WO2014004863A2

WO2014004863A2 - Compounds, compositions, and therapeutic uses thereof

Info

Publication number: WO2014004863A2
Application number: PCT/US2013/048243
Authority: WO
Inventors: Paul R. Sebahar; Robert J. Halter; Donald A. Mcleod; Daniel P. Parker; Kraig M. Yager; Mark D. Shenderovich; Ryan C. Holcomb; Burt Richards; Paul L. Bartel; Se-Ho Kim; Paul M. Slattum; Rajendra Tangallapally; Richard Trovato; Ashantai J. Yungai
Original assignee: Alzheimer's Institute Of America, Inc.
Priority date: 2012-06-27
Filing date: 2013-06-27
Publication date: 2014-01-03
Also published as: WO2014004863A3

Abstract

The invention relates to compounds, pharmaceutical compositions and medicaments comprising such compounds, and the use of these compounds, compositions, and medicaments in methods of treating a variety of diseases and disorders.

Description

COMPOUNDS, COMPOSITIONS, AND THERAPEUTIC USE S THEREOF

RELATED APPLICATIONS

[001] This application claims priority to United States Provisional Application No. 61/665,270 filed on June 27, 2012 and titled "Compounds, Compositions, and Therapeutic Uses Thereof," the contents of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

[002] The present invention relates generally to the field of medicinal chemistry. Specifically, the present invention provides compounds that inhibit IK -related kinase epsilon (ΙΚΚε), ΤΑΝΚ-binding kinase 1 (TBK1), or both ΙΚ ε and TBK1. The invention also provides methods for making these compounds, pharmaceutical compositions comprising these compounds, and methods for treating diseases with these compounds and compositions.

BACKGROUND OF THE INVENTION

[003] The protein "I-kappa-B kinase epsilon" or "ΙΚΚε" (also known as "inducible IkappaB kinase" or "IKK-i") is a member of the ΙκΒ family of kinases, and contains a kinase domain in its N-terminus, which shares substantial identity to that of I-kappa-B kinase alpha (IK a) or I-kappa-B kinase beta (ΙΚ β), and even greater identity with the kinase domain of TANK-binding kinase 1 (TBK1). ΙΚ ε was first identified as a protein whose encoding messenger RNA is substantially induced by lipopolysaccharide (LPS). (Shimada, et al.; IKK-i, a novel lipopolysaccharide-inducible kinase that is related to ΙκΒ kinases; Int. Immunol., 11 : 1357-1362, 1999.) Subsequent studies revealed that the expression of ΙΚΚε is induced by activation of the inflammatory NF-κΒ signaling pathway. (Matsuda, et al.; Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways; Oncogene, 22:3307-3318, 2003.) ΙΚΚε is expressed mainly in immune cells, and is induced in response to pro-inflammatory cytokines such as tumor necrosis factor-alpha, IL-1 and IL-6, in addition to lipopolysaccharide (LPS). Overexpression of wild-type ΙΚΚε results in the phosphorylation of ΙκΒ alpha, and stimulation of NF-kappaB activation. (Shimada, et al.; Int. Immunol., 11 :1357-1362, 1999.) [004] While all of its functions are not completely understood, ΙΚΚε has been found to play many important roles in human cells. For example, it has been known for some time that ΙΚ ε plays a key role in integrating signals induced by pro-inflammatory stimuli. (Kravchenko et al., IK i/IKKepsilon plays a key role in integrating signals induced by proinflammatory stimuli; J. Biol. Chem., 278:26612-26619, 2003.) Further, it is known that ΙΚΚε is involved in the antiviral interferon (IFN) response, and that, along with TBK1, ΙΚ ε forms a virus-activated kinase complex that phosphorylates interferon regulatory factors 3 and 7 (IRF3 & IRF7). (Sharma et al.; Triggering the interferon antiviral response through an IKK-related pathway; Science, 300: 1148-1151, 2003.) Additionally, ΙΚΚε, along with TBK1, has been shown to play a role in maintaining macrophages in an activated, inflammatory state, following activation of the interferon response. (Solis, et al.; Involvement of TBK1 and IKKepsilon in lipopolysaccharide-induced activation of the interferon response in primary human macrophages; Eur. J. Immunol., 37:529-539, 2007.)

[005] TBK1 is highly related to ΙΚΚε and is constitutively expressed in most cell types (Clement et al., The IKK-related kinases: from innate immunity to oncogenesis; Cell Res., 18:889-899, 2008). Similar to ΙΚΚε, TBK1 is responsible for phosphorylation of IRF3 & IRF7and NF-kB transcription factors after activation of innate immune receptors leading to transcription of several proinflammatory proteins (Chau et al., Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated?; Trends Biochem Sci., 33: 171-180, 2008). TBK1 and ΙΚΚε protein share redundant and possibly overlapping roles in innate immune signaling and possibly autoimmune diseases, therefore inhibition of both kinases may prove advantageous.

[006] In view of the roles identified for ΙΚΚε in the interferon antiviral response, and in the maintenance of macrophages in an activated, inflammatory state, it is perhaps not surprising that ΙΚΚε, as part of the kinase complex, has also been found to play a role in the synovial inflammation, extracellular matrix destruction and activation of the viral program and innate immune response in rheumatoid arthritis (RA). (Sweeney et al., Regulation of c- Jun phosphorylation by the ΙκΒ kinase-ε complex in fibroblast-like synoviocytes; J. Immunol., 174:6424-6430, 2005.) Indeed, further studies of the role of ΙΚΚε and its downstream phosphorylation target IRF3 in RA, have demonstrated that ΙΚΚε and IRF3 protein levels are significantly elevated in RA synovium compared to osteoarthritic synovium, and that an ΙΚΚε-dependent mechanism results in the increased production of interferon beta, and RANTES in cultured synoviocytes. ΙΚΚε null mice demonstrated reduced inflammation and erosion as well as a decrease in clinical arthritis in the collagen- induced arthritis model (Corr et al.; Synergistic benefit in inflammatory arthritis by targeting IKB kinase ε and interferon β; Ann. Rheum. Dis., 68:257-263, 2009). These results suggest that the ΙΚ ε-dependent pathway may be an important therapeutic target in the treatment of RA. (Sweeney et al.; Antiviral gene expression in rheumatoid arthritis; Arthritis Rheum., 56:743-752, 2007).

[007] Systemic lupus erythematosus (SLE) is an autoimmune disease principally affecting women of child-bearing age. The disease is caused by an inappropriate immune response directed against intranuclear, self-antigens. It manifests systemically with involvement of many organs, including the kidneys, joints, skin and nervous system. The underlying inflammatory state predisposes patients to infections and cardiovascular disease, which are the major causes of mortality and morbidity in SLE. The current model for the molecular pathology of SLE is deregulation of T, B, and dendritic cell populations via an undetermined mechanism. This leads to imbalances of several cytokines and chemokines in T and B cell compartments eventually leading to organ damage (Crispin et al.; Pathogenesis of human systemic lupus erythematosus: recent advances; Trends Mol. Med., 16:47-57, 2010). In addition, the inability of dendritic cells to properly integrate signals from apoptotic cell debris or bacterial and viral infections leads to overproduction of the type I interferons (IFNa/β). In approximately half of all SLE patients a characteristic interferon gene signature has been identified (Baechler et al.; Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus; Proc. Natl. Acad. Sci. U.S.A., 100:2610-2615, 2003). The expression of many of the interferon-regulated genes coincides with flares or periods of increased disease symptoms in SLE patients. While a single underlying cause has not been described to date, it is clear that adaptive and innate immune responses are compromised which leads to aberrant regulation of the entire immune system in SLE patients. The increase in ΙΚΝα/β production in SLE patients is due to activation of tolllike receptors (TLRs) and possibly intracellular nucleic acid receptors (Baccala et al.; TLR- dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity; Nat. Med., 13:543551, 2007). One of the downstream effects of receptor engagement is activation of the ΙΚ ε and TBKl kinases leading to phosphorylation of transcription factors IRF3 and IRF7. Upon phosphorylation, the IRFs move into the nucleus and mediate upregulation of IFNa/β and associated interferon signature genes, including OAS1, OAS2, MX1, MX2, PKR, ISG54, ISG56, RANTES, CXCL-10, as well as others. [008] ΙΚΚε and TBKl are involved in autoimmune diseases associated with accumulation of cytosolic nucleic acids. Several autoimmune diseases including; Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, retinal vasculopathy and cerebral leukodystrophy (RVCL) appear to be caused by mutations in genes such as TPvEXl, SAMHD1, and R ASEH2A-C, which encode proteins involved in degrading viral nucleic acids or accumulated endogenous cytosolic nucleic acids (Crow and Rehwinkel; Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity; Hum. Mol. Genet., 18; 130- 136, 2009; and Kavanagh, et al.; New roles for the major human 3'-5' exonuclease TREX1 in human disease; Cell Cycle, 7: 1718-1725, 2008). Patients carrying mutations that result in reduction or complete loss of protein activity have elevated expression of ΙΚΝβ and a set of "interferon signature" genes, and this elevated expression is dependent on IRF3 (Stetson et al.; Trexl prevents cell- intrinsic initiation of autoimmunity; Cell, 134:587-598, 2008). IRF3 is phosphorylated by ΙΚΚε and/or TBKl in response to signals from nucleic acid receptors, such as RIG-I, MDA5, DAI, IFI16, and others (Unterholzner et al.; IFI16 is an innate immune sensor for intracellular DNA; Nat. Immunol., E-pub Oct. 3, 2010), and phosphorylation of IFR3 leads to type I interferon production.

[009] Systemic sclerosis, Sjogrens syndrome, dermatomyositis, polymyositis (Walsh et al.; Type I Interferon-Inducible Gene Expression in Blood Is Present and Reflects Disease Activity in Dermatomyositis and Polymyositis; Arthritis Rheum., 56:3784-3792, 2007) and plaque psoriasis (Delgado-Vega, et al.; Genetic associations in type I interferon related pathways with autoimmunity; Arthritis Res. Ther., Apr 14; 12 Suppl 1 :S2, 2010) are autoimmune diseases characterized by elevated type I interferons and a characteristic interferon gene signature (Sozzani, et al.; Type I interferons in systemic autoimmunity; Autoimm., 43:196-203, 2010). Signaling pathways involving ΙΚΚε and TBKl increase type I interferon expression following activation of upstream TLR3, TLR4, and cytosolic nucleic acid receptors (Honda et al.; Regulation of the type I IFN induction: a current view; Intern. Immunol, 17: 1367-1378, 2005) consistent with a role in systemic sclerosis and myositis. Increased type I IFN signaling and the upregulation of viral dsRNA receptors including; TLR3, RIG1, and MDA5 in psoriatic skin support a role for ΙΚΚε and TBKl in the pathogenesis of psoriasis (Prens et al.; IFN-alpha enhances poly-IC responses in human keratinocytes by inducing expression of cytosolic innate RNA receptors: relevance for psoriasis; J. Invest. Dermatol., 128: 932-938, 2008). [010] Chronic obstructive pulmonary disease (COPD) is characterized by inflammation of the lungs and narrowing of the airways. Exacerbation of COPD is caused by viral and bacterial infections that can prove fatal. Viral and bacterial pulmonary infections are recognized by toll-like receptors or cytosolic nucleic acid receptors (Takaoka and Taniguchi; Cytosolic DNA recognition for triggering innate immune response; Adv. Drug Delivery Rev., 60:847-857, 2008), which activate ΙΚ ε and TBK1 kinases and lead to proinflammatory response. The involvement of ΙΚ ε and TBK1 kinases in this response is supported by findings that several IRF3 and IRF7 responsive proinflammatory genes {e.g., IFN , IP- 10 and IL-8) are induced during rhinovirus-induced COPD (Wang et al.; Role of double-stranded RNA pattern recognition receptors in rhinovirus-induced airway epithelial cell responses; J. Immunol, 183:6989-6997, 2009).

[011] Inflammatory bowel disease (IBD) is an autoimmune-like disease characterized by an abnormal response to bacteria in the gut. TLRs have been implicated in IBD based on single-nucleotide polymorphisms in IBD patients (Cario; Toll-like receptors in inflammatory bowel diseases: a decade later; Inflamm. Bowel Dis., 16: 1583-1597, 2010). The TLR4 protein is a bacterial lipopolysaccharide-recognizing receptor that activates the IRF3 pathway through ΙΚ ε and TBK1 kinases leading to RANTES and MCP-1 secretion. Elevation of both RANTES and MCP-1 protein levels are associated with IBD (McCormack et al.; Tissue cytokine and chemokine expression in inflammatory bowel disease; Inflamm. Res., 50:491- 495, 2001).

[012] It has been shown that a high-fat diet can increase NF-κΒ activation in mice, which leads to sustained elevation in the level of ΙΚ ε in liver, adipocytes, and adipose tissue macrophages. {See Chiang et al.; The protein kinase ΙΚ ε regulates energy balance in obese mice; Cell, 138:961-975, 2009) Further, mice in which the gene encoding ΙΚΚε was knocked out were found to be protected from high-fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis, and whole-body insulin resistance. These ΙΚ ε knockout mice were found to have increased energy expenditure and thermogenesis, and maintained insulin sensitivity in both liver and fat, without activation of the TNK pathway. Finally, these knockout mice were also found to have reduced expression of inflammatory cytokines, and altered expression of regulatory proteins and enzymes involved in glucose and lipid metabolism. In view of these observations, Chiang and coworkers concluded that ΙΚ ε may represent an attractive therapeutic target for obesity, insulin resistance, non-insulin-dependent diabetes mellitus (type 2 diabetes or NIDDM), metabolic syndrome, and other complications associated with these, and other, metabolic diseases and disorders. (Chiang et al.; Cell, 138:961-975, 2009.)

[013] Additionally, TBK1 was implicated as a regulator of the insulin receptor in obese Zucker rats (an art-accepted model of insulin resistance/diabetes), suggesting TBK1 could be involved in mediating insulin resistance (Munoz et al.; TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance; J. Endocrinol., 201 : 185-197, 2009).

[014] In addition to the above-described roles in macrophage activation, antiviral response, and inflammation, the gene encoding ΙΚ ε (i.e., IKBKE; Entrez Gene ID: 9641) has been identified as a breast cancer oncogene (Boehm, et al.; Integrative genomic approaches identify IKBKE as a breast cancer oncogene; Cell, 129:1065-1079, 2007). Further, ΙΚΚε has been found to directly phosphorylate the tumor suppressor CYLD in vivo, thereby decreasing the activity of CYLD, and leading to transformation and tumorigenesis (Hutti, et al.; Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKKepsilon promotes cell transformation; Mol. Cell, 34:461-472, 2009). In agreement with these observations, it has recently been discovered that overexpression of ΙΚΚε is a recurrent event in human ovarian cancer, and that this overexpression could play a role in both tumor progression and the development of cisplatin resistance (Guo, et al.; Deregulation of IKBKE is associated with tumor progression, poor prognosis, and cisplatin resistance in ovarian cancer; Am. J. Pathol., 175:324-333, 2009).

[015] Another role for ΙΚΚε has recently been described in triggering an NF-kB antiapoptotic response in response to DNA damage. After genotoxic stress, ΙΚΚε translocates to the nucleus and phosphorylates PML to prevent cell death (Renner, et al.; SUMOylation-dependent localization of ΙΚΚε in PML nuclear bodies is essential for protection against DNA-damage-triggered cell death; Mol. Cell., 37:503-515, 2010). This newly described activity may contribute to ΙΚΚε'β role as an oncogene and further support its role as a cancer target.

[016] Additionally, TBK1 (Entrez Gene ID: 29110) has been identified as a proangiogenic gene that is induced under hypoxic conditions and is overexpressed in breast and colon cancers (Korherr, et al; Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway; Proc. Natl. Acad. Sci. USA, 103:4240-4245, 2006). In cancer cells, TBK1 was found to restrict initiation of apoptotic programs typically engaged in the context of oncogenic stress (Chien et al. ; RalB GTPase-mediated activation of the ΙκΒ family kinase TBK1 couples innate immune signaling to tumor cell survival; Cell, 127:157-170, 2006). TBK1 was also recently discovered to exhibit synthetic lethality with oncogenic Ras mutations in cancer cell lines. An RNA interference screen demonstrated potent reduction of cell viability when TBK1 protein was reduced in a Ras mutant background (Barbie, et al.; Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1; Nature, 462: 108-112, 2009).

[017] In view of the above, there is a clear need for compounds that selectively inhibit the kinase activities of ΙΚ ε, TBK1, or both ΙΚ ε and TBK1.

BRIEF SUMMARY OF THE INVENTION

[018] The present invention provides chemical compounds that selectively inhibit the kinase activities of ΙΚ ε, TBK1, or both ΙΚ ε and TBK1. Consequently, these compounds may be used in the treatment of inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders.

[019] Specifically, the present invention provides compounds having structures according to Formula I {i.e., compounds according to Formula I):

Formula I;

and pharmaceutically acceptable salts thereof; wherein Y, Z, Rl and R2 are as defined herein below; and with the proviso that the compound of Formula I is NOT:

Benzamide, 2,6-difluoro-A^r-[3-[ l -(phenylmethyl)- I H-pyrazoi-4-yl]-l H- pyrrok>[2 -b]pyridm~5-y]]~3-[( ropylsu.]fonyI)arninoj- (CAS Registry Number: 1 186500-41 -3);

Benzonitrile, 3-[5-(3-aminophenyl)-lH-pyrrolo[2,3-¾]pyridin-3-yl]- (CAS Registry No.: 1377503-50-8); Benzonitrile, 3-[5-(3-hydroxyphenyl)-lH-pyrrolo[2,3-¾]pyridin-3-yl]- (CAS Registry No.: 875637-47-1);

Benzonitrile, 4-[3-[l-(triphenylmethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-¾]pyridin-5- yl]- (CAS Registry No.: 757979-81-0);

Methanone, [4-[5-[4-(dimethylamino)phenyl]- lH-pyrrolo[2,3-¾]pyridin-3-yl]- 1H- pyrazol-l-yl]phenyl- (CAS Registry No.: 757979-75-2);

Benzenamine, N,N-dimethyl-4-[3 - [ 1 -(triphenylmethyl)- 1 H-pyrazol-4-yl] - 1 H- pyrrolo[2,3-6]pyridin-5-yl]- (CAS Registry No.: 757980-01-1);

Methanone, [5-[4-(dimethylamino)phenyl]-3-[ 1 -(triphenylmethyl)- lH-pyrazol-4-yl]- lH-pyrrolo[2,3- yridin-l-yl]phenyl- (CAS Registry No.: 757982-21-1);

Benzonitrile, 4-[ 1 -(phenylsulfonyl)-3 -[ 1 -(triphenylmethyl)- 1 H-pyrazol-4-yl] - 1 H- pyrrolo[2,3-6]pyridin-5-yl]- (CAS Registry No.: 757982-04-0);

lH-Pyrrolo[2,3-£]pyridine, 5-(4-fluorophenyl)- 1 -(phenylsulfonyl)-3-[ 1 - (triphenylmethyl)- lH-pyrazol-4-yl]- (CAS Registry No.: 757981-88-7);

lH-Pyrrolo[2,3-£]pyridine, 5-(4-methoxyphenyl)- 1 -(phenylsulfonyl)-3-[ 1 - (triphenylmethyl)- lH-pyrazol-4-yl]- (CAS Registry No.: 757982-00-6);

lH-Pyrrolo[2,3-£]pyridine, 5-(2,3-dihydro-5-benzofuranyl)-l-(phenylsulfonyl)-3-[l- (triphenylmethyl)-lH-pyrazol-4-yl]- (CAS Registry No.: 757978-21-5);

lH-Pyrrolo[2,3-£]pyridine, 5-(l,3-benzodioxol-5-yl)-l-(phenylsulfonyl)-3-[l- (triphenylmethyl)-lH-pyrazol-4-yl]- (CAS Registry No.: 757981-82-1);

Benzoic acid, 4- [ 1 -(phenylsulfonyl)-3 - [ 1 -(triphenylmethyl)- 1 H-pyrazol-4-yl] - 1 H- pyrrolo[2,3-¾]pyridin-5-yl]-, ethyl ester (CAS Registry No.: 757982-06-2);

lH-Pyrrolo[2,3-£]pyridine, 5-(3,4-dimethoxyphenyl)-l-(phenylsulfonyl)-3-[l- (triphenylmethyl)-lH-pyrazol-4-yl]- (CAS Registry No.: 757981-94-5); or

lH-Pyrrolo[2,3-£]pyridine, 5-[4-(4-morpholinyl)phenyl]- 1 -(phenylsulfonyl)-3-[ 1 - (triphenylmethyl)-lH-pyrazol-4-yl]- (CAS Registry No.: 757982-13-1).

[020] The compounds of the present invention include the compounds according to Formula I as illustrated herein, as well as geometric isomers, enantiomers, diastereomers, or racemates thereof. The compounds of the present invention also include the pharmaceutically acceptable salts of such compounds.

[021] As noted above, the present invention provides chemical compounds that selectively inhibit the kinase activities of ΙΚ ε, TBKl, or both ΙΚΚε and TBKl, and therefore can be used in the treatment of inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi- Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders. Thus, the present invention also provides methods for treating inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders, by administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention, particularly a compound according to Formula I, or a pharmaceutically acceptable salt thereof.

[022] Also provided is the use of at least one of the compounds according to Formula I for the manufacture of a medicament useful for therapy, including therapy for the treatment of inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders. In addition, the present invention also provides pharmaceutical compositions having at least one compound according to Formula I and one or more pharmaceutically acceptable excipients. Further, methods for the treatment of inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi- Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders, by administering to a patient in need of such treatment, a pharmaceutical composition of the invention, are also encompassed.

[023] In addition, the present invention also provides methods for treating or delaying the onset of the symptoms associated with inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi- Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders. These methods comprise administering an effective amount of a compound of the present invention, generally in the form of a pharmaceutical composition or medicament, to an individual having, or at risk of having, inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders.

[024] The compounds according to Formula I may also be used in combination therapies. Thus, combination therapy methods are also provided for treating or delaying the onset of the symptoms associated with inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi- Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders. Such methods comprise administering to a patient in need thereof a compound of the present invention and, together or separately, at least one other anti-cancer, anti-inflammation, anti-rheumatoid arthritis, anti-obesity, anti-insulin resistance, anti-metabolic syndrome, anti-type 2 diabetes, anti-SLE, or anti-psoriasis therapy.

[025] For the convenience of combination therapy, the compound of the present invention may be administered together in the same formulation with another agent or therapeutic compound used for treating inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi- Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer. Thus, the present invention also provides pharmaceutical compositions or medicaments for combination therapy, comprising an effective amount of at least one compound according to the present invention, and an effective amount of at least one other therapeutic agent or compound, which is different from the compounds according to Formula I.

[026] The foregoing and other advantages and features of the invention, and the manner in which they are accomplished, will become more readily apparent upon consideration of the following detailed description of the invention taken in conjunction with the accompanying examples, which illustrate embodiments of the present invention. [027] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative and and not intended to be limiting.

[028] Other features and advantages of the invention will be apparent to one of skill in the art from the following detailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

1. Definitions

[029] As used herein, the terms "alkyl" or "alkyl group," as employed herein alone or as part of another group refers to a saturated aliphatic hydrocarbon straight chain group having, unless otherwise specified, 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms), or a saturated aliphatic hydrocarbon branched chain group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. An alkyl group may be optionally substituted with one or more substituents as valencies allow (generally one to three substitutents except in the case of halogen substituents, e.g., perchloro). As used herein, a Ci_₆ alkyl group refers to an alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms (e.g., including methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, and hexyl), which may be optionally substituted.

[030] The term "lower alkyl" as used herein, refers to an alkyl group, as defined above, but containing 1, 2, 3, 4, 5, or 6 carbon atoms (i.e., a Ci_₆ alkyl group).

[031] The term "alkylene," or "alkylene group," as used herein means a saturated aliphatic hydrocarbon straight chain group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms or a saturated aliphatic hydrocarbon branched chain group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms having two connecting points. For example, an "ethylene" group represents the group -CH₂- CH₂-. Alkylene groups may also be optionally substituted with one or more substituents.

[032] The term "alkenyl" as employed herein by itself or as part of another group means a straight chain radical of 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms or a branched chain radical of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, unless the chain length is limited thereto, including at least one double bond between two of the carbon atoms in the chain. The alkenyl group may be optionally substituted with one or more substituents (generally one to three substitutents except in the case of halogen substituents, e.g., perchloro or perfluoroalkyls). For example, a C₃_₆ alkenyl group refers to a straight or branched chain radical containing 3, 4, 5 or 6 carbon atoms and having at least one double bond between two of the carbon atoms in the chain {e.g., ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl and 2- butenyl, which may be optionally substituted).

[033] The term "alkenylene" as used herein means an alkenyl group having two connecting points. For example, "ethenylene" represents the group -CH=CH-. Alkenylene groups may also be optionally substituted with one or more substituents.

[034] The term "alkynyl" as used herein by itself or as part of another group means a straight chain radical of 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms or branched chain radical of 4, 5, 6, 7, 8, 9, or 10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain. The alkynyl group may be optionally substituted with one or more substituents as valencies allow (generally one to three substitutents except in the case of halogen substituents, e.g., perchloro or perfluoroalkyls). For example, a C₄_6 alkynyl group refers to a straight or branched chain radical containing 4, 5, or 6 carbon atoms and having at least one triple bond between two of the carbon atoms in the chain {e.g., ethynyl, 1-propynyl, l-methyl-2-propynyl, 2-propynyl, 1- butynyl and 2-butynyl), which may be optionally substituted.

[035] The term "alkynylene" as used herein means an alkynyl having two connecting points. For example, "ethynylene" represents the group -C≡C-. Alkynylene groups may also be optionally substituted with one or more substituents.

[036] The term "carbocycle" as used herein by itself or as part of another group means cycloalkyl and non-aromatic partially saturated carbocyclic groups such as cycloalkenyl and cycloalkynyl. A carbocycle may be optionally substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for the uses of the present invention.

[037] The term "cycloalkyl" as used herein by itself or as part of another group refers to a fully saturated 3, 4, 5, 6, 7, or 8-membered cyclic hydrocarbon ring {i.e., a cyclic form of an alkyl) alone ("monocyclic cycloalkyl") or fused to another cycloalkyl, cycloalkynyl, cycloalkenyl, heterocycle, aryl or heteroaryl ring {i.e., sharing an adjacent pair of carbon atoms with such other rings) ("polycyclic cycloalkyl"). Thus, a cycloalkyl may exist as a monocyclic ring, bicyclic ring, or a spiral ring. When a cycloalkyl is referred to as a C_x cycloalkyl, this means a cycloalkyl in which the fully saturated cyclic hydrocarbon ring (which may or may not be fused to another ring) has x number of carbon atoms. When a cycloalkyl is recited as a substituent on a chemical entity, it is intended that the cycloalkyl moiety is attached to the entity through a carbon atom within the fully saturated cyclic hydrocarbon ring of the cycloalkyl. In contrast, a substituent on a cycloalkyl can be attached to any carbon atom of the cycloalkyl. A cycloalkyl group may be optionally substituted with one or more substitutents so long as the resulting compound is sufficiently stable and suitable for the uses of the present invention. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[038] The term "cycloalkenyl" as used herein by itself or as part of another group refers to a non-aromatic partially saturated 3, 4, 5, 6, 7, or 8-membered cyclic hydrocarbon ring having at least one double bond therein (i.e., a cyclic form of an alkenyl) alone ("monocyclic cycloalkenyl") or fused to another cycloalkyl, cycloalkynyl, cycloalkenyl, heterocycle, aryl or heteroaryl ring (i.e., sharing an adjacent pair of carbon atoms with such other rings) ("polycyclic cycloalkenyl"). Thus, a cycloalkenyl may exist as a monocyclic ring, bicyclic ring, polycyclic or a spiral ring. When a cycloalkenyl is referred to as a C_x cycloalkenyl, this means a cycloalkenyl in which the non-aromatic partially saturated cyclic hydrocarbon ring (which may or may not be fused to another ring) has x number of carbon atoms. When a cycloalkenyl is recited as a substituent on a chemical entity, it is intended that the cycloalkenyl moiety is attached to the entity through a carbon atom within the non-aromatic partially saturated ring (having a double bond therein) of the cycloalkenyl. In contrast, a substituent on a cycloalkenyl can be attached to any carbon atom of the cycloalkenyl. A cycloalkenyl group may be optionally substituted with one or more substitutents. Examples of cycloalkenyl groups include cyclopentenyl, cycloheptenyl and cyclooctenyl.

[039] The term "heterocycle" (or "heterocyclyl" or "heterocyclic") as used herein by itself or as part of another group means a saturated or partially saturated 3, 4, 5, 6, or 7- membered non-aromatic cyclic ring formed with carbon atoms and from one to four heteroatoms independently chosen from O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen can be optionally quatemized ("monocyclic heterocycle"). The term "heterocycle" also encompasses a group having the non-aromatic heteroatom-containing cyclic ring above fused to another monocyclic cycloalkyl, cycloalkynyl, cycloalkenyl, heterocycle, aryl or heteroaryl ring (i.e., sharing an adjacent pair of atoms with such other rings) ("polycyclic heterocylce"). Thus, a heterocycle may exist as a monocyclic ring, bicyclic ring, polycyclic or a spiral ring. When a heterocycle is recited as a substituent on a chemical entity, it is intended that the heterocycle moiety is attached to the entity through an atom within the saturated or partially saturated ring of the heterocycle. In contrast, a substituent on a heterocycle can be attached to any suitable atom of the heterocycle. In a "saturated heterocycle" the non-aromatic heteroatom-containing cyclic ring described above is fully saturated, whereas a "partially saturated heterocyle" contains one or more double or triple bonds within the non-aromatic heteroatom-containing cyclic ring regardless of the other ring it is fused to. A heterocycle may be optionally substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for the uses of the present invention.

[040] Some examples of saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.

[041] As used herein, "aryl" by itself or as part of another group means an all-carbon aromatic ring with 6 or 8 carbon atoms in the ring ("monocylic aryl"). In addition to monocyclic aromatic rings, the term "aryl" also encompasses a group having the all-carbon aromatic ring above fused to another cycloalkyl, cycloalkynyl, cycloalkenyl, heterocycle, aryl or heteroaryl ring (i.e., sharing an adjacent pair of carbon atoms with such other rings) ("polycyclic aryl"). When an aryl is referred to as a C_x aryl, this means an aryl in which the all-carbon aromatic ring (which may or may not be fused to another ring) has x number of carbon atoms. When an aryl is recited as a substituent on a chemical entity, it is intended that the aryl moiety is attached to the entity through an atom within the all-carbon aromatic ring of the aryl. In contrast, a substituent on an aryl can be attached to any suitable atom of the aryl. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. An aryl may be optionally substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for the uses of the present invention.

[042] The term "heteroaryl" as employed herein refers to a stable aromatic ring having 5, 6 or 7 ring atoms with 1, 2, 3 or 4 hetero ring actoms in the ring which are oxygen, nitrogen or sulfur or a combination thereof ("monocylic heteroaryl"). In addition to monocyclic hetero aromatic rings, the term "heteroaryl" also encompasses a group having the monocyclic hetero aromatic ring above fused to another cycloalkyl, cycloalkynyl, cycloalkenyl, heterocycle, aryl or heteroaryl ring (i.e., sharing an adjacent pair of atoms with such other rings) ("polycyclic heteroaryl"). When a heteroaryl is recited as a substituent on a chemical entity, it is intended that the heteroaryl moiety is attached to the entity through an atom within the hetero aromatic ring of the heteroaryl. In contrast, a substituent on a heteroaryl can be attached to any suitable atom of the heteroaryl. A heteroaryl may be optionally substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for the uses of the present invention.

[043] Heteroaryl groups include, for example, thienyl (thiophenyl), including without limitation 2-thienyl, benzo[¾]thienyl, naphtho[2,3-¾]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl, including without limitation imidazol-4-yl, and imidazol- 5-yl, pyrazolyl, including without limitation pyrazol-4-yl, and pyrazol-5-yl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, including without limitation pyrazin-3-yl, pyrimidinyl, including without limitation pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl, pyridazinyl, including without limitation pyridazinyl-3-yl, and pyridazinyl-4-yl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, oxazolyl, including without limitation oxazol-2-yl, isoxazolyl, including without limitation isoxazol-5-yl, thiazolyl, including without limitation thiazol-2-yl, triazolyl, including without limitation 1, 2, 4- triazol-3-yl furazanyl, phenoxazinyl, l,4-dihydroquinoxaline-2,3-dione, 7-amino- isocoumarin, pyrido[l,2-a]pyrimidin-4-one, pyrazolo[l,5-a]pyrimidinyl, including without limitation pyrazolo[l,5-a]pyrimidin-3-yl, l,2-benzoisoxazol-3-yl, benzimidazolyl, 2- oxindolyl and 2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

[044] As used herein, the term "halo" refers to fluoro, chloro, bromo, or iodo substitutents.

