NIK compounds

Abstract

Compounds having the following formula (I) or a stereoisomer or pharmaceutically-acceptable salt thereof, where all substituents are as defined herein, are inhibitors of NF-kB-inducing kinase (NIK) useful for treating diseases including, among others, autoimmune and inflammatory disorders and cancer.

Description

[0001] NIK COMPOUNDS

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No.

[0004] 63 / 762,890, filed February 25, 2025, the entire content of which is hereby incorporated herein by reference.

[0005] FIELD

[0006] This invention relates to compounds which are inhibitors of NF-kB-inducing kinase (NIK) useful for treating diseases including, among others, autoimmune and inflammatory disorders and cancer. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to the inhibition of NF-kB-inducing kinase in a mammal.

[0007] BACKGROUND OF THE INVENTION NF-kB-inducing kinase (NIK) is a serine / threonine kinase also known as MAPK kinase kinase 14 (MAP3K14) and is a member of the MAPK family of kinases. NIK is a critical regulator of the non-canonical nuclear factor-kappa B (NF-kB) pathway and is present at low levels in resting cells due to its association with tumor necrosis factor receptor associated factor 3 (TRAF3) that results in its ubiquitination by cellular inhibitor of apoptosis (cIAP) (Gyrd-Hansen andMeier, Nat. Rev. Cancer. 2010, 10, 561-574). NIK is activated and stabilized following interaction of a subset of TNF receptor superfamily (TNFRSF) members such as B-cell activating factor receptor (BAFF-R), CD40, lymphotoxin P-receptor (LTpR), Fnl4, RANK and 0X40 with their respective ligands Sun, Cell Res. 2011, 21, 71-85).. Activated NIK phosphorylates IkB kinase-a (IKKa), leading to the partial proteolysis of pl 00; liberating p52 which then heterodimerizes with RelB, translocates to the nucleus and mediates expression of genes, many of which are involved in inflammation.

[0008] NF-kB signaling pathway when activated drives multiple cellular functions such as apoptosis, proliferation and inflammation etc. Additionally aberrant upregulation of the NF-kB signaling pathway is a hallmark of many cancers and scientific studies show that blocking the NF-kB signaling pathway in cancer cells causes such cells to ceaseproliferating, to die, or to become more sensitive to the action of anti-cancer therapies (Maubach et al, 2019, 1871, 40-49). Enhanced and abnormal upregulation of NF-kB signaling pathway also contributes to septic shock, metabolic diseases and multiple autoimmune disorders (Herrington etal, 2016, 21, 223-242).

[0009] A large number of cancer indications display constitutive NFkB pathway activity. NF-kB signaling promotes oncogenesis, cancer progression and resistance to standard-of-care (SOC) therapies. The NF-kB pathway can be dissected into canonical and non-canonical pathways, each regulated by distinct sets of molecular pathway constituents. NIK (gene: MAP3K14) is a central regulator of the alternative NF-kB pathway and typically expressed at very low levels in healthy tissue and upregulated in response to a variety of growth factors or other extracellular stimuli. In a variety of cancers, genetic mutations and / or deletions in negative regulators result in protein stabilization of NIK. NIK stabilization as a result of genetic lesions enables this kinase to mediate downstream constitutive signaling that promotes tumor growth and the upregulation of anti-apoptotic factors vital for cancer cell survival. Indications where NIK is known to play a key role include heme indications such as multiple myeloma, lymphomas, CML and AML. Several solid indications such as pancreatic, skin, breast and colorectal cancers have also been shown to be dependent on NIK. Studies have shown that genetic ablation of the MAP3K14 gene sensitizes these indications to cell cycle arrest and apoptosis. Furthermore, genetic silencing of MAP3K14 sensitizes several indications to radiation and chemotherapies currently being used as frontline therapies in the clinic.

[0010] The NIK driven non-canonical NF-kB pathway drives signals downstream of TNFRSF members that are associated with metabolic diseases (Sheng et al, 2012;

[0011] 18:943-949), kidney disease (Poveda et al, 2013; 4:447) and various autoimmune diseases such as SLE, RA and IBD among others (Sun, 2017,17, 545-558). Hence, pharmaceutical agents capable of inhibiting NIK and thereby reducing NF-kB signaling can have a therapeutic benefit for the treatment of diseases and disorders for which undesired or over-activation of NF-kB signaling is observed.

[0012] SUMMARY

[0013] The present disclosure provides compounds that modulate the expression or activity of NIK. The disclosure also provides compositions, including pharmaceuticalcompositions, kits that include the compounds, and methods of using (or administering) and making the compounds. The compounds provided herein are useful in treating diseases, disorders, or conditions that are mediated by NIK. The disclosure also provides compounds for use in therapy. The disclosure further provides compounds for use in a method of treating a disease, disorder, or condition that is mediated by NIK. Moreover, the disclosure provides uses of the compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by (or mediated, at least in part, by) NIK.

[0014] In one aspect, provided are compounds of Formula (I):

[0015]

[0016] Formula (I)

[0017] or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof; wherein n is 1, 2 or 3;

[0018] m is 0, 1, 2, 3 or 4;

[0019] X is selected from -N(R5)- and -C(R5)(R6)-;

[0020] each R1is independently selected from hydrogen, halo, cyano, hydroxy, amino, - C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, - S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, Ci-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100; or,

[0021] alternatively, two R1groups, together with the atoms to which they are attached, combine to form a C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, or 4-10 membered heterocyclylcontaining 1 to 4 heteroatoms selected from N, O, and S; wherein each C3-8 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;

[0022] each R2R3, R4, R6and R7is independently selected from hydrogen, halo, cyano, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;

[0023] R5is selected from absent, hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R200;

[0024] each Raand Rbis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R200;

[0025] each R100is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -N(Rc)C(O)Rd, -S(O)NRcRd, -S(O)2NRcRd, -S(O)Rh, -S(O)2Rh, -NRcRd, -ORC, -SRC, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201;

[0026] each Rcand Rdis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S;

[0027] each R200and R201is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, - S(O)NReRf, -S(O)2NReRf, -8(0)^, -8(0)2^, -NReRf, -ORe, -SRe, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four 300.

[0028] each Rg, Rhand R1is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R300;

[0029] wherein each R300is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, - S(O)NReRf, -S(O)2NReRf, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0030] each Reand Rfis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0031] In one aspect, provided are processes and intermediates for making the compounds of of Formula I, II, III and IV.

[0032] In one aspect, provided are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds disclosed herein.

[0033] The present application also provides methods for the inhibition of NF-kB-inducing kinase (NIK) comprising administering a therapeutically effective amount of at least one of Formula I, II, III or IV.

[0034] The present application also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering toa host in need of such treatment a therapeutically effective amount of at least one of the compounds disclosed herein.

[0035] In one aspct, provided is a method for treating inflammatory and autoimmune diseases or diseases. Inflammatory and autoimmune disease or disorder includes any disease having an inflammatory or autoimmune component.

