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Title:
INHIBITORS OF URAT1 AND PHARMACEUTICAL USES THEREOF
Document Type and Number:
WIPO Patent Application WO/2022/169974
Kind Code:
A1
Abstract:
The present invention relates to pharmaceutical compounds, compositions, combinations, and methods, especially as they are related to compositions and methods for the treatment and/or prevention of conditions such as gout that are associated with excessive levels of uric acid. The invention provides compounds of Formula (I) as further described herein, which inhibit activity of urate reabsorption transporter 1 (URAT1, also known as SLC22A12). The compounds are useful to treat conditions associated with excessive levels of uric acid, such as gout.

Inventors:
WU TOM YAO-HSIANG (US)
JIN QIHUI (US)
Application Number:
PCT/US2022/015115
Publication Date:
August 11, 2022
Filing Date:
February 03, 2022
Export Citation:
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Assignee:
NEXYS THERAPEUTICS INC (US)
International Classes:
C07D471/04; A61K31/437; A61K31/4985; A61K31/519; A61P19/06; C07D487/04
Domestic Patent References:
WO2012048058A22012-04-12
WO2017041732A12017-03-16
WO2018017368A12018-01-25
WO2018090921A12018-05-24
WO2012048058A22012-04-12
Foreign References:
EP3348557A12018-07-18
US20130225673A12013-08-29
US10005750B22018-06-26
US4400387A1983-08-23
US20120184587A12012-07-19
US20110028467A12011-02-03
Other References:
AZAVEDO ET AL., ADVANCES RHEUMATOL, vol. 59, no. 37, 2019
BENN ET AL., FRONTEIRSMED., vol. 5, 2018, pages 4
MCDONALD ET AL., CHEM. RES. TOXICOL., vol. 20, 2007, pages 1833 - 42
N. CHO ET AL., DRUG MET. PHARMACOKIN., vol. 32, 2017, pages 46 - 52
DRUG. METAB. DISPOS., vol. 47, 2019, pages 1281 - 90
UDA ET AL., ACSMED. CHEM. LETT., vol. 11, no. 10, 2020, pages 2017 - 23
"Remington's Pharmaceutical Sciences", 2000, LIPPINCOTT WILLIAMS AND WILKINS PUBLISHING COMPANY, pages: 780 - 857
STAHLWERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
"Science of Synthesis: Houben-Weyl Methods of Molecular Transformation", 2005, GEORG THIEME VERLAG
J. F. W. MCOMIE: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
T. W. GREENEP. G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY
"The Peptides", vol. 3, 1981, ACADEMIC PRESS
JOCHEN LEHMANN: "Chemie der Kohlenhydrate: Monosaccharide und Derivate", vol. 15/1, 1974, GEORG THIEME VERLAG
H.-D. JAKUBKEH. JESCHKEIT: "Aminosauren, Peptide, Proteine", 1982, VERLAG CHEMIE
Attorney, Agent or Firm:
SMITH, Michael et al. (US)
Download PDF:
Claims:
CLAIMS

1. A compound of Formula (I): wherein: one or two of W, X, Y and Z is N or N→ 0, and the other two or three of W, X, Y and Z are each CR6;

R1 is C1-6 alkyl optionally substituted with up to three groups selected from halo, hydroxy, CN, Ci-4 alkoxy, and C1-4 haloalkoxy, or R1 is H;

R2 is selected from -(Co-4 alkyl)-C3-6 cycloalkyl, C1-6 alkyl, and H, wherein each alkyl and cycloalkyl is optionally substituted with up to three groups selected from C1-2 alkyl, halo, hydroxy, CN, C1-2 alkoxy, C1-2haloalkyl, and C 1-2 haloalkoxy;

R3 and R5 are each independently selected from halo, C1-2haloalkyl, CN, C1-2 thioalkyl, and C2-4 alkynyl,

R4 is H, C1-6 acyl, or C1-6 alkyl sulfonyl; and each R6 is independently selected from H, halo, hydroxy, CN, C1-2 alkyl, C1-2 alkoxy, C1-2haloalkyl, and C1-2 haloalkoxy; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein W and X each represent CR6; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein Y is N; or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein Z is N; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or 2, wherein Y is N and Z is CR6, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 or 2, wherein Y is CR6 and Z is N; or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, wherein R2 is selected from C1-6 alkyl and C3-6 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with up to three groups selected from C1-2 alkyl, halo, hydroxy, CN, C1-2 alkoxy, C1-2haloalkyl, and C1-2 haloalkoxy; or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7, wherein R1 is C1-6 alkyl optionally substituted with C1-4 alkoxy; or a pharmaceutically acceptable salt thereof.

9. The compound of any one of the preceding claims, wherein R3 and R5 are independently selected from F, Br, Cl, CN, SMe and ethynyl; or a pharmaceutically acceptable salt thereof.

10. The compound of any of the preceding claims, wherein R4 is H; or a pharmaceutically acceptable salt thereof.

11. The compound of claim 6, wherein each R6 is independently selected from H, Me, and OMe; or a pharmaceutically acceptable salt thereof.

12. The compound of any one of the preceding claims, which is a compound of one of the following formulas:

or a pharmaceutically acceptable salt thereof.

13. A compound of claim 1 that is selected from the compounds in Table 1 and Table 2 and the pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising a compound of any of the preceding claims admixed with at least one pharmaceutically acceptable carrier or excipient.

15. A method to treat gout, which comprises administering to a subject in need thereof an effective amount of a compound of any one of claims 1-13, or a pharmaceutical composition of claim 14.

16. A compound according to any one of claims 1-13 for use in therapy.

17. Use of a compound according to any one of claims 1-13 for use in the manufacture of a medicament.

18. A pharmaceutical combination comprising an effective amount of a compound according to any one of claims 1-13 and an additional therapeutic agent.

Description:
INHIBITORS OF URAT1 AND PHARMACEUTICAL USES THEREOF

Related Applications

[0001] The present application claims priority to U.S. provisional patent application No. 63/146,406 filed on February 05, 2021, the disclosure and content of which is incorporated herein by reference in its entirety for all purposes

Field of the Invention

[0002] The field of this invention is compounds, pharmaceutical compositions and methods, especially inhibitors of URAT1, and compositions and methods of using these inhibitors for the treatment of conditions such as gout.

Background of the Invention

[0003] The present invention relates to novel indole-derived compounds having an attached phenolic group, which inhibit activity of urate reabsorption transporter 1 (URAT1, also known as SLC22A12). The compounds are most useful to treat conditions associated with excessive levels of uric acid, such as gout. The invention provides pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat conditions associated with excess uric acid.

[0004] Hyperuricemia is caused by the overproduction or under-excretion of uric acid, and is considered to be a causative factor of several diseases that significantly impair the quality of life. For example, hyperuricemia is considered the causative factor of gout, which is the most prevalent form of inflammatory arthritis, and is characterized by severe pain and tenderness in joints due to urate crystal accumulation.

[0005] Uricosuric agents and xanthine oxidase inhibitors are often prescribed to lower uric acid levels and treat an underlying cause of gout. Xanthine oxidase inhibitors such as allopurinol or febuxostat can reduce the formation of uric acid, and uricosuric agents can inhibit the absorption of uric acid from the kidney back to the blood, which occurs via the URAT1 transporter.

[0006] Benzbromarone is a uricosuric agent that is reported to be a non-competitive inhibitor of xanthine oxidase, and is known to be highly effective in lowering serum uric acid (sUA). It is reported to work at least in part by inhibition of URAT1. Azavedo, et al., Advances Rheumatol. 2019, 59(37); Benn, et al., Fronteirs Med. 2018, vol. 5, art. 160 at pg. 4. Excretion of uric acid occurs mainly by glomerular filtration; however, as much as 90% of uric acid filtered out is then reabsorbed in the proximal tubules by the action of URAT1. Thus blocking the activity of URAT1 greatly increases uric acid excrection. It has been found that therapy using benzbromarone can lead to lowering of serum uric acid (sUA) levels following a single dose, and its effectiveness continues to lower sUA following multiple doses. Continued benzbromarone therapy can bring sUA down to target levels of <6 mg/dL.

[0007] Unfortunately, like many other drugs, benzbromarone exhibits toxic side effects. It is associated with rare cases of hepatotoxicity and acute liver failure. The drug was never approved for us in the U.S., and while it was approved in Europe, it was reduced to limited use in the European market by its sponsor in 2003.

[0008] Studies suggest that the hepatotoxicity of benzbromarone is likely a result of sequential oxidative metabolism. McDonald, et al., Chem. Res. Toxicol. 2007, vol. 20, 1833-42. It has been shown that oxidation occurs initially in two particular places, the alkyl side chain and the phenyl ring fused to the furan. The initial phenyl ring hydroxylation may, in fact, make the compound more effective against URAT1, as it promotes renal clearance: the hydroxylated metabolite exhibits higher renal clearance than the parent drug, which may mean it is more available in the region where URAT1 activity occurs. However, secondary oxidative metabolism may produce bioactivated metabolites that promote the observed hepatotoxicity. N. Cho, et al., Drug Met. Pharmacokin., vol. 32, 46-52 (2017); Drug. Metab. Dispos. 2019, 47, 1281-90.

[0009] Several attempts have been made to formulate alternative compounds and pharmaceuticals with high potency on URAT1 and reduced toxicity, for example, U.S. 2013/0225673 (to Wempe et al., now US Patent No. 10,005,750) describes uric acid transport inhibitors that can potentially be applied topically. Similarly, Uda, et al., ACS Med. Chem. Lett. 2020, 11(10), 2017-23. See also U.S. 4,400,387; WO2017/041732; WO2018/017368; US2012/0184587; WO2017/041732; US2011/028467; WO2018/090921; and W02012/048058.

[0010] These and all other extrinsic materials discussed herein are incorporated by reference in their entirety. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. [0011] In spite of the efforts described in these references, there is still a need in the art for a highly potent gout/hyperuricemia drug with reduced toxicity. The invention provides compounds that address this unmet need and methods and compositions using these compounds.

Summary of the Invention

[0012] In one aspect, the present disclosure provides a heterocyclic compound having a structure according to Formula I: one or two of W, X, Y and Z is N or N→ O (i.e., N-oxide, having N as a ring atom in the form of an N-oxide), and the other two or three of W, X, Y and Z are each CR 6 ;

R 1 is C 1-6 alkyl optionally substituted with up to three groups selected from halo, hydroxy, CN, C 1-4 alkoxy, and Ci-4 haloalkoxy, or R 1 is H;

R 2 is selected from -(C 0-4 alkyl)-C3-6 cycloalkyl, C 1-6 alkyl, and H, wherein each alkyl and cycloalkyl is optionally substituted with up to three groups selected from C 1-2 alkyl, halo, hydroxy, CN, C 1-2 alkoxy, C 1-2 haloalkyl, and C 1-2 haloalkoxy;

R 3 and R 5 are each independently selected from halo, C 1-2 haloalkyl, CN, C 1-2 thioalkyl, and C2-4 alkynyl,

R 4 is H, C 1-6 acyl, or C 1-6 alkyl sulfonyl; and each R 6 is independently selected from H, halo, hydroxy, CN, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 haloalkyl, and C 1-2 haloalkoxy; or a pharmaceutically acceptable salt thereof.

[0013] Other aspects of the invention relate to pharmaceutical compositions comprising a compound of Formula (I) and particularly one of Formulas (Ila)-(IIj) as described below. In other aspects, the invention provides methods of using the compounds and compositions of the invention for treating hyperuricemic conditions such as gout, as further disclosed herein. Additional aspects of the invention are disclosed herein.

[0014] Where depicted as a specific tautomer, it is understood that the compounds of Formula (I) include other tautomers.

[0015] The compounds described herein can be used for many suitable purposes. In some embodiments, the compound described above can be used in therapy, particularly therapy for treatment of conditions associated with elevated uric acid levels such as gout.

[0016] In still another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) or any one of Formulas (Ila)-(IIj), or any of the subformulae described herein, admixed with at least one pharmaceutically acceptable carrier or excipient.

[0017] In yet another aspect, the disclosure provides a method for treating and/or preventing conditions associated with hyperuricemia such as gout, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or any one of Formulas (Ila)-(IIj), or any of other the sub-formulae described herein, or a pharmaceutical composition containing at least one such compound.

[0018] In yet another aspect, the present disclosure provides a use of a compound of Formula (I) or any one of Formulas (Ila)-(IIj), or any of the sub-formulae described herein for the manufacture of a medicament. The compounds of the invention are particularly useful for manufacture of a medicament for use to treat gout or other hyperuricemic conditions.

[0019] In yet another aspect, the present disclosure provides a combination for treating and/or preventing a hyperuricemic disorder in a subject, which combination comprises an effective amount of Formula (I) or any one of Formulas (Ila)-(IIj) or any of the sub-formulae described herein, or a pharmaceutically acceptable salt therof, and a second therapeutic agent useful to reduce uric acid levels.

[0020] In yet another aspect, the present disclosure provides for a method for inhibiting an activity of URAT1, which comprises administering to a subject in need thereof, or contacting a cell that possesses such activity, with an effective amount of Formula (I) or any one of Formulas (Ila)-(IIj), or any of the sub-formulae described herein, or a pharmaceutical composition a combination containing such compound. [0021] Other aspects and embodiments of the invention are described in or will be apparent from the detailed description and examples below.

Detailed Description

[0022] 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 invention belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0023] As used herein, “a” or “an” means “at least one” or “one or more”.

[0024] As used herein, the term “subject” refers to an animal. In certain aspects, the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a human. A “patient” as used herein refers to a human subject.

[0025] As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0026] As used herein, the term “treat”, “treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.

[0027] In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0028] As used herein, the term "a,” "an,” "the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. [0029] "Optionally substituted" means the group referred to can be unsubstituted or can be substituted at one or more positions by any one or any combination of the radicals suitable for substitution on that group, or those specified. The number, placement and selection of substituents is understood to encompass only those substitutions that a skilled chemist would expect to be reasonably stable; thus ‘oxo’ would not be a substituent on an aryl or heteroaryl ring, for example, and a single carbon atom would not have three hydroxy or amino substituents.

[0030] "Halo" or "halogen", as used herein, may be fluorine, chlorine, bromine or iodine.

[0031] " C 1 -C 6 alkyl", or “C 1-6 alkyl” and similar terms as used herein, denote straight chain or branched alkyl having 1-6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, then the definition is to be amended accordingly, such as "C 1 -C 4 alkyl" will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0032] " C 1 -C 6 alkoxy", or “C 1-6 alkoxy” as used herein, denotes straight chain or branched alkoxy having 1-6 carbon atoms. If a different number of carbon atoms is specified, such as C4 or C3, then the definition is to be amended accordingly, such as "C 1 -C 4 alkoxy" will represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0033] " C 1 -C 4 haloalkyl" or “C 1-4 haloalkyl” as used herein, denotes straight chain or branched alkyl having 1-4 carbon atoms wherein at least one hydrogen has been replaced with a halogen. The number of halogen replacements can be from one up to the number of hydrogen atoms on the unsubstituted alkyl group. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly. Thus " C 1 -C 4 haloalkyl" will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl that have at least one hydrogen substituted with halogen, such as where the halogen is fluorine: CF 3 CF 2 -, (CF 3 ) 2 CH-, CH 3 -CF 2 -, CF 3 CF 2 -, CF 3 , CF 2 H-, CF 3 CF 2 CHCF 3 or CF 3 CF 2 CF 2 CF 2 -.

[0034] “ C 3 -C 8 cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. If a different number of carbon atoms is specified, such as C 3 -C 6 , then the definition is to be adapted accordingly.

[0035] “3-6 membered cyclic ether” as used herein refers to a 3-6 membered saturated heterocyclic ring containing one oxygen atom as a ring member, including oxirane, oxetane, tetrahydrofuran, and tetrahydropyran. These 3-6 membered cyclic ethers can be substituted with groups suitable as substituents on other heterocyclic ring moieties. [0036] “4- to 8-Membered heterocyclyl”, “5- to 6-membered heterocyclyl”, “3- to 10- membered heterocyclyl”, “3- to 14-membered heterocyclyl”, “4- to 14-membered heterocyclyl” and “5- to 14-membered heterocyclyl”, refers, respectively, to 4- to 8-membered, 5- to 6- membered, 3- to 10-membered, 3- to 14-membered, 4- to 14-membered and 5- to 14-membered heterocyclic rings; unless otherwise specified, such rings contain 1 to 7, 1 to 5, or 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur as ring members, and the rings may be saturated, or partially saturated but not aromatic. The heterocyclic group can be attached at a heteroatom or a carbon atom. The term “heterocyclyl” includes single ring groups, fused ring groups and bridged groups. Examples of such heterocyclyl include, but are not limited to pyrrolidine, piperidine, piperazine, pyrrolidine, pyrrolidinone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1,4-oxathiane, 8-aza-bicyclo[3.2.1]octane, 3,8- diazabicyclo[3.2.1]octane, 3-Oxa-8-aza-bicyclo[3.2.1]octane, 8-Oxa-3-aza-bicyclo[3.2.1]octane, 2-Oxa-5-aza-bicyclo[2.2.1]heptane, 2,5-Diaza-bicyclo[2.2.1]heptane, azetidine, ethylenedi oxo, oxetane or thiazole. Preferred heterocycles or heterocyclic groups are 5-membered saturated rings containing one heteroatom selected from N, O and S, and 6-membered saturated rings containing one or two heteroatoms that are not adjacent, and are selected from N, O and S.

[0037] "Heteroaryl" is a completely unsaturated (aromatic) ring. The term "heteroaryl" refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O or S. Typically, the heteroaryl is a 5-10 membered ring or ring system (e.g., 5-7 membered monocyclic group or an 8-10 membered bicyclic group), often a 5-6 membered ring. Typical heteroaryl groups include furan, isothiazole, thiadiazole, oxadiazole, indazole, indole, quinoline, 2- or 3 -thienyl, 2- or 3 -furyl, 2- or 3 -pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5- oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(l ,2, 3-triazolyl), tetrazolyl, triazine, pyrimidine, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.

[0038] The term “hydroxy” or “hydroxyl” refers to the group -OH.

[0039] The term “alkyl” as used herein refers to saturated hydrocarbon groups in a straight, branched, or cyclic configuration or any combination thereof, and particularly contemplated alkyl groups include those having ten or less carbon atoms, especially 1-6 carbon atoms, and lower alkyl groups having 1-4 carbon atoms. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, etc.

[0040] Alkyl groups can be unsubstituted, or they can be substituted to the extent that such substitution makes sense chemically. Typical substituents include, but are not limited to, halo, =0, =N-CN, =N-OR a , =NR a , -OR a , -NR a 2 , -SR a , -SO 2 R a , -SO 2 NR a 2 , -NR a SO 2 R a , -NR a CONR a 2 , - NR a C00R a , -NR a COR a , -CN, -COOR a , -CONR a 2 , -OOCR a , -COR a , and -NO 2 , wherein each R a is independently H, C 1 -C 8 alkyl, C 2 -C 8 heteroalkyl, C 3 -C 8 heterocyclyl, C 4 -C 10 heterocyclyclalkyl, C 1 -C 8 acyl, C 2 -C 8 heteroacyl, C 2 -C 8 alkenyl, C 2 -C 8 heteroalkenyl, C 2 -C 8 alkynyl, C 2 -C 8 heteroalkynyl, C 6 -C 10 aryl, or C5-C10 heteroaryl, and each R a is optionally substituted with halo, =O, =N-CN, =N-OR b , =NR b , OR b , NR b 2 , SR b , SO 2 R b , SO 2 NR b 2 , NR b SO 2 R b , NR b CONR b 2 , NR b COOR b , NR b COR b , CN, COOR b , CONR b 2 , OOCR b , COR b , and NO 2 , wherein each R b is independently H, , C 1 -C 8 alkyl, C 2 -C 8 heteroalkyl, C 3 -C 8 heterocyclyl, C 4 -C 10 heterocyclyclalkyl, C 1 -C 8 acyl, C 2 -C 8 heteroacyl, C 2 -C 8 alkenyl, C 6 -C 10 aryl, or C 5 -C 10 heteroaryl. Alkyl, alkenyl and alkynyl groups can also be substituted by C 1 -C 8 acyl, C 2 -C 8 heteroacyl, C 6 -C 10 aryl or C 5 -C 10 heteroaryl, each of which can be substituted by the substituents that are appropriate for the particular group. Where a substituent group contains two R a or R b groups on the same or adjacent atoms (e.g., -NR b 2 , or -NR b -C(O) R b ), the two R a or R b groups can optionally be taken together with the atoms in the substituent group to which are attached to form a ring having 5-8 ring members, which can be substituted as allowed for the R a or R b itself, and can contain an additional heteroatom (N, O or S) as a ring member.

[0041] The term “alkenyl” as used herein refers to an alkyl as defined above having at least two carbon atoms and at least one carbon-carbon double bond. Thus, particularly contemplated alkenyl groups include straight, branched, or cyclic alkenyl groups having two to ten carbon atoms (e.g., ethenyl, propenyl, butenyl, pentenyl, etc.) or 5-10 atoms for cyclic alkenyl groups. Alkenyl groups are optionally substituted by groups suitable for alkyl groups as set forth herein.

[0042] Similarly, the term “alkynyl” as used herein refers to an alkyl or alkenyl as defined above and having at least two (preferably three) carbon atoms and at least one carbon-carbon triple bond. Especially contemplated alkynyls include straight, branched, or cyclic alkynes having two to ten total carbon atoms (e.g., ethynyl, propynyl, butynyl, cyclopropylethynyl, etc.). Alkynyl groups are optionally substituted by groups suitable for alkyl groups as set forth herein.

[0043] The term “cycloalkyl” as used herein refers to a cyclic alkane (i.e., in which a chain of carbon atoms of a hydrocarbon forms a ring), preferably including three to eight carbon atoms. Thus, exemplary cycloalkanes include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls also may include one or two double bonds, which form the “cycloalkenyl” groups. Cycloalkyl groups are optionally substituted by groups suitable for alkyl groups as set forth herein.

[0044] The term “aryl” or “aromatic moiety” as used herein refers to an aromatic ring system, which may further include one or more non-carbon atoms. These are typically 5-6 membered isolated rings, or 8-10 membered bicyclic groups, and can be substituted. Thus, contemplated aryl groups include (e.g., phenyl, naphthyl, etc.) and pyridyl. Further contemplated aryl groups may be fused (i.e., covalently bound with 2 atoms on the first aromatic ring) with one or two 5- or 6-membered aryl or heterocyclic group, and are thus termed “fused aryl” or “fused aromatic”.

[0045] Aromatic groups containing one or more heteroatoms (typically N, O or S) as ring members can be referred to as heteroaryl or heteroaromatic groups. Typical heteroaromatic groups include monocyclic 5-6 membered aromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, and imidazolyl and the fused bicyclic moieties formed by fusing one of these monocyclic groups with a phenyl ring or with any of the heteroaromatic monocyclic groups to form an 8-10 membered bicyclic group such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, pyrazolopy rimidyl, quinazolinyl, quinoxalinyl, cinnolinyl, and the like. Any monocyclic or fused ring bicyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition. It also includes bicyclic groups where at least the ring which is directly attached to the remainder of the molecule has the characteristics of aromaticity. Typically, the ring systems contain 5-12 ring member atoms. Preferred heteroaryl groups are 5-6 membered rings.