[045] As used herein, the term "hydro" refers to a bound hydrogen (i.e., an -Η group).

[046] As used herein, the term "hydroxyl" refers to an -ΟΗ group.

[047] As used herein, the term "alkoxy" refers to an -O-(alkyl). Lower alkoxy refers to -0-(lower alkyl) groups.

[048] As used herein, the term "alkenyloxy" refers to an -0-( alkenyl).

[049] As used herein, the term "alkynyloxy" refers to an -O-(alkynyl). [050] As used herein, the term "cycloalkyloxy" refers to an -O-cycloakyl group.

[051] As used herein, the term "heterocycloxy" refers to an -O-heterocycle group.

[052] As used herein, the term "mercapto" group refers to an -SH group.

[053] The term "alkylthio" group refers to an -S-alkyl group.

[054] The term "arylthio" group refers to an -S-aryl group.

[055] The term "arylalkyl" is used herein to mean an alkyl group, as defined above, substituted with an aryl group, as defined above. Examples of arylalkyl groups include benzyl, phenethyl and naphthylmethyl, etc. An arylalkyl group may be optionally substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for the uses of the present invention.

[056] The term "heteroarylalkyl" is used herein to mean an alkyl group, as defined above, substituted with a heteroaryl group, as defined above. A heteroarylalkyl may be optionally substituted with one or more substituents so long as the resulting compound is sufficiently stable and suitable for the uses of the present invention.

[057] The term "arylalkynyl" is used herein to mean any of the above-defined alkynyl groups substituted with any of the above-defined aryl groups.

[058] The term "heteroarylalkenyl" is used herein to mean any of the above-defined alkenyl groups substituted with any of the above-defined heteroaryl groups.

[059] The term "aryloxy" is used herein to mean aryl-O- or -O-aryl wherein aryl is as defined above. Aryloxy groups include phenoxy and 4-methylphenoxy.

[060] The term "hetero aryloxy" is used herein to mean heteroaryl-O- or -O-heteroaryl wherein heteroaryl is as defined above.

[061] The term "arylalkoxy" is used herein to mean an alkoxy group substituted with an aryl group as defined above. Arylalkoxy groups include benzyloxy and phenethyloxy.

[062] "Hetero arylalkoxy" is used herein to mean any of the above-defined alkoxy groups substituted with any of the above-defined heteroaryl groups.

[063] "Haloalkyl" means an alkyl group that is substituted with one or more fluorine, chlorine, bromine or iodine atoms. Haloalkyl groups include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-dif uoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.

[064] As used herein, the term "oxo" refers to an oxygen atom double bonded to another atom (i.e., "=0"). [065] As used herein, the term "carbonyl" group refers to a -C(=0)R" group, where R" is chosen from hydro, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocyclyl (bonded through a ring carbon), as defined herein.

[066] As used herein, the term "aldehyde" group refers to a carbonyl group where R" is hydro.

[067] As used herein, the term "cycloketone" refer to a cycloalkyl group in which one of the carbon atoms which form the ring has a "=0" bonded to it; i.e. one of the ring carbon atoms is a -C(=0)-group.

[068] As used herein, the term "thiocarbonyl" group refers to a -C(=S)R" group, with R" as defined herein. "Alkylthiocarbonyl" refers to an alkyl-C(=S)- group.

[069] "Alkanoyl," as used herein, refers to an alkyl-C(=0)- group.

[070] As used herein the term "acetyl" group refers to a -C(=0)CH₃ group.

[071] As used herein term "heterocyclonoyl" group refers to a heterocyclocarbonyl, or heterocyclo-C(=0)- group.

[072] The term "heterocycloketone," as used herein refers to a heterocycle group in which one of the carbon atoms which form the ring has an oxygen double-bonded to it— i.e., one of the ring carbon atoms is a -C(=0)- group.

[073] As used herein the term "O-carboxy" group refers to a R"C(=0)0- group, where R" is as defined herein.

[074] The term "C-carboxy" group, as used herein, refers to a -C(=0)OR" groups where R" is as defined herein.

[075] As used herein, the term "carboxylic acid" refers to a C-carboxy group in which R" is hydro. In other words, the term "carboxylic acid" refers to -COOH.

[076] As used herein, the term "ester" is a C-carboxy group, as defined herein, wherein R" is as defined above, except that it is not hydro. Example ester groups include, methyl ester, ethyl ester, propyl ester, and lower alkyl ester).

[077] As used herein, the term "C-carboxy salt" refers to a -C(=0)0^" M⁺ group wherein M⁺ is chosen from lithium, sodium, magnesium, calcium, potassium, barium, iron, zinc and quaternary ammonium.

[078] The term "carboxyalkyl," as used herein, refers to -Ci_₆ alkyl ene-C(=0)OR" (that is, a Ci_6 alkyl group connected to the core structure wherein the alkyl group is substituted wth -C(=0)OR" with R" being defined herein). Examples of carboxyalkyl include, but are not limited to, -CH₂COOH, -(CH₂)₂COOH, -(CH₂)₃COOH, -(CH₂)₄COOH, and - (CH₂)₅COOH. [079] "Carboxyalkenyl" refers to -alkenylene-C(=0)OR" with R" being defined herein.

[080] The term "carboxyalkyl salt" refers to a -(CH₂)_rC(=0)0^"M⁺ wherein M⁺ is chosen from lithium, sodium, potassium, calcium, magnesium, barium, iron, zinc and quaternary ammonium, wherein r is 1, 2, 3, 4, 5, or 6.

[081] The term "carboxyalkoxy" refers to -0-(CH₂)_rC(=0)OR" wherein r is 1 ,2, 3, 4, 5, or 6, and R" is as defined herein.

[082] "C_x carboxyalkanoyl" means a carbonyl group (-C(=0)-) attached to an alkyl or cycloalkylalkyl group that is substituted with a carboxylic acid or carboxyalkyl group, wherein the total number of carbon atom is x (an integer of 2 or greater).

[083] "C_x carboxyalkenoyl" means a carbonyl group (-C(=0)-) attached to an alkenyl or alkyl or cycloalkylalkyl group that is substituted with a carboxylic acid or carboxyalkyl or carboxyalkenyl group, wherein at least one double bond (-CH=CH-) is present and wherein the total number of carbon atom is x (an integer of 2 or greater).

[084] "Carboxyalkoxyalkanoyl" means refers to R"OC(=0)-Ci_₆ alkylene-0-Ci_₆ alkylene-C(=0)-, R" is as defined herein.

[085] As used herein, the term "heterocycloyl", by itself or as part of another group, means a radical of formula heterocycle-C(=0)-.

[086] "Amino" refers to an -NR^xR^y group, with R^x and R^y as defined herein.

[087] "Alkylamino," as used herein, means an amino group with at least one alkyl substituent.

[088] "Aminoalkyl" means an alkyl group connected to the core structure of a molecule and having at least one amino substituent.

[089] "Quaternary ammonium" refers to a -⁺N(R^x)(R^y)(R^z) group wherein R^x, R^y, and R^z are as defined herein.

[090] The term "nitro" refers to a -N0₂ group.

[091] As used herein the term "O-carbamyl" refers to a -OC(=0)N(R )(R^y) group with R^x and R^y as defined herein.

[092] The term "N-carbamyl," as used herein, refers to a R^yOC(=0)N(R^x)- group, with R^x and R^y as defined herein.

[093] As used herein the term "O-thiocarbamyl" refers to a -OC(=S)N(R^x)(R^y) group with R and R^y as defined herein.

[094] The term "N-thiocarbamyl," as used herein, refers to a R^xOC(=S)NR^y- group, with R^x and R^y as defined herein. [095] As used herein the term "C-amido" refers to a -C(=0)N(R^x)(R^y) group with R^x and R^y as defined herein.

[096] "N-amido," as used herein, refers to a R^xC(=0)N(R^y)- group with R^x and R^y as defined herein.

[097] "Carbamoylamino" or "carbamide linker" are used alternatively herein to refer to a R"N(R^y)C(=0)N(R^x)- group with R^x, R^y and R" as defined herein.

[098] "Aminothiocarbonyl" refers to a -C(=S)N(R^x)(R^y) group with R^x and R^y as defined herein.

[099] "Hydroxyaminocarbonyl" means a -C(=0)N(R )(OH) group with R^x as defined herein.

[0100] "Alkoxyaminocarbonyl" means a -C(=0)N(R^x)(alkoxy) group with R^x as defined herein.

[0101] The terms "cyano," "cyanyl," and "nitrile" group, as used interchangably herein, refer to a -C≡N group.

[0102] The term "cyanato" refers to a -CNO group.

[0103] The term "isocyanato" refers to a -NCO group.

[0104] The term "thiocyanato" refers to a -CNS group.

[0105] The term "isothiocyanato" refers to a -NCS group.

[0106] The term "sulfinyl" refers to a -S(=0)R" group, where R" is as defined herein.

[0107] The term "sulfonyl" refers to a -S(=0)₂R" group, where R" is as defined herein.

[0108] The term "sulfonamide" or "sulfamoyl" are used interchangeably herein to refer to an -N(R^x)-S(=0)₂R" group, with R"and R^x as defined herein.

[0109] "Aminosulfonyl" means (R^x)(R^y)N-S(=0)₂- with R^x and R^y as defined herein.

[0110] "Aminosulfonyloxy" means a (R^x)(R^y)N-S(=0)₂-0- group with R^x and R^y as defined herein.

[0111] "Sulfonamidecarbonyl" means R"-S(=0)₂-N(R^x)-C(=0)- with R" and R^x as defined herein.

[0112] "Alkanoylaminosulfonyl" refers to an alkyl-C(=0)-N(R^x)-S(=0)₂- group with R^x as defined herein.

[0113] The term "trihalomethylsulfonyl" refers to a X_?CS(=0)₂- group with X being halo.

[0114] The term "trihalomethylsulfonamide" refers to a X₃CS(=0)₂N(R^x)- group with X being halo and R^x as defined herein. [0115] R" is chosen from hydro, alkyl, cycloalkyl, aryl, heteroaryl and heterocycle, each being optionally substituted.

[0116] R^x, R^y, and R^z are independently chosen from hydro and optionally substituted alkyl.

[0117] The term "bioisostere," as used herein, generally refers to compounds or moieties that have chemical and physical properties producing broadly similar biological properties. Examples of carboxylic acid bioisosteres include, but are not limited to, carboxyalkyl, carboxylic acid ester, tetrazole, oxadiazole, isoxazole, hydroxythiadiazole, thiazolidinedione, oxazolidinedione, sulfonamide, aminosulfonyl, sulfonamidecarbonyl, C-amido, sulfonylcarboxamide, phosphonic acid, phosphonamide, phosphinic acid, sulfonic acid, alkanoylaminosufonyl, mercaptoazole, trifluoromethylcarbonyl, and cyanamide.

[0118] "Pharmaceutical composition" refers to at least one compound and a pharmaceutically acceptable vehicle, with which the compound is administered to a patient.

[0119] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which a compound is administered.

[0120] "Patient" includes humans. The terms "human" and "patient" are used interchangeably herein.

[0121] "Preventing" or "prevention" refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease).

[0122] "Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., 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 ameliorating at least one physical parameter, which may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0123] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated. [0124] Unless specifically stated otherwise or indicated by a bond symbol (dash, double dash, or triple dash, etc.), the point at which a recited substituent group connects to the remainder of the molecule will be via the right-most stated moiety. Further, the names of chemical moieties, as defined above, can simply be linked together to identify more complex substituent groups. In such instances, the point at which the recited complex substituent is connected to the remainder of the molecule will be through the right-most stated moiety. Thus, for example, a "hydroxyalkyl" group is connected to the remainder of the molecule through the alkyl moiety while the hydroxyl is a substituent on the alkyl. Similarly, for example, a "heterocyclealkyl" group is connected to the remainder of the molecule through the alkyl moiety while the heterocycle is a substituent on the alkyl.

[0125] In most instances names for the compounds disclosed were generated in accordance with International Union of Pure and Applied Chemistry (IUPAC) conventions using Advanced Chemistry Development, Inc., (ACD/Labs) (Toronto, Ontario, Canada) ACD/Name IUPAC nomenclature software release 12.00, version 12.01. In some cases, however, names for compounds and synthetic intermediates were generated using the IUPAC naming feature supplied with either the Symyx® Draw package, version 3.2 or 3.3, available from Symyx Technologies, Inc. (Santa Clara, CA), or the Autonom 2000 plug-in for the Isis™/Draw 2.5 SP1 chemical drawing program, formerly available from MDL Information Systems, a division of Symyx Technologies, Inc. (Santa Clara, CA). In all cases, if there is a conflict between a name and a structure when a structure is provided along with a name, the structure is to be taken as ultimately defining the compound being described.

2. Compounds of the Present Invention

[0126] The present invention provides chemical compounds that selectively inhibit the kinase activities of ΙΚΚε and/or TBK1. Consequently, these compounds may be used in the treatment of inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders.

[0127] Specifically, the present invention provides compounds having structures according to Formula I (i.e., compounds according to Formula I):

Formula I;

and pharmaceutically acceptable salts thereof, wherein Y is CH or N;

Z can be present or absent, and when present is a linking group selected from - N(H)-, -S-, -N(H)C(=0)-, -C(=0)-, partially-saturated C₃ alkynyl (e.g., -prop- 1 - en-l -yl-), partially-saturated -N(H)- C₂_4 alkenyl-, or partially-saturated - C(=0)- C₂-4 alkenyl-;

Rl is o tionally-substituted aryl optionally-substituted heteroaryl,

R2 is halo, hydroxyl, carboxyl, amino, trihalomethyl, or optionally-substituted Ci_₄ alkyl, Ci_₄ hydroxyalkyl, C₂ alkynyl, NH₂, heterocyclo, Ci_₆ alkox alkylamino,

hydroxyalkylamino, alkoxyamino, dialkoxyamino aryl, heteroar l,

R4 wherein in Rl and R2 R3 is independently hydro, Ci_₆ alkyl, benzyl, R5

R4 is independently hydro, halo, Ci_₆ alkyl, Ci_₆ alkyloxy, -CF₃, Ci_₆ alkoxy, amino

carbox l, -S0₂OH, -CN, acetamide, heterocyclo, carboxamido, sulfonamido,

N

' k

R4

R5 is NH₂, heteroaryl, heterocycloalkyl, or ; and R6 is hydro, carboxyl, sulfonyl, Ci_₆ alkyl, Ci_₆ alkyloxy, carbocyclo, heterocyclo, or

with the proviso that the compound of Formula I is NOT:

Benzamide, 2,6-difiuoro-A^r-[3-[l-(ph eny].methyl )-l H-pyrazof-4-yl]-l H- pyrroio[2,3-&]pyridin-5-yl]-3-[(propylsulfonyI)ammo]- (CAS Registry Number: 1 186500-41 -3);

Benzonitrile, 3-[5-(3-aminophenyl)-lH-pyrrolo[2,3-¾]pyridin-3-yl]- (CAS Registry No.: 1377503-50-8);

Benzonitrile, 3-[5-(3-hydroxyphenyl)-lH-pyrrolo[2,3-¾]pyridin-3-yl]- (CAS Registry No.: 875637-47-1);

Benzenamine, N,N-dimethyl-4-[3 - [ 1 -(triphenylmethyl)- 1 H-pyrazol-4-yl] - 1 H- pyrrolo[2,3- yridin-5-yl]- (CAS Registry No.: 757980-01-1);

Benzonitrile, 4-[ 1 -(phenylsulfonyl)-3 -[ 1 -(triphenylmethyl)- 1 H-pyrazol-4-yl] - 1 H- pyrrolo[2,3- yridin-5-yl]- (CAS Registry No.: 757982-04-0);

Benzoic acid, 4- [ 1 -(phenylsulfonyl)-3 - [ 1 -(triphenylmethyl)- 1 H-pyrazol-4-yl] - 1 H- pyrrolo[2,3-¾]pyridin-5-yl]-, ethyl ester (CAS Registry No.: 757982-06-2); lH-Pyrrolo[2,3-£]pyridine, 5-(3,4-dimethoxyphenyl)-l-(phenylsulfonyl)-3-[l- (triphenylmethyl)-lH-pyrazol-4-yl]- (CAS Registry No.: 757981-94-5); or

lH-Pyrrolo[2,3-¾]pyridine, 5-[4-(4-morpholinyl)phenyl]-l -(phenylsulfonyl)-3-[ l - (triphenylmethyl)-lH-pyrazol-4-yl]- (CAS Registry No. : 757982- 13- 1).

[0128] In particular embodiments of the compounds of Formula I, Y is CH, and the compound is one having a structure according to Formula II,

Formula II

and pharmaceutically acceptable salts thereof, wherein Z, Rl, and R2, are as defined above or below.

[0129] In some embodiments of Formula II, Rl is optionally substituted and is selected from aryl and heteroaryl, including, for example, phenyl, 4-pyrazolyl, 3-pyrrolyl, 3-pyridinyl, 4-pyridinyl, and 5-pyrimidinyl.

[0130] In some embodiments of Formula II, when Rl is a phenyl substitutent it is substituted at the meta position with a nitrile group, optionally further substituted at the para position. When Rl is a phenyl substitutent substituted at the meta position with a nitrile group, and further substituted at the para position, the further substitutent at the para position can be linked through an ether group. In such embodiments where Rl is a phenyl substitutent substituted at the meta position with a nitrile group, and further substituted at the para position through an ether group, the further substitution is selected from hydro, hydroxyl, optionally- substituted Ci-C₆ alkyl, optionally- substituted C₁-C₄ alkoxyl, optionally- substituted C₁-C₄ aminoalkyl, C₁-C₄ alkylamino, C₁-C₄ alkylamido, cyclopropylmethyl, cyclopropylmethylamino, benzyl, or an optionally-substituted heterocycle selected from 4- piperidinyl, 4-tetrahydropyranyl, 3-pyrolodinyl, or ethylene-linked 4-morpholinyl. In other embodiments where Rl is a phenyl substitutent substituted at the meta position with a nitrile group and further substituted at the para position, the further substituent is selected from methylene-linked heterocycle, wherein the heterocycle is selected from 4-tetrahydropyranyl or 4-morpholinyl. In still other embodiments where Rl is a phenyl substitutent substituted at the meta position with a nitrile group and further substituted at the para position, the further substituent is amino-linked or amide-linked substituent selected from C₁-C5 alkyl, C₃-C₄ cylcloalkyl, and a 3- or 4-membered heterocyclic group.

[0131] In some embodiments of Formula II, Rl is 4-pyrazolyl substituent that is further substituted at the 1 -position with a benzyl group. In such embodiments, the benzyl group is optionally further substituted with halo (i.e., chloro, fluoro, or bromo), trihaloalkyl, C₁-C₄ alkyl, C₁-C₄ alkoxyl, or sulphonyl. In other embodiments the 4-pyrazolyl substituent at Rl is optionally further substituted with C₁-C₅ alkyl, aminomethyl, amidoalkyl, or an ethylene- linked phenyl or heterocycle selected from 4-morpholinyl, 4-tetrahydropyranyl, or a methylene-linked cyclohexyl, 2-pyridinyl or 3-pyridinyl.

[0132] In some embodiments of Formula II, R2 is optionally substituted at least once, and is a directly-linked substituent selected from an amine, Ci-C₆ alkoxyl, Ci-C₆ alkamino, 4, 5, 6, or 7-membered heterocyclyl, aryl, or heteroaryl group, including, for example, phenyl, 4- pyrazolyl, 5-pyrazolyl, 2-thiozolyl, 4-thiozolyl, 5-thiozolyl, 4-pyridinyl, 4-(3,4- tetrahydro)pyridinyl, 1-piperizinyl, and (3,6-dihydro)pyranyl. In some embodiments of Formula II, the R2 substituent is linked to the pyrrolopyridine core through a C₁-C₅ alkanyl linking group. In some embodiments the R2 substituent is linked to the pyrrolopyridine core through a linking group selected from an amino group, a bridging sulfur (i.e., thioether group), or an amide group. In some of these embodiments R2 is substituted phenyl. In other embodiments R2 comprises a partially-saturated C₂-C₃ alkenyl linking group or a partially- saturated C₂-C₃ carbonylalkenyl linking group, to which an optionally- substituted 5 or 6- membered heterocycle is attached. Optional substitutents on the directly-linked or C₂-C₃ carbonylalkenyl-linked substituents are themselves optionally substituted at least once where possible, and are selected from hydroxyl, amino, C₁-C₅ alkyl, C₁-C₄ alkoxyl, nitrile, amido, alkylamido, arylalkyl, 4, 5, 6, or 7-membered heterocyclyl, 6-membered heterocyclylalkyl, ether-linked 6-membered heterocyclylalkyl, amino-linked 6-membered heterocyclylalkyl, a carboxyl-linked C₁-C5 alkoxy, C₃ cyloalkyl, amino group, 4, 5 or 6-membered heterocyclic group, or an C₁-C₃ alkanyl, amide, aminoalkyl, sulfonyl, or urea-linked optionally substituted 4, 5 or 6-membered heterocyclic group or C₃-C6 cycloalkyl group.

[0133] In particular embodiments of the compounds of Formula I, Y is N, and the compound is one having a structure according to Formula III,

Formula III

and pharmaceutically acceptable salts thereof, wherein Z, Rl, and R2 are as defined above or below.

[0134] In particular embodiments of com ounds of Formulae II, Rl is an optionally

substituted 33--ccyyaannoopphheennyyll ggrroouupp (( ), and the compound is one according to

Formula Ila

Formula Ila

and pharmaceutically acceptable salts thereof, wherein Z and R2 are as defined above or below.

[0135] When the 3-cyanophenyl group is substituted, in certain embodiments it is substituted with a single substitutent at the para position on the phenyl group. In such embodiments the single substituent is attached at the para position on the phenyl group through an -O- linker. Specifically, in those embodiments when the 3-cyanophenyl group is substituted, the compounds of Formula Ila, are compounds according to Formula Ila',

Formula Ila'

and pharmaceutically acceptable salts thereof, wherein R2 is as defined above and R7 is selected from hydro, hydroxyl, optionally-substituted C i-C₆ alkyl, optionally- substituted C ₁-C₄ alkoxyl, optionally-substituted C ₁-C₄ aminoalkyl, C ₁-C₄ alkylamino, C ₁-C₄ alkylamido, cyclopropylmethyl, cyclopropylmethylamino, benzyl, or an optionally-substituted 5-, or 6-membered heterocycle, wherein said 5-, or 6- membered heterocycle can be selected from 4-piperidinyl, 4-tetrahydropyranyl, 3- pyrolodinyl, or ethylene-linked 4-morpholinyl.

[0136] When the 3-cyanophenyl group is substituted, in other embodiments it is substituted with a single substitutent at the para position on the phenyl group through an - N(H)- linker. Specifically, in those embodiments when the 3-cyanophenyl group is substituted, the compounds of Formula Ila, are according to Formula Ila",

Formula Ila"

and pharmaceutically acceptable salts thereof, wherein R2 is as defined above and R7 is as defined above for compounds of Formula Ila'.

[0137] In other particular embodiments of com ounds of Formulae II, Rl is an optionally

substituted l-benzylpyrazol-4-yl group ( ), and the compound is one according to

Formula lib,

Formula lib

and pharmaceutically acceptable salts thereof, wherein Z and R2 are as defined above,

with the proviso that when Z is an amide linking group and R2 is a substituted phenyl, the compounds of the present invention specifically exclude Benzamide, 2,6-difiuoro-.¥-[3- [ 1 -(phenylmethyi)- 1 H-pyrazol-4-yl] - lH~ yrrolo [2 ,3 -6]pyridin-5 -yl] -3 - [(propyls ifotiyl)amino3- (CAS Registry Number: 1 186500-41 -3).

[0138] When the l-benzylpyrazol-4-yl group is substituted, it is substituted with a single substitutent selected from halo, methyl, -SO₃H, methoxyl, or trihalomethyl. In these embodiments, the substitutent on the l-benzylpyrazol-4-yl group is present at the ortho or para position on the phenyl group.

[0139] In some embodiments of the compounds of Formulae II, Z is a direct bond to R2. In other embodiments of the compounds of Formulae II, Z is a is a linking group chosen from -NH-, -S-, or -C(=0)NH-.

[0140] In particular embodiments of the compounds of Formulae II, where Z is a direct bond to R2, R2 is an optionally substituted 5- or 6-membered cyclic group selected from a phenyl group or a heterocyclic group, including partially-saturated hetercyclic groups.

[0141] In other embodiments of compounds of Formula II, R2 is an optionally substituted phenyl group and Z is a linking group chosen from -NH-, -S-, or -C(=0)NH-.

[0142] In still other embodiments of compounds of Formula II, R2 is an optionally substituted 5- or 6-membered heterocyclic group, including partially-saturated hetercyclic groups and Z is a linking group chosen from -NH-, -S-, or -C(=0)NH-.

[0143] In those embodiments in which R2 is an optionally-substituted phenyl group having at least one substitutent, the substituents on the phenyl group, which themselves are optionally-substituted, where possible, are chosen from hydroxyl, halo, nitrile, C-amido, Ci- C₄ alkyl N-amido, sulfonamide, Ci-C₆ alkyl, C₁-C4 alkoxyl, C₁-C4 aminoalkyl, C₁-C4 alkylamino, C₁-C4 alkylamido, cyclopropylmethyl, cyclopropylmethylamino, benzyl, a heterocycle selected from 4-piperidinyl, 4-tetrahydropyranyl, 3-pyrolodinyl, 4-morpholinyl, or ethylene-linked 4-morpholinyl. In other embodiments in which R2 is an optionally- substituted phenyl group having at least one substitutent, the substituents on the phenyl group, which themselves are optionally-substituted, the substituent on the phenyl group is a heterocycle linked through a C₁-C4 alkanyl linker, a heterocycle linked through a partially- saturated C₂-C4 alkenyl linker, a heterocycle linked through C₁-C4 alkanyl-O- linker, or a heterocycle linked through an amino linker.

[0144] In those embodiments in which R2 is an optionally-substituted 5- or 6-membered heterocyclic group having at least one substitutent, the substituents on the heterocyclic group, which themselves are optionally-substituted, where possible, are chosen from hydroxyl, halo, nitrile, C-amido, C₁-C4 alkyl N-amido, sulfonamide, Ci-C₆ alkyl, C₁-C4 alkoxyl, C₁-C4 aminoalkyl, C₁-C4 alkylamino, C₁-C4 alkylamido, cyclopropylmethyl, cyclopropylmethylamino, benzyl, a heterocycle selected from 4-piperidinyl, 4- tetrahydropyranyl, 3-pyrolodinyl, 4-morpholinyl, or ethylene-linked 4-morpholinyl. In other embodiments in which R2 is an optionally-substituted 5- or 6-membered heterocyclic group having at least one substitutent, the substituents on the heterocyclic group, which themselves are optionally- substituted, is a heterocycle linked through a C₁-C₄ alkanyl linker, a heterocycle linked through a partially-saturated C₂-C₄ alkenyl linker, a heterocycle linked through C₁-C₄ alkanyl-O- linker, or a heterocycle linked through an amino linker. In these embodiments the optional substituents are chosen from keto, dimethylamine, Ci_₄ alkyl, Ci_₄ alkylcarbonyl, Ci_₄ alkoxy, or Ci_₆ alkylcarboxyl.

[0145] In particular subembodiments of compounds of Formulae II where Z is a direct bond to R2, and R2 is an optionally substituted heterocylic group, R2 is selected from an optionally-substituted 4-piperidyl; l,2,3,6-tetrahydropyridin-4-yl; lH-pyrazol-4-yl; thiazol-5- yl; or thiazol-4-yl group. In other words, in these particular subembodiments, Z is a direct bond to R2 and R2 is an optionally substituted heterocyclic group selected from

[0146] In those embodiments of the compounds of Formulae Ila,

Formula Ila,

in which Z is a direct bond to R2, and R2 is an optionally substituted phenyl group, the compounds of the present invention specifically exclude the following substances:

Benzonitrile, 3-[5-(3-aminophenyl)-lH-pyrrolo[2,3-¾]pyridin-3-yl]- (CAS Registry No.: 1377503-50-8); and

Benzonitrile, 3-[5-(3-hydroxyphenyl)- lH-pyrrolo[2,3-£]pyridin-3-yl]-(CAS Registry No.: 875637-47-1).

[0147] In those embodiments of the compounds of Formulae lib,

Formula lib,

in which Z is a direct bond to R2, and R2 is an optionally substituted phenyl group, the compounds of the present invention specifically exclude:

Benzonitrile, 4-[3-[ 1 -(triphenylmethyl)- lH-pyrazol-4-yl]- lH-pyrrolo[2,3-¾]pyridin- 5-yl]- (CAS Registry No.: 757979-81-0);

Methanone, [4-[5-[4-(dimethylamino)phenyl]-lH-pyrrolo[2,3-¾]pyridin-3-yl]-lH- pyrazol-l-yl]phenyl- (CAS Registry No.: 757979-75-2);

Benzenamine, N,N-dimethyl-4-[3-[ 1 -(triphenylmethyl)- lH-pyrazol-4-yl]-lH- pyrrolo[2,3-6]pyridin-5-yl]-; (CAS Registry No.: 757980-01-1);

Methanone, [5 -[4-(dimethylamino)phenyl] -3 -[ 1 -(triphenylmethyl)- 1 H-pyrazol-4-yl] - lH-pyrrolo[2,3- yridin-l-yl]phenyl- (CAS Registry No.: 757982-21-1);

Benzonitrile, 4- [ 1 -(phenylsulfonyl)-3 - [ 1 -(triphenylmethyl)- 1 H-pyrazol-4-yl] - 1 H- pyrrolo[2,3-6]pyridin-5-yl]- (CAS Registry No.: 757982-04-0);

lH-Pyrrolo[2,3-£]pyridine, 5-(4-fluorophenyl)-l -(phenylsulfonyl)-3-[ 1 - (triphenylmethyl)- lH-pyrazol-4-yl]- (CAS Registry No.: 757981-88-7);

lH-Pyrrolo[2,3-£]pyridine, 5-(4-methoxyphenyl)-l -(phenylsulfonyl)-3-[ 1 - (triphenylmethyl)- lH-pyrazol-4-yl]- (CAS Registry No.: 757982-00-6);

lH-Pyrrolo[2,3-£]pyridine, 5-(2,3-dihydro-5-benzofuranyl)- 1 -(phenylsulfonyl)-3-[ 1 - (triphenylmethyl)- lH-pyrazol-4-yl]- (CAS Registry No.: 757978-21-5);

lH-Pyrrolo[2,3-£]pyridine, 5-(l ,3-benzodioxol-5-yl)- 1 -(phenylsulfonyl)-3-[ 1 - (triphenylmethyl)-lH-pyrazol-4-yl]- (CAS Registry No.: 757981-82-1);

Benzoic acid, 4-[ 1 -(phenylsulfonyl)-3-[ 1 -(triphenylmethyl)- lH-pyrazol-4-yl]- 1H- pyrrolo[2,3-¾]pyridin-5-yl]-, ethyl ester (CAS Registry No.: 757982-06-2);

lH-Pyrrolo[2,3-£]pyridine, 5-(3,4-dimethoxyphenyl)- 1 -(phenylsulfonyl)-3-[ 1 - (triphenylmethyl)- lH-pyrazol-4-yl]- (CAS Registry No.: 757981-94-5); and

lH-Pyrrolo[2,3-£]pyridine, 5-[4-(4-morpholinyl)phenyl]-l-(phenylsulfonyl)-3-[l- (triphenylmethyl)-lH-pyrazol-4-yl]- (CAS Registry No.: 757982-13-1). [0148] Further description of exemplary compounds according to Formulae I-III are provided in the Examples section below, in the form of over two hundred specific example compounds made by one of the three synthetic schemes disclosed. The structures and IUPAC names of exemplary compounds according to Formulae I-III are provided in Tables 1, 2 and 3, below, along with corresponding physicochemical characterization data, where available.

[0149] The compounds of the present invention include not only the compounds according to Formulae I-III and the compounds of Tables 1, 2, and 3, but all geometric isomers, enantiomers, diastereomers, or racemates thereof. The compounds of the present invention also include the pharmaceutically acceptable salts of the compounds according to Formulae I-III and the compounds of Tables 1, 2, and 3, as described herein.

[0150] For therapeutic use, salts of the compounds according to Formulae I-III are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0151] The pharmaceutically acceptable addition salts as mentioned herein are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds according to Formulae I-III are able to form. The latter can be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxy-acetic, 2-hydroxypropanoic, 2- oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy- 1,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.

[0152] The compounds according to Formulae I-III containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2- amino-2-(hydroxymethyl)-l,3-propanedi-ol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely, the salt form can be converted by treatment with acid into the free acid form.