[0036] DETAILED DESCRIPTION

[0037] In a first aspect, provided are compounds of formula (I) that function as inhibitors of NF-kB-inducing kinase (NIK):

[0038]

[0039] Formula (I)

[0040] or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof; wherein n is 1, 2 or 3;

[0041] m is 0, 1, 2, 3 or 4;

[0042] X is selected from -N(R5)- and -C(R5)(R6)-;

[0043] each R1is independently selected from hydrogen, halo, cyano, hydroxy, amino, - C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, - S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, Ci-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100; or,

[0044] alternatively, two R1groups, together with the atoms to which they are attached, combine to form a C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, or 4-10 membered heterocyclylcontaining 1 to 4 heteroatoms selected from N, O, and S; wherein each C3-8 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;

[0045] each R2R3, R4, R6and R7is independently selected from hydrogen, halo, cyano, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;

[0046] R5is selected from absent, hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R200;

[0047] each Raand Rbis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R200;

[0048] each R100is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -N(Rc)C(O)Rd, -S(O)NRcRd, -S(O)2NRcRd, -S(O)Rh, -S(O)2Rh, -NRcRd, -ORC, -SRC, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201;

[0049] each Rcand Rdis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S;

[0050] each R200and R201is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, -S(O)2NReRf, -8(0)^, -8(0)2^, -NReRf, -0Re, -SRe, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four 300.

[0051] each Rg, Rhand R1is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R300;

[0052] wherein each R300is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(0)NReRf, -N(Re)C(0)Rf, -S(O)NReRf, -S(O)2NReRf, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;

[0053] each Reand Rfis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0054] In one embodiment, provided are compounds of formula (II):

[0055]

[0056] Formula (II)

[0057] or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof; wherein m, X, R2, R3R4and R7are as defined above.In one embodiment, provided are compounds of formula (III):

[0058]

[0059] Formula (III)

[0060] or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof; wherein X and R3are defined as above.

[0061] In a preferred embodiment, the application relates to a compound of Formula II or III wherein each R7is independently Ci-6 alkyl or Ci-6 alkyl substituted with -ORC; wherein Rcis as defined above.

[0062] In one embodiment, provided are compounds of formula (IV):

[0063]

[0064] Formula (V)

[0065] or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof; wherein X and R3are defined as above.

[0066] In a preferred embodiment, provided are compounds according formula I, II, III or IV wherein R3is selected from -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, Ci-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 memberedheterocyclyl is optionally substituted with one to four R100; wherein Ra, Rb, Rgand R100are as defined above.

[0067] In a preferred embodiment, provided are compounds according formula I, II, III or IV wherein R3is selected from -C(O)ORb, -C(O)NRaRb, and Ce-io aryl; wherein Ce-io aryl is optionally substituted with one to four R100; wherein Ra, Rband R100are as defined above.

[0068] In a preferred embodiment, provided are compounds according formula I, II, III or IV wherein each Raand Rbis independently selected from hydrogen and Ci-6 alkyl; wherein each Ci-6 alkyl is optionally substituted with one to four R200; wherein R200is as defined above.

[0069] In a preferred embodiment, provided are compounds according formula I, II, III or IV wherein R200is Ce-io aryl.

[0070] In a preferred embodiment, provided are compounds according formula I, II, III or IV wherein R3is -C(O)ORb; wherein Rbis Ci-6 alkyl.

[0071] In a preferred embodiment, provided are compounds according formula I, II, III or IV wherein R3is Ce-io aryl; wherein said Ce-io aryl is optionally substituted with one to four R100and wherein R100is as defined above; preferably, halo or Ci-6 alkyl.

[0072] In a preferred embodiment, provided are compounds according formula I, II, III or IV wherein R3is selected from

[0073]

[0074] wherein p is 1, 2, 3, 4 or 5; and R100and R200are as defined above.

[0075] In a preferred embodiment, provided are compounds according formula I, II, III or IV wherein X is -N(R5)-; wherein X and R5are as defined above.

[0076] In a preferred embodiment, provided are compounds according formula I, II, III or IV wherein X is -C(R5)(R6)-; wherein X, R5and R6are as defined above.

[0077] In another embodiment, there is provided a pharmaceutical composition comprising one or more compounds of formula I and a pharmaceutically acceptable carrier or diluent.

[0078] The application relates to methods of treating an inflammatory or autoimmune disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases) comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I.

[0079] The present invention also provides a method for treating a disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I, wherein the disease is rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, Crohn's Disease, psoriatic arthritis, Sjogren's syndrome, systemic scleroderma, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult onset Stills, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes, insulin dependent diabetes mellitus, sepsis, septic shock, Shigellosis, pancreatitis (acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pulmonary inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.The present invention also provides a method of treating an inflammatory or autoimmune disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of said diseases), comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I, wherein the disease is selected from systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, Crohn's Disease, ulcerative colitis, type 1 diabetes, psoriasis, rheumatoid arthritis, systemic onset juvenile idiopathic arthritis and ankylosing spondylitis.

[0080] The present invention also provides a method for treating a rheumatoid arthritis (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of rheumatoid arthritis, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I.

[0081] In addition, the present invention also provides a method of treating a condition (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these conditions) comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I

[0082] In addition, the present application also provides a method for the treatment of a haematological malignancy or solid tumor. Such methods include the treatment of haematological malignancies, including multiple myeloma, non-Hodgkin's lymphoma, Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma. In some embodiments, the application provides methods for the treatment of solid tumors, including treatment for pancreatic cancer, breast cancer, melanoma and non-small cell lung cancer.

[0083] The present application further provides a method for treating carcinomas, for example a carcinoma of the bladder, breast, colon (including colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung (including adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, squamous lung cancer), oesophagus, head and neck, gall bladder, ovary, pancreas (including exocrine pancreatic carcinoma), stomach, gastrointestinal cancer (including gastrointestinal stromal tumors), cervix, endometrium, thyroid, prostate, or skin (including squamous cell carcinoma and dermatofibrosarcoma protuberans); pituitarycancer, a hematopoietic tumor of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (including diffuse large B-cell lymphoma, mantle cell lymphoma), T-cell leukaemia, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, for example leukemias, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocyte leukemia; multiple myeloma; thyroid follicular cancer; hepatocellular cancer, a tumor of mesenchymal origin (including fibrosareoma and rhabdomyosarcoma) a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma (including glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

[0084] The present invention also provides the compounds of the present invention for use in therapy.

[0085] In another embodiment, compounds of formula I are selected from exemplified compounds or combinations of exemplified compounds or other embodiments herein.

[0086] In another embodiment are compounds having an ICso < 1000 nM in at least one of the assays described below.

[0087] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects and / or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

[0088] DETAILED DESCRIPTION OF THE INVENTION

[0089] The following are definitions of terms used in this specification and appended claims. The initial definition provided for a group or term herein applies to that group orterm throughout the specification and claims, individually or as part of another group, unless otherwise indicated.

[0090] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0091] Compounds of this invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and / ra / 7.s-geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

[0092] When any variable (e.g., R3) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R3, then said group may optionally be substituted with up to two R3groups and R3at each occurrence is selected independently from the definition of R3. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0093] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0094] In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g.,MCPBA and / or hydrogen peroxides) to afford other compounds of this invention. Thus, all shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N®0) derivative.

[0095] In accordance with a convention used in the art,

[0096]

[0097] is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0098] A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.

[0099] The term "optionally substituted" in reference to a particular moiety of the compound of Formula I (e.g., an optionally substituted heteroaryl group) refers to a moiety having 0, 1, 2, or more substituents. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and / or inherently unstable.

[0100] As used herein, the term "at least one chemical entity" is interchangeable with the term "a compound".

[0101] The prefix "Cu-v" indicates that the following group has from u to v carbon atoms. For example, "C1-6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0102] As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-10 alkyl" (or alkylene), is intended to include Ci, C2, C3, C4, Cs, Ce, C7, Cs, C9, and C10 alkyl groups. Additionally, for example, "Ci-Ce alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group. Example alkyl groupsinclude, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, / -butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0103] "Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration and having one or more double carbon-carbon bonds that may occur in any stable point along the chain. For example, "C2-6 alkenyl" (or alkenylene), is intended to include C2, C3, C4, Cs, and Ce alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3 -pentenyl, and the like.