[0046] As also used herein, the terms “heterocycle”, “cycloheteroalkyl”, and “heterocyclic moieties” are used interchangeably herein and refer to any compound in which a plurality of atoms form a ring via a plurality of covalent bonds, wherein the ring includes at least one atom other than a carbon atom as a ring member. Particularly contemplated heterocyclic rings include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine, indole, pyridine, thiazole, tetrazole etc.). Typically, these rings contain 0-1 oxygen or sulfur atoms, at least one and typically 2-3 carbon atoms, and up to four nitrogen atoms as ring members. Further contemplated heterocycles may be fused (i.e., covalently bound with two atoms on the first heterocyclic ring) to one or two carbocyclic rings or heterocycles, and are thus termed “fused heterocycle” or “fused heterocyclic ring” or “fused heterocyclic moieties” as used herein. Where the ring is aromatic, these can be referred to herein as ‘heteroaryl’ or heteroaromatic groups.

[0047] Heterocyclic groups that are not aromatic can be substituted with groups suitable for alkyl group substituents, as set forth above.

[0048] Aryl and heteroaryl groups can be substituted where permitted. Suitable substituents include, but are not limited to, halo, -OR a , -NR a 2 , -SR a , -SC 2 R a , -SO 2 NR a 2 , -NR a SO 2 R a , - NR a CONR a 2 , -NR a COOR a , -NR a COR a , -CN, -COOR a , -CONR a 2 , -OOCR a , -COR a , and -NO 2 , wherein each R a is independently H, C 1 -C 8 alkyl, C 2 -C 8 heteroalkyl, C 3 -C 8 heterocyclyl, C 4 -C 10 heterocyclyclalkyl, C 1 -C 8 acyl, C 2 -C 8 heteroacyl, C 2 -C 8 alkenyl, C 2 -C 8 heteroalkenyl, C 2 -C 8 alkynyl, C 2 -C 8 heteroalkynyl, C 6 -C 10 aryl, or C5-C10 heteroaryl, and each R a is optionally substituted with halo, =O, =N-CN, =N-OR b , =NR b , OR b , NR b 2 , SR b , SO 2 R b , SO 2 NR b 2 , NR b SO 2 R b , NR b CONR b 2 , NR b COOR b , NR b COR b , CN, COOR b , CONR b 2 , OOCR b , COR b , and NO2, wherein each R b is independently H, C 1 -C 8 alkyl, C 2 -C 8 heteroalkyl, C3-C8 heterocyclyl, C 4 -C 10 heterocyclyclalkyl, C 1 -C 8 acyl, C 2 -C 8 heteroacyl, C 2 -C 8 alkenyl, C 6 -C 10 aryl, or C 5 -C 10 heteroaryl. Alkyl, alkenyl and alkynyl groups can also be substituted by C 1 -C 8 acyl, C 2 -C 8 heteroacyl, C 6 -C 10 aryl or C 5 - C 10 heteroaryl, each of which can be substituted by the substituents that are appropriate for the particular group. Where a substituent group contains two R a or R b groups on the same or adjacent atoms ( e.g., -NR b 2 , or -NR b -C(O) R b ), the two R a or R b groups can optionally be taken together with the atoms in the substituent group to which are attached to form a ring having 5-8 ring members, which can be substituted as allowed for the R a or R b itself, and can contain an additional heteroatom (N, O or S) as a ring member.

[0049] The term “alkoxy” as used herein refers to a hydrocarbon group connected through an oxygen atom, e.g., -O-Hc, wherein the hydrocarbon portion He may have any number of carbon atoms, typically 1-10 carbon atoms, may further include a double or triple bond and may include one or two oxygen, sulfur or nitrogen atoms in the alkyl chains, and can be substituted with aryl, heteroaryl, cycloalkyl, and/or heterocyclyl groups. For example, suitable alkoxy groups include methoxy, ethoxy, propyloxy, isopropoxy, methoxyethoxy, benzyloxy, allyloxy, and the like. Similarly, the term “alkylthio” refers to alkylsulfides of the general formula -S-Hc, wherein the hydrocarbon portion He is as described for alkoxy groups. For example, contemplated alkylthio groups include methylthio, ethylthio, isopropylthio, methoxyethylthio, benzylthio, allylthio, and the like.

[0050] The term ‘amino’ as used herein refers to the group -NH2. The term “alkylamino” refers to amino groups where one or both hydrogen atoms are replaced by a hydrocarbon group He as described above, wherein the amino nitrogen “N” can be substituted by one or two He groups as set forth for alkoxy groups described above. Exemplary alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, etc. Also, the term “substituted amino” refers to amino groups where one or both hydrogen atoms are replaced by a hydrocarbon group He as described above, wherein the amino nitrogen “N” can be substituted by one or two He groups as set forth for alkoxy groups described above.

[0051] The term ‘acyl’ as used herein refers to a group of the formula -C(=O)-D, where D represents an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle as described above. Typical examples are groups wherein D is a C 1 -C 10 alkyl, C 2 -C 10 alkenyl or alkynyl, or phenyl, each of which is optionally substituted. In some embodiments, D can be H, Me, Et, isopropyl, propyl, butyl, C 1 -C 4 alkyl substituted with -OH, -OMe, or NH 2 , phenyl, halophenyl, alkylphenyl, and the like.

[0052] The term “aryloxy” as used herein refers to an aryl group connecting to an oxygen atom, wherein the aryl group may be further substituted. For example, suitable aryloxy groups include phenyloxy, etc. Similarly, the term “arylthio” as used herein refers to an aryl group connecting to a sulfur atom, wherein the aryl group may be further substituted. For example, suitable arylthio groups include phenylthio, etc.

[0053] The hydrocarbon portion of each alkoxy, alkylthio, alkylamino, and aryloxy, etc. can be substituted as appropriate for the relevant hydrocarbon moiety.

[0054] The following enumerated embodiments are representative of some aspects of the invention:

1. A compound of Formula (I):

wherein: one or two of W, X, Y and Z is N or N→ 0 (i.e., N-oxide, having N as a ring atom in the form of an N-oxide), and the other two or three of W, X, Y and Z are each CR 6 ;

R 1 is C 1-6 alkyl optionally substituted with up to three groups selected from halo, hydroxy, CN, C 1-4 alkoxy, and C 1-4 haloalkoxy, or R 1 is H;

R 2 is selected from -(C 0-4 alkyl)-C 3-6 cycloalkyl, C 1-6 alkyl, and H, wherein each alkyl and cycloalkyl is optionally substituted with up to three groups selected from C 1-2 alkyl, halo, hydroxy, CN, C 1-2 alkoxy, C 1-2 haloalkyl, and C 1-2 haloalkoxy;

R 3 and R 5 are each independently selected from halo, C 1-2 haloalkyl, CN, C 1-2 thioalkyl, and C2-4 alkynyl,

R 4 is H, C 1-6 acyl, or C 1-6 alkyl sulfonyl; and each R 6 is independently selected from H, halo, hydroxy, CN, C 1-2 alkyl, C 1-2 alkoxy, C 1-2 haloalkyl, and C 1-2 haloalkoxy; or a pharmaceutically acceptable salt thereof.

In these embodiments, typically not more than one of W, X, Y and Z is N→ O. In preferred embodiments of these compounds, one or two of W, X, Y and Z is N, i.e., none of W, X, Y and Z is N→O.

2. The compound of embodiment 1, wherein W and X each represent CR 6 ; or a pharmaceutically acceptable salt thereof. In some of these embodiments, each R 6 is H.

3. The compound of embodiment 1 or 2, wherein Y is N; or a pharmaceutically acceptable salt thereof.

4. The compound of any one of embodiments 1-3, wherein Z is N; or a pharmaceutically acceptable salt thereof.

5. The compound of embodiment 1 or 2, wherein Y is N and Z is CR 6 , or a pharmaceutically acceptable salt thereof. In preferred examples of this embodiment, each R 6 is H.

6. The compound of embodiment 1 or 2, wherein Y is CR 6 and Z is N; or a pharmaceutically acceptable salt thereof. In preferred examples of this embodiment, each R 6 is H.

7. The compound of any one of embodiments 1-6, wherein R 2 is selected from C 1-6 alkyl and C 3-6 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with up to three groups selected from C 1-2 alkyl, halo, hydroxy, CN, C 1-2 alkoxy, C 1-2 haloalkyl, and C 1-2 haloalkoxy; or a pharmaceutically acceptable salt thereof.

In some of these embodiments, R 2 is C 2 -C 6 alkyl or C 3 -C 5 cycloalkyl. In a preferred embodiment, R 2 is selected from ethyl, isopropyl, cyclopropyl and cyclobutyl.

8. The compound of any one of embodiments 1-7, wherein R 1 is C 1-6 alkyl optionally substituted with C 1-4 alkoxy; or a pharmaceutically acceptable salt thereof.

9. The compound of any one of the preceding embodiments, wherein R 3 and R 5 are independently selected from F, Br, Cl, CN, SMe and ethynyl; or a pharmaceutically acceptable salt thereof.

In some of these embodiments, R 3 and R 5 are each independently selected from F, Cl and Br. In these embodiments R 3 and R 5 may be the same or different. In some of these embodiments, R 3 and R 5 are the same and are selected from Cl and Br.

10. The compound of any of the preceding embodiments, wherein R 4 is H; or a pharmaceutically acceptable salt thereof. 11. The compound of embodiment 6, wherein each R 6 is independently selected from H, Me, and OMe; or a pharmaceutically acceptable salt thereof. In some embodiments, each R 6 is H.

12. The compound of any one of the preceding embodiments, which is a compound of one of the following formulas:

or a pharmaceutically acceptable salt thereof.

13. A compound of embodiment 1 that is selected from the compounds in Table 1 and Table 2, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of any of the preceding embodiments admixed with at least one pharmaceutically acceptable carrier or excipient.

15. A method to treat gout, which comprises administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-13, or a pharmaceutical composition of embodiment 14. 16. A compound according to any one of embodiments 1-13 for use in therapy. Typically, the use in therapy is for treatment of gout.

17. Use of a compound according to any one of embodiments 1-13 for use in the manufacture of a medicament. Typically, the medicament is for treatment of gout.

18. A pharmaceutical combination comprising an effective amount of a compound according to any one of embodiments 1-13 and an additional therapeutic agent. Typically, the additional therapeutic agent is for treating gout.

[0055] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

[0056] It should further be recognized that all of the above-defined groups may further be substituted with one or more substituents, which may in turn be substituted with hydroxy, amino, cyano, C 1 -C 4 alkyl, halo, or C 1 -C 4 haloalkyl. For example, a hydrogen atom in an alkyl or aryl can be replaced by an amino, halo or C 1 -C 4 haloalkyl or alkyl group.

[0057] It is understood that in all substituted groups defined above, compounds arrived at by defining substituents with further substituents to themselves e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl.

[0058] As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0059] The term “an optical isomer” or “a stereoisomer” refers to any of the various stereoisomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. The term "chiral" refers to molecules which have the property of non- superimposability on their mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. “Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic” mixture. The term is used to designate a racemic mixture where appropriate. "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0060] Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. The present invention is meant to include all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms except where otherwise specified. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a di- or tri-substituted double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0061] Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers or diastereomers, for example, by chromatography and/or fractional crystallization. [0062] Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di- 0,0'- -toluoyl tartaric acid, mandelic acid, malic acid or camphor- 10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral stationary phase, for example.

[0063] Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0064] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0065] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

[0066] Organic solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the complex where the solvent molecule is water.

[0067] The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs. [0068] As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the present invention. “Salts” include in particular “pharmaceutically acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

[0069] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandi sulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.

[0070] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0071] The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0072] The compounds and compositions described herein can be administered to a subject in need of treatment for a hyperuricemic condition such as gout.

[0073] The subject for treatment with compounds and pharmaceutical compositions of the invention is typically a mammal diagnosed as being in need of treatment for one or more of such hyperuricemia disorders, and frequently the subject is a human diagnosed with gout. The methods comprise administering an effective amount of at least one compound of the invention; optionally the compound may be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful for treating gout in the particular subject.

[0074] Compounds of the invention may be used in the treatment of states, disorders or diseases as described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases. The invention provides methods of use of compounds of the present invention in the treatment of these diseases or for preparation of pharmaceutical compositions having compounds of the present invention for the treatment of these diseases.

[0075] The term “pharmaceutical composition” includes preparations suitable for administration to mammals, e.g., humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of a compound of Formula (I) or any one of Formulas (Ila)-(IIj), or any subgenus thereof described herein as active ingredient in combination with a pharmaceutically acceptable excipient, and optionally two or more pharmaceutically acceptable excipients.

[0076] The phrase “pharmaceutically acceptable excipient” is understood by those of skill in the art, and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals. The excipients include liquid or solid filler, diluent, carrier, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body, or in making the drug product more easly formulated, tableted, stored, used, or administered. Each excipient must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable excipients include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Typically, pharmaceutically acceptable excipients are sterilized and/or substantially pyrogen-free.

[0077] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0078] Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α- tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0079] Formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.

[0080] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier or excipient and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid excipient, or finely divided solid excipient, or both, and then, if necessary, shaping the product.

[0081] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, for example, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[0082] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0083] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0084] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0085] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0086] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0087] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [0088] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0089] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable excipient, and with any preservatives, buffers, or propellants that may be required.

[0090] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0091] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0092] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable carriers such as sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0093] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, glycol ethers, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0094] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0095] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0096] The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories.

[0097] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. Intravenous infusion is sometimes a preferred method of delivery for compounds of the invention. Infusion may be used to deliver a single daily dose or multiple doses. In some embodiments, a compound of the invention is administered by infusion over an interval between 15 minutes and 4 hours, typically between 0.5 and 3 hours. Such infusion may be used once per day, twice per day or up to three times per day.

[0098] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intraci sternally and topically, as by powders, ointments or drops, including buccally and sublingually.

[0099] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.

[00100] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[00101] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[00102] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[00103] In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day. An effective amount is an amount that achieves a desired or observable therapeutic effect.

[00104] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Compounds delivered orally or by inhalation, are commonly administered in one to four doses per day. Compounds delivered by injection are typically administered once per day, or once every other day. Compounds delivered by infusion are typically administered in one to three doses per day. [00105] While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition such as those described herein.

Pharmaceutical compositions, combinations, and other related uses

[00106] In still another aspect, the present disclosure provides for a pharmaceutical composition comprising a compound of Formula (I) or any one of Formulas (Ila)-(IIj), or any of the subformulae thereof described herein, admixed with at least one pharmaceutically acceptable carrier or excipient.

[00107] The above described compounds can be used for any suitable purpose. For example, the present compounds can be used in therapy and/or testing.

[00108] In yet another aspect, the present disclosure provides for a method for treating and/or preventing a hyperuricemic disorder such as gout. The compounds, compositions and methods are particularly useful for conditions associated with excessive levels of sUA or excessive activity of URAT 1.

[00109] In yet another aspect, the present disclosure provides for a use of a compound described above for the manufacture of a medicament.

[00110] In yet another aspect, the present disclosure provides for a combination for treating and/or preventing gout or other conditions caused by elevated sUA levels, which combination comprises an effective amount of a compound of Formula (I) or any one of Formulas (Ila)-(IIj), or any of the subformulae thereof disclosed herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a second prophylactic or therapeutic agent for treating and/or preventing gout.

[00111] In yet another aspect, the present disclosure provides for a method for inhibiting an activity of URAT 1 in a subject, which comprises admistering to the subject an effective amount of a compound of Formula (I) or Formula (II) as described herein.

[00112] In another aspect, the invention provides a method to inhibit activity of URAT 1 in a tissue or cell, which comprises contacting the tissue or cell with an effective amount of a compound of Formula (I) or any one of Formulas (Ila)-(IIj) as described herein.

[00113] In some embodiments, the compound is any of the compounds of the Examples disclosed herein. Formulations

[00114] Any suitable formulation of the compounds described herein can be prepared. See generally, Remington's Pharmaceutical Sciences, (2000) Hoover, J. E. editor, 20 th edition, Lippincott Williams and Wilkins Publishing Company, Easton, Pa., pages 780-857. A formulation is selected to be suitable for an appropriate route of administration. In cases where compounds are sufficiently acidic to form stable nontoxic base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts are obtained using standard procedures well known in the art, for example, by a sufficiently basic compound such as an amine with a suitable acid, affording a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal e.g., calcium) salts, as well as amine salts of carboxylic acids and tetrazoles also are made.

[00115] Where contemplated compounds are administered in a pharmacological composition, it is contemplated that the compounds can be formulated in admixture with a pharmaceutically acceptable excipient and/or carrier. For example, contemplated compounds can be administered orally as neutral compounds or as pharmaceutically acceptable salts, or intravenously in a physiological saline solution. Conventional buffers such as phosphates, bicarbonates or citrates can be used for this purpose. Of course, one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration. In particular, contemplated compounds may be modified to render them more soluble in water or other vehicle, which for example, may be easily accomplished with minor modifications (salt formulation, esterification, etc.) that are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to select or modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in a patient. [00116] The compounds of Formula (I) or any one of Formulas (Ila)-(IIj) or any subformula thereof as described herein are generally soluble in organic solvents such as chloroform, di chloromethane, ethyl acetate, ethanol, methanol, isopropanol, acetonitrile, glycerol, N,N- dimethylformamide, N,N-dimetheylaceatmide, dimethylsulfoxide, etc. In one embodiment, the present invention provides formulations prepared by mixing a compound having formula I-II with a pharmaceutically acceptable excipient. In one aspect, the formulation may be prepared using a method comprising: a) dissolving a described compound in a water-soluble organic solvent, a non-ionic solvent, a water-soluble lipid, a vitamin such as tocopherol, a fatty acid, a fatty acid ester, or a combination thereof, to provide a solution; and b) adding saline or a buffer containing 1-10% carbohydrate solution. In one example, the carbohydrate comprises dextrose. The pharmaceutical compositions obtained using the present methods are stable and useful for animal and clinical applications.

[00117] Illustrative examples of water soluble organic solvents for use in the present methods include and are not limited to polyethylene glycol (PEG), alcohols, acetonitrile, N-methyl-2- pyrrolidone, N,N-dimethyl form am ide, N,N-dimethyl acetamide, dimethyl sulfoxide, or a combination thereof. Examples of alcohols include but are not limited to methanol, ethanol, isopropanol, glycerol, or propylene glycol.

[00118] Illustrative examples of water soluble non-ionic surfactants for use in the present methods include and are not limited to CREMOPHOR® EL, polyethylene glycol modified CREMOPHOR® (polyoxyethyleneglyceroltriricinoleat 35), hydrogenated CREMOPHOR® RH40, hydrogenated CREMOPHOR® RH60, PEG-succinate, polysorbate 20, polysorbate 80, SOLUTOL® HS (polyethylene glycol 660 12-hydroxy stearate), sorbitan monooleate, pol oxamer, LABRAFIL® (ethoxylated persic oil), LABRASOL® (capryl-caproyl macrogol-8-glyceride), GELUCIRE® (glycerol ester), SOFTIGEN® (PEG 6 caprylic glyceride), glycerin, glycol- polysorbate, or a combination thereof.

[00119] Illustrative examples of water soluble lipids for use in the present methods include but are not limited to vegetable oils, triglycerides, plant oils, or a combination thereof. Examples of lipid oils include but are not limited to castor oil, polyoxyl castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, a triglyceride of coconut oil, palm seed oil, and hydrogenated forms thereof, or a combination thereof. [00120] Illustrative examples of fatty acids and fatty acid esters for use in the present methods include but are not limited to oleic acid, monoglycerides, diglycerides, a mono- or di- fatty acid ester of PEG, or a combination thereof.

[00121] One of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration. In particular, the compounds may be modified to render them more soluble in water or other vehicle. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in a patient.

Drug combinations

[00122] The methods of the embodiments comprise administering an effective amount of at least one exemplary compound of the present disclosure; optionally the compound may be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful for treating the condition or disease afflicting the subject, such as gout.

[00123] The additional active ingredients may be administered in a separate pharmaceutical composition from at least one exemplary compound of the present disclosure or may be included with at least one exemplary compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of at least one exemplary compound of the present disclosure.

[00124] Suitable additional active ingredients or therapeutic agents for use in such methods and combinations include non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, corticosteroids, xanthine oxidase inhibitors such as allopurinol and febuxostat, and other uricosuric drugs such as probenecid or lesinurad.

Methods of using the exemplary compounds and pharmaceutical compositions thereof

[00125] The present invention also provides pharmaceutical compositions for the treatment and/or prevention of a hyperuricemia disorder such as gout, comprising any compound of Formula (I) or any one of Formulas (Ila)-(IIj) or any subformula thereof as described herein, or any of the compounds in Table 1 or Table 2 herein. [00126] To practice the method of the present invention, compounds having formula and pharmaceutical compositions thereof may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, or other drug administration methods. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[00127] A sterile injectable composition, such as a sterile injectable aqueous or oleaginous suspension, may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed include mannitol, water, Ringer’s solution and isotonic sodium chloride solution. Suitable carriers and other pharmaceutical excipient are typically sterile.

[00128] In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or di glycerides). Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents. Various emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation.

[00129] A composition for oral administration may be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, can also be added. For oral administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If needed, certain sweetening, flavoring, or coloring agents can be added. A nasal aerosol or inhalation compositions can be prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in, for example saline, employing suitable preservatives (for example, benzyl alcohol), absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents known in the art.

[00130] In addition, the compounds of Formula (I) or any one of Formulas (Ila)-(IIj) or any subformula thereof as described herein, may be administered alone or in combination with other therapeutic agents (active ingredients), e.g., therapeutic agents for the treatment of a subject in need of treatment for gout. Combination therapies according to the present invention comprise the administration of at least one exemplary compound of Formula (I) or any one of Formulas (Ila)-(IIj) or any subformula thereof as described herein and at least one additional pharmaceutically active ingredient. The compound of the invention and additional pharmaceutically active agents may be administered separately or together. The amounts of the compound of the invention and of the additional pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

[00131] The compounds as described herein may be synthesized by the general synthetic routes below, specific examples of which are described in more detail in the Examples.

[00132] Within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a “protecting group,” unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as e.g., Science of Synthesis: Houben- Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp. (URL: http://www.science-of-synthesis.com (Electronic Version, 48 Volumes)); J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be removed readily (i.e., without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g., by enzymatic cleavage).

[00133] Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se. For example, salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethyl hexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used. Acid addition salts of compounds of the present invention are obtained in customary manner, e.g., by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g., a free carboxy group and a free amino group, may be formed, e.g., by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g., with weak bases, or by treatment with ion exchangers.

[00134] Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.

[00135] Mixtures of isomers obtainable according to the invention can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by, e.g., medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.

[00136] Intermediates and final products can be worked up and/or purified according to standard methods, e.g., using chromatographic methods, distribution methods, (re-) crystallization, and the like. [00137] The process steps to synthesize the compounds of the invention can be carried out under reaction conditions that are known per se, including those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g., in the H+ form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about - 100 °C to about 190°C, including, for example, from approximately -80°C to approximately 150°C, for example at from -80 to -60°C, at room temperature, at from -20 to 40°C or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.