[0153] The term addition salt also comprises the hydrates and solvent addition forms which the compounds according to Formulae I-III are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

[0154] The term "quaternary amine" as used herein defines the quaternary ammonium salts which the compounds according to Formulae I-III are able to form by reaction between a basic nitrogen of a compound according to Formulae I-III and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate, among others. The counterion of choice can be introduced using ion exchange resins.

[0155] Pharmaceutically acceptable salts of the compound of the present invention include all salts and are exemplified by alkaline salts with an inorganic acid or a salt with an organic acid that are known in the art. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, as well as acid salts of organic bases. Their hydrates, solvates, and the like are also encompassed in the present invention. In addition, N-oxide compounds are also encompassed in the present invention.

[0156] It will be appreciated that some of the compounds according to Formulae I-III and their N-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.

[0157] The term "stereochemically isomeric forms" as used hereinbefore defines all possible stereoisomeric forms which the compounds according to Formulae I-III, and their N- oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of the compounds according to Formulae I-III and their N-oxides, salts, solvates or quaternary amines substantially free, i.e. associated with less than about 10%, less than about 5%, less than about 2% and less than about 1% of the other isomers. Stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E- or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds according to Formulae I-III are fully intended to be embraced within the scope of the present invention.

[0158] The N-oxide forms of the compounds according to Formulae I-III are meant to comprise the compounds according to Formulae I-III wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.

[0159] Some of the compounds according to Formulae I-III may also exist in their tautomeric form. Such forms, although not explicitly indicated in the above formulae, are intended to be included within the scope of the present invention.

[0160] Whenever used hereinafter, the term "compounds according to Formulae Ι-ΙΠ" is meant to also include the N-oxide forms, salts, and quaternary amines, as well as the stereochemically isomeric forms of the compound according to Formulae I-III. Of particular interest are those compounds according to Formulae I-III that are stereochemically pure.

[0161] Some compounds according to Formulae I-III are provided having an IC₅₀, as determined in the in-vitro ΙΚ ε kinase inhibition assays as described below (i.e., In-Vitro ΙΚΚε and TBK1 Kinase Assays), ranging from about 490 nM to about 50 nM. Other compounds according to Formulae I-III are provided having an IC₅₀, as determined in the in- vitro ΙΚ ε kinase inhibition assays as described below, ranging from about 50 nM to about 5 nM. Other compounds according to Formulae I-III are provided having an IC₅₀, as determined in the in-vitro ΙΚ ε kinase inhibition assays as described below, of less than about 5 nM.

[0162] It is believed that compounds according to Formulae I-III and having an ΙΚ ε kinase inhibitory activity (IC₅₀ value) of less than about 0.005 μΜ (5 nM), as determined in the in-vitro ΙΚ ε kinase inhibition assays as described below, are sufficiently active for the uses disclosed hereinafter. These compounds include, for example, Example Compounds 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 21, 22, 23, 27, 29, 30, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 71, 75, 76, 77, 78, 79, 80, 81, 82, 83, 87, 88, 89, 94, 95, 102, 104, 109, 111, 117, 119, 121, 123, 126, 127, 128, 130, 131, 138, 139, 141, 142, 143, and 149, as identified below. [0163] It should also be understood that in the compounds according to Formulae I-III, reference to any bound hydrogen atom may also encompass a deuterium atom bound at the same position. Substitution of hydrogen atoms with deuterium atoms is conventional in the art. See, e.g., U.S. Pat. Nos. 5,149,820 & 7,317,039. Such deuteration sometimes results in a compound that is functionally indistinct from its hydrogenated counterpart, but occasionally results in a compound having beneficial changes in the properties relative to the non- deuterated form. For example, in certain instances, replacement of specific bound hydrogen atoms with deuterium atoms dramatically slows the catabolism of the deuterated compound, relative to the non-deuterated compound, such that the deuterated compound exhibits a longer half-life in the bodies of individuals administered such compounds. This is particularly the case when the catabolism of the hydrogenated compound is mediated by cytochrome P450 systems. See Kushner et al., Can. J. Physiol. Pharmacol. 77:79-88, 1999.

3. Pharmaceutical Compositions and Formulations

[0164] The present invention also provides medicaments or pharmaceutical compositions comprising a therapeutically or prophylactically effective amount of at least one compound according to the present invention (i.e., at least one compound according to Formulae I-III). Particularly, the present invention also provides medicaments or pharmaceutical compositions comprising a therapeutically or prophylactically effective amount of at least one compound according to the present invention having an ΙΚ ε kinase inhibitory activity (IC50 value) of less than about 0.005 μΜ (5 nM), as determined in the in-vitro ΙΚ ε kinase inhibition assays as described below. These compounds include, for example, Example Compounds 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 21, 22, 23, 27, 29, 30, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 71, 75, 76, 77, 78, 79, 80, 81, 82, 83, 87, 88, 89, 94, 95, 102, 104, 109, 111, 117, 119, 121, 123, 126, 127, 128, 130, 131, 138, 139, 141, 142, 143, and 149, as identified below.

[0165] Typically, therapeutic compounds, such as the compounds according to Formulae I-III, may be effective at an amount ranging from about 0.01 μg/kg to about 100 mg/kg per day based on total body weight of a human patient. The effective amount of a therapeutic compound in such a medicament or pharmaceutical formulation may be administered all at once and at one time, or may be divided into a number of smaller doses that are administered at predetermined intervals of time, or predetermined times of the day, for a specific duration of time or a specified number of days. The suitable dosage unit containing the effective amount of a therapeutic compound may, for each administration, range in total mass from about 1 μg to about 2000 mg, or may range from about 5 μg to about 1000 mg.

[0166] In the case of combination therapy, a therapeutically effective amount of one or more other therapeutically effective compounds can be administered in a separate pharmaceutical composition, or alternatively can be included in the pharmaceutical composition according to the present invention along with at least one compound according to Formulae I-III. The pharmacology and toxicology of many of such other therapeutically effective compounds are known in the art. See e.g., Physicians Desk Reference, Medical Economics, Montvale, NJ; and The Merck Index, Merck & Co., Rahway, NJ. The therapeutically effective amounts and suitable unit dosage ranges of such other therapeutically effective compounds used in art can be equally applicable in the present invention.

[0167] It should be understood that the dosage ranges set forth above are exemplary and are not intended to limit the scope of the present invention. The therapeutically effective amount for each therapeutically effective compound may vary with factors including but not limited to the activity of the compound used, stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the active compound by the body, the age and sensitivity of the patient to be treated, and the like, as will be apparent to a skilled artisan. The amount of administration of therapeutically effective compounds may be adjusted as the various factors change over time.

[0168] In the pharmaceutical compositions of the present invention, the one or more compounds according to Formulae I-III can be in any pharmaceutically acceptable salt form, as described above.

[0169] For oral administration, the one or more compounds according to Formulae I-III may be incorporated into a pharmaceutical formulation that includes one or more pharmaceutically acceptable vehicles, excipients or carriers such as binders, lubricants, disintegrating agents, and sweetening or flavoring agents, as known in the art. The formulation can be incorporated into enclosed gelatin capsules or compressed tablets. Capsules and tablets can be prepared using conventional techniques. The capsules and tablets may also be coated with various coatings known in the art to modify the flavors, tastes, colors, and shapes of the capsules and tablets. In addition, liquid carriers such as fatty oil may also be included in capsules. [0170] Suitable oral formulations can also be in the form of suspensions, syrups, chewing gum, wafers, elixirs, and the like. If desired, conventional agents for modifying flavors, tastes, colors, and shapes of the various forms may also be included.

[0171] The compounds according to Formulae I-III can also be administered parenterally in the form of a preformed solution or suspension, or a solution or suspension prepared from a lyophilized form before use. In such formulations, pharmaceutically acceptable diluents or pharmaceutically acceptable carriers such as sterile water, saline and buffered saline can be used. Other conventional and pharmaceutically acceptable solvents, pH buffers, stabilizers, anti-bacterial agents, surfactants, and antioxidants can be included. The parenteral formulations may be stored in conventional containers such as vials and ampoules that may be sized for preparing or delivering single doses of the formulation.

[0172] Routes of topical administration include, but are not limited to, dermal, nasal, bucal, mucosal, rectal, or vaginal applications. For topical administration, the active compounds may be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, one or more thickening agents, humectants, and stabilizing agents may be included in the formulations. One form of topical administration is delivery by a transdermal patch. Methods for preparing transdermal patches are disclosed, e.g., in Brown, et al,; Annual Review of Medicine, 39:221-229, 1988.

[0173] Subcutaneous implantation for sustained release of the one or more compounds according to Formulae I-III may also be a suitable route of administration. This entails surgical procedures for implanting an active compound in any suitable formulation into a subcutaneous space, e.g., beneath the anterior abdominal wall. See, e.g., Wilson et al.; J. Clin. Psych., 45:242-247, 1984. Hydrogels may be used as a carrier for the sustained release of the active compounds. Hydrogels are generally known in the art. They are typically made by crosslinking high molecular weight biocompatible polymers into a network, which swells in water to form a gel like material. For the therapeutic methods of the present invention, hydrogels that are biodegradable or biosorbable are preferred. See, e.g., Phillips et al.; J. Pharmaceut. Sci., 73:1718-1720, 1984.

[0174] The compounds according to Formulae I-III may also be conjugated to a water soluble non-immunogenic, non-peptidic, high molecular weight polymer to form a polymer conjugate. For example, one or more compounds according to Formulae I-III may be covalently linked to polyethylene glycol to form a conjugate. Typically, such a conjugate exhibits improved solubility, stability, and reduced toxicity and immunogenicity. Thus, when administered to a patient, the one or more compounds according to Formulae I-III in the conjugate can have a longer half-life in the body, and exhibit better efficacy. See generally, Burnham; Am. J. Hosp. Pharm., 15:210-218, 1994. PEGylated proteins are currently being used in protein replacement therapies and for other therapeutic uses. For example, PEGylated interferon (PEG-INTRON A^®) is clinically used for treating Hepatitis B. PEGylated adenosine deaminase (ADAGEN^®) is being used to treat severe combined immunodeficiency disease (SCIDS). PEGylated L-asparaginase (ONCAPSPAR^®) is being used to treat acute lymphoblastic leukemia (ALL). In some embodiments of the present invention the covalent linkage between the polymer and the therapeutic compound or the polymer itself is hydrolytically degradable under physiological conditions. Such conjugates represent a type of "prodrug" that may readily release the active compound inside the body. Controlled release of an active compound may also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels, as generally known in the art.

[0175] Liposomes may also be used as carriers for the compounds according to Formulae I-III. Liposomes are micelles made of various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. Various modified lipids can also be used. Liposomes can reduce the toxicity of the active compounds, and increase their stability. Methods for preparing liposomal suspensions containing active ingredients therein are generally known in the art. See, e.g., U.S. Patent No. 4,522,811; Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., 1976.

[0176] The one or more compounds according to Formulae I-III may also be administered in combination with one or more other therapeutic compounds that synergistically treats or prevents the same symptoms or is effective for another disease or symptom for which the patient is being treated, so long as the one or more other therapeutic compounds does not interfere with, or adversely affect, the effects of the compounds according to Formulae I-III. Such other therapeutic compounds include, but are not limited to, anti-inflammation agents, antiviral agents, antibiotics, antifungal agents, antithrombotic agents, cardiovascular drugs, cholesterol-lowering agents, anti-cancer drugs, hypertension drugs, and the like.

4. Therapeutic Methods

a. Treating Inflammation

[0177] In view of the discovery that ΙΚΚε plays a central role in integrating signals induced by pro-inflammatory stimuli (Kravchenko et al.; J. Biol. Chem., 278:26612-26619, 2003); and that ΙΚ ε, along with TBKl, has been shown to be involved in maintaining macrophages in an activated inflammatory state following activation of the interferon response (Solis, et al.; Eur. J. Immunol.; 37:529-539, 2007); it is believed that inhibition of ΙΚΚε kinase activity, TBK1 kinase activity, or the kinase activities of both ΙΚ ε and TBK1 would be effective in treating inflammation resulting from a wide range of causes, including both systemic and chronic inflammation. Hence, the present invention provides methods of treating inflammation, and complications associated with inflammation, comprising administering a therapeutically effective amount of one or more ΙΚ ε and/or TBK1- inhibiting compounds according to Formulae I-III to a patient in need of such treatment. b. Treating Rheumatoid Arthritis (RA)

[0178] In view of the discovery that ΙΚ ε, as part of a complex kinases, has been found to play a role in the synovial inflammation, extracellular matrix destruction and activation of the anti-viral program and innate immune response in RA (Sweeney et al.; J. Immunol., 174:6424-6430, 2005), it is believed that inhibition of ΙΚ ε and/or TBK1 kinase activity would be effective in treating RA. Consequently, the present invention provides methods of treating RA, and complications associated with RA, comprising administering a therapeutically effective amount of one or more ΙΚΚε and/or TBK1 -inhibiting compounds according to Formulae I-III to a patient in need of such treatment.

c. Treating Systemic Lupus Erythematosus (SLE)

[0179] In view of the role of phosphorylated transcription factors IRF3 and IRF7 in mediating the upregulation of IFNa/β and associated type I interferon signature genes that is a hallmark of flare-ups of SLE symptoms in SLE patients, and further view of the roles of ΙΚΚε and TBK in respectively phosphorylating IFR3 and IRF7, it is believed that inhibition of ΙΚ ε and/or TBK activity might be provide an effective means to reduce the intensity and longevity of such flare-ups in patients suffering from SLE. Consequently, the present invention provides methods of treating SLE, and complications associated with SLE flare- ups, comprising administering a therapeutically effective amount of one or more ΙΚΚε and/or TBK 1 -inhibiting compounds according to Formulae I-III to a patient in need of such treatment.

d. Treating Diseases Associated with Aberrant Accumulation of Cytosolic Nucleic Acids: Sjogrens Syndrome, Aicardi-Goutieres Syndrome, Certain Forms of Systemic Lupus Erythematosus, Chilblain Lupus, Retinal

Vasculopathy and Cerebral Leukodystrophy (RVCL)

[0180] Sjogrens syndrome, Aicardi-Goutieres syndrome, certain forms of systemic lupus erythematosus, chilblain lupus, RVCL are commonly associated with mutations in at least one of the following genes: TREX1; RNASEH2B; RNASEH2C; RNASEH2A; and SAMHD1 (Crow and Rehwinkel; Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity; Hum. Mol. Genet., 18:130-136, 2009; Kavanagh, et al.; New roles for the major human 3 -5' exonuclease TREXl in human disease; Cell Cycle, 7:1718-1725, 2008). These proteins are involved in degrading nucleic acids that are aberrantly located in the cytosolic compartment. If nucleic acids accumulate in the cytosol and are recognized by DNA or RNA receptors {i.e., RIG-I, MDA5, DAI, and others) this recognition leads to type I interferon production and autoimmune disease. The TBK1 and ΙΚ ε kinases are part of the signal cascade that leads to type I interferon production through phosphorylation of IRF3 and/or IRF7, and NFKB transcription factors (Hornung and Latz; Intracellular DNA Recognition; Nat. Rev. Immunol., 10:123-130, 2010). As such, small molecule inhibitors of ΙΚ ε and/or TBK1 kinases are expected to block type I interferon expression and provide therapeutic benefits to patients who are unable to properly degrade aberrantly localized cytosolic nucleic acids. Consequently, the present invention provides methods of treating deseases associated with the abberent accumulation of cytosolic nucleic acids, including Sjogrens syndrome, Aicardi-Goutieres syndrome, certain forms of systemic lupus erythematosus, chilblain lupus, RVCL, and complications associated with these diseases, comprising administering a therapeutically effective amount of one or more ΙΚ ε and/or TBK1 -inhibiting compounds according to Formulae I-III to a patient in need of such treatment.

e. Treating Systemic Sclerosis

[0181] Systemic sclerosis is an autoimmune disease that targets connective tissue. The immune abnormalities cause increased production of extracellular matrix proteins in skin and vascular tissues through the interactions of several cell types, including endothelial cells, lymphocytes, macrophages, and fibroblast cells. A recognized feature of this disease is an abnormal type I interferon-gene expression signature (Assassi, et al.; Systemic sclerosis and lupus: points in an interferon-mediated continuum; Arthritis Rheum., 62:589-598, 2010). As with other autoimmune diseases, the exact cause of systemic sclerosis is not completely understood, but inhibition of type I interferons and fibrogenic cytokines {e.g. TGF-β) through TLR3 pathway inhibition may be therapeutically useful (Farina, et al.; Poly(LC) Drives Type I IFN- and TGFbeta-Mediated Inflammation and Dermal Fibrosis Simulating Altered Gene Expression in Systemic Sclerosis; J. Invest. Dermato., epub, Jul 8, 2010). The ΙΚ ε and/or TBK1 kinases are essential for production of type I interferon and for TGF-β signaling through TLR3 receptor activation. Small molecule inhibitors of the ΙΚ ε & TBKl kinases, such as the compounds according to Formulae I-III, may benefit patients suffering from systemic sclerosis. Consequently, the present invention provides methods of treating systemic sclerosis, and complications associated with systemic sclerosis, comprising administering a therapeutically effective amount of one or more ΙΚΚε and/or TBK1- inhibiting compounds according to Formulae I-III to a patient in need of such treatment. f. Treating Dermatomyositis and Polymyositis - Subtypes of Myositis

[0182] Myositis describes a collection of several poorly defined autoimmune diseases represented by the most common subtypes; dermatomyositis, polymyocitis, and inclusion- body myositis. Production of autoantibodies that target unknown muscle tissue antigens result in muscle weakness and skin abnormalities (Dalakas; Immunotherapy of Myositis: Issues, Concerns and Future Prospects; Nat. Rev. Rheum., 6: 129-137, 2010). A recently identified feature of dermatomyositis and polymyositis is an aberrent type I interferon-gene expression signature profile in both muscle and PBMC samples from diseased patients (Baechler, et al.; An Interferon Signature in the Peripheral Blood of Dermatomyositis Patients is Associated with Disease Activity; Mol. Med., 13:59-68, 2007). The interferon- gene signature results from elevated IFN-α/β cytokines that are aberrantly produced. The ΙΚΚε/ΤΒΚΙ pathway is essential for the production of IFN-α/β proteins upon activation of TLR3, TLR4, and cytosolic nucleic acid receptors; RIG-I, MDA5, DAI, and others. It is expected that patients suffering from dermatomyositis and polymyocitis would benefit from treatment with small molecule ΙΚΚε and/or TBKl inhibitors such as the compounds according to Formulae I-III. Consequently, the present invention provides methods of treating dermatomyositis and polymyocitis, and complications associated with these diseases, comprising administering a therapeutically effective amount of one or more ΙΚΚε and/or TBKl -inhibiting compounds according to Formulae I-III to a patient in need of such treatment.

g. Treating Psoriasis

[0183] In view of the fact that psoriasis is a chronic inflammatory skin disorder involving up-regulation of interleukins IL-23, IL-17A and IL-22, and in further view of the discovery that ΙΚΚε plays a role in integrating signals induced by pro-inflammatory stimuli (Kravchenko et al.; J. Biol. Chem.; 278:26612-26619, 2003.); and that ΙΚΚε, along with TBKl, has been shown to play a role in maintaining macrophages in an activated, inflammatory state, following activation of the interferon response (Solis, et al.; Eur. J. Immunol.; 37:529-539, 2007); it is believed that inhibition of ΙΚΚε and TBK activity might provide an effective means to treating psoriasis. Consequently, the present invention provides methods of treating psoriasis, and complications associated with psoriasis, comprising administering a therapeutically effective amount of one or more ΙΚΚε and/or TBK 1 -inhibiting compounds according to Formulae I-III to a patient in need of such treatment.

h. Treating Chronic Obstructive Pulmonary Disease (COPD)

[0184] COPD is characterized by chronic inflammation of the lungs and narrowing of the airways often caused by cigarette smoke (Churg, et ah; Mechanisms of cigarette smoke- induced COPD: Insights from animal models; Am. J. Physiol. Lung Cell. Mol. Physiol, 294:612-631, 2008). Viral and bacterial infections exacerbate the chronic inflammation in patients with COPD and result in approximately 120,000 deaths each year. Pulmonary infections can be recognized by nucleic acid receptors that activate ΙΚΚε/ΤΒΚΙ signaling, leading to proinflammatory chemokine secretion of RANTES, IP-10 and IL-8. These chemokines recruit a variety of proinflammatory cells, including T-cells, eosinophils, basophils, neutrophils, natural killer and dendritic cells, to lungs. Recruitment of proinflammatory cells to the lungs results in lung tissue damage. Eosinophils and T cells play a primary role in causing tissue damage due to their release of cytotoxic proteins and proteases. Inhibition of the ΙΚΚε/ΤΒΚΙ pathway is likely to have therapeutic benefits in Asthma and COPD patients. Consequently, the present invention provides methods of treating COPD, and complications associated with COPD, comprising administering a therapeutically effective amount of one or more ΙΚΚε and/or TBK 1 -inhibiting compounds according to Formulae I-III to a patient in need of such treatment.

i. Treating Inflammatory Bowel Disease (IBD)

[0185] IBD is an autoimmune-like disorder characterized by chronic inflammation of the intestinal mucosal tissue. The gut is an immunologically unique organ, which must protect the host from pathogens while being tolerant to dietary antigens and essential commensal bacteria. The intestinal wall is therefore an actively regulated barrier. IBD is characterized by a dysregulated immune response to commensal bacteria in genetically susceptible patients. Toll-like receptor (TLR) transmembrane proteins are a central component of the intestinal bacterial surveillance system expressed by intestinal epithelial cells, T cells, antigen- presenting macrophages, and dendritic cells. TLRs have been genetically implicated in IBD based on the identification of single-nucleotide polymorphisms in a number of TLRs (TLR1, 2, 4, 6, and 9) that are associated with increase disease susceptibility or extent of disease in IBD patients (Cario; Toll-like Receptors in Inflammatory Bowel Diseases: A Decade Later; Inflamm. Bowel Dis., 16:1583-1597, 2010). TLR4 is upregulated in IBD, whereas in normal intraepithelial cells it is expressed at such low levels as to be undetectable. TLR4 is a bacterial lipopolysaccharide-recognizing receptor, and one of the outputs from the TLR4 receptor signaling complex involves ΙΚ ε and/or TBK1 kinases. This pathway directs the activation of the transcription factor IRF3 via phosphorylation by ΙΚ ε and/or TBK1 kinase, which induces expression of proinflammatory chemokines RANTES and MCPl . Modulation of overactive TLR4 signaling, via inhibition of the ΙΚ ε/ΤΒΚΙ signaling pathway by a compound of the present invention may have therapeutic benefit to IBD patients. Consequently, the present invention provides methods of treating IBD, and complications associated with IBD, comprising administering a therapeutically effective amount of one or more ΙΚ ε and/or TBK1 -inhibiting compounds according to Formulae I-III to a patient in need of such treatment.

j. Treating Obesity, Insulin Resistance, Type 2 Diabetes (NIDDM), and Metabolic Syndrome

[0186] In view of the discovery that ΙΚ ε knockout mice were protected from high-fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis, and whole-body insulin resistance; and in further view of the fact that these ΙΚ ε knockout mice were found to have increased energy expenditure and thermogenesis, maintained insulin sensitivity in both liver and fat, reduced expression of inflammatory cytokines, and altered expression of regulatory proteins and enzymes involved in glucose and lipid metabolism (Chiang et al.; Cell, 138:961-975, 2009); it is believed that inhibition of ΙΚ ε kinase activity would be effective in treating obesity, insulin resistance, NIDDM, and metabolic syndrome, and complications associated with these and other metabolic diseases and disorders. Consequently, the present invention provides methods of treating obesity, insulin resistance, metabolic syndrome, type 2 diabetes, and complications associated with these diseases,, and other metabolic diseases and disorders, comprising administering a therapeutically effective amount of one or more ΙΚ ε and/or TBK1 -inhibiting compounds according to Formulae I-III to a patient in need of such treatment.

[0187] In further view of the discovery that TBK1 mediates phosphorylation of insulin receptor at serine residue 994, and thereby provides a potential link between inflammation and insulin resistance (Munoz et al; J. Endocrinol., 201 :185-197, 2009), it is believed that inhibition of TBK1 kinase activity might be effective in treating insulin resistance. Consequently, the present invention provides methods of treating insulin resistance, and complications associated with insulin resistance, comprising administering a therapeutically effective amount of one or more ΙΚ ε and/or TBK1 -inhibiting compounds according to Formulae I-III to a patient in need of such treatment,

k. Treating Cancer:

[0188] In view of the discovery that the gene encoding ΙΚ ε (i.e., IKBKE; Entrez Gene Gene ID: 9641) has been identified as a breast cancer oncogene (Boehm, et al.; Cell; 129: 1065-1079, 2007); that ΙΚ ε directly phosphorylates the tumor suppressor CYLD in vivo, thereby decreasing the activity of CYLD, and leading to transformation and turmorigenesis (Hutti, et al.; Mol. Cell; 34:461-472, 2009); and that overexpression of ΙΚ ε is a recurrent event in human ovarian cancer, and that this overexpression could play a pivotal role in both tumor progression and the development of cisplatin resistance (Guo, et al.; Am. J. Pathol.; 175:324-333, 2009); it is believed that inhibition of ΙΚ ε kinase activity would be effective in treating of a wide range of cancers. Consequently, the present invention provides methods of treating a wide range of cancers comprising administering a therapeutically effective amount of one or more ΙΚ ε-inhibiting compounds according to Formulae I-III to a patient in need of such treatment.

[0189] In further view of the discovery that GTPase-mediated activation of TBK1 couples innate immune signaling to tumor cell survival (Chien et al.; Cell; 127:157-170, 2006), it is believed that inhibition of TBK1 kinase activity would be effective in treating of a wide range of cancers. Consequently, the present invention provides methods of treating a wide range of cancers comprising administering a therapeutically effective amount of one or more TBK1 -inhibiting compounds according to Formulae I-III to a patient in need of such treatment.

[0190] As used herein, the term "cancer" has its conventional meaning in the art. Cancer includes any condition of the animal or human body characterized by abnormal cellular proliferation. The cancers to be treated comprise a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. Compounds of the the invention have been shown to be effective in cell-based cancer models, and are thus thought to have utility in treating a broad range of cancers. However, therapeutic methods of the present invention would best be directed towards cancers that are found to respond favorably to treatment with an ΙΚ ε and/or TBK1 kinase inhibitor. Further, "treating cancer" should be understood as encompassing treating a patient who is at any one of the several stages of cancer, including diagnosed but as yet asymptomatic cancer. A patient having cancer can be identified by conventional diagnostic techniques known in the art, and the identified patient may be treated with a compound of the present invention, once their cancer has been found to be susceptible to treatment with an ΙΚ ε and/or TBK1 kinase inhibitor.

[0191] As noted, cancers that may be treated by the methods of the invention are those cancers that respond favorably to treatment with an ΙΚ ε and/or TBK1 kinase inhibitor. Such cancers may include, but are not limited to, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, and prostatic carcinoma.

[0192] The present invention further provides methods for combination therapy for treating cancer by treating a patient (either a human or another animal) in need of such treatment with a compound of the present invention together with one or more other anticancer therapies. Such other anti-cancer therapies include traditional chemotherapy agents, targeted agents, radiation therapy, surgery, hormone therapy, etc. In the combination therapy, the compound of the present invention may be administered separately from, or together with the one or more other anti-cancer therapies.

[0193] As noted above, it is believed that inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi- Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer are disease and disorders that will respond favorably to therapy with an ΙΚΚε or TBK1 kinase inhibitor. Consequently, the present invention provides therapeutic methods for treating inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders. These therapeutic methods involve treating a patient (either a human or another animal) in need of such treatment, with a therapeutically effective amount of at least one compound according to Formulae I-III, or a pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to Formulae I-III. These therapeutic methods also administering to a patient (either a human or another animal) in need of such treatment, a therapeutically effective amount of at least one compound according to Formulae I-III, or a pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to Formulae I-III.

[0194] It is believed that compounds according to Formulae I-III and having an ΙΚ ε kinase inhibitory activity (IC50 value) of less than about 0.005 μΜ (5 nM), as determined in the in-vitro ΙΚ ε kinase inhibition assays as described below, are sufficiently active for the therapeutic methods proposed. These compounds include, for example, Example Compounds 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 21, 22, 23, 27, 29, 30, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 71, 75, 76, 77, 78, 79, 80, 81, 82, 83, 87, 88, 89, 94, 95, 102, 104, 109, 111, 117, 119, 121, 123, 126, 127, 128, 130, 131, 138, 139, 141, 142, 143, and 149, as identified below.

[0195] The present invention also comprises treating isolated cells with a therapeutically effective amount of at least one compound according to Formulae I-III, or a pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to Formulae I-III.

[0196] As used herein, the phrase "treating ... with ... a compound" means either administering a compound according to Formulae I-III, or a pharmaceutical compositions comprising a compound according to Formulae I-III, directly to isolated cells or to an animal, or administering to cells or an animal another agent to cause the presence or formation of a compound according to Formulae I-III inside the cells or the animal. Consequently, the methods of the present invention comprise administering to cells in vitro or to a warm-blood animal, particularly a mammal, and more particularly a human, a pharmaceutical composition comprising an effective amount of at least one compound according to Formulae I-III, or causing the presence or formation of at least one compound according Formulae I-III inside the cells or the animal.

[0197] As would be appreciated by the skilled artisan, at least one therapeutic compound according to Formulae I-III may be administered in one dose at one time, or may be divided into a number of smaller doses to be administered at predetermined intervals of time. The suitable dosage unit for each administration may be determined based on the effective daily amount and the pharmacokinetics of the compounds. In the case of combination therapy, a therapeutically effective amount of one or more other therapeutically effective compound can be administered in a separate pharmaceutical composition, or alternatively included in the pharmaceutical composition according to the present invention which contains a compound according to the present invention. The pharmacology and toxicology of many therapeutically effective compounds are known in the art. See e.g., Physicians Desk Reference, Medical Economics, Montvale, NJ; and The Merck Index, Merck & Co., Rahway, NJ. The therapeutically effective amounts and suitable unit dosage ranges of such compounds used in art can be equally applicable in the present invention.

[0198] It should be understood that the dosage range set forth herein is exemplary and is not intended to limit the scope of the present invention. The therapeutically effective amount for each active compound of the invention may vary with factors including but not limited to the activity of the compound used, stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the active compound by the body, the age and sensitivity of the patient to be treated, and the like, as will be apparent to a skilled artisan. The amount of administration may be adjusted as the various factors change over time.

[0199] The present invention also provides methods for methods for combination therapy for treating inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders, by treating a patient in need therof, with a therapeutically effective amount of at least one compound according to Formulae I-III, together with with a therapeutically effective amount of one or more other compounds that have been shown to be effective in the treatment of inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders. [0200] For the convenience of combination therapy, at least one compound according to Formulae I-III can be administered together in the same formulation with the one or more other compounds that have been shown to be effective in the treatment of inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders, in the same formulation or dosage form. Thus, the present invention also provides pharmaceutical compositions or medicaments for combination therapy, comprising an effective amount of at least one compound according to Formulae I-III, and an effective amount of at least one other compound that has been shown to be effective in the treatment of inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders.

5. Methods of Making the Compounds According to Formulae I-III

[0201] Methods of making the compounds of Formula I, and intermediates used in their synthesis, are provided in the Examples section below. Appraised of the general synthetic schemes, specific intermediates, and detailed example of specific syntheses disclosed in the following section, the skilled artisan would be enabled to make the remaining compounds disclosed in Table 3. In all cases, the syntheses were begun using commercially-available starting materials.

EXAMPLES

Chemical Examples

General Synthetic Scheme 1

Reagents: (a) NaH, DMF, ArS0₂Cl (b) Pd(PPh₃)₄, NaHC0₃, H₂0, Dioxane, 90 °C (c) NBS, DMF (d) Pd(PPh₃)₄, NaHC0₃, H₂0, Dioxane, 90 °C (e) K₂C0₃, MeOH, 60 °C.

[0202] Generally, the compounds of the present invention can be synthesized using methods known in the art combined with the disclosure herein. In general, compounds of the invention can be synthesized according to Scheme 1. For example, 5-bromo-lH-pyrrolo[2,3- b]pyridine was converted to the corresponding 5-bromo-l-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridine. Conversion to 5-substitued pyrrolopyridines was achieved by reacting the boronic acids or boranate esters with dichloropyrimidine in the presence of Pd(PPh₃)₄. Repeating the procedure with another boronic acid or boranate ester and cleavage of the protecting group affords 3-5-disubstituted pyrrolopyrdines.

