aceto nitrile. Solvent was removed to give the title compound as a brown solid (0.05g, 46.97%).

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.479min, m/z =447.17 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 5.988min 1H ¹H NMR: (400 MHz, DMSO) δ 12.36(s, 1H), 8.41-8.38(t, J = 5.6 Hz, 1H), 7.54(s, 1H), 7.11-7.09(m, 2H), 7.06-7.04(m, 1H), 6.99(s, 1H), 6.68(s, 1H), 6.54(s, 1H), 3.58(s, 3H), 3.49-3.46(m, 2H), 3.29-3.25(m, 3H), 2.07(s, 6H), 1.41-1.10(t, J = 7.2 Hz, 3H).

Example 66: N-(tert-butyl)-4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide

See for illustration the compound labelled AA’2 herein.

Preparation 86: N-(tert-butyl)-4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(5-(2,6-dimethylphenoxy)-l-methyl-

2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-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) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, Acidic, 4.0min): 1.69min, m/z = 475.2 [M+1H] +.m

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.881min ¹H ¹H NMR: (400 MHz, DMSO) δ 12.44(s, 1H), 7.88(s, 1H), 7.53(s, 1H), 7.11 (d, J = 7.4 Hz, 2H), 7.06(m, 1H), 6.98 (s, 1H), 6.67(s, 1H), 6.53(s, 1H), 3.59(s, 3H), 3.30(s, 3H), 2.08(s, 6H), 1.37(s, 9H)

Example 67: N-(bicyclo[l.l.l]pentan-l-yl)-4-(5-(2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’3 herein.

Preparation 87: N-(bicyclo[l.l.l]pentan-l-yl)-4-(5-(2,6-dimethylphenoxy)-l-methyl-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 85, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (15.6 mg, 0.04 mmol) and bicyclo[l.l.l]pentan-l- amine hydrochloride (16.7 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.682min, m/z =485.22 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min):

6.859min ¹H ¹H NMR: (400 MHz, DMSO) δ 12.31(s, 1H), 8.92(s, 1H), 7.54(s, 1H), 7.11(d, J = 7.2 Hz, 2H), 7.06 - 7.04(m, 1H), 7.01(s, 1H), 6.68 (s, 1H), 6.54 (s, 1H), 3.57(s, 3H), 3.33(s, 3H), 2.46(s, 2H), 2.07(s, 11H).

Example 68: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin- 4-yl)-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

See for illustration the compound labelled AA’4 herein.

Preparation 88: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)- 6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (15.6 mg, 0.04 mmol) and 2,2,2-trifluoroethan-l-amine (0.011 mL, 0.14 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.641min, m/z =501.12 [M+1H] ⁺.

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.513min 1H ¹H NMR (400 MHz, DMSO) δ 12.60(s, 1H), 9.02(s, 1H), 7.56(s, 1H), 7.14(s, 1H), 7.11(d, J = 7.3 Hz, 2H), 7.08 - 7.02(m, 1H), 6.70(s, 1H), 6.56(s, 1H), 4.13 - 4.09(m, 2H), 3.59(s, 3H), 3.32(s, 3H), 2.07(s, 6H).

Example 69: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-

4-yl)-N-isopropyl-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide See for illustration the compound labelled AA’5 herein.

Preparation 89: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-

6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7- oxo-6, 7-dihydro-lH-pyrrolo[2,3-c] pyridine-2 -carboxylic acid (0.200g, 0.477mmol) was dissolved in DMF (2.0mL) under argon. EDC.HC1 (0.274g, 1.4mmoL) was added to the reaction mixture followed by HOBT (0.193g, 1.4mmoL) at room temperature and allowed stir for 45 min. Propan-2 -amine (83mg, 1.4mmol) was added to the reaction mixture and allowed to stir for 2 h. TLC (9.5:0.5:0.1 DCM: MeOH: NH3) showed no starting material remaining. The mixture was neutralized by NaHCO3 solution (50mL). The mixture was stirred for 5 min before separating the phases. The aqueous phase was extracted with ethyl acetate (3 x 50mL). The combined organics were washed (brine), dried (Na2SO4), filtered and evaporated. The residue was purified on silica, eluting with 69:31 water/acetonitrile. Solvent was removed to give the title compound as a pale-yellow solid (0.83g, 34.7%)

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, Acidic, 4.0min): 1.555 min, m/z = 461.17 [M+1H] ⁺.

HPLC t_R (Waters Alliance e2695 with 2998 detector, 17.0min): 6.326 min 1H ¹H NMR (400 MHz, DMSO): 8 12.382 (s, 1H), 8.250-8.232 (d, / = 7.2 Hz, 1H), 7.546 (s, 1H), 7118-7.099 (m, 2H), 7.065-7.010 (m, 2H), 6.697 (s, 1H), 6.559 (s, 1H), 3.586 (s, 3H), 3.332 (s, 3H), 2.077 (s, 6H), 1.228 (s, 1H), 1.165-1.149 (d, J = 6.4 Hz, 6H). Example 70: N-cyclobutyl-4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide

See for illustration the compound labelled AA’6 herein.

Preparation 90: N-cyclobutyl-4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 85, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (0.250g, 0.59mmol) and cyclobutanamine (0.19 mL, 2.24 mmol) was reacted to give the title compound (0.155g, 55.03%).

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.617min, m/z =473.17 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.608min 1H ¹H NMR: (400 MHz, DMSO) δ 12.36(s, 1H), 8.60(d, J = 7.6 Hz, 1H), 7.54(s, 1H), 7.11 - 7.01 (m, 4H), 6.68(s, 1H), 6.54(s, 1H), 4.38(dd, J = 15.8, 7.9 Hz, 1H), 3.58(s, 3H), 3.30(s 3H), 2.24- 2.22(m, 2H), 2.07(s, 6H), 2.02 - 1.97(m, 2H), 1.67(dd, J = 15.9, 8.5 Hz, 2H).

Example 71: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin- 4-yl)-6-methyl-N-(2-morpholinoethyl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

See for illustration the compound labelled AA’7 herein. Preparation 91: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)- 6-methyl-N-(2-morpholinoethyl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 85, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (15.6 mg, 0.04 mmol) and 2-morpholinoethan-l-amine (0.018 mL, 0.14 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.218min, m/z =532.2 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 5.622min ¹H ¹H NMR: (400 MHz, DMSO) δ 12.44(s, 1H), 8.40(s, 1H), 7.54(s, 1H), 7.11-7.09(m, 2H), 7.06-7.02(m, 1H), 6.99(s, 1H), 6.68(s, 1H), 6.54(s, 1H), 3.58-3.47(m, 8H), 3.32(s, 4H), 2.32(s, 6H), 2.07(s, 6H).

Example 72: N-(2-(dimethylamino)ethyl)-4-(5-(2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’8 herein.

Preparation 92: N-(2-(dimethylamino)ethyl)-4-(5-(2,6-dimethylphenoxy)-l-methyl-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 85, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (15.6 mg, 0.04 mmol) and N,N-dimethylethane-l,2- diamine (0.015 mL, 0.14 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.223min, m/z =489.24 [M] ⁺.

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.076min 1H ¹H NMR (400 MHz, DMSO) δ 12.46(s, 1H), 8.39(t, J = 5.3 Hz, 1H), 7.55(s, 1H), 7.11(d, J = 7.3 Hz, 2H), 7.04(dd, J = 8.5, 6.3 Hz, 1H), 7.00(s, 1H), 6.68(s, 1H), 6.54(s, 1H), 3.59(s, 3H), 3.37 - 3.32 (m, 5H), 2.40 (t, J = 6.4 Hz, 2H), 2.19 (s, 6H), 2.08 (s, 6H).

Example 73: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin- 4-yl)-6-methyl-N-(l-methylpiperidin-4-yl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

See for illustration the compound labelled AA’9 herein.

Preparation 93: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)- 6-methyl-N-(l-methylpiperidin-4-yl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 85, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (15.6 mg, 0.04 mmol) and l-methylpiperidin-4-amine (0.018 mL, 0.14 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.22min, m/z =516.25 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.18min 1H ¹H NMR: (400 MHz, DMSO) δ 12.40 (s, 1H), 8.26(d, J = 6.7 Hz, 1H), 7.54(s, 1H), 7.07(m, 4H), 6.68(s, 1H), 6.54(s, 1H), 3.71(s, 1H), 3.31(s, 3H), 3.58(s, 3H), 2.76 (d, J = 10.0 Hz, 2H), 2.18(d, J = 35.7 Hz, 3H), 2.07(s, 6H), 2.02(m, 2H), 1.81-1.78(d, J = 10.5 Hz, 2H), 1.51(d, J = 10.5 Hz, 2H).

Example 74: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin- 4-yl)-6-methyl-N-(l-methylpiperidin-3-yl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

See for illustration the compound labelled AA’10 herein.