[0104] "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either straight or branched configuration and having one or more triple carbon-carbon bonds that may occur in any stable point along the chain. For example, "C2-6 alkynyl" (or alkynylene), is intended to include C2, C3, C4, Cs, and Ce alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

[0105] One skilled in the field will understand that, when the designation "CO2" is used o II

[0106] herein, this is intended to refer to the group c o

[0107] When the term "alkyl" is used together with another group, such as in "arylalkyl", this conjunction defines with more specificity at least one of the substituents that the substituted alkyl will contain. For example, "arylalkyl" refers to a substituted alkyl group as defined above where at least one of the substituents is an aryl, such as benzyl. Thus, the term aryl(Co-4)alkyl includes a substituted lower alkyl having at least one aryl substituent and also includes an aryl directly bonded to another group, i.e., aryl(Co)alkyl. The term "heteroarylalkyl" refers to a substituted alkyl group as defined above where at least one of the substituents is a heteroaryl.

[0108] When reference is made to a substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group, these groups are substituted with one to three substituents as defined above for substituted alkyl groups.

[0109] The term "alkoxy" refers to an oxygen atom substituted by alkyl or substituted alkyl, as defined herein. For example, the term "alkoxy" includes the group -O-Ci-ealkylsuch as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. "Lower alkoxy" refers to alkoxy groups having one to four carbons.

[0110] The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or polycyclic ring systems. C3-7 cycloalkyl is intended to include C3, C4, Cs, Ce, and C7 cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,

[0111] [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g.,

[0112] [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

[0113] The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, and naphthyl groups, each of which may be substituted.

[0114] Accordingly, in compounds of formula I, the term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclooctyl, etc., as well as the following ring systems:

[0115]

[0116]

[0117] and the like, which optionally may be substituted at any available atoms of the ring(s).

[0118] The term "halo" or "halogen" refers to chloro, bromo, fluoro and iodo.

[0119] The term "haloalkyl" means a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono, bi, and trifluoromethyl.

[0120] The term "haloalkoxy" means an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF3.

[0121] The terms "heterocycle", "heterocycloalkyl", "heterocyclo", "heterocyclic", or "heterocyclyl" may be used interchangeably and refer to substituted and unsubstituted 3-to 7-membered monocyclic groups, 7- to 11 -membered bicyclic groups, and 10- to 15-membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S or N), said heteroatom containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. As used herein the terms "heterocycle", "heterocycloalkyl", "heterocyclo", "heterocyclic", and "heterocyclyl" include "heteroaryl" groups, as defined below.

[0122] In addition to the heteroaryl groups described below, exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro- 1,1 -di oxothienyl and the like. Exemplary bicyclic heterocyclo groups include quinuclidinyl.The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or nonaromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. As valence allows, if said further ring is cycloalkyl or heterocyclo it is additionally optionally substituted with =0 (oxo).

[0123] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

[0124] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodi oxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrol opyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.

[0125] Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

[0126] In compounds of formula I, preferred heteroaryl groups include:

[0127]

[0128]

[0129] the like, which optionally may be substituted at any available carbon or nitrogen atom.

[0130] Unless otherwise indicated, when reference is made to a specifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclo (e.g, pyrrolidinyl, piperidinyl, and morpholinyl) or heteroaryl (e.g, tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl) the reference is intended to include rings having 0 to 3, preferably 0 to 2, substituents selected from those recited above for the aryl, cycloalkyl, heterocyclo and / or heteroaryl groups, as appropriate.

[0131] The term "carbocyclyl" or "carbocyclic" refers to a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and aryl rings. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of mono- and bicyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent- 1-enyl, l-cyclopent-2-enyl, 1-cy cl opent-3 -enyl, cyclohexyl, 1 -cyclohex- 1-enyl, l-cyclohex-2-enyl, 1 -cyclohex-3 -enyl, phenyl and naphthyl. The carbocyclic ring may be substituted in which case the substituents are selected from those recited above for cycloalkyl and aryl groups.

[0132] The term "alkylthio" refers to the group "alkyl-S-".

[0133] The term "acyl" refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0134] The term "amido" refers to both a "C-amido" group which refers to the group — C(O)NRgRhand an "N-amido" group which refers to the group -NRgC(O)Rh, wherein Rgand Rhare independently selected from hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.The term "amino" refers to the group -NRgRhwherein Rgand Rhare independently selected from hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.

[0135] The term "azido" refers to -N3.

[0136] The term "carbamoyl" refers to both an "O-carbamoyl" group which refers to the group -O-C(O)NR1Riand an "N-carbamoyl" group which refers to the group -NR1C(O)ORi, wherein R1and R> are independently selected from hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0137] The term "carboxyl" refers to -C(O)OH.

[0138] The term "carboxyl ester" refers to both -OC(O)R and -C(O)ORg, wherein Rgis hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0139] The term "cyano" or "carbonitrile" refers to the group -CN.

[0140] The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C. sub.3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C. sub.3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C. sub.3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C.sub.3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C. sub.3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0141] The term "heteroatoms" shall include oxygen, sulfur and nitrogen.

[0142] When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.

[0143] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds and compounds useful as pharmaceutically-acceptable compounds and / or intermediate compounds useful in making pharmaceutically-acceptable compounds.It should be understood that the selections for all groups, including for example, alkoxy, thioalkyl, and aminoalkyl, will be made by one skilled in the field to provide stable compounds.

[0144] The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo, or keto, ( / .< ., =0) then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0145] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and subsequent formulation into an efficacious therapeutic agent. It is preferred that the presently recited compounds do not contain aN-halo, S(O)2H, or S(O)H group.

[0146] The compounds of formula I may exist in a free form (with no ionization) or can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to the free form and to salts thereof. The term "salt(s)" denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "salt(s)" may include zwitterions (inner salts), e.g, when a compound of formula I, contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable ( / .< ., non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, e.g, in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the invention. Salts of the compounds of the formula I may be formed, for example, by reacting a compound of the formula I with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0147] Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxy ethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3 -phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0148] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-P-phenethylamine, 1 -ephenamine, 7V,7V'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Preferred salts include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate salts.

[0149] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings andanimals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0150] As used herein, "pharmaceutically-acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically-acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically-acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

[0151] The pharmaceutically-acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.

[0152] All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers may include compounds which are optical isomers through possession of one or more chiral atoms, as well as compounds which are optical isomers by virtue of limited rotation about one or more bonds (atropisomers). The definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation orcrystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0153] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include13C and14C.

[0154] Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0155] Prodrugs and solvates of the inventive compounds are also contemplated. The term "prodrug" denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, and / or a salt and / or solvate thereof. Any compound that will be converted in vivo to provide the bioactive agent ( / .< ., the compound for formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I include Ci-ealkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl,

[0156] Ci-ealkanoyloxy-Ci-ealkyl, e.g., acetoxymethyl, pivaloyloxymethyl or

[0157] propionyl oxy methyl, Ci-ealkoxycarbonyloxy-Ci-ealkyl, e.g., methoxy carbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-l,3-dioxolen-4-yl)-methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0158] Compounds of the formula I and salts thereof may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that the all tautomeric forms, insofar as they may exist, are included within the invention. Additionally, inventive compounds may have trans- and cv.s-isomers.