General Synthetic Scheme 2

X = C, N X = C, N

Reagents: (a) NIS, DMF (b) NaH, DMF, ArS0₂Cl (c) Pd(PPh₃)₄, NaHC0₃, H₂0, Dioxane, 90 °C (d) Pd(PPh₃)₄, NaHC0₃, H₂0, Dioxane, 90 °C (e) K₂C0₃, MeOH, 60 °C.

[0203] Generally, the compounds of the present invention can be synthesized using methods known in the art combined with the disclosure herein. In general, compounds of the invention can be synthesized according to Scheme 2. For example, 5-bromo-lH-pyrrolo[2,3- b]pyridine was converted to the corresponding 5-bromo-3-iodopyrrolo[2,3-b]pyridine. Protection of the pyrrolo group was accomplished with either a benzene sulfonyl or tosyl group. Conversion to 3-substitued pyrrolopyridines was achieved by reacting the boronic acids or boranate esters with the protected 5-bromo-3-iodopyrrolo[2,3-b]pyridine in the presence of Pd(PPh3)4. Repeating the procedure with another boronic acid or boranate ester and cleavage of the protecting group affords 3-5-disubstituted pyrrolopyridines.

General Synthetic Scheme 3

Reagents: (a) RuPhos, LiHMDS, Pd(OAc)₂, 60 °C, 2- 16h; (b) NIS or NBS, DMF, rt 2- 16h; (c) NaH, RS0₂C1, DMF, rt, 2-16h; Pd(PPh₃)₄, NaHC0₃, H₂0, Dioxane, 90 °C (d) Pd(PPh₃)₄, NaHC0₃, H₂0, Dioxane, 90 °C (e) K₂C0₃, MeOH, 60 °C.

[0204] Generally, the compounds of the present invention can be synthesized using methods known in the art combined with the disclosure herein. In general, compounds of the invention can be synthesized according to Scheme 3. For example, 5-bromo-lH-pyrrolo[2,3- b]pyridine was converted to the corresponding 5-aminopyrrolo[2,3-b]pyridine via palladium catalyzed coupling with the requisite amine and RuPhos. Conversion to 3-5-substitued pyrrolopyridines was achieved by halogenating at the 3-positon, protecting the pyrrolo group and reacting resulting product with a boronic acids or boranate esters in the presence of Pd(PPh₃)₄. Cleavage of the protecting group and any further functionalization afforded the 3- 5-disubstituted pyrrolopyridines.

Preparation of Intermediates

Standard Methods

Standard Method A; Nitro Reduction [0205] The nitro compound was hydrogenated for 4-18 h in MeOH with catalytic Pd/C. The suspension was filtered through Celite and concentrated to provide the aniline. If necessary, purification was performed by MPLC (Si0₂, EtOAc/Hexanes, 0-100%, optionally followed by a gradient from 100% EtOAc to 100% of 1 : 1 CH₂Cl₂/MeOH).

Standard Method B; BOC Deprotection

[0206] A solution of the BOC protected amine in CH₂C1₂ was treated with TFA (30%). The solvent was evaporated to afford the TFA salt or aqueous work-up with saturated NaHC0₃, extraction with EtOAc, drying over Na₂S0₄ and evaporation of the solvent to afford the free amine.

Standard Method C ; Ester Hydrolysis

[0207] A solution of the ester in THF/H₂0 (2: 1) was treated with LiOH (1.0-10 eq) at 25- 65 C for 1-18 h. A IN solution of aq. HC1 was added until pH 4-5. The precipitate was collected, washed with H₂0 and dried under high vacuum to provide the desired compound.

Standard Method D; HATU Coupling

[0208] A solution of the carboxylic acid, the amine (1.0-1.5 eq), DIPEA (1.0-1.5 eq) in was added HATU (1.0-1.5 eq). The reaction mixture was stirred at rt for 16 h. The solvent was evaporated and the residue purified by RP-MPLC (C¹⁸, MeOH/H₂0, 0-100% w/ 0.1% TFA) to provide the desired compounds. The desired fractions were collected and the solvent evaporated under reduced pressure. The resulting solid was recrystallized from EtOAc/Hexanes to afford the desired compound.

Preparation of Specific Intermediates 5-Bromo-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile.

Reagents: (a) NaH, DMF, 45 °C, 16 h; (b) PdCl₂(dppf)₂, KOAc, Dioxane 90 °C, 16 h.

[0209] Step 1 : 5-Bromo-2-tetrahydropyran-4-yloxy-benzonitrile: To tetrahydropyranol (7.1 g, 69.5 mmol) in DMF (130 mL) at 0 °C was added NaH (2.78 g, 69.5 mmol). 5-Bromo- 2-fluorobenzonitrile (11.6 g, 57.9 mmol) was added dropwise as a solution in DMF (63 mL). The reaction was stirred at 45 °C for 16 h. The reaction was cooled to room temperature and quenched by pouring the reaction into H₂0 (1.5 L). The precipitate was filtered and dried under vacuum to provide 16.8 g of material (88%). The product was used without further purification. 1H NMR (DMSO) δ 8.02 (s, 1H), 7.82 (d, 1H), 7.35 (d, 1H), 4.85-4.76 (m, 1H), 3.90-3.80 (m, 2H), 3.58-3.49 (m, 2H), 2.04-1.95 (m, 2H), 1.70-1.60 (m, 2H).

[0210] Step 2: 2-Tetrahydropyran-4-yloxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile: To 5-bromo-2-tetrahydropyran-4-yloxy-benzonitrile (7.8 g, 23.5 mmol) in p- dioxane (78 mL) was added bis(pinacolato)diboron (8.9 g, 35.3 mmol), KOAc (6.9 g, 70.5 mmol), and Pd(dppf)Cl₂ (0.86 g, 1.2 mmol). The reaction was heated to 90 °C for 16 h. The reaction was quenched with H₂0 (50 mL), followed by extraction with EtOAc (3 x 25 mL). The aqueous and organic layers were separated. The organic layer was washed with saturated NaCl(aq) solution and dried (Na₂S0₄). Purification by column chromatography (0-100%) EtOAc/Hexanes) provided 7.6 g (98%) material. 1H NMR (CDC1₃) δ 8.04 (s, 1H), 7.90 (d, 1H), 6.95 (d, 1H), 4.77-4.70 (m, 1H), 4.10-4.00 (m, 2H), 3.67-3.60 (m, 2H), 2.10-2.00 (m, 2H), 1.90-1.81 (m, 2H), 1.15 (s, 12H).

4-[(E)-3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)allyl]morpholine.

Reagents: (a) Morpholine, K₂C0₃, ACN, rt. 2h; Pinnacol, MgS0₄, 15h. [0211] Step 1 : 4-[(E)-3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)allyl]morpholine: To a solution of [(E)-3-chloroprop-l-enyl]boronic acid (0.10 g, 0.83 mmol) in ACN (5 mL) was added K₂CO₃ (0.23 g, 1.66 mmol) and morpholine (0.08 mL, 0.91 mmol) and the reaction mixture stirred for 2h. Pinnacol (0.12 g, 1.0 mmol) and MgS0₄ were added and the reaction mixture stirred overnight. The solid was filtered off and the solvent removed under reduced pressure. Purification by column chromatography (0-50% EtOAc/Hexanes) provided 0.19 g (90%) material. 1H NMR (DMSO) δ 6.42 (dt, 1H), 5.50 (d, 1H), 3.56 (t, 4H), 3.00 (dd, 2H), 2.31 (s, 4H), 1.19 (s, 12H). LC-MS [M+H]⁺ 254.0

Intermediate 1 : 5-bromo-2-(cyclopropylmethoxy)benzonitrile.

[0212] NaH (60%> in oil, 1.357 g, 34 mmol) was added to a solution of cyclopropylmethanol (2.0 mL, 27.7 mmol) in DMF (30 mL). The reaction was stirred for ~ 30 min., then 5-bromo-2-fluoro-benzonitrile (5.532 g, 27.7 mmol) was added and the solution heated to 45 °C for 2 h. The reaction was poured into H₂0 and extracted with EtOAc (4 times). The combined organics were dried (MgS0₄), filtered and concentrated. Purification by MPLC (Si0₂, EtOAc/Hexanes, 0 - 50%) provided the title compound. 1H NMR (400 MHz, DMSO-de) δ ppm 8.00 (d, 1 H), 7.81 (dd, 1 H), 7.20 (d, 1 H), 4.00 (d, 2 H), 1.20 - 1.29 (m, 1 H), 0.56 - 0.63 (m, 2 H), 0.34 - 0.39 (m, 2 H).

Intermediate 2: 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzonitrile.

[0213] A mixture of 5-bromo-2-(cyclopropylmethoxy)benzonitrile (1.321 g, 5.24 mmol), bis(pinacolato)diborane (1.460 g, 5.75 mmol), KOAc (1.535 g, 15.6 mmol) and Pd (dppf)C12 (427 mg, 0.52 mmol) in /?-dioxane (30 mL) was heated to 100 °C under N₂ overnight. The reaction was cooled to rt, diluted with EtOAc and washed with brine. The aqueous layer was extracted once with EtOAc. The combined organics were dried (MgS0₄), filtered and concentrated. Purification by MPLC (Si0₂, EtOAc/Hexanes, 0 - 50%) provided the title compound. 1H NMR (400 MHz, DMSO- ₆) δ ppm 7.88 (d, 1 H), 7.85 (s, 1 H), 7.24 (d, 1 H), 4.04 (d, 2 H), 1.29 (s, 12 H), 1.25-1.32 (m, 1 H), 0.61 (d, 2 H), 0.38 (d, 2 H).

Intermediate 3: 5-[5-bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2- (cyclopropylmethoxy)benzonitrile.

[0214] A mixture of 5-bromo-3-iodo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (253 mg, 0.53 mmol), 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile (166 mg, 0.55 mmol) NaHC0₃ (140 mg, 1.7 mmol) and Pd(PPh₃)₄ in MeCN/H₂0 (3: 1, 4 mL) was heated to 80 °C under N₂ overnight. The reaction was cooled to rt, diluted with EtOAc, washed with brine, dried (MgS0₄), filtered and concentrated. Purification by MPLC (Si0₂, EtOAc/Hexanes, 0 - 50%) provided the title compound. 1H NMR (400 MHz, DMSO- ₆) δ ppm 8.58 (s, 1 H), 8.54 (s, 1 H), 8.37 (s, 1 H), 8.20 (s, 1 H), 8.01 - 8.09 (m, 3 H), 7.41 - 7.46 (m, 2 H), 7.31 (d, 1 H), 4.07 (d, 2 H), 2.35 (s, 3 H), 1.24 - 1.34 (m, 1 H), 0.60 - 0.65 (m, 2 H), 0.38 - 0.43 (m, 2 H).

Intermediate 4: 2-(cyclopropylmethoxy)-5-[5- [(E)-3-morpholinoprop-l-enyl]-l- (p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]benzonitrile.

[0215] A mixture of 5-[5-bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2- (cyclopropylmethoxy)benzonitrile (188 mg, 0.23 mmol), 4-[(E)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)allyl]morpholine (61 mg, 0.24 mmol), NaHC0₃ (58 mg, 0.69 mmol) and Pd(PPh₃)₄ (26 mg, 0.023 mmol) in MeCN/H₂0 (3: 1, 4 mL) was heated to 80 °C under N₂ overnight. The reaction was cooled to rt, diluted with EtOAc, washed with brine, dried (MgS0₄), filtered and concentrated. Purification by MPLC (Si0₂, EtOAc/Hexanes, 0 - 100%) provided the title compound. 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.58 (s, 1 H), 8.54 (s, 1 H), 8.37 (s, 1 H), 8.20 (s, 1 H), 8.01 - 8.09 (m, 3 H), 7.41 - 7.46 (m, 2 H), 7.31 (d, 1 H), 4.07 (d, 2 H), 2.35 (s, 3 H), 1.24 - 1.34 (m, 1 H), 0.60 - 0.65 (m, 2 H), 0.38 - 0.43 (m, 2 H).

Intermediate 5: tert-buty\ 4-[4-[5-bromo-l-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridin-3-yl]-2-cyano-phenoxy]piperidine-l-carboxylate. [0216] The title compound was prepared from 5-bromo-3-iodo-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine and tert-butyl 4-(4-bromo-2-cyano-phenoxy)piperidine- 1-carboxylate using a method similar to Intermediate 2. 1H NMR (400 MHz, DMSO- ₆) δ ppm 8.59 (s, 1 H), 8.54 (s, 1 H), 8.38 (s, 1 H), 8.21 (s, 1 H), 8.07 (d, 1 H), 8.01 - 8.05 (m, 2 H), 7.42 - 7.48 (m, 3 H), 4.87 - 4.94 (m, 1 H), 3.54 - 3.63 (m, 2 H), 3.30 - 3.39 (m, 2 H), 2.35 (s, 3 H), 1.90 - 1.98 (m, 2 H), 1.60 - 1.70 (m, 2 H), 1.42 (s, 9 H).

Intermediate 6: tert-butyl 4-[2-cyano-4-[5- [(E)-3-morpholinoprop-l-enyl]-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]phenoxy]piperidine-l-carboxylate.

[0217] The title compound was prepared from tert-butyl 4-[4-[5-bromo-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-cyano-phenoxy]piperidine- 1 -carboxylate and 4- [(E)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)allyl]morpholine using a method similar to Intermediate 4. Purification by MPLC (Si0₂, EtOAc/hexanes 50 - 100%, then EtOAc - CH₂Cl₂/MeOH (1 : 1), 0 - 100%) provided the title compound. 1H NMR (400 MHz, DMSO- d₆) δ ppm 8.53 (s, 1 H), 8.36 (s, 1 H), 8.29 (s, 1 H), 8.21 (s, 1 H), 8.06 - 8.12 (m, 1 H), 7.98 - 8.05 (m, 2 H), 7.40 - 7.48 (m, 3 H), 6.65 - 6.72 (m, 1 H), 6.48 - 6.57 (m, 1 H), 4.85 - 4.95 (m, 1 H), 3.54 - 3.63 (m, 6 H), 3.30 - 3.40 (m, 3 H), 3.10 (d, 2 H), 2.36 - 2.43 (m, 3 H), 2.34 (s, 3 H), 1.91 - 2.00 (m, 2 H), 1.61 - 1.71 (m, 2 H), 1.42 (s, 9 H).

Intermediate 7: 5-[5-[(E)-3-morpholinoprop-l-enyl]-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-(4-piperidyloxy)benzonitrile.

[0218] The title compound was prepared from tert-butyl 4-[2-cyano-4-[5-[(E)-3- morpholinoprop-l-enyl]-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]phenoxy]piperidm^ carboxylate using standard method B. 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.53 (s, 1 H), 8.35 (s, 1 H), 8.27 (s, 1 H), 8.19 (s, 1 H), 8.00 - 8.09 (m, 3 H), 7.38 - 7.46 (m, 3 H), 6.64 - 6.74 (m, 1 H), 6.48 - 6.56 (m, 1 H), 4.70 - 4.77 (m, 1 H), 3.53 - 3.61 (m, 4 H), 3.15 - 3.20 (m, 1 H), 3.05 - 3.13 (m, 2 H), 2.92 - 3.01 (m, 2 H), 2.57 - 2.65 (m, 2 H), 2.39 (s, 4 H), 2.34 (s, 3 H), 1.90 - 1.98 (m, 2 H), 1.51 - 1.61 (m, 2 H).

Intermediate 8: 4-(4-bromo-2-fluoro-phenoxy)tetrahydropyran.

[0219] A solution of tetrahydropyran-4-ol (914 mg, 8.96 mmol), 4-bromo-2-fluoro- phenol (1.926 g, 10.0 mmol) and PPh₃ (2.588 g, 9.9 mmol) in toluene (30 mL) was treated with diethyl azodicarboxylate (40 wt% in toluene, 5 mL, 10 mmol) and stirred for 30 min. The reaction was diluted with EtOAc, washed with H₂0 and brine, dried (MgS0₄), filtered and concentrated. Purification by two MPLC columns (Si0₂, EtOAc/Hexanes, 0 - 50%) provided the title compound. 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.54 (dd, 1 H), 7.29 - 7.34 (m, 1 H), 7.22 - 7.28 (m, 1 H), 4.56 - 4.63 (m, 1 H), 3.84 (dt, 2 H), 3.42 - 3.50 (m, 2 H), 1.92 - 1.99 (m, 2 H), 1.54 - 1.63 (m, 2 H)

Intermediate 9: 2-(3-fluoro-4-tetrahydropyran-4-yloxy-phenyl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane.

[0220] The title compound was prepared from 4-(4-bromo-2-fluoro- phenoxy)tetrahydropyran and bis(pinacolato)diborane using a method similar to Intermediate 2. 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.40 - 7.44 (m, 1 H), 7.34 (dd, 1 H), 7.27 (t, 1 H),

4.64 - 4.71 (m, 1 H), 3.81 - 3.88 (m, 2 H), 3.44 - 3.52 (m, 2 H), 1.94 - 2.01 (m, 2 H), 1.56 -

1.65 (m, 2 H), 1.28 (s, 12 H)

Intermediate 10: 5-bromo-3-(3-fluoro-4-tetrahydropyran-4-yloxy-phenyl)-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine.

[0221] The title compound was prepared from 2-(3-fluoro-4-tetrahydropyran-4-yloxy- phenyl)-4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolane and 5 -bromo-3-iodo- 1 -(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine using a method similar to Intermediate 3. 1H NMR (400 MHz, DMSO-dg) δ ppm 8.50 - 8.56 (m, 2 H), 8.29 (s, 1 H), 8.01 - 8.06 (m, 2 H), 7.73 (dd, 1 H), 7.55 (d, 1 H), 7.41 - 7.48 (m, 2 H), 7.29 - 7.38 (m, 1 H), 4.63 - 4.71 (m, 1 H), 3.82 - 3.91 (m, 2 H), 3.44 - 3.54 (m, 2 H), 2.35 (s, 3 H), 1.93 - 2.06 (m, 2 H), 1.58 - 1.69 (m, 2 H).

Intermediate 11 : 2- [(E)-3-chloroprop-l-enyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane.

[0222] A mixture of [(E)-3-chloroprop-l-enyl]boronic acid (509 mg, 4.22 mmol), pinacol (560 mg, 4.74 mmol) and MgS0₄ (1.091 g, 9.1 mmol) in CH₂C1₂ (20 mL) was stirred for 1 h at rt. The reaction was filtered and concentrated to provide the title compound. 1H NMR (400 MHz, DMSO-de) δ ppm 6.52 (dt, 1 H), 5.67 (dt, 1 H), 4.27 (dd, 2 H), 1.21 (s, 12 H).

Intermediate 12: 5-[5-[(E)-3-(2-hydroxyethyl(methyl)amino)prop-l-enyl]-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-tetrahydropyran-4-yloxy- benzonitrile.

[0223] 1. A mixture of 2-[(E)-3-chloroprop-l-enyl]-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (205 mg, 1.01 mmol), 2-(methylamino)ethanol (0.09 mL, 1.12 mmol) and Et₃N (0.4 mL) in THF (5 mL) was stirred for 2 d. The reaction was concentrated to provide 2-[methyl-[(E)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)allyl]amino]ethanol which was used without further purification in the next step. 2. A suspension of 5-[5-bromo-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-tetrahydropyran-4-yloxy-benzonitrile (193 mg, 0.35 mmol), 2-[methyl-[(E)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)allyl] amino] ethanol (-1.0 mmol), and PdC12(PPh₃)2 (23 mg, 0.033 mmol) in MeCN (3 mL) and 2 M Na₂C0₃ (1 mL) was heated to 80 °C for 2 h. The reaction was cooled to rt, diluted with EtOAc and washed with H₂0. The aqueous layer was extracted twice with EtOAc. The combined organics were dried (MgS0₄), filtered and concentrated. Purification by MPLC (Si0₂, EtOAc/Hexanes, 50 - 100% then to 100% CH₂Cl₂/MeOH (1 : 1)) provided the title compound. 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.53 (s, 1 H), 8.26 - 8.35 (m, 2 H), 8.14 - 8.22 (m, 1 H), 7.99 - 8.10 (m, 3 H), 7.38 - 7.48 (m, 3 H), 6.68 (d, 1 H), 6.47 - 6.56 (m, 1 H), 4.87 - 4.94 (m, 1 H), 4.37 - 4.45 (m, 1 H), 3.84 - 3.91 (m, 2 H), 3.48 - 3.59 (m, 4 H), 3.11 - 3.29 (m, 3 H), 2.34 (s, 3 H), 2.15 - 2.24 (m, 3 H), 1.96 - 2.09 (m, 2 H), 1.64 - 1.73 (m, 2 H).

Intermediate 13: 5-[5-(l-methylpyrazol-4-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridin-3-yl]-2-tetrahydropyran-4-yloxy-benzonitrile.

[0224] A suspension of 5-[5-bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2- tetrahydropyran-4-yloxy-benzonitrile (319 mg, 0.58 mmol), l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazole (129 mg, 0.62 mmol), PdC12(PPh₃)2 in MeCN (3 mL) and Na₂C0₃ (2M, 1 mL) was heated to 80 °C under N₂ overnight. The reaction was cooled to rt, diluted with EtOAc, washed with brine, dried (MgS0₄), filtered and concentrated. Purification by MPLC (Si0₂, EtOAc/hexanes, 0 - 100% then to 100% CH₂Cl₂/MeOH (1 : 1)) provided the title compound. 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.65 - 8.75 (m, 1 H), 8.34 - 8.42 (m, 1 H), 8.26 - 8.33 (m, 2 H), 8.18 - 8.25 (m, 1 H), 8.02 - 8.12 (m, 3 H), 7.81 (s, 1 H), 7.56 (s, 1 H), 7.41 - 7.50 (m, 2 H), 4.88 - 4.95 (m, 1 H), 3.88 (s, 5 H), 3.51 - 3.60 (m, 2 H), 2.34 (s, 3 H), 1.99 - 2.08 (m, 2 H), 1.64 - 1.74 (m, 2 H).

Intermediate 14: 4-(4-bromophenoxy)tetrahydropyran.

[0225] The title compound was prepared from 4-bromophenol and tetrahydropyran-4-ol using a method similar to Intermediate 8. 1H NMR (400 MHz, CDC1₃) δ ppm 7.34 - 7.40 (m, 2 H), 6.77 - 6.83 (m, 2 H), 4.44 (tt, 1 H), 3.94 - 4.01 (m, 2 H), 3.54 - 3.61 (m, 2 H), 1.97 - 2.06 (m, 2 H), 1.73 - 1.82 (m, 2 H).

Intermediate 15: 4,4,5,5-tetramethyl-2-(4-tetrahydropyran-4-yloxyphenyl)- 1,3,2-dioxaborolane.

[0226] The title compound was prepared from 4-(4-bromophenoxy)tetrahydropyran and bis(pinacolato)diborane using a method similar to Intermediate 2. 1H NMR (400 MHz, DMSO-dg) δ ppm 7.56 - 7.63 (m, 2 H), 6.94 - 7.00 (m, 2 H), 4.59 - 4.67 (m, 1 H), 3.80 - 3.87 (m, 2 H), 3.44 - 3.52 (m, 2 H), 1.90 - 2.03 (m, 2 H), 1.52 - 1.62 (m, 2 H), 1.24 - 1.30 (m, 12 H)

Intermediate 16: 5-bromo-l-(p-tolylsulfonyl)-3-(4-tetrahydropyran-4- yloxyphenyl)pyrrolo [2, 3-b] pyridine.

[0227] The title compound was prepared from 4,4,5, 5-tetramethyl-2-(4-tetrahydropyran- 4-yloxyphenyl)-l,3,2-dioxaborolane and 5-bromo-3-iodo-l-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridine using a method similar to Intermediate 3. 1H NMR (400 MHz, DMSO-^) δ ppm 8.53 (d, 1 H), 8.44 (d, 1 H), 8.19 (s, 1 H), 8.01 - 8.08 (m, 2 H), 7.67 - 7.72 (m, 2 H), 7.39 - 7.49 (m, 2 H), 7.07 - 7.13 (m, 2 H), 4.62 - 4.69 (m, 1 H), 3.81 - 3.90 (m, 2 H), 3.45 - 3.54 (m, 2 H), 2.35 (s, 3 H), 1.96 - 2.03 (m, 2 H), 1.56 - 1.65 (m, 2 H).

Intermediate 17: 2-hydroxy-5-[5-[(E)-3-morpholinoprop-l-enyl]-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]benzonitrile.

[0228] 2-(methoxymethoxy)-5-[5-[(E)-3-morpholinoprop- 1 -enyl]- 1 -(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]benzonitrile (0.44 g, 0.79 mmol) was treated with 2M HC1 in Et₂0 (6 mL) along with THF and i-PrOH to solubilize starting material. The reaction was stirred until complete then concentrated. The residue was suspended in MeOH and concentrated (twice), then suspended in CH₂C1₂ and concentrated (twice). The residue was treated with satd NaHC0₃ and extracted with CHCl₃/i-PrOH (3: 1) to provide the title compound. [M+H]⁺ 515, [M-H]^~ 513.

[0229] Other intermediates were synthesized using the methods outlined above and/or standard methods that are well known in the art using commercially available starting materials.

Preparation of Specific Example Compounds Example 6: 3-{3-[3-(Benzyloxy)-5-fluorophenyl]-lH-pyrrolo[2,3-b]pyridin-5- yl}benzonitrile:

Reagents: (a) NBS, DMF, 4h; (b) NaH, Benzenesulfonyl chloride, DMF, 2h; (c) Pd(PPh₃)₄, Na₂C0₃, Dioxane/H₂0, 90 °C, 15 h; (d) Pd₂(dba)₃, K₃P0₄, rc-Butanol, 100 °C, 8- 15 h.

[0230] Step 1 : 3-Bromo-5-chloro-lH-pyrrolo[2,3-b]pyridine. N-Bromosuccinimide (1.08 g, 6.1 mmol) was added to a solution of 5-chloro-lH-pyrrolo[2,3-¾]pyridine (0.85 g, 5.5 mmol) in DMF (25 mL) and stirred for 4 h at it. Water (100 mL) was added the mixture extracted with EtOAc (3 x 50 mL), the organics combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) afforded the desired product (1.28 g, quant.). 1H NMR (400 MHz, DMSO-^) δ ppm 12.3 (br. s), 8.30 (d, 1 H), 7.93 (d, 1H), 7.84 (s, 1H)

[0231] Step 2: l-(Benzenesulfonyl)-3-bromo-5-chloro-pyrrolo[2,3-b]pyridine. NaH (60% dispersion in oil, 0.33 g, 8.3 mmol) was added to a solution of 3-bromo-5-chloro-lH- pyrrolo[2,3-b]pyridine (1.28 g, 5.5 mmol) in DMF (25 mL) at room temperature. The reaction was stirred for 10 min. and then /?-toluenesulfonyl chloride (1.06 mL, 8.3 mmol) was added and the reaction stirred for an additional 2 h. Water (50 mL) was added, the mixture extracted with EtOAc (3 x 50 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) and recrystallization from hex/EtOAc afforded the desired product (1.45 g, 70%). 1H NMR (400 MHz, DMSO- e) δ ppm 8.50 (d, 1 H), 8.35 (s, 1 H), 8.13 (dd, 1H), 8.12 (d, 2H), 7.76 (dt, 1 H), 7.65 (t, 2 H). [0232] Step 3: l-(Benzenesulfonyl)-3-(3-benzyloxy-5-fluoro-phenyl)-5-chloro- pyrrolo[2,3-b]pyridine. A solution of l-(benzenesulfonyl)-3-bromo-5-chloro-pyrrolo[2,3- b]pyridine (1.0 g, 2.69 mmol), 2-(3-benzyloxy-5-fluoro-phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (0.97 g, 2.96 mmol) and 2 N Na₂C0₃ (3.5 mL) in dioxane (10 mL) was sparged with N₂ (g) for 5 min. Tetrakis palladium triphenylphosphine (0.30 g, 0.27 mmol) was added and the reaction mixture heated to 90 °C overnight. The reaction was cooled to rt., the layers separated and the aq. layer extracted with EtOAC (10 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) afforded the desired product (0.9 g, 68%). 1H NMR (DMSO-de) δ 8.48 (d, 1H), 8.46 (s, 1H), 8.34 (d, 1H), 8.17 (s, 1H), 8.16 (d, 2H), 7.75 (dt, 1H), 7.65 (t, 2H), 7.50 (d, 2H), 7.42 (t, 2H), 7.37 (dt, 1H), 7.28-7.24 (m, 2H), 6.94 (dt, 1H), 5.24 (s, 2H).

[0233] Step 4: 3-[3-(3-Benzyloxy-5-fluoro-phenyl)-lH-pyrrolo[2,3-b]pyridin-5- yljbenzonitrile. To a solution of l-(benzenesulfonyl)-3-(3-benzyloxy-5-fluoro-phenyl)-5- chloro-pyrrolo[2,3-b]pyridine (0.90 g, 0.183 mmol), (3-cyanophenyl)boronic acid (0.040 g, 0.274 mmol) and K₃CO₄ (0.075 g, 0.36 mmol) in butanol (5 mL) was sparged with N₂ (g) for 5 min. Pd₂(dba)₃ (0.008 g, 0.01 mmol) and X-phos (0.012 g, 0.21 mmol) were added and the reaction mixture heated to 100 °C overnight. The reaction was cooled to rt., water (3 mL) and EtOAc were added. The layers separated and the aq. layer extracted with EtOAC (2x10 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) afforded the desired product (0.01 g, 13%) 1H NMR (DMSO-de) δ 12.1 (br s, 1H), 8.63 (d, 1H), 8.48 (d, 1H), 8.34 (t, 1H), 8.16-8.13 (m, 1H), 8.06 (d, 1H), 7.84 (dt, 1H), 7.70 (t, 1H), 7.51-7.48 (m, 2H), 7.41-7.38 (m, 2H), 7.34-7.30 (m, 1H), 7.28-7.25 (m, 5H), 6.81 (dt, 1H), 5.24 (s, 2H). LC-MS [M+H]⁺ 420.1511.

[0234] Examples 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13 and 19 were prepared in a similar fashion to Example 6. In some instances removal on the sulfonyl was required via the standard protocol.

Example 16: 3-(l-Benzyl-lH-pyrazol-4-yl)-5-(3,4-dimethoxyphenyl)-lH- pyrrolo[2,3-b] pyridine:

Reagents: (a) NIS, Acetone, RT, lh; (b) NaH, TsCl, DMF, 2h; (c) Pd(PPh₃)₄,

NaHC0₃, Dioxane/H₂0, 90 °C, 8- 15 h; (d) Pd(PPh₃)₄, NaHC0₃, Dioxane/H₂0, 90 °C, 8- 15 h; (e) K₂C0₃, MeOH, 60 °C, 16 h.

[0235] Step 1 : 5-Bromo-3-iodo-lH-pyrrolo[2,3-¾]pyridine: N-Iodosuccinimide (6.75 g, 30.0 mmol) was added to a solution of 5-bromo-lH-pyrrolo[2,3-¾]pyridine (5.39 g, 27.4 mmol) in acetone (130 mL) and stirred for 1 h at rt. The resulting solid was collected by vacuum filtration and washed with acetone to afford 6.65 g (75%) of the desired product as an off-white to gray solid. 1H NMR (400 MHz, DMSO-^) δ ppm 12.4 (br. s, 1H), 8.32 (s, 1 H), 7.87 (s, 1H), 7.81 (s, 1H)

[0236] Step 2: 5-Bromo-3-iodo-l-(/?-tolylsulfonyl)pyrrolo[2,3-¾]pyridine. NaH (60% dispersion in oil, 1.0 g, 25 mmol) was added to a solution of 5-bromo-3-iodo-lH-pyrrolo[2,3- ¾]pyridine (6.97 g, 21.6 mmol) in DMF (40 mL) at room temperature. The reaction was stirred for 30 min. and then /?-toluenesulfonyl chloride (4.5 g, 23.6 mmol) was added and the reaction stirred for an additional 2 h. Water (100 mL) was added and the resulting solid collected via vacuum filtration. The solid was washed with water and dried under high vacuum overnight to afford (10.4 g, quant.) of the desired product. 1H NMR (400 MHz, DMSO-dg) δ ppm 8.52 (s, 1 H), 8.23 (s, 1 H), 7.99 - 8.04 (m, 3 H), 7.42 - 7.47 (m, 2 H), 2.35 (s, 3 H).