[00138] At all stages of the reactions, mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described in Science of Synthesis: Houben-Weyl Methods of Molecular Transformation, Georg Thieme Verlag, Stuttgart, Germany, 2005.

[00139] The solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofurane or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2- propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in working up, for example by chromatography or partitioning.

[00140] The compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present. [00141] The invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.

[00142] In accordance with the foregoing the present invention provides in a yet further aspect:

[00143] A pharmaceutical combination comprising a) a first agent which is a compound of the invention, e.g. a compound of Formula (I) or any subformulae thereof, particularly ones disclosed herein, and b) a co-agent, e.g. an additional pharmaceutically active agent as defined above.

[00144] A method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a compound of the invention, e.g. a compound of Formula I or any subformulae thereof, and a co-agent, e.g. an additional therapeutic agent as defined above.

[00145] The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. Fixed combinations are also within the scope of the present invention. The administration of a pharmaceutical combination of the invention results in a beneficial effect, e.g. a synergistic therapeutic effect, compared to a monotherapy applying only one of its pharmaceutically active ingredients.

[00146] Each component of a combination according to this invention may be administered separately, together, or in any combination thereof.

[00147] The compound of the invention and any additional agent may be formulated in separate dosage forms. Alternatively, to decrease the number of dosage forms administered to a patient, the compound of the invention and any additional agent may be formulated together in any combination. For example, the compound of the invention inhibitor may be formulated in one dosage form and the additional agent may be formulated together in another dosage form. Any separate dosage forms may be administered at the same time or different times. [00148] Alternatively, a composition of this invention comprises an additional agent as described herein. Each component may be present in individual compositions, combination compositions, or in a single composition.

ABBREVIATIONS

Ac acetyl

ACN Acetonitrile

AcOEt / EtO Ac Ethyl acetate

AcOH acetic acid aq. aqueous

Ar aryl

Bn benzyl

Bu butyl (nBu = n-butyl, tBu = tert-butyl)

CDI Carbonyldiimidazole

CH3CN Acetonitrile

DBU 1,8-Diazabicyclo[5.4.0]-undec-7-ene

DBDMH 1,3-Dibromo-5,5-Dimethylhydantoin

Boc 2 O di -tert-butyl dicarbonate

DCE 1,2-Dichloroethane

DCM Dichloromethane

DIBAL-H Diisobutylaluminum Hydride

DIPEA N-Ethyl dii sopropy 1 amine

DMA N,N-dimethylacetamide

DMAP Dimethylaminopyridine

DMF N,N’-Dimethylformamide

DMP Dess-Martin Periodinane

DMSO Dimethylsulfoxide

El Electrospray ionisation

Et 2 O Diethylether

Et 3 N Triethylamine eq Equivalent

Ether Diethylether EtOAc or EA Ethylacetate

EtOH Ethanol

FC Flash Chromatography h hour(s)

HATU O-(7- Azabenzotri azole- 1 -yl)-N,N,N’N’ - tetramethyluronium hexafluorophosphate

HBTU O-(Benzotriazol-l-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate

HC1 Hydrochloric acid

HMPA Hexamethylphosphoramide

HOBt 1 -Hydroxybenzotri azole

HPLC High Performance Liquid Chromatography

H 2 O Water

L liter(s)

LC-MS Liquid Chromatography Mass Spectrometry

LDA Lithium di-isopropyl amide

LiHMDS Lithium bis(trimethylsilyl)amide mCPBA meta-chloroperoxybenzoic acid

MgSO 4 Magnesium Sulfate

Me methyl

Mel lodomethane

MeOH Methanol mg milligram min minute(s) mL milliliter

MS Mass Spectrometry

MTO methyltrioxorhenium

NaHCO 3 Sodium Bicarbonate

Na 2 SO 4 Sodium Sulfate

NBS N-Bromosuccinimide

NH 2 OH hydroxylamine

Pd/C palladium on charcoal Pd(OH) 2 palladium hydroxide

PE petroleum ether

PG protecting group

Ph phenyl

PI13P triphenyl phosphine

Prep Preparative

Rf ratio of fronts

RP reverse phase

Rt Retention time

RT or rt Room temperature sat. Saturated

SiC 2 Silica gel

SOCl 2 Thionyl Chloride

TBAF Tetrabutylammonium fluoride

TBDMS t-Butyldimethylsilyl

TEA Triethylamine

TFA Trifluoroacetic acid

TFAA Trifluoroacetic anhydride

TfOH Triflic acid

THF Tetrahydrofuran

TLC Thin Layer Chromatography

TsCl toluene sulfonyl chloride

[00149] The compounds of the invention can be produced by organic synthesis methods known to one of ordinary skill in the art with reference to the following reaction schemes and examples. General methods for synthesis of compounds of Formula (I) are provided in Schemes 1-5 below.

General Synthetic Procedures

[00150] Compounds of the present invention are prepared from commonly available compounds using procedures known to those skilled in the art in view of the examples and Scheme 1.

[00151] Compounds of Formula (I) can be prepared according to Scheme 1 using available starting materials and reagents. Acylation of amine-containing starting material A gives intermediate B, which can be cyclized by LDA to afford intermediate C. Treatment of intermediate C with alkylation reagent such as R 1 -halide or Me 2 SO 4 under basic condition will afford the key intermediate D. A formyl group can be installed by reacting intermediate D with dichloro(methoxy)methane to give intermediate E. Treatment of intermediate E with (4- (benzyloxy)phenyl)magnesium bromide will give intermediate F which can be oxidized with MnO 2 or DMP to give intermediate G. Deprotection of benzyl group can be achieved by TFA and TfOH, and the final product I can be produced by bromination of intermediate H with NBS or DBDMH or similarly chlorinated with an electrophilic chlorinating reagent such as NCS. Depending on the choice of R 1 and R 2 , the product can be a compound of Formula (I) or a precursor to such compounds. Scheme 2.

[00152] Compounds of formula (I) can also be prepared according to Scheme 2. Starting from key intermediate D, a Friedel-Crafts reaction can afford intermediate J. The methyl group may be removed by AlCl 3 during the reaction and acylated to give R-protected phenol. Removal of R group can be achieved by NaOH or by other known means, depending on the protecting group R that is chosen, to give the final product K. In case the methyl group was not removed by AlCl 3 , BBr 3 can be used to remove the methyl group. Again, depending on the choice of R 1 , R 2 , R 3 and R 5 , the product can be a compound of Formula (I) or a precursor to such compounds.

Scheme 3

[00153] Intermediate C can be also prepared according to Scheme 3. A Sonogashira reaction of starting material L and R 2 carrying alkyne will give intermediate M, which can be cyclized to intermediate C by treatment of t-BuOK (potassium tert-butoxide).

Scheme 4. [00154] The intermediate H can also be prepared according to Scheme 4. Intermediate D is reacted with protected 4-hydroxylbenzoyl chloride under AlCl 3 to give intermediate N. Depending on the R group, different methods can be used to remove protecting group R to give the intermediate H.

Scheme 5.

[00155] Intermediate G can also be prepared according to Scheme 5. Intermediate O is prepared by reacting of intermediate M with TFAA. Upon treatment of intermediate O with Pd(PPh 3 ) 4 under CO atmosphere, a tandem reaction of cyclization, CO insertion and coupling with benzyl protected phenol takes place to provide the intermediate P. Alkylation of P with alkylation reagent such as R 1 -halide or Me 2 SO 4 gives the intermediate G.

[00156] Using these and known alternative starting materials, the skilled person can prepare a wide variety of compounds of Formula (I).

EXAMPLES

[00157] Example 1 : (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1H-pyrrolo[2,3-c]pyrid in-3- yl)methanone

[00158] Step 1 : N-(4-methylpyridin-3-yl)propionamide.

[00159] To a solution of 4-methylpyri din-3 -amine (2.0 g, 18.5 mmol, 1.0 eq) in THF (40 mL) were slowly added TEA (2.8 g, 27.8 mmol, 1.5 eq), propionyl chloride (2.04 g, 22.2 mmol, 1.2 eq) in THF at 0 °C. The mixture was stirred at r.t for 3 h under Ar. The reaction was monitored with LC-MS until completion. The mixture was quenched with aq. NH 4 Cl and extracted with DCM. The combined organic layer was washed with brine, dried over Na 2 SO 4 , concentrated under reduced pressure to give the title compound (3.3 g, 99.6 %) as yellow solid. LC-MS (m/z): [M+H]+ = 165.3.

[00160] Step 2: 2-ethyl-1H-pyrrolo[2,3-c]pyridine.

[00161] To a solution of N-(4-methylpyridin-3-yl)propionamide (1.0 g, 6.1 mmol, 1.0 eq) in THF (50 mL) was added 2.0 M LDA (15.2 mL, 30.5 mmol, 5.0 eq) at 0 °C. The mixture was stirred at 70 °C for 48 h, and then quenched with NH4CI (aq). The mixture was extracted with DCM, and the combined organic phase was washed with brine, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 0-5% DCM/MeOH) to give the title compound (310 mg, 34.6%) as a solid. LC-MS (m/z): [M+H] + = 147.1.

[00162] Step 3: 2-ethyl-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde.

[00163] At 0 °C, to a stirring solution of 2-ethyl-1H-pyrrolo[2,3-c]pyridine (310 mg, 2.12 mmol, 1.0 eq) in CH 3 NO 2 /DCE (15 mL/15 mL) was added dichloro(methoxy)methane (1.22 g, 10.6 mmol, 5.0 eq), then followed by AICL (849 mg, 6.37 mmol, 3.0 eq). The stirring was continued for 16 h at RT. The reaction mixture was adjusted to pH 7-8 with NaHCCF (aq) at 0 °C, and then extracted with DCM. The combined organic phase was washed with brine, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 0-10% DCM/MeOH) to give the title compound (180 mg, 23.6%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 175.1.

[00164] Step 4: (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl) methanol.

[00165] At 0 °C, to a solution of 2-ethyl-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (275 mg,

I.58 mmol, 1.0 eq) in THF (10 mL) was added (4-(benzyloxy)phenyl)magnesium bromide (0.8 M, 2.96 mL, 2.37 mmol, 1.5 eq). The mixture was warmed up and stirred at RT for 0.5 h before being quenched with sat. NH4CI solution. The mixture was extracted with DCM, and the combined organics were dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 10% DCM/MeOH) to give the title compound (378 mg, 66.7 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 359.1.

[00166] Step 5: (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl) methanone.

[00167] To a solution of (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[2,3-c]pyridin-3- yl)methanol (398 mg, 1.1 mmol, 1.0 eq) in DCM/THF (1 : 1, 10 mL) was added Mn02 (965 mg,

11.1 mmol, 10.0 eq), and the reaction mixture was stirred at 40 °C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel (eluent: 0-10% DCM/MeOH) to give the title compound (200 mg, 51%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 357.5.

[00168] Step 6: (2-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4-hydroxyphenyl)meth anone.

[00169] To a solution of (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[2,3-c]pyridin-3- yl)methanone (30 mg, 0.08 mmol, 1.0 eq) in DCM (20 mL) were added TFA (0.5 mL) and TfOH (0.2 mL), and it was stirred for 1 h at RT. The mixture was adjusted to pH >7 with 1 N NaOH then to pH 6 with NH 4 CI (aq). It was extracted with DCM, and the combined organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound (22 mg, 100%) as yellow solid which was used in next step without further purification. LC-MS: [M+H]+ (m/z) = 267.4.

[00170] Step 7: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1H-pyrrolo[2,3-c]pyrid in-3- yl)methanone.

[00171] At 0 °C, to a stirring solution of (2-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4- hydroxyphenyl)methanone (22 mg, 0.084 mmol, 1.0 eq) in MeCN/THF/DCM (5/1/1 mL) was added slowly a solution of NBS (117 mg, 0.66 mmol, 2.2 eq) in MeCN, and the resulting mixture was stirred for 10 min at 0 °C. The mixture was quenched with Na 2 S 2 O 3 (aq), and filtered. The filtrate was concentrated and purified by prep-HPLC (mobile phase: CH3CN/H2O with 0.1% HCO 2 H) to give the title compound (16 mg, 45.5 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 422.8; 1 H NMR (400 MHz, CD 3 OD) δ 8.89 (s, 1H), 8.20 (d, J = 6.4 Hz, 1H), 7.88 (s, 2H), 7.60 (d, J = 6.0 Hz, 1H), 3.09 (q, J = 7.6 Hz, 2H), 1.40 (t, J = 7.6 Hz, 3H).

[00172] Example 2: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[2, 3- c]pyridin-3-yl)methanone

[00173] Step 1 : (4-(benzyloxy)phenyl)(2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyri din-3- yl)methanone.

[00174] At 0 °C, to a solution of (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[2,3-c]pyridin-3- yl)methanone (80 mg, 0.22 mmol, 1.0 eq) in dry DMF (2 mL) was added NaH (13 mg, 0.34 mmol, 1.5 eq). The mixture was stirred for 0.5 h at 0 °C, and then a solution of Mel (35 mg, 0.25 mmol, 1.1 eq) in DMF was added dropwise. The mixture was stirred for another 30 min at 0 °C before being quenched with aq. NH4CI, and then extracted with EA. The combined organic layer was dried over Na 2 SO 4 , concentrated under reduced pressure and purified by prep-TLC (eluent: 10% DCM/MeOH) to give the title compound (16 mg, 14%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 371.2.

[00175] Step 2: (2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4- hydroxyphenyl)m ethanone.

[00176] To a solution of (4-(benzyloxy)phenyl)(2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyri din- 3-yl)methanone (19 mg, 0.05 mmol, 1.0 eq) in DCM (3 mL) were added TFA (0.5 mL) and TfOH (0.2 mL). After it was stirred for 1 h at RT, the mixture was adjusted to pH>7 with IN NaOH, then to pH 6-7 with NH4CI (aq). The mixture was extracted with DCM, and the combined organic layer was dried over Na 2 SO 4 , and concentrated under reduced pressure to give the title compound (14 mg, 100 %) as a yellow solid which was used in the next step without further purification. LC-MS: [M+H]+ (m/z) = 281.2.

[00177] Step 3: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[2, 3-c]pyridin- 3-yl)methanone.

[00178] At 0 °C, to a stirring solution of (2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4- hydroxyphenyl)methanone (14 mg, 0.05 mmol, 1.0 eq) in THF (5 mL) was slowly added a solution of NBS (20 mg, 0.11 mmol, 2.2 eq) in THF. The mixture was stirred at 0 °C for 10 min before being quenched with Na 2 SO 3 (aq). The mixture was filtered, and the filtrate was concentrated and purified by Prep-HPLC (mobile phase: CH 3 CN/H 2 O with 0.1% HCO2H) to give the title compound (11.12 mg, 50 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 436.8; 1 H NMR (400 MHz, CD 3 OD) δ 8.95 (s, 1H), 8.16 (d, J = 6.0 Hz, 1H), 7.84 (s, 2H), 7.33 (d, J = 5.6 Hz, 1H), 4.01 (s, 3 H), 3.14 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H).

[00179] Example 3: (3,5-dibromo-4-hydroxyphenyl)(1,2-diethyl-1H-pyrrolo[2,3-c]p yridin-3- yl)methanone

[00180] Step 1 : (4-(benzyloxy)phenyl)(1,2-diethyl-1H-pyrrolo[2,3-c]pyridin-3 -yl)methanone.

[00181] At 0 °C, to a solution of (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[2,3-c]pyridin-3- yl)methanone (230 mg, 0.64 mmol, 1.0 eq) in dry DMF (10 mL) was added CS2CO3 (13 mg, 0.70 mmol, 1.1 eq). The mixture was stirred for 0.5 h at 0 °C, and then a solution of C2H5I (35 mg, 0.25 mmol, 1.1 eq) in DMF was added dropwise. The reaction mixture was stirred at RT for 16 h, and then quenched with ice-water. The mixture was extracted with EA, and the combined organic layer was dried over Na 2 SO 4 , concentrated under reduced pressure and purified by prep- TLC (eluent: 8% DCM/MeOH) to give the title compound (50 mg, 37.3 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 385.5.

[00182] Step 2: (1,2-diethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4-hydroxyphenyl) methanone.

[00183] To a mixture of (4-(benzyloxy)phenyl)(1,2-diethyl-1H-pyrrolo[2,3-c]pyridin-3 - yl)methanone (50 mg, 0.13 mmol, 1.0 eq) in DCM (5 mL) were added TFA (0.5 mL) and TfOH (0.25 mL), and the reaction mixture was stirred at RT for 1 h. The mixture was adjusted to pH>7 with IN NaOH, then to pH6-7 with NH4CI (aq). It was extracted with DCM, and the combined organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound (38 mg, 100%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 295.5.

[00184] Step 3: (3,5-dibromo-4-hydroxyphenyl)(1,2-diethyl-1H-pyrrolo[2,3-c]p yridin-3- yl)methanone. At 0 °C, to a stirring solution of (1,2-diethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4- hydroxyphenyl)methanone (38 mg, 0.13 mmol, 1.0 eq) in THF (10 mL) was added slowly a solution of NBS (46 mg, 0.26 mmol, 2.0 eq) in THF. The mixture was stirred at 0 °C for 30 min, and then quenched with Na 2 SO 3 (aq). The mixture was filtered, and the filtrate was concentrated and purified by prep-HPLC (mobile phase: CH 3 CN/H 2 O with 0.1% HCO2H) to give the title compound (31.84 mg, 54.3%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 450.9; 1 H NMR (400 MHz, CD 3 OD) δ 8.99 (s, 1H), 8.16 (d, J = 6.0 Hz, 1H), 7.84 (s, 2H), 7.30 (d, J = 6.0 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 3.15 (q, J =7.6 Hz, 2H), 1.52 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.6 Hz, 3H).

[00185] Example 4: (3, 5-dibromo-4-hydroxyphenyl)(2-ethyl-1-(2-methoxyethyl)-1H- pyrrolo[2,3-c]pyridin-3-yl)methanone [00186] Step 1 : (4-(benzyloxy)phenyl)(2-ethyl-1-(2-methoxyethyl)-1H-pyrrolo[ 2,3-c]pyridin- 3-yl)methanone.

[00187] To a solution of (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[2,3-c]pyridin-3- yl)methanone (300 mg, 0.84 mmol, 1.0 eq) in dry DMF (10 mL) was added CS2CO3 (301 mg, 0.92 mmol, 1.1 eq), and the mixture was stirred at 80 °C for 0.5 h. A solution of l-bromo-2- methoxyethane (117 mg, 0.84 mmol, 1.0 eq) in DMF was added dropwise to the above mixture, and the mixture was stirred at RT for 16 h under Ar. The mixture was quenched with ice-water, and extracted with EA. The combined organic layer was dried over Na 2 SO 4 , concentrated under reduced pressure and purified by Prep-TLC (eluent: 8% DCM/MeOH) to give the title compound (40 mg, 11.4%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 415.5.

[00188] Step 2: (2-ethyl-1-(2-methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)(4 - hydroxyphenyl)m ethanone.

[00189] To a solution of (4-(benzyloxy)phenyl)(2-ethyl-1-(2-methoxyethyl)-1H-pyrrolo[ 2,3- c]pyri din-3-yl)methanone (40 mg, 0.096 mmol, 1.0 eq) in DCM (10 mL) was added TFA (0.5 mL), and followed by TfOH (0.25 mL). The mixture was stirred for 1 h at RT, and adjusted to pH>7 with IN NaOH then to pH6-7 with NH 4 CI (aq). The mixture was extracted with DCM, and the combined organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound (31.37 mg, 100%) as a yellow solid which was used in next step without further purification. LC-MS: [M+H]+ (m/z) = 325.5.

[00190] Step 3: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1-(2-methoxyethyl)-1H- pyrrolo[2,3- c]pyri din-3-yl)methanone.

[00191] At 0 °C, to a stirring solution of (2-ethyl-1-(2-methoxyethyl)-1H-pyrrolo[2,3- c]pyridin-3-yl)(4-hydroxyphenyl)methanone (31.37 mg, 0.096 mmol, 1.0 eq) in THF (10 mL) was added slowly a solution of NBS (34.3 mg, 0.19 mmol, 2.0 eq) in THF. The mixture was stirred for 10 min at 0 °C, and then quenched with Na 2 SO 3 (aq). The mixture was filtered, and the filtrate was concentrated and purified by Prep-HPLC (mobile phase: CH 3 CN/H 2 O with 0.1% HCO2H) to give the title compound (25 mg, 53.6%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 481.0; 1 H NMR (400 MHz, CD 3 OD) δ 8.96 (s, 1H), 8.14 (d, J = 6.4 Hz, 1H), 7.84 (s, 2H), 7.30 (d, J = 5.6 Hz, 1H), 4.64 (t, J = 4.8 Hz, 2H), 3.80 (t, J = 4.8 Hz, 2H), 3.17 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H). [00192] Example 5: (3,5-dibromo-4-hydroxyphenyl)(l-methyl-1H-pyrrolo[2,3-c]pyri din-3- yl)methanone

[00193] Step 1 : 1-methyl-1H-pyrrolo[2,3-c]pyridine.

[00194] At 0 °C, to a solution of 1H-pyrrolo[2,3-c]pyridine (1000 mg, 8.46 mmol, 1.0 eq) in DMF (10 mL) was added NaH (677 mg, 16.9 mmol, 2.0 eq) under Ar. The mixture was stirred at 0 °C for 10 min, and then treated with Me 2 SO 4 (0.81 ml, 8.46 mmol, 1.0 eq). The mixture was further stirred at 0 °C for 2 h before it was quenched with sat. NH4CI and diluted with EA/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 2% MeOH in DCM) to give the title compound (800 mg, 71%). LC-MS: [M+H]+ (m/z) = 133.

[00195] Step 2: (4-methoxyphenyl)(l-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)met hanone.

[00196] At 0 °C, to a solution of l-methyl-1H-pyrrolo[2,3-c]pyridine (300 mg, 2.27 mmol, 1.0 eq) in CS 2 (15 mL) was added AlCl 3 (759 mg, 5.68 mmol, 2.5 eq). The mixture was stirred at 0 °C for 0.5 h under Ar, and then 4-methoxybenzoyl chloride (583 mg, 3.40 mmol, 1.5 eq) was added. The resulting mixture was stirred at RT for 16 h before it was quenched with 1.0 M aq. NaOH solution. The mixture was extracted with DCM, and the combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by Prep-TLC (eluent: 15: 1 DCM/MeOH) to give the title compound (250 mg, 42%). LC-MS: [M+H]+ (m/z) = 267.

[00197] Step 3: (4-hydroxyphenyl)(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)met hanone.

[00198] At 0 °C, to a solution of (4-methoxyphenyl)(l-methyl-1H-pyrrolo[2,3-c]pyridin-3- yl)methanone (100 mg, 0.38 mmol, 1.0 eq) in DCM (2 mL) was added slowly BBr 3 (15 ml, 2M). The reaction mixture was stirred for 16 h at RT under Ar, and then quenched with ice-water. The mixture was adjusted to pH 8 by saturated NaHCO 3 , and then extracted with DCM. The combined organic layer was dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (25 mg, 26%). LC-MS: [M+H]+ (m/z) = 253.