Preparation 94: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)- 6-methyl-N-(l-methylpiperidin-3-yl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 89, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (15.6 mg, 0.04 mmol) and l-methylpiperidin-3 -amine (0.018 mL, 0.14 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.24min, m/z =516.13 [M+1H] ⁺ HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.280min 1H ¹H NMR: (400 MHz, DMSO) 8 12.48(s, 1H), 8.24-8.22(d, J = 7.6 Hz, 1H), 7.53(s, 1H), 7.11-7.09(m, 2H), 7.06-7.04(m, 1H), 7.010(s, 1H), 6.67(s, 1H), 6.54(s, 1H), 3.92(s, 1H), 3.58(m, 3H), 3.30(s, 3H), 2.77-2.72(m, 2H), 2.16(s, 3H), 2.07(s, 6H), 1.95(m, 3H), 1.73(m, 3H)

Example 75: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin- 4-yl)-6-methyl-N-(l-methylazetidin-3-yl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

See for illustration the compound labelled AA’ll herein.

Preparation 95: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)- 6-methyl-N-(l-methylpiperidin-3-yl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 89, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (15.6 mg, 0.04 mmol) and l-methylazetidin-3 -amine (0.013 mL, 0.14 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.20min, m/z =487.22 [M] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Acidic, 17.0min): 5.34min 1H ¹H NMR: (400 MHz, DMSO) δ 12.43 (s, 1H), 8.75 (d, J = 6.6 Hz, 1H), 7.54 (s, 1H), 7.08 (dd, J = 23.5, 9.6 Hz, 4H), 6.69 (s, 1H), 6.55 (s, 1H), 4.41 (dd, J = 13.9, 6.9 Hz, 1H), 3.62 - 3.51 (m, 5H), 3.33 (d, J = 7.5 Hz, 3H), 2.89 (t, J = 7.0 Hz, 2H), 2.24 (s, 3H), 2.07 (s, 6H). Example 76: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin- 4-yl)-6-methyl-7-oxo-N-(l-(trifluoromethyl)cyclopropyl)-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’12 herein.

Preparation 96: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)- 6-methyl-7-oxo-N-(l-(trifluoromethyl)cyclopropyl)-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 85, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (0.3g, 0.715mmol) and 1- (trifluoromethyl)cyclopropan-l-amine hydrochloride (437 mg, 2.69 mmol) and DIPEA (0.36 mL, 2.69 mmol) was reacted to give the title compound (0.145g, 38.5%).

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.675min, m/z =527.22 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min):

6.713min 1H ¹H NMR (400 MHz, DMSO) δ 12.49(s, 1H), 9.13(s, 1H), 7.55(d, J = 16.8 Hz, 1H), 7.14 - 7.02(m, 4H), 6.70(s, 1H), 6.55(s, 1H), 3.58(s, 3H), 3.32(s, 3H), 2.07(s, 6H), 1.32 (t, J = 6.6 Hz, 2H), 1.16 - 1.15 (m, 2H).

Example 77: N-(4,4-difluorocyclohexyl)-4-(5-(2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide See for illustration the compound labelled AA’13 herein.

Preparation 97: N-(4,4-difluorocyclohexyl)-4-(5-(2,6-dimethylphenoxy)-l-methyl-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 89, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (0.250g, 0.59mmol) and 4,4-difluorocyclohexan-l- amine hydrochloride (383 mg, 2.24 mmol) and DIPEA (30 mL, 2.24 mmol) was reacted to give the title compound (0.207g, 64.72%) .

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.735min, m/z =537.21 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.950min

1H ¹H NMR: (400 MHz, DMSO) δ 12.18(s, 1H), 8.28(d, J = 7.6 Hz, 1H), 7.54(s, 1H), 7.11(d, J = 7.3 Hz, 2H), 7.05 - 7.02(m, 2H), 6.68(s, 1H), 6.54(s, 1H), 4.01-3.97(m, 1H), 3.58(s, 3H), 3.34(d, J = 6.8 Hz, 3H), 2.07(s, 9H), 1.91(m, 3H), 1.64-1.55 (m, 2H).

Example 78: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin- 4-yl)-6-methyl-7-oxo-N-(l,l,l-trifluoro-2-methylpropan-2-yl)-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’14 herein.

Preparation 98: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)- 6-methyl-7-oxo-N-(l,l,l-trifluoro-2-methylpropan-2-yl)-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 85, 4-(5-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (0.3g, 0.715mmol) and l,l,l-trifluoro-2-methylpropan- 2 -amine (352 mg, 2.69 mmol) was reacted to give the title compound (0.108g, 28.57%).

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.795min, m/z =529.27 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min):

7.220min 1H ¹H NMR (400 MHz, DMSO) δ 12.58(s, 1H), 8.11(s, 1H), 7.55(s, 1H), 7.11 - 7.04(m, 4H), 6.68(s, 1H), 6.54(s, 1H), 3.59(s, 3H), 3.31(s, 3H), 2.07(s, 6H), 1.61(s, 6H).

Example 79: N-(2,2-difluoro-l-methylcyclopropyl)-4-(5-(2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’15 herein.

Preparation 99: N-(2,2-difluoro-l-methylcyclopropyl)-4-(5-(2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6- methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c] pyridine-2 -carboxylic acid (0.150g, 0.357mmol) and 2,2-difluoro-l-methylcyclopropan-l-amine hydrochloride (0.261g, 1.78mmol) were dissolved in DCM (4.5mL) under nitrogen. Pyridine (0.426g, 5.369mmoL) was added to the reaction mixture at 0 °C and followed by drop wise addition of POCI3 (0.383g, 2.505mmol) at same temperature. The resulting suspension was allowed to stir at room temperature for 2 h. TLC (9:1 DCM: MeOH) showed no starting material remaining. The resulting solution was directly concentrated to vacuum reduced pressure and residue was purified on silica, eluting with 65:35 Water/Acetonitrile. Solvent was removed to give the title compound as a solid (0.060g, 34.64%)

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.646min, m/z =509.17 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 6.172min

1H ¹H NMR (400 MHz, DMSO) δ 12.48(s, 1H), 8.86(s, 1H), 7.55(s, 1H), 7.11- 7.02(m, 4H), 6.69(s, 1H), 6.55(s, 1H), 3.58(s, 3H), 3.31(s, 3H), 2.07(s, 6H), 1.73 - 1.59(m, 2H), 1.45(s, 3H).

Example 80: N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

See for illustration the compound labelled AA’16 herein.

Preparation 100: N-ethyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and 30% ethylamine solution (0.07 mL, 0.14 mmol) in THF react to give the title compound.

Example 81: N-(tert-butyl)-4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

See for illustration the compound labelled AA’17 herein.

Preparation 101: N-(tert-butyl)-4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and 2-amino-2- methylpropane (0.015 mL, 0.14 mmol) react to give the title compound.

Example 82: N-(bicyclo[l.l.l]pentan-l-yl)-4-(5-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’18 herein.

Preparation 102: N-(bicyclo[l.l.l]pentan-l-yl)-4-(5-(4-fluoro-2,6-dimethylphenoxy)- l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and bicyclo[l.l.l]pentan-l-amine hydrochloride (16.7 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Example 83: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’19 herein.

Preparation 103: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxylic acid (17.5 mg, 0.04 mmol) and 2,2,2-trifluoroethan-l-amine (0.011 mL, 0.14 mmol) react to give the title compound. Example 84: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-N-isopropyl-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’20 herein.

Preparation 104: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-N-isopropyl-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and propan-2 -amine (0.012 mL, 0.14 mmol) react to give the title compound.

Example 85: N-cyclobutyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

See for illustration the compound labelled AA’21 herein.

Preparation 105: N-cyclobutyl-4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and cyclobutanamine (0.012 mL, 0.14 mmol) react to give the title compound.

Example 86: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(2-morpholinoethyl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’22 herein.

Preparation 106: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(2-morpholinoethyl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and 2-morpholinoethan-l-amine (0.018 mL, 0.14 mmol) react to give the title compound.

Example 87: N-(2-(dimethylamino)ethyl)-4-(5-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’23 herein.

Preparation 107: N-(2-(dimethylamino)ethyl)-4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and N,N-dimethylethane-l, 2 -diamine (0.015 mL, 0.14 mmol) react to give the title compound.

Example 88: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylpiperidin-4-yl)-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’24 herein.

Preparation 108: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylpiperidin-4-yl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and l-methylpiperidin-4-amine (0.018 mL, 0.14 mmol) react to give the title compound. Example 89: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylpiperidin-3-yl)-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’25 herein.

Preparation 109: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylpiperidin-3-yl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and l-methylpiperidin-3 -amine (0.018 mL, 0.14 mmol) react to give the title compound.