[0237] Step 3: 3-(l-Benzylpyrazol-4-yl)-5-bromo-l-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridine. A solution of 5-bromo-3-iodo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (1.0 g, 2.1 mmol), l-benzyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (0.63 g, 2.2 mmol) and NaHC0₃ ( 0.44 g, 5.25 mmol) in dioxane/water (5: 1, 20 mL) was sparged with N₂ (g) for 5 min. Tetrakis palladium triphenylphosphine (0.25 g, 0.21 mmol) was added and the reaction mixture heated to 90 °C overnight. The reaction was cooled to r , filtered through celite and the solvents evaporated. Purification of the residue by column chromatography (EtOAc/Hexanes) afforded the desired product (0.55 g, 52%). 1H NMR (DMSO-de) δ 8.59 (d, 2H), 8.52 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.97 (d, 2H), 7.42-7.28 (m, 7H), 7.45-7.30 (m, 7H), 5.36 (s, 2H), 2.33 (s, 3H).

[0238] Step 4: 3-(l-Benzylpyrazol-4-yl)-5-(3,4-dimethoxyphenyl)-l-(p-tolylsulfonyl) pyrrolo[2,3-b]pyridine. A solution of 3-(l-benzylpyrazol-4-yl)-5-bromo-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine (0.10 g, 0.197 mmol), (3,4-dimethoxyphenyl)boronic acid (0.054 g, 0.296 mmol) and NaHC0₃ (0.05 g, 0.59 mmol) in dioxane/water (5: 1, 6 mL) was sparged with N₂ (g) for 5 min. Tetrakispalladium triphenylphosphine (0.023 g, 0.02 mmol) was added and the reaction mixture heated to 90 °C overnight. The reaction was cooled to rt., filtered through celite and the solvents evaporated to afford the crude product.

[0239] Step 5: 3-(l-Benzyl-lH-pyrazol-4-yl)-5-(3,4-dimethoxyphenyl)-lH-pyrrolo[2,3- b]pyridine. To the crude mixture of 3-(l-benzylpyrazol-4-yl)-5-(3,4-dimethoxyphenyl)-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine (0.1 g, 0.19 mmol) in methanol (5 mL) was added K₂C0₃ (0.135 g, 0.98 mmol). The solution was heated to 60 °C for 4h. The solvent was evaporated and the material purified by column chromatography (0-100% Hexanes/EtOAc to 20% MeOH/CH₂Cl₂) to afford the desired product (0.02 g, . 1H NMR (DMSO-d₆) δ 11.7 (br s, 1H), 8.52 (d, 1H), 8.40 (s, 1H), 8.31 (d, 1H), 7.96 (s, 1H), 7.74 (d, 1H), 7.38-7.30 (m, 7H), 7.06 (d, 1H), 5.38 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H). LC-MS [M+H]⁺ 411.1815.

Alternative Procedure:

Reagents: (a) NaH, TsCl, DMF, 2h; (b) Pd₂(dba)₃, K₃P0₄, dioxane, 100 °C, 8- 15h; (c) NBS, DMF, 2h; (d) Pd₂(dba)₃, K₃P0₄, rc-butanol, 100 °C, 8-15h.

[0240] Step 1 : l-(Benzenesulfonyl)-5-chloro-pyrrolo[2,3-b]pyridine. NaH (60% dispersion in oil, 0.39 g, 9.8 mmol) was added to a solution of 5-chloro-lH-pyrrolo[2,3- b]pyridine (1.25 g, 8.17 mmol) in DMF (40 mL) at room temperature. The reaction was stirred for 15 min. and then benzenesulfonyl chloride (1.3 mL, 10.2 mmol) was added and the reaction stirred for an additional 15 h. Water (50 mL) was added, the mixture extracted with EtOAc (3 x 50 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) afforded the desired product (1.7 g, 71%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.41 (d, 1 H), 8.22 (d, 1 H), 8.11 (dd, 1H), 8.09 (d, 1H) 8.02 (d, 1H), 7.74 (dt, 1H), 7.64 (dt, 2H), 6.83 (d, 1H).

[0241] Step 2: l-(Benzenesulfonyl)-5-(3,4-dimethoxyphenyl)pyrrolo[2,3-b]pyridine:

[0242] To a solution of l-(benzenesulfonyl)-5-chloro-pyrrolo[2,3-b]pyridine (1.5 g, 5.1 mmol) and (3,4-dimethoxyphenyl)boronic acid (1.4 g, 7.6 mmol) in dioxane (25 mL) was added K₃C0₄ (2.17 g, 10.2 mmol). The reaction mixture was sparged with N₂ (g) for 5 min., Pd₂(dba)₃ (0.23 g, 0.25 mmol) and X-phos (0.25 g, 0.51 mmol) were added and the reaction mixture heated to 90 °C for 4h. The reaction was cooled to rt, water (25 mL) and EtOAc (25 mL) were added. The layers separated and the aq. layer extracted with EtOAC (2x25 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) afforded the desired product (0.9 g, 45%). 1H NMR (DMSO-de) δ 8.67 (d, IH), 8.29 (d, IH), 8.14-8.12 (m, 2H), 7.96 (d, IH), 7.74 (dt, IH), 7.64 (t, H), 7.28 (d, IH), 7.23 (dd, IH), 7.05 (d, IH), 6.86 (dt, IH), 3.84 (s, 3H), 3.79 (s, 3H).

[0243] Step 3: l-(Benzenesulfonyl)-3-bromo-5-(3,4-dimethoxyphenyl)pyrrolo[2,3- b]pyridine: N- Bromosuccinimide (0.45 g, 2.51 mmol) was added to a solution of 1- (benzenesulfonyl)-5-(3,4-dimethoxyphenyl)pyrrolo[2,3-b]pyridine (0.9 g, 2.28 mmol) in DMF (5 mL) and stirred for 1 h at rt. The resulting solid was poured into water (10 mL) and EtOAc (25 mL) added. The layers were separated and the mixture extracted with EtOAc (2 x 25 mL), the organics combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) afforded the desired product (0.5 g, 46%).

[0244] Step 4: 3-(l-Benzyl-lH-pyrazol-4-yl)-5-(3,4-dimethoxyphenyl)-lH-pyrrolo[2,3- b]pyridine. To a solution of l-(benzenesulfonyl)-3-bromo-5-(3,4- dimethoxyphenyl)pyrrolo[2,3-b]pyridine (0.19 g, 0.19 mmol) and l-benzyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (0.08 g, 0.28 mmol) in n-butanol (3 mL) was added K₃CO₄ (0.08 g, 0.38 mmol). The reaction mixture was sparged with N₂ (g) for 3 min., Pd₂(dba)₃ (0.009 g, 0.01 mmol) and X-phos (0.009 g, 0.02 mmol) were added and the reaction mixture heated to 90 °C for 15h. The reaction was cooled to rt., water (3 mL) and EtOAc (3 mL) were added. The layers separated and the aq. layer extracted with EtOAC (2x5 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc to EtOAc/ 10%MeOH) afforded the desired product. 1H NMR (DMSO- ₆) δ 11.7 (br s, IH), 8.52 (d, IH), 8.40 (s, IH), 8.31 (d, IH), 7.96 (s, IH), 7.74 (d, IH), 7.38-7.30 (m, 7H), 7.06 (d, IH), 5.38 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H). LC-MS [M+H]⁺ 411.1815.

[0245] Examples 14, 15, 16, 17, 18, 20, 21, 22, 23, 30, 31, 85, 90, 91, 92, 158, 159, 160, 178, 179, 180, 181, 182, 183, 184, 185, 186, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204 and 205 were prepared in a similar fashion to Example 16. In some instances removal on the sulfonyl was required via the standard protocol.

Example 29: 3-(l-Benzyl-lH-pyrazol-4-yl)-N-(2-methoxyphenyl)-lH- pyrrolo [2,3-b] pyridin-5-amine :

Reagents: (a) Pd₂(dba)₃, K₃PO₄, n-Butanol, 100 °C, 15 h. (b) K₂C0₃, MeOH, 60 °C, 15 h.

[0246] Step 1 : 3-(l-Benzylpyrazol-4-yl)-l-(p-tolylsulfonyl)-N-(3,4,5- trimethoxyphenyl)pyrrolo[2,3-b]pyridin-5-amine: A solution of 3-(l-benzylpyrazol-4-yl)-5- bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (0.05 g, 0.098 mmol), 3,4,5- trimethoxyaniline (0.027 g, 0.147 mmol) and K₃C0₄ (0.042 g, 0.197 mmol) in dioxane (2 mL) was sparged with N₂ (g) for 5 min. Pd₂(dba)₃ (0.009 g, 0.010 mmol) and X-phos (0.010 g, 0.019 mmol) were added and the reaction mixture heated to 100 °C overnight. The reaction was cooled to rt, water (5 mL) and EtOAc (10 mL) were added. The layers separated and the aq. layer extracted with EtOAC (2x10 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) afforded the desired product (0.03 g, 50%) 1H NMR (DMSO-d₆) δ 8.37 (d, 1H), 8.24 (s, 1H), 8.16 (d, 1H), 8.06 (s, 1H), 7.94 (d, 2H), 7.97 (s, 1H), 7.91 (d, 1H), 7.39 (d, 2H), 7.37-7.29 (m, 3H), 7.25-7.23 (m, 2H) 6.34 (s, 2H), 5.36 (s, 2H), 3.59 (s, 3H), 3.50 (s, 3H), 3.33 (s, 3H), 2.33 (s, 3H).

[0247] Step 2: 3-(l-Benzyl-lH-pyrazol-4-yl)-N-(3,4,5-trimethoxyphenyl)-lH- pyrrolo[2,3-b]pyridin-5-amine: A solution of 3-(l-benzylpyrazol-4-yl)-5-bromo-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine (0.03 g, 0.05 mmol) in methanol (3 mL) was added K₂C0₃ (0.034 g, 0.25 mmol). The solution was heated to 60 °C for 15h. The solvent was evaporated and the material purified by column chromatography (0-100% Hexanes/EtOAc to 20% MeOH/CH₂Cl₂) to afford the desired product (0.005 g, 23%) 1H NMR (DMSO-d₆) δ 11.5 (br s, 1H), 8.37 (d, 1H), 8.24 (s, 1H), 8.16 (d, 1H), 8.06 (s, 1H), 7.94 (d, 2H), 7.97 (s, 1H), 7.91 (d, 1H), 7.39 (d, 2H), 7.37-7.29 (m, 3H), 7.25-7.23 (m, 2H), 6.22 (s, 2H), 5.36 (s, 2H), 3.65 (s, 6H), 3.57 (s, 3H). LC-MS [M+H]⁺ 456.2029.

[0248] Examples 36 and 51 were prepared in similar fashion to Example 29.

Example 37: 7-(l-Benzyl-lH-pyrazol-4-yl)-2-(3,4-dimethoxyphenyl)-4H- pyrrolo[2,3-b]pyrazine:

Reagents: (a) Pd(PPh₃)₄, K₃CO₃, dioxane, H₂0, 90 °C, 6h; (b) NBS, DMF, 2h; (c) Pd(PPh₃)₄, NaHC0₃, dioxane, H₂0, 95 °C, 15h.

[0249] Step 1 : 5-(Benzenesulfonyl)-2-(3,4-dimethoxyphenyl)pyrrolo[2,3-b]pyrazine. A solution of 5-(benzenesulfonyl)-2-bromo-pyrrolo[2,3-b]pyrazine (0.55 g, 1.63 mmol), (3,4- dimethoxyphenyl)boronic acid (0.45 g, 2.44 mmol) and K₂C0₃ (0.45 g, 3.25 mmol) in dioxane/water (3: 1, 12 mL) was sparged with N₂ for 2 min. and Pd(PPh₃)₄ (0.19 g, 0.16 mmol) was added. The reaction mixture heated to 90 °C and stirred for 6h. The reaction was cooled to r , water (5 mL) and EtOAc (5 mL) were added. The layers separated and the aq. layer extracted with EtOAC (2x25 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) afforded the desired product (0.25 g, 38%) along with 2-(3,4- dimethoxyphenyl)-5H-pyrolo[2,3-b]pyrazine (0.25 g, 60%). LC-MS [M+H]⁺ 396.1.

[0250] Step 2: l-(Benzenesulfonyl)-3-bromo-5-(3,4-dimethoxyphenyl)pyrrolo[2,3- b]pyridine: N- Bromosuccinimide (0.135 g, 0.76 mmol) was added to a solution of 1- (benzenesulfonyl)-5-(3,4-dimethoxyphenyl)pyrrolo[2,3-b]pyridine (0.25 g, 0.63 mmol) in DMF (10 mL) and stirred for 1 h at rt. The resulting solid was poured into water (10 mL) and EtOAc (10 mL) added. The layers were separated and the mixture extracted with EtOAc (3 x 10 mL), the organics combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) afforded the desired product (0.2 g, 58%). 1H NMR (DMSO-de) δ 9.11 (s, 1H), 8.63 (s, 1H), 8.16 (dd, H), 8.40 (s, 1H), 8.31 (d, 1H), 7.96 (s, 1H), 7.74 (d, 1H), 7.81.-7.73 (m, 2H), 7.72-7.65 (m, 3H), 7.11 (d, 1H), 3.86 (s, 3H), 3.83 (s, 3H). LC-MS [M+H]⁺ 474.1, 476.1.

[0251] Step 3: 7-(l-Benzyl-lH-pyrazol-4-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrrolo[2,3- b]pyrazine. To a solution of l-(benzenesulfonyl)-3-bromo-5-(3,4- dimethoxyphenyl)pyrrolo[2,3-b]pyridine (0.05 g, 0.15 mmol), l-benzyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (0.043 g, 0.22 mmol) and NaHC0₃ (0.025 g, 0.30 mmol). in dioxane/water (3: 1, 4 mL) was added Pd(PPh₃)4 (0.017 g, 0.015 mmol) and the reaction mixture heated to 95 °C for 15h. The reaction was cooled to rt., water (5 mL) and EtOAc (10 mL) were added. The layers separated and the aq. layer extracted with EtOAC (2x10 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc to EtOAc/ 20%MeOH) afforded the desired product (0.007 g, 16%). 1H NMR (DMSO-d₆) δ 12. (s, 1H), (8.87, s, 1H), 8.43 (s, 1H), 8.12 (dd, 1H), 8.11 (s, 1H), 7.79 (d, 1H), 7.60 (dd, 1H), 7.39-7.35 (m, 2H), 7.32-7.30 (m, 3H), 7.09 (d, 1H), 5.43 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H).

Example 38: 5-[2-(3,4-Dimethoxyphenyl)-4H-pyrrolo[2,3-b]pyrazin-7-yl]-2- methoxybenzonitrile:

Reagents: (a) Pd(PPh₃)₄, NaHC0₃, dioxane, H₂0, 95 °C, 16h;

[0252] Step 1 : 5-[2-(3,4-Dimethoxyphenyl)-4H-pyrrolo[2,3-b]pyrazin-7-yl]-2- methoxybenzonitrile. A solution of 7-bromo-2-(3,4-dimethoxyphenyl)-5H-pyrrolo[2,3- b]pyrazine (0.04 g, 0.12 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile (0.045 g, 0.18 mmol) and NaHC0₃ (0.025 g, 0.30 mmol) in dioxane/water (3:1, 12 mL) was sparged with N₂ for 2 min. and Pd(PPh₃)₄ (0.014 g, 0.012 mmol) was added. The reaction mixture heated to 95 °C for 15h. The reaction was cooled to rt., water (5 mL) and EtOAc (5 mL) were added. The layers separated and the aq. layer extracted with EtOAC (2 x 25 mL). The organic layers were combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc to EtOAc/20% MeOH) and recrystallization from hex/EtOAc afforded the desired product (0.009 g, 20%). 1H NMR (DMSO- ₆) δ 12.3 (s, IH), 8.94 (s, IH), 8.81 (d, IH), 8.61 (dd, IH), 8.50 (d, IH), 7.87 (d, IH), 7.76 (d, IH), 7.38 (d, IH), 7.12 (d, IH), 3.97 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H). LC-MS [M+H]⁺ 387.14504.

[0253] Examples 28, 34 and 35 was prepared in a similar fashion to Example 38.

Example 40: 5-(3,4-Dimethoxyphenyl)-3-[l-(tetrahydro-2H-pyran-4-ylmethyl)- lH-pyrazol-4-yl]-lH-pyrrolo [2,3-b]pyridine:

Reagents: ((a) Pd(PPh₃)₄, NaHC0₃, dioxane, H₂0, 95 °C, 16h; (b) Pd(PPh₃)₄,

NaHC0₃, dioxane, H₂0, 95 °C, 16h; (c) HC1, MeOH, Et₂0; (d) NaH, DMF, 4h; (c) Pd(PPh₃)₄, NaHC0₃, Dioxane/H₂0, 90 °C, 8- 15 h;(e) K₂C0₃, MeOH, 60 °C, 16 h.

[0254] Step 1 : l-(Benzenesulfonyl)-5-bromo-3-(l-tetrahydropyran-2-ylpyrazol-4- yl)pyrrolo[2,3-b]pyridine. A solution of l-(benzenesulfonyl)-5-bromo-3-iodo-pyrrolo[2,3- b]pyridine (2.0 g, 4.3 mmol), l-tetrahydropyran-2-yl-4-(4,4, 5,5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)pyrazole (1.8 g, 6.4 mmol) and NaHC0₃ ( 0.72 g, 8.6 mmol) in dioxane/water (3: 1, 32 mL) was sparged with N₂ (g) for 5 min. Tetrakis palladium triphenylphosphine (0.05 g, 0.43 mmol) was added and the reaction mixture heated to 90 °C overnight. The reaction was cooled to rt, water (5 mL) and EtOAc (25 mL) were added, the layers separated and the aq. layer extracted with EtOAc (2 x 50 mL). The organic layers were combined, dried, filtered and evaporated. Purification of the residue by column chromatography (EtOAc/Hexanes) afforded the desired product (1.5 g, 71%). 1H NMR (DMSO-de) δ 8.65 (d, IH), 8.62 (s, IH), 8.52 (d, IH), 8.34 (s, IH), 8.15 (d, IH), 8.11-8.08 (m, 2H), 7.73 (dt, IH), 7.63 (dt, 2H), 5.43 (dd, IH), 3.96 (d, IH), 3.68-3.62 (m, IH), 2.33- 2.16 (m, IH), 1.95 (t, 2H), 1.76-1.65 (m, IH), 1.59-1.53 (m, 2H). LC-MS [M+H]⁺ 489.1.

[0255] Step 2: l-(Benzenesulfonyl)-5-(3,4-dimethoxyphenyl)-3-(l-tetrahydropyran-2- ylpyrazol-4-yl)pyrrolo[2,3-b]pyridine. A solution of l-(benzenesulfonyl)-5-bromo-3-(l- tetrahydropyran-2-ylpyrazol-4-yl)pyrrolo[2,3-b]pyridine (0.25 g, 0.51 mmol), (3,4- dimethoxyphenyl)boronic acid (0.14 g, 0.77 mmol) and NaHC0₃ (0.90 g, 1.03 mmol) in dioxane/water (3: 1, 20 mL) was sparged with N₂ (g) for 5 min. Tetrakis palladium triphenylphosphine (0.057 g, 0.05 mmol) was added and the reaction mixture heated to 90-95 °C overnight. The reaction was cooled to rt., water (5 mL) and EtOAc (25 mL) were added, the layers separated and the aq. layer extracted with EtOAc (2 x 50 mL). The organic layers were combined, dried, filtered and evaporated. Purification of the residue by column chromatography (EtOAc/Hexanes) afforded the desired product (0.2 g, 72%). 1H NMR (DMSO- e) δ 8.68 (d, IH), 8.63 (s, IH), 8.42 (d, IH), 8.28 (s, H), 8.11-8.08 (m, 2H), 7.72 (dt, IH), 7.63 (dt, 2H), 7.33-7.30 (m, 2H), 7.07 (d, IH), 5.45 (dd, IH), 3.96 (d, IH), 3.86 (s, 3H), 3.80 (s, 3H), 3.68-3.62 (m, IH), 2.33-2.16 (m, IH), 2.01-1.92 (m, 2H), 1.76-1.65 (m, IH), 1.59-1.53 (m, 2H). LC-MS [M+H]⁺ 545.3.

[0256] Step 3: l-(Benzenesulfonyl)-5-(3,4-dimethoxyphenyl)-3-(lH-pyrazol-4- yl)pyrrolo[2,3-b]pyridine. To a solution of l-(benzenesulfonyl)-5-(3,4-dimethoxyphenyl)-3- (l-tetrahydropyran-2-ylpyrazol-4-yl)pyrrolo[2,3-b]pyridine (1.0 g, 1.8 mmol) in MeOH (100 mL) was added HC1 in Et₂0 (2N, 10 mL). The reaction was stirred for 4 h. Et₂0 was added and the resulting solid collected via vacuum filtration to afford 0.45 g of the desired product as the HC1 salt. 1H NMR (400 MHz, DMSO- ₆) δ ppm 8.69 (d, IH), 8.40 (d, IH), 8.22 (s, H), 8.12 (dd, 2H), 7.72 (dt, IH), 7.63 (dt, 2H), 7.35-7.31 (m, 2H), 7.06 (d, IH), 3.86 (s, 3H), 3.80 (s, 3H). LC-MS [M+H]⁺ 368.3.

[0257] Step 4: l-(Benzenesulfonyl)-5-(3,4-dimethoxyphenyl)-3-[l-(tetrahydropyran-4- ylmethyl)pyrazol-4-yl]pyrrolo[2,3-b]pyridine. To a solution of l-(benzenesulfonyl)-5-(3,4- dimethoxyphenyl)-3-(lH-pyrazol-4-yl)pyrrolo[2,3-b]pyridine (0.05 g, 0.10 mmol), in DMF (2 mL) was added NaH (60% dispersion in oil, 0.006 g, 0.16 mmol). The reaction mixture was stirred for 5 min., bromomethylcyclohexane (0.040 g, 0.21 mmol) added and stirred an additional 4h at rt. A sat. NaCl solution (2 mL) was added the solution extracted with EtOAc (3 x 10 mL). The organic layers were combined, dried, filtered and evaporated. Purification of the residue by column chromatography (EtOAc/Hexanes) afforded the desired product (0.03 g, 50%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.69 (d, 1H), 8.47 (s, 1H), 8.38 (d, 1H), 8.22 (s, 1H), 8.14-8.12 (m, 3H) 7.75-7.71 (m, 1H), 7.63 (dt, 2H), 7.34-7.29 (m, 2H), 7.07 (d, 1H), 3.89-3.81 (m, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.25 (dt, 2H), 2.17-2.06 (m, 1H), 1.46-1.39 (m, 2H), 1.31-1.23 (m, 2H).

[0258] Step 5: 5-(3,4-Dimethoxyphenyl)-3-[l-(tetrahydro-2H-pyran-4-ylmethyl)-lH- pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridine. To a solution of l-(benzenesulfonyl)-5-(3,4- dimethoxyphenyl)-3-[l-(tetrahydropyran-4-ylmethyl)pyrazol-4-yl]pyrrolo[2,3-b]pyridine (0.03 g, 0.054 mmol) in methanol (3 mL) was added K₂C0₃ (0.037 g, 0.27 mmol). The solution was heated to 66 °C for 4h. The solvent was evaporated and the material purified by column chromatography (0-100% Hexanes/EtOAc to 20% MeOH/CH₂Cl₂) and recrystallization from hex/EtOAc afforded the desired product (0.01 g, 44%). 1H NMR (DMSO-de) δ 11.7 (br s, 1H), 8.51 (d, 1H), 8.30 (d, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 7.71 (d, 1H), 7.32-7.26 (m, 2H), 7.07 (d, 1H), 4.05 (d, 2H), 3.88 (s, 3H), 3.86-3.81 (m, 2H), 3.81 (s, 3H), 3.32-3.23 (m, 2H), 2.18-2.05 (m, 1H), 1.48-1.38 (m, 2H) 1.33-1.23 (m, 2H). LC-MS [M+H]⁺ 419.2097.

[0259] Examples 32, 33, 34, 35, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 52, 53, 54, 56, 57 and 55 were prepared in similar fashion to Example 40.

Example 88: 5-[5-(3-Methoxyazetidine-l-carbonyl)-lH-pyrrolo [2,3-b]pyridin-3- yl]-2-tetrahydropyran-4-yloxy-benzonitrile:

Reagents: (a) Pd(PPh₃)₄, NaHC0₃, ACN/H₂0, 90 °C, 15 h; (b) CO (g), TEA, MeOH, Xanthphos, Pd(OAc)₂, 70 °C, 15h; (c) LiOH, THF, H₂0; (d) HATU, DMF, DIPEA.

[0260] Step 1 : 5-[5-Bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2- tetrahydropyran-4-yloxy-benzonitrile: A solution of 5-bromo-3-iodo-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine (1.4 g, 2.93 mmol), 2-tetrahydropyran-4-yloxy-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (0.61 g, 3.2 mmol) and NaHC0₃ (0.75 g, 8.80 mmol) in ACN/water (3: 1, 20 mL) was sparged with N₂ (g) for 2 min. Tetrakispalladium triphenylphosphine (0.25 g, 0.21 mmol) was added and the reaction mixture heated to 90 °C overnight. The reaction was cooled, EtOAc (25 mL) added, the layers separated and the aq. layer extracted with EtOAc (2 x 25 mL). The organic layers were combined, dried over Na₂S0₄, filtered and evaporated. Purification by column chromatography (0-10% MeOH, CH₂C1₂) afforded the title compound. 1H NMR (DMSO- ₆) δ 8.59 (d, 1H), 8.53 (d, 1H), 8.37 (s, 1H), 8.21 (d, 1H), 8.06 (dd, 1H), 8.03 (d, 2H), 7.46-7.43 (m, 3H), 4.94-4.86 (m, 1H), 3.89-3.85 (m, 2H), 3.58-3.53 (m, 2H), 2.35 (s, 3H), 2.04-1.99 (m, 2H), 1.72-1.64 (m, 2H). [0261] Step 2: Methyl 3-(3-cyano-4-tetrahydropyran-4-yloxy-phenyl)-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine-5-carboxylate. A solution of 5-[5-bromo-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-tetrahydropyran-4-yloxy-benzonitrile (0.025 g, 0.45 mmol) in TEA (2 mL) and MeOH (0.1 mL) was sparged with N₂ (g) for 2 min. Xanthphos (0.026 g, 0.045 mmol) and PdOAc2 (0.005 g, 0.022 mmol) were added and the system was flushed with CO (g) for 2 min. A ballon filled with CO was attached and the reaction mixture stirred @ 70 °C overnight. The solvent was evaporated and purification by column chromatography affored the title compound (0.10 g, 41%). 1H NMR (400 MHz, DMSO- e) δ ppm δ 8.96 (d, 1H), 8.65 (d, 1H), 8.44 (s, 1H), 8.23 (d, 1H), 8.08 (d, 2H), 8.05 (dd, 1H), 7.51 (d, 1H), 7.45 (d, 2H), 4.94-4.86 (m, 1H), 3.89-3.85 (m, 2H), 3.58-3.53 (m, 2H), 2.35 (s, 3H), 2.04-1.99 (m, 2H), 1.72-1.64 (m, 2H). LC-MS [M+H]⁺ 532.2.

[0262] Step 3: 3-(3-Cyano-4-tetrahydropyran-4-yloxy-phenyl)-lH-pyrrolo[2,3- b]pyridine-5-carboxylic acid. To a solution of methyl 3-(3-cyano-4-tetrahydropyran-4-yloxy- phenyl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine-5-carboxylate (0.1 g, 0.19 mmol) in THF/Water (2: 1, 6 mL) was added LiOH monohydrate (0.40 g, 0.94 mmol). The reaction mixture heated to 70 °C and stirred overnight. The reaction was cooled and the solvent evaporated. Purification of the residue by reverse phase column chromatography afforded the title compound (0.068 g, 70%). 1H NMR (DMSO- ₆) δ 13.0 (s, 1H), 12.4 (s, 1H), 8.50 (s, 1H), 8.71 (s, 1H), 8.07-8.05 (m, 2H), 7.99 (dd, 1H), 7.48 (d, 1H), 4.89-4.82 (m, 1H), 3.91- 3.86 (m, 2H), 3.58-3.52 (m, 2H), 2.08-2.00 (m, 2H), 1.72-1.64.

[0263] Step 4: 5-[5-(3-Methoxyazetidine-l-carbonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2- tetrahydropyran-4-yloxy-benzonitrile. The standard method D HATU Coupling with 3-(3- cyano-4-tetrahydropyran-4-yloxy-phenyl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylic acid (0.02 g, 0.055 mmol) and 3-methoxyazetidine hydrochloride (0.010 g, 0.026 mmol) was utilized and yielded the title compound (5 mg, 21%). 1H NMR (DMSO- ₆) δ 12.3 (s, 1H), 8.55 (s, 1H), 8.45 (s, 1H), 8.05 (dd, 2H), 7.99 (dd, 1H), 7.45 (d, 1H), 4.90-4.82 (m, 1H), 4.56-4.50 (br s, 1H), 4.30-4.20 (m, 4H), 3.91-3.85 (m, 2H), 3.58-3.52 (m, 2H), 3.22 (s, 3H), 2.07-1.99 (m, 2H), 1.74-1.64 (m, 2H). LC-MS [M+H]⁺ 433.1872.

[0264] Example 87 and 89 were prepared in similar fashion to 88.

Example 93 : 2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-(5-{l-[2-

(morpholin-4-yl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridin-3- yl)benzonitrile:

Reagents: (a) TFA CH₂C1₂, rt., 4 h; (b) HATU, DMF, DIPEA; (c) Pd(PPh₃)₄,

NaHCOs, ACN/H₂0, 90 °C, 15 h; (d) K₂C0₃, MeOH, 60 °C, 16 h.

[0265] Step 1 : 5-[5-Bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-(4- piperidyloxy)benzonitrile: The standard method B Boc Deprotection with 5-tert-butyl-4-[4- [5-bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-cyano-phenoxy]piperidine-l- carboxylate (1.0 g, 1.53 mmol) was utilized to afford the title compound (0.8 g, 95%). 1H NMR (DMSO-dg) δ 8.59 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.25 (d, 1H), 8.11 (d, 1H), 8.03 (d, 2H), 7.45-7.43 (m, 3H), 5.00-4.92 (m, 1H), 3.54-3.32 (m, 2H), 3.28-3.17 (m, 2H), 2.35 (s, 3H), 2.18-2.10 (m, 2H), 1.98-1.88 (m, 2H).

[0266] Step 2: 5-[5-Bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-[[l-[(2S)-2- hydroxypropanoyl]-4-piperidyl]oxy]benzonitrile. The standard method D HATU Coupling with 5-[5-bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-(4- piperidyloxy)benzonitrile (0.9 g, 1.63 mmol) was utilized to afford the title compound (0.8 g, 78% ). 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (s, 1H), 8.54 (s, 1H), 8.38 (s, 1H), 8.22 (d, 1H), 8.08 (d, 1H), 8.03 (d, 2H), 7.47-7.43 (m, 3H), 5.00-4.92 (m, 2H), 4.68 (quint., 1H), 3.82-3.63 (m, 2H), 3.59-3.40 (m, 2H), 2.35 (s, 3H), 2.04-1.90 (m, 2H), 1.79-1.60 (m, 2H), 1.20 (d, 3H).

[0267] Step 3: 2-[[l-[(2S)-2-Hydroxypropanoyl]-4-piperidyl]oxy]-5-[5-[l-(2- morpholinoethyl)pyrazol-4-yl]- 1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]benzonitrile: A solution of 5-[5-Bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-[[l-[(2S)-2- hydroxypropanoyl]-4-piperidyl]oxy]benzonitrile (0.075 g, 0.12 mmol), 4-[2-[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]ethyl]morpholine (0.055 g, 0.18 mmol) and NaHC0₃ (0.03 g, 0.36 mmol) in Dioxane/Water (3: 1, 3 mL) was sparged with N₂ (g) for 2 min. Tetrakispalladium triphenylphosphine (0.013 g, 0.012 mmol) was added and the reaction mixture heated to 90-95 °C overnight. The reaction mixture was filtered through celite and the solvent removed. Purification by column chromatography (0-20% MeOH/CH₂Cl₂) afforded the title compound (0.05 g, 57%). 1H NMR (DMSO-d₆) δ 8.69 (s, IH), 8.36 (s, IH), 8.35 (s, IH), 8.28 (s, IH), 8.23 (d, IH), 8.11 (d, IH), 8.05-8.03 (m, 3H), 7.48 (d, IH), 7.43 (d, 2H), 4.99-4.95 (m, 2H), 4.47 (quint, IH), 4.25 (t, 2H), 3.83-3.65 (m, 2H), 3.56-3.45 (m, 6H), 2.73 (t, 2H), 2.41 (s, 4H), 2.34 (s, 3H), 2.06-1.91 (m, 2H), 1.80-1.61 (m, 2H), 1.20 (d, 3H).