[00199] Step 4: (3,5-dibromo-4-hydroxyphenyl)(l-methyl-1H-pyrrolo[2,3-c]pyri din-3- yl)methanone.

[00200] At 0 °C, NBS (50 mg, 0.28 mmol, 2.0 eq) was added slowly to a stirring solution of (4-hydroxyphenyl)(l-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)met hanone (35 mg, 0.14 mmol, 1.0 eq) in THF (2 mL). The mixture was stirred for 1 h at 0 °C before it was quenched with icewater. The mixture was extracted with DCM, and the combined organic layer was dried with Na 2 SO 4 and concentrated. The residue was purified by Prep-HPLC (eluent: MeCN/H2O with 0.1% HCO 2 H), to give the title compound (6.9 mg, 12%) as a white solid. LC-MS: [M+H]+ (m/z) = 408.8; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.01 (s, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.35 (s, 1H), 8.07 (d, J = 5.6 Hz, 1H), 7.95 (s, 2H), 4.01 (s, 3H).

[00201] Example 6: (3,5-dibromo-4-hydroxyphenyl)(1,2-dimethyl-1H-pyrrolo[2,3-c] pyridin- 3-yl)methanone

[00202] Step 1 : N-(4-methylpyridin-3-yl)acetamide.

[00203] At 0 °C under an Ar atmosphere, to a solution of 4-methylpyri din-3-amine (2.0 mg, 18.5 mmol, 1.0 eq) in THF (30 mL) was added TEA (2.80 g, 27.8 mmol, 1.5 eq), followed by acetyl chloride (1.74 g, 22.2 mmol, 1.2 eq). The mixture was stirred for 16 h before it was diluted with sat. NH 4 Cl and DCM. The organic layer was separated and dried over Na 2 SO 4 . It was concentrated, and purified by flash chromatography on silica gel (eluent: 3% MeOH in DCM) to give the title compound (1.10 g, 39%). LC-MS: [M+H]+ (m/z) = 151.

[00204] Step 2: 2-methyl-1H-pyrrolo[2,3-c]pyridine. [00205] At 0 °C, to a solution of N-(4-methylpyridin-3-yl)acetamide (1.0 g, 6.66 mmol, 1.0 eq) in THF (50 mL) was added LDA (17 ml, 2M, 5.0 eq) under Ar. The mixture was stirred at 70 °C for 48h, and then diluted with sat. NH4CI and DCM. The organic layer was separated and dried over Na 2 SO 4 , It was concentrated and purified by flash chromatography on silica gel (eluent: 3% MeOH in DCM) to give the title compound (350 mg, 28%). LC-MS: [M+H]+ (m/z) = 133.

[00206] Step 3: 1,2-dimethyl-1H-pyrrolo[2,3-c]pyridine.

[00207] At 0 °C, to a solution of 2-methyl-1H-pyrrolo[2,3-c]pyridine (260 mg, 2.0 mmol, 1.0 eq) in DMF (6 mL) was added NaH (160 mg, 4.0 mmol, 2.0 eq) under Ar. The mixture was stirred at 0 °C for 10 min, and then treated with Me2SO4 (252 mg, 2.0 mmol, 1.0 eq). The mixture was stirred for 16 h before it was diluted with sat. NH4CI and DCM. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 2% MeOH in DCM) to give the title compound (110 mg, 38%). LC-MS: [M+H]+ (m/z) = 147.

[00208] Step 4: (1,2-dimethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4-hydroxyphenyl )methanone.

[00209] At 0 °C, to a solution of 1,2-dimethyl-1H-pyrrolo[2,3-c]pyridine (90 mg, 0.62 mmol, 1.0 eq) in CS2 (12 mL) was added A1CL (350 mg, 2.6 mmol, 4.0 eq). The mixture was stirred at 0 °C for 0.5 h under Ar, and 4-(tert-butoxy)benzoyl chloride (276 mg, 1.3 mmol, 2.0 eq) was then added. The resulting mixture was stirred at r.t for 16 h before quenched with 1.0 M aq. NaOH. The mixture was extracted with DCM. The aqueous layer was adjusted to pH 7 with saturated NH 4 CI, and extracted with DCM. The combined organic layer was dried over Na 2 SO 4 , and concentrated to give the title compound (40 mg, 24%). LC-MS: [M+H]+ (m/z) = 267.

[00210] Step 5: (3,5-dibromo-4-hydroxyphenyl)(1,2-dimethyl-1H-pyrrolo[2,3-c] pyridin-3- yl)methanone. At 0 °C, NBS (53 mg, 0.30 mmol, 2.0 eq) was added slowly to a stirring solution of (1,2-dimethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4-hydroxyphenyl )methanone (40 mg, 0.15 mmol, 1.0 eq) in THF/DMF (4 mL/8 ml). The mixture was stirred at 0 °C for 1 h before it was quenched with ice-water. The mixture was extracted with DCM. The combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by Prep-HPLC (eluent: MeCN/H2O with 0.1% HCO2H) to give the title compound (22.2 mg, 35%) as a white solid. LC- MS: [M+H]+ (m/z) = 422.8; 1 H NMR (400 MHz, CD 3 OD) δ 8.92 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 7.84 (s, 2H), 7.44 (d, J = 5.6 Hz, 1H), 3.95 (s, 3H), 2.65 (s, 3H). [00211] Example 7: (2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(3,5-d ibromo-4- hydroxyphenyl)methanone

[00212] Step 1 : N-(4-methylpyridin-3-yl)cyclopropanecarboxamide.

[00213] At 0 °C, to a solution of 4-methylpyri din-3 -amine (1.04 mg, 9.60 mmol, 1.0 eq) in THF (16 mL) were added TEA (1.45 g, 14.4 mmol, 1.5 eq) and cyclopropanecarbonyl chloride (1.2 g, 11.5 mmol, 1.2 eq) under Ar. The mixture was stirred for 16 h before it was diluted with sat. NH4CI and DCM. The organic layer was separated and dried over Na 2 SO 4 . It was concentrated and purified by flash chromatography on silica gel (eluent: 5% MeOH in DCM) to give the title compound (1.50 g, 92%). LC-MS: [M+H]+ (m/z) = 177.

[00214] Step 2: 2-cyclopropyl-1H-pyrrolo[2,3-c]pyridine.

[00215] At 0 °C, to a solution of N-(4-methylpyridin-3-yl)cyclopropanecarboxamide (1.40 g, 7.95 mmol, 1.0 eq) in THF (70 mL) was added LDA (20 ml, 2M, 5.0 eq) under Ar. The mixture was stirred at 70 °C for 48h before it was diluted with sat. NH4CI and DCM. The organic layer was separated, and dried over Na 2 SO 4 . It was concentrated, and purified by flash chromatography on silica gel (eluent: 3% MeOH in DCM) to give the title compound (350 mg, 28%). LC-MS: [M+H]+ (m/z) = 159.

[00216] Step 3: 2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine.

[00217] At 0 °C, to a solution of 2-cyclopropyl-1H-pyrrolo[2,3-c]pyridine (350 mg, 2.21 mmol, 1.0 eq) in DMF (6 mL) was added NaH (180 mg, 4.4 mmol, 2.0 eq) under Ar. After 10 min, Me 2 SO 4 (280 mg, 2.21 mmol, 1.0 eq) was added, and the mixture was stirred for 16 h. The reaction was quenched with sat. NH4CI and DCM. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 2% MeOH in DCM) to give the title compound (190 mg, 50%). LC-MS: [M+H]+ (m/z) = 173. [00218] Step 4: (2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4- hydroxyphenyl)methanone. At 0 °C, to a stirred solution of 2-cyclopropyl- 1 -methyl- 1H- pyrrolo[2,3-c]pyridine (170 mg, 0.99 mmol, 1.0 eq) in CS2 (15 mL) was added AlCl 3 (533 mg, 4.0 mmol, 4.0 eq). After 30 min, 4-(tert-butoxy)benzoyl chloride (425 mg, 2.0 mmol, 2.0 eq) was added, and the resulting mixture was stirred at RT for 16 h. The reaction was quenched with 1.0 M aq. NaOH solution, and the mixture was extracted with DCM. The aqueous layers was adjusted to pH 7 with saturated NH4CI, and extracted with DCM. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated to give the title compound (60 mg, 17%). LC-MS: [M+H]+ (m/z) = 293.

[00219] Step 5: (2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(3,5-d ibromo-4- hydroxyphenyl)methanone.

[00220] At 0 °C, NBS (61 mg, 0.34 mmol, 2.0 eq) was added slowly to a stirred solution of (2-cyclopropyl- 1 -methyl- 1H-pyrrolo[2,3-c]pyridin-3-yl)(4-hydroxyphenyl)methanone (50 mg, 0.17 mmol, 1.0 eq) in THF/DMF (4 mL/8 ml). After 1 h, the reaction was quenched with ice- water, and the mixture was extracted with DCM. The combined organic layers were dried with Na 2 SO 4 and concentrated. The residue was purified by Prep-HPLC (eluent: MeCN/H 2 O with 0.1% HCO2H) to give the title compound (27.7 mg, 36%) as a white solid. LC-MS: [M+H]+ (m/z) = 448.8; 1 H NMR (400 MHz, CD 3 OD) δ 8.93 (s, 1H), 8.20 (d, J = 5.6 Hz, 1H), 7.92 (s, 2H), 7.72 (d, J = 5.6 Hz, 1H), 4.07 (s, 3H), 2.06-1.99 (m, 1H), 1.01-0.96 (m, 2H), 0.62-0.58 (m, 2H).

[00221] Example 8: (3,5-dibromo-4-hydroxyphenyl)(2-isopropyl-1-methyl-1H-pyrrol o[2,3- c]pyri din-3 -yl)methanone

[00222] Step 1 : N-(4-methylpyridin-3-yl)isobutyramide.

[00223] To a solution of 4-methylpyri din-3-amine (2.0 g, 18.5 mmol, 1.0 eq) in THF (30 mL) were added TEA (2.8 g, 27.8 mmol, 1.5 eq) and isobutyryl chloride (2.37 g, 22.2 mmol, 1.2 eq). The mixture was stirred overnight at RT under Ar. The reaction was quenched with NH4CI (aq), and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0-5% MeOH/DCM) to give the title compound (2.4 g, 72.9 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 179.2.

[00224] Step 2: 2-isopropyl-1H-pyrrolo[2,3-c]pyridine.

[00225] At 0 °C, to a solution of N-(4-methylpyridin-3-yl)isobutyramide (2.4 g, 13.5 mmol, 1.0 eq) in THF (50 ml) was added LDA (2M, 33.7 ml, 67.5 mmol, 5.0 eq) under Ar. After stirring at 70 °C for 16 h under Ar, the mixture was diluted with ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0-3% MeOH/DCM) to give the title compound (800 mg, 37%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 161.1.

[00226] Step 3: 2-isopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine.

[00227] At 0 °C, to a stirred solution of 2-isopropyl-1H-pyrrolo[2,3-c]pyridine (750 mg, 4.69 mmol, 1.0 eq) in DMF (20 mL) was added NaH (375 mg, 9.38 mmol, 2.0 eq) under Ar. The resulting mixture was stirred at 0 °C for 15 min before it was treated with Me 2 SO 4 (591 mg, 4.69 mmol, 1.0 eq). The mixture was stirred overnight at r.t. under Ar, and then diluted with NH4CI (aq) and extracted with DCM. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0-3% MeOH/DCM) to give the title compound (90 mg, 11%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 175.1.

[00228] Step 4: 2-isopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyd e.

[00229] At 0 °C, to a mixture of 2-isopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (90 mg, 0.52 mmol, 1.0 eq), dichloro(methoxy)methane (299 mg, 2.6 mmol, 5.0 eq) in DCE/CH3NO2 (1 : 1, 5 mL) was added AlCl 3 (208 mg, 1.56 mmol, 3.0 eq) under Ar. The mixture was stirred overnight at RT, quenched with NaHCO 3 (aq) at 0 °C, and extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , concentrated under reduced pressure, and purified by Prep-TLC (eluent: 5% MeOH/DCM) to give the title compound (70 mg, 67 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 203.1.

[00230] Step 5: (4-(benzyloxy)phenyl)(2-isopropyl-1-methyl-1H-pyrrolo[2,3-c] pyridin-3- yl)m ethanol.

[00231] At 0 °C, to a solution of 2-isopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine-3- carbaldehyde (70 mg, 0.34 mmol, 1.0 eq) in THF (3 mL) was added (4- (benzyloxy)phenyl)magnesium bromide (0.64 mL, 0.51mmol, 1.5 eq) under Ar. The mixture was stirred at RT for 30 min. The mixture was quenched with NH4CI (aq), and extracted with DCM. The organic layer was dried over Na 2 SO 4 , concentrated under reduced pressure. The residue was purified by Prep-TLC (eluent: 5% MeOH/DCM) to give the title compound (96 mg, 73 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 387.1.

[00232] Step 6: (4-(benzyloxy)phenyl)(2-isopropyl-1-methyl-1H-pyrrolo[2,3-c] pyridin-3- yl)methanone. At 0 °C, to a solution of (4-(benzyloxy)phenyl)(2-isopropyl-1-methyl-1H- pyrrolo[2,3-c]pyridin-3-yl)methanol (96 mg, 0.25 mmol, 1.0 eq) in DCM (10 mL) was added DMP (21 Img, 0.5mmol, 2.0 eq) under Ar. After 1 h, the reaction was quenched with NaHCO 3 (aq) at 0 °C, and the mixture was filtered. The filtrate was dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound (94 mg, 73%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 385.2.

[00233] Step 7: (4-hydroxyphenyl)(2-isopropyl-1-methyl-1H-pyrrolo[2,3-c]pyri din-3- yl)methanone. [00234] To a solution of (4-(benzyloxy)phenyl)(2-isopropyl-1-methyl-1H-pyrrolo[2,3- c]pyri din-3 -yl)methanone (96 mg, 0.24 mmol, 1.0 eq) in DCM was added a solution of TFA (1 ml) and TfOH (0.5 ml) in DCM (7 mL). The reaction mixture was stirred for 1 h at RT, the pH was adjusted to ≥ 7 with 2N NaOH, and then concentrated under reduced pressure. The residue was washed with DCM/MeOH (9/1) and filtered, and the filtrate was concentrated to give the title compound (70.56 mg, 100%) as a white solid. LCMS: [M+l]+ (m/z) = 295.5.

[00235] Step 8: (3,5-dibromo-4-hydroxyphenyl)(2-isopropyl-1-methyl-1H-pyrrol o[2,3- c]pyri din-3-yl)methanone.

[00236] At 0 °C, to a solution of (4-hydroxyphenyl)(2-isopropyl-1-methyl-1H-pyrrolo[2,3- c]pyri din-3 -yl)methanone (71 mg, 0.24 mmol, 1.0 eq) in THF (10 mL) was added NBS (85 mg, 0.48 mmol, 2.0 eq) under Ar. After stirrint for 1 h at RT under Ar, the mixture was treated with Na 2 SO 3 (aq) and extracted with DCM. The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the title compound (22.1 mg, 20%) as a white solid. LCMS: [M+l]+ (m/z) = 451.2; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.96 (s, 1H), 8.13 (s, HCO 2 H), 8.12 (m, 1H), 7.70 (s, 2H), 7.11 (m, 1H), 3.96 (s, 3H), 3.56 - 3.47 (m, 1H), 1.37 (d, J = 7.6 Hz, 6H).

[00237] Example 9: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-methoxy-1-methyl-1H- pyrrolo[2,3-c]pyridin-3-yl)methanone

[00238] Step 1 : N-(6-methoxy-4-methylpyridin-3-yl)propionamide. [00239] At 0 °C, to a solution of 6-methoxy-4-methylpyridin-3-amine (2.0 g, 14.47 mmol, 1.0 eq) in THF (40 mL) were added TEA (2.2 g, 21.71 mmol, 1.5 eq) and propionyl chloride (1.6 g, 17.36 mmol, 1.2 eq) under Ar. The reaction mixture was stirred for 16 h, and then treated with sat. NH4CI and diluted with DCM. The organic layer was separated, washed with brine and then dried over Na 2 SO 4 . The solvent was removed, and the residue was purified by flash chromatography on silica gel (eluent: 5% MeOH in DCM) to give the title compound (2.9 g, 100 %). LC-MS: [M+H]+ (m/z) = 195.1.

[00240] Step 2: 2-ethyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine.

[00241] At 0 °C, to a solution of N-(6-methoxy-4-methylpyridin-3-yl)propionamide (2.9 g, 14.9 mmol, 1.0 eq) in THF (30 mL) was added LDA (38 ml, 2 M, 5.0 eq) under Ar. The mixture was stirred at 75 °C for 16 h. Sat. NH 4 CI and DCM were added, and the organic layer was separated and dried over Na 2 SO 4 . It was filtered, concentrated and purified by flash chromatography on silica gel (eluent: 3% MeOH in DCM) to give the title compound (145 mg, 6%). LC-MS: [M+H]+ (m/z) = 177.1.

[00242] Step 3: 2-ethyl-5-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine.

[00243] At 0 °C, to a solution of 2-ethyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine (235 mg, 1.34 mmol, 1.0 eq) in DMF (1 mL) was added NaH (107 mg, 2.67 mmol, 2.0 eq) under Ar. The mixture was stirred at 0 °C for 10 min. Me2SO4 (169 mg, 1.34 mmol, 1.0 eq) was added, and the stirring was continued for 2 h. The reaction was quenched with sat. NH4CI, and the mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 2% MeOH in DCM) to give the title compound (180 mg, 71%). LC-MS: [M+H]+ (m/z) = 191.5.

[00244] Step 4: 2-ethyl-5-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carba ldehyde.

[00245] At 0 °C, to a solution of 2-ethyl-5-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine (180 mg, 0.95 mmol, 1.0 eq) and dichloro(methoxy)methane (546 mg, 4.75 mmol, 5.0 eq) in DCE/CH 3 NO 2 (10 mL/10 mL) was added A1CL (380 mg, 2.85 mmol, 3.0 eq). The mixture was stirred for 16 h at RT, and the reaction was quenched with NaHCCF (aq) at 0 oC. The mixture was extracted with DCM, and the combined organic phases were dried over Na 2 SO 4 , concentrated under reduced pressure, and purified by flash chromatography on silica gel (eluent: 0-5% DCM/MeOH) to give the title compound (145 mg, 70%) as a yellow oil. LC-MS: [M+H]+ (m/z) = 219.2. [00246] Step 5: (4-(benzyloxy)phenyl)(2-ethyl-5-methoxy-1-methyl-1H-pyrrolo[ 2,3- c]pyridin-3-yl)methanol.

[00247] At 0 °C, to a solution of 2-ethyl-5-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine-3- carbaldehyde (145 mg, 0.67 mmol, 1.0 eq) in THF (10 mL) was added (4- (benzyloxy)phenyl)magnesium bromide (0.8 M) (1.25 mL, 1.0 mmol, 1.5 eq). The mixture was allowed to warm up to RT, and the stirring was continued for 1 h at RT. The reaction was quenched with sat. NH4CI, and the mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , concentrated under reduced pressure and purified by Prep-TLC (eluent: 2: 1 PEZEA) to give the title compound (250 mg, 93%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 403.2.

[00248] Step 6: (4-(benzyloxy)phenyl)(2-ethyl-5-methoxy-1-methyl-1H-pyrrolo[ 2,3- c]pyri din-3-yl)methanone.

[00249] At 0 °C, to a solution of (4-(benzyloxy)phenyl)(2-ethyl-5-methoxy-1-methyl-1H- pyrrolo[2,3-c]pyridin-3-yl)methanol (250 mg, 0.62 mmol, 1.0 eq) in DCM (5 mL) was added DMP (526 mg, 1.24 mmol, 2.0 eq). After stirring for 16 h at RT, the mixture was treated with NaHCO 3 (aq) at 0 °C and extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , concentrated under reduced pressure and purified by Prep-TLC (eluent: 3: 1 PEZEA) to give the title compound (248 mg, 100%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 401.6.

[00250] Step 7: (2-ethyl-5-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4 - hydroxyphenyl)m ethanone.

[00251] To a solution of (4-(benzyloxy)phenyl)(2-ethyl-5-methoxy-1-methyl-1H-pyrrolo[ 2,3- c]pyri din-3-yl)methanone (248 mg, 0.62 mmol, 1.0 eq) in DCM (10 mL) were added TFA (1 mL) and TfOH (0.5 mL). The mixture was stirred for 1 h at RT, and then adjusted to pH 7-8 with IN NaOH. The mixture was extracted with DCM, and combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (192 mg, 100%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 311.5.

[00252] Step 8: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-methoxy-1-methyl-1H- pyrrolo[2,3-c]pyridin-3-yl)methanone.

[00253] At 0 °C, to a stirred solution of (2-ethyl-5-methoxy-1-methyl-1H-pyrrolo[2,3- c]pyridin-3-yl)(4-hydroxyphenyl)methanone (114 mg, 0.37 mmol, 1.0 eq) in DCM/THF (10mL/5 mL) was added slowly 3-dibromo-5,5-dimethylhydantoin (DBDMH, 105 mg, 0.37 mmol, 1.0 eq). The mixture was stirred at RT for 0.5 h, and the reaction was quenched with ice- water and Na 2 S 2 O 3 (aq). The concentrated residue was purified by Prep-HPLC (mobile phase: CH 3 CN/H 2 O with 0.1% HCO 2 H) to give the title compound (85 mg, 52%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 466.9; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (d, J = 0.4 Hz, 1H), 8.14 (s, HCO2H), 7.75 (s, 2H), 6.33 (s, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 2.98 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H).

[00254] Example 10: 3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethyl-1-methyl-1,6-dihydr o-5H-

[00255] To a solution of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-methoxy-1-methyl-1H- pyrrolo[2,3-c]pyridin-3-yl)methanone (25 mg, 0.05 mmol, 1.0 eq; Example 9) in DMF (2 mL) was added NaSEt (90 mg, 1.07 mmol, 20.0 eq). The resulting mixture was stirred at 130 °C for 16 h. The solvent was removed, and the residue was purified by Prep-HPLC (mobile phase: CH 3 CN/H 2 O with 0.1% HCOOH) to give the title compound (4.85 mg, 20 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 452.9; 1 H NMR (400 MHz, CD 3 OD) δ 8.66 (s, 1H), 7.89 (s, 2H), 6.67 (s, 1H), 3.97 (s, 3H), 3.15 (q, J = 7.6 Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H).

[00256] Example 11 : (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-methoxy-1-methyl-1H- pyrrolo[2,3-c]pyridin-3-yl)methanone

[00257] Step 1 : 2-ethyl-7-methoxy-1H-pyrrolo[2,3-c]pyridine.

[00258] At 0 °C, to a solution of 2-methoxy-4-methylpyridin-3-amine (2.0 g, 14.49 mmol, 1.0 eq) in THF (40 mL) were added TEA (2.2 g, 21.74 mmol, 1.5 eq) and propionyl chloride (1.6 g, 17.39 mmol, 1.2 eq) under Ar. The reaction mixture was stirred for 16 h, and then diluted in DCM and sat. NH 4 CI. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 5% MeOH in DCM) to give the title compound (2.9 g, 100%). LC-MS: [M+H]+ (m/z) = 195.5.