Example 90: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylazetidin-3-yl)-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’26 herein.

Preparation 110: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylazetidin-3-yl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and l-methylazetidin-3 -amine (0.013 mL, 0.14 mmol) react to give the title compound.

Example 91: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(l-(trifluoromethyl)cyclopropyl)-6,7- dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’27 herein.

Preparation 111: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(l-(trifluoromethyl)cyclopropyl)-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and l-(trifluoromethyl)cyclopropan-l-amine hydrochloride (22.7 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Example 92: N-(4,4-difluorocyclohexyl)-4-(5-(4-fluoro-2,6-dimethylphenoxy)- l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’28 herein.

Preparation 112: N-(4,4-difluorocyclohexyl)-4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and

4,4-difluorocyclohexan-l-amine hydrochloride (23.9 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Example 93: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(l,l,l-trifluoro-2-methylpropan-2- yl)-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’29 herein.

Preparation 113: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(l,l,l-tnfluoro-2-methylpropan-2-yl)-6,7- dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and l,l,l-trifluoro-2-methylpropan-2 -amine (18.3 mg, 0.14 mmol) react to give the title compound. Example 94: N-(2,2-difluoro-l-methylcyclopropyl)-4-(5-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA’30 herein.

Preparation 114: N-(2,2-difluoro-l-methylcyclopropyl)-4-(5-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7- dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

2,2-difluoro-l-methylcyclopropan-l-amine hydrochloride (20.5 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Example 95: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin- 4-yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

See for illustration the compound labelled AA1 herein.

Preparation 115: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and

30% ethylamine solution (0.07 mL, 0.14 mmol) in THF react to give the title compound.

Example 96: N-(tert-butyl)-4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide

See for illustration the compound labelled AA2 herein.

Preparation 116: N-(tert-butyl)-4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

2 -amino-2 -methylpropane (0.015 mL, 0.14 mmol) react to give the title compound.

Example 97: N-(bicyclo[l.l.l]pentan-l-yl)-4-(3-(2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA3 herein.

Preparation 117: N-(bicyclo[l.l.l]pentan-l-yl)-4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and bicyclo[l.l.l]pentan-l-amine hydrochloride (16.7 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Example 98: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin- 4-yl)-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

See for illustration the compound labelled AA4 herein.

Preparation 118: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and 2,2,2-trifluoroethan-l-amine (0.011 mL, 0.14 mmol) react to give the title compound. Example 99: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin- 4-yl)-N-isopropyl-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

See for illustration the compound labelled AA5 herein.

Preparation 119: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-N-isopropyl-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and propan-2 -amine (0.012 mL, 0.14 mmol) react to give the title compound.

Example 100: N-cyclobutyl-4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide

See for illustration the compound labelled AA6 herein.

Preparation 120: N-cyclobutyl-4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and cyclobutanamine (0.012 mL, 0.14 mmol) react to give the title compound.

Example 101: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(2-morpholinoethyl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA7 herein.

Preparation 121 : 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-N-(2-morpholinoethyl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and 2-morpholinoethan-l-amine (0.018 mL, 0.14 mmol) react to give the title compound.

Example 102: N-(2-(dimethylamino)ethyl)-4-(3-(2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA8 herein.

Preparation 122: N-(2-(dimethylamino)ethyl)-4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and N,N-dimethylethane-l,2- diamine (0.015 mL, 0.14 mmol) react to give the title compound.

Example 103: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylpiperidin-4-yl)-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA9 herein.

Preparation 123: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-N-(l-methylpiperidin-4-yl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide

Followingthe procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and l-methylpiperidin-4-amine (0.018 mL, 0.14 mmol) react to give the title compound.

Example 104: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylpiperidin-3-yl)-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide See for illustration the compound labelled AA10 herein.

Preparation 124: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-N-(l-methylpiperidin-3-yl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide

Followingthe procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and l-methylpiperidin-3 -amine (0.018 mL, 0.14 mmol) react to give the title compound.

Example 105: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylazetidin-3-yl)-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA11 herein.

Preparation 125: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-N-(l-methylazetidin-3-yl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine- 2-carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl-

2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and l-methylazetidin-3 -amine (0.013 mL, 0.14 mmol) react to give the title compound.

Example 106: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(l-(trifluoromethyl)cyclopropyl)-6,7- dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA12 herein.

Preparation 126: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-7-oxo-N-(l-(trifluoromethyl)cyclopropyl)-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and 1- (trifluoromethyl)cyclopropan-l-amine hydrochloride (22.7 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Example 107: N-(4,4-difluorocyclohexyl)-4-(3-(2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA13 herein.

Preparation 127: N-(4,4-difluorocyclohexyl)-4-(3-(2,6-dimethylphenoxy)-l-methyl-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and 4,4-difluorocyclohexan-l- amine hydrochloride (23.9 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Example 108: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(l,l,l-trifluoro-2-methylpropan-2- yl)-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA14 herein.

Preparation 128: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-7-oxo-N-(l,l,l-trifluoro-2-methylpropan-2-yl)-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and l,l,l-trifluoro-2- methylpropan-2 -amine (18.3 mg, 0.14 mmol) react to give the title compound. Example 109: N-(2,2-difluoro-l-methylcyclopropyl)-4-(3-(2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA15 herein.

Preparation 129: N-(2,2-difluoro-l-methylcyclopropyl)-4-(3-(2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(2,6-dimethylphenoxy)-l-methyl- 2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2 -carboxylic acid (16.8 mg, 0.04 mmol) and 2,2-difluoro-l- methylcyclopropan-l-amine hydrochloride (20.5 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Example 110: N-(bicyclo[l.l.l]pentan-l-yl)-4-(3-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA16 herein.

Preparation 130: N-(bicyclo[l.l.l]pentan-l-yl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)- l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and bicyclo[l.l.l]pentan-l-amine hydrochloride (16.7 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Example 111: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA17 herein.

Preparation 131: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and 2,2,2- trifluoroethan-1 -amine (0.011 mL, 0.14 mmol) react to give the title compound. Example 112: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-N-isopropyl-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA18 herein.

Preparation 132: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-N-isopropyl-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and propan-2 -amine (0.012 mL, 0.14 mmol) react to give the title compound.

Example 113: N-cyclobutyl-4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2- oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

See for illustration the compound labelled AA19 herein.

Preparation 133: N-cyclobutyl-4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2- carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and cyclobutanamine (0.012 mL, 0.14 mmol) react to give the title compound.

Example 114: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(2-morpholinoethyl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA20 herein.

Preparation 134: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(2-morpholinoethyl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and 2- morpholinoethan-l-amine (0.018 mL, 0.14 mmol) react to give the title compound.

Example 115: N-(2-(dimethylamino)ethyl)-4-(3-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA21 herein.

Preparation 135: N-(2-(dimethylamino)ethyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and N,N- dimethylethane-1, 2 -diamine (0.015 mL, 0.14 mmol) react to give the title compound.

Example 116: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylpiperidin-4-yl)-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA22 herein.

Preparation 136: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylpiperidin-4-yl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and 1- methylpiperidin-4-amine (0.018 mL, 0.14 mmol) react to give the title compound. Example 117: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-6-methyl-N-(l-methylpiperidin-4-yl)-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA23 herein.

Preparation 137: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-6-methyl-N-(l-methylpiperidin-4-yl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and 1- methylpiperidin-4-amine (0.018 mL, 0.14 mmol) react to give the title compound.

Example 118: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylazetidin-3-yl)-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA24 herein.

Preparation 138: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-N-(l-methylazetidin-3-yl)-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and 1- methylazetidin-3 -amine (0.013 mL, 0.14 mmol) react to give the title compound.

Example 119: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(l-(trifluoromethyl)cyclopropyl)-6,7- dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA25 herein.

Preparation 139: 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-7-oxo-N-(l-(trifluoromethyl)cyclopropyl)-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and 1- (trifluoromethyl)cyclopropan-l-amine hydrochloride (22.7 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Example 120: N-(4,4-difluorocyclohexyl)-4-(3-(4-fluoro-2,6- dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo- 6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide

See for illustration the compound labelled AA26 herein.

Preparation 140: N-(4,4-difluorocyclohexyl)-4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxamide

Following the procedure in preparation 81, 4-(3-(4-fluoro-2,6-dimethylphenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-3-yl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2,3 -c]pyridine-2 -carboxylic acid (17.5 mg, 0.04 mmol) and 4,4- difluorocyclohexan-l-amine hydrochloride (23.9 mg, 0.14 mmol) and DIPEA (0.019 mL, 0.14 mmol) react to give the title compound.

Comparative Example 3: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one

Preparation 141: 2-chloro-5-(4-fluoro-2,6-dimethylphenoxy)-4-nitropyridine 1-oxide

Following the procedure in preparation 7, 4-fluoro-2,6-dimethylphenol (15.0 g, 77.9 mmol) wasreacted to give the title compound (16.0 g, 64%).