[0159] It should further be understood that solvates (e.g., hydrates) of the compounds of Formula I are also with the scope of the present invention. Methods of solvation are generally known in the art.

[0160] Generally, the compounds disclosed herein are useful for the treatment of diseases or conditions mediated by NF-kB-inducing kinase (NIK or MAP3K14). The compounds herein can be useful for treating or preventing diseases such as autoimmune disorders, inflammatory disorders, cancer, diabetes and metabolic disorders.

[0161] In some embodiments, the disease is an autoimmune disease. In particular embodiments, the autoimmune disease is selected from inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriasis, systemic lupus erythematosus (SLE), myestenia gravis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, sepsis, Sjoegren's syndrome, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD).

[0162] In some embodiments, the disease or condition mediated by NIK is inflammatory bowel disease (IBD). The most common forms of IBD are ulcerative colitis and Crohn's disease. Other forms of IBD that can be treated include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behcet's disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation induced enteritis, short bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, and chronic diarrhea.

[0163] Treating or preventing IBD also includes ameliorating or reducing one or more symptoms of IBD. As used herein, the term "symptoms of IBD" includes abdominal pain,diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications, such as dehydration, anemia and malnutrition. A number of such symptoms are subject to quantitative analysis (e.g. weight loss, fever, anemia, etc.). Some symptoms are readily determined from a blood test (e.g. anemia) or a test that detects the presence of blood (e.g. rectal bleeding).

[0164] The course of IBD varies, and is often associated with intermittent periods of disease remission and disease exacerbation. Various methods have been described for characterizing disease activity and severity of IBD as well as response to treatment in subjects having IBD. Treatment according to the present methods are generally applicable to a subject having IBD of any level or degree of disease activity.

[0165] Criteria useful for assessment of disease activity in subjects with ulcerative colitis can be found in, e.g., Truelove et al. (1955) Br Med J 2:1041-1048.) Using these criteria, disease activity can be characterized in a subject having IBD as mild disease activity or severe disease activity. Subjects who do not meet all the criteria for severe disease activity, and who exceed the criteria for mild disease activity are classified as having moderate disease activity.

[0166] The presently disclosed treatment methods can also be applied at any point in the course of the disease. In certain embodiments, the methods are applied to a subject having IBD during a time period of remission (i.e., inactive disease). In such embodiments, the present methods provide benefit by extending the time period of remission (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. In other embodiments, methods may be applied to a subject having IBD during a period of active disease. Such methods provide benefit by reducing the duration of the period of active disease, reducing or ameliorating one or more symptoms of IBD, or treating IBD.

[0167] Measures for determining efficacy of treatment of IBD in clinical practice have been described and include, for example, the following: symptom control; fistula closure; extent of corticosteroid therapy required; and, improvement in quality of life. Heath-related quality of life (HRQL) can be assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is extensively used in clinical practice to assess quality of life in a subject with IBD. (See Guyatt et al. (1989) Gastroenterology 96:804-810.)Improvements in any of the foregoing response criteria are specifically provided by the methods of the present disclosure.

[0168] In some embodiments, the disease or condition mediated by NIK is diabetes. In some embodiments, diabetes includes type 1 and type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, impaired fasting glycaemia and impaired glucose tolerance. Type 1 diabetes is also known as Insulin Dependent Diabetes Mellitus (IDDM). Type 2 is also known as Non-Insulin-Dependent Diabetes Mellitus (NIDDM). In some embodiments, the metabolic disorder is selected from non-alcohol steatohepatitis, alcohol steatohepatitis, obesity, hyperlipidemia, hyperglycemia and hyperinsulinemia.

[0169] In one embodiment, the compounds herein can be useful in the treatment of solid tumors or haematological malignancies. In one embodiment, hematological malignancy is selected from multiple myeloma, non-Hodgkin's lymphoma, Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma. In one embodiment solid tumor is selected from pancreatic cancer, breast cancer, melanoma and non-small cell lung cancer.

[0170] In one embodiment, cancer is selected from a carcinoma, preferably a carcinoma of the bladder, breast, colon (including colorectal carcinomas, such as colon adenocarcinoma and colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung (including adenocarcinoma, small cell lung cancer, non-small cell lung carcinomas and squamous lung cancer), oesophagus, head and neck, gall bladder, ovary, pancreas (including exocrine pancreatic carcinoma), stomach, gastrointestinal cancer (including gastrointestinal stromal tumors), cervix, endometrium, thyroid, prostate and skin.

[0171] In one embodiment, the cancer is selected from pituitary cancer, a hematopoietic tumor of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (e.g. diffuse large B-cell lymphoma, mantle cell lymphoma), T-cell leukaemia / lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, for example leukemias, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia;multiple myeloma; thyroid follicular cancer; hepatocellular cancer, a tumor of mesenchymal origin (e.g. Ewing's sarcoma), for example fibrosarcoma or rhabdomyosarcoma; a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

[0172] The disclosure herein further relates to compounds of Formula (I), the tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, for use as a medicament. Furthermore, the disclosure herein relates to the use of a compound of Formula (I), a tautomer or a stereoisomeric form thereof, or a pharmaceutically acceptable addition salt, or a solvate thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament.

[0173] The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.

[0174] Accordingly, the present invention further includes compositions comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.

[0175] A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals.

[0176] Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agentcontaining composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders,etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington's Pharmaceutical Sciences, 17th Edition (1985), which is incorporated herein by reference in its entirety.

[0177] The compounds of Formula I may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin-related diseases, and systematic treatment preferred for cancerous or pre-cancerous conditions, although other modes of delivery are contemplated. For example, the compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aq. or non-aq. solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release.

[0178] Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.

[0179] Exemplary compositions for topical administration include a topical carrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

[0180] Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may also be orally delivered by sublingual and / or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolvingdiluents such as mannitol, lactose, sucrose, and / or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and / or maleic anhydride copolymer (e.g., GANTREZ®); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.

[0181] Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and / or bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0182] Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3 -butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[0183] Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug.

[0184] The therapeutically-effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to 1000 mg / kg; 1-1000 mg / kg; 1-50 mg / kg; 5-250 mg / kg; 250-1000 mg / kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like. Thus, when the term "patient" is used herein, this term is intended to include all subjects, most preferably mammalian species that are affected by modulation of IL-23, IL-12 and / or IFNa-mediated functions.

[0185] METHODS OF PREPARATION

[0186] The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.

[0187] The compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in thecompounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Third Edition, Wiley and Sons, 1999).

[0188] Compounds of Formula (I) may be prepared by reference to the methods illustrated in the following Schemes. As shown therein the end product is a compound having the same structural formula as Formula (I). It will be understood that any compound of Formula (I) may be produced by the schemes by the suitable selection of reagents with appropriate substitution. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Constituents of compounds are as defined herein or elsewhere in the specification.

[0189] The synthesis of the compounds of Formula (I) can be effected using the methods summarized in Schemes 1 and 2.

[0190] Scheme 1

[0191]

[0192] Step 1 : The first step of Scheme 1 begins with a suitably functionalized pyrrolo[2,3-b]pyridine-5-carboxylate or pyrazolo[3,4-b]pyridine-5-carboxylate (i). The bromide of compound (i) can be tranformed to the group R found in molecule (ii). This transformation may be effected by reacting compound (i) with an optionally protected aromatic or heteroaromatic boronic acid or boronic ester, a catalyst such as XPhos Pd G2 complex, and a base such as tripotassium phosphate in a solvent mixture such as dioxane and water at a temperature as high as 100 °C. If the group installed contains a protecting group, a further optional step may be conducted to remove that protecting group under appropriate conditions if desired.

[0193] Step 2: In step 2 of Scheme 1, when X is Ts, Compounds ii can be tranformed to compounds (iii). This transformation may be effected using an acid such as TFA.

[0194] Step 3: Alternatively, the bromide of compound i can be converted to a boronate, as in compound iv. This transformation may be effected by reacting compound (i) with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane, a catalyst such as PdC12(dppf), and a base such as potassium acetate in a solvent such as dioxane at a temperature as high as 90 °C.

[0195] Step 4: In step 4 of Scheme 1, the boronate of compound (iv) can be tranformed to the group R found in molecule (ii). This transformation may be effected by reacting compound (iv) with an optionally protected aromatic or heteroaromatic bromide, a catalyst such as XPhos Pd G2 complex, and a base such as tripotassium phosphate in a solvent mixture such as dioxane and water at a temperature as high as 100 °C. If the group installed contains a protecting group, a further optional step may be conducted to remove that protecting group under appropriate conditions if desired.

[0196] Step 5: In step 5 of Scheme 1, the methyl ester of compound (ii) can be tranformed to a carboxylic acid (v). This transformation may be effected using a base such as IN NaOH in water and a solvent such as methanol.

[0197] Step 6: In step 6 of Scheme 1, the carboxylic acid of compound (v) can be tranformed to a amide (vi). This transformation may be effected using a base such as tri ethylamine, a coupling agent such as 1-propanephosphonic anhydride, and a suitably functionalized amine in a solvent such as DMF. If the group installed contains aprotecting group, a further optional step may be conducted to remove that protecting group under appropriate conditions if desired.

[0198] Scheme 2

[0199]

[0200] Step 1 : The first step of Scheme 2 begins with a suitably functionalized 3-bromo-5-chloro-pyrrolo[2,3-b]pyridine or 3-bromo-5-chloro-pyrazolo[3,4-b]pyridine (vii). The bromide of compound (vii) can be tranformed to the group R found in molecule (viii). This transformation may be effected by reacting compound (vii) with an optionally protected aromatic or heteroaromatic boronic acid or boronic ester, a catalyst such as XPhos Pd G2 complex, and a base such as tripotassium phosphate in a solvent mixture such as dioxane and water at a temperature as high as 70 °C. If the group installed contains a protecting group, a further optional step may be conducted to remove that protecting group under appropriate conditions if desired.

[0201] Step 2: In step 2 of Scheme 1, the chlorine of compound (viii) can be tranformed to the group R1found in molecule (ix). This transformation may be effected by reacting compound (viii) with an optionally protected aromatic or heteroaromatic boronic acid or boronic ester, a catalyst such as XPhos Pd G2 complex, and a base such as tripotassium phosphate in a solvent mixture such as dioxane and water at a temperature as high as 95 °C. If the group installed contains a protecting group, a further optional step may be conducted to remove that protecting group under appropriate conditions if desired.

[0202] EXAMPLES

[0203] Preparation of compounds of Formula (I), and intermediates used in the preparation of compounds of Formula (I), can be prepared using procedures shown in the following Examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these Examples, are not meant to be limiting, but are meant to demonstrate how the compounds of Formula (I) can be prepared. Starting materials and reagents used in these examples, when not prepared by a proceduredescribed herein, are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature.

[0204] Abbreviations

[0205] Ac acetyl

[0206] ACN acetonitrile

[0207] anhyd. anhydrous

[0208] aq. aqueous

[0209] Bn benzyl

[0210] Boc-anhydride di-t -butyl dicarbonate

[0211] Bu butyl

[0212] Boc / -butoxy carbonyl

[0213] CV Column Volumes

[0214] DCE di chloroethane

[0215] DCM dichloromethane

[0216] DMAP dimethylaminopyridine

[0217] DMF dimethylformamide

[0218] DMSO dimethylsulfoxide

[0219] EtOAc ethyl acetate

[0220] Et ethyl

[0221] Et3N triethylamine

[0222] H orH2hydrogen

[0223] h, hr or hrs hour(s)

[0224] hex hexane

[0225] i iso

[0226] HC1 hydrochloric acid

[0227] HPLC high pressure liquid chromatography

[0228] LC liquid chromatography

[0229] LCMS liquid chromatography-mass spectroscopy

[0230] LiAlHi lithium aluminum hydride

[0231] M molar

[0232] mM millimolar

[0233] Me methyl

[0234] MeOH methanol

[0235] MHz megahertz

[0236] min. minute(s)

[0237] mins minute(s)

[0238] M+1(M+H)+

[0239] MS mass spectrometry

[0240] n or N normal

[0241] NBS n-bromosuccinimide

[0242] NCS n-chlorosuccinimide

[0243] nm nanometer

[0244] nM nanomolar

[0245] NMP V-methylpyrrolidinone

[0246] Pd / C palladium on carbon

[0247] PdCh(dppf) [ 1 , 1’ -Z>A(diphenylphosphino)ferrocene]dichloropalladium(II)Ph phenyl

[0248] Pr propyl

[0249] PSI pounds per square inch

[0250] Ret Time retention time

[0251] sat. saturated

[0252] SFC supercritical fluid chromatography

[0253] TEA triethylamine

[0254] TFA trifluoroacetic acid

[0255] THF tetrahydrofuran

[0256] XPhos Precatalyst chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1'- biphenyl)[2-(2'-amino- 1 , 1 '-biphenyl)]palladium(II) Analytical HPLC conditions:

[0257] Method A: L3 Acquity: Column: (LCMS) UPLC BEH C 18, 2.1 x 50 mm, 1.7 pm particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98%B (to 1.5 min) 98%-2% B (to 1.6 min); Gradient Time: 1.6 min; Flow Rate: 0.8 mL / min; Analysis Time: 2.2 min; Detection: Detector 1: UV at 220 nm; Detector 2: MS (ESI+).

[0258] Method B: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-pm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL / min;

[0259] Detection: UV at 220 nm.

[0260] Method C (AA): Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-pm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;

[0261] Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL / min; Detection: UV at 220 nm.

[0262] Method D (TFA): Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Temperature: 50°C;

[0263] Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL / min; Detection: UV at 220 nm.

[0264] Preparative HPLC conditions:

[0265] Column: XB ridge Cl 8, 19 x 200 mm, 5-pm particles;Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-50% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL / min. Detection: UV at 220 nm. Column: XBridge C18, 19 x 200 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 6-46% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL / min. Detection: UV at 220 nm.

[0266] Shimadzu prep HPLC, Luna® C1830 x 100 mm, 5 pm (Phenomenex Inc.); 2 mL injection; Mobile Phase : 0.1% TFA in Water; Mobile Phase B: 0.1% TFA in MeOH; Temperature: 50 °C; Gradient: 20-100% B over 5 min, then a 10 min hold at 100% B, Flow: 30 mL / min; Detection: UV at 220 nm.

[0267] Intermediate INT-1: Preparation of methyl 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5- carb oxy late

[0268]

[0269] Step-1

[0270] To a mixture of methyl 3-bromo-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (500 mg, 1.960 mmol) in DMF (5 mL) was added sodium hydride (94 mg, 2.352 mmol). After stirring 30 minutes, p-toluenesulfonyl chloride (448 mg, 2.352 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was quenched with water then diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSCU, filtered and concentrated. The crude material was purified on a silica gel cartridge using an EtOAc / Hex gradient (0-100% EtOAc over 13 min) to afford methyl 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (580 mg, 1.417 mmol, 72.3 % yield). MS (M+1) m / z: 409 / 411(MH+ / MH2+). LC retention time 1.09 min [A],Intermediate INT-2: Preparation of methyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate

[0271]

[0272] Step-1

[0273] A solution of methyl 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (200 mg, 0.489 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (186 mg, 0.733 mmol), potassium acetate (72mg, 0.733 mmol) and PdC12(dppf) (18 mg, 0.024 mmol) in dioxane (12 mL) was degassed with nitrogen for 10 min. The vial was sealed and then heated at 90 °C. After 12 hours, the reaction was diluted with DCM and dried over magnesium sulfate, then filtered and concentrated. The crude material was purified on a silica gel cartridge to afford methyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (66.9 mg, 0.147 mmol, 30 % yield). MS (M+1) m / r. 457 (MH+). LC retention time 1.17 min [A],

[0274] Intermediate INT-3: Preparation of l,4-dioxaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate

[0275]

[0276] Step-1

[0277] To a mixture of 3-bromo-5-chloro-lH-pyrrolo[2,3-b]pyridine (2g, 8.64 mmol) in DMF (20 mL) was added sodium hydride (0.415 g, 10.37 mmol). The reaction mixturewas stirred for 1 hour, then p-toluenesulfonyl chloride (1.977 g, 10.37 mmol) was added. The reaction was stirred at rt for 4 hours then quenched with water. The reaction mixture was diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (80 g) using an EtOAc / Hex gradient (0-100% EtOAc over 13 min) to afford 3-bromo-5-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridine (2.8 g, 84% yield).

[0278] Example 1. Preparation of methyl (R)-3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylate

[0279]

[0280] 1A. methyl (R)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate

[0281]

[0282] To a mixture of methyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (30 mg, 0.066 mmol), tert-butyl-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindoline-l-carboxylate (isomer 2, 30 mg, 0.062 mmol), and 2nd generation XPHOS precatalyst (4.90 mg, 6.23 pmol) in dioxane (2 mL) was added potassium phosphate tribasic (0.093 mL, 0.187 mmol).

[0283] Reaction mixture was sparged with nitrogen for 5 minutes then sealed and heated at 50 °Covernight. The reaction mixture was diluted with ethyl acetate and dried with MgSC>4, filtered and concentrated. The crude material was purified on a silica gel cartridge (12g) using a hexanes / EtOAc gradient (0-50% EtOAc over 11 min) to afford methyl (R)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (40 mg, 0.055 mmol, 88 % yield). LC retention time 1.38 min [A],

[0284] Example 1. methyl (R)-3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-py rrol o [2, 3 -b ] py ri dine- 5 -carb oxy 1 ate

[0285]

[0286] To a mixture of methyl (R)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (40 mg, 0.055 mmol) in THF (1 mL) was added IM TBAF in THF (0.547 mL, 0.547 mmol). The reaction mixture was stirred for 2 hours then diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSCU, filtered and concentrated. This crude material was treated with TFA / DCM (1 : 1) for 30 minutes. The reaction mixture was concentrated in vacuo then purified by HPLC to afford methyl -3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (2.3 mg, 6.35 pmol, 11.60 % yield). 1H NMR (500 MHz, DMSO-d6) 8 12.25 (br s, 1H), 8.84 (d, J=1.2 Hz, 1H), 8.65 (d, J=1.2 Hz, 1H), 7.87 (s, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 6.77 (d, J=0.6 Hz, 1H), 5.02 (br t, J=4.9 Hz, 1H), 3.90 (s, 3H), 3.63 (d, J=9.8 Hz, 1H), 3.48 - 3.38 (m, 1H), 3.25 (br d, J=9.5 Hz, 1H), 3.18 (d, J=4.6 Hz, 1H), 1.31 (s, 3H); MS (M+1) m / r. (MH+) 362.9. LC retention time min 1.26 [C],Example 2. Preparation of methyl-(S)-3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylate

[0287]

[0288] 2A. methyl (S)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate

[0289]

[0290] To a mixture of methyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (46 mg, 0.101 mmol), tert-butyl-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindoline-l-carboxylate (isomer 1, 48.5 mg, 0.101 mmol), and 2nd generation XPHOS precatalyst (7.93 mg, 10.08 pmol) in dioxane (2 mL) was added potassium phosphate tribasic (0.151 mL, 0.302 mmol). Reaction mixture was sparged with nitrogen for 5 minutes then sealed and heated at 50 °C overnight. The reaction mixture was diluted with ethyl acetate and dried with MgSC>4, filtered and concentrated. The crude material was purified on a silica gel cartridge (12g) using a hexanes / EtOAc gradient (0-50% EtOAc over 11 min) to afford methyl (S)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (40 mg, 0.055 mmol, 54.3 % yield). MS (M+1) m / z (MH+) 731.4. LC retention time min 1.34 [A],Example 2.

[0291]

[0292] To a mixture of methyl (S)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (40 mg, 0.055 mmol) in THF (1 mL) was added IM TBAF in THF (0.547 mL, 0.547 mmol). The reacion mixture was stirred at rt for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSCU, filtered and concentrated. This crude residue was treated with TFA (0.5 mL) for one hour. The solvent was removed under a stream of N2 then purified by HPLC to afford methyl-(S)-3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (3.9 mg, 10.76 pmol, 19.67 % yield). 1H NMR (500 MHz, DMSO-d6) 8 12.26 (br s, 1H), 8.84 (d, J=1.9 Hz, 1H), 8.65 (d, J=1.7 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 6.78 (s, 1H), 5.03 (t, J=5.3 Hz, 1H), 3.90 (s, 3H), 3.63 (br d, J=9.8 Hz, 1H), 3.45 (s, 2H), 3.25 (d, J=9.8 Hz, 1H), 1.31 (s, 3H); MS (M+1) m / z (MH+) 362.9. LC retention time min 1.42 [C],

[0293] Example 3. Preparation of (R)-N-benzyl-3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide

[0294]

[0295] 3 A. (R)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylic acid

[0296]

[0297] To a mixture of methyl (R)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (38 mg, 0.052 mmol) in MeOH (1 mL) was added INNaOH (1 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was adjusted to pH ~7 with IN HC1 then diluted with di chloromethane and washed with sat NaCl. The organic layer was dried with MgSC>4, filtered and concentrated to afford (R)-3-(l -(tertbutoxy carbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylic acid (24 mg, 0.043 mmol, 82 % yield). MS (M+1) m / z'. (MH+). LC retention time min 1.2 [A],

[0298] 3B. tert-butyl (R)-5-(5-(benzylcarbamoyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindoline-l-carboxylate

[0299]

[0300] To a mixture of (R)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylic acid (24 mg, 0.043 mmol), TEA (11.89 pl, 0.085 mmol), and 1-propanephosphonic anhydride (49.8 pl, 0.085 mmol) in DMF (2 mL) was added benzylamine (9.32 pl, 0.085 mmol). The reaction mixture was stirred for one hour. The reaction mixture was diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSC , filtered and concentrated to afford tert-butyl (R)-5-(5-(benzylcarbamoyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindoline-l-carboxylate (28 mg, 0.043 mmol, 101 % yield). MS (M+1) m / z 389.2 (MH+). LC retention time 1.27 min [A], Example 3. (R)-N-benzyl-3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-py rrol o [2, 3 -b ] py ri dine- 5 -carb oxami de

[0301]