[00259] Step 2: 2-ethyl-7-methoxy-1H-pyrrolo[2,3-c]pyridine.

[00260] At 0 °C, to a solution of 2-ethyl-7-methoxy-1H-pyrrolo[2,3-c]pyridine (2.9 g, 14.9 mmol, 1.0 eq) in THF (30 mL) was added LDA (38 mL, 2 M, 5.0 eq) under Ar. The resulting mixture was stirred at 75 °C for 16 h, and then quenched with sat. NH4CI and diluted with DCM. The organic layer was separated, dried over Na 2 SO 4 , concentrated and purified by flash chromatography on silica gel (eluent: 3% MeOH in DCM) to give the title compound (800 mg, 31%). LC-MS: [M+H]+ (m/z) = 177.5.

[00261] Step 3: 2-ethyl-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine.

[00262] At 0 °C, to a solution of 2-ethyl-7-methoxy-1H-pyrrolo[2,3-c]pyridine (50 mg, 0.28 mmol, 1.0 eq) in DMF (1 mL) was added NaH (23 mg, 0.56 mmol, 2.0 eq) under Ar. After 10 min, a solution of Me 2 SO 4 (36 mg, 0.28 mmol, 1.0 eq) in DMF was added, and the stirring was continued for 2 h. The reaction was quenched with sat. NH 4 CI, and the mixture was diluted with DCM. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 2% MeOH in DCM) to give the title compound (45 mg, 85%). LC-MS: [M+H]+ (m/z) = 191.5.

[00263] Step 4: 2-ethyl-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carba ldehyde.

[00264] At 0 °C, to a mixture of 2-ethyl-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.53 mmol, 1.0 eq) and 1,1 -di chlorodimethyl ether (302 mg, 2.63 mmol, 5.0 eq) in DCE/CH3NO2 (1 : 1, 5 mL) was added AlCl 3 (211.5 mg, 1.59 mmol, 3.0 eq). The reaction mixture was stirred for 16 h at RT before it was quenched with NaHCCf (aq) at 0 oC. The mixture was extracted with DCM, and the combined organic layers were dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 0-5% DCM/MeOH) to give the title compound (50 mg, 44%) as a yellow oil. LC-MS: [M+H]+ (m/z) = 219.2.

[00265] Step 5: (4-(benzyloxy)phenyl)(2-ethyl-7-methoxy-1-methyl-1H-pyrrolo[ 2,3- c]pyridin-3-yl)methanol.

[00266] At 0 °C, to a solution of 2-ethyl-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine-3- carbaldehyde (50 mg, 0.23 mmol, 1.0 eq) in THF (2 mL) was added (4- (benzyloxy)phenyl)magnesium bromide (0.8 M) (0.43 mL, 0.35 mmol, 1.5 eq). The reaction mixture was warmed to RT and stirred for 1 h and then quenched with sat. NH4CI. The crude product was purified by Prep-TLC (eluent: 2: 1 PEZEA) to give the title compound (70 mg, 76%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 403.5.

[00267] Step 6: (4-(benzyloxy)phenyl)(2-ethyl-7-methoxy-1-methyl-1H-pyrrolo[ 2,3- c]pyri din-3 -yl)methanone.

[00268] At 0 °C, to a solution of (4-(benzyloxy)phenyl)(2-ethyl-7-methoxy-1-methyl-1H- pyrrolo[2,3-c]pyridin-3-yl)methanol (63 mg, 0.16 mmol, 1.0 eq) in DCM (5 mL) was added DMP (133 mg, 0.32 mmol, 2.0 eq). The resulting mixture was stirred at RT for 16 h, and then quenched with NaHCCf (aq) at 0 oC. It was extracted with DCM, and the combined organic layers were dried over Na 2 SO 4 , filtered, and purified by Prep-TLC (eluent: 3: 1 PEZEA) to give the title compound (60 mg, 93%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 401.6.

[00269] Step 7: (2-ethyl-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4 - hydroxyphenyl)m ethanone.

[00270] To a mixture of (4-(benzyloxy)phenyl)(2-ethyl-7-methoxy-1-methyl-1H-pyrrolo[ 2,3- c]pyri din-3 -yl)methanone (200 mg, 0.50 mmol, 1.0 eq) in DCM (10 mL) was added TFA(1 mL), followed by TfOH (0.5 mL). The resulting mixture was stirred at RT for 1 h. The pH of the mixture was adjusted to 7-8 with IN NaOH, and the mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (200 mg, 100%) as a yellow solid. LC-MS: [M+H] + (m/z) = 311.5.

[00271] Step 8: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-methoxy-1-methyl-1H- pyrrolo[2,3-c]pyridin-3-yl)methanone.

[00272] At 0 °C, NBS (86 mg, 0.48 mmol, 1.5 eq) was added slowly to a stirring solution of (2-ethyl-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4 -hydroxyphenyl)methanone (100 mg, 0.32 mmol, 1.0 eq) in DCM (5 mL). The mixture was stirred for 0.5 h at RT before it was quenched with ice-water and Na 2 S 2 O 3 (aq). The mixture was concentrated and purified by prep- HPLC (mobile phase: CH3CN/H2O with 0.1% HCOOH) to give the title compound (127 mg, 85%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 467.2; 1 H NMR (400 MHz, CD 3 OD) δ 7.72 (s, 2H), 7.51 (d, J = 5.6 Hz, 1H), 6.57 (d, J = 6.0 Hz, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 2.95 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H).

[00273] Example 12: 3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethyl-1-methyl-1,6-dihydr o-7H- pyrrolo[2,3-c]pyridin-7-one

[00274] A solution of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-methoxy-1-methyl-1H- pyrrolo[2,3-c]pyridin-3-yl)methanone (50 mg, 0.11 mmol, 1.0 eq; Example 11) in BBr 3 (2M in DCM, 5 mL) was stirred at RT for 16 h. The reaction mixture was quenched with ice-water, and neutralized with NaHCCf (aq). The crude product was purified by Prep-HPLC (mobile phase: CH 3 CN/H 2 O with 0.1% HCO 2 H) to give the title compound (5.79 mg, 12%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 453.3; 1 H NMR (400 MHz, CD 3 OD) δ 7.73 (s, 2H), 6.84 (d, J = 7.2 Hz, 1H), 6.05 (d, J = 6.8 Hz, 1H), 4.11 (s, 3H), 2.88-2.86 (m, 2H), 1.17 (t, J = 7.6 Hz, 3H).

[00275] Example 13 : (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[3, 2- c]pyridin-3-yl)methanone

[00276] Step 1 : 3-(but-1-yn-1-yl)pyridin-4-amine.

[00277] A mixture of 3-bromopyridin-4-amine (1.0 g, 5.78 mmol, 1.0 eq), but-l-yn-1- yltrimethylsilane (1.1 g, 8.67 mmol, 1.5 eq), TEA (1.6 mL, 11.56 mmol, 2.0 eq), Cui (55 mg, 0.29 mmol, 0.05 eq), KF (336 mg, 5.78 mmol, 1.0 eq) and Pd(PPh 3 ) 2 Cl 2 (204 mg, 0.29 mmol, 0.05 eq) in DMF (10 mL) was stirred overnight at 60 °C under Ar. The mixture was concentrated and purified by flash chromatography on silica gel (eluent: 0-2% MeOH/DCM) to give the title compound (370 mg, 44 %) as a light yellow oil. LC-MS: [M+H]+ (m/z) = 147.2.

[00278] Step 2: N-(3-(but-1-yn-1-yl)pyridin-4-yl)-2,2,2-trifluoroacetamide.

[00279] To a solution of 3-(but-1-yn-1-yl)pyridin-4-amine (370 mg, 2.53 mmol, 1.0 eq) in DCM (10 mL) were added TEA (0.7 mL, 5.06 mmol, 2.0 eq) and TFAA (0.43 mL, 3.04 mmol, 1.2 eq) at RT. The resulting mixture was stirred for 1 h before being quenched with ice water. The mixture was extracted with DCM. The combined organic phase was dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (674 mg, 100 %) as a yellow oil. LC-MS: [M+H]+ (m/z) = 243.0.

[00280] Step 3: (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[3,2-c]pyridin-3-yl) methanone.

[00281] A mixture of N-(3-(but-1-yn-1-yl)pyridin-4-yl)-2,2,2-trifluoroacetamide (674 mg, 2.78 mmol, 1.0 eq), 1-(benzyloxy)-4-iodobenzene (1.04 g, 3.34 mmol, 1.2 eq), K 2 CO 3 (1.9 g, 13.9 mmol, 5.0 eq) and Pd(PPh 3 ) 4 (161 mg, 0.14 mmol, 0.05 eq) in MeCN (50 mL) was stirred overnight at 45 °C under CO. The mixture was cooled to RT, and diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 0-2% MeOH/DCM) to give the title compound (130 mg, 13 %) as a light yellow solid. LC-MS: [M+H]+ (m/z) = 357.5.

[00282] Step 4: (4-(benzyloxy)phenyl)(2-ethyl-1-methyl-1H-pyrrolo[3,2-c]pyri din-3- yl)methanone.

[00283] At 0 °C, to a solution of (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[3,2-c]pyridin-3- yl)methanone (130 mg, 0.36 mmol, 1.0 eq) in DMF (5 mL) was added NaH (29 mg, 0.72 mmol, 2.0 eq) under Ar. The reaction mixture was stirred at 0 °C for 10 min before it was treated with Me2SO4 (45 mg, 0.36 mmol, 1.0 eq), and the stirring was continued for another 2 h. The mixture was then quenched with sat. NH 4 CI, and diluted with EA/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by prep-TLC (eluent: 5% MeOH in DCM) to give the title compound (40 mg, 30 %). LC-MS: [M+H]+ (m/z) = 371.1.

[00284] Step 5: (2-ethyl-1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)(4- hydroxyphenyl)m ethanone.

[00285] To a solution of (4-(benzyloxy)phenyl)(2-ethyl-1-methyl-1H-pyrrolo[3,2-c]pyri din- 3-yl)methanone (141 mg, 0.38 mmol, 1.0 eq) in DCM (5 mL) were added TFA (1 mL) and TfOH (0.5 mL). The resulting mixture was stirred for 30 min at RT, and then quenched with 1 NaOH at 0 oC. The mixture was washed with sat. NH 4 CI, and the aqueous layer was extracted with 15% i-PrOH in DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (85 mg, 80%). LC-MS: [M+H]+ (m/z) =281.0.

[00286] Step 6: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[3, 2-c]pyridin- 3-yl)methanone.

[00287] At 0 °C, to a solution of (2-ethyl-1-methyl-1H-pyrrolo[3,2-c]pyridin-3-yl)(4- hydroxyphenyl)methanone (85 mg, 0.30 mmol, 1.0 eq) in THF/DCM/DMF (10:5:2, 8.5 mL) was added 1, 3 -dibromo-5, 5 -Dimethylhydantoin (DBDMH, 172 mg, 0.60 mmol, 1.0 eq) under Ar. The resulting mixture was stirred at 0 oC for 10 min before it was quenched with sat. Na 2 SO 3 . The mixture was filtered, and the filtrate was purified by Prep-HPLC to give the title compound (63.7 mg, 48%) as a white solid. LC-MS: [M+H]+ (m/z) = 436.8; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.68 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.84 (s, 2H), 3.93 (s, 3H), 2.97 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H). [00288] Example 14: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[3, 2- b]pyridin-3-yl)methanone

[00289] Step 1 : 2-ethyl-1H-pyrrolo[3,2-b]pyridine.

[00290] A mixture of 2-bromopyri din-3 -amine (2.0 g, 11.56 mmol, 1.0 eq), 2-bromobut-l- ene (2.34 g, 17.34 mmol, 1.5 eq), t-BuONa (3.3 g, 34.68 mmol, 3.0 eq), Pd 2 (dba) 3 (423 mg, 0.46 mmol, 0.04 eq) and Xphos (2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 219 mg, 0.46 mol, 0.04 eq) in t-BuOH (30 mL) was stirred at 110 °C for 48 h under Ar. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluent: 0-3% MeOH/DCM) to give the title compound (500 mg, 30 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 147.5.

[00291] Step 2: 2-ethyl-1-methyl-1H-pyrrolo[3,2-b]pyridine.

[00292] At 0 °C, to a stirred solution of 2-ethyl-1H-pyrrolo[3,2-b]pyridine (530 mg, 3.63 mmol, 1.0 eq) in DMF (20 mL) was added NaH (290 mg, 7.26 mmol, 2.0 eq) under Ar. After 15 min, Me2SO4 (457 mg, 3.63 mmol, 1.0 eq ) was added, and stirring was continued overnight at RT under Ar. The mixture was diluted with NH4CI (aq), and the aqueous layer was extracted with DCM. The combined organic layers were washed brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0-3% MeOH/DCM) to give the title compound (178 mg, 31 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 161.1. [00293] Step 3: 2-ethyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde.

[00294] At 0 °C, to a mixture of 2-ethyl-1-methyl-1H-pyrrolo[3,2-b]pyridine (178 mg, 1.22 mmol, 1.0 eq) and dichloro(methoxy)methane (701 mg, 6.10 mmol, 5.0 eq) in DCE/CH 3 NO 2 (1 : 1, 5 mL) was added AlCl 3 (488 mg, 3.66 mmol, 3.0 eq) under Ar, and the reaction mixture was stirred overnight at RT. Sat. NaHCO 3 (aq) was added at 0 °C, and the mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, concentrated, under reduced pressure and purified by Prep-TLC (5% MeOH/DCM) to give the title compound (185 mg, 89%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 189.1.

[00295] Step 4: (4-(benzyloxy)phenyl)(2-ethyl-1-methyl-1H-pyrrolo[3,2-b]pyri din-3- yl)m ethanol.

[00296] At 0 °C, to a solution of 2-ethyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (185 mg, 0.98 mmol, 1.0 eq) in THF (10 mL) was added (4-(benzyloxy)phenyl)magnesium bromide (1.85 mL, 1.48 mmol, 1.5 eq) under Ar. The reaction mixture was stirred at RT for 30 min before quenched with NH 4 CI (aq). The mixture was extracted with DCM. The combined organic layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (eluent: 5% MeOH/DCM) to give the title compound (271 mg, 74 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 373.5.

[00297] Step 5: (4-(benzyloxy)phenyl)(2-ethyl-1-methyl-1H-pyrrolo[3,2-b]pyri din-3- yl)methanone.

[00298] At 0 °C, to a solution of (4-(benzyloxy)phenyl)(2-ethyl-1-methyl-1H-pyrrolo[3,2- b]pyri din-3 -yl)methanol (271 mg, 0.73 mmol, 1.0 eq) in DCM (10 mL) was added DMP (618 mg, 1.46 mmol, 2.0 eq) under Ar. The mixture was stirred at RT for 1 h under Ar before it was quenched with NaHCO 3 (aq) at 0 °C. The resulting mixture was filtered, and the filtrate was dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound (300 mg, 100 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 371.1.

[00299] Step 6: (2-ethyl-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)(4- hydroxyphenyl)methanone.

[00300] To a solution of (4-(benzyloxy)phenyl)(2-ethyl-1-methyl-1H-pyrrolo[3,2-b]pyri din- 3-yl)methanone (300 mg, 0.81 mmol, 1.0 eq) in DCM were added TFA (1 ml) and TfOH (0.5 ml) in DCM (10 mL), and the resulting mixture was stirred for 1 h under Ar. The mixture was then adjusted to pH 7 with 2N NaOH, and most of the solvent was removed under reduced pressure. The residue was re-dissolved in DCM/MeOH (9/1) and filtered. The filtrate was concentrated to give the title compound (123 mg, 54%) as a white solid. LCMS: [M+l]+ (m/z) = 281.4.

[00301] Step 7: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[3, 2-b]pyridin- 3-yl)methanone.

[00302] At 0 °C, to a solution of (2-ethyl-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)(4- hydroxyphenyl)methanone (123 mg, 0.44 mmol, 1.0 eq) in THF/DCM/DMF (10 mL/5 mL/2 mL) was added NBS (157 mg, 0.88 mmol, 2.0 eq) under Ar. The reaction mixture was stirred at RT for 10 min under Ar before it was quenched with Na 2 SO 3 (aq). The mixture was extracted with DCM. The combined organic layer was dried over Na 2 SO 4 , concentrated, under reduced pressure. The residue was purified by Prep-HPLC to give the title compound (74.6 mg, 39%) as a white solid. LCMS: [M+l]+ (m/z) = 436.8; 'H NMR (400 MHz, DMSO-d 6 ) δ 10.73 (s, 1H), 8.31 (d, J = 4.4 Hz, 1H), 8.07 (m, 1H), 7.86 (s, 2H), 7.26 (m, 1H), 3.87 (s, 3H), 3.06 (t, J = 7.6 Hz, 2H), 1.26 (t, J = 7.4 Hz, 4H).

[00303] Example 15: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[2, 3- b]pyri din-3 -yl)methanone

[00304] Step 1 : 3-(but-1-yn-1-yl)pyridin-2-amine.

[00305] A mixture of 3-bromopyridin-2-amine (1.0 g, 5.8 mmol, 1.0 eq), but-l-yn-1- yltrimethylsilane (1.1 g, 8.7 mmol, 1.5 eq), TEA (1.2 g, 11.6 mmol, 2.0 eq), Cui (55 mg, 0.29 mmol, 0.05 eq), KF (335 mg, 5.8 mmol, 1.0 eq) and Pd(PPh 3 ) 2 Cl P (203 mg, 0.29 mmol, 0.05 eq) in MeCN (12 mL) was stirred for 72 h at 60 °C under Ar. The mixture was concentrated and purified by flash chromatography on silica gel (eluent: 0-2% MeOH/DCM) to give the title compound (840 mg, 99 %) as a light yellow oil. LC-MS: [M+H]+ (m/z) = 147.4.

[00306] Step 2: N-(3-(but-1-yn-1-yl)pyridin-2-yl)-2,2,2-trifluoroacetamide.

[00307] To a solution of 3-(but-1-yn-1-yl)pyridin-2-amine (840 mg, 5.75 mmol, 1.0 eq) in DCM (20 mL) were added TEA (1.16 g, 11.51 mmol, 2.0 eq) and TFAA (1.45 g, 6.90 mmol, 1.2 eq) at RT. The resulting mixture was stirred at RT for 1 h before it was quenched with ice water. The mixture was extracted with DCM. The combined organic phase was dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (1.39 g, 100 %) as a yellow oil. LC-MS: [M+H]+ (m/z) = 243.1.

[00308] Step 3: (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl) methanone.

[00309] A mixture of N-(3-(but-1-yn-1-yl)pyridin-2-yl)-2,2,2-trifluoroacetamide (1.4 g, 5.8 mmol, 1.0 eq), l-(benzyloxy)-4-iodobenzene (2.2 g, 7.0 mmol, 1.2 eq), K 2 CO 3 (4.0 g, 29.0 mmol, 5.0 eq) and Pd(PPh 3 ) 4 (335 mg, 0.29 mmol, 0.05 eq) in MeCN (100 mL) was stirred overnight at 45 °C under CO. After the reaction was complete, the reaction mixture was cooled to RT, and diluted with DCM/water. The organic phase was separated, dried over Na 2 SO 4 and concentrated. The residue was purified by flash chromatography on silica gel (eluent 0-2% MeOH/DCM) to give the title compound (240 mg, 12 %) as a light yellow solid. LC-MS: [M+H]+ (m/z) = 357.1.

[00310] Step 4: (4-(benzyloxy)phenyl)(2-ethyl-1-methyl-1H-pyrrolo[2,3-b]pyri din-3- yl)methanone.

[00311] At 0 °C, to a solution of (4-(benzyloxy)phenyl)(2-ethyl-1H-pyrrolo[2,3-b]pyridin-3- yl)methanone (100 mg, 0.28 mmol, 1.0 eq) in DMF (3 mL) was added NaH (23 mg, 0.56 mmol, 2.0 eq) under Ar. After 10 min, Me2SO4 (35 mg, 0.28 mmol, 1.0 eq) was added, and the stirring was continued for 2 h at 0 oC. The reaction was quenched with sat. NH 4 CI, and the mixture was diluted with EA/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by prep-TLC (eluent: 5% MeOH in DCM) to give the title compound (49 mg, 43%). LC-MS: [M+H]+ (m/z) = 371.1.

[00312] Step 5: (2-ethyl-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(4- hydroxyphenyl)m ethanone. [00313] To a solution of (4-(benzyloxy)phenyl)(2-ethyl-1-methyl-1H-pyrrolo[2,3-b]pyri din- 3-yl)methanone (49 mg, 0.13 mmol, 1.0 eq) in DCM (5 mL) were added TFA (1 mL) and TfOH (0.5 mL). The resulting mixture was stirred for 30 min at RT, and then quenched with IN NaOH at 0 oC. The mixture was washed with sat. NH 4 CI, and the aqueous layer was extracted with 15% i-PrOH in DCM. The combined organic layers were dried over Na 2 SO 4 and concentrated to give the title compound (37 mg. 100 %). LC-MS: [M+H]+ (m/z) = 281.0.

[00314] Step 6: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[2, 3-b]pyridin- 3-yl)methanone.

[00315] At 0 °C, to a solution of (2-ethyl-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(4- hydroxyphenyl)methanone (37 mg, 0.13 mmol, 1.0 eq) in THF/DCM/DMF (10:5:2, 8.5 mL) was added 1, 3 -dibromo-5, 5 -dimethylhydantoin (37 mg, 0.13 mmol, 1.0 eq) under Ar. The resulting mixture was stirred for 10 min before it was quenched with sat. Na 2 SO 3 . The mixture was filtered, and the filtrate was purified by Prep-HPLC to give the title compound (17 mg, 30 %) as a white solid. LC-MS: [M+H]+ (m/z) = 437.2; 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (br s, 1H), 8.30 (dd, J = 4.8, 1.6 Hz, 1H), 7.80 (s, 2H), 7.52 (dd, J = 8.0, 1.2 Hz, 1H), 7.16 (dd, J = 8.0, 4.8 Hz, 1H), 3.88 (s, 3H), 3.02 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).

[00316] Example 16: (3,5-dibromo-4-hydroxyphenyl)(6-ethyl-5-methyl-5H-pyrrolo[2, 3- b]pyrazin-7-yl)methanone [00317] Step 1 : 3-(but-1-yn-1-yl)pyrazin-2-amine.

[00318] A mixture of 3-bromopyrazin-2-amine (1.0 g, 5.7 mmol, 1.0 eq), but-1-yn-1- yltrimethylsilane (1.1 g, 8.6 mmol, 1.5 eq), TEA (1.2 g, 11.4 mmol, 2.0 eq), CuI (55 mg, 0.29 mmol, 0.05 eq), KF (331 mg, 5.7 mmol, 1.0 eq) and Pd(PPh 3 ) 2 Cl 2 (204 mg, 0.29 mmol, 0.05 eq) in DMF (10 mL) was stirred overnight at 60 °C under Ar. The mixture was concentrated and purified by flash chromatography on silica gel (eluent: 0-2% MeOH/DCM) to give the title compound (800 mg, 95 %) as a light yellow oil. LC-MS: [M+H]+ (m/z) = 148.2.