¹H NMR (400 MHz, CDC13) δ 8.25 (s, 1H), 7.69 (s, 1H), 6.88 (d,J = 8.4 Hz, 2H), 2.183 (s, 6H).

Preparation 142: 2,4-dibromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridine 1-oxide

Following the procedure in preparation 8, 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%).

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

Preparation 143: 2, 4-dibromo-5-(4-fluoro-2,6-dimethylphenoxy) pyridine

Following the procedure in preparation 9, 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%).

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

Preparation 144: 4-bromo-5-(4-fluoro-2,6-dimethylphenoxy)pyridin-2(1H)-one

Following the procedure in preparation 10, 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%).

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

Preparation 145: 4-bromo-5-(4-fluoro-2,6-dimethylphenoxy)-l-methylpyridin-2(1H)- one

Following the procedure in preparation 11, 4-bromo-5-(4-fluoro-2,6- dimethylphenoxy)pyridin-2(lH)-one (6.24 g, 20.0 mmol) was reacted to give the title compound (1.42 g, 22%). ¹H NMR (500 MHz, DMS0-d6) δ 7.04 (d, / =8.8 Hz, 2H), 6.92 (s, 1H), 6.82(s, lH), 3.27(s, 3H), 2.12(s, 6H)

Preparation 146: 4-(5-(4-fluoro-2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethylphenoxy)pyridin-2(lH)-one (152 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) was reacted to give the title compound (77 mg, 42%).

HPLC t_R (Agilent, acidic, 3.5 min): 1.36 min, m/z = 394.1 [M+H]⁺. 1H ¹H NMR (400 MHz, DMSO-d6) δ 12.17 (bs, 1H), 7.46 (s, 1H), 7.36 - 7.33 (m, 1H), 7.00 - 6.96 (m, 2H), 6.72 (s, 1H), 6.51 - 6.50 (m, 1H), 6.34 (t, J=2.3 Hz, 1H), 3.58 (s, 3H), 3.34 (s, 3H), 2.09 (s, 6H).

Comparative Example 4a: 4-(5-(2,6-dichlorophenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Preparation 147: 4-(5-(2,6-dichlorophenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dichlorophenoxy)-l- methylpyridin-2(lH)-one (164 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.403min, m/z = 417.97 [M+2H] ⁺ ¹H ¹H NMR: (400 MHz, DMSO) δ 12.15 (br, 1H), 7.58 (d, J=8 Hz, 2H), 7.49 (s, 1H), 7.33-7.29 (m, 2H), 7.02 (s, 1H), 6.53 (s, 1H), 6.42(s, 1H), 3.34 (s, 3H), 3.14 (s, 3H).

Comparative Example 4b: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Preparation 148: 4-(5-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dimethylphenoxy)-l- methylpyridin-2(lH)-one (145 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4c: 4-(5-(2,6-bis(difluoromethyl)phenoxy)-l-methyl-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one

Preparation 149: 4-(5-(2,6-bis(difluoromethyl)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 5-(2,6-bis(difluoromethyl)phenoxy)-4- bromo-l-methylpyridin-2(lH)-one (177 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4d: 4-(5-(2,6-bis(trifluoromethyl)phenoxy)-l-methyl-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one

Preparation 150: 4-(5-(2,6-bis(trifluoromethyl)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 5-(2,6-bis(trifluoromethyl)phenoxy)-4- bromo-l-methylpyridin-2(lH)-one (196 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4e: 4-(5-(2,6-dimethoxyphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one Preparation 151: 4-(5-(2,6-dimethoxyphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dimethoxyphenoxy)-l- methylpyridin-2(lH)-one (160 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4f: 4-(5-(2,6-bis(methyl-d3)phenoxy)-l-methyl-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

Preparation 152: 4-(5-(2,6-bis(methyl-d3)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 5-(2,6-bis(methyl-d3)phenoxy)-4- bromo-l-methylpyridin-2(lH)-one (148 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound. Comparative example 4g: 4-(5-(2,6-dichloro-4-fluorophenoxy)-l-methyl-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one

Preparation 153: 4-(5-(2,6-dichloro-4-fluorophenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6-dichloro-4- fluorophenoxy)-l-methylpyridin-2(lH)-one (172 mg, 0.47 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4h: 4-(5-(2,6-bis(difluoromethyl)-4-fluorophenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

Preparation 154: 4-(5-(2,6-bis(difluoromethyl)-4-fluorophenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 5-(2,6-bis(difluoromethyl)-4- fluorophenoxy)-4-bromo-l-methylpyridin-2(lH)-one (187 mg, 0.47 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.47 mmol) react to give the title compound. Comparative example 4i: 4-(5-(4-fluoro-2,6-bis(trifluoromethyl)phenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

Preparation 155: 4-(5-(4-fluoro-2,6-bis(trifluoromethyl)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Followingthe procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- bis(trifluoromethyl)phenoxy)-l-methylpyridin-2(lH)-one (204 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4j: 4-(5-(4-fluoro-2,6-bis(trifluoromethyl)phenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

Preparation 156: 4-(5-(4-fluoro-2,6-bis(trifluoromethyl)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6- dimethoxyphenoxy)-l-methylpyridin-2(lH)-one (168 mg, 0.47 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4k: 4-(5-(4-fluoro-2,6-bis(methyl-d3)phenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

Preparation 157: 4-(5-(4-fluoro-2,6-bis(methyl-d3)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(4-fluoro-2,6-bis(methyl- d3)phenoxy)-l-methylpyridin-2(lH)-one (156 mg, 0.47 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4l: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Preparation 158: 4-(3-(2,6-dimethylphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethylphenoxy)-l- methylpyridin-2(lH)-one (145 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4m: 4-(3-(2,6-dichlorophenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Preparation 159: 4-(3-(2,6-dichlorophenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dichlorophenoxy)-l- methylpyridin-2(lH)-one (164 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4n: 4-(3-(2,6-bis(difluoromethyl)phenoxy)-l-methyl-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one

Preparation 160: 4-(3-(2,6-bis(difluoromethyl)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 3-(2,6-bis(difluoromethyl)phenoxy)-4- bromo-l-methylpyridin-2(lH)-one (179 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4o: 4-(3-(2,6-bis(trifluoromethyl)phenoxy)-l-methyl-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one

Preparation 161: 4-(3-(2,6-bis(trifluoromethyl)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 3-(2,6-bis(trifluoromethyl)phenoxy)-4- bromo-l-methylpyridin-2(lH)-one (194 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4p: 4-(3-(2,6-dimethoxyphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Preparation 162: 4-(3-(2,6-dimethoxyphenoxy)-l-methyl-2-oxo-l,2-dihydropyridin-4- yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dimethoxyphenoxy)-l- methylpyridin-2(lH)-one (160 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4q: 4-(3-(2,6-bis(methyl-d3)phenoxy)-l-methyl-2-oxo- l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7- one

Preparation 163: 4-(3-(2,6-bis(methyl-d3)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 3-(2,6-bis(methyl-d3)phenoxy)-4- bromo-l-methylpyridin-2(lH)-one (148 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4r: 4-(3-(2,6-dichloro-4-fluorophenoxy)-l-methyl-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one Preparation 164: 4-(3-(2,6-dichloro-4-fluorophenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(2,6-dichloro-4- fluorophenoxy)-l-methylpyridin-2(lH)-one (172 mg, 0.47 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4s: 4-(3-(2,6-bis(difluoromethyl)-4-fluorophenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

Preparation 165: 4-(3-(2,6-bis(difluoromethyl)-4-fluorophenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 3-(2,6-bis(difluoromethyl)-4- fluorophenoxy)-4-bromo-l-methylpyridin-2(lH)-one (187 mg, 0.47 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.47 mmol) react to give the title compound. Comparative example 4t: 4-(3-(4-fluoro-2,6-bis(trifluoromethyl)phenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

Preparation 166: 4-(3-(4-fluoro-2,6-bis(trifluoromethyl)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- bis(trifluoromethyl)phenoxy)-l-methylpyridin-2(lH)-one (204 mg, 0.47 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4u: 4-(3-(4-fluoro-2,6-dimethoxyphenoxy)-l-methyl-2- oxo-1, 2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin- 7-one

Preparation 167: 4-(3-(4-fluoro-2,6-dimethoxyphenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6- dimethoxyphenoxy)-l-methylpyridin-2(lH)-one (168 mg, 0.47 mmol) and 6- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (200 mg, 0.47 mmol) react to give the title compound.

Comparative example 4v: 4-(3-(4-fluoro-2,6-bis(methyl-d3)phenoxy)-l- methyl-2-oxo-l,2-dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one

Preparation 168: 4-(3-(4-fluoro-2,6-bis(methyl-d3)phenoxy)-l-methyl-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-3-(4-fluoro-2,6-bis(methyl- d3)phenoxy)-l-methylpyridin-2(lH)-one (156 mg, 0.47 mmol) and 6-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H-pyrrolo[2,3- c]pyridin-7-one (200 mg, 0.47 mmol) react to give the title compound.

Example 121: 4-(5-(2,6-dimethylphenoxy)-l-(2-hydroxyethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

See for illustration the compound labelled NA’44 herein.

Preparation 169: 4-(5-(2,6-dimethylphenoxy)-l-(2-hydroxyethyl)-2-oxo-l,2- dihydropyridin-4-yl)-6-methyl-l,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Following the procedure in preparation 12, 4-bromo-5-(2,6- dimethylphenoxy)-l-(2-hydroxyethyl)pyridin-2(lH)-one (105 mg, 0.31 mmol) and 6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l,6-dihydro-7H- pyrrolo[2,3-c]pyridin-7-one (124 mg, 0.29 mmol) was reacted to give the title compound.

LCMS t_R (Waters Acquity UPLC with QDA mass Detector, Acidic, 4.0min): 1.324min, m/z =406.17 [M+1H] ⁺

HPLC t_R (Waters Alliance e2695 with 2998 detector, Basic, 17.0min): 5.176min 1H ¹H NMR: (400 MHz, DMSO) δ 12.17 (s, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 7.11- 7.04 (m, 3H), 6.56-6.51 (m, 2H), 6.36 (s, 1H), 4.77 (s, 1H), 3.79 (s, 2H), 3.58 (s, 3H), 3.53 (s, 2H), 2.08 (s, 6H).

Primary activity

The dissociation constant (Kd) of Comparative examples 1-3 and Process examples 1-4, from BRD4 BD1 and BD2 are determined. BRD4 is a representative example of the BET family. Dissociation constants are determined as described below and are represented in Table 1.

Bromodomain assay procedure

T7 phage strains displaying bromodomains were grown in parallel in 24- well blocks in an E. coli host derived from the BL21 strain. E. coli were grown to logphase and infected with T7 phage from a frozen stock (multiplicity of infection = 0.4) and incubated with shaking at 32°C until lysis (90-150 min). The lysates were centrifuged (5,000 x g) and filtered (0.2 pm) 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. The 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 to reduce non-specific phage binding. Binding reactions were assembled by combining bromodomains, ligated affinity beads, and test compounds in lx binding buffer (16 % SeaBlock, 0.32x PBS, 0.02%BSA, 0.04 % Tween 20, 0.004% Sodium azide, 7.9 mM DTT). Test compounds were prepared as 1000X stocks in 100% DMSO and subsequently diluted 1:25 in MEG. The compounds were then diluted directly into the assays such that the final concentrations of DMSO and MEG are 0.1% and 2.4%, respectively. All reactions were performed in polypropylene 384-well plates in a final volume of 0.02 ml. The assay plates were incubated at RT with shaking for 1 hr and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated at RT with shaking for 30 min. The bromodomain concentration in the eluates was measured by quantitative polymerase chain reaction (qPCR).

An 11 -point 3 -fold serial dilution of each test compound was prepared in 100% DMSO at lOOOx final test concentration. All compounds were distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO is 0.09%. Most dissociation constants were determined using a compound top concentration = 10,000 nM. If the initial dissociation constant determined is < 0.169 nM (the lowest concentration tested), the measurement was repeated with a serial dilution starting at a lower top concentration.

Table 1: Dissociation constants of Comparative examples 1-3 and Process examples 1-4 from BRD4 BD1 and BD2

Key

+ Kd > lμM

++ Kd > O.lμM and ≤ lμM

+++ Kd > 0.01 μM and ≤ O.lμM

++++ Kd ≤ O.OlμM

In one or more embodiments BET BDII protein inhibitors exhibit a Kd of < 0.1 μM, or ≤ 0.05 μM, or of ≤ 0.01 μM for BRD4 BDII. Preferably, BET BDII selective protein inhibitors exhibit a Kd of < 0.01 μM for BRD4 BDII and a Kd of > 0.1 μM for BRD4 BDI . BET BDII selective protein inhibitors with a Kd of < 0.01 μM for BRD4 BD II and a Kd of > 0.1 μM for BRD4 BDI are promising drug candidates.

BET selectivity

The selectivity of Process example 1 of the current invention, against BRD2,3,4 and T BDI and BD2 are determined as described below and are represented in Table 2.

Bromodomain assay procedure

The same bromodomain assay procedure as that outlined above was used. Example compounds are screened at 30 times their Kd, and results for primary screen binding interactions are reported as '% Ctrl', where lower numbers indicate stronger hits in the matrix.

Test compound = A compound of formula (I), such as example 1

Negative control = DMSO (100% Ctrl)

Positive control = control compound (0% Ctrl)

Table 2: Single point concentration binding interactions of exemplified compounds

Process BRD2(1) BRD3(1) BRD4(1) BRDT(l) example % Ctrl % Ctrl % Ctrl % Ctrl 1 100 85 90 100

Process BRD2(2) BRD3(2) BRD4(2) BRDT(2) example % Ctrl % Ctrl % Ctrl % Ctrl 1 0.1 2.3 8.7 13

Preferably, BET protein inhibitors exhibit a % Ctrl of <10 for BRD 2,3,4 and T BD2 or T BD1 and BD2. BET protein inhibitors with % Ctrl of <10 for BRD 2,3,4 and T BD2 are promising drug candidates. The data of Table 2 show that Process example 1 is a promising drug candidate.

BET selectivity dose response

The dissociation constants (Kd) of Process example 1 of the current invention, from BRD2,3,4 and T BD1 and BD2 is determined as described below and tabulated in Table 3.

Bromodomain assay procedure

The same bromodomain assay procedure as that outlined above is used. Table 3: Dose response binding interactions of exemplified compounds

Process BRD2(1) BRD3(1) BRD4(1) BRDT(l) example Kd (nM) Kd (nM) Kd (nM) Kd (nM)

1 >3000 >3000 >3000 >3000

Process BRD2(2) BRD3(2) BRD4(2) BRDT(2) example Kd (nM) Kd (nM) Kd (nM) Kd (nM)

1 <10 <10 <10 <10

BET protein inhibitors with a Kd of < 10 nM for BRD 2,3,4 and selectively T BD2 are promising drug candidates. Process example 1 exhibits a Kd of < 10 nM for BRD4(2) and a Kd of > 3000 nM for BRD4(1). Thus, Process example 1 is a promising drug candidate.

Cellular activity - IL-4

The parameter EC50 abbreviates for 'half maximal effective concentration'. In a pharmacological context, this can be the concentration of a drug that is necessary to cause half of the maximum possible effect. The lower the EC50, the less the concentration of a drug is required to produce 50% of maximum effect and the higher the potency.

The EC50 values of specific Example compounds in the reduction of IL-4 levels produced by CD4+ T-cells activated with CD2, CD3 and CD28 antibodies were determined as described below and tabulated in Table 4.

Assay procedure

1. CD4⁺ T-cells were isolated from cryopreserved human peripheral blood mononuclear cells (PBMCs) using EasySep™ Kit (Cat. No. 17952, Stemcell Technologies).

2. CD2, CD3 and CD28 antibodies coated beads from T cell Activation/Expansion Kit (Cat. No. 130-091-441, Miltenyi Biotec) were added to the CD4⁺ T-cells at a bead-to-cell ratio of 1:2.

3. CD4⁺ T-cells along with the beads were seeded at 2 x 10⁵ cells/well in a round bottom 96-well plate and treated with different compounds and controls in a total volume of 200 μl. 4. The cells were cultured for 48 hrs at 37°C, 5% CO2.

5. Supernatant was collected and IL-4 is analysed by ELISA.

Table 4: EC50 values of exemplified compounds. The measured drug response is the reduction of IL-4 levels in CD4+ T-cells stimulated by CD2, CD3 and CD28 antibodies

Example IL-4

Comparative +++ example 1

Comparative ++ example 2

Process +++ example 1

Process ++ example 2

Process ++ example 3

Process ++ example 4

Comparative ++ example 3

Key

+ EC50 > 1 μM

++ EC50 > 0.1 μM and ≤ 1 μM

+++ EC50 > 0.01 μM and ≤ 0.1 μM

++++ EC50 ≤ 0.01 μM

Preferably, BET protein inhibitors exhibit cellular EC50 values of < 0.1 μM for the reduction of IL-4 levels Process example 1 exhibit cellular EC50 values of < 0.1 μM in CD4+ T-cells stimulated by CD2, CD3 and CD28 antibodies coated beads from T cell Activation/Expansion Kit.

Human tissue data - Th2 and Thl7 stimulation of human skin explants

The % reduction of Process example 1 at 2.5 μM listed below in IL-4 or IL- 17A mRNA in healthy human skin stimulated by a Th2 or Thl7 biasing cocktail were determined as described below and tabulated in Table 5. Assay procedure

1. Freshly excised healthy human skin tissue from abdominoplasties was defatted, cleaned and sectioned into 7mm biopsies.

2. The biopsies were placed in Transwell® inserts with the epidermis apical and exposed to air and the dermis submerged in media in the basal chamber.

3. The biopsies were pre-treated overnight at 37°C, 5% CO2 with different compounds and controls added to the media in the basal chamber.

4. The next day, contents of the basal chamber was replaced with fresh media containing the test compound and a stimulation cocktail for either Th2 inflammation (proprietary Medpharm cocktail) or Thl7 inflammation (mix of antibodies against CD3, CD28, IL-4, IFNy and recombinant IL-lp, IL-6, IL- 21, TGF-P).

5. The biopsies were incubated at 37°C, 5% CO2 for a further 24 hrs.

6. After harvesting, the biopsies are cut in half, and one half was homogenized and used for RNA extraction by standard methods. IL-4 or IL-17A is assessed by RT-qPCR.

Table 5: % reduction in IL-4 and IL-17A mRNA of Process example 1 at 2.5 pM. The measured drug response is the reduction of IL-4 or IL-17 A mRNA levels in healthy human skin stimulated by a Th2 or Thl7 biasing cocktail.

Key

+ > 25% reduction

++ > 50% reduction

+++ > 75% reduction

In one or more embodiments the compounds described herein can help reduce inflammation by reduction of certain cytokines involved in an inflammatory response. In one or more embodiments certain cytokine levels are reduced by >50%, or >60% or >70% or >75%. Preferably, BET protein inhibitors exhibit > 50% reduction of IL-4 or IL-17 levels, Process example 1 exhibits > 50% reduction in healthy human skin stimulated by a Th2 or Thl7 biasing cocktail. Primary cellular activity

Exemplary compounds are active against BRD4 BD2 and selective over BRD4 BD1. BRD4 is a representative example of the BET family, as the binding sites of all BET family members are structurally similar. The half maximal inhibitory concentration (IC50) of various Examples are described herein against BRD4 BD1 and BD2 and the fold selectivity calculated (IC50 BD1/IC50 BD2). IC50s and fold selectivity's are determined as described below and are represented in Table 6 and 7.

Cellular Bromodomain assay procedure

NanoBRET assay was carried out according to the manufacturer’s suggested protocol (Promega, Madison, WI). HEK293 cells were transfected using NanoLuc- BRD4-BD1 or NanoLuc-BRD4-BD2 fusion vectors and incubated at 37°C in an atmosphere of 5% CO2 for 20-24 hours. The transfected cells were then dispensed into 96-well plates using 90 pl cell suspension per well containing 2xl0⁵ cells/ml in Opti-MEM and lx final concentration of tracer. 90 pl per well of cell suspension without tracer was also dispensed into at least 3 wells as "No tracer control samples” for background correction. Serially diluted test compounds were prepared at lOOOx concentration in DMSO and further diluted to 10X concentration in Opti- MEM. 10 pl per well of the serially diluted 10X test compound was added to the 96- well plates containing cells with lx tracer. Plates were then incubated at 37°C + 5% CO2 incubator for 2 hours. Immediately prior to BRET measurements, a 3x solution consisting of 1:166 dilution of Nano-Gio® Substrate plus a 1:500 dilution of Extracellular NanoLuc Inhibitor in Opti-MEM was prepared and 50 pl per well was added to the cells. Donor emission (450nm) and acceptor emission (610nm) were measured using PHERAstar (BMG LabTech). For data analysis, the raw BRET ratio was generated and converted to milliBRET units with background correction using the formula: [(Acceptor_sampie / Donor_sampie) - (Acceptor no tracer control/Donor no tracer control)] x 1000. The mBU data was plotted as a function of compound concentration and IC50s for BRET assay were determined by nonlinear regression analysis of concentration response curves using the GraphPad Prism software.

Table 6: IC50s of Comparative examples 1-3 and Process examples 1-4 against BRD4

BD1 and BD2

Table 7: IC50s o/Examples against BRD4 BD1 and BD2

Key

+ BRD4 BD2 IC50 > 0.2 μM and ≤ 2μM

++ BRD4 BD2 IC5O > 0.05 μM and ≤ 0.2μM +++ BRD4 BD2 IC5O ≤ 0.05μM

# BRD4 BDl IC50 > lμM

## BRD4 BD1 IC5O > 0.5μM and ≤ lμM

### BRD4 BD1 IC5O > 0.1 μM and ≤ 0.5μM x Fold >2 and ≤50 xx Fold >50 and ≤200 xxx Fold >200 Preferably, BET BDII selective protein inhibitors exhibit an IC50 of < 0.05 μM for BRD4 BDII, an IC50 of > 1 μM for BRD4 BDI and a Fold selectivity of >200 for BDII over BDI. BET BDII selective protein inhibitors with an IC50 of < 0.05 μM for BRD4 BD II, an IC50 of > 1 μM for BRD4 BDI and a Fold selectivity of >200 for BDII over BDI are promising drug candidates.

Intrinsic clearance in mouse liver microsomes

BET protein inhibitors with a low rate of clearance in mouse liver microsomes are promising drug candidates. Some of the exemplary compounds of the current invention have low clearance in mouse liver microsomes, the rate of which is expressed as a % of liver blood flow.

PART A - The experimental methods and results (Table 8) are provided hereinafter.

Assay procedure for Table 8

Test compound (0.5 μM) was incubated with female CD1 mouse liver microsomes (Xenotech LLC TM; 0.5 mg/mL 50 mM potassium phosphate buffer, pH 7.4) and the reaction started with addition of excess NADPH (8 mg/mL 50 mM potassium phosphate buffer, pH 7.4). Immediately, at time zero, then at 3, 6, 9, 15 and 30 min an aliquot (50 uL) of the incubation mixture was removed and mixed with acetonitrile (100 pL) to stop the reaction. Internal standard was added to all samples, the samples centrifuged to sediment precipitated protein and the plates then sealed prior to UPLCMSMS analysis using a Quattro Premier XE (Waters Corporation, USA). XLfit (IDBS, UK) was used to calculate the exponential decay and consequently the rate constant (k) from the ratio of peak area of test compound to internal standard at each timepoint.

Table 8: Intrinsic clearance (% Liver Blood Flow) of Comparative examples 1-3 and Process examples 1-4 in mouse liver microsomes

Example % Liver Blood

Flow

Comparative 26 example 1

Comparative 71 example 2

Process 43 example 1

Process 76 example 2

Process 87 example 3

Process 37 example 4

Comparative 27 example 3

In one or more embodiments, e.g., for systemic delivery, e.g., oral delivery, BET BDII selective inhibitors may exhibit lower clearance rates of <50%, or <45%, or <40%, or <35%, or <30%. Preferably, BET BDII selective inhibitors for use as oral drugs exhibit intrinsic clearance rates ≤30% liver blood flow in mouse liver microsomes. Comparative Example compounds exhibit intrinsic clearance rates of ≤30% liver blood flow. The corollary can also apply, namely that BET inhibitors for use as topical drugs will exhibit higher clearance rates of >30%, or > 40%, or >50%, or > 60%, or >70% liver blood flow.

Intrinsic clearance in mouse liver microsomes - Continued

PART -B The experimental methods and results (Table 9) are provided hereinafter.

Assay procedure for Table 9

A 50 mM stock solution (in DMSO) was prepared for the compound. From the stock solution, a working solution of 0.5 mM was prepared by diluting the compound in DMSO (final concentration of 1 uM with 0.1% DMSO. The compound (1 uL of working solution) was spiked in PBS with pH 7.4 (22 uL) at a concentration of 1 uM. Subsequently, 110 uL of 10 mM NADPH is added (as a co-factor). The aforementioned sample was incubated at 37 °C for 15 min. Following this, prewarmed mouse microsomes (27.5 uL; final protein cone. 0.5 mg/mL) were added. The samples were then incubated at 37°C. Aliquots of samples were withdrawn at 0, 5, 15, 30, 45 and 60 min. The reaction was stopped by using chilled acetonitrile containing internal standard. The samples were centrifuged and the supernatants analysed by LC-MS/MS. The percent compound remaining at each time point was calculated with respect to that of the 0 min sample. The data was then analysed to calculate half-life and intrinsic clearance (CLint). Note that control samples were run without NADPH and blank samples are prepared using DMSO (without the test compound).

Table 9: Intrinsic clearance (% Liver Blood Flow) of Examples 1-79 in mouse liver microsomes

Example % Liver Blood Flow

Example 1 51

Example 2 20

Example 3 62

Example 4 78

Example 5 79

Example 6 45

Example 7 13

Example 8 41

Example 10 25

Example 11 59

Example 12 41

Example 13 37

Example 14 17

Example 15 81

Example 16 28

Example 121 73

Example 65 19

Example 66 76

Example 67 77

Example 68 13

Example 69 15 Example 70 30

Example 71 10

Example 72 10

Example 73 <10

Example 74 19

Example 75 27

Example 76 29

Example 77 21

Example 78 30

Example 79 16

Comparative example 4a, 30 see for illustration, compound NA’17

In one or more embodiments, e.g., for systemic delivery, e.g., oral delivery, BET BDII selective inhibitors may exhibit lower clearance rates of <50%, or <45%, <40%, or <35%, or <30% or <25%, or <20%. Preferably, BET BDII selective inhibitors for use as oral drugs exhibit intrinsic clearance rates ≤30% liver blood flow in mouse liver microsomes. Example compounds exhibit intrinsic clearance rates of ≤30% liver blood flow. The corollary can also apply, namely that BET inhibitors for use as topical drugs will exhibit higher clearance rates of >30%, or > 40%, or >50%, or > 60%, or >70% liver blood flow.

Stability in mouse plasma

BET protein inhibitors with high stability in mouse plasma are promising oral drug candidates. Some of the Exemplary compounds and compounds of the current invention have high stability in mouse plasma, the stability of which is expressed as a % remaining after 120 minutes. The experimental methods and results (Table 10 and Table 11) are provided hereinafter.

Assay procedure

The stock solution of compound (10 mM) was prepared in DMSO. From the stock solution, a working solution of compound (500 uM) was prepared in DMSO (100%). To 735 pL of mouse plasma, working solution of compound is added - resulting in a final concentration of 1 μM (1% DMSO) for the compound. The sample was then incubated at 37 °C. Aliquot was withdrawn at time-points - 0, 15, 30, 60, 90 and 120 mins. The reaction was stopped by using chilled acetonitrile containing internal standard (IS). The samples were centrifuged and the supernatants analyzed using LCMS/MS. The percent remaining of the compound at each time point was calculated with respect to the control sample (0 min time-point).

Table 10: Plasma stability of Process examples 1 and 2 in mouse plasma

Process % Remaining at example 120 minutes

1 7

2 100

Table 11: Plasma stability of Examples 65 - 79 in mouse plasma

Example % Remaining at 120 minutes

Example 65 92

Example 66 100

Example 67 78

Example 68 27

Example 69 96

Example 70 51

Example 71 96

Example 72 80

Example 73 76

Example 74 80

Example 75 81

Example 76 83

Example 77 81

Example 78 92

Example 79 61 In one or more embodiments, e.g., for systemic delivery, e.g., oral delivery, BET BDII selective inhibitors may exhibit higher plasma stability of >50%, or > 60%, or >70%, or > 80%, or >90%. Preferably, BET BDII selective inhibitors for use as oral drugs exhibit plasma stability of >50% after 120 minutes in mouse plasma. Process example compounds exhibit plasma stability of >50%. Example compounds exhibit exhibit plasma stability of >50%. The corollary can also apply, namely that BET inhibitors for use as topical drugs can exhibit lower plasma stability of <50%, or <45%, <40%, or <35%, or <30%

Cellular activity - IL-17A and 22

The lower the EC50, the less the concentration of a drug is required to produce 50% of maximum effect and the higher the potency.

The EC50 values of specific Example compounds in the reduction of IL-17 and IL-22 levels produced by human peripheral blood mononuclear cells activated with CD2, CD3 and CD28 antibodies are determined as described below and tabulated in Table 12.

Assay procedure

1. Cryopreserved human peripheral blood mononuclear cells (PBMCs) were thawed according to the supplier’s protocol in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS).

2. CD2, CD3 and CD28 antibodies coated beads from T cell Activation/Expansion Kit (Cat. No. 130-091-441, Miltenyi Biotec) were added to the PBMCs at a bead-to-cell ratio of 1:2.

3. PBMCs along with the beads were seeded at 2 x 10⁵ cells/well in a round bottom 96-well plate and treated with different compounds and controls in a total volume of 200 pl.

4. The cells were cultured for 72 hrs at 37°C, 5% CO2.

5. Supernatant was collected and IL-17A/IL-22 was analysed by ELISA.

Table 12: EC50 values of Examples 65 - 79. The measured drug response is the reduction of IL-17A and IL-22 levels in human peripheral blood mononuclear cells stimulated by CD2, CD3 and CD28 antibodies Example IL-17 A IL-22

Example 65 ++++ ++++

Example 68 ++++ +++

Example 69 - ++++

Example 70 ++++ ++++

Example 76 +++ +++

Example 77 +++ ++++

Example 78 ++ +++

Example 79 +++ +++

Example 5 ++ +++

Example 6 ++ +++

Example 7 ++ ++

Example 10 ++ +++

Example 12 ++ +++

Example 13 ++ +++

Key

+ EC50 > 1 μM

++ EC50 > 0.1 μM and ≤ 1 μM +++ EC50 > 0.01 μM and ≤ 0.1 μM

++++ EC50 ≤ 0.01 μM

In one or more embodiments the compounds described herein have an improved potency with an EC50 of ≤ 0.1 μM, or ≤ 0.01 μM. Preferably, BET protein inhibitors exhibit cellular EC50 values of < 0.1 μM for the reduction of IL-17A and IL-22 levels. Examples can exhibit cellular EC50 values of < 0.1 μM in human peripheral blood mononuclear cells stimulated by CD2, CD3 and CD28 antibodies coated beads from T cell Activation/Expansion Kit. Table 13: Illustrative summary of data for compounds from Examples 65, 69,

70, 76, 77, 78 and 79 with appropriate activity, selectivity, stability and range indicating suitability for systemic (e.g., oral) application.

"y" indicates that the compound satisfies the indicated criteria.

Claims

1. A compound of formula (I):

Ri is selected from the group consisting of: (f) CONHC₁-C₄alkyl, (ii) CONH₂, (iii) CONHC₁-C₆fluoroalkyl, (iv) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl, (vi) CONHC₁-C₄alkylN(C₁-C₂alkyl)2, (vii) CONHC₀-C₄alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo, and (viii) CONHC₃-C₆cycloalkylC₀-C₄alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₂ is C₁-C₆alkyl or C₃-C₆cycloalkyl, wherein in each substituent, optionally one or more carbons is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; R₃, R₄ and R₅ are each independently selected from the group consisting of

H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuterated C₁-C₂alkyl, and halo; and with the proviso when Q₂ is oxo, R₃, R₄ and R₅ are not simultaneously selected to be methyl, methyl and fluoro respectively; or (b)

Ri is H; R₂ is selected from the group consisting of: (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii] C₁-C₆alkylol, (iv) C₁-C₅alkyloxy, (v) C₁-C₅alkylamino, (vi) C₁-C₃alkylCON(C₁-C₄alkyl)2, (vii) C₁-C₆fluoroalkyl, (viii) C₁-C₅fluoroalkyloxy, (ix) C₁-C₅fluoroalkylamino and (X) C₁-C₂alkyl[N, 0 or SO₂]C₁-C₂alkyl; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₃, R₄ and R₅ are each independently selected from the group consisting of

H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuterated C₁-C₂alkyl, and halo; or (c)

Ri is selected from the group consisting of: (f) CONHC₁-C₄alkyl, (ii) CONH2, (iii) CONHC₁-C₆fluoroalkyl, (iv) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl, (vi) CONHC₁-C₄alkylN(C₁-C₂alkyl)2, (vii) CONHC₀-C₄alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo, (viii) CONHC₃-C₈cycloalkylC₀-C₄alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₂ is selected from the group consisting of; (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₁-C₅alkyloxy, (v) C₁-C₅alkylamino, (vi) C₁-C₃alkylCON(C₁-C₄alkyl)2, (vii) C₁-C₆fluoroalkyl, (viii) C₁-C₅fluoroalkyloxy, (ix) C₁-C₅fluoroalkylamino, and (X) C₁-C₂alkyl[N, 0 or SO₂]C₁-C₂alkyl; R₃, R₄ and R₅ are each independently selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuterated C₁-C₂alkyl, and halo. A compound of claim 1, wherein:

Ri is selected from the group consisting of: (f) CONHC₁-C₄alkyl, (ii) CONH2, (iii) CONHC₁-C₆fluoroalkyl, (iv) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl, (vi) CONHC₁-C₄alkylN(C₁-C₂alkyl)2, (vii) CONHC₀-C₄alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo, and (viii) CONHC₃-C₆cycloalkylC₀-C₄alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₂ is C₁-C₆alkyl or C₃-C₆cycloalkyl, wherein in each substituent, optionally one or more carbons is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; R₃, R₄ and R₅ are each independently selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuterated C₁-C₂alkyl, and halo; and with the proviso when Q₂ is oxo, R₃, R₄ and R₅ are not simultaneously selected to be methyl, methyl and fluoro respectively.

3. A compound of claim 1, wherein:

Ri is H; R₂ is selected from the group consisting of: (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₁-C₅alkyloxy, (v) C₁-C₅alkylamino, (vij C₁-C₃alkylCON(C₁-C₄alkyl)2, (vif) C₁-C₆fluoroalkyl, (viii) C₁-C₅fluoroalkyloxy, (ix) C₁-C₅fluoroalkylamino and (X) C₁-C₂alkyl[N, 0 or SO₂]C₁-C₂alkyl; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₃, R₄ and R₅ are each independently selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuterated C₁-C₂alkyl, and halo;

4. A compound of claim 1, wherein:

Ri is selected from the group consisting of: (f) CONHC₁-C₄alkyl, (ii) CONH2, (iii) CONHC₁-C₆fluoroalkyl, (iv) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl, (vi) CONHC₁-C₄alkylN(C₁-C₂alkyl)2, (vii) CONHC₀-C₄alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo, (viii) CONHC₃-C₈cycloalkylC₀-C₄alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₂ is selected from the group consisting of; (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₁-C₅alkyloxy, (v) C₁-C₅alkylamino, (vi) C₁-C₃alkylCON(C₁-C₄alkyl)2, (vii) C₁-C₆fluoroalkyl, (viii) C₁-C₅fluoroalkyloxy, (ix) C₁-C₅fluoroalkylamino, and (x) C₁-C₂alkyl[N, 0 or SO₂]C₁-C₂alkyl; R₃, R₄ and R₅ are each independently selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₂alkoxy, deuterated C₁-C₂alkyl, and halo.

5. A compound of any one of claims 1 to 4, wherein R₃, R₄ and R₅ are each independently selected from the group consisting of H, methyl, CF3, CHF₂, methoxy, CD3 and halo.

6. A compound of claim 5 wherein R₃ and R₄ are methyl and R₅ is F.

7. A compound of claim 5 wherein R₃ and R₄ are methyl and R₅ is H.

8. A compound of any one of the preceding claims wherein the pyridone is a 5- pyridone.

9. A compound as claims in any one of the preceding claims comprising sections (a) or (c) wherein R₂ is methyl.

10. A compound as claimed in any one of the preceding claims wherein Ri is selected from the group consisting of: (f) CONHC₁-C₄alkyl, (ii) CONHC₁-C₃fluoroalkyl, (iii) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (iv) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₁-C₂alkylN(Me)2, (vi) CONHC₀-C₂alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with an oxygen or nitrogen, and/or is optionally substituted at one or more carbon atoms or nitrogen atoms if with a methyl, ethyl or halo, and (vii) CONHC₃-C₆cycloalkylC₀-C₂alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo.

11. A compound as claimed in claim 10 wherein Ri is selected from the group consisting of: (f) CONHC₂-C₃alkyl, (ii) CONHC₁-C₃fluoroalkyl, (iii) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl, (iv) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl, and (v) CONHC₃-C₆cycloalkylC₀-C₂alkyl optionally substituted at one or more carbon atoms with one or more halos.

12. A compound as claimed in either claim 10 or 11 wherein: R₃ and R₄ are methyl and R₅ is H; the pyridone is a 5-pyridone; and wherein R₂ is methyl.

13. A compound as claimed in either claim 10 or 11 wherein: R₃ and R₄ are methyl and R₅ is H; the pyridone is a 2 -pyridone; and wherein R₂ is methyl.

14. A compound of any one of claims 1-8 comprising section (b) or section (c) wherein R₂ is selected from the group consisting of; (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₀-C₃alkylCONHC₁-C₄alkyl, (v) C₁-C₆fluoroalkyl, and (vi) C₁-C₂alkyl[N, 0, or SO₂]C₁-C₂alkyl.

15. A compound as claimed in claim 14 wherein R₂ is selected from the group consisting of; (i) fluoromethyl, C₂-C₃alkyl, (ii) C₀-C₂alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with an oxygen or nitrogen and/or is optionally substituted at one or more carbon atoms or nitrogen atoms with a methyl, ethyl or halo; (iii) C₁-C₄alkylol, (iv) C₁-C₂alkylCONHC₁-C₂alkyl, (v) C₁-C₄fluoroalkyl, and (vi) C₁-C₂alkyl[N or O]C₁-C₂alkyl.

16. A compound a claimed in claim 15 wherein: R₃ and R₄ are methyl or chloro, and R₅ is H; and the pyridone is a 5-pyridone.

17. A compound as claimed in claim 15 wherein: R₃ and R₄ are methyl or chloro, and R₅ is H; and the pyridone is a 2 -pyridone.

18. A compound as claimed in claim 1 wherein: the pyridone is a 5-pyridone; R₂ is methyl; R₅ is H; and R₃ and R₄ are each independently methyl, CF3, CHF₂, methoxy, or CD3.

19. A compound as claimed in claim 1 wherein: the pyridone is a 2 -pyridone; R₂ is methyl; R₅ is H; and R₃ and R₄ are each independently methyl, CF3, CHF₂, methoxy, or CD3.

20. A compound of any one of claims 1-8 comprising section (c) wherein:

Ri is selected from the group consisting of: (f) CONHC₁-C₄alkyl, (ii) CONHC₁-C₄fluoroalkyl, (iii) CONHC₃-C₆cycloalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (iv) CONHC₃-C₆cyclofluoroalkyl optionally substituted at one or more carbon atoms with a methyl or ethyl; (v) CONHC₁-C₂alkylN(Me)2, (vi) CONHCO-C₂alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with an oxygen or nitrogen, and/or is optionally substituted at one or more carbon atoms or nitrogen atoms if present with a methyl, ethyl or halo, (vii) CONHC₃-C₆cycloalkylC₀-C₂alkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; and either Q₁ is H and Q₂ is oxo, or Q₁ is oxo and Q₂ is H; R₂ is selected from a group consisting of: (i) C₂-C₆alkyl, (ii) C₀-C₃alkylC₃-C₈cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with a heteroatom and/or is optionally substituted at one or more carbon atoms or heteroatoms if present with a methyl, ethyl or halo; (iii) C₁-C₆alkylol, (iv) C₀-C₃alkylCONHC₁-C₄alkyl, (v) C₁-C₆fluoroalkyl, and (vi) C₁-C₂alkyl[N, 0, or SO₂]C₁-C₂alkyl; and R₃, R₄ and R₅ are each independently selected from the group consisting of H, C₁-C₄alkyl, C₁-C₄fluoroalkyl, methoxy, deuteratedC₁-C₄alkyl and halo.

21. A compound of claim 20 wherein R₂ is selected from the group consisting of: (i) fluoromethyl, (ii) C₂-C₃alkyl, (iii) C₀-C₂alkylC₃-C₆cycloalkyl, wherein optionally one or more carbons in the cycloalkyl is replaced with an oxygen or nitrogen and/or optionally substituted at one or more carbon atoms or nitrogen atoms with a methyl, ethyl or halo; (iv) C₁-C₄alkylol, (v) C₁-C₂alkylCONHC₁-C₂alkyl, (vi) C₁-C₄fluoroalkyl, and (vii) C₁-C₂alkyl[N or O]C₁-C₂alkyl.

22. A compound of Claim 1 wherein the compound is selected from:



24. The compound of any one of claims 1 to 23, in the form of a pharmaceutically acceptable salt. 25. A pharmaceutical composition comprising any one or a combination of two or more of the compounds defined in any one of claims 1 to 24, in combination with one or more pharmaceutically 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. The compound or pharmaceutical composition of claim 26 wherein the medicament is for topical or systemic use, such as oral use.

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

29. The compound or pharmaceutical composition for the use of claim 28, wherein the use is in a method of treatment or prophylaxis of inflammation or cancer of the gut, skin or lung.

30. A compound as defined in any one of claims 1 to 24, or a pharmaceutical composition as defined in any one of claims 25 to 27, for use in the inhibition of Bromodomain and Extra-Terminal proteins.

31. A method for the treatment or prophylaxis of inflammatory disorders, inflammatory skin disorders, respiratory diseases, gastrointestinal diseases, eye diseases, cancers, rheumatic diseases, demyelinating diseases and fibrotic diseases, said method 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 any one of claims 25 to 27.

32. The method according to claim 31, wherein the method is for the treatment or prophylaxis of fibrosis of inflammation or cancer of the gut, skin or lung.

33. A method of inhibiting Bromodomain and Extra-Terminal protein activity in a subject, said method 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 any one of claims 25 to 27.