[0268] Step 4: 2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-(5-{l-[2- (morpholin-4-yl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile. The standard method G Desulphonylation with 2-[[l-[(2S)-2-hydroxypropanoyl]-4- piperidyl]oxy]-5-[5-[ 1 -(2-morpholinoethyl)pyrazol-4-yl]- 1 -(p-tolylsulfonyl)pyrrolo[2,3- b]pyridin-3-yl]benzonitrile (0.05 g, 0.06 mmol) and K₂C0₃ (0.05 g, 0.30 mmol) was utilized and yielded the title compound (25 mg, 63%). 1H NMR (DMSO-d₆) δ 12.0 (s, IH), 8.54 (d, IH), 8.37 (s, IH), 8.30 (s, IH), 8.08 (s, IH), 8.06 (d, IH), 8.00 (s, IH), 7.93 (s, 2H), 7.43 (d, IH), 4.98-4.82 (m, 2H), 4.47 (quint, IH), 4.26 (t, 2H), 3.83-3.65 (m, 2H), 3.51-3.48 (m, 6H), 2.76 (t, 2H), 2.43 (s, 4H), 2.06-1.91 (m, 2H), 1.80-1.61 (m, 2H), 1.20 (d, 3H). LC-MS [M+H]⁺ 570.2825.

Example 99: 2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-[5-(l,2,3,6- tetrahydropyridin-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile:

Reagents: (a) Pd(PPh₃)₄, NaHC0₃, ACN/H₂0, 90 °C, 15 h; (b) K₂C0₃, MeOH, 60 °C, 16 h; (c) TFA CH₂C1₂, rt, 4 h;

[0269] Step 1 : tert-Butyl 4-[3-[3-cyano-4-[[l-[(2S)-2-hydroxypropanoyl]-4- piperidyl]oxy]phenyl]-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-5-yl]-3,6-dihydro-2H- pyridine-l-carboxylate: A solution of 5-[5-bromo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-

3- yl]-2-[[l-[(2S)-2-hydroxypropanoyl]-4-piperidyl]oxy]benzonitrile (0.75 g, 0.115 mmol), tert-butyl 4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)-3 ,6-dihydro-2H-pyridine- 1 - carboxylate (0.055 g, 0.17 mmol) and NaHC0₃ (0.045 g, 0.52 mmol) in Dioxane/Water (5: 1, 6 mL) was sparged with N₂ (g) for 2 min. Tetrakispalladium triphenylphosphine (0.007 g, 0.006 mmol) was added and the reaction mixture heated to 90 °C overnight. The solvent was evaporated and the reaction mixture was used without purification.

[0270] Step 2: tert-Butyl 4-{3-[3-cyano-4-({l-[(2S)-2-hydroxypropanoyl]piperidin-4- yl}oxy)phenyl]-lH-pyrrolo[2,3-b]pyridin-5-yl}-3,6-dihydropyridine-l(2H)-carboxylate. The standard method G Desulphonylation with crude reaction mixture of tert-butyl 4-[3-[3-cyano-

4- [[ 1 -[(2S)-2-hydroxypropanoyl]-4-piperidyl]oxy]phenyl]- 1 -(p-tolylsulfonyl)pyrrolo[2,3- b]pyridin-5-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (assumed 0.083 g, 0.115 mmol) and K₂C0₃ (0.080 g, 0.575 mmol) was utilized and yielded the title compound (0.058 g, 88%). 1H NMR (DMSO-de) δ 1H NMR (DMSO-d₆) δ 12.0 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 8.03 (d, 1H), 7.92 (d, 1H), 7.42 (d, 1H), 6.23-6.16 (m, 1H), 4.96 (d, 1H), 4.96-4.89 (m, 1H), 4.49-4.45 (m, 1H), 4.03 (s, 2H), 3.83-3.65 (m, 2H), 3.61-3.50 (m, 4H), 2.60 (m, 2H), 2.06-1.90 (m, 2H), 1.80-1.61 (m, 2H), 1.44 (s, 9H), 1.20 (d, 3H). LC-MS [M+H]⁺ 572.2801.

[0271] Step 3: 2-[[l-[(2S)-2-Hydroxypropanoyl]-4-piperidyl]oxy]-5-[5-[l-(2- morpholinoethyl)pyrazol-4-yl] - 1 -(p-to

The standard method B Boc Deprotection with tert-butyl 4-{3-[3-cyano-4-({l-[(2S)-2- hydroxypropanoyl]piperidin-4-yl}oxy)phenyl]-lH-pyrrolo[2,3-b]pyridin-5-yl}-3,6- dihydropyridine-l(2H)-carboxylate (0.025 g, 0. mmol), 4-[2-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazol-l-yl]ethyl]morpholine (0.055 g, 0.043 mmol) was utilized. Purification by reverse phase column chromatography (0-20% MeOH/CH₂Cl₂) afforded the title compound (0.05 g, 24%). 1H NMR (DMSO-d₆) δ 1H NMR (DMSO-d₆) δ 12.1 (s, 1H), 8.87 (br s, 2H), 8.45 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 8.02 (d, 1H), 7.98 (s, 1H), 7.44 (d, 1H), 6.29 (s, 1H), 4.96-4.89 (m, 2H), 4.49-4.45 (m, 1H), 3.81-3.65 (m, H), 3.61-3.50 (m, 2H), 2.83 (s, 2H), 2.06-1.90 (m, 2H), 1.80-1.61 (m, 2H), 1.20 (d, 3H). LC-MS [M+H]⁺ 472.2325.

[0272] Examples 206, 207, 208, 209 and 210 were prepared in a similar fashion to Example 99.

Example 105: 2-(Cyclopropylmethoxy)-5-{5-[(lE)-3-(morpholin-4-yl)prop-l-en- l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile.

[0273] 2-(cyclopropylmethoxy)-5-[5-[(E)-3-morpholinoprop-l-enyl]-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]benzonitrile was dissolved in MeOH and treated with excess K₂CO₃ overnight. The reaction was diluted with EtOAc, washed with brine, dried (MgS0₄), filtered and concentrated. Purification by MPLC (Si0₂, EtOAc/Hexanes, 0 - 100%, then EtOAc - CH₂Cl₂/MeOH (1 : 1), 0 - 100%) provided the title compound. 1H NMR (400 MHz, DMSO-dg) δ ppm 11.96 (s, 1 H), 8.37 (d, 2 H), 8.01 - 8.09 (m, 2 H), 7.92 (s, 1 H), 7.28 (d, 1 H), 6.70 (d, 1 H), 6.38 - 6.46 (m, 1 H), 4.05 (d, 2 H), 3.54 - 3.63 (m, 4 H), 3.12 (d, 2 H), 2.37 - 2.46 (m, 4 H), 1.27 - 1.34 (m, 1 H), 0.60 - 0.66 (m, 2 H), 0.38 - 0.44 (m, 2 H). TOF LC-MS [M+H]⁺ 415.2180.

[0274] Examples 136, 137, 138, 139, 140, 148, 149, 155, 156, 157, 168, 169, 170, 171, 172, 176, 177, 193 andl94 were made in a similar fashion to Example 105.

Example 106: 2-{[l-(Hydroxyacetyl)piperidin-4-yl]oxy}-5-{5-[(lE)-3- (morpholin-4-yl)prop-l-en-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile.

[0275] 1. 5-[5-[(E)-3-morpholinoprop-l-enyl]-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin- 3-yl]-2-(4-piperidyloxy)benzonitrile was treated with HATU and glycolic acid using standard method D to provide 2-[[l-(2-hydroxyacetyl)-4-piperidyl]oxy]-5-[5-[(E)-3-morpholinoprop- l-enyl]-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]benzonitrile, which was used in the next step without purification. 2. A solution of 2-[[l-(2-hydroxyacetyl)-4-piperidyl]oxy]-5-[5- [(E)-3-morpholinoprop- 1 -enyl]- 1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]benzonitrile in MeOH/CH₂Cl₂ (2: 1) was treated with excess K₂CO₃ and stirred for 3 h. The reaction was diluted with EtOAc, washed with ¾0, dried (MgSC^), filtered and concentrated. Purification by 2 MPLC columns (Si0₂, CH₂Cl₂/MeOH, 0 - 50%) provided the title compound. 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.97 (br. s., 1 H), 8.32 - 8.44 (m, 2 H), 8.07 (s, 1 H), 8.01 - 8.06 (m, 1 H), 7.93 (s, 1 H), 7.42 (d, 1 H), 6.71 (d, 1 H), 6.39 - 6.47 (m, 1 H), 4.92 (s, 1 H), 4.58 (t, 1 H), 4.06 - 4.16 (m, 3 H), 3.53 - 3.62 (m, 5 H), 3.08 - 3.19 (m, 4 H), 2.36 - 2.45 (m, 4 H), 1.90 - 2.02 (m, 2 H), 1.66 - 1.77 (m, 2 H). TOF LC/MS [M+H]⁺ 502.2436.

[0276] Examples 106, 107, 108, 111, 112, 113, 114, 119 and 120 were made using a method similar to Example 106.

Example 128: 2-(2-Cyano-4-{5-[(lE)-3-(morpholin-4-yl)prop-l-en-l-yl]-lH- pyrrolo[2,3-b]pyridin-3-yl}phenoxy)acetamide.

[0277] A mixture of 2-hydroxy-5-[5-[(E)-3-morpholinoprop-l-enyl]-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]benzonitrile (0.185 mmol) in DMF (3 mL) was treated with 2-bromoacetamide (1 eq) and K₂CO₃ (2 eq) and heated to 60 °C for 16 h. The reaction was cooled to rt. MeOH (1 mL), acetone (1 mL) and 50% KOH (0.5 mL) were added and the reaction stirred at rt for 2 h. CH₂CI₂ was then added and the layers separated. The organics were concentrated and purified by MPLC (Si0₂, CH₂Cl₂/MeOH, 0 - 20% (w/ 0.1% NH₄OH)). A second MPLC column (Si0₂, EtOAc - CH₂Cl₂/MeOH (1 : 1), 0 - 100%) provided the title compound. 1H NMR (MeOH-d₄) δ 8.42 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.76 (d, 1H), 7.66 (s, 1H), 7.49 (d, 1H), 6.81 (d,lH), 6.41-6.34 (m, 1H), 3.79-3.68 (m, 4H), 3.35 (s, 2H), 3.28 (d, 2H), 2.67-2.61 (m, 4H). TOF LC-MS [M+H]⁺ 418.1894.

[0278] Examples 129 and 130 were made using a method similar to Example 128.

Example 146: (2E)-3-{3-[3-Cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH- pyrrolo[2,3-b]pyridin-5-yl}prop-2-enamide:

Reagents: (a) Pd(OAc)₂, P(o-Tolyl)₃,DMF, 90 °C, 15h; (b) LiOH, THF, Water 60 °C, 15h; (c) LiOH, THF, H₂0; (d) HATU, DMF, DIPEA, NH₃ (g).

[0279] Step 1 : Ethyl (E)-3-[3-(3-cyano-4-tetrahydropyran-4-yloxy-phenyl)-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-5-yl]prop-2-enoate: A solution of 5-[5-Bromo-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-tetrahydropyran-4-yloxy-benzonitrile (0.5 g, 0.91 mmol), ethyl acrylate (0.2 mL, 1.36 mmol), P(-o-tolyl)₃ (0.055 g, 0.018 mmol) and Pd(OAc)₂ in DMF (10 mL) was sparged with N₂ (g) for 2 min. and sealed in a vial. The reaction mixture ws heated to 90 °C and stirred overnight. The reaction was cooled and the solvent removed. Purification by column chromatography (hex/EtOAc) afforded the title compound (0.35 g, 67%). 1H NMR (DMSO- ₆) δ 8.78 (s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.18-8.03 (m, 3H), 7.83 (d, 1H), 7.45-7.41 (m, 3H), 6.97 (s, 1H), 4.94-4.86 (m, 1H), 4.23 (q, 2H), 3.89-3.85 (m, 2H), 3.58-3.53 (m, 2H), 2.36 (s, 3H), 2.04-1.99 (m, 2H), 1.72-1.64 (m, 2H), 1.24 (t, 3H).

[0280] Step 2: (E)-3-[3-(3-Cyano-4-tetrahydropyran-4-yloxy-phenyl)-lH-pyrrolo[2,3- b]pyridin-5-yl]prop-2-enoic acid. Standard method C Ester Hydrolysis with ethyl (E)-3-[3-(3- cyano-4-tetrahydropyran-4-yloxy-phenyl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-5-yl]prop- 2-enoate (0.125 g, 0.22 mmol) and LiOH (0.05 g, 2.2 mmol) was utilized. Purification by reverse phase column chromatography and afforded the title compound as the TFA salt (0.12 g, quant.). 1H NMR (400 MHz, DMSO- ₆) δ ppm δ 12.3 (s, 1H), 12.2 (s, 1H), 8.68 (s, 1H), 8.61 (s, 1H), 8.12 (s, 1H), 8.07-7.94 (m, 2H), 7.80 (d, 1H), 7.41 (d, 1H), 6.73 (s, 1H), 4.92- 4.83 (m, 1H), 3.90-3.84 (m, 2H), 3.58-3.53 (m, 2H) 2.04-1.99 (m, 2H), 1.72-1.65 (m, 2H).

[0281] Step 3: 3(2E)-3-{3-[3-Cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH- pyrrolo[2,3-b]pyridin-5-yl}prop-2-enamide: A solution of (E)-3-[3-(3-Cyano-4- tetrahydropyran-4-yloxy-phenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]prop-2-enoic acid (0.03 g, 0.06 mmol), DIPEA (0.03 mL, 0.17 mmol) and HATU (0.03 g, 0.075 mmol) in DMF (2 mL) was sparged with N₂ (g) for 3 min. The reaction mixture was sealed and stirred at rt overnight. The solvent was evaporated and the residue purified by reverse phase column chromatography to afford the title compound (0.010 g, 33%). 1H NMR (DMSO-d₆) δ 12.1 (s, 1H), 8.50 (d, 2H), 8.09 (d, 1H), 8.02 (dd, 1H), 7.97 (d, 1H), 7.62 (d, 1H), 7.50 (br s, 1H), 7.42 (d, 1H), 7.08 (br s, 1H), 6.71 (d, 1H), 4.90-4.82 (m, 1H), 3.91-3.86 (m, 2H), 3.58-3.53 (m, 2H), 2.07-1.99 (m, 2H), 1.73-1.64 (m, 2H). LC-MS [M+H]⁺ 389.1596.

[0282] Examples 143, 144 and 145 were prepared in similar fashion to Example 146.

Example 157: 3-[3-Fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-(l- methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b] pyridine.

[0283] A suspension of 5-bromo-3-(3-fluoro-4-tetrahydropyran-4-yloxy-phenyl)-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine, l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazole, PdCl₂(PPh₃)₂ and MeCN/ 2 N Na₂C0₃ (1 :1) was heated it 150 °C in the microwave for 10 min. The reaction was cooled to rt, diluted with EtOAc, washed with brine, dried (MgS0₄), filtered and concentrated. Purification by MPLC (Si0₂, EtOAc/Hexanes, 0 - 100% then EtOAc - CH₂Cl₂/MeOH (1 : 1), 0 - 100%) provided the title compound. 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.90 (d, 1 H), 8.52 (d, 1 H), 8.34 (d, 1 H), 8.26 (s, 1 H), 7.98 (s, 1 H), 7.85 (d, 1 H), 7.61 (dd, 1 H), 7.51 - 7.56 (m, 1 H), 7.26 - 7.35 (m, 1 H), 4.56 - 4.63 (m, 1 H), 3.85 - 3.91 (m, 5 H), 3.45 - 3.53 (m, 2 H), 1.96 - 2.04 (m, 2 H), 1.60 - 1.70 (m, 2 H). TOF LC/MS [M+H]⁺ 393.1764. Example 166: l-{4-[3-(l-Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]piperazin-l-yl}-2-hydroxyethanone:

Reagents: (a) LiHMDS, RuPhos, Pd(OAc)₂, THF, 60 °C, 6h; (b) NIS, DMF, rt, 15h; (c) NaH, TsCl, DMF, 2h; (d) Pd(PPh₃)₄, NaHC0₃, Dioxane/H₂0, 90 °C, 8- 15 h; (e) K₂C0₃, MeOH, 60 °C, 16 h; (f) TFA, CH₂C1₂, rt; (g) HATU, DMF, DIPEA, Glycolic Acid.

[0284] Step 1 : tert- utyl 4-(lH-pyrrolo[2,3-b]pyridin-5-yl)piperazine-l-carboxylate: A solution of 5-bromo-lH-pyrrolo[2,3-b]pyridine (0.25 g, 1.27 mmol) and boc-piperazine (0.35 g, 1.9 mmol) in THF (3 mL) was sparged with N₂ (g) for 2 min. RuPhos (0.10 g, 0.38 mmol) and Pd(OAc)₂ (0.03 g, 0.12) were added followed by LiHMDS (1.0 M in THF, 3.8 mL) The reaction mixture was heated to 60 °C and stirred for 6h. The reaction was cooled and the solvents evaporated. Purification of the residue by column chromatography (EtOAc/Hexanes) afforded the desired product (0.25 g, 65%). 1H NMR (400 MHz, DMSO- d₆) δ ppm 11.4 (s, 1H), 8.07 (d, 1 H), 7.51 (d, 1H), 7.38 (dd, lh), 6.32(dd, 1H), 3.49 (t, 4H), 3.01 (t, 4H), 1.43 (s, 9H). [0285] Step 2: tert-Butyl 4-(3-iodo-lH-pyrrolo[2,3-b]pyridin-5-yl)piperazine-l- carboxylate. To a solution of tert-butyl 4-(lH-pyrrolo[2,3-b]pyridin-5-yl)piperazine-l- carboxylate (0.25 g, 0.83 mmol) in DMF (5 mL) was N-iodosuccinimde (0.2 g, 0.91 mmol). The reaction was stirred overnight. Water (10 mL) was added and the resulting solid collected via vacuum filtration. The solid was washed with water and dried under high vacuum overnight to afford the title compound (0.25 g, 70%) of the desired product. 1H NMR (400 MHz, DMSO-ί ί) δ ppm 11.9 (s, 1H), 8.12 (d, 1 H), 7.62 (d, 1H), 7.13 (d, 1H), 3.50 (t, 4H), 3.08 (t, 4H), 1.41 (s, 9H).

[0286] Step 3: tert-Butyl 4-[3-iodo-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-5- yl]piperazine-l-carboxylate. NaH (60%> dispersion in oil, 0.006 g, 0.14 mmol) was added to a solution of tert-butyl 4-(3-iodo-lH-pyrrolo[2,3-b]pyridin-5-yl)piperazine-l-carboxylate (0.05 g, 0.12 mmol) in DMF (3 mL) at room temperature. The reaction was stirred for 10 min. and then /?-toluenesulfonyl chloride (0.025 g, 8.3 mmol) was added and the reaction stirred for an additional 6 h. Water (5 mL) was added, the mixture extracted with EtOAc (3 x 50 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated to dryness. Purification by column chromatography (hex/EtOAc) and recrystallization from hex/EtOAc afforded the desired product (0.05 g, 73%). 1H NMR (400 MHz, DMSO^) δ ppm 8.22 (d, 1 H), 8.04 (s, 1H), 7.96 (d, 2H), 7.41 (d, 2H), 7.14 (d, 1H), 3.47 (t, 4H), 3.14 (t, 4H), 2.34 (s, 3H), 1.42 (s, 9H).

[0287] Step 4: tert-Butyl 4-[3-(l-benzylpyrazol-4-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridin-5-yl]piperazine-l-carboxylate. A solution of tert-butyl 4-[3-iodo-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-5-yl]piperazine-l-carboxylate. (0.05 g, 0.08 mmol), 1- benzyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (0.025 g, 0.128 mmol) and NaHCC"3 (0.015 g, 0.16 mmol) in dioxane/water (5: 1, 3 mL) was sparged with N₂ (g) for 5 min. Tetrakispalladium triphenylphosphine (0.01 g, 0.008 mmol) was added and the reaction mixture heated to 90 °C overnight. The reaction was cooled to rt, filtered through celite to afford the title compound as a crude mixture.

[0288] Step 5: tert-Butyl 4-[3-(l-benzylpyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]piperazine-l-carboxylate. To the crude mixture of tert-butyl 4-[3-(l-benzylpyrazol-4-yl)- l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-5-yl]piperazine-l-carboxylate in methanol (5 mL) was added K₂CO₃ (0.06 g, 0.43 mmol). The solution was heated to 60 °C and stirred overnight. The solvent was evaporated and the material purified by column chromatography (0-100% Hexanes/EtOAc to 20% MeOH/CH₂Cl₂) to afford the desired product (0.025 g, 63% two steps). 1H NMR (DMSO-d₆) δ 11.4 (s, 1H), 8.31 (s, 1H), 8.(d, 1H), 7.89 (s, 1H), 7.68 (d, 1H), 7.64 (d, 1H), 7.38-7.34 (m, 2H), 7.31-7.26 (m, 3H), 5.37 (s, 2H), 3.52 (t, 4H), 3.08 (t, 4H), 1.43 (s, 9H). LC-MS [M+H]⁺ 459.2518.

[0289] Step 6: 3-(l-Benzyl-lH-pyrazol-4-yl)-5-(piperazin-l-yl)-lH-pyrrolo[2,3- b]pyridine. The standard method B Boc Deprotection with tert-butyl 4-[3-(l-benzylpyrazol- 4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]piperazine-l-carboxylate (0.020 g, 0.043 mmol). Evaporation of solvent and recrystallization (hex/EtOAc) afforded the title compound (0.020 g, quant.) as aTFA salt. 1H NMR (DMSO-d₆) δ 11.4 (s, 1H), 8.72 (br s, 2H), 8.29 (s, 1H), 8.13 (d, 1H), 7.92 (d, 1H), 7.71 (d, 1H), 7.68 (d, 1H), 7.38-7.34 (m, 2H), 7.31-7.26 (m, 3H), 5.38 (s, 2H), 3.35 (t, 4H), 3.31 (br s, 4H). LC-MS [M+H]⁺ 359.2008.

[0290] Step 7: 3 l-{4-[3-(l-Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]piperazin-l-yl}-2-hydroxyethanone. The standard method D HATU Coupling with 3-(l- benzyl-lH-pyrazol-4-yl)-5-(piperazin-l-yl)-lH-pyrrolo[2,3-b]pyridine (0.020 g, 0.055 mmol) and glycolic acid (0.005 g, 0.07 mmol) to afford the title compound as the TFA salt after purification by reverse phase column chromatography (0.015 g, 66%). 1H NMR (DMSO-^) δ 11.6 (s, 1H), 8.31 (s, 1H), 8.15 (br s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.68 (d, 1H), 7.38-7.34 (m, 2H), 7.31-7.26 (m, 3H), 5.38 (s, 2H), 4.16 (s, 2H), 3.69 (s, 2H), 3.56 (s, 2H), 3.17 (s, 4H). LC-MS [M+H]⁺ 417.2019.

Example 175: 5-[5-(l-Methyl-lH-pyrazol-4-yl)-lH-pyrrolo [2,3-b]pyridin-3-yl]- 2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile.

[0291] A suspension of 5-[5-[(E)-3-(2-hydroxyethyl(methyl)amino)prop-l-enyl]-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-tetrahydropyran-4-yloxy-benzonitrile (115 mg, 0.21 mmol) and LiOH (25 mg, 0.60 mmol) in MeOH (3 mL) and H₂0 (1 mL) was stirred at rt overnight. The reaction was quenched was sat. NaHCOs and extracted twice with EtOAc. The combined organics were dried (MgS0₄), filtered and concentrated. Purification by MPLC (Si0₂, EtOAc/Hexanes, 50 - 100% then to 100% CH₂Cl₂/MeOH (1 : 1)) provided the title compound. 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.97 (br. s., 1 H), 8.39 (br. s., 1 H), 8.34 (br. s., 1 H), 8.07 (d, 1 H), 7.97 - 8.05 (m, 1 H), 7.92 (br. s., 1 H), 7.41 (d, 1 H), 6.69 (d, 1 H), 6.36 - 6.46 (m, 1 H), 4.81 - 4.89 (m, 1 H), 4.35 - 4.43 (m, 1 H), 3.84 - 3.92 (m, 2 H), 3.47 - 3.59 (m, 4 H), 3.16 (d, 2 H), 2.41 - 2.49 (m, 2 H), 2.22 (s, 3 H), 1.99 - 2.07 (m, 2 H), 1.64 - 1.73 (m, 2 H); TOF LC/MS [M+H]⁺433.2233.

Example 176: 5-(5-{(lE)-3-[(2-Hydroxyethyl)(methyl)amino]prop-l-en-l-yl}- lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile.

[0292] The title compound was prepared from 5-[5-(l-methylpyrazol-4-yl)-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-tetrahydropyran-4-yloxy-benzonitrile using a method similar to Example 175. 1H NMR (400 MHz, CDC1₃) δ ppm 10.08 (br. s., 1 H), 8.53 - 8.60 (m, 1 H), 8.11 - 8.20 (m, 1 H), 7.81 - 7.87 (m, 2 H), 7.78 (dd, 1 H), 7.71 (s, 1 H), 7.48 - 7.54 (m, 1 H), 7.11 (d, 1 H), 4.67 - 4.75 (m, 1 H), 4.03 - 4.10 (m, 2 H), 4.01 (s, 3 H), 3.62 - 3.71 (m, 2 H), 2.06 - 2.14 (m, 2 H), 1.90 - 1.99 (m, 2 H); TOF [M+H]⁺ LC/MS 400.1757.

Example 177: 3-[3-Chloro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-(l- methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b] pyridine.

[0293] 1. 3-(3-chloro-4-tetrahydropyran-4-yloxy-phenyl)-5-(l -methylpyrazol-4-yl)- 1 -(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine was prepared from 5-bromo-3-(3-chloro-4- tetrahydropyran-4-yloxy-phenyl)- 1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine and 1 -methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole using a method similar to Intermediate 13. 2. The title compound was prepared from 3-(3-chloro-4-tetrahydropyran-4-yloxy- phenyl)-5-(l-methylpyrazol-4-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine using a method similar to Example 175. 1H NMR (400 MHz, DMSO-d6)□ ppm 11.90 (br. s., 1 H), 8.52 (br. s., 1 H), 8.31 (s, 1 H), 8.24 (s, 1 H), 7.97 (s, 1 H), 7.86 (d, 1 H), 7.77 (d, 1 H), 7.69 (dd, 1 H), 7.31 (d, 1 H), 4.66 - 4.74 (m, 1 H), 3.85 - 3.92 (m, 5 H), 3.48 - 3.57 (m, 2 H), 1.96 - 2.05 (m, 2 H), 1.63 - 1.72 (m, 2 H). TOF LC/MS [M+H]+ 409.1473.

Example 187: 5-(l-Methyl-lH-pyrazol-4-yl)-3-[4-(tetrahydro-2H-pyran-4- yloxy)phenyl]-lH-pyrrolo[2,3-b]pyridine.

[0294] 1. 5-(l-methylpyrazol-4-yl)-l-(p-tolylsulfonyl)-3-(4-tetrahydropyran-4- yloxyphenyl)pyrrolo[2,3-b]pyridine was prepared from 5-bromo-l-(p-tolylsulfonyl)-3-(4- tetrahydropyran-4-yloxyphenyl)pyrrolo[2,3-b]pyridine and l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazole using a method similar to Intermediate 13. 2. The title compound was prepared from 5-(l-methylpyrazol-4-yl)-l-(p-tolylsulfonyl)-3-(4- tetrahydropyran-4-yloxyphenyl)pyrrolo[2,3-b]pyridine using a method similar to Example 175. 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.79 (br. s., 1 H), 8.51 (d, 1 H), 8.31 (d, 1 H), 8.23 (s, 1 H), 7.96 (s, 1 H), 7.74 (d, 1 H), 7.62 - 7.69 (m, 2 H), 7.04 - 7.09 (m, 2 H), 4.53 - 4.64 (m, 1 H), 3.88 (s, 3 H), 3.81 - 3.93 (m, 2 H), 3.44 - 3.54 (m, 2 H), 1.93 - 2.08 (m, 2 H), 1.56 - 1.67 (m, 2 H). TOF LC/MS [M+H]⁺ 375.1818.

Example 188: 3-[3-Fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-{l-[2- (morpholin-4-yl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine.

[0295] 1. 4-[2-[4-[3-(3-fluoro-4-tetrahydropyran-4-yloxy-phenyl)-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-5-yl]pyrazol-l-yl]ethyl]morpholine was prepared from 4- [2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazol-l-yl]ethyl]morpholine using a method similar to Intermediate 13 2. The title compound was prepared from 4-[2-[4-[3-(3- fluoro-4-tetrahydropyran-4-yloxy-phenyl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-5- yl]pyrazol-l-yl]ethyl]morpholine and THF using a method similar to Example 175. 1H NMR (400 MHz, CDCls) δ ppm 9.14 (br. s., 1 H), 8.51 (d, 1 H), 8.21 (d, 1 H), 7.82 (s, 1 H), 7.78 (s, 1 H), 7.45 (d, 1 H), 7.38 (dd, 1 H), 7.30 - 7.36 (m, 1 H), 7.08 - 7.16 (m, 1 H), 4.45 - 4.55 (m, 1 H), 4.32 (t, 2 H), 4.00 - 4.08 (m, 2 H), 3.67 - 3.74 (m, 4 H), 3.53 - 3.65 (m, 2 H), 2.89 (t, 2 H), 2.48 - 2.56 (m, 4 H), 2.00 - 2.11 (m, 2 H), 1.82 - 1.93 (m, 2 H); TOF LC/MS [M+H]⁺ 492.2375.

[0296] The structures and physicochemical characterization of synthesized example compounds are provided in Tables 1 and 2 below. The compounds were synthesized using the methods and intermediates outlined above using commercially available starting materials that are well known in the art.

Table 1: Example Compound Structure and LCMS Data



Table 2: IUPAC Name and 1H NMR Data

Example IUPAC Name NMR carboxamide

1 - {3-[3 -( 1 -Benzyl- 1 H-pyrazol-4-yl)-

192 lH-pyrrolo[2,3-b]pyridin-5- yl]phenyl}-3-piperidin-4-ylurea

4-[3-(l-Benzyl-lH-pyrazol-4-yl)-lH-

193 pyrrolo[2,3-b]pyridin-5- yljbenzenesulfonamide

3-(l-Benzyl-lH-pyrazol-4-yl)-5-[4-

194 (piperazin- 1 -ylsulfonyl)phenyl] - 1 H- pyrrolo[2,3-b]pyridine

3-(l-Benzyl-lH-pyrazol-4-yl)-5-[3-

195 (piperazin- 1 -ylmethyl)phenyl] - 1 H- pyrrolo[2,3-b]pyridine

3-(l-Benzyl-lH-pyrazol-4-yl)-5-[3-

196 (morpholin-4-ylmethyl)phenyl]-lH- pyrrolo[2,3-b]pyridine

3-(l-Benzyl-lH-pyrazol-4-yl)-5-{4- [(3 -methoxyazetidin- 1 -

197

yl)methyl]phenyl}-lH-pyrrolo[2,3- b] pyridine

3-(l-Benzyl-lH-pyrazol-4-yl)-5-{4- [(4-methylpiperazin- 1 -

198

yl)methyl]phenyl}-lH-pyrrolo[2,3- b] pyridine

3-(l-Benzyl-lH-pyrazol-4-yl)-5-[4-

199 (morpholin-4-ylmethyl)phenyl]-lH- pyrrolo[2,3-b]pyridine

5-{5-[l-(L-Prolyl)-l,2,3,6- tetrahydropyridin-4-yl] - 1 H-

200 pyrrolo[2,3-b]pyridin-3-yl}-2- (tetrahydro-2H-pyran-4- yloxy)benzonitrile

N-{4-[3-(l-Benzyl-lH-pyrazol-4-yl)-

201 lH-pyrrolo[2,3-b]pyridin-5- yl]phenyl} -2-hydroxyacetamide

N-{3-[3-(l-Benzyl-lH-pyrazol-4-yl)-

202 lH-pyrrolo[2,3-b]pyridin-5- yl]phenyl} -2-hydroxyacetamide

3-(l-Benzyl-lH-pyrazol-4-yl)-5-{3- [(3 -methoxyazetidin- 1 -

203

yl)methyl]phenyl}-lH-pyrrolo[2,3- b] pyridine

N-{3-[3-(l-Benzyl-lH-pyrazol-4-yl)-

204 lH-pyrrolo[2,3-b]pyridin-5- yl]benzyl}piperidin-4-amine

3-(l-Benzyl-lH-pyrazol-4-yl)-5-[4-

205 (piperazin- 1 -ylmethyl)phenyl] - 1 H- pyrrolo[2,3-b]pyridine Example IUPAC Name NMR

4- {3-[3-Cyano-4-(tetrahydro-2H- pyran-4-yloxy)phenyl]- lH-

206 pyrrolo[2,3-b]pyridin-5-yl} -N- cyclopentyl-3,6-dihydropyridine- 1 (2H)-carboxamide

5 - {5 -[ 1 -(Pyrrolidin- 1 -ylcarbonyl)- l ,2,3,6-tetrahydropyridin-4-yl]- lH-

207 pyrrolo[2,3-b]pyridin-3-yl} -2-

(tetrahydro-2H-pyran-4- yloxy)benzonitrile

5 - {5 -[ 1 -(Piperazin- 1 -ylcarbonyl)- l ,2,3,6-tetrahydropyridin-4-yl]- lH-

208 pyrrolo[2,3-b]pyridin-3-yl} -2-

(tetrahydro-2H-pyran-4- yloxy)benzonitrile

4- {3-[3-Cyano-4-(tetrahydro-2H- pyran-4-yloxy)phenyl]- lH-

209 pyrrolo[2,3-b]pyridin-5-yl} -N- (piperidin-4-yl)-3,6-dihydropyridine- 1 (2H)-carboxamide

4- {3-[3-Cyano-4-(tetrahydro-2H- pyran-4-yloxy)phenyl]- lH-

210 pyrrolo[2,3-b]pyridin-5-yl} -N-(2- methoxyethyl)-3,6-dihydropyridine- 1 (2H)-carboxamide

[0297] The HPLC conditions used to characterize each compound listed in Tables 1 and 2 are as folows:

Flow: 1 .2 mL/minute

Solvents : A: H₂0 + 0.01 % TFA

B : ACN + 0.01 % TFA

Gradient: 5 % B for 1 minute

5 % B to 100% B in 9 minutes

at 100% B for 2.4 minutes

to 0% B in 0. 1 minutes

at 0% for 0.5 minutes

Overall time : 13.00 minutes

Column: XTerra MS C i₈ 3.5um 4.6x 150mm [0298] Tables 1 and 2 show only those Experimental Compounds that were synthesized and underwent physicochemical characterization. In addition to those compounds exemplified in Tables 1 and 2, above, the compounds in Table 3, below, are also representative of the therapeutic compounds of the present invention. As would be appreciated by the skilled artisan, these compounds can be made following procedures similar to those presented above.

Table 3. Additional Representative Compounds That Could Be Synthesized Using Procedures Similar to Those Described Above.

1 - {4-[3-(l -benzyl- 1 H-pyrazol- 4-yl)- lH-pyrrolo[2,3- b]pyridin-5- yl]phenyl}methanamine

N- {4-[3-(l -benzyl- 1 H-pyrazol- 4-yl)- lH-pyrrolo[2,3- b]pyridin-5- yljbenzyl} acetamide

N- {4-[3-(l -benzyl- 1 H-pyrazol- 4-yl)- lH-pyrrolo[2,3- b]pyridin-5- yljbenzyl} glycinamide

N- {4-[3-(l -benzyl- 1 H-pyrazol- 4-yl)- lH-pyrrolo[2,3- b]pyridin-5- yl]benzyl}methanesulfonamide

N- {4-[3-(l -benzyl- 1 H-pyrazol- 4-yl)- lH-pyrrolo[2,3- b]pyridin-5-yl]benzyl} -2- hydroxyacetamide

N- {4-[3-(l -benzyl- 1 H-pyrazol- 4-yl)- lH-pyrrolo[2,3- b]pyridin-5- yl]benzyl}morpholine-4- carboxamide

N- {4-[3-(l -benzyl- 1 H-pyrazol- 4-yl)- lH-pyrrolo[2,3- b]pyridin-5- yl]phenyl}piperazine- 1 - carboxamide

N- {4-[3-(l -benzyl- 1 H-pyrazol- 4-yl)- lH-pyrrolo[2,3- b]pyridin-5-yl]phenyl} -4- methylpiperazine- 1 - carboxamide

4-acetyl-N- {4-[3-(l -benzyl- 1 H-pyrazol-4-yl)- 1 H- pyrrolo[2,3-b]pyridin-5- yl]phenyl}piperazine- 1 - carboxamide

l - {4-[3-(l -benzyl- 1 H-pyrazol- 4-yl)- lH-pyrrolo[2,3- b]pyridin-5-yl]phenyl} -3- piperidin-4-ylurea

4-[3-(l -benzyl-lH-pyrazol-4- yl)-lH-pyrrolo[2,3-b]pyridin- 5-yl]benzenesulfonamide

N H₂

3 -(1 -benzyl- lH-pyrazol-4-yl)- 5-[4-(piperazin-l- ylsulfonyl)phenyl] - 1 H- pyrrolo[2,3-b]pyridine

O I ¹

3 -(1 -benzyl- lH-pyrazol-4-yl)- 5- {4-[(4-methylpiperazin- 1 - yl)sulfonyl]phenyl} - 1 H- pyrrolo[2,3-b]pyridine

O I ¹

4-[3-(l -benzyl-lH-pyrazol-4- yl)-lH-pyrrolo[2,3-b]pyridin- 5-yl]-N-(piperidin-4- yl)benzenesulfonamide

3 -(1 -benzyl- lH-pyrazol-4-yl)- 5-[4-(morpholin-4- ylsulfonyl)phenyl] - 1 H- pyrrolo[2,3-b]pyridine

3 -(1 -benzyl- lH-pyrazol-4-yl)- 5 -(2-methoxy- 1 ,3 -thiazol-5 - yl)-lH-pyrrolo[2,3-b]pyridine

methyl 5-[3-(l-benzyl-lH- pyrazol-4-yl)-lH-pyrrolo[2,3- s'S b]pyridin-5-yl]-l ,3-thiazole-2- carboxylate

0—

{5-[3-(l-benzyl-lH-pyrazol-4- yl)-lH-pyrrolo[2,3-b]pyridin- 5-yl]-l ,3-thiazol-2-yl} (3- methoxyazetidin- 1 - yl)methanone o—

5-[3-(l -benzyl-lH-pyrazol-4- yl)-lH-pyrrolo[2,3-b]pyridin- s S 5-yl]-l ,3-thiazole-2- carboxamide

N H₂

{5-[3-(l-benzyl-lH-pyrazol-4- yl)-lH-pyrrolo[2,3-b]pyridin- 5-yl]-l ,3-thiazol-2-yl} [3-=( (dimethylamino)azetidin- 1 - yljmethanone

£* N—

/

[0299] The structures and physicochemical characterization of synthesized example compounds are provided in the specific examples delineated above. The compounds were synthesized using the methods and intermediates as outlined above using commercially available starting materials that are well known in the art. IUPAC names for the compounds depicted were generated using Advanced Chemistry Development, Inc., (ACD/Labs) (Toronto, Ontario, Canada) ACD/Name IUPAC nomenclature software release 12.00, version 12.01

Biochemical and Biological Examples

In-Vitro ΙΚΚε and TBK1 Kinase Assays

[0300] ΙΚΚε enzyme was produced as a His-tag fusion in Sf9 cells or purchased as a GST-tag fusion (Invitrogen, Carlsbad, CA). TBK1 enzyme was produced as a His-tag fusion in Sf9 cells. Kinase reactions were carried out in reaction buffer using myelin basic protein (Millipore, Ballerica, MA), casein or dephosphorylated casein (Sigma, St. Louis, MO) as substrate at an ATP concentration equal to twice the K_m,ATP value for each enzyme, corresponding to 32 μΜ ATP for ΙΚ ε and 60 μΜ ATP for TBK1. Radiolabeled [γ³³]ΑΤΡ (PerkinElmer, Waltham, MA) in the amount of 0.3 mCi (IK e, "normal") or 0.7 μθι (ΙΚ ε, "sensitized") or 1.25 μCi (TBK1) was added to each assay. Final enzyme concentrations were 0.1 or 0.015 μ^πιΐ (ΙΚΚε) and 0.1 or 0.02 μ^πιΐ (TBK1) for the "normal" and "sensitized" assay, respectively, and "sensitized" assays were conducted using only dephosphorylated casein as substrate. Test compounds (or DMSO solvent as a control) were added prior to initiation of the reactions. Reactions were terminated after 30-45 minutes by adding 3% phosphoric acid. Terminated reactions were transferred to P-81 cellulose phosphate filterplates (Whatman, Inc., Piscataway, NJ) and washed with 1% phosphoric acid on a vacuum apparatus. After air drying, scintillant (PerkinElmer, Waltham, MA) was added and the plates were read on a PerkinElmer TopCount NXT instrument. Counts were normalized to DMSO controls after background subtraction.

[0301] IC₅o values determined with the assays for ΙΚ ε inhibition described above are shown in Table 4, below, for representative example compounds.

[0302] Generally, compounds found to inhibit the kinase activity of ΙΚ ε are also be expected to inhibit the kinase activity of TBK1, given the high degree of similarity similarity of the amino acid sequences encoding these two closely-related kinases, and particulary those sequences encoding the kinase domains of these enzymes.

Assays to Detect the In-Situ Phosphorylation of IRF3 (and IRF7)

[0303] HEK293T cells were cotransfected in a 10-cm dish with IRF3 and ΙΚ ε expression plasmids using Lipofectamine 2000 (Invitrogen, Carlsbad, CA). The following day, cells were replated at 20,000 per well in 96-well plates and treated with test compounds (compounds according to Formulae I-III) for 20 hours. Cell lysates were prepared and analyzed using an ELISA for phospho-Ser396 (anti-IRF3 capture antibody, Santa Cruz Biotechnology, Inc., Santa Cruz, CA; anti-p-Ser396 IRF3 detection antibody, Cell Signaling, Danvers, MA). pIRF3 levels in compound treated cells were normalized to DMSO treated cells (no compound). Cell viability was assayed in a parallel set of plates to monitor cytotoxic effects of the test compounds (CellTiter-Glo, Promega, Inc., Madison, WI). TBK1 activity was tested by Western blotting using a phospho-specific IRF7 antibody. Similar to above, HEK293T cells were transfected with IRF7 and TBK1 expression plasmids. Cells were seeded in 12-well plates at 150,000 per well and treated overnight with test compounds. Protein lysates were prepared and processed for Western blotting followed by detection using a phosphor-Ser477/Ser479 IRF7 antibody (BD Biosciences, San Jose, CA)

[0304] EC₅₀ values determined with the assays for In-Situ Phosphorylation of IRF3 described above are shown in Table 4, below, for representative example compounds.

Table 4: Activity Data for Representative Example Compounds

35 1

36 2

0.5

37 0.07 0.022 5

38 0.13

39 0.15

40 0.16

41 0.5

42 0.5

43 0.28

44 0.1 1

45 0.39

46 0.5

47 0.18

48 0.25

49 0.5

50 0.5

51 0.5

52 0.17

53 0.2

54 0.031

55 0.5

56 0.22

57 0.38

58 0.15

59 0.16

60 0.56

61 0.43

62 0.18

63 2

64 2

65 2

66 0.045

67 0.21

68 0.066

0.047 0.37

69 0.0067 0.0025 0.25

0.0054 0.12

0.00084 0.091

70 0.5

71 0.28

72 0.0066 0.0017 0.075

0.0012 0.28

73 0.5 74 0.038

75 0.5

76 0.084

77 0.24

78 0.019

79 0.052

80 0.5

81 0.047

82 0.076

83 0.13

84 0.072

85 0.00026 0.031

86 0.0085 0.35

87 0.2 5

88 0.026 5

89 0.2 5

90 0.0086

91 0.0002 0.064

92 0.0034 0.28

93 0.0017 0.35

94 0.064 5

95 0.0062 5

96 0.002 5

97 0.0016 0.11

98 0.0043

99 0.081 5

100 0.2 5

101 0.044 5

102 0.0053 5

103 0.036 5

104 0.2 5

105 0.033 5

106 0.012 3.9

107 0.14 5

108 0.0087 4.7

109 0.014

110 0.014

111 0.17 5

112 0.037 5

113 0.17 5

114 0.04 5

115 0.018

116 0.15 5

117 0.2 5 1 18 0.0013 0.2

1 19 0.026 1.7

120 0.14 5

121 0.012 1.7

122 0.04 5

123 0.2 5

124 0.0014 0.068

125 0.19 5

126 0.2

127 0.018 2.5

128 0.2 5

129 0.084 0.81

130 0.2 5

131 0.0012 0.1

132 0.00054 0.053

133 0.0012 0.24

134 0.002 0.32

135 0.049 5

136 0.14 3.7

137 0.018 0.94

138 0.0056 0.25

139 0.0051 0.22

140 0.024 0.31

141 0.001 1 0.49

142 0.006 0.49

143 0.0015 0.17

144 0.00074 0.14

145 0.0016 0.32

146 0.0027 1.5

147 0.2 5

148 0.0034 0.37

149 0.0037 0.09

150 0.0025

151 0.0041 0.33

152 0.2 5

153 0.2 5

154 0.2 5

155 0.0016 0.36

156 0.0035 0.47

157 0.01 1

158 0.0072 0.2

159 0.015

160 0.0048 0.18

161 0.052 5 162 0.0013 0.42

163 0.00068 0.19

164 0.001 1 0.49

165 0.013 0.9

166 0.2

167 0.17

168 0.0073 0.2

169 0.0055 0.21

170 0.001 1 0.17

171 0.0038 0.14

172 0.0039 0.24

173 0.2

174 0.012

175 0.024 1.1

176 0.0004 0.039

177 0.0081 0.71

178 0.0059 0.13

179 0.0079 0.076

180 0.02 0.69

181 0.03

182 0.029

183 0.029

184 0.032

185 0.019 0.55

186 0.068

187 0.16

188 0.021

189 0.041

190 0.038

191 0.028

192 0.037

193 0.068

194 0.072

195 0.062

196 0.045

197 0.024

198 0.0095

199 0.0051

200 0.038

201 0.029

202 0.02

203 0.055

204 0.029

205 0.021 206 0.0013

207 0.00084

208 0.00079

209 0.00094

210 0.00074

[0305] All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which the present invention pertains. The mere mentioning of the publications and patent applications does not necessarily constitute an admission that they are prior art to the instant application.

[0306] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be clear to the skilled artisan that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

What is claimed is:

1. A compound according to Formula

Formula I;

and pharmaceutically acceptable salts thereof, wherein Y is CH or N;

Z is present or absent, and when present is a linking group selected from -N(H)-, - S-, -N(H)C(=0)-, -C(=0)-, partially-saturated C₃ alkynyl (e.g., -prop- l -en- l -yl-), partially-saturated -N(H)- C₂-4 alkenyl-, or partially-saturated - C(=0)- C₂-4 alkenyl-;

Rl is o tionally-substituted aryl optionally-substituted hetero

hydroxyalkylamino, alkoxyamino, dialkoxyamino aryl, heteroaryl,

R4 wherein in Rl and R2 R3 is independently hydro, Ci_₆ alkyl, benzyl, R5

carbox l, -S0₂OH, -CN, acetamide, heterocyclo, carboxamido, sulfonamido,

N

' k

R4

R5 is NH₂, heteroaryl, heterocycloalkyl, or ; and dro, carboxyl, sulfonyl, Ci_₆ alkyl, Ci_₆ alkyloxy, carbocyclo, heterocyclo, or

with the proviso that the compound of Formula I is NOT:

Benzamide, 2,6-difluoro-iV- [3 - [ 1 -(phenylmethyl)- 1 H-pyrazol-4 - yl] - 1 H~ pyrrok>[2₅3-b]pyridm~5-y]]~3-[( ropylsu.]fonyl)arninoj- (CAS Registry Number: 1 186500-41 -3);

2. A compound according to claim 1 in which Y is CH, and the compound is one according to Formula II,

Formula II

and pharmaceutically acceptable salts thereof, wherein Z, Rl , and R2, are as defined above.

3. A compound according to claim 1 in which Y is N, and the compound is one according to Formula III,

Formula III

4. A compound according to any one of claims 1 , 2, or 3, and pharmaceutically acceptable salts thereof, wherein

Z, when present, is a linking group selected from -N(H)-, -S-, -N(H)C(=0)- , -C(=0)-, partially-saturated C₃ alkynyl (e.g., -prop-l -en-l -yl-), partially-saturated -N(H)- C₂-4 alkenyl-, or partially-saturated - C(=0)- C₂-4 alkenyl-;

Rl is selected from an optionally substituted aryl or heteroaryl group, including, for example, phenyl, 4-pyrazolyl, 3-pyrrolyl, 3-pyridinyl, 4-pyridinyl, and 5-pyrimidinyl.; and R2 is optionally substituted at least once, and is selected from an amine, Ci- C₆ alkoxyl, Ci-C₆ alkamino, 4, 5, 6, or 7-membered heterocyclyl, aryl, or heteroaryl group, including, for example, phenyl, 4-pyrazolyl, 5-pyrazolyl, 2-thiozolyl, 4- thiozolyl, 5-thiozolyl, 4-pyridinyl, 4-(3,4-tetrahydro)pyridinyl, 1 -piperizinyl, and (3 ,6-dihydro)pyranyl;

and pharmaceutically acceptable salts thereof.

5. A compound accordin to claim 2 in which Rl is an optionally substituted 3-

cyanophenyl group ( ), and the compound is one according to Formula

Ila,

Formula Ila

and pharmaceutically acceptable salts thereof, wherein Z and R2 are as defined above.

6. A compound according to claim 2 in which Rl is an optionally substituted 1 -

benzylpyrazol-4-yl group ( ), and the compound is one according to

Formula lib,

Formula lib

with the proviso that when Z is an amide linking group and R2 is a substituted phenyl, the compounds of the present invention specifically exclude Benzamide, 2,6-difluoro-N-[3- [l-(phenylmethyl)-] H-pyraz.ol-4-yl]-! :i-pyiTolo[2,3-6]pyridin~5-yi]-3- [(propylsulfonyl)amino]- (CAS Registry Number: 1 186500-41 -3 .

7. A compound according to claim 2 in which Rl is , and the compound is one according to Formula Ila'

Formula Ila'

and pharmaceutically acceptable salts thereof, wherein R2 is as defined above and R7 is selected from hydro, hydroxyl, optionally-substituted C i-C₆ alkyl, optionally- substituted C ₁-C₄ alkoxyl, optionally-substituted C ₁-C₄ aminoalkyl, C ₁-C₄

alkylamino, C ₁-C₄ alkylamido, cyclopropylmethyl, cyclopropylmethylamino, benzyl, or an optionally-substituted 5 -, or 6-membered heterocycle, wherein said 5 -, or 6- membered heterocycle is selected from 4-piperidinyl, 4-tetrahydropyranyl, 3- pyrolodinyl, or ethylene-linked 4-morpholinyl.

8. A compound according to claim 2 in which Rl is , and the compound is one according to Formula Ila"

Formula Ila'

alkylamino, C ₁-C₄ alkylamido, cyclopropylmethyl, cyclopropylmethylamino, benzyl, or an optionally-substituted 5-, or 6-membered heterocycle, wherein said 5-, or 6- membered heterocycle is selected from 4-piperidinyl, 4-tetrahydropyranyl, 3- pyrolodinyl, or ethylene-linked 4-morpholinyl.

9. A compound according to claim 2 in which Rl is an optionally substituted 1 -

benzylpyrazol-4-yl group ( ), and the compound is one according to Formula lib,

Formula lib

with the proviso that when Z is an amide linking group and R2 is a substituted phenyl, the compounds of the present invention specifically exclude Benzamide, 2,6- difl.uoro-.iV~ [3 -(ph.enyi.rn etliyi)- l.H-py.razol~4-yl]- l./ -pyrrolo[2,3-d] pyridin-5 -yI]-3- [(propylsulfonyl)amino] - (CAS Registry Number: 1 186500-41 -3).

10. A compound according to claim 5, wherein

Z is a direct bond to R2, and

R2 is an optionally substituted phenyl group;

with the proviso that the compound is NOT:

Benzonitrile, 3-[5-(3-aminophenyl)-lH-pyrrolo[2,3-¾]pyridin-3-yl]- (CAS Registry No.: 1377503-50-8); or

1 1. A compound according to claim 6 wherein

Z is a direct bond to R2, and

R2 is an optionally substituted phenyl group;

with the proviso that the compound is NOT:

Benzonitrile, 4-[3-[ 1 -(triphenylmethyl)- lH-pyrazol-4-yl]- lH-pyrrolo[2,3-¾]pyridin- 5-yl]- (CAS Registry No. : 757979-81-0);

Benzenamine, N,N-dimethyl-4-[3-[ 1 -(triphenylmethyl)- lH-pyrazol-4-yl]-lH- pyrrolo[2,3-6]pyridin-5-yl]-; (CAS Registry No.: 757980-01-1); Methanone, [5 -[4-(dimethylamino)phenyl] -3 -[ 1 -(triphenylmethyl)- 1 H-pyrazol-4-yl] - lH-pyrrolo[2,3- yridin-l-yl]phenyl- (CAS Registry No.: 757982-21-1);

lH-Pyrrolo[2,3-£]pyridine, 5-[4-(4-morpholinyl)phenyl]-l-(phenylsulfonyl)-3-[l- (triphenylmethyl)-lH-pyrazol-4-yl]- (CAS Registry No.: 757982-13-1).

12. A compound according to Formula I, as specified in Tables 1 , 2 and 3.

13. A compound selected from:

3-[3-(Benzyloxy)-5-fluorophenyl]-5-(2-methoxyphenyl)- lH-pyrrolo[2,3-b]pyridine; 3-[3-(Benzyloxy)-5-fluorophenyl]-5-(3,4-dimethoxyphenyl)-l H-pyrrolo[2,3- b]pyridine;

3-(Benzyloxy)-5-[5-(3,4-dimethoxyphenyl)- lH-pyrrolo[2,3-b]pyridin-3- yljbenzonitrile;

3-[3-(Benzyloxy)-5-fluorophenyl]-5-(4-methoxyphenyl)- lH-pyrrolo[2,3-b]pyridine; 3-[3-(Benzyloxy)-5-fluorophenyl]-5-(3,5-dimethoxyphenyl)-l H-pyrrolo[2,3- b]pyridine;

3- {3-[3-(Benzyloxy)-5 -fluorophenyl]- lH-pyrrolo[2,3-b]pyridin-5-yl}benzonitrile;

4- {3-[3-(Benzyloxy)-5 -fluorophenyl]- lH-pyrrolo[2,3-b]pyridin-5-yl}benzonitrile; 3- [3 -(Benzyloxy)-5 -fluorophenyl] -5 -(3 -methoxy-4-methylphenyl)-l H-pyrrolo [2,3- b]pyridine;

4- {3-[3-(Benzyloxy)-5 -fluorophenyl]- lH-pyrrolo[2,3-b]pyridin-5-yl}benzamide; N-(3- {3-[3-(Benzyloxy)-5-fluorophenyl]-lH-pyrrolo[2,3-b]pyridin-5- yl}phenyl)acetamide;

3- {3-[3-(Benzyloxy)-5 -fluorophenyl]- lH-pyrrolo[2,3-b]pyridin-5- yl}benzenesulfonamide;

3- {5-[3-(Benzyloxy)-5 -fluorophenyl]- lH-pyrrolo[2,3-b]pyridin-3- yl}benzenesulfonamide;

3-[5-(3,4-Dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]benzenesulfonamide;

5- (3,4-Dimethoxyphenyl)-3-(2-fluoropyridin-3-yl)-lH-pyrrolo[2,3-b]pyridine;

5-(3,4-Dimethoxyphenyl)-3-(6-methoxypyridin-3-yl)-lH-pyrrolo[2,3-b]pyridine; 3-(l -Benzyl- lH-pyrazol-4-yl)-5-(3,4-dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridine; 5-[5-(3,4-Dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-2-amine;

5 -(3 ,4-Dimethoxyphenyl)-3 -( 1 H-pyrazol-4-yl)- 1 H-pyrrolo [2,3 -b]pyridine;

3-[3-(Benzyloxy)-5-fluorophenyl]-5-(3-methoxyphenyl)-lH-pyrrolo[2,3-b]pyridine; 3-[5-(3,4-Dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]benzamide;

3-[5-(3,4-Dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]aniline;

5-(3,4-Dimethoxyphenyl)-3-(lH-pyrazol-3-yl)-lH-pyrrolo[2,3-b]pyridine;

5-(3,4-Dimethoxyphenyl)-3-(pyridin-4-yl)-lH-pyrrolo[2,3-b]pyridine;

5 -(3 ,4-Dimethoxyphenyl)-3 -( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H-pyrrolo [2,3 -b]pyridine; 5 -(3 ,4-Dimethoxyphenyl)-3 -( 1 -propyl- 1 H-pyrazol-4-yl)- 1 H-pyrrolo [2,3 -b]pyri dine; 3 -(1 -Benzyl- lH-pyrazol-4-yl)-5 -(3,4,5 -trimethoxyphenyl)-l H-pyrrolo [2,3- b]pyridine;

5 -(3 ,4-Dimethoxyphenyl)-3 - { 1 -[2-(morpholin-4-yl)ethyl] - 1 H-pyrazol-4-yl} - 1 H- pyrrolo[2,3-b]pyridine;

5-[5-(3,4-Dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-methoxybenzonitrile; 3 -(1 -Benzyl- lH-pyrazol-4-yl)-N-(3, 4,5 -trimethoxyphenyl)-l H-pyrrolo [2,3- b]pyridin-5-amine;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-5-[4-(morpholin-4-yl)phenyl]-l H-pyrrolo [2,3- b]pyridine;

N- {3 -[3 -(1 -Benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yl]phenyl} acetamide; 3 - [ 1 -(4-Chlorobenzyl)- 1 H-pyrazol-4-yl] -5 -(3 ,4-dimethoxyphenyl)- 1 H-pyrrolo [2,3 - b]pyridine;

5 -(3 ,4-Dimethoxyphenyl)-3 -[ 1 -(4-methylbenzyl)- 1 H-pyrazol-4-yl] - 1 H-pyrrolo [2,3 - b]pyridine;

5-(3,4-Dimethoxyphenyl)-3-(3-fluoro-4-methoxyphenyl)- lH-pyrrolo[2,3-b]pyridine; 5-(3,4-Dimethoxyphenyl)-3-[3-fluoro-4-(propan-2-yloxy)phenyl]- lH-pyrrolo[2,3- b]pyridine;

3 - (1 -Benzyl- lH-pyrazol-4-yl)-N-(2-methoxyphenyl)- l H-pyrrolo [2,3 -b]pyridin-5- amine;

7-(l -Benzyl- lH-pyrazol-4-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrrolo[2,3-b]pyrazine; 5-[2-(3 ,4-Dimethoxyphenyl)-4H-pyrrolo[2,3-b]pyrazin-7-yl]-2-methoxybenzonitrile;

4- ({4-[5-(3,4-Dimethoxyphenyl)- lH-pyrrolo[2,3-b]pyridin-3-yl]- lH-pyrazol- l - yl}methyl)benzenesulfonic acid;

5 -(3 ,4-Dimethoxyphenyl)-3 -[ 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H-pyrazol-4-yl] - lH-pyrrolo[2,3-b]pyridine;

5 -(3 ,4-Dimethoxyphenyl)-3 -[ 1 -(3 -methylbutyl)- 1 H-pyrazol-4-yl] - 1 H-pyrrolo [2,3 - b]pyridine;

5 -(3 ,4-Dimethoxyphenyl)-3 -[ 1 -(4-methoxybenzyl)- 1 H-pyrazol-4-yl] - 1 H-pyrrolo [2,3 - b]pyridine;

5 -(3 ,4-Dimethoxyphenyl)-3 -[ 1 -(2-phenylethyl)- 1 H-pyrazol-4-yl] - 1 H-pyrrolo [2,3 - b]pyridine;

5 - (3, 4-Dimethoxyphenyl)-3-[ l -(l -phenylethyl)- lH-pyrazol-4-yl]-l H-pyrrolo [2,3- b]pyridine;

3 - [ 1 -(Cyclohexylmethyl)- 1 H-pyrazol-4-yl] -5 -(3 ,4-dimethoxyphenyl)- 1 H- pyrrolo[2,3-b]pyridine;

6- ({4-[5-(3,4-Dimethoxyphenyl)- lH-pyrrolo[2,3-b]pyridin-3-yl]- lH-pyrazol- l - yl}methyl)-2,3-dimethylquinazolin-4(3H)-one;

5 -(3 ,4-Dimethoxyphenyl)-3 -[ 1 -(pyridin-3 -ylmethyl)- 1 H-pyrazol-4-yl] - 1 H- pyrrolo[2,3-b]pyridine;

5 -(3 ,4-Dimethoxyphenyl)-3 -[ 1 -(pyridin-2-ylmethyl)- 1 H-pyrazol-4-yl] - 1 H- pyrrolo[2,3-b]pyridine;

2- {4-[5 -(3, 4-Dimethoxyphenyl)-l H-pyrrolo [2,3 -b]pyridin-3-yl]- l H-pyrazol-1 - yl} acetamide;

5-(3,4-Dimethoxyphenyl)-3-(3-methyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine; 4- [3-(l -Benzyl-lH-pyrazol-4-yl)- lH-pyrrolo[2,3-b]pyridin-5-yl]piperazin-2-one; 5 -(3 ,4-Dimethoxyphenyl)-3 -[ 1 -(pyrimidin-5 -ylmethyl)- 1 H-pyrazol-4-yl] - 1 H- pyrrolo[2,3-b]pyridine;

5 -(3 ,4-Dimethoxyphenyl)-3 - { 1 -[2-(trif uoromethyl)benzyl] - 1 H-pyrazol-4-yl} - 1 H- pyrrolo[2,3-b]pyridine;

5- (3,4-Dimethoxyphenyl)-3-[ l -(2-fluorobenzyl)-l H-pyrazol-4-yl]- lH-pyrrolo[2,3- b]pyridine;

3-(l -Benzyl-3-methyl- lH-pyrazol-4-yl)-5-(3,4-dimethoxyphenyl)- lH-pyrrolo[2,3- b]pyridine;

3 - [ 1 -(2-Chlorobenzyl)- 1 H-pyrazol-4-yl] -5 -(3 ,4-dimethoxyphenyl)- 1 H-pyrrolo [2,3 - b]pyridine;

5 -(3 ,4-Dimethoxyphenyl)-3 -[ 1 -(2-methylbenzyl)- 1 H-pyrazol-4-yl] - 1 H-pyrrolo [2,3 - b]pyridine;

3- [3 -(1 -Benzyl- lH-pyrazol-4-yl)- l H-pyrrolo [2, 3 -b]pyridin-5-yl] aniline;

4- [3 -(1 -Benzyl- lH-pyrazol-4-yl)- l H-pyrrolo [2, 3 -b]pyridin-5-yl]-2-methoxyphenol; 3-[3-(l -Benzyl- lH-pyrazol-4-yl)- lH-pyrrolo[2,3-b]pyridin-5-yl]-N,N- dimethylaniline;

3- (l -Benzyl- lH-pyrazol-4-yl)-5-(3,5-dimethoxyphenyl)- lH-pyrrolo[2,3-b]pyridine;

4- [3 -(1 -Benzyl- lH-pyrazol-4-yl)- l H-pyrrolo [2, 3 -b]pyridin-5-yl] aniline;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-N-(3-methoxyphenyl)- l H-pyrrolo [2,3 -b]pyridin-5- amine;

3 -(1 -Benzyl- 1 H-pyrazol-4-yl)-N-(2, 5 -dimethoxyphenyl)- l H-pyrrolo [2,3 -b]pyridin-5- amine;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-N-(3, 5 -dimethoxyphenyl)- l H-pyrrolo [2,3 -b]pyridin-5- amine;

5- [5-(3 ,4-Dimethoxyphenyl)- lH-pyrrolo[2,3-b]pyridin-3-yl]-2-(tetrahydro-2H- pyran-4-yloxy)benzonitrile;

5- [3 -(1 -Benzyl- lH-pyrazol-4-yl)- l H-pyrrolo [2, 3 -b]pyridin-5-yl]-2-methoxyphenol; N- {4-[3-(l -Benzyl- lH-pyrazol-4-yl)- l H-pyrrolo [2,3 -b]pyridin-5- yl]phenyl} acetamide;

5-[5-(3 ,4-Dimethoxyphenyl)- lH-pyrrolo[2,3-b]pyridin-3-yl]-2- {[ l -

(hydroxyacetyl)piperidin-4-yl]oxy}benzonitrile;

tert- utyl 4- {2-cyano-4-[5-(3 ,4-dimethoxyphenyl)- lH-pyrrolo[2,3-b]pyridin-3- yl]phenoxy}piperidine-l -carboxylate; 5-[5-(3,4-Dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-(piperidin-4- yloxy)benzonitrile;

2- (Tetrahydro-2H-pyran-4-yloxy)-5-[5-(3,4,5-trimethoxyphenyl)-lH-pyrrolo[2,3- b]pyridin-3-yl]benzonitrile;

3- (l -Benzyl- lH-pyrazol-4-yl)-5-[(3,5-dimethoxyphenyl)sulfanyl]-lH-pyrrolo[2, 3- b]pyridine;

2-(Methoxymethoxy)-5-[5-(3,4,5-trimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3- yljbenzonitrile;

2- Hydroxy-5-[5-(3,4,5-trimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3- yljbenzonitrile;

3- (l-Benzyl-lH-pyrazol-4-yl)-N- {4-[2-(morpholin-4-yl)ethoxy]phenyl}-lH- pyrrolo[2,3-b]pyridin-5-amine;

3-(l-Benzyl-lH-pyrazol-4-yl)-N- {3-[2-(morpholin-4-yl)ethoxy]phenyl}-lH- pyrrolo[2,3-b]pyridin-5-amine;

{4- [3 -(1 -Benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5-yl]phenyl} methanol; l-[4-(2-{4-[3-(l -Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-2- methoxyphenoxy} ethyl)piperidin- 1 -yljethanone;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-N-(l-methylpiperidin-4-yl)-lH-pyrrolo [2,3 -b]pyridin-

5 -amine;

5-[5-(3,4-Dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-({ l -[(2S)-2- hydroxypropanoyl]piperidin-4-yl}oxy)benzonitrile;

5-[5-(3,4-Dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-[2-

(dimethylamino)ethoxy]benzonitrile;

5-[5-(3,4-Dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-(2- methoxyethoxy)benzonitrile;

3-(l-Benzyl-lH-pyrazol-4-yl)-N-phenyl-lH-pyrrolo[2,3-b]pyridine-5-carboxamide; 5-(5- { l-[2-(Morpholin-4-yl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridin-3-yl)-

2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5- {5-[(lE)-3-(Morpholin-4-yl)prop-l-en-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-2-

(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5-[5-(Morpholin-4-ylcarbonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-(tetrahydro-2H- pyran-4-yloxy)benzonitrile;

5- {5-[(3-Methoxyazetidin-l-yl)carbonyl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-2-

(tetrahydro-2H-pyran-4-yloxy)benzonitrile; 5-[5-(Piperazin-l-ylcarbonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-(tetrahydro-2H- pyran-4-yloxy)benzonitrile;

2-(l ,4-Dioxan-2-ylmethoxy)-5-(5- { 1 -[2-(morpholin-4-yl)ethyl]-l H-pyrazol-4-yl} - lH-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile;

5-[5-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-(tetrahydro-2H-pyran-4- yloxy)benzonitrile;

5-{5-[4-(Morpholin-4-ylmethyl)-l,3-thiazol-2-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-2-

(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-(5-{l-[2-(morpholin-4- yl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile;

5-(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-({l-[(2S)-2- hydroxypropanoyl]piperidin-4-yl}oxy)benzonitrile;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-[5-(lH-pyrazol-4-yl)-lH- pyrrolo[2,3-b]pyridin-3-yl]benzonitrile;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-[5-(lH-pyrazol-3-yl)-lH- pyrrolo[2,3-b]pyridin-3-yl]benzonitrile;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-[5-(l -methyl- 1 H-pyrazol-4- yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile;

tert- utyl 4- {3-[3-cyano-4-({ 1 -[(2S)-2-hydroxypropanoyl]piperidin-4- yl}oxy)phenyl]-lH-pyrrolo[2,3-b]pyridin-5-yl}-3,6-dihydropyridine-l(2H)- carboxylate;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-[5-(l,2,3,6- tetrahydropyridin-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-(5-{(lE)-3-[(2- methoxyethyl)amino]prop- 1 -en- 1 -yl} - 1 H-pyrrolo[2,3-b]pyridin-3- yl)benzonitrile;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-{5-[(lE)-3-(piperazin-l- yl)prop-l-en-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-[5-(l,3-thiazol-2-yl)-lH- pyrrolo[2,3-b]pyridin-3-yl]benzonitrile;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-{5-[(lE)-3-(morpholin-4- yl)prop-l-en-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-{5-[(lE)-3-(tetrahydro-2H- pyran-4-ylamino)prop-l-en-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile; 2-(Cyclopropylmethoxy)-5-{5-[(lE)-3-(morpholin-4-yl)prop-l-en-l-yl]-lH- pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

2-{[l-(Hydroxyacetyl)piperidin-4-yl]oxy}-5-{5-[(lE)-3-(morpholin-4-yl)prop-l-en- l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

2-({(3R)-l-[(2S)-2-Hydroxypropanoyl]pyrrolidin-3-yl}oxy)-5-{5-[(lE)-3-

(morpholin-4-yl)prop-l-en-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

2- {[(3R)-l-(Hydroxyacetyl)pyrrolidin-3-yl]oxy}-5-{5-[(lE)-3-(morpholin-4-yl)prop- l-en-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

3- (l -Benzyl- lH-pyrazol-4-yl)-5-{l-[2-(morpholin-4-yl)ethyl]-lH-pyrazol-4-yl}-lH- pyrrolo[2,3-b]pyridine;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-5-(l -methyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3- b]pyridine;

5-(5-{(lE)-3-[Bis(2-methoxyethyl)amino]prop-l-en-l-yl}-lH-pyrrolo[2,3-b]pyridin- 3-yl)-2-({l-[(2S)-2-hydroxypropanoyl]piperidin-4-yl}oxy)benzonitrile;

5-{5-[(lE)-3-(l,l-Dioxidothiomorpholin-4-yl)prop-l-en-l-yl]-lH-pyrrolo[2,3- b]pyridin-3-yl}-2-({l-[(2S)-2-hydroxypropanoyl]piperidin-4- yl}oxy)benzonitrile;

2-{[(3R)-l-(Hydroxyacetyl)pyrrolidin-3-yl]oxy}-5-{5-[3-(morpholin-4-yl)propyl]- lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

2- {[(3R)-l-(3-Hydroxypropanoyl)pyrrolidin-3-yl]oxy}-5-{5-[(lE)-3-(morpholin-4- yl)prop-l-en-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

3 - (1 -Benzyl- lH-pyrazol-4-yl)-5-(lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyri dine;

tert- utyl 4-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-3,6- dihydropyridine- 1 (2H)-carboxylate;

3-(l -Benzyl- lH-pyrazol-4-yl)-5-( 1,2,3, 6-tetrahydropyridin-4-yl)-lH-pyrrolo[2, 3- b]pyridine;

2-({l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-{5-[l-(morpholin-4- ylcarbonyl)- 1,2,3, 6-tetrahydropyridin-4-yl]-lH-pyrrolo[2,3-b]pyridin-3- yl}benzonitrile;

2- { [(3R)- 1 -Formylpyrrolidin-3-yl]oxy} -5 - {5 -[(1 E)-3-(morpholin-4-yl)prop- 1 -en- 1 - yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

2- { [(3R)- 1 -Acetylpyrrolidin-3-yl]oxy} -5 - {5 -[(1 E)-3-(morpholin-4-yl)prop- 1 -en- 1 - yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile; 5-[5-(3,6-Dihydro-2H-pyran-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-({ l-[(2S)-2- hydroxypropanoyl]piperidin-4-yl}oxy)benzonitrile;

3- (l -Benzyl- lH-pyrazol-4-yl)-5-[l-(methylsulfonyl)- 1 ,2,3, 6-tetrahydropyridin-4-yl]- lH-pyrrolo[2,3-b]pyridine;

3 -( 1 -Benzyl- 1 H-pyrazol-4-yl)-5 -( 1 -methyl- 1 ,2,3 ,6-tetrahydropyridin-4-yl)- 1 H- pyrrolo[2,3-b]pyridine;

5-[5-(l -Acetyl- 1 ,2,3, 6-tetrahydropyridin-4-yl)-lH-pyrrolo[2, 3 -b]pyridin-3-yl]-2-

(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5- { 1 -[(4-Methylphenyl)sulfonyl]-5-[ 1 -(1 ,3 -thiazol-2-ylcarbonyl)- 1 ,2,3,6- tetrahydropyridin-4-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-2-(tetrahydro-2H- pyran-4-yloxy)benzonitrile;

5-(l-[(4-Methylphenyl)sulfonyl]-5- { l-[(4-methylpiperazin-l-yl)carbonyl]-l ,2,3,6- tetrahydropyridin-4-yl}-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(tetrahydro-2H- pyran-4-yloxy)benzonitrile;

5- { l-[(4-Methylphenyl)sulfonyl]-5-[l-(morpholin-4-ylcarbonyl)-l ,2,3,6- tetrahydropyridin-4-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-2-(tetrahydro-2H- pyran-4-yloxy)benzonitrile;

2-(2-Cyano-4-{5-[(lE)-3-(morpholin-4-yl)prop-l-en-l-yl]-lH-pyrrolo[2,3-b]pyridin-

3-yl}phenoxy)acetamide;

2-(2-Methoxyethoxy)-5- {5-[(lE)-3-(morpholin-4-yl)prop-l-en-l-yl]-lH-pyrrolo[2,3- b]pyridin-3-yl}benzonitrile;

-[2-(Morpholin-4-yl)ethoxy]-5-{5-[(lE)-3-(morpholin-4-yl)prop-l-en-l-yl]-lH- pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

5-(5- { 1-[(1 -Methyl- lH-pyrazol-3-yl)carbonyl]- 1 ,2,3, 6-tetrahydropyridin-4-yl} -1 H- pyrrolo[2,3-b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

4- {3-[3-Cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH-pyrrolo[2,3-b]pyridin-5- yl} -N,N-dimethyl-3 ,6-dihydropyridine- 1 (2H)-carboxamide;

Methyl 4- {3-[3-cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH-pyrrolo[2,3- b]pyridin-5-yl}-3,6-dihydropyridine-l (2H)-carboxylate;

5- {5-[l-(Tetrahydro-2H-pyran-4-ylcarbonyl)-l ,2,3,6-tetrahydropyridin-4-yl]-lH- pyrrolo[2,3-b]pyridin-3-yl}-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile; 5-(5- {3-Methoxy-4-[2-(morpholin-4-yl)ethoxy]phenyl}-lH-pyrrolo[2,3-b]pyridin-3- yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile; 2-(Morpholin-4-ylmethyl)-5- {5-[(lE)-3-(morpholin-4-yl)prop-l-en-l-yl]-lH- pyrrolo[2,3-b]pyridin-3-yl}benzonitrile;

2-(Morpholin-4-ylmethyl)-5-[5-(3,4,5-trimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-

3-yl]benzonitrile;

5-[5-(l -Methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-(morpholin-4- ylmethyl)benzonitrile;

5-(5- { l-[2-(Morpholin-4-yl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridin-3-yl)-

2- (morpholin-4-ylmethyl)benzonitrile;

2-[2-(Dimethylamino)ethoxy]-5-(5- { l-[2-(morpholin-4-yl)ethyl]-lH-pyrazol-4-yl} - lH-pyrrolo[2,3-b]pyridin-3-yl)benzonitrile;

5-[5-(4-Hydroxy-3-methoxyphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-(tetrahydro- 2H-pyran-4-yloxy)benzonitrile;

4- {3-[3-Cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH-pyrrolo[2,3-b]pyridin-5- yl} -N,N-dimethyl-3 ,6-dihydropyridine- 1 (2H)-sulfonamide;

5- {5-[(lE)-3-(3-Methoxyazetidin-l-yl)-3-oxoprop-l-en-l-yl]-lH-pyrrolo[2,3- b]pyridin-3-yl}-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5- {5-[(lE)-3-Oxo-3-(pyrrolidin-l-yl)prop-l-en-l-yl]-lH-pyrrolo[2,3-b]pyridin-3- yl}-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

(2E)-3- {3-[3-Cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH-pyrrolo[2,3- b]pyridin-5-yl}-N-(2-methoxyethyl)prop-2-enamide;

(2E)-3- {3-[3-Cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH-pyrrolo[2,3- b]pyridin-5-yl}prop-2-enamide;

2-({ l-[(2S)-2-Hydroxypropanoyl]piperidin-4-yl}oxy)-5-(lH-pyrrolo[2,3-b]pyridin-

3- yl)benzonitrile;

N- {2-Cyano-4- [5 -(1 -methyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-3 - yl]phenyl}-3-methylbutanamide;

N- {2-Cyano-4- [5 -(1 -methyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-3- yl]phenyl}-2-cyclopropylacetamide;

5-(5- { 1 -[(4-Methylpiperazin-l-yl)sulfonyl]- 1 ,2,3, 6-tetrahydropyridin-4-yl} -1 H- pyrrolo[2,3-b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile; 5- {5-[l-(Cyclopropylcarbonyl)-l ,2,3,6-tetrahydropyridin-4-yl]-lH-pyrrolo[2,3- b]pyridin-3-yl}-2-({ l-[(2S)-2-hydroxypropanoyl]piperidin-4- yl}oxy)benzonitrile; tert-Butyl 4-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]piperazine- 1 -carboxylate;

3-(l-Benzyl-lH-pyrazol-4-yl)-5-(piperazin-l-yl)-lH-pyrrolo[2,3-b]pyridine;

tert- utyl 4-{3-[3-cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH-pyrrolo[2,3- b]pyridin-5-yl}piperidine-l -carboxylate;

2-[(2-Methylpropyl)amino]-5-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3- b]pyridin-3-yl]benzonitrile;

2- [(Cyclopropylmethyl)amino]-5-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3- b]pyridin-3-yl]benzonitrile;

3- [3-Fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-(l-methyl-lH-pyrazol-4-yl)- lH-pyrrolo[2,3-b]pyridine;

{4-[3-(l-Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-2- methoxyphenyl } (3 -methoxyazetidin- 1 -yl)methanone;

4- [3-(l-Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-2-methoxy-N-(2- methoxyethyl)benzamide;

{4-[3-(l-Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-2- methoxyphenyl}(morpholin-4-yl)methanone;

5- (5-Ethynyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-({l-[(2S)-2- hydroxypropanoyl]piperidin-4-yl}oxy)benzonitrile;

5-(5-{l-[2-(4-Methylpiperazin-l-yl)-2-oxoethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3- b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5-(5-{l-[2-(3-Methoxyazetidin-l-yl)-2-oxoethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3- b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

2-(4-{3-[3-Cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH-pyrrolo[2,3- b]pyridin-5-yl} - 1 H-pyrazol- 1 -yl)acetamide;

5-(5-Methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4- yloxy)benzonitrile;

l-{4-[3-(l -Benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5-yl]piperazin-l-yl}-

2-hydroxyethanone;

5-{5-[l-(Hydroxyacetyl)piperidin-4-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-2-

(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

N- {2-Cyano-4- [5 -(1 -methyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-3- yl]phenyl} -2-methylpropanamide; N-[2-Cyano-4-(5- { l-[2-(morpholin-4-yl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3- b]pyridin-3-yl)phenyl]-2-methylpropanamide;

2- [(2-Methylpropyl)amino]-5-(5-{ l -[2-(morpholin-4-yl)ethyl]-lH-pyrazol-4-yl}-lH- pyrrolo[2,3-b]pyridin-3-yl)benzonitrile;

N-[2-Cyano-4-(5- { l-[2-(morpholin-4-yl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3- b]pyridin-3-yl)phenyl]-3-methylbutanamide;

N- {2-Cyano-4- [5 -(1 -methyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-3- yl]phenyl}cyclopropanecarboxamide;

3 - (1 -Benzyl- lH-pyrazol-4-yl)-5-methoxy-lH-pyrrolo [2,3 -b]pyridine;

5-(5- {4-Methoxy-3-[2-(morpholin-4-yl)ethoxy]phenyl}-lH-pyrrolo[2,3-b]pyridin-3- yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5-(5- {(lE)-3-[(2-Hydroxyethyl)(methyl)amino]prop-l-en-l-yl}-lH-pyrrolo[2,3- b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5-[5-(l -Methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-2-(tetrahydro-2H- pyran-4-yloxy)benzonitrile;

3-[3-Chloro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5-(l-methyl-lH-pyrazol-4-yl)- lH-pyrrolo[2,3-b]pyridine;

{4-[3-(l-Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-2- methoxyphenyl} [3-(dimethylamino)azetidin-l-yl]methanone;

{4-[3-(l-Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-2- methoxyphenyl } (piperazin- 1 -yl)methanone;

N-{4-[3-(l -Benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5- yl]phenyl}piperazine- 1 -carboxamide;

N-{4-[3-(l -Benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5-yl]phenyl} -4- methylpiperazine- 1 -carboxamide;

l- {4-[3-(l -Benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5-yl]phenyl} -3- piperidin-4-ylurea;

N-{4-[3-(l -Benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5- yl]phenyl}prolinamide;

N-{3-[3-(l -Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]phenyl} -4- methylpiperazine- 1 -carboxamide;

N-{3-[3-(l -Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]phenyl}prolinamide; 3 -(1 -Benzyl- lH-pyrazol-4-yl)-5-[4-(morpholin-4-ylsulfonyl)phenyl]-lH-pyrrolo [2,3- b]pyridine;

5 -(1 -Methyl- lH-pyrazol-4-yl)-3-[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH- pyrrolo[2,3-b]pyridine;

3- [3-Fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-5- { l-[2-(morpholin-4- yl)ethyl]-lH-pyrazol-4-yl}-lH-pyrrolo[2,3-b]pyridine;

4- Acetyl-N- {4-[3-( 1 -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5- yl]phenyl}piperazine- 1 -carboxamide;

N- {3 -[3 -(1 -Benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yl]phenyl}piperazine- 1 -carboxamide;

4-Acetyl-N- {3-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]phenyl}piperazine- 1 -carboxamide;

l- {3-[3-(l -Benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]phenyl} -3- piperidin-4-ylurea;

4- [3 -(1 -Benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yljbenzenesulfonamide;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-5 - [4-(piperazin- 1 -ylsulfonyl)phenyl] - 1 H-pyrrolo [2,3 - b]pyridine;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-5 - [3 -(piperazin- 1 -ylmethyl)phenyl] - 1 H-pyrrolo [2,3 - b]pyridine;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-5 - [3 -(morpholin-4-ylmethyl)phenyl] - 1 H-pyrrolo [2,3 - b]pyridine;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-5 - {4- [(3 -methoxyazetidin- 1 -yl)methyl]phenyl} - 1 H- pyrrolo[2,3-b]pyridine;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-5 - {4-[(4-methylpiperazin- 1 -yl)methyl]phenyl} - 1 H- pyrrolo[2,3-b]pyridine;

3 -(1 -Benzyl- lH-pyrazol-4-yl)-5 -[4-(morpholin-4-ylmethyl)phenyl]-l H-pyrrolo [2, 3- b]pyridine;

5- {5-[l-(L-Prolyl)-l ,2,3,6-tetrahydropyridin-4-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-2-

(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

N-{4-[3-(l -Benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5-yl]phenyl} -2- hydroxyacetamide;

N-{3-[3-(l -Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]phenyl} -2- hydroxyacetamide; 3-(l-Benzyl-lH-pyrazol-4-yl)-5- {3-[(3-methoxyazetidin-l-yl)methyl]phenyl}-lH- pyrrolo[2,3-b]pyridine;

N-{3-[3-(l -Benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]benzyl}piperidin-4-amine;

3 - (1 -Benzyl- lH-pyrazol-4-yl)-5-[4-(piperazin-l-ylmethyl)phenyl]-lH-pyrrolo [2,3- b]pyridine;

4- {3-[3-Cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH-pyrrolo[2,3-b]pyridin-5- yl} -N-cyclopentyl-3 ,6-dihydropyridine- 1 (2H)-carboxamide;

5- {5-[l-(Pyrrolidin-l-ylcarbonyl)-l ,2,3,6-tetrahydropyridin-4-yl]-lH-pyrrolo[2,3- b]pyridin-3-yl}-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5- {5-[l-(Piperazin-l-ylcarbonyl)-l ,2,3,6-tetrahydropyridin-4-yl]-lH-pyrrolo[2,3- b]pyridin-3-yl}-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

4- {3-[3-Cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH-pyrrolo[2,3-b]pyridin-5- yl} -N-(piperidin-4-yl)-3 ,6-dihydropyridine- 1 (2H)-carboxamide;

4- {3-[3-Cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-lH-pyrrolo[2,3-b]pyridin-5- yl} -N-(2-methoxyethyl)-3 ,6-dihydropyridine- 1 (2H)-carboxamide;

3-(l-benzyl-lH-pyrazol-4-yl)-5-[3-(morpholin-4-ylmethyl)phenyl]-lH-pyrrolo[2,3- b]pyridine;

3-(l-benzyl-lH-pyrazol-4-yl)-5-[3-(piperazin-l-ylmethyl)phenyl]-lH-pyrrolo[2,3- b]pyridine;

3-(l-benzyl-lH-pyrazol-4-yl)-5- {3-[(3-methoxyazetidin-l-yl)methyl]phenyl}-lH- pyrrolo[2,3-b]pyridine;

N- {3 -[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]benzyl}piperidin-4-amine;

l- {3-[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]phenyl}methanamine;

N- {3 -[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yljbenzyl} acetamide;

N- {3 -[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yljbenzyl} glycinamide;

N- {3 -[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]benzyl}methanesulfonamide;

N-{3-[3-(l -benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]benzyl}-2- hydroxyacetamide; 1- {3-[3-(1 -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]benzyl}urea; 3 -(1 -benzyl- lH-pyrazol-4-yl)-5-[4-(piperazin-l-ylmethyl)phenyl]-l H-pyrrolo [2,3- b]pyridine;

3-(l-benzyl-lH-pyrazol-4-yl)-5- {4-[(4-methylpiperazin-l-yl)methyl]phenyl}-lH- pyrrolo[2,3-b]pyridine;

3 -(1 -benzyl- lH-pyrazol-4-yl)-5-[4-(morpholin-4-ylmethyl)phenyl]-l H-pyrrolo [2,3- b]pyridine;

3- (l-benzyl-lH-pyrazol-4-yl)-5- {4-[(3-methoxyazetidin-l-yl)methyl]phenyl}-lH- pyrrolo[2,3-b]pyridine;

1 - {4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yl]phenyl}methanamine;

N-{4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yljbenzyl} acetamide;

N- {4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yljbenzyl} glycinamide;

N-{4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yl]benzyl}methanesulfonamide;

N-{4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5-yl]benzyl} -2- hydroxyacetamide;

N-{4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yl]benzyl}morpholine-4-carboxamide;

N-{4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yl]phenyl}piperazine- 1 -carboxamide;

N-{4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5-yl]phenyl} -4- methylpiperazine- 1 -carboxamide;

4- acetyl-N- {4- [3 -(1 -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yl]phenyl}piperazine- 1 -carboxamide;

l- {4-[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]phenyl} -3- piperidin-4-ylurea;

pyrrolidin-2-yl {4-[3 -( 1 -benzyl- 1 H-pyrazol-4-yl)- 1 H-pyrrolo [2,3 -b]pyridin-5 - yl]phenyl} carbamate;

N-{4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5-yl]phenyl} -2- hydroxyacetamide; Ν-{4-[3-(1 -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yl]phenyl}prolinamide;

N-{4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5-yl]phenyl} -

N~3~,N~3— dimethyl-beta-alaninamide;

N-{4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5-yl]phenyl} -2- hydroxyethanesulfonamide;

N- {3 -[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]phenyl}piperazine- 1 -carboxamide;

4-acetyl-N- {3- [3 -(1 -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5- yl]phenyl}piperazine- 1 -carboxamide;

pyrrolidin-2-yl {3 -[3 -( 1 -benzyl- 1 H-pyrazol-4-yl)- 1 H-pyrrolo [2,3 -b]pyridin-5 - yl]phenyl} carbamate;

N-{3-[3-(l -benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]phenyl} -2- hydroxyacetamide;

N- {3 -[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]phenyl}prolinamide;

N- {3 -[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5- yl]phenyl} acetamide;

N- {3 -[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]phenyl} -

N~3~,N~3— dimethyl-beta-alaninamide;

N-{3-[3-(l -benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]phenyl} -2- hydroxyethanesulfonamide;

4- [3 -(1 -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2, 3 -b]pyridin-5-yl]benzenesulfonamide; 3 -(1 -benzyl- lH-pyrazol-4-yl)-5-[4-(piperazin-l-ylsulfonyl)phenyl]-l H-pyrrolo [2,3- b]pyridine;

3- (l-benzyl-lH-pyrazol-4-yl)-5- {4-[(4-methylpiperazin-l-yl)sulfonyl]phenyl}-lH- pyrrolo[2,3-b]pyridine;

4- [3 -(1 -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5-yl] -N-(piperidin-4- yl)benzenesulfonamide; 3 -(1 -benzyl- lH-pyrazol-4-yl)-5-[4-(morpholin-4-ylsulfonyl)phenyl]-lH-pyrrolo [2,3- b]pyridine;

3- (l-benzyl-lH-pyrazol-4-yl)-5-(2-methoxy-l ,3-thiazol-5-yl)-lH-pyrrolo[2,3- b]pyridine;

methyl 5-[3-(l -benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-l ,3- thiazole-2-carboxylate;

{5-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-l ,3-thiazol-2- yl } (3 -methoxyazetidin- 1 -yl)methanone;

5-[3-(l -benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-l ,3-thiazole-2- carboxamide;

{5-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-l ,3-thiazol-2- yl} [3-(dimethylamino)azetidin-l-yl]methanone;

{5-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-l ,3-thiazol-2- yl} (pyrrolidin- 1 -yl)methanone;

{5-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-l ,3-thiazol-2- yl } (piperazin- 1 -yl)methanone;

{4-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-l ,3-thiazol-2- yl}(morpholin-4-yl)methanone;

{4-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-l ,3-thiazol-2- yl } (3 -methoxyazetidin- 1 -yl)methanone;

4- [3-(l -benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-N-(2- methoxyethyl)- 1 ,3 -thiazole-2-carboxamide;

{4-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-l ,3-thiazol-2- yl} (pyrrolidin- 1 -yl)methanone;

{4-[3-(l-benzyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-l ,3-thiazol-2- yl } (piperazin- 1 -yl)methanone;

2- {4-[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5-yl]-l H-pyrazol-1 - yl}acetamide;

2- {4-[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5-yl]-l H-pyrazol-1 - yl } - 1 -(piperazin- 1 -yl)ethanone;

2- {4-[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5-yl]-l H-pyrazol-1 - yl} - 1 -(4-methylpiperazin- 1 -yl)ethanone;

2- {4-[3-(l -benzyl- lH-pyrazol-4-yl)-lH-pyrrolo [2,3 -b]pyridin-5-yl]-l H-pyrazol-1 - yl} - 1 -(morpholin-4-yl)ethanone; 2- {4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5-yl]- l H-pyrazol- 1 - yl} -N-(2-methoxyethyl)acetamide;

2- {4-[3-(l -benzyl- lH-pyrazol-4-yl)-l H-pyrrolo [2,3 -b]pyridin-5-yl]- l H-pyrazol- 1 - yl } - 1 -(pyrrolidin- 1 -yl)ethanone;

4- {3-[3-cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]- lH-pyrrolo[2,3-b]pyridin-5- yl} -N-cyclopentyl-3 ,6-dihydropyridine- 1 (2H)-carboxamide;

5- {5-[ 1 -(pyrrolidin- 1 -ylcarbonyl)- 1 ,2,3 ,6-tetrahydropyridin-4-yl]- 1 H-pyrrolo[2,3 - b]pyridin-3-yl} -2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5-(5- { l -[(4-methylpiperazin- l -yl)carbonyl]- 1 ,2,3, 6-tetrahydropyridin-4-yl} -1 H- pyrrolo[2,3-b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile; 4- {3-[3-cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]- lH-pyrrolo[2,3-b]pyridin-5- yl} -N-(piperidin-4-yl)-3 ,6-dihydropyridine- 1 (2H)-carboxamide;

4- {3-[3-cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]- lH-pyrrolo[2,3-b]pyridin-5- yl} -N-[2-(dimethylamino)ethyl]-3,6-dihydropyridine- l (2H)-carboxamide;

4- {3-[3-cyano-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]- lH-pyrrolo[2,3-b]pyridin-5- yl} -N-(2-methoxyethyl)-3 ,6-dihydropyridine- 1 (2H)-carboxamide;

5- (5- { l -[(2R)-2-hydroxypropanoyl]- l ,2,3,6-tetrahydropyridin-4-yl} - lH-pyrrolo[2,3- b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5-(5- { l -[(2S)-2-hydroxypropanoyl]-l ,2,3,6-tetrahydropyridin-4-yl} -lH-pyrrolo[2,3- b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

5- {5-[ l -(N,N-dimethylglycyl)-l ,2,3,6-tetrahydropyridin-4-yl]-l H-pyrrolo[2,3- b]pyridin-3-yl} -2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile; and

5-[5-(l -prolyl- 1 ,2,3, 6-tetrahydropyridin-4-yl)-lH-pyrrolo[2, 3 -b]pyridin-3-yl]-2-

(tetrahydro-2H-pyran-4-yloxy)benzonitrile;

and pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising at least one compound of any one of claims 1 through 13 and a pharmaceutically acceptable vehicle.

15. A method of treating inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders, in a human patient, comprising identifying a patient in need of such treatment and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

16. A method of treating inflammation, comprising identifying a human patient having inflammation and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

17. A method of treating RA, comprising identifying a human patient having RA and administering a therapeutically effective amount of a compound of any one of claims 1 through 13 , or composition of claim 14, to said patient.

18. A method of treating SLE, comprising identifying a human patient having SLE and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

19. A method of treating a disease associated with aberrant accumulation of cytosolic nucleic acids, comprising identifying a human patient having disease associated with aberrant accumulation of cytosolic nucleic acids and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

20. A method of treating Sjogrens syndrome, comprising identifying a human patient having Sjogrens syndrome and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

21. A method of treating Aicardi-Goutieres syndrome, comprising identifying a human patient having Aicardi-Goutieres syndrome and administering a

therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

22. A method of treating a subtype of lupus associated with aberrant

accumulation of cytosolic nucleic acids, comprising identifying a human patient having a subtype of lupus associated with aberrant accumulation of cytosolic nucleic acids and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

23. A method of treating chilblain lupus, comprising identifying a human patient having chilblain lupus and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

24. A method of treating RVCL, comprising identifying a human patient having RVCL and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

25. A method of treating systemic sclerosis, comprising identifying a human patient having systemic sclerosis and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

26. A method of treating myositis, comprising identifying a human patient having myositis and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

27. A method of treating dermatomyositis, comprising identifying a human patient having dermatomyositis and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

28. A method of treating polymyositis, comprising identifying a human patient having polymyositis and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

29. A method of treating psoriasis, comprising identifying a human patient having psoriasis and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

30. A method of treating COPD, comprising identifying a human patient having COPD and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

31. A method of treating IBD, comprising identifying a human patient having IBD and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

32. A method of treating obesity, comprising identifying a human patient having obesity and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

33. A method of treating insulin resistance, comprising identifying a human patient having insulin resistance and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

34. A method of treating NIDDM, comprising identifying a human patient having NIDDM and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

35. A method of treating metabolic syndrome, comprising identifying a human patient having metabolic syndrome and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

36. A method of treating cancer, comprising identifying a human patient having cancer and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

37. A method of delaying the onset, or reducing the severity of, one or more symptoms of inflammation, RA, SLE, diseases associated with aberrant

accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi- Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders, in a human patient, comprising identifying a patient in need of such treatment and administering a therapeutically effective amount of a compound of any one of claims 1 through 13, or composition of claim 14, to said patient.

38. A method of making a compound of any one of claims 1 through 13, comprising following one of the general synthetic schemes 1 , 2 or 3, asdisclosed herein.

39. The use of a compound of any one of claims 1 through 13 for the manufacture of a medicament useful for human therapy.

40. The use of claim 39, wherein said therapy comprises therapy for

inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders, in a human patient.

41. The use of claim 39, wherein said therapy comprises delaying the onset of, or reducing the symptoms of, inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi- Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders, in a human patient.

42. A composition for treating inflammation, RA, SLE, diseases associated with aberrant accumulation of cytosolic nucleic acids (including Sjogrens syndrome, Aicardi-Goutieres syndrome, subtypes of SLE, chilblain lupus, and RVCL), systemic sclerosis, myositis (including dermatomyositis and polymyositis), psoriasis, COPD, IBD, obesity, insulin resistance, NIDDM, metabolic syndrome and cancer, and complications associated with these diseases and disorders, in a human patient, said composition comprising a compound of any one of claims 1 through 13.

43. A method of inhibiting the kinase activity of ΙΚΚε, TBK1 , or both ΙΚΚε and TBK1 in human cells comprising, contacting said cells with a compound of any one of claims 1 through 13.

44. The method of claim 43 wherein said cells are within the body of a human patient.

45. The method of claim 43 or 44, wherein said method consists of inhibiting the kinase activity of ΙΚΚε.

46. The method of claim 43 or 44, wherein said method consists of inhibiting the kinase activity of TBK1.

47. The method of claim 43 or 44, wherein said method consists of inhibiting the kinase activity of ΙΚΚε and TBK1.