[00319] Step 2: N-(3-(but-1-yn-1-yl)pyrazin-2-yl)-2,2,2-trifluoroacetamide.

[00320] To a solution of 3-(but-1-yn-1-yl)pyrazin-2-amine (800 mg, 5.4 mmol, 1.0 eq) in DCM (20 mL) were added TEA (1.1 g, 10.9 mmol, 2.0 eq) and TFAA (1.4 g, 6.5 mmol, 1.2 eq) at RT. The resulting mixture was stirred for 1 h before it was quenched with ice water. The mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (1.25 g, 95 %) as a yellow oil. LC-MS: [M+H]+ (m/z) = 244.1.

[00321] Step 3: (4-(benzyloxy)phenyl)(6-ethyl-5H-pyrrolo[2,3-b]pyrazin-7-yl) methanone. [00322] A mixture of N-(3-(but-1-yn-1-yl)pyrazin-2-yl)-2,2,2-trifluoroacetamide (342 mg,

1.4 mmol, 1.0 eq), l-(benzyloxy)-4-iodobenzene (521 mg, 1.7 mmol, 1.2 eq), K 2 CO 3 (967 mg, 7.0 mmol, 5.0 eq) and Pd(PPh 3 ) 4 (81 mg, 0.07 mmol, 0.05 eq) in MeCN (20 mL) was stirred overnight at 45 °C under CO. After the reaction was complete, the mixture was cooled to RT and diluted with DCM/water. The organic phase was separated, dried over Na 2 SO 4 and concentrated. The crude product was purified by flash chromatography on silica gel (eluent: 0-2% MeOH/DCM) to give the title compound (225 mg, 45 %) as a light yellow solid. LC-MS: [M+H]+ (m/z) = 358.2.

[00323] Step 4: (4-(benzyloxy)phenyl)(6-ethyl-5-methyl-5H-pyrrolo[2,3-b]pyra zin-7- yl)methanone.

[00324] At 0 °C, to a solution of (4-(benzyloxy)phenyl)(6-ethyl-5H-pyrrolo[2,3-b]pyrazin-7- yl)methanone (225 mg, 0.63 mmol, 1.0 eq) in DMF (5 mL) was added NaH (48 mg, 1.26 mmol, 2.0 eq) under Ar. After 10 min, Me 2 SO 4 (79 mg, 0.63 mmol, 1.0 eq) was added, and the stirring was continued for 2h at 0 °C. Sat. NH 4 CI was added, and the mixture was diluted with EA/water. The organic layer was separated, dried over Na 2 SO 4 and concentrated. The crude product was purified by Prep-TLC (eluent: 5% MeOH in DCM) to give the title compound (90 mg, 38 %). LC-MS: [M+H]+ (m/z) = 372.1. [00325] Step 5: (6-ethyl-5-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4- hydroxyphenyl)m ethanone.

[00326] To a solution of (4-(benzyloxy)phenyl)(6-ethyl-5-methyl-5H-pyrrolo[2,3-b]pyra zin- 7-yl)methanone (90 mg, 0.24 mmol, 1.0 eq) in DCM (5 mL) were added TFA (1 mL) and TfOH (0.5 mL). The resulting mixture was stirred for 30 min at RT and then quenched with 1 NaOH at 0 °C. The mixture was washed with sat. NH 4 CI, and the aqueous layer was extracted with 15% i- PrOH in DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (68 mg. 100 %) as a crude product. LC-MS: [M+H]+ (m/z) = 282.0.

[00327] Step 6: (3,5-dibromo-4-hydroxyphenyl)(6-ethyl-5-methyl-5H-pyrrolo[2, 3-b]pyrazin- 7-yl)methanone.

[00328] At 0 °C, to a solution of (6-ethyl-5-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)(4- hydroxyphenyl)methanone (68 mg, 0.24 mmol, 1.0 eq) in THF/DCM/DMF (5:2.5: 1, 8.5 mL) was added 1, 3 -dibromo-5, 5 -dimethylhydantoin (69 mg, 0.24 mmol, 1.0 eq) under an Ar atmosphere. The resulting mixture was stirred at 0 °C for 10 min before it was quenched with sat. Na 2 SO 3 . The mixture was filtered, and the filtrate was purified by Prep-HPLC to give the title compound (44 mg, 41 %) as a white solid. LC-MS: [M+H]+ (m/z) = 437.8; 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.79 (br s, 1H), 8.40 (d, J = 2.8 Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H), 7.88 (s, 2H), 3.90 (s, 3H), 3.16 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H).

[00329] Example 17: (3,5-dibromo-4-hydroxyphenyl)(6-ethyl-5-methyl-5H-pyrrolo[3, 2- d]pyrimidin-7-yl)methanone

[00330] Step 1 : 4-(but-1-yn-1-yl)pyrimidin-5-amine.

[00331] A mixture of 4-bromopyrimidin-5-amine (1.0 g, 5.7 mmol, 1.0 eq), but-1-yn-1- yltrimethylsilane (1.1 g, 8.6 mmol, 1.5 eq), TEA (1.2 g, 11.4 mmol, 2.0 eq), Cui (55 mg, 0.29 mmol, 0.05 eq), KF (331 mg, 5.7 mmol, 1.0 eq) and Pd(PPh 3 ) 2 Cl 2 (204 mg, 0.29 mmol, 0.05 eq) in DMF (10 mL) was stirred overnight at 60 °C under Ar. The mixture was concentrated and purified by flash chromatography on silica gel (eluent: 0-2% MeOH/DCM) to give the title compound (745 mg, 80 %) as a light yellow oil. LC-MS: [M+H]+ (m/z) = 148.2.

[00332] Step 2: N-(4-(but-1-yn-1-yl)pyrimidin-5-yl)-2,2,2-trifluoroacetamide .

[00333] To a solution of 4-(but-1-yn-1-yl)pyrimidin-5-amine (745 mg, 5.1 mmol, 1.0 eq) in DCM (20 mL) were added TEA (1.4 mL, 10.1 mmol, 2.0 eq) and TFAA (0.87 mL, 6.1 mmol, 1.2 eq) at RT. The resulting mixture was stirred for Ih before being quenched with ice water. The mixture was extracted with DCM. The combined organic phase was dried over Na 2 SO 4 , filtered and concentrated to give the title compound (800 mg, 65%) as a yellow oil. LC-MS: [M+H]+ (m/z) = 244.1.

[00334] Step 3: (4-(benzyloxy)phenyl)(6-ethyl-5H-pyrrolo[3,2-d]pyrimidin-7-y l)methanone.

[00335] A mixture of N-(4-(but-1-yn-1-yl)pyrimidin-5-yl)-2,2,2-trifluoroacetamide (740 mg, 3.04 mmol, 1.0 eq), 1-(benzyloxy)-4-iodobenzene (1.1 g, 3.65 mmol, 1.2 eq), K 2 CO 3 (2.5 g, 18.25 mmol, 5.0 eq) and Pd(PPh 3 ) 4 (176 mg, 0.15 mmol, 0.05 eq) in MeCN (100 mL) was stirred overnight at 45 °C under CO. The mixture was cooled to RT, and diluted with DCM/water. The organic phase was separated, dried over Na 2 SO 4 and purified by flash chromatography on silica gel (eluent: 0-2% MeOH/DCM) to give the title compound (340 mg, 31%) as a light yellow solid. LC-MS: [M+H]+ (m/z) = 358.2.

[00336] Step 4: (4-(benzyloxy)phenyl)(6-ethyl-5-methyl-5H-pyrrolo[3,2-d]pyri midin-7- yl)methanone.

[00337] At 0 °C, to a solution of (4-(benzyloxy)phenyl)(6-ethyl-5H-pyrrolo[3,2-d]pyrimidin- 7-yl)methanone (340 mg, 0.95 mmol, 1.0 eq) in DMF (5 mL) was added NaH (76 mg, 1.9 mmol, 2.0 eq) under Ar, and the resulting mixture was stirred for 10 min before it was treated with Me2SO4 (120 mg, 0.95 mmol, 1.0 eq). The reaction was quenched with sat. NH4CI after 2 h. The mixture was diluted with EA/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by Prep-TLC (eluent: 5% MeOH in DCM) to give the title compound (173 mg, 49 %). LC-MS: [M+H]+ (m/z) = 372.1.

[00338] Step 5: (6-ethyl-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4- hydroxyphenyl)m ethanone.

[00339] To a solution of (4-(benzyloxy)phenyl)(6-ethyl-5-methyl-5H-pyrrolo[3,2- d]pyrimidin-7-yl)methanone (173 mg, 0.47 mmol, 1.0 eq) in DCM (5 mL) were added TFA (1 mL) and TfOH (0.5 mL). The resulting mixture was stirred for 30 min at RT before it was quenched with 1N NaOH at 0 °C. The mixture was washed with sat. NH4CI, and the aqueous layer was extracted with 15% i-PrOH in DCM. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give the crude title compound (131 mg, 100 %). LC-MS: [M+H]+ (m/z) = 282.0.

[00340] Step 6: (3,5-dibromo-4-hydroxyphenyl)(6-ethyl-5-methyl-5H-pyrrolo[3, 2- d]pyrimidin-7-yl)methanone.

[00341] At 0 °C, to a solution of (6-ethyl-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)(4- hydroxyphenyl)methanone (131 mg, 0.47 mmol, 1.0 eq) in THF/DCM/DMF (10:5:2, 8.5 mL) was added 1, 3 -dibromo-5, 5 -dimethylhydantoin (134 mg, 0.47 mmol, 1.0 eq) under Ar, and the resulting mixture was stirred at 0 oC for 10 min before it was quenched with sat. Na 2 SO 3 . The mixture was filtered, and the filtrate was purified by prep-HPLC to give the title compound (64 mg, 31 %) as a white solid. LC-MS: [M+H]+ (m/z) = 437.8; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 8.79 (s, 1H), 7.86 (s, 2H), 3.95 (s, 3H), 3.11 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). [00342] Example 18: (3,5-dibromo-4-hydroxyphenyl)(6-ethyl-7-methyl-7H-pyrrolo[2, 3- d]pyrimidin-5-yl)methanone

[00343] Step 1 : 5-(but-1-yn-1-yl)pyrimidin-4-amine.

[00344] A mixture of 5-bromopyrimidin-4-amine (1.0 g, 5.7 mmol, 1.0 eq), but-l-yn-1- yltrimethylsilane (1.1 g, 8.6 mmol, 1.5 eq), TEA (1.2 g, 11.4 mmol, 2.0 eq), Cui (55 mg, 0.29 mmol, 0.05 eq), KF (331 mg, 5.7 mmol, 1.0 eq), and Pd(PPh 3 ) 2 Cl 2 (204 mg, 0.29 mmol, 0.05 eq) in DMF (10 mL) was stirred overnight at 60 °C under Ar. The mixture was concentrated and purified by flash chromatography on silica gel (eluent: 0-2% MeOH/DCM) to give the title compound (864 mg, 100 %) as a light yellow oil. LC-MS: [M+H]+ (m/z) = 148.2.

[00345] Step 2: N-(5-(but-1-yn-1-yl)pyrimidin-4-yl)-2,2,2-trifluoroacetamide .

[00346] To a solution of 5-(but-1-yn-1-yl)pyrimidin-4-amine (1.0 g, 6.8 mmol, 1.0 eq) in DCM (20 mL) were added TEA (1.4 g, 13.6 mmol, 2.0 eq) and TFAA (1.7 g, 8.2 mmol, 1.2 eq), and the resulting mixture was stirred at RT for 1 h. Ice water was added, and the mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (1.32 g, 80 %) as a yellow oil. LC-MS: [M+H]+ (m/z) =

244.1.

[00347] Step 3: (4-(benzyloxy)phenyl)(6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-y l)methanone.

[00348] A mixture of N-(5-(but-1-yn-1-yl)pyrimidin-4-yl)-2,2,2-trifluoroacetamide (1.3 g, 5.4 mmol, 1.0 eq), l-(benzyloxy)-4-iodobenzene (2.0 g, 6.5 mmol, 1.2 eq), K 2 CO 3 (3.8 g, 27.2 mmol, 5.0 eq) and Pd(PPh 3 ) 4 (314 mg, 0.27 mmol, 0.05 eq) in MeCN (100 mL) was stirred overnight at 45 °C under CO. The mixture was diluted with DCM/water. The organic phase was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 0-2% MOH/DCM) to give the title compound (540 mg, 28 %) as a light yellow solid. LC-MS: [M+H]+ (m/z) = 358.2.

[00349] Step 4: (4-(benzyloxy)phenyl)(6-ethyl-7-methyl-7H-pyrrolo[2,3-d]pyri midin-5- yl)methanone.

[00350] At 0 °C, to a solution of (4-(benzyloxy)phenyl)(6-ethyl-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone (100 mg, 0.28 mmol, 1.0 eq) in DMF (3 mL) was added NaH (22 mg, 0.56 mmol, 2.0 eq) under Ar, and the resulting mixture was stirred at 0 °C for 10 min. Me2SO4 (35 mg, 0.28 mmol, 1.0 eq) was added, and the stirring was continued for 2h at 0 °C. The reaction was quenched with sat. NH 4 CI, and the mixture was diluted with EA/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by Prep-TLC (eluent: 5% MeOH in DCM) to give the title compound (45 mg, 43%). LC-MS: [M+H]+ (m/z) = 372.1.

[00351] Step 5: (6-ethyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- hydroxyphenyl)m ethanone.

[00352] To a solution of (4-(benzyloxy)phenyl)(6-ethyl-7-methyl-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone (45 mg, 0.12 mmol, 1.0 eq) in DCM (5 mL) were added TFA (1 mL) and TfOH (0.5 mL), and the resulting mixture was stirred for 30 min at RT. The reaction was quenched with IN NaOH at 0 °C, and the mixture was washed with sat. NH 4 Cl. The aqueous layer was extracted with 15% i-PrOH in DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (34 mg, 100 %). LC-MS: [M+H]+ (m/z) = 282.1.

[00353] Step 6: (3,5-dibromo-4-hydroxyphenyl)(6-ethyl-7-methyl-7H-pyrrolo[2, 3- d]pyrimidin-5-yl)methanone.

[00354] At 0 °C, to a solution of (6-ethyl-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- hydroxyphenyl)methanone (34 mg, 0.12 mmol, 1.0 eq) in THF/DCM/DMF (10:5:2, 8.5 mL) was added 1, 3 -dibromo-5, 5 -dimethylhydantoin (34 mg, 0.12 mmol, 1.0 eq) under Ar, and the resulting mixture was stirred for 10 min at 0 °C. The reaction was then quenched with sat. Na 2 SO 3 , and the mixture was filtered. The filtrate was purified by Prep-HPLC to give the title compound (43 mg, 81%) as a white solid. LC-MS: [M+H]+ (m/z) = 437.9; NMR (400 MHz, DMSO-d 6 ) δ 8.87 (s, 1H), 8.54 (s, 1H), 7.87 (s, 2H), 3.87 (s, 3H), 3.02 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).

[00355] Example 19: (3,5-dichloro-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[2 ,3- c]pyridin-3-yl)methanone

[00356] Step 1 : 2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridine.

[00357] At 0 °C, to a solution of 2-ethyl-1H-pyrrolo[2,3-c]pyridine (300 mg, 2.04 mmol, 1.0 eq; from Example 1, Step 2) in DMF (8 mL) was added NaH (163 mg, 4.08 mmol, 2.0 eq) under Ar, and the resulting mixture was stirred at 0 °C for 10 min. Me2SO4 (257 mg, 2.04 mmol, 1.0 eq) was added, and the mixture was stirred overnight at RT under Ar. The reaction was quenched with ice water, and the mixture was worked up and purified by flash chromatography on silica gel (eluent: 0-3% MeOH/DCM) to give the title compound (190 mg, 58 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 161.1.

[00358] Step 2: (3,5-dichloro-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[2 ,3-c]pyridin- 3-yl)methanone.

[00359] At 0 °C, to a solution of 2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (190 mg, 1.18 mmol, 1.0 eq) and 3,5-dichloro-4-methoxybenzoyl chloride ( 846 mg, 3.54 mmol, 3.0 eq) in CS2 (20 mL) was added AlCl 3 (787 mg, 5.9 mmol, 5.0 eq), and the resulting mixture was stirred at RT for 16 h. The reaction was quenched with NaHCC 3 (aq) at 0 °C, and the mixture was extracted with DCM. The combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue (200 mg crude, major LC-MS: [M+H]+ (m/z) = 553.3) was re-dissolved in MeOH (5 mL), treated with LON NaOH (2 mL) and stirred at 50 °C for 1 h. The mixture was filtered, concentrated, and purified by Prep-HPLC to give the title compound (27.35 mg, 22 %) as a white solid. LC-MS: [M+H]+ = 349.4; 1 H NMR (400 MHz, CD 3 OD) δ 9.28 (s, 1H), 8.25 (d, J = 6.4 Hz, 1H), 7.73 (s, 2H), 7.64 (d, J = 6.4 Hz, 1H), 4.11 (s, 3H), 3.19 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H). [00360] Example 20: (2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(3,5-d ichloro- 4-hydroxyphenyl)methanone

[00361] At 0 °C, to a mixture of 3,5-dichloro-4-methoxybenzoyl chloride (1.1 g, 4.63 mmol, 3.0 eq) and 2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (266 mg, 1.54 mmol, 1.0 eq; from Example 7, Step 3) in CS2 (40 mL) was added AlCl 3 (1.03 g, 7.72 mmol, 5.0 eq), and the resulting mixture was stirred overnight at 30 °C under Ar. The reaction was quenched with sat. NaHCC 3 , and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue (849 mg, crude) was redissolved in MeOH (10 mL), treated with IN NaOH (2 mL), and stirred at 50 °C for 2 h. The crude product was purified by Prep-HPLC (mobile phase: MeCN/H 2 O with 0.1% 10N HC1) to give the title compound (46.6 mg, 8 % for two steps). LC-MS: [M+H]+ (m/z) = 361.0; 1 H NMR (400 MHz, CD 3 OD) δ 9.18 (s, 1H), 8.21 (d, J = 6.8 Hz, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.74 (s, 2H), 4.07 (s, 3H), 2.06-2.00 (m, 1H), 0.95-0.90 (m, 2H), 0.58-0.54 (m, 2H).

[00362] Example 21 : (2-cyclobutyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(3,5-di chloro-4- hydroxyphenyl)methanone [00363] Step 1 : N-(4-methylpyridin-3-yl)cyclobutanecarboxamide.

[00364] To a solution of 4-methylpyridin-3-amine (1.0 g, 9.25 mmol, 1.0 eq) in THF (20 mL) were added cyclobutanecarbonyl chloride (1.3 g, 11.10 mmol, 1.2 eq) and TEA (1.4 g, 13.88 mmol, 1.5 eq), and the resulting mixture was stirred overnight at RT. The reaction was quenched with sat. NH 4 CI, and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the title compound (1.69 g, 96 %). LC-MS: [M+H]+ (m/z) =191.5.

[00365] Step 2: 2-cyclobutyl-1H-pyrrolo[2,3-c]pyridine.

[00366] At 0 °C, to a solution of N-(4-methylpyridin-3-yl)cyclobutanecarboxamide (1.69 g, 8.9 mmol, 1.0 eq) in THF (50 mL) was added LDA (22 mL, 44.5 mmol, 5.0 eq) under Ar, and the resulting mixture was stirred overnight at 70 °C. The reaction was quenched with sat. NH4CI, and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography on silica gel (eluent: 0- 5% MeOH/DCM) to give the title compound (1.03 g, 67 %) as a light yellow solid. LC-MS: [M+H]+ (m/z) =173.1.

[00367] Step 3: 2-cyclobutyl-1-methyl-lH-pyrrolo[2,3-c]pyridine.

[00368] At 0 °C under an Ar atmosphere, to a solution of 2-cyclobutyl-1H-pyrrolo[2,3- c]pyridine (281 mg, 1.63 mmol, 1.0 eq) in DMF (10 mL) was added NaH (130 mg, 3.26 mmol, 2.0 eq). After stirred at 0 °C for 10 min, the reaction mixture was treated with Me 2 SO 4 (205 mg, 1.63 mmol, 1.0 eq) and stirred for another 2 h. The reaction was quenched with sat. NH4CI, and the mixture was diluted with DCM. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 2% MeOH in DCM) to give the title compound (205 mg, 68 %). LC-MS: [M+H]+ (m/z) = 187.5.

[00369] Step 4: (2-cyclobutyl-1-methyl-lH-pyrrolo[2,3-c]pyridin-3-yl)(3,5-di chloro-4- hydroxyphenyl)m ethanone.

[00370] At 0 °C, to a mixture of 3,5-dichloro-4-methoxybenzoyl chloride (743 mg, 3.3 mmol, 3.0 eq) and 2-cyclobutyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (205 mg, 1.1 mmol, 1.0 eq) in CS 2 (10 mL) was added A1Cl 3 (735 mg, 5.5 mmol, 5.0 eq), and the resulting mixture was stirred overnight at RT under Ar. The reaction was quenched with sat. NaHCO 3 , and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , filtered, and concentrated. The residue (636 mg, crude) was retaken in MeOH (10 mL), treated with IN NaOH (2 mL) and stirred at 50 °C for 2 h. The crude product was purified by Prep-HPLC (mobile phase: MeCN/H 2 O with 0.1% IN HCl) to give the title compound (54 mg). LC-MS: [M+H]+ (m/z) = 375.0; 1 HNMR (400 MHz, DMSO-d 6 ) δ 9.25 (s, 1H), 8.25 (d, J = 6.4 Hz, 1H), 7.81 (s, 1H), 7.78 (d, J = 6.4 Hz, 1H), 4.21-4.12 (m, 1H), 4.05 (s, 3H), 2.41-2.25 (m, 4H), 2.16- 2.09 (m, 1H), 1.89-1.85 (m, 1H).

[00371] Example 22: (3-chloro-5-fluoro-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrr olo[2,3- c]pyridin-3-yl)methanone

[00372] Step 1 : 3-chloro-5-fluoro-4-hydroxybenzoic acid.

[00373] To a solution of 3-fluoro-4-hydroxybenzoic acid (2.97 g, 19 mmol, 1.0 eq) in HO Ac (50 mL) and DMF (3 mL) was added SO 2 CI 2 (4.7 mL, 70 mmol, 3.7 eq), and the resulting mixture was stirred for 2 h at 60 °C under Ar. The reaction was quenched with ice-water, and the mixture was filtered. The filtrate was extracted with DCM, and the combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (525 mg, 25 %) as a yellow solid. LC-MS: [M-H]- (m/z) = 189.1.

[00374] Step 2: methyl 3-chloro-5-fluoro-4-methoxybenzoate.