[0302] To a mixture of tert-butyl 5-(5-(benzylcarbamoyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindoline-l-carboxylate (28 mg, 0.043 mmol) in THF (1 mL) was added TBAF (0.043 mL, 0.043 mmol). The reaction mixture was stirred for one hour. The solvents were removed and the residue was purified by HPLC to afford (R)-N-benzyl-3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide (4.8 mg, 10.97 pmol, 25.5 % yield). 1HNMR (500 MHz, DMSO-d6) 8 12.06 (br s, 1H), 9.21 (br t, J=5.8 Hz, 1H), 8.79 (s, 1H), 8.65 (s, 1H), 7.83 (br s, 1H), 7.54 (d, J=1.9 Hz, 2H), 7.40 - 7.32 (m, 4H), 7.28 - 7.19 (m, 1H), 4.54 (br d, J=5.8 Hz, 2H), 3.80 - 3.57 (m, 4H), 3.49 - 3.34 (m, 1H), 3.24 (d, J=9.6 Hz, 1H), 1.30 (d, J=1.7 Hz, 3H); MS (M+1) m / z (MH+) 438.1. LC retention time min 1.5 [C],Example 4. Preparation of (S)-N-benzyl-3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide

[0303]

[0304] 4A. (S)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylic acid

[0305]

[0306] To a mixture of methyl-(S)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (Ex 2, stepl; 50 mg, 0.087 mmol) in MeOH (1 mL) was added IN NaOH (1 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was adjusted to pH ~7 with IN HC1 then diluted with dichloromethane and washed with sat NaCl. The organic layer was dried with MgSCU, filtered and concentrated to afford (S)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylic acid (41 mg, 0.073 mmol, 84 % yield). MS (M+1) m / r. (MH+) 563.3. LC retention time min 1.22 [A],4B. (S)-N-benzyl-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide

[0307]

[0308] To a mixture of (S)-3-(l-(tert-butoxycarbonyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxylic acid (20 mg, 0.036 mmol), TEA (9.91 pl, 0.071 mmol), and benzylamine (7.76 pl, 0.071 mmol) in DMF (1 mL) was added 1-propanephosphonic anhydride (0.041 mL, 0.071 mmol). The reaction mixture was stirred for one hour. The reaction mixture was diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSCU, filtered and concentrated to afford (S)-N-benzyl-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide (19 mg, 0.034 mmol, 97 % yield). MS (M+1) m / z (MH+) 652.3. LC retention time min 2.67 [B],

[0309] Example 4. (S)-N-benzyl-3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-py rrol o [2, 3 -b ] py ri dine- 5 -carb oxami de

[0310]

[0311] To a mixture of N-benzyl-3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide (19.86 mg, 0.036 mmol) in THF (1 mL) was added TBAF (0.108 mL, 0.108 mmol). The reaction mixture was stirred for one hour. To this was added lOeq of calcium carbonate and lOOmg ofDOWEX resin to remove excess TBAF. The reaction mixture was stirred for 30 minutes then filtered and the filtrate was concentrated and purified by HPLC to afford (S)-N-benzyl-3-(7-cyano-3-(hydroxymethyl)-3-methylindolin-5-yl)-lH-pyrrolo[2,3-b]pyridine-5-carboxamide (1.5 mg, 3.40 pmol, 9.45 % yield). 1HNMR (500 MHz, DMSO-d6) 6 9.20 (br t, J=5.8 Hz, 1H), 8.79 (d, J=1.8 Hz, 1H), 8.66 (d, J=1.8 Hz, 1H), 7.83 (s, 1H), 7.54 (s, 2H), 7.40 - 7.32 (m, 4H), 7.29 - 7.17 (m, 1H), 6.72 (s, 1H), 4.55 (d, J=5.8 Hz, 2H), 3.91 (s, 1H), 3.64 (d, J=9.8 Hz, 1H), 3.53 - 3.35 (m, 1H), 3.24 (br d, J=9.5 Hz, 1H), 1.31 (s, 3H) [2 exchangeable protons not detected]; MS (M+1) m / z (MH+) 438.1. LC retention time min 1.45 [C],

[0312] Example 5. Preparation of (S)-5-(5-(5-cyano-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-3-(hydroxymethyl)-3-methylindoline-7-carbonitrile

[0313]

[0314] 5 A. tert-butyl (S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-7-cyano-3-methylindoline-l-carboxylate

[0315]

[0316] To a mixture of 3-bromo-5-chloro-lH-pyrrolo[2,3-b]pyridine (36.8 mg, 0.159 mmol), tert-butyl (S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-cyano-3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l-carboxylate (70 mg, 0.132 mmol), and 2nd generation XPHOS precatalyst (10.42 mg, 0.013 mmol) in dioxane (2 mL) was added potassium phosphate tribasic (0.199 mL, 0.397 mmol). Reaction mixture was sparged with nitrogen for 5 minutes then sealed and heated at 70 °C overnight. The reaction mixture was diluted with ethyl acetate and dried with MgSC , filtered andconcentrated in vacuo. The crude material was purified on a silica gel cartridge (12g) using a hexanes / EtOAc gradient (0-50% EtOAc over 11 min) to afford tert-butyl (S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-7-cyano-3 -methylindoline- 1 -carboxylate (58 mg, 0.105 mmol, 79 % yield). MS (M+1) m / z'.

[0317] 553.3 (MH+). LC retention time 1.37 min [A],

[0318] 5B. tert-butyl (S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(5-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-7-cyano-3-methylindoline-l-carboxylate (38 mg, 0.054 mmol, 74.3 % yield)

[0319]

[0320] To a mixture of tert-butyl (S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-7-cyano-3-methylindoline-l-carboxylate (40 mg, 0.072 mmol) in DMF (2 mL) was added sodium hydride (4 mg, 0.100 mmol). After stirring for 30 min, p-toluenesulfonyl chloride (17 mg, 0.089 mmol) was added and the reaction was stirred at rt overnight. The reaction mixture was quenched with water then diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSC , filtered and concentrated. The crude material was purified on a silica gel cartridge (12g) using an EtOAc / Hex gradient (0-100% EtOAc over 12 min) to afford tert-butyl (S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(5-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-7-cyano-3-methylindoline-l-carboxylate (38 mg, 0.054 mmol, 74.3 % yield). MS (M+1) m z 707 (MH+). LC retention time 3.29 min [B],5C. tert-butyl (S)-7-cyano-5-(5-(5-cyano-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-3-(hydroxymethyl)-3 -methylindoline- 1 -carboxylate

[0321]

[0322] To a mixture of tert-butyl (S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(5-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-7-cyano-3-methylindoline-l-carboxylate (19 mg, 0.027 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (9.80 mg, 0.040 mmol), and 2nd generation XPHOS precatalyst (2.113 mg, 2.69 pmol) in dioxane (2 mL) was added potassium phosphate tribasic (0.040 mL, 0.081 mmol). Reaction mixture was sparged with nitrogen for 5 minutes then sealed and heated at 95 °C overnight. The reaction mixture was diluted with ethyl acetate washed with sat NaCl and dried with MgSC , filtered and concentrated. The crude material was then treated with TBAF (0.269 mL, 0.269 mmol) in THF (ImL) for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with sat NaCl (2x). The organic layer was dried with MgSCU, filtered and concentrated to afford tert-butyl (S)-7-cyano-5-(5-(5-cyano-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-3-(hydroxymethyl)-3-m ethylindoline- 1 -carboxylate (14 mg , 0.027 mmol). MS (M+1) m / z'. 520.2 (MH+). LC retention time 1.97 min [B],

[0323] Example 5. (S)-5-(5-(5-cyano-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-3-(hydroxymethyl)-3-methylindoline-7-carbonitrile

[0324]

[0325] tert-butyl (S)-7-cyano-5-(5-(5-cyano-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-3-(hydroxymethyl)-3 -methylindoline- 1 -carboxylate (14 mg, 0.027 mmol) was treated withTFA (0.5 mL) for one hour. The solvent was removed under a stream of nitrogen then purified by HPLC to afford (S)-5-(5-(5-cyano-2-methylphenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-3-(hydroxymethyl)-3-methylindoline-7-carbonitrile (4.3 mg, 9.92 pmol, 36.8 % yield). 1HNMR (500 MHz, DMSO-d6) 8 11.94 (br s, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 7.82 (br d, J=3.1 Hz, 2H), 7.76 (br d, J=7.6 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.53 (d, J=4.0 Hz, 2H), 3.61 (d, J=9.8 Hz, 1H), 3.49 - 3.34 (m, 1H), 3.22 (d, J=9.8 Hz, 1H), 3.18 (s, 1H), 2.36 (s, 3H), 1.29 (s, 3H) [2 exchangeable protons not detected]; MS (M+1) m / r.

[0326] 420.3 (MH+). LC retention time 1.6 min [C],

[0327] Biological Evaluation: HTRF Binding Assay

[0328] A solution was prepared containing 0.2 nM Anti-HIS-Terbium (Cisbio, 64CUSTAZU), 9.0 nM probe and 3.4 nM His-TVMV-NIK (330-679)-S549D in FRET Buffer (20 mM HEPES, 10 mM MgC12, 0.015% Brij-35, 4mM DTT, 0.05 mg / mL BSA). Using Formulatrix Tempest for liquid handling, the detection antibody / enzyme / probe solution (2 mL) was dispensed into wells of a 1536 plate (Black Low Binding Polystyrene 1536 Plate (Corning, 3724) containing 10 nL of compounds of interest at appropriate concentration in DMSO. The plate was incubated at room temperature for 1 h. FRET was measured using the EnVision plate reader (Excitation: 340 nM, Emission: 520 nM / 495 nM). Total signal (0% inhibition) was calculated from wells containing 10 nL DMSO only. Blank signal (100% inhibition) calculated from wells containing 10 nL of 15 nM staurosporine and internal controls.

[0329] In the table below:

[0330] Examples 6 through 72 were prepared in a similar fashion as described in the procedures for Examples 1-5, starting with the appropriate starting material.Table 1

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Claims

WE CLAIM:

1. A compound having the structure of formula (I):Formula (I)or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof; wherein n is 1, 2 or 3;m is 0, 1, 2, 3 or 4;= represents a single or double bond;X is selected from -N(R5)- and -C(R5)(R6)-;each R1is independently selected from hydrogen, halo, cyano, hydroxy, amino, - C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, - S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, Ci-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100; or,alternatively, two R1groups, together with the atoms to which they are attached, combine to form a C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, or 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C3-8 cycloalkyl, Ce-io aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;each R2R3, R4, R6and R7is independently selected from hydrogen, halo, cyano, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, -S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100;R5is selected from absent, hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R200;each Raand Rbis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R200;each R100is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -N(Rc)C(O)Rd, -S(O)NRcRd, -S(O)2NRcRd, -S(O)Rh, -S(O)2Rh, -NRcRd, -ORC, -SRC, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R201;each Rcand Rdis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S;each R200and R201is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, -S(O)NReRf, -S(O)2NReRf, -8(0)^, -8(0)^, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroarylcontaining 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four 300.each Rg, Rhand R1is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, is optionally substituted with one to four R300;wherein each R300is independently selected from hydrogen, halo, cyano, hydroxy, amino, oxo, thioxo, vinyl, -C(O)Re, -C(O)ORe, -C(O)NReRf, -N(Re)C(O)Rf, - S(O)NReRf, -S(O)2NReRf, -NReRf, -ORe, -SRe, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;each Reand Rfis independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

2. A compound of claim 1 having the structure of formula (II:Formula (II)or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof.

3. A compound of claim 1 having the structure of formula (III):Formula (III)or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof.

4. A compound of claim 3 wherein each R7is independently Ci-6 alkyl or Ci-6 alkyl substituted with -ORC.

5. A compound of claim 1 having the structure of formula (IV):Formula (IV)or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof.

6. A compound according to any of the above claims or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof;wherein R3is selected from -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -N(Ra)C(O)Rb, - S(O)NRaRb, -S(O)2NRaRb, -S(O)Rg, -S(O)2Rg, -NRaRb, -ORa, -SRb, Ci-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and 4-10 membered heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; wherein each C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R100.

7. A compound according to any of the above claims or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof;wherein R3is selected from -C(O)ORb, -C(O)NRaRb, and Ce-io aryl; wherein Ce-io aryl is optionally substituted with one to four R100.

8. A compound according to claim 7 or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof;wherein each Raand Rbis independently selected from hydrogen and C1-6 alkyl; wherein each C1-6 alkyl is optionally substituted with one to four R200.

9. A compound according to claim 8 or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof;wherein R200is Ce-io aryl.

10. A compound according to any of the above claims or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof;wherein R3is -C(O)ORb; wherein Rbis Ci-6 alkyl.

11. A compound according to claim 7, or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof;wherein R3is Ce-io aryl; wherein Ce-io aryl is optionally substituted with one to four R100.

12. A compound according to claim 11, or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof;wherein each R100is independently selected from halo and Ci-6 alkyl.

13. A compound according to any of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof;wherein R3is selected fromwherein p is 1, 2, 3, 4 or 5.

14. A compound according to any of the above claims wherein X is -N(R5)-.

15. A compound according to any of claims 1-13 wherein X is -C(R5)(R6)-.

16. A compound selected from table below:>><> >er a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof.

17. A pharmaceutical composition comprising one or more compounds according to any of the above claims and a pharmaceutically acceptable carrier or diluent.- Ti18. A pharmaceutical composition comprising one or more compounds according to claim 17 and a pharmaceutically acceptable carrier or diluent.

19. A method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound according to claim 1, wherein the disease is an autoimmune disease.

20. The method of claim 18 wherein the autoimmune disease is rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn’s Disease, Sjogren’s syndrome or scleroderma.

21. A method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound according to claim 1, wherein the disease is cancer.

22. A method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound according to claim 1, wherein the disease is a haematological malignancy or solid tumor.

23. The method according to claim 20, wherein the disease is a haematological malignancy selected from multiple myeloma, non-Hodgkin's lymphoma, Hodgkin lymphoma, T-cell leukaemia, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and mantle cell lymphoma.

24. The method according to claim 20, wherein said disease is a solid tumor selected from pancreatic cancer, breast cancer, melanoma and non-small cell lung cancer.

25. A method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound according to claim 1, wherein the disease is selected from carcinoma of the bladder, breast, colon, kidney, urothelial, uterus, epidermis, liver, lung, oesophagus, head and neck, gall bladder, ovary, pancreas stomach, cervix, endometrium, thyroid, prostate and skin; gastrointestinal cancer, pituitary cancer, a hematopoietic tumor of lymphoid lineage, T-cell leukaemia, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplasticsyndrome, promyelocyte leukemia; multiple myeloma; thyroid follicular cancer; hepatocellular cancer, a tumor of mesenchymal origin, a tumor of the central or peripheral nervous system, astrocytoma, neuroblastoma, glioma, glioblastoma multiforme, schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; and Kaposi's sarcoma.

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