[00375] A mixture of 3-chloro-5-fluoro-4-hydroxybenzoic acid (1.0 g, 5.26 mmol, 1.0 eq), CH 3 I (7.47 g, 52.6 mmol, 10.0 eq) and K 2 CO 3 (2.91 g, 21.05 mmol, 4.0 eq) in acetone (10 mL) was stirred overnight at 65 °C under Ar. The reaction mixture was filtered, and the filtrate was diluted with water and extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , concentrated under reduced pressure, and purified by flash chromatography on silica gel (eluent 1-10% EA/PE) to give the title compound (780 mg, 68 %) as a white solid.

[00376] Step 3: 3-chloro-5-fluoro-4-methoxybenzoic acid.

[00377] To a solution of methyl 3-chloro-5-fluoro-4-methoxybenzoate (780 mg, 3.58 mmol, 1.0 eq) in THF/H2O (16 mL/6 mL) was added LiOH●H 2 O (600 mg, 14.31 mmol, 4.0 eq), and the resulting mixture was stirred for 2 h at RT. HC1 (IN) was added, and the mixture was extracted with EA. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (691 mg, 94.7%) as a white solid. LC-MS: [M-H]- (m/z) = 203.0.

[00378] Step 4: 3-chloro-5-fluoro-4-methoxybenzoyl chloride.

[00379] At 0 °C, to a solution of 3-chloro-5-fluoro-4-methoxybenzoic acid (250 mg, 1.23 mmol, 1.0 eq) in DCE (20 mL) were added SOCL (2 mL) and 2 drops of DMF. The mixture was stirred at 80 °C for 2 h under Ar, and then concentrated to give the title compound (271.5 mg, 100 %) which was used in the next step without further purification.

[00380] Step 5: (3-chloro-5-fluoro-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrr olo[2,3- c]pyri din-3 -yl)methanone.

[00381] At 0 °C, to a mixture of 2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (86 mg, 0.54 mmol, 1.0 eq; from Example 19, Step 1) and 3-chloro-5-fluoro-4-methoxybenzoyl chloride (218 mg, 0.98 mmol, 1.8 eq) in CS2 (30 mL) was added AlCl 3 (288 mg, 2.16 mmol, 4.0 eq), and the mixture was stirred for 16 h at RT under Ar. The reaction was quenched with ice-water, and the mixture was adjusted to pH 8 with NaHCO 3 and extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was dissolved in MeOH (10 mL), treated with IN NaOH (1 mL), and stirred at 50 °C for 2 h. The crude product was purified by Prep-HPLC (eluent: MeCN/H 2 O with 0.1% formic acid) to give the title compound (15.13 mg, 11.8 %) as a white solid. LC-MS: [M+H]+ (m/z) = 333.1; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.93 (s, 1H), 8.16-8.14 (m, 2H, including HCO2H), 7.46 (s, 1H), 7.41 (dd, J = 10.8, 1.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 3.92 (s, 3H), 3.02 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H).

[00382] Example 23 : 3-chloro-5-(2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-car bonyl)-2- hydroxybenzonitrile

[00383] Step 1 : methyl 3-bromo-4-hydroxybenzoate.

[00384] At 0 °C, to a stirred solution of methyl 4-hydroxybenzoate (5.0 g, 32.9 mmol, 1.0 eq) in CHCl 3 /MeOH (50 mL, 9:1) was added dropwise a solution of Br 2 (1.7 mL, 32.9 mmol, 1.0 eq) in CHC13 (6 mL). After stirring for 2h, the reaction mixture was diluted with H 2 O/CHCI 3 , and extracted with CHCL. The combined organic phases were washed with sat. Na 2 S 2 O 3 then with brine, dried over Na 2 SO 4 , and concentrated to give the title compound (7.6 g, 100 %). LCMS: [M+H]+ (m/z) = 230.9.

[00385] Step 2: methyl 3-cyano-4-hydroxybenzoate.

[00386] To a solution of methyl 3-bromo-4-hydroxybenzoate (1.0 g, 4.3 mmol, 1.0 eq) in DMF (20 mL) was added CuCN (0.58 g, 6.5 mmol, 1.5 eq). The reaction mixture was stirred at 150 °C for 16 h. The mixture was filtered, and the filtrate was diluted with EA/H2O and then filtered again. The organic layer was separated, and aqueous layer was extracted with EA. The combined organic layers were washed with brine and dried over Na 2 SO 4 . The crude product was purified by flash chromatography on silica gel (eluent: PE/EA 6: 1~2: 1) to give the title compound (280 mg, 36 %) as a white solid. LCMS: [M-H]- (m/z) = 176.0.

[00387] Step 3: methyl 3-chloro-5-cyano-4-hydroxybenzoate.

[00388] To a mixture of methyl 3-cyano-4-hydroxybenzoate (1.5 g, 8.47 mmol, 1.0 eq) in HC1 (3 M in EA, 5.1 mL) and CHCl 3 /MeOH (15 mL/5 mL) was added NCS (2.75 g, 20.3 mmol, 2.4 eq), and the reaction mixture was stirred for 2 h at RT. The mixture was concentrated under reduced pressure to give the title compound (1.5 g, 84 %) as a yellow solid. LC-MS: [M-H]- (m/z) = 210.0. [00389] Step 4: methyl 3-chloro-5-cyano-4-methoxybenzoate.

[00390] To a mixture of methyl 3-chloro-5-cyano-4-hydroxybenzoate (1.0 g, 4.47 mmol, 1.0 eq) in acetone (10 mL) were added CH3I (6.73 g, 47.4 mmol, 10.0 eq) and K 2 CO 3 (2.62 g, 18.96 mmol, 4.0 eq). The mixture was stirred overnight at 65 °C under Ar. The mixture was filtered, and the filtrate was diluted with water and then extracted with DCM. The organic layer was dried over Na 2 SO 4 , concentrated under reduced pressure, and purified by flash chromatography on silica gel (PEZEA 100: 1 to10: 1) to give the title compound (320 mg, 30 %) as a white solid.

[00391] Step 5: 3-chloro-5-cyano-4-methoxybenzoic acid.

[00392] To a solution of methyl 3-chloro-5-cyano-4-methoxybenzoate (320 mg, 1.42 mmol, 1.0 eq) in THF/H 2 O (2: 1, 12 mL) was added LiOH●H 2 O (238 mg, 5.69 mmol, 4.0 eq), and the mixture was stirred at RT for 2 h. The reaction was quenched with IN HC1, and the mixture was extracted with EA. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (300 mg, 100%) as a white solid. LC-MS: [M-H]- (m/z) = 210.0.

[00393] Step 6: 3-chloro-5-cyano-4-methoxybenzoyl chloride.

[00394] To a solution of 3-chloro-5-cyano-4-methoxybenzoic acid (240 mg, 1.14 mmol, 1.0 eq) in DCE (10 mL) were added SOCI 2 (1.5 mL) and DMF (2 drops). The resulting mixture was stirred at 80 °C for 2 h under Ar. The mixture was concentrated to give the title compound (259 mg, 100 %).

[00395] Step 7: 3-chloro-5-(2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-car bonyl)-2- hydroxybenzonitrile.

[00396] At 0 °C, to a mixture of 3-chloro-5-cyano-4-methoxybenzoyl chloride (259 mg, 1.14 mmol, 1.5 eq) and 2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (122 mg, 0.76 mmol, 1.0 eq; from Example 19, Step 1) in CS2 (15 mL) was added A1CL (304 mg, 2.28 mmol, 3.0 eq), and the resulting mixture was stirred overnight at 45 °C under Ar. The reaction was quenched with sat. NaHCO 3 , and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , and concentrated. The residue (300 mg) was retaken into MeOH (10 mL), treated with IN NaOH (1 mL), and stirred at 50 °C for 2 h. The mixture was worked up, and the crude product was purified by Prep-HPLC (mobile phase: MeCN/H 2 O with 0.1% formic acid) to give the title compound (11.8 mg). LC-MS: [M+H]+ (m/z) = 340.1; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.95 (s, 1H), 8.16-8.14 (m, 2H), 7.65 (d, J = 2.8 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), 3.91 (s, 3H), 2.98 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). [00397] Example 24: 5-(2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)-2- hydroxy-

3-(methylthio)benzonitrile

[00398] Step 1 : methyl 3-cyano-4-hydroxy-5-iodobenzoate.

[00399] At 0 °C, to a solution of methyl 3-cyano-4-hydroxybenzoate (3.2 g, 18.0 mmol, 1.0 eq) in CHCl 3 (40 mL) and MeOH (5 mL) were added NIS (4.28 g, 19.0 mmol, 1.05 eq) and TfOH (1.3 mL). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with H 2 O/CHCI 3 , and extracted with CHCl 3 . The combined organic phases were washed with brine, dried over Na 2 SO 4 , and concentrated to give the title compound (5.3 g, 96 %). LCMS: [M-H]- (m/z) = 301.8.

[00400] Step 2: methyl 3-cyano-4-hydroxy-5-(methylthio)benzoate.

[00401] A mixture of methyl 3-cyano-4-hydroxy-5-iodobenzoate (3.20 g, 10.6 mmol, 1.0 eq), 2,2’ -bipyridyl (165 mg, 1.06 mmol, 0.1 eq), Zn powder (1.40 g, 21.2 mmol, 2.0 eq), NiBr 2 (232 mg, 1.06 mmol, 0.1 eq) and MeSSMe (1.50 g, 15.9 mmol, 1.5 eq) in DMF (32 mL) was stirred at 90 °C for 16 h under Ar. The reaction mixture was filtered, and the filtrate was diluted with EA/water. The organic layer was separated, washed with brine, dried over Na 2 SO 4 , and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 1-5% DCM/MeOH) to give the title compound (1.16 g, 37 %) as a white solid. LCMS: [M-H]- (m/z) = 222.0.

[00402] Step 3: methyl 3-cyano-4-methoxy-5-(methylthio)benzoate. [00403] At 0 °C, to a solution of methyl 3-cyano-4-hydroxy-5-(methylthio)benzoate (1.16 g, 5.19 mmol, 1.0 eq) in DMF (25 mL) were added K 2 CO 3 (7.17 g, 52 mmol, 10.0 eq) and Me2SO4 (3.28 g, 26 mmol, 5.0 eq). The reaction mixture was stirred for 16 h at RT. The mixture was filtered, and the filtrate was diluted with EA/water. The organic phase was separated, washed with brine, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 15: 1 to 5: 1 PE./EA) to give the title compound (0.91 g, 74 %) as a white solid.

[00404] Step 4: 3-cyano-4-methoxy-5-(methylthio)benzoic acid.

[00405] To a solution of methyl 3-cyano-4-methoxy-5-(methylthio)benzoate (0.91 g, 3.84 mmol, 1.0 eq) in THF/H 2 O (2: 1, 24 mL) was added LiOH●H 2 O (0.647 g, 15.4 mmol, 4.0 eq). The mixture was stirred at RT for 4 h, and then adjusted to pH 3. The mixture was extracted with EA, and the combined organic phases were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure to give the title compound (1.0 g, 97 %) as a white solid. LCMS: [M-H]- (m/z) = 222.0.

[00406] Step 5: 3-cyano-4-methoxy-5-(methylthio)benzoyl chloride.

[00407] To a solution of 3-cyano-4-methoxy-5-(methylthio)benzoic acid (300 mg, 1.34 mmol, 1.0 eq) in DCE (10 mL) were added SOCI 2 (1.5 mL) and DMF (2 drops). The resulting mixture was stirred at 80 °C for 2 h under Ar, and then concentrated to give the title compound (324 mg, 100 %).

[00408] Step 6: 5-(2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)-2- hydroxy-3- (methylthio)benzonitrile.

[00409] At 0 °C, to a mixture of 3-cyano-4-methoxy-5-(methylthio)benzoyl chloride (324 mg, 1.34 mmol, 3.0 eq) and 2-ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (77 mg, 0.45 mmol, 1.0 eq; from Example 19, Step 1) in CS 2 (20 mL) was added A1CL (300 mg, 2.25 mmol, 5.0 eq), and the resulting mixture was stirred overnight at 40 oC under Ar. The reaction was quenched with sat. NaHCO 3 , and the mixture was partitioned between DCM/water. The organic layer was separated, dried over Na 2 SO 4 , and concentrated. The residue (100 mg) was retaken in MeOH (10 mL), treated with 2 N NaOH (3 mL), and stirred at 40 °C for 2 h. The crude product was purified by Prep-HPLC (mobile phase: MeCN/H 2 O with 0.1% formic acid) to give the title compound (26 mg). LC-MS: [M+H]+ (m/z) = 352.1; 1 HNMR (400 MHz, CD 3 OD) δ 9.30 (s, 1H), 8.26 (d, J = 6.4 Hz, 1H), 8.10 (s, 0.4H, HCO2H), 7.98 (s, 1H), 7.83 (s, 1H), 7.63 (d, J = 6.8 Hz, 1H), 4.13 (s, 3H), 3.23 (q, J = 7.6 Hz, 2H), 2.44 (s, 3H), 1.40 (t, J = 7.6 Hz, 3H). [00410] Example 25: (3-chloro-5-fluoro-4-hydroxyphenyl)(2-cyclopropyl-1-methyl-1 H- pyrrolo[2,3-c]pyridin-3-yl)methanone

[00411] At 0 °C, to a mixture of 2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (84 mg, 0.49 mmol, 1.0 eq; from Example 7, Step 3) and 3-chloro-5-fluoro-4-methoxybenzoyl chloride (328 mg, 1.47 mmol, 3.0 eq) in CS2 (30 mL) was added AlCl 3 (327 mg, 2.45 mmol, 5.0 eq). The mixture was then stirred at 30 °C for 16 h under Ar. The reaction was quenched with ice-water, and the mixture was adjusted to pH 8 with saturated NaHCCf and extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. The residue was retaken into MeOH (6 mL), treated with IN NaOH (6 mL), and stirred at 40 °C for 2 h. The solvent was removed, and the residue was purified by Prep-HPLC (eluent: MeCN/H 2 O with 0.1% formic acid) to give the title compound (12.8 mg, 8 %) as a white solid. LC-MS: [M+H]+ (m/z) = 345.0; 1 H NMR (400 MHz, CD 3 OD) δ 8.91 (s, 1H), 8.22 (d, J = 5.6 Hz, 1H), 7.70 (d, J = 6.0 Hz, 1H), 7.66-7.65 (m, 1H), 7.55 (dd, J = 10.8, 2.0 Hz, 1H), 4.09 (s, 3H), 2.06-2.01 (m, 1H), 1.00-0.95 (m, 2H), 0.62-0.57 (m, 2H).

[00412] Example 26: 3-chloro-5-(2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine -3- carbonyl)-2-hydroxybenzonitrile

[00413] At 0 °C, to a mixture of 3-chloro-5-cyano-4-methoxybenzoyl chloride (326 mg, 1.42 mmol, 3.0 eq) and 2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (81 mg, 0.47 mmol, 1.0 eq; from Example 7, Step 3) in CS2 (20 mL) was added AlCl 3 (313 mg, 2.35 mmol, 5.0 eq). The resulting mixture was stirred overnight at 40 °C under Ar. The reaction was quenched with sat. NaHCOs, and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , and concentrated (100 mg, crude). The residue was dissolved in MeOH (10 mL), treated with 2N NaOH (3 mL), and stirred at 40 °C for 2 h. The crude product was purified by Prep-HPLC (mobile phase: MeCN/H 2 O with 0.1% formic acid) to give the title compound (35.6 mg). LC-MS: [M+H]+ (m/z) = 352.3; 1 HNMR (400 MHz, CD 3 OD) δ 9.26 (s, 1H), 8.31 (d, J = 6.8 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 6.4 Hz, 1H), 8.06 (s, 0.5H, HCO2H), 8.04 (d, J = 2.0 Hz, 1H), 4.15 (s, 3H), 2.02 (m, 1H), 1.00-0.97 (m, 2H), 0.64-0.62 (m, 2H).

[00414] Example 27: 5-(2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbon yl)-3- fluoro-2-hydroxybenzonitrile

[00415] Step 1 : methyl 3-fluoro-4-hydroxy-5-iodobenzoate.

[00416] To a stirred solution of methyl 3-fluoro-4-hydroxybenzoate (5.0 g, 29.4 mmol, 1.0 eq) in THF (150 mL) were added K 2 CO 3 (8.1 g, 58.8 mmol, 2.0 eq) and E (9.0 g, 35.3 mmol, 1.2 eq). The resulting mixture was stirred overnight at RT under Ar before it was quenched with sat. Na 2 SO 3 and sat. NH 4 CI. The solid was collected by filtration, and dried under vacuum to give the title compound (4.3 g, 49 %). LC-MS: [M+H]+ (m/z) = 294.8.

[00417] Step 2: methyl 3-cyano-5-fluoro-4-hydroxybenzoate.

[00418] A mixture of methyl 3-fluoro-4-hydroxy-5-iodobenzoate (4.3 g, 14.5 mmol, 1.0 eq) and CuCN (454 mg, 5.07 mmol, 1.5 eq) in DMF (10 mL) was stirred at 140 °C for 6 h before being concentrated to give the title compound which was used directly in the next step without further purification.

[00419] Step 3: methyl 3-cyano-5-fluoro-4-methoxybenzoate.

[00420] A mixture of methyl 3-cyano-5-fluoro-4-hydroxybenzoate (2.8 g, 14.5 mmol, 1.0 eq), Mel (1.4 mL, 21.8 mmol, 1.5 eq), and K 2 CO 3 (4.0 g, 29.0 mmol. 2.0 eq) in acetone was stirred overnight at 65 °C under Ar. The mixture was concentrated, and diluted with EA/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated and purified by flash chromatography on silica gel to give the title compound (270 mg. 6 %).

[00421] Step 4: 3-cyano-5-fluoro-4-methoxybenzoic acid.

[00422] To a stirred solution of methyl 3-cyano-5-fluoro-4-methoxybenzoate (270 mg, 1.29 mmol, 1.0 eq) in THF/water (2: 1, 15 mL) was added LiOH (217 mg, 5.16 mmol, 4.0 eq). The resulting mixture was stirred overnight at RT, and neutralized with IN HC1. The mixture was extracted with EA, and the combined organic layers were concentrated to give the title compound (252 mg, 100 %).

[00423] Step 5: 3-cyano-5-fluoro-4-methoxybenzoyl chloride.

[00424] To a solution of 3-cyano-5-fluoro-4-methoxybenzoic acid (252 mg, 1.29 mmol, 1.0 eq) in DCE (10 mL) were added SOCI2 (1.5 mL) and DMF (2 drops). The resulting mixture was stirred at 80 °C for 2 h under Ar. The mixture was concentrated to give the title compound (296 mg, 100 %).

[00425] Step 6: 5-(2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbon yl)-3-fluoro- 2-hydroxybenzonitrile.

[00426] At 0 °C, to a mixture of 3-cyano-5-fluoro-4-methoxybenzoyl chloride (296 mg, 1.29 mmol, 3.0 eq) and 2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (74 mg, 0.43 mmol, 1.0 eq; from Example 7, Step 3) in CS2 (20 mL) was added AICL (340 mg, 2.55 mmol, 5.0 eq), and the reaction mixture was stirred overnight at 40 °C under Ar. The reaction was quenched with sat. NaHCO 3 , and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , and concentrated (100 mg). The residue was dissolved in MeOH (10 mL), and treated with 2N NaOH (3 mL). The reaction mixture was stirred at 40 °C for 2 h. The solvent was removed, and the residue was purified by Prep-HPLC (mobile phase: MeCN/H 2 O with 0.1% HCO2H) to give the title compound (18.17 mg, 13%). LC-MS: [M+H]+ (m/z) = 336.1; 1 HNMR (400 MHz, CD 3 OD) δ 9.29 (s, 1H), 8.34 (d, J = 6.4 Hz, 1H), 8.14 (d, J = 6.4 Hz, 1H), 7.98-7.94 (m, 2H), 4.19 (s, 3H), 2.19-2.12 (m, 1H), 1.06-1.01 (m, 2H), 0.69-0.65 (m, 2H). [00427] Example 28: (2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(3,5-d ichloro- 4-hydroxyphenyl)methanone

[00428] Step 1 : 3-(cyclopropylethynyl)pyridin-2-amine.

[00429] A mixture of 3-bromopyridin-2-amine (1.0 g, 5.78 mmol, 1.0 eq), ethynylcyclopropane (3.82 g, 57.8 mmol, 10.0 eq), TEA (1.75 g, 17.3 mmol, 3.0 eq), Cui (440 mg, 2.31 mmol, 0.4 eq) and Pd(PPh 3 ) 2 Cl 2 (814 mg, 1.16 mmol, 0.2 eq) in THF (10 mL) was stirred overnight at 80 °C under Ar. The mixture was worked up and purified by flash chromatography on silica gel (eluent: 0-3% MeOH/DCM) to give the title compound (542 mg, 59 %) as a yellow solid. LC-MS: [M+H]+ (m/z) = 159.2.

[00430] Step 2: 2-cyclopropyl-1H-pyrrolo[2,3-b]pyridine.

[00431] To a mixture of 3-(cyclopropylethynyl)pyridin-2-amine (480 mg, 3.03 mmol, 1.0 eq) in DMF (20 mL) was added t-BuOK (1.7 g, 15.2 mmol, 5.0 eq), and the reaction mixture was stirred at 80 °C under Ar for 16 h. The reaction was quenched with sat. NaHCO 3 , and the mixture was extracted with EA. The combined organic layers were dried over Na 2 SO 4 , filtered, concentrated, and purified by Prep-HPLC (mobile phase: MeCN/H 2 O with 0.1% 10N HC1) to give the title compound (120 mg, 24 %). LC-MS: [M+H]+ (m/z) = 159.1.

[00432] Step 3: 2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-b]pyridine.

[00433] At 0 °C, to a mixture of 2-cyclopropyl-1H-pyrrolo[2,3-b]pyridine (175 mg, 1.1 mmol, 1.0 eq) in DMF (10 mL) was added NaH (60%, 88 mg, 2.2 mmol, 2.0 eq) under Ar. After 10 min, a solution of Me2SO4 (139 mg, 1.1 mmol, 1.0 eq) in DMF (0.5 mL) was added dropwise, and the resulting mixture was stirred overnight at RT under Ar. The reaction was quenched with cold water, and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by Prep-TLC (eluent: 50% EA/PE) to give the title compound (90 mg, 47%) as a yellow oil. LC-MS: [M+H]+ (m/z) = 173.2.

[00434] Step 4: (2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)(3,5-d ichloro-4- hydroxyphenyl)m ethanone.

[00435] At 0 °C, to a mixture of 3,5-dichloro-4-methoxybenzoyl chloride (312 mg, 1.3 mmol, 3.0 eq) and 2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-b]pyridine (75 mg, 0.43 mmol, 1.0 eq) in CS2 (20 mL) was added AlCl 3 (289 mg, 2.17 mmol, 5.0 eq), and the resulting mixture was stirred overnight at 35 °C under Ar. The reaction was quenched with sat. NaHCO 3 , and the mixture was partitioned in DCM/water. The organic layer was separated, dried over Na 2 SO 4 and concentrated. The residue was retaken in MeOH (10 mL), treated with IN NaOH (2 mL), and stirred at 50 °C for 2 h. The solvent was removed, and the residue was purified by Prep-HPLC (mobile phase: MeCN/H 2 O with 0.1% 10N HC1) to give the title compound (37.53 mg, 28.6% for two steps). LC-MS: [M+H]+ (m/z) = 361.0; 1 H NMR (400 MHz, CD 3 OD) δ 8.31 (dd, J = 4.8, 1.6 Hz, 1H), 8.07 (dd, J = 8.0, 1.6 Hz, 1H), 7.76 (s, 2H), 7.21 (dd, J = 8.0, 4.8 Hz, 1H), 3.97 (s, 3H), 1.99-1.94 (m, 1H), 0.91-0.86 (m, 2H), 0.54-0.50 (m, 2H).

[00436] Example 29: (3,5-dichloro-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[2 ,3- b]pyridin-3-yl)methanone

[00437] Step 1 : 3-(but-1-yn-1-yl)pyridin-2-amine.

[00438] A mixture of 3-bromopyridin-2-amine (1.0 g, 5.78 mmol, 1.0 eq), but-l-yn-1- yltrimethylsilane (1.1 g, 8.67 mmol, 1.5 eq), TEA (1.6 mL, 11.56 mmol, 2.0 eq), Cui (55 mg, 0.29 mmol, 0.05 eq), KF (336 mg, 5.78 mmol, 1.0 eq) and Pd(PPh 3 ) 2 Cl 2 (204 mg, 0.29 mmol, 0.05 eq) in THF (10 mL) was stirred overnight at 80 °C under Ar. The mixture was worked up and purified by flash chromatography on silica gel (eluent: 0-2% MeOH/DCM) to give the title compound (770 mg, 90 %) as a light yellow oil. LC-MS: [M+H]+ (m/z) = 147.3.

[00439] Step 2: 2-ethyl-1H-pyrrolo[2,3-b]pyridine.

[00440] A mixture of 3-(but-1-yn-1-yl)pyridin-2-amine (770 mg, 5.27 mmol, 1.0 eq) and t- BuOK (2.96 g, 26.35 mmol, 5.0 eq) in DMF (20 mL) was stirred overnight at 80 °C under Ar. The reaction was quenched with ice water, and the mixture was extracted with DCM. The combined organic phases were concentrated and purified by Prep-HPLC (eluent: MeCN/TLO with 0.1% HCO2H) to give the title compound (95 mg, 12 %) as a white solid.

[00441] Step 3: 2-ethyl-1-methyl-1H-pyrrolo[2,3-b]pyridine.

[00442] At 0 °C, to a solution of 2-ethyl-1H-pyrrolo[2,3-b]pyridine (95 mg, 0.65 mmol, 1.0 eq) in DMF (5 mL) was added NaH (52 mg, 1.30 mmol, 2.0 eq) under Ar. After 10 min, Me2SO4 (82 mg, 0.65 mmol, 1.0 eq) was added, and the mixture was stirred for 2 h. The reaction was quenched with sat. NH 4 CI, and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 2% MeOH in DCM) to give the title compound (100 mg, 96 %). LC-MS: [M+H]+ (m/z) = 161.3.

[00443] Step 4: (3,5-dichloro-4-hydroxyphenyl)(2-ethyl-1-methyl-1H-pyrrolo[2 ,3-b]pyridin- 3-yl)methanone.

[00444] At 0 °C, to a mixture of 2-ethyl-1-methyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.63 mmol, 1.0 eq) and 3,5-dichloro-4-methoxybenzoyl chloride (453 mg, 1.90 mmol, 3.0 eq) in CS 2 (30 mL) was added A1CL (417 mg, 3.10 mmol, 5.0 eq). The mixture was heated up to 35 °C, and stirred for 16 h under Ar. Ice-water was added, and the mixture was adjusted to pH 8 with saturated NaHCO 3 and extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was dissolved in MeOH (6 mL), and treated with IN NaOH (6 mL). The resulting mixture was stirred at 40 °C for 2 h. The solvent was removed, and the residue was purified by Prep-HPLC (eluent: MeCN/H 2 O with 0.1% HCO2H) to give the title compound (79 mg, 36 %) as a white solid. LC-MS: [M+H]+ (m/z) = 349.0; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30-8.28 (m, 1H), 7.62 (m, 2H), 7.53-7.51 (m, 1H), 7.17-7.13 (m, 1H), 3.87 (s, 3H), 3.01 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). [00445] Example 30: (2-(tert-butyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(3,5- dibromo-4- hydroxyphenyl)methanone

[00446] Step 1 : N-(4-methylpyridin-3-yl)pivalamide.

[00447] At 0 °C, to a solution of 4-methylpyri din-3 -amine (1.0 g, 9.26 mmol, 1.0 eq) in THF (20 mL) were added TEA (1.4 g, 13.89 mmol, 1.5 eq) and pivaloyl chloride (1.34 g, 11.11 mmol, 1.2 eq) under Ar, and the reaction mixture was stirred for 16 h. The reaction was quenched with sat. NH 4 Cl, and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 5% MeOH in DCM) to give the title compound (1.78 g, 100%). LC-MS: [M+H]+ (m/z) = 193.5.

[00448] Step 2: 2-(tert-butyl)-1H-pyrrolo[2,3-c]pyridine.

[00449] At 0 °C, to a solution of N-(4-methylpyri din-3 -yl)pivalamide (1.78 g, 9.26 mmol, 1.0 eq) in THF (20 mL) was added LDA (23 ml, 2M, 5.0 eq) under Ar. The mixture was stirred at 75 °C for 72 h. After the completion of the reaction, the mixture was cooled to RT, and diluted with sat. NH4CI and DCM. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 3% MeOH in DCM) to give the title compound (600 mg, 37 %). LC-MS: [M+H]+ (m/z) = 175.2.

[00450] Step 3: 2-(tert-butyl)-l-methyl-1H-pyrrolo[2,3-c]pyridine. [00451] At 0 °C, to a solution of 2-(tert-butyl)-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.58 mmol, 1.0 eq) in DMF (1 mL) was added NaH (46 mg, 1.15 mmol, 2.0 eq) under Ar. After 10 min, Me2SO4 (73 mg, 0.58 mmol, 1.0 eq) was added, and the stirring was continued for 2 h. The reaction was quenched with sat. NH4CI, and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by flash chromatography on silica gel (eluent: 2% MeOH in DCM) to give the title compound (46 mg, 42%). LC-MS: [M+H]+ (m/z) = 189.4.

[00452] Step 4: 2-(tert-butyl)-l-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbalde hyde.

[00453] At 0 °C, to a solution of 2-(tert-butyl)-l-methyl-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.53 mmol, 1.0 eq) in DCE/CH3NO2 (1 : 1, 16 mL) was added dichloro(methoxy)methane (305 mg, 2.66 mmol, 5.0 eq) under Ar, then followed by AlCl 3 (212 mg, 1.60 mmol, 3.0 eq). The reaction mixture was stirred for 4 h at RT under Ar. The reaction was quenched with sat. NaHCO 3 , and the mixture was extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, concentrated, and purified by Prep-TLC (eluent: 10% MeOH/DCM) to give the title compound (30 mg, 26 %) as a light yellow solid. LC-MS: [M+H]+ (m/z) = 217.2.

[00454] Step 5: (4-(benzyloxy)phenyl)(2-(tert-butyl)-l-methyl-1H-pyrrolo[2,3 -c]pyridin-3- yl)m ethanol.

[00455] At 0 °C, to a stirred solution of 2-(tert-butyl)-l-methyl-1H-pyrrolo[2,3-c]pyridine-3- carbaldehyde (140 mg, 0.65 mmol, 1.0 eq) in THF (10 mL) was added (4- (benzyloxy)phenyl)magnesium bromide (0.8 M, 1.22 mL, 0.97 mmol, 1.5 eq). After 0.5 h, the reaction was quenched with sat. NH4CI, and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by Prep-TLC (eluent: 10% MeOH in DCM) to give the title compound (76 mg, 29%). LC-MS: [M+H]+ (m/z) = 401.2.

[00456] Step 6: (4-(benzyloxy)phenyl)(2-(tert-butyl)-1-methyl-1H-pyrrolo[2,3 -c]pyridin-3- yl)methanone.

[00457] A mixture of (4-(benzyloxy)phenyl)(2-(tert-butyl)-l-methyl-1H-pyrrolo[2,3 - c]pyri din-3 -yl)methanol (76 mg, 0.19 mmol, 1.0 eq) and DMP (161 mg, 0.38 mmol, 2.0 eq) in DCM (10 mL) was stirred for 16 h at RT under Ar. The reaction was quenched with sat. NaHCOs at 0 °C, and the mixture was diluted with DCM/water. The organic layer was separated, dried over Na 2 SO 4 , concentrated, and purified by Prep-TLC (eluent with 10% MeOH in DCM) to give the title compound (40 mg, 53%). LC-MS: [M+H]+ (m/z) = 399.2. [00458] Step 7: (2-(tert-butyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4- hydroxyphenyl)m ethanone.

[00459] To a solution of (4-(benzyloxy)phenyl)(2-(tert-butyl)-l-methyl-1H-pyrrolo[2,3 - c]pyridin-3-yl)methanone (40 mg, 0.10 mmol, 1.0 eq) in DCM (5 mL) were added TFA (0.5 mL) and TfOH (0.25 mL). The resulting mixture was stirred for 1 h at RT, and the reaction was quenched with 1 NaOH at 0 °C. The mixture was washed with sat. NH4CI, and the aqueous layer was extracted with 15% i-PrOH in DCM. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated to give the title compound (60 mg. 100%). LC-MS: [M+H]+ (m/z) = 309.2.

[00460] Step 8: (2-(tert-butyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(3,5- dibromo-4- hydroxyphenyl)m ethanone.

[00461] At 0 °C, to a solution of (2-(tert-butyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(4- hydroxyphenyl)methanone (60 mg, 0.19 mmol, 1.0 eq) in THF/DCM/DMF (10:5:2, 17 mL) was added DBDMH (56 mg, 0.19 mmol, 1.0 eq) under Ar, and the mixture was stirred at 0 °C for 10. The reaction was quenched with sat. Na 2 SO 3 , and the mixture was filtered. The filtrate was purified by Prep-HPLC to give the title compound (13.97 mg, 15.4%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 464.9; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.86 (s, 1H), 8.90 (s, 1H), 8.15 (d, J = 3.2 Hz, 1H), 7.59 (s, 2H), 7.47 (d, J = 4.0 Hz, 1H), 4.31 (s, 3H), 1.43 (s, 9H).

[00462] Example 31 : 5-(2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbon yl)-2- hydroxybenzonitrile

[00463] At 0 °C, to a mixture of 2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine (172 mg, 1.0 mmol, 1.0 eq; from Example 7, Step 3) and 3-cyano-4-methoxybenzoyl chloride (590 mg, 3.0 mmol, 3.0 eq; prepared using similar scheme as described in Example 23, Steps 1-6 but without use of NCS in Step 3) in CS 2 (35 mL) was added A1CL (667 mg, 5.0 mmol, 5.0 eq), and the reaction mixture was stirred at 40 °C for 40 h under Ar. The reaction was quenched with ice- water, and the mixture was adjusted to pH 8 by adding saturated NaHCO 3 . The aqueous layer was extracted with DCM, and the combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. The residue was dissolved in MeOH (6 mL), treated with NaOH (6 mL, IN), and stirred at 40 °C for 2 h. The solvent was removed, and the residue was purified by Prep-HPLC (eluent: MeCN/H 2 O with 0.1% HCO 2 H) to give the title compound (16 mg, 5.0%) as a light brown solid. LC-MS: [M+H]+ (m/z) = 318.1; 1 H NMR (400 MHz, CD 3 OD) δ 9.17 (s, 1H), 8.28 (d, J = 6.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 8.03-8.00 (m, 2H), 7.09 (d, J = 8.8 Hz, 1H), 4.14 (s, 3H), 2.10-2.08 (m, 1H), 0.99-0.96 (m, 2H), 0.64-0.61 (m, 2H).

[00464] Example 32: 5-(2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbon yl)-2- hy dr oxy-3 -iodob enzonitril e

[00465] At 0 °C, to a stirred solution of 5-(2-cyclopropyl-1-methyl-1H-pyrrolo[2,3- c]pyridine-3-carbonyl)-2-hydroxybenzonitrile (16 mg, 0.05 mmol, 1.0 eq; Example 31) in DMF (3 mL) was added NIS (17 mg, 0.075 mmol, 1.5 eq) in one portion. The reaction mixture was stirred for 16 h at RT. The mixture was purified by Prep-HPLC (eluent: MeCN/H2O with 0.1% HCO2H) to give the title compound (8.87 mg, 40%) as a white solid. LC-MS: [M+H]+ (m/z) = 443.9; 1 HNMR (400 MHz, CD 3 OD) δ 9.20 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 4.15 (s, 3H), 2.15-2.11 (m, 1H), 1.09- 1.05 (m, 2H), 0.70-0.66 (m, 2H).

[00466] Example 33: (3,5-dichloro-4-hydroxyphenyl)(l-methyl-1H-pyrrolo[2,3-c]pyr idin-3- yl)methanone

[00467] Step 1 : 3,5-dichloro-4-methoxybenzoyl chloride.

[00468] To a solution of 3,5-dichloro-4-methoxybenzoic acid (1.0 g, 4.52 mmol, 1.0 eq) in DCE (20 mL) was added DMF (2 drops), followed by SOCL (1.08 g, 9.05 mmol, 2.0 eq). The mixture was stirred at 85 °C for 2 h under Ar. The solvent was removed under reduced pressure, and the residue was used directly in the next step without further purification.

[00469] Step 2: 2,6-dichloro-4-(l-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbony l)phenyl 3,5- dichioro-4-methoxybenzoate.

[00470] At 0 °C, to a solution of 1-methyl-1H-pyrrolo[2,3-c]pyridine (150 mg, 1.135 mmol, 1.0 eq; from Example 5, Step 1) in CS 2 (10 mL) was added AlCl 3 (757 mg, 5.67 mmol, 5.0 eq). After 0.5h, 3,5-dichloro-4-methoxybenzoyl chloride (815 mg, 3.40 mmol, 3.0 eq) was added. The resulting mixture was stirred for 16 h at RT before it was quenched with 1.0 M aq. NaOH solution. The mixture was extracted with DCM, and the combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (DCM/MeOH 1 :0~50: 1) to give the title compound (200 mg crude) as a yellow solid. LC-MS: [M+H]+ (m/z) = 522.9; 1 H NMR (400 MHz, CD 3 OD) δ 8.63 (d, J = 5.2 Hz, 1H), 7.56 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.36-7.31 (m, 1H), 7.25-7.21 (m, 1H), 2.86 (q, J = 7.2 Hz, 2H), 2.62 (s, 3H), 1.31 (t, J = 7.6 Hz, 3H).

[00471] Step 3: (3,5-dichloro-4-hydroxyphenyl)(l-methyl-1H-pyrrolo[2,3-c]pyr idin-3- yl)methanone.

[00472] To a suspension of 2,6-dichloro-4-(l-methyl-1H-pyrrolo[2,3-c]pyridine-3- carbonyl)phenyl 3,5-dichloro-4-methoxybenzoate (200 mg, 0.38 mmol, 1.0 eq) in MeOH (5.0 mL) was added 2.0 M aq. NaOH (1.9 mL, 3.82 mmol, 10 eq). The mixture was heated up to 50 °C and stirred for 1 h. The solvent was removed under reduced pressure, and the residue was purified by Prep-HPLC (mobile phase: MeCN/H 2 O with 0.1% HCO 2 H) to give the title compound (50.63 mg, 14% over 2 steps) as a white solid in formic acid form. LC-MS: [M+H]+ (m/z) = 321.0; 'H NMR (400 MHz, DMSO-d 6 ) δ 8.95 (s, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.26 (s, 1H), 8.14 (s, 0.5H, formic acid), 8.01 (d, J = 5.6 Hz, 1H), 7.73 (s, 2H), 3.98 (s, 3H).

[00473] Example 34: (3,5-dibromo-4-hydroxyphenyl)(l-(tetrahydro-2H-pyran-4-yl)-1 H- pyrrolo[2,3-c]pyridin-3-yl)methanone

[00474] Step 1 : (E)-2-(3-bromopyridin-4-yl)-N,N-dimethylethen-1-amine.

[00475] A mixture of 3 -bromo-4-m ethylpyridine (2.0 g, 11.63 mmol, 1.0 eq), 1-tert-butoxy- N,N,N',N' -tetramethylmethanediamine (2.6 g, 15.12 mmol, 1.3 eq) in DMF (8 mL) was stirred for 5 h at 135 °C under Ar. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel (eluent: 0-50% EA/PE) to give the title compound (2.0 g, 76 %). LC-MS: [M+H]+ (m/z) = 227.1.

[00476] Step 2: 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-c]pyridine.

[00477] A mixture of (E)-2-(3-bromopyridin-4-yl)-N,N-dimethylethen-1-amine (500 mg, 2.20 mmol, 1.0 eq), tetrahydro-2H-pyran-4-amine (223 mg, 2.20 mmol, 1.0 eq), t-BuONa (740 mg, 7.7 mmol, 3.5 eq), Xantphos (75 mg, 0.13 mmol, 0.06 eq) and Pd 2 (dba) 3 (60 mg, 0.07 mmol, 0.03 eq) in toluene (5 mL) was stirred at 110 °C for 3 h under Ar. The mixture was cooled to RT, and then poured into ice water. The organic layer was separated, dried over Na 2 SO 4 , and then concentrated. The residue was purified by flash chromatography on silica gel (eluent: 0-50% EA/PE) to give the title compound (482 mg, 99 %). LC-MS: [M+H]+ (m/z) =

203.2.

[00478] Step 3: (4-hydroxyphenyl)(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2, 3-c]pyridin-3- yl)methanone.

[00479] At 0 °C, to a solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.49 mmol, 1.0 eq) in CS 2 (12 mL) was added AlCl 3 (261 mg, 1.96 mmol, 4.0 eq) under Ar. The resulting mixture was stirred at 0 °C for 20 min before it was treated with a solution of 4-(tert-butoxy)benzoyl chloride (208 mg, 0.98 mmol, 2.0 eq) in DCM (1 mL), and the stirring was continued overnight at RT. The mixture was poured into ice water, adjusted to pH 10 by adding 1N NaOH, and then extracted with DCM. The aqueous phase was adjusted to pH 7 with sat. NH 4 CI, and then extracted with DCM three times. The combined organic phases were dried, and then concentrated to give the title compound (60 mg, 38 %). LC-MS: [M+H]+ (m/z) = 323.1.

[00480] Step 4: (3,5-dibromo-4-hydroxyphenyl)(1-(tetrahydro-2H-pyran-4-yl)-1 H- pyrrolo[2,3-c]pyridin-3-yl)methanone.

[00481] At 0 °C, to a solution of (4-hydroxyphenyl)(1-(tetrahydro-2H-pyran-4-yl)-1H- pyrrolo[2,3-c]pyridin-3-yl)methanone (70 mg, 0.22 mmol, 1.0 eq) in THF/MeCN/DMF/DCM

[00482] (1 : 1 : 1 : 1 : 1, 4 mL) was added NBS (78 mg, 0.44 mmol, 2.0 eq) under Ar. The resulting mixture was stirred at 0 °C for 15 min before it was quenched with sat. Na 2 SO 3 . The mixture was concentrated and purified by Prep-HPLC (mobile phase: CH3CN/H 2 O with 0.1% HCO 2 H) to give the title compound (4.23 mg, 4%) as a white solid. LC-MS: [M+H]+ (m/z) = 479.3; 1 H NMR (400 MHz, CD 3 OD) δ 9.58 (br s, 1H), 8.88 (s, 1H), 8.64 (br s, 1H), 8.48 (br s, 1H), 8.05 (s, 2H), 5.03 (m, 1H), 4.15 (dd, J = 11.2, 3.6 Hz, 2H), 3.70 (t, J = 11.6 Hz, 2H), 2.33 - 2.03 (m, 4H).

[00483] Example 35: 2-cyclopropyl-3-(3,5-dichloro-4-hydroxybenzoyl)-l-methyl-1H- pyrrolo[2,3-c]pyridine 6-oxide [00484] A mixture of (2-cyclopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)(3,5-d ichloro- 4-hydroxyphenyl)methanone (30 mg, 0.084 mmol, 1.0 eq; Example 20), MTO (2.0 mg), H 2 O 2 (30%, 0.5 mL) in DCM (2 mL) was stirred at RT for 16 h. Aqueous solution of Na 2 S 2 O 3 was added, and the mixture was stirred for 10 min. The solvent was removed under reduced pressure, and the residue was purified by Prep-HPLC (mobile phase: MeOH/H 2 O with 0.1% HCO2H) and then Prep-TLC to give the title compound (4.5 mg, 4.8%) as a yellow solid. LC-MS: [M+H]+ (m/z) = 377.0; 1 H NMR (400 MHz, CD 3 OD) δ 8.79 (s, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.78 (s, 2H), 7.76 (d, J = 7.2 Hz, 1H), 3.98 (s, 3H), 2.00-1.95 (m, 1H), 0.94-0.85 (m, 2H), 0.57-0.53 (m, 2H).

BIOLOGICAL ACTIVITY hURAT1 assay:

[00485] hURAT1 transfected HEK293 cells were propagated once in complete medium (DMEM + 10% FBS + 500 pg/mL G418 + 1% P/S) at 37 °C in an atmosphere of 5% CO 2 . The cell suspension was transferred to a 15 mL centrifuge tube and centrifuged at 1000 rpm for 5 minutes. The supernatant was aspirated, the cell pellets were resuspended with 11 mL medium, and the cell number was counted by cell counter.

[00486] The cells were plated into a Poly-D-Lysine coated 96-well at a density of 70,000 cells/well, and incubated at 37 °C for 12-24h in an atmosphere of 5% CO2. The cells were washed with 200 pL/well of pre-warmed Cl- free HBSS buffer, and uric acid [8- 14 C] (1.25 pCi/ml) and testing article (or positive control benzbromarone) in CT free HBSS buffer (50 pL/well) was then added. The plate was incubated for 8 min, and then washed three times with CT free HBSS Buffer. The cells were treated with 50 pL lysis buffer (lOOmM NaOH), and the plate was agitated at 900 rpm for 5 min. MicroScint™-40 cocktail (150 pL/well) was added, and the plate was agitated at 900 rpm for 5 min again. Plate was then read in a MicroBeta2 (PerkinElmer) reader. The data was analyzed, and IC50 was calculated using GraphPad Prism 6 software.

[00487] %inhibition =100-100*(Raw data - Min)/(Max -Min) where Min is the readout with lOOpM of benzbromarone, and Max is the readout with DMSO vehicle. [00488] Examples of the compounds of Formula (I) include the following compounds in

Table 1.

Table 1. Exemplary compounds of Formula (I) and their URAT1 activity. [00489] For comparison, the following compounds from the prior art were tested in the same assay conditions used for the compounds in Table 1.

[00490] Using synthesis schemes and methods disclosed herein the compounds in Table 2 can be prepared.

Table 2. Additional compounds of Formula (I).

[00491] The detailed description set-forth above is provided to aid those skilled in the art in practicing the present invention. However, the invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the invention. Any apparent alternative or additional embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.

[00492] All publications, patents, patent applications and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention.