NIK compounds

Abstract

Compounds having the following formula I: 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 autoimmune and inflammatory disorders.

Description

[0001] NIK COMPOUNDS

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

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

[0004] 63 / 762,812, 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 A is selected from:

[0018]

[0019] each R1and R2is independently selected from hydrogen, halo, hydroxy, -NRaRb, -ORa, -SRb, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted with one to four R100;

[0020] each R3and R4is independently selected from hydrogen, halo, hydroxy, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C(O)Ra, -C(O)ORb, -C(O)NRaRband -N(Ra)C(O)Rb; wherein each C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted with one to four R100;

[0021] R5is selected from hydrogen, halo, cyano, hydroxy, amino and C1-6 alkyl;

[0022] R6is independently selected from hydrogen, halo, hydroxy, -NRaRband -C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one to four R100;

[0023] R7is selected from hydrogen, halo, cyano, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -C(O)N(Ra)C(O)Rb, -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, C2-6 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;

[0024] R8is selected from hydrogen, halo, cyano, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -C(O)N(Ra)C(O)Rb, -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, C2-6 alkynyl, C3-8 cycloalkyl 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 and 4-10 membered heterocyclyl is optionally substituted with one to four R100; each Raand Rbis 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; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-io aryl, 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 is optionally substituted with one to four R200;alternatively, Raand Rbtogether with the atoms to which they are attached forms a C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl 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 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 R202;

[0027] each R200, R201and R202is 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, -S(O)Ri, -S(O)2Ri, -NReRf, -ORe, -SRe, 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 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;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(0)NReRf, - S(0)2NReRf, -S(O)2Re, -NReRf, -0Re, -SRe, Ci-6 alkyl, C2-6alkenyl and C2-6alkynyl; each Reand Rfis independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.

[0029] In one aspect, provided are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds disclosed herein.

[0030] The present application also provides methods for the inhibition of NF-kB- inducing kinase (NIK) comprising administering a therapeutically effective amount of a compound of Formula I.

[0031] The present application also provides a method for treating metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds disclosed herein.

[0032] 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.

[0033] DETAILED DESCRIPTION

[0034] In a first aspect, provided are compounds of formula (I) that function as inhibitors

[0035]

[0036] or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof;wherein A is selected from:

[0037]

[0038] each R1and R2is independently selected from hydrogen, halo, hydroxy, -NRaRb, - ORa, -SRb, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted with one to four R100;

[0039] each R3and R4is independently selected from hydrogen, halo, hydroxy, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C(O)Ra, -C(O)ORb, -C(O)NRaRband - N(Ra)C(O)Rb; wherein each C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted with one to four R100;

[0040] R5is selected from hydrogen, halo, cyano, hydroxy, amino and C1-6 alkyl;

[0041] R6is independently selected from hydrogen, halo, hydroxy, -NRaRband -C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one to four R100;

[0042] R7is selected from hydrogen, halo, cyano, hydroxy, amino, -C(O)Ra, -C(O)ORb, - C(O)NRaRb, -C(O)N(Ra)C(O)Rb, -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, C2-6 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 4heteroatoms 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;

[0043] R8is selected from hydrogen, halo, cyano, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -C(O)N(Ra)C(O)Rb, -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, C2-6 alkynyl, C3-8 cycloalkyl 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 and 4-10 membered heterocyclyl is optionally substituted with one to four R100; each Raand Rbis 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; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-io aryl, 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 is optionally substituted with one to four R200; alternatively, Raand Rbtogether with the atoms to which they are attached forms a C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl is optionally substituted with one to four R200;

[0044] 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, C2-6 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 R201;

[0045] 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; 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 R202;

[0046] each R200, R201and R202is 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, -S(O)Ri, -S(O)2Ri, -NReRf, -ORe, -SRe, 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 300.

[0047] 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;

[0048] 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, -S(O)2Re, -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.

[0049] In a preferred embodiment, the application relates to a compound of Formula I wherein each R1-OH.

[0050] In a preferred embodiment, the application relates to a compound of Formula I wherein each R2-CH3.

[0051] In a preferred embodiment, the application relates to a compound of Formula I wherein each R3-H.

[0052] In a preferred embodiment, the application relates to a compound of Formula I wherein each R4-H.

[0053] In a preferred embodiment, the application relates to a compound of Formula I wherein each R5-H.In a preferred embodiment, the application relates to a compound of Formula I wherein each R6-N(H)(CH3).

[0054] In a preferred embodiment, the application relates to a compound of Formula I wherein each R8is selected from -H and -CH3.

[0055] In a preferred embodiment, the application relates to a compound of Formula I wherein each R7is selected from -CN, cyclopropyl, phenyl, -C(0)N(H)CH3,

[0056] In a preferred embodiment, the application relates to a compound of Formula I wherein each R7is selected from:

[0057]

[0058] ōeO

[0059]

[0060]

[0061] In another embodiment, there is provided a pharmaceutical composition comprising one or more compounds of formula I and a pharmaceutically acceptable carrier or diluent.

[0062] 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.

[0063] 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, antiphospholipidsyndrome, 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.

[0064] 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.

[0065] 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.

[0066] 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

[0067] The present invention also provides the compounds of the present invention for use in therapy.

[0068] In another embodiment, compounds of formula I are selected from exemplified compounds or combinations of exemplified compounds or other embodiments herein.

[0069] In another embodiment are compounds having an ICso < 1000 nM in at least one of the assays described below.

[0070] 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 anyand 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.

[0071] DETAILED DESCRIPTION OF THE INVENTION

[0072] 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 or term throughout the specification and claims, individually or as part of another group, unless otherwise indicated.

[0073] 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.

[0074] 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.

[0075] 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 occurrenceis selected independently from the definition of R3. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0076] 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.

[0077] 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.

[0078] In accordance with a convention used in the art,

[0079]

[0080] 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.

[0081] 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.

[0082] 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.As used herein, the term "at least one chemical entity" is interchangeable with the term "a compound".

[0083] The prefix " Cu-v" indicates that the following group has from u to v carbon atoms. For example, " Ci-6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0084] 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, " Ci-io 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 groups include, 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.

[0085] " 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.

[0086] " 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.

[0087] One skilled in the field will understand that, when the designation " CO2" is used o II

[0088] herein, this is intended to refer to the group c o

[0089] 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 groupas 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, / .<?., 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.

[0090] 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.

[0091] 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-ealkyl such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, te / 7-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.

[0092] 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,

[0093] [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.,

[0094] [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 abridge 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.

[0095] 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.

[0096] Accordingly, in compounds of formula I, the term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclooctyl, etc., as well as the following ring systems:

[0097]

[0098] and the like, which optionally may be substituted at any available atoms of the ring(s).

[0099] The term "halo" or "halogen" refers to chloro, bromo, fluoro and iodo.

[0100] The term "haloalkyl" means a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono, bi, and trifluoromethyl.

[0101] The term "haloalkoxy" means an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF3.

[0102] 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 atomsand 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.

[0103] 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.

[0104] 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).

[0105] 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.

[0106] 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.

[0107] Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

[0108] In compounds of formula I, preferred heteroaryl groups include:

[0109]

[0110] be substituted at any available carbon or nitrogen atom.

[0111] 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.

[0112] 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.

[0113] The term "alkylthio" refers to the group "alkyl-S-".

[0114] 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.

[0115] 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.

[0116] 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.

[0117] The term "azido" refers to -N3.

[0118] 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.

[0119] The term "carboxyl" refers to -C(O)OH.

[0120] 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.

[0121] The term "cyano" or "carbonitrile" refers to the group -CN.

[0122] 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.

[0123] The term "heteroatoms" shall include oxygen, sulfur and nitrogen.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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, (i.e., =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).

[0128] 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.

[0129] 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 formand 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 an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0130] 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.

[0131] 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 pharmaceuticallyacceptable 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.

[0132] 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 and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0133] 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.

[0134] 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, MackPublishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.

[0135] 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 or crystallization 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.

[0136] 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.

[0137] 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.

[0138] 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 usedwhere 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,

[0139] Ci-ealkanoyloxy-Ci-ealkyl, e.g., acetoxymethyl, pivaloyloxymethyl or

[0140] 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.

[0141] 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).

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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).

[0146] 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'sdisease. 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.

[0147] 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).

[0148] 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.

[0149] 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.

[0150] 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 IBDduring 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] Accordingly, the present invention further includes compositions comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.

[0155] A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals.

[0156] 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 thecomposition; 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.

[0157] 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.

[0158] 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.

[0159] Exemplary compositions for topical administration include a topical carrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

[0160] 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 maycontain, 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-dissolving diluents 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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 beadministered 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 and diet 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.

[0165] METHODS OF PREPARATION

[0166] 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.

[0167] 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 toobtain 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 the compounds 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).

[0168] EXAMPLES

[0169] 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 procedure described 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.

[0170] 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.

[0171] The synthesis of the compounds of Formula (I) can be effected using the method summarized in Schemes 1-3.Scheme la

[0172]

[0173] Step 1: In step 1 of scheme 1, an appropriately substituted methyl 4,6-dichloronicotinate (i), either purchased or prepared by one skilled in the art by methods know in the literature, may be converted to an methyl 4,6-dichloronicotinate (ii) by treatment of (ii) with an appropriately substituted amine in the presence of Hunig’s base in solvents such as 1,4-di oxane, tetrahydrofuran, or acetonitrile at a temperature between 0 °C and room temperature or at an elevated temperature such as 100 °C in a solvent such as 1,4-di oxane.Step 2: In step 2 of scheme la, an appropriately substituted compound (ii) can be converted to compound (iv) by treating compound (ii) with an appropriately substituted pyridyl ammie (iii) utilizing a transition metal mediated cross-coupling with a catalyst such as XPhos Pd G2 complex or JosiPhos Pd G3 or Pd2(dba)3 / xantphos in the presence of base such as cesium carbonate or DBU / sodium trifluoroacteate in a solvent such as

[0174] 1,4-dioxane at a temperature in the range of 75-120 °C.

[0175] Step 3: In step 3 of scheme la, the methyl ester of compound (iv) can be

[0176] converted to carboxylic acid (v) by treatment with a base such as lithium hydroxide in an aqueous solvent mixture of methonal and tetrahydrofuran. Alternatively, compound (iv) can be converted to carboxylic acid (v) by treatment with sodium hydroxide in a solvent such as methanol.

[0177] Step 4: In step 4 of scheme la, compund (v) may be transformed into compound (vi) by treatment of compound (v) with a appropriately substituted amine, either purchased or prepare by one skilled in the art, in the presence of a coupling reagent such as BOP, HATU, or COMU(R) in the presence of a base such as tri ethylamine or Hunig’s base in a solvent such as acetonitrile or dimethylformamide at a room between room temperature and 50 °C.

[0178] Step 5: Step 5 of scheme 1 is an optional step or series of steps to transform the groups NR.1R.2, NR4R5, R3, R6, and NR7R8in compound (vi) into A, R6, R5, R8, and R7found in formula (I).

[0179] One skilled in art will recognize that the order of steps may be modified to prepare compound (vi), as examplified in Scheme lb. Additional modications to the sequence may be envisioned by one skilled in the art.

[0180] Scheme 2a

[0181] (X = Cl, Br, or I)

[0182]

[0183] (ix) (xi)Scheme 2b

[0184] (X = Cl, Br, or I)

[0185]

[0186] (ix) Step 1: In step 1 of scheme 2a, an appropriately substituted compound (ix), either purchased or prepared by one skilled in the art by methods know in the literature, can be converted to compound (x) by treating compound (ix) with an appropriately substituted pyridyl ammie (iii) utilizing a transition metal mediated cross-coupling with a catalyst such as XPhos Pd G2 complex or JosiPhos Pd G3 or Pd2(dba)3 / xantphos in the presence of base such as cesium carbonate or DBU / sodium trifluoroacteate in a solvent such as 1,4-dioxane at a temperature in the range of 75-120 °C.

[0187] Step 2: In step 2 of scheme 2a, an appropriately substituted compound (x) may be transformed into compound (xi) by treatment of compound (x) with a appropriately substituted, optionally protected aromatic or heteroaromatic boronic acid or ester, either purchased or prepare by one skilled in the art, under Suzuki-Miyaura coupling conditions in the presence of a catalyst such as ChPd(dppf) or XPHOS PD G3 and in the presence of a base such as 2M aqueous potassium phosphate, tribasic or aquesous potassium carbonate in a solvent such as 1,4-dioxane at a temperature as high as 100 °C.

[0188] Alternatively, compound (xi) can be derived under Buchwald coupling conditions by treatment of compound (x) with an appropriately substitued amine, either purchased or prepared by one skilled in the art, in presence of Pd2(dba)3 and Xantphos and in the presence of a base such as cesium carbonate in a solvent such at 1,4-dioxane at a temperature such as 100 °C.

[0189] Step 3: In step 3 of scheme 2a, the functional group derived from step 2 in compound (xi) may be optionally transformed into the desired functionality, by one skilled in the art.Step 4: Step 4 of scheme 2a is an optional step or series of steps to transform the groups NR.1R.2, NR4R5, R3, R6, and R9in compound (xi) into A, R6, R5, R8, and R7found in formula (I).

[0190] One skilled in art will recognize that the order of steps may be modified to prepare compound (xi), as examplified in Scheme 2b. Additional modications to the sequence may be envisioned by one skilled in the art.

[0191] Scheme 3a

[0192]

[0193] (xii) (xiii) (xiv) Scheme 3b

[0194] (X = Cl, Br, or I)

[0195]

[0196] (xv) (xiv) Step 1: In step 1 of scheme 3a, an appropriately substituted compound (xii) can be converted to compound (xiii) by treating compound (xii) with an appropriately substituted pyridyl ammie (iii) utilizing a transition metal mediated cross-coupling with a catalyst such as XPhos Pd G2 complex or JosiPhos Pd G3 or Pd2(dba)3 / xantphos in the presence of base such as cesium carbonate or DBU / sodium trifluoroacteate in a solvent such as 1,4-dioxane at a temperature in the range of 75-120 °C.

[0197] Step 2: In step 2 of scheme 3a, an appropriately substituted compound (xiii) may be transformed into compound (xiv) by treatment of compound (xiii) with a appropriately substituted, optionally protected aromatic or heteroaromatic boronic acid or ester, either purchased or prepare by one skilled in the art, under Suzuki-Miyaura coupling conditionsin the presence of a catalyst such as C12Pd(dppf) or XPHOS PD G3 and in the presence of a base such as 2M aqueous potassium phosphate, tribasic or aquesous potassium carbonate in a solvent such as 1,4-di oxane at a temperature as high as 100 °C.

[0198] Alternatively, compound (xiv) can be derived under Buchwald coupling conditions by treatment of compound (xiii) with an appropriately substitued amine, either purchased or prepared by one skilled in the art, in presence of Pd2(dba)s and Xantphos and in the presence of a base such as cesium carbonate in a solvent such at 1,4-di oxane at a temperature such as 100 °C.

[0199] Step 3: In step 3 of scheme 3a, the functional group derived from step 2 in compound (xiv) may be optionally transformed into the desired functionality, by one skilled in the art.

[0200] Step 4: Step 4 of scheme 3a is an optional step or series of steps to transform the groups NR.1R.2, R10, R3, R6, and R9in compound (xv) into A, R6, R5, R8, and R7found in formula (I).

[0201] One skilled in art will recognize that the order of steps may be modified to prepare compound (xv), as examplified in Scheme 3b. Additional modications to the sequence may be envisioned by one skilled in the art.

[0202] ABBREVIATIONS

[0203] Ac acetyl

[0204] ACN acetonitrile

[0205] anhyd. anhydrous

[0206] aq. aqueous

[0207] Bn benzyl

[0208] B oc-anhy dri de di -tert-butyl di carb onate

[0209] Bu butyl

[0210] Boc tert-butoxycarbonyl

[0211] CV Column Volumes

[0212] DCE di chloroethane

[0213] DCM dichloromethane

[0214] DMAP dimethylaminopyridine

[0215] DMF dimethylformamide

[0216] DMSO dimethylsulfoxide

[0217] EtOAc ethyl acetate

[0218] Et ethyl

[0219] Et3N triethylamine

[0220] H or H2 hydrogen

[0221] h, hr or hrs hour(s)

[0222] hex hexanei iso

[0223] HC1 hydrochloric acid

[0224] HPLC high pressure liquid chromatography

[0225] LC liquid chromatography

[0226] LCMS liquid chromatography-mass spectroscopy

[0227] LiAlH4 lithium aluminum hydride

[0228] M molar

[0229] mM millimolar

[0230] Me methyl

[0231] MeOH methanol

[0232] MHz megahertz

[0233] min. minute(s)

[0234] mins minute(s)

[0235] M+l (M+H)+

[0236] MS mass spectrometry

[0237] n or N normal

[0238] NBS n-bromosuccinimide

[0239] NCS n-chlorosuccinimide

[0240] nm nanometer

[0241] nM nanomolar

[0242] NMP N-methylpyrrolidinone

[0243] Pd / C palladium on carbon

[0244] PdC12(dppf) [1 J’-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0245] Ph phenyl

[0246] Pr propyl

[0247] PSI pounds per square inch

[0248] Ret Time retention time

[0249] sat. saturated

[0250] SFC supercritical fluid chromatography

[0251] TEA triethylamine

[0252] TFA trifluoroacetic acid

[0253] THF tetrahydrofuran

[0254] XPhos Precatalyst chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1'-biphenyl)[2-(2'-amino- 1, 1 '-biphenyl)]palladium(II)

[0255] Analytical Methods

[0256] Method A: Column: Waters XB ridge Cl 8, 2.1 mm 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 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: ImL / min; Detection: MS and UV (220 nm).

[0257] Method B: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 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; Temperature: 50 °C; Gradient: 0 %Bto 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm).

[0258] Method C: Column: Waters Acquity BEH C18, 2.1 x 50 mm, 1.7 pm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50°C; Gradient: 0 %B to 100 % B over 1.00 min, then a 0.50 min hold at 100 % B; Flow: 0.8 mL / min; Detection: MS and UV (254nm & 220 nm). Method D: Column: Acquity UPLC BEH C18, 1.7 pm particles; Mobile Phase A:

[0259] 99.95:0.05 water: TFA; Mobile Phase B: 99.95:0.05 acetonitrile: TFA; Temperature: 50 °C; Gradient: 2 %B to 98 %B over 1.00 min, then a 0.50 min hold at 98 %B; Flow: 0.8 mL / min; Detection: MS and UV (254 nm).

[0260] Method E: Column: XBridge BEH Cl 8, 2.1 mm x 50 mm, 2.5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 0.1 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.1 % TFA; Temperature: 50°C; Gradient: 0-100 % B (0.0-3.0 min); Flow: 1.1 mL / min; Detection: UV (220 nm) and MS (ESI +).

[0261] Method F: Column: XBridge BEH Cl 8, 2.1 mm x 50 mm, 2.5 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; Temperature: 50°C; Gradient: 0 % B to 100 % B over 3 min; Flow: 1.1 mL / min; Detection: UV (220 nm) and MS (ESI +). Method G: Column: Waters XBridge Cl 8, 2.1 mm x 50 mm, 1.7 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; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.50 min hold at 100 %B; Flow: 1 mL / min; Detection: MS and UV (220 nm).

[0262] Method H: Column: Waters XBridge Cl 8, 2.1 mm 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 %B to 100 %B over 3 min, then a 0.50-minute hold at 100 %B; Flow: 1 mL / min

[0263] Method I: Column: Waters Acquity UPLC BEH C 18, 2.1 x 50 mm, 1.7-pm particles; Mobile Phase A: 100% water with 0.05% TFA; Mobile Phase B: 100% acetonitrile with0.05% TFA; Temperature: 50 °C; Gradient: 2-98% B over 1.6 minutes, then a 0.2-minute hold at 100% B; Flow: 1 mL / min.

[0264] Method J: Column: Waters Acquity UPLC BEH Cl 8, 3.0 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile:water with 2.5 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 2.5 mM ammonium acetate; Temperature: 50 °C;

[0265] Gradient: 0-80 %B over 2 min, then a 0.50-minute hold at 100 %B; Flow: 0.7 mL / min. Biological Evaluation: HTRF Binding Assay

[0266] 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.

[0267] Intermediate 1. 6-Amino-2-chloronicotinonitrile

[0268] Cl

[0269]

[0270] To a stirred solution of 2,6-dichloronicotinonitrile (80 g, 462 mmol) was added ammonia in IPA (1000 mL, 46.2 mol) (NH3 gas purged in IPA at -78 °C). The reaction mixture was heated to 90 °C in a 3L autoclave for 18h. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The crude material was recrystallized from acetone and pet. ether. The resulting solid was filtered and dried to afford 6-amino-2-chloronicotinonitrile (45 g, 293 mmol, 63% yield). LC / MS (M+H)+: 154.2; ret. time = 1.17 min. [Method E], ‘H-NMR (500 MHz, DMSO-de) 67.77 (d,lH), 7.46 (d, H).Intermediate 2. 6-Amino-2-((3aR,5r,6aS)-5-hydroxy-5-(methoxymethyl)hexa-hydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0271] O HQ }

[0272] CN

[0273]

[0274] Step A. (3aR,6aS)-Hexahydrocyclopenta[c]pyrrol-5(lH)-one

[0275]

[0276] H

[0277] To a stirred solution of tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (10 g, 44.4 mmol) in CM (120 mL) was added TFA (17.10 mL, 222 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to afford (3aR,6aS)-hexahydrocyclopenta[c]pyrrol-5(lH)-one, TFA (10 g, 41.8 mmol, 94 % yield) as a colorless semi liquid. The crude product was directly used for next step without any purification. 'H-NMR (300 MHz, DMSO-tL) 6 ppm 3.31 - 3.59 (m, 2 H), 3.01 - 3.05 (m, 4 H), 2.34 - 2.47 (m, 2 H), 2.10 - 2.31 (m, 2 H).

[0278] Step B. 6-Amino-2-((3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0279] N JI

[0280]

[0281] hfTo a stirred solution of (3aR,6aS)-hexahydrocyclopenta[c]pyrrol-5(lH)-one, TFA (10 g, 41.8 mmol) in dioxane (150 mL) were added potassium carbonate (14.44 g, 105 mmol) and 6-amino-2-chloronicotinonitrile (7.06 g, 46.0 mmol). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with water (20 mL), and the aqueous solution was extracted with EtOAc (2 x 250 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 6-amino-2-((3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (6 g, 24.8 mmol, 59 % yield) as a white solid. LC / MS (M+H)+: 243. ‘H-NMR (300 MHz, DMSO-tL) 6 ppm 7.23 - 7.48 (m, 1 H), 6.42 - 6.68 (m, 2 H), 5.64 - 5.92 (m, 1 H), 3.82 -4.01 (m, 2 H), 3.38 - 3.55 (m, 2 H), 2.89 - 3.09 (m, 2 H), 2.37 - 2.46 (m, 2 H), 2.02 - 2.22 (m, 2 H).

[0282] Step C. 6-Amino-2-((3aR,5r,6aS)-tetrahydro-lH-spiro[cyclopenta[c]pyrrole-5,2'-oxiran]-2(3H)-yl)nicotinonitrile

[0283]

[0284] In a nitrogen purged round bottom flask, trimethyl sulfonium iodide (4548 mg, 22.29 mmol) was dissolved in THF (100 mL) and DMSO (67 mL) follwed by addition of 6-amino-2-((3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (1800 mg, 7.43 mmol). The mixture was cooled to -5 °C, and KO / Bu (1251 mg, 11.14 mmol) dissolved in 50 ml of THF was added dropwise over 10 minutes. The reaction was stirred at -5 °C - 0 °C for 1.5 h. The reaction mixture was quenched with brine at 0 °C and extracted several times with EtOAc. Pooled organic layers were combined, washed with cold water, brine, dried over sodium sulfate. Solvent was removed under vacuum to afford a yellow colored solid of 6-amino-2-((3aR,5r,6aS)-tetrahydro-lH-spiro[cyclopenta[c]pyrrole-5,2'-oxiran]-2(3H)-yl)nicotinonitrile (1850 mg, 7.22 mmol, 97 % yield). LC / MS (M+H)+: 257. ‘H-NMR (300 MHz, DMSO-tL) 6 ppm 7.38 (d, J= 8.31 Hz, 1 H), 6.58 (br s, 2 H), 5.81 (d, = 8.31 Hz, 1 H), 3.85 (br dd, J= 10.95, 7.55 Hz, 2H), 3.57 (dd, J= 11.14, 4.34 Hz, 2 H), 2.67 - 2.85 (m, 4 H), 2.25 (br dd, J= 14.54, 8.12 Hz, 2 H), 1.49 (dd, J= 14.54, 3.97 Hz, 2 H).

[0285] Step D. 6-Amino-2-((3aR,5r,6aS)-5-hydroxy-5- (methoxymethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0286]

[0287] To a stirred solution of 6-amino-2-((3aR,5r,6aS)-tetrahydro-lH-spiro[cyclopenta[c]pyrrole-5,2'-oxiran]-2(3H)-yl)nicotinonitrile (2 g, 7.80 mmol) in methanol (40 mL) was added sodium methoxide (1.265 g, 23.41 mmol). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = pet ether, B = EtOAc; 30 min gradient.; 0% B to 70% B). The pure fractions were combined, concentrated and dried in vacuum to afford 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-(methoxymethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (2 g, 6.94 mmol, 89 % yield) as a white gum solid. LC / MS (M+H)+: 289; ret. time = 0.89 min (Method J); ‘H-NMR (300 MHz, DMSO4) 6 ppm 7.28 - 7.45 (m, 1 H), 6.43 - 6.67 (m, 2 H), 5.65 - 5.96 (m, 1 H), 4.51 - 4.71 (m, 1 H), 3.52 - 3.91 (m, 4 H), 2.59 - 2.73 (m, 2 H), 1.88 - 2.08 (m, 2 H), 1.42 - 1.57 (m, 2 H).

[0288] Ret

[0289] INT. Obs. MS Analytical structure time

[0290] No. Ion LC-MS method (min)

[0291] 0

[0292] HO \

[0293] 3 303.1 0.65 D

[0294] H7 TH

[0295] IT

[0296] N^VCN

[0297] jl I

[0298]

[0299] H2N^^Ret

[0300] INT. Obs. MS Analytical structure time

[0301] No. Ion LC-MS method (min)

[0302] HO^O^F

[0303] HH — HH

[0304] 4 353.3 1.24 F

[0305] FT

[0306] JL J

[0307]

[0308] H2I\T —

[0309] Intermediate 5. 6-Amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol -2(lH)-yl)nicotinonitrile

[0310]

[0311] Step A. tert-Butyl (3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate

[0312] QH

[0313] HH — HH

[0314]

[0315] i

[0316] Boc

[0317] A 3.0 M ether solution of methylmagnesium chloride (0.25 mL, 0.75 mmol) was added to a THF solution (4 mL) of Zc / V-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(177)-carboxylate (110 mg, 0.51 mmol) at 0 °C. After stirring for 2 h, the reaction mixture was quenched by water, extracted three times with ethyl acetate. The ethyl acetate layers were combined, dried (Na2SC>4), filtered and concentrated. Silica gel chromatography, eluting with 0 to 50% ethyl acetate in hexanes, gave the desired Zc / V-butyl (3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (96 mg, 79% yield). 'H-NMR (499 MHz, CHLOR. OFOR. M-t / ) 6 = 3.48 (dd, J= 11.3, 8.2 Hz, 2H), 3.34 (dd, J= 11.2, 3.6 Hz, 2H), 2.72 - 2.61 (m, 2H), 2.10 (s, 1H), 1.92 (dd, J= 13.4, 8.5 Hz, 2H), 1.67 (dd, J = 13.4, 5.1 Hz, 2H), 1.44 (s, 9H), 1.31 (s, 3H).

[0318] Step B. (3aR,5r,6aS)-5-Methyloctahydrocyclopenta[c]pyrrol-5-ol

[0319] OH

[0320] HH — r" H

[0321] ^hf

[0322]

[0323] H

[0324] A 4.0 M dioxane solution of HC1 (1.0 mL, 4.0 mmol) was added to a MeOH (3 mL) solution of tert-butyl (3t / 7,5 / ',6aS')-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(lrt)-carboxylate (96 mg, 0.40 mmol) at 0 °C. The reaction mixture was stirred for 2 hours before removal of solvent. The crude material was triturated with diethyl ether, and the desired (3aR,5r,6aS)-5-methyloctahydrocyclopenta[c]pyrrol-5-ol was collected as aHCl salt (71 mg, 100% yield). ‘H-NMR (499 MHz, METHANOL-tA) 6 = 3.33 (dt, J = 3.3, 1.6 Hz, 2H), 3.32 -3.29 (m, 3H), 3.11 - 3.04 (m, 2H), 1.96 (dd, J= 13.8, 9.2 Hz, 2H), 1.76 (s, 1H), 1.73 (s, 1H), 1.37 (s, 3H).

[0325] Step C. 6-Amino-2-((3aA,5r,6a5)-5-Hydroxyhexahydrocyclopenta[c]pyrrol-2(lrt)-yl)nicotinonitrile

[0326]

[0327] A DMSO (10 mL) solution of potassium carbonate (2.00 g, 14.5 mmol), 6-amino-2-chloronicotinonitrile (0.555 g, 3.62 mmol), (3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-ol, HC1 salt (0.710 g, 4.34 mmol) was heated at 80 °C overnight. The reaction mixture was cooled down to room temperature, partitioned between ethyl acetate and water. Theethyl acetate layer was separated, washed with water, dried (Na2SC>4), filtered and concentrated. Silica gel chromatography, eluting with EtOAc / hexanes (0-100% gradient), provided the desired 6-amino-2-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(U7)-yl)nicotinonitrile (640 mg, 73% yield). LC / MS (M+H)+: 245; ret. time = 0.48 min (Method I); 'H-NMR (499 MHz, CHLOROFORM- ) 8 = 7.45 (d, J= 8.3 Hz, 1H), 5.84 (d, J= 8.3 Hz, 1H), 4.65 (br s, 2H), 4.37 (t, J= 6.1 Hz, 1H), 3.86 (s, 2H), 3.85 (s, 2H), 2.79 - 2.70 (m, 2H), 2.24 (ddd, J= 13.7, 8.3, 6.5 Hz, 2H), 1.66 - 1.63 (m, 2H).

[0328] Intermediate 6. 6-Amino-2-((3aR,5r,6aS)-5-Hydroxyhexahydrocyclopenta[c]pyrrol-2(U7)-yl)nicotinonitrile

[0329]

[0330] Step A. tert-Butyl (3aR,5r,6aS)-5-Hydroxyhexahydrocyclopenta[c]pyrrole-2(177)-carb oxy late

[0331] OH

[0332]

[0333] I

[0334] Boc

[0335] Sodium borohydride (101 mg, 2.66 mmol) was added to the mixture of tert-butyl (3aR,6aS -5-oxohexahydrocyclopenta[c]pyrrole-2(177)-carboxylate (200 mg, 0.89 mmol) in MeOH (3 mL) at 0 °C. The resultant mixture was warmed to room temperature and stirred for 2 h. The reaction was carefully quenched with a saturated aqueous solution of NH4Q and extracted three times with ethyl acetate. The ethyl acetate layers were combined, dried (Na2SC>4), filtered and concentrated to give the desired tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate as crude material (234 mg). LC / MS (M+H)+: 172; ret. Time = 0.78 min (Method I).Step B & C. 6-Amino-2-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(l H)-yl)nicotinonitrile

[0336]

[0337] Following similar procedures as step A & B of the synthesis of intermediate 2, tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(177)-carboxylate (234 mg, 1.03 mmol) was converted to intermediate 6 (70 mg, 42% yield for 3 steps). 'H-NMR (499 MHz, DMSO-t / e) 6 = 9.28 (br s, 1H), 8.66 (br s, 1H), 4.16 - 4.09 (m, 1H), 3.21 (dt, J = 11.2, 5.8 Hz, 2H), 3.06 (br dd, J= 11.1, 4.5 Hz, 2H), 2.77 (br d, J= 2.9 Hz, 2H), 1.84 (ddd, J= 13.1, 8.2, 4.8 Hz, 2H), 1.55 (br d, J= 13.4 Hz, 2H).

[0338] Intermediate 7. 4-Amino-2-((3aR,6aS)-2,2-dioxidotetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)benzonitrile

[0339]

[0340] Step A. tert-Butyl (3aR,6aS)-tetrahydro-lH-thieno[3,4-c]pyrrole-5(3H)-carboxylate 2,2-dioxide

[0341]

[0342] N

[0343] i

[0344] BocBoc-anhydride (2 M in EtOAc) (1.21 mL, 2.41 mmol) was added to a stirred solution of (3aR,6aS)-hexahydro-lH-thieno[3,4-c]pyrrole hydrochloride (250 mg, 1.51 mmol), triethylamine (0.421 mL, 3.02 mmol) in CH2CI2 (8 mL). Carbon dioxide evolution was observed. The mixture was diluted with EtOAc (30 mL), washed with water (10 mL), washed with brine (10 mL), dried (MgSO4) and concentrated to give tert-butyl (3aA,6a5)-tetrahydro-lH-thieno[3,4-c]pyrrole-5(3H)-carboxylate. The crude product was used in the next reaction without purification. LC / MS (M+H)+: 174; ret. time = 0.98 min (Method D). mCPBA (77% pure) (1353 mg, 6.04 mmol) was added to a stirred solution of crude tert-butyl (3aR,6aS)-tetrahydro-lH-thieno[3,4-c]pyrrole-5(3H)-carboxylate (346 mg, 1.509 mmol) in CH2CI2 (20 mL). After stirring for 15 h, the mixture was diluted with CH2CI2 (30 mL), washed with 1: 1 mixture of 20% Na2S2O / lN NaOH (2x10 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with EtOAc / hexanes (30-100% gradient) afforded tert-butyl (3aR,6aS)-tetrahydro-l H-thieno[3,4-c]pyrrole-5(3H)-carboxylate 2,2-dioxide as white solid (355 mg, 90% yield over 2 steps). 1H-NMR (400 MHz, CHLOROFORM-d) 83.73 (dd, J=11.7, 7.6 Hz, 2H), 3.41 (br d, J=8.8 Hz, 2H), 3.31 (br dd, J=13.5, 8.2 Hz, 2H), 3.18 - 3.06 (m, 2H), 3.05 -2.94 (m, 2H), 1.47 (s, 9H).

[0345] Step B & C. 6-amino-2-((3aR,6aS)-2,2-dioxidotetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)nicotinonitrile

[0346]

[0347] Following similar procedures as step A & B of the synthesis of intermediate 6, tert-butyl (3aR,6aS)-tetrahydro-lH-thieno[3,4-c]pyrrole-5(3H)-carboxylate 2,2-dioxide (355 mg, 1.36 mmol) was converted to intermediate 7 (104 mg, 71% yield for 2 steps). 'H-NMR (400 MHz, 1:1 mixture of CDC13-METHANOL-d4) 67.45 - 7.35 (m, 1H), 5.99 - 5.89 (m, 1H), 4.07 (dd, J=11.6, 7.3 Hz, 2H), 3.83 (dd, J=11.6, 4.7 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.31 - 3.20 (m, 2H), 3.17 - 3.08 (m, 2H).Intermediate 8. 4-Amino-2-((3aR,5r,6aS)-5-hydroxy-5-(trifluoromethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)benzonitrile

[0348]

[0349] Step A. tert-Butyl (3aR,5r,6aS)-5-hydroxy-5-(trifluoromethyl)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate

[0350]

[0351] To a stirred solution of tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (1.00 g, 4.44 mmol) and trimethyl(trifluoromethyl)silane (0.757 g, 5.33 mmol) in THF (10 mL) at 0 °C was added TBAF (1 M in THF) (4.44 mL, 4.44 mmol). After stirring at 0 °C for 30 min and at room temperature for 2 h, the reaction mixture was concentrated, diluted with EtOAc (80 mL), washed with water (2x20 mL), washed with brine (10 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with EtOAc / hexanes (10-50% gradient), gave the desired product as white solid in 65% yield (852 mg). 'H-NMR (400 MHz, CHLOROFORM-d) 83.56 (dd, J=11.3, 8.1 Hz, 2H), 3.41 (dd, J=11.4, 4.1 Hz, 2H), 2.82 (brtd, J=7.7, 4.0 Hz, 2H), 2.40 - 2.32 (m, 3H), 1.80 (br d, J=12.5 Hz, 2H), 1.46 (s, 9H).

[0352] Step B & C. 4-Amino-2-((3aR,5r,6aS)-5-hydroxy-5- (trifluoromethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)benzonitrile

[0353]

[0354] Following similar procedures as step A & B of the synthesis of intermediate 2, tert-Butyl (3aR,5r,6aS)-5-hydroxy-5-(trifhioromethyl)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (181 mg, 4.44 mmol) was converted to intermediate 8 (187 mg, 92% yield for 2 steps). 'H-NMR (500 MHz, METHANOL-d4) 8 7.37 (d, J=8.4 Hz, 1H), 5.87 (d, J=8.4 Hz, 1H), 3.95 (dd, J=11.2, 7.9 Hz, 2H), 3.80 (dd, J=11.2, 4.3 Hz, 2H), 2.90 (td, J=7.8, 4.5 Hz, 2H), 2.40 (dd, J=14.7, 8.4 Hz, 2H), 1.86 (dd, J=14.7, 3.0 Hz, 2H).

[0355] Intermediate 9. 4-Amino-2-((3aR,5r,6aS)-5-cyclopropyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)benzonitrile

[0356]

[0357] N

[0358] Step A. tert-Butyl (3aR,5r,6aS)~ 5-cyclopropyl-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate

[0359] HO, P

[0360] HH — HH

[0361]

[0362] i

[0363] Boo

[0364] A mixture of tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (500 mg, 2.22 mmol) and CeCh (1488 mg, 3.99 mmol) in THF (15 mL) was stirred for 1 hour at room temperature. The reaction mixture was cooled to -78 °C and cyclopropylmagnesium bromide in THF (7.99 mL, 3.99 mmol) was added dropwise over 10 min. The reaction mixture was stirred 2 hr -78 °C. The reaction mixture was quenched at -78 °C with 10% aq. solution of acetic acid (20 mL) and the aqueous solution was extracted with EtOAc (2 x30 mL). The combined organic layers were washed with an aqueous solution of NaHCCh, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to afford tert-butyl (3a / ,5r,6aS')-5-cyclopropyl-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (505 mg, 1.89 mmol, 85 % yield) as yellow oil.Step B & C. 4-Amino-2-((3aR,5r,6aS)-5-cyclopropyl-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)benzonitrile

[0365] CN

[0366]

[0367] H2N

[0368] Following similar procedures as step A & B of the synthesis of intermediate 2, tert- Butyl (3aR,5r,6aS)-5-cyclopropyl-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (505 mg, 1.9 mmol) was converted to intermediate 8 (230 mg, 46% yield for 2 steps). LC / MS (M+H)+: 285; ret. time = 1.11 min (Method C).

[0369] Intermediate 10. 4-Amino-2-((lA,55,65)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile

[0370]

[0371] Step A. / c / 7-Butyl (3aR,5r,6aS)-5-cyclopropyl-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate

[0372] N

[0373] ■ )=O >=O

[0374]

[0375] trans- product cis- product

[0376] first-eluding isomer second-eluding isomer To a toluene (115 mL) solution of 1 -benzyl- lH-pyrrole-2, 5-dione (15 g, 80 mL) in a 3 -neck flask equipped with a nitrogen inlet, reflux condenser and addition funnel was added a solution of ethyl 2-(dimethyl-14-sulfaneylidene)acetate (8.21 g, 55.4 mmol) intoluene (115 mL) via the addition funnel. The resulting solution was heated at 100 °C for 3 h. The solvent was evaporated, and the crude material was purified by flash column chromatography to afford the cis and trans isomers: First-eluding trans isomer: ethyl (lA,55,6r)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (3.32 g, 12.2 mmol, 26 % yield) LC / MS (M+H)+: 296; ret. time = 0.94 min (Method I). 'H-NMR (400 MHz, CHLOROFORM-d) 87.36 - 7.30 (m, 5H), 4.54 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 2.89 (d, J=2.8 Hz, 2H), 2.30 (t, J=2.8 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H). Second eluding ethyl cis isomer: (lR,5S,6s)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (3.1524 g, 11.54 mmol, 24.99 % yield); LC / MS (M+H)+: 296; ret. time = 0.89 min (Method I). ‘H-NMR (400 MHz, CHLOROFORM-d) 67.40 - 7.35 (m, 2H), 7.33 - 7.28 (m, 2H), 7.25 (s, 1H), 4.49 (s, 2H), 4.03 (q, J=7.1 Hz, 2H), 2.79 (d, J=8.4 Hz, 2H), 2.58 -2.48 (m, 1H), 1.20 (t, J=7.1 Hz, 3H).

[0377] Step B. ((U?,55,65)-3-Benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol

[0378]

[0379] To a IM THF solution of lithium aluminum hydride (29.3 mL, 29.3 mmol) was added a THF (15 mL) solution of ethyl (lR,5S,6s)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (2 g, 7.32 mmol) at 0 °C dropwise over 5 min. The mixture was warmed up to room temperature and stirred for 10 min. The reaction was then heated at reflux for 2 h. After cooling to room temperature, the mixture was quenched by slowly adding IM NaOH (5 mL) and ethanol (5 mL). The resulting suspension was filtered through a short bed of Celite. The bed was washed with MeOH (3x20 mL) and CH2CI2 (3x20 mL). The combined filtrate was concentrated. The resulting residue was mixed with water (20 mL) and extracted with EtOAc (3x30 mL). The combined EtOAc phase was washed with water (3x20 mL) followed by brine (3x20 mL) and then dried over MgSO4. The resulting suspension was filtered. The filtrate was concentrated to give crude ((lA,55,65)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol (1.40 g, 6.88 mmol, 94 % yield). LC / MS (M+H)+: 204; ret. time = 0.52 min (Method I). ‘H-NMR (400 MHz, CHLOROFORM-d) 67.34 - 7.23 (m, 5H), 5.40 - 5.20 (m, 1H), 4.09(d, J=5.0 Hz, 2H), 3.66 (s, 2H), 3.16 (d, J=9.6 Hz, 2H), 2.57 (ddd, J=9.5, 2.5, 1.3 Hz, 2H), 1.55 (ddd, J=8.3, 2.5, 1.3 Hz, 2H), 1.04 (tt, J=8.4, 4.9 Hz, 1H).

[0380] Step C. ((lR,5S,6s)-3-Benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol

[0381] OH

[0382] I )=°

[0383] Y " H

[0384]

[0385] HO^

[0386] A MeOH (10 mL) solution of ((lA,55,65)-3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol (250 mg, 1.230 mmol) and Pd-C (50 mg, 0.047 mmol) was hydrogenated under 1 atm H2 at room temperature for 17 h. As the reaction was incomplete, the hydrogenation was continued under 50 psi H2 for an additional 3 days after the addition of more Pd-C (50 mg, 0.047 mmol). The reaction mixture was evacuated and backfilled with nitrogen (2x) then filtered. The filtrate was concentrated to give ((lR,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (100.6 mg, 0.711 mmol, 57.8 % yield). LC / MS (M+H)+: 114; ret. time = 0.24 min (Method I). ‘H-NMR (400 MHz, CHLOROFORM-d) 83.82 (d, J=6.1 Hz, 2H), 3.17 - 3.07 (m, 4H), 1.63 - 1.57 (m, 2H), 1.14 - 1.04 (m, 1H) indicating ~5:1 ratio of product and SM.

[0387] Step D. 4-Amino-2-((lA,5£,6s)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile

[0388] HO^

[0389] _x-L. CN

[0390]

[0391] A DMSO (0.5 mL) solution of 6-amino-2-chloronicotinonitrile (12 mg, 0.078 mmol), ((lR,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)methanol (17.68 mg, 0.156 mmol) and potassium carbonate (32.4 mg, 0.234 mmol) was heated at 120 °C in a sealed safety vial for 4 h. The crude material was purified by preparative, reverse-phase HPLC. The desired product co-eluded out with an impurity. This impure product fraction was concentrated. The resulting brown oil was further purified by silica gel chromatography (0-100% EtOAc / Hex) to give 6-amino-2-((lA,55,65)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)nicotinonitrile (3.7 mg, 0.016 mmol, 21 % yield). LC / MS (M+H)+: 231; ret. time = 0.52 min (Method I). 'H-NMR (400 MHz, CHLOROFORM-d) 67.42 (d, J=8.4 Hz, 1H), 5.80 (d, J=8.4 Hz, 1H), 4.68 - 4.51 (m, 2H), 4.02 - 3.94 (m, 2H), 3.92 - 3.84 (m, 2H), 3.62 (d, J=7.4 Hz, 2H), 1.88 (ddd, J=8.0, 3.3, 1.6 Hz, 2H), 1.31 (d, J=7.9 Hz, 1H).

[0392] Similar to the synthesis of step C of intermediate 2, intermediates in Table 1 were prepared by treatment of 6-amino-2-chloronicotinonitrile with appropriate amines.

[0393] Table 1

[0394] MS HPLC ret.

[0395] Int. o HPLC Structure z observed time

[0396] No. method (M+H)+(min.)

[0397] 11 231 0.54 G

[0398] z

[0399] O OH

[0400] z

[0401] x1

[0402] 12 233 0.53 / 0.54 G XT

[0403] H2N'^-^

[0404] OH

[0405] 13 b 219 0.50 I XT

[0406] H2N"^

[0407] 14 219 0.57 I

[0408] \ OH

[0409] 15 247 0.64 I

[0410] XT

[0411]

[0412] H2N^"MS HPLC ret.

[0413] Int. HPLC Structure observed time

[0414] No. method (M+H)+(min.)

[0415] \ OH

[0416] 16 247 0.61 I M-#K / CN

[0417] H2N'^ /

[0418] 17 hq 247 0.61 I z

[0419] 0

[0420] H2N-^

[0421] 18 Q 232 0.47 I N< K / CN

[0422] 2XJ z

[0423] H N'^X

[0424] BocHN—

[0425] A 262.2 (M- 19 1.29 C tbutyl+H)

[0426] AJ

[0427] H2N'^ /

[0428] 20 318 0.76 D

[0429] 21 332.2 1.38 C

[0430] BocHN— \

[0431] 22 Q 332.2 1.39 C H2N A"'^ —CN

[0432] 23 247 0.61 I

[0433]

[0434] MS HPLC ret.

[0435] Int. HPLC Structure observed time

[0436] No. method (M+H)+(min.)

[0437] 24 206 0.57 C

[0438] X? r K>

[0439] 25 8 229.2 1.38 C

[0440] o o z z

[0441] 26 206.1 0.51 I

[0442] z

[0443] 27 X o 247 0.75 I

[0444]

[0445] Ol z

[0446] I

[0447] Intermediate 28. 6-Amino-2-((U?,47?,55)-5-hydroxy-2-azabicyclo[2.2. l]heptan-2-yl)nicotinonitrile

[0448]

[0449] To a stirred solution of 6-amino-2-chloronicotinonitrile (1.1 g, 7.16 mmol) in DMSO (15 mL) were added (lA,4A,55)-2-azabicyclo[2.2.1]heptan-5-ol (commercially available) (1.95 g, 8.60 mmol) and potassium carbonate (2.97 g, 21.5 mmol). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give crude product as a light yellow oil. The crude product was purified using Combi Flash (silica gel 60-120 mesh; 35% ethyl acetate in pet. ether as eluent). The fraction was concentrated using high vacuum at 50 °C to give 6-amino-2-((lA,4A,55)-5-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl)nicotinonitrile (1.30 g, 5.48 mmol, 76 % yield) as an off white solid. LC / MS (M+H)+:231; ret. time = 0.48 min (Method J);JH-NMR400 MHz, DMSO-fifc: 6 = 7.32 (d, J= 8.80 Hz, 1H), 5.78 (d, J= 8.40 Hz, 1H), 4.68 (s, 1H), 3.51-3.55 (m, 1H), 2.97-3.00 (m, 1H), 2.41-2.42 (m, 1H), 1.92-1.96 (m, 1H), 1.73-1.76 (m, 1H), 1.47-1.49 (m, 1H), 1.35-1.38 (m, 1H).

[0450] Intermediate 29. 6-Amino-2-((15',45',5A)-5-hydroxy-2-azabicyclo[2.2. l]heptan-2-yl)nicotinonitrile

[0451]

[0452] Similar to the synthesis intermediate 28, intermediate 29 was prepared by treatment of 6-amino-2-chloronicotinonitrile with (LS',4A',5 / ?)-2-azabicyclo[2.2. l]heptan-5-ol. LC / MS (M+H)+: 231.

[0453] Intermediate 30. 6-Amino-2-((lA,45,6A)-6-hydroxy-2-azabicyclo[2.2. l]heptan-2-yl)nicotinonitrile

[0454]

[0455] Similar to the synthesis intermediate 28, intermediate 30 was prepared by treatment of 6-amino-2-chloronicotinonitrile with (1 A,45,6A)-2-azabicyclo[2.2.1]heptan-6-ol LC / MS (M+H)+: 231.

[0456] Intermediate 31. 6-Amino-2-((15,4A,65)-6-hydroxy-2-azabicyclo[2.2. l]heptan-2-yl)nicotinonitrile

[0457]

[0458] Similar to the synthesis intermediate 28, intermediate 31 was prepared by treatment of 6-amino-2-chloronicotinonitrile with (15,4A,65)-2-azabicyclo[2.2.1]heptan-6-ol. LC / MS (M+H)+: 231.Intermediate 32. 6-amino-2-((15',45',55)-5-hydroxy-2-azabicyclo[2.2. l]heptan-2-yl)nicotinonitrile

[0459] OH

[0460]

[0461] Similar to the synthesis intermediate 28, intermediates 32 was prepared by treatment of 6-amino-2-chloronicotinonitrile with (15,45,55)-2-azabicyclo[2.2.1]heptan-5-ol. LC / MS (M+l): 231.

[0462] Intermediate 33. 6-amino-2-((lA,4A,5A)-5-hydroxy-2-azabicyclo[2.2. l]heptan-2-yl)nicotinonitrile

[0463]

[0464] Similar to the synthesis intermediate 28, intermediates 33 was prepared by treatment of 6-amino-2-chloronicotinonitrile with (lA,4A,5A)-2-azabicyclo[2.2.1]heptan-6-ol. LC / MS (M+H)+: 231.

[0465] Intermediate 34. 6-Amino-2-((3aR,5r,6aS)-5-hydroxy-5- (methoxymethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0466]

[0467] Step A. tert-Butyl (3aR,5r,6aS)-tetrahydro-lH-spiro[cyclopenta[c]pyrrole-5,2'-oxirane]-2(3H)-carboxylate

[0468]

[0469] i

[0470] Boc

[0471] Trimethyl sulfonium iodide (7.07 g, 34.6 mmol) was added to a stirred suspension of sodium hydride (1.065 g, 26.6 mmol, 60% in mineral oil) in THF (30 mL) and DMSO (30 mL). The mixture was stirred at 0 °C for 10 min, at room temperature for 30 min, and cooled back to 0 °C. FL evolution did not occur. A solution of tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (3.00 g, 13.3 mmol) in THF (15 mL) was added dropwise (H2 evolution started during the addition). The resulting mixture was stirred overnight while allowing the ice-water bath to slowly warm to room temperature. The mixture was quenched with water (50 mL), and the THF solvent was removed in vacuo. The residue was extracted with EtOAc (200 mL). The organic phase was washed with water (50 mL), washed with brine (25 mL), dried (MgSCU) and concentrated. Silica gel chromatography, eluting with EtOAc / hexanes (10-40% gradient) gave the desired product as colorless liquid (2.67 g, 84% yield).1H NMR (400 MHz, CDCh) 63.60 (br t, J=8.3 Hz, 2H), 3.46 - 3.20 (m, 2H), 2.77 (s, 2H), 2.73 (br s, 2H), 2.19 (br dd, J=14.8, 8.0 Hz, 2H), 1.65 (br d, J=13.1 Hz, 2H), 1.46 (s, 9H).

[0472] Step B. tert-Butyl (3aR,5r,6aS)-5-hydroxy-5-(methoxymethyl)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate

[0473]

[0474] Boc

[0475] A mixture of tert-butyl (3aR,5r,6aS)-tetrahydro-lH-spiro[cyclopenta[c]pyrrole-5,2'-oxirane]-2(3H)-carboxylate (0.310 g, 1.30 mmol), a 25% methanol solution of sodium methoxide (1.481 mL, 6.48 mmol) and MeOH (5 mL) in a sealed vial was stirred at 65 °C for 5 h. The resulting mixture was cooled to room temperature and quenchedwith water (10 mL) followed by brine (5 mL). After removal of MeOH in vacuo, the aqueous residue was extracted with CH2CI2 (3x15 mL). The combined organic extracts were dried (MgSO-t) and concentrated. Silica gel chromatography, eluting with EtOAc / hexanes (20-100% gradient), provided the desired product as colorless liquid (340 mg, 97% yield). ‘HNMR (400 MHz, CDCh) 63.53 (dd, J=11.2, 8.1 Hz, 2H), 3.40 (s, 3H), 3.39 - 3.31 (m, 1H), 3.29 (s, 2H), 2.68 - 2.56 (m, 2H), 2.50 (s, 1H), 1.99 (dd, J=14.0, 8.3 Hz, 2H), 1.65 (dd, J=14.0, 5.0 Hz, 2H), 1.45 (s, 9H).

[0476] Step C. (3aR,5r,6aS)-5-(Methoxymethyl)octahydrocyclopenta[c]pyrrol-5-ol

[0477]

[0478] A 4 M dioxane solution of HC1 (3.13 mL, 12.53 mmol) was added to a stirred solution of tert-butyl (3aR,5r,6aS)-5-hydroxy-5-(methoxymethyl)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (340 mg, 1.25 mmol) in CH2CI2 (3 mL). After stirring for 2 h, the mixture was concentrated and pumped under vacuum to give hydrochloride salt of the desired product as brown liquid (261 mg). The crude material was used in the next step without purification.

[0479] Step D. 6-Amino-2-((3aR,5r,6aS)-5-hydroxy-5-(methoxymethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0480]

[0481] Potassium carbonate (288 mg, 2.08 mmol) was added to a mixture of 6-amino-2-chloronicotinonitrile (80 mg, 0.521 mmol) and crude (3aR,5r,6aS)-5-(methoxymethyl)octahydrocyclopenta[c]pyrrol-5-ol hydrochloride (141 mg) from the previous step in DMSO (2 mL). The reaction vial was sealed and stirred at 80 °C for 15 h. The mixture was cooled to room temperature, treated with EtOAc (30 mL), washedwith water (8 mL), brine (5 mL), dried (MgSC ) and concentrated. Silica gel chromatography, eluting with EtOAc / hexanes (30-100% gradient, then holding at 100%), to give product as tan liquid (130 mg, 87% yield). 'H NMR (400 MHz, CDCh) 67.41 (d, J=8.4 Hz, 1H), 5.79 (d, J=8.3 Hz, 1H), 4.59 (br s, 2H), 3.93 (dd, J=11.4, 8.0 Hz, 2H), 3.81 (dd, J=11.3, 4.1 Hz, 2H), 3.41 (s, 3H), 3.31 (s, 2H), 2.78 - 2.67 (m, 2H), 2.56 (s, 1H), 2.11 - 1.99 (m, 2H), 1.73 (dd, J=14.0, 4.8 Hz, 2H); LC / MS (M+H)+: 289.1; ret. time = 0.59 min. (method: A).

[0482] Intermediate 35. Azetidin- 1 -yl(4,6-dichloropyridin-3-yl)methanone

[0483]

[0484] Oxalyl chloride (0.753 mL, 8.60 mmol) was added to the CH2CI2 (40 mL) (3 drop of DMF) solution of 4,6-dichloronicotinic acid (1.27 g, 6.61 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours. The solvent was removed via vacuum and to the crude reaction mixture was added di chloroethane. The mixture was concentrated to dryness. This was done 2 times to drive off the excess of oxalyl chloride. To the reaction was added azetidine hydrochloride (0.804 g, 8.60 mmol) and DCM (20 mL), and the mixture was cooled to 0°C. Hunig's base (3.47 mL, 19.84 mmol) was added dropwise to the reaction mixture, and the reaction was stirred for an additional 2 hours. The reaction mixture was diluted with DCM and washed with water (lx). The DCM layer was separated, dried (Na2SO4), filtered and concentrated. Flash silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 100%, gave the desired product. (0.58 g, 38% yield). 'H NMR (499 MHz, CHLOROFORM-d) 88.25 (s, 1H), 7.34 (s, 1H), 4.11 (t,. / =7,9 Hz, 2H), 3.92 (t,. / =7,7 Hz, 2H), 2.31 - 2.21 (m, 2H). LC / MS (M+H)+: 231.1; ret. time = 0.69 min. (method A).

[0485] Intermediate 36. Azetidin- l-yl(6-chloro-4-(methylamino)pyri din-3 -yl)methanone

[0486]

[0487] COMU(R) (0.1167 g, 0.272 mmol) was added to a EtOAc (0.874 ml) solution of 6-chloro-4-(methylamino)nicotinic acid (0.0326 g, 0.175 mmol), Hunig's base (0.12 mL, 0.699 mmol) at room temperature. After 30 min, azetidine hydrochloride (0.026 g, 0.280 mmol) was added, and the reaction was stirred for 1 hour. The crude reaction mixture was purified by flash silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 50% to 100%, to give the desired product (17 mg, 43 % yield).1H NMR (499 MHz, CHLOROFORM-d) 88.06 (s, 1H), 7.93 - 7.84 (m, 1H), 6.52 (s, 1H), 4.45 - 4.16 (m, 4H), 2.87 (d, J=5.1 Hz, 3H), 2.37 (quin, J=7.8 Hz, 2H); LC / MS (M+H)+: 226.1]; ret. time = 0.48 min. (method A).

[0488] Intermediate 37. Azeti din- l-yl(6-chloro-4-(cy cl opropylamino)pyri din-3 -yl)m ethanone

[0489]

[0490] A mixture of azeti din- 1 -yl(4,6-di chi oropyri din-3 -yl)m ethanone (0.049 g, 0.212 mmol) and cyclopropanamine (0.048 g, 0.848 mmol) in dioxane (0.8 mL) was heated at 100 °C for 2 hours. The reaction was diluted with ethyl acetate and was washed with brine (lx). The ethyl acetate layer was separated, dried (Na2SC>4), filtered and concentrated. The product was purified by flash silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 100%, to give the desired product (44 mg, 82% yield). L LC / MS (M+H)+: 252.1; ret. time = 0.63 (Method A).

[0491] Intermediate 38. Azeti din- l-yl(6-chloro-4-(ethylamino)pyri din-3 -yl)methanone

[0492]

[0493] Following the procedure outlined for intermediate 37, obtained 38.4 mg, 84% desired product.1H NMR (499 MHz, CHLOROFORM-d) 68.04 (s, 1H), 7.86 (br s, 1H), 6.50 (s, 1H), 4.46 - 4.12 (m, 4H), 3.17 (qd, J=7.2, 5.3 Hz, 2H), 2.40 - 2.31 (m, 2H), 1.29 (t,. / =7,2 Hz, 3H). LC / MS (M+H)+: 240.1; ret. time = 0.56 min. (Method A).Intermediate 39. Azeti din- l-yl(6-chloro-4-(cy cl opropylamino)pyri din-3 -yl)m ethanone

[0494]

[0495] Following the procedure outlined for intermediate 37, obtained 43.6 mg, 82% desired product. LC / MS (M+H)+: 252.1]; ret. time = 0.63 min. (method A).

[0496] Intermediate 40. 6-Chloro-N,2-dimethyl-4-(methylamino)nicotinamide

[0497]

[0498] Following the procedure outlined for intermediate 37, obtained 290 mg, 56% yield.

[0499] Intermediate 41. Methyl 6-chloro-4-(cyclobutylamino)nicotinate

[0500]

[0501] The reaction mixture of methyl 4,6-dichloronicotinate (0.50 g, 2.41 mmol) and cyclobutanamine (0.41 mL, 4.82 mmol) in THF (12 mL) was stirred at room temperature for 18 hours. The solvent was removed via vacuum, and the crude was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (Na2SC>4), filtered and concentrated. Flash silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 35%, gave the desired product (0.381 g, 66%). 'H NMR (499 MHz, CHLOROFORM-d) 88.60 (s, 1H), 8.18 (br d, J=3.6 Hz, 1H), 6.38 (s, 1H), 3.91 (dd, J=13.7, 7.5 Hz, 1H), 3.84 (s, 3H), 2.51 - 2.39 (m, 2H), 1.99 - 1.89 (m, 2H), 1.88 - 1.75 (m, 2H). LC / MS (M+H)+: 241.1; ret. time = 0.97 min. (Method D).Intermediate 42. 6-((5-Chloro-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0502] OH

[0503] CN

[0504]

[0505] Step A. 2,5-Dichloro-N-methylpyridin-4-amine

[0506] HI\K

[0507]

[0508] To a 40 mL reaction vial was added 2,4,5-trichloropyridine (2.70 g, 14.8 mmol), DMA (lOmL), DIPEA (7.76 mL, 44.4 mmol), and methanamine (2.79 g, 29.6 mmol). The reaction was capped and heated to 50 °C overnight. The reaction was diluted with water and extracted 3x with ethyl acetate. The combined organics were washed with water, washed with brine, dried over anhydrous sodium sulfate were filtered, and concentrated to give 2,5-dichloro-N-methylpyridin-4-amine (2.2 g). 'H-NMR. (499 MHz, DMSO-d6), 87.97 (s, 1H), 6.81 (br d, J=4.1 Hz, 1H), 6.62 (s, 1H), and 2.82 - 2.77 (m, 3H).

[0509] Step B. 6-((5-chloro-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0510]

[0511] To a 2 dram vial was added 2,5-dichloro-N-methylpyridin-4-amine (0.741 g, 4.18 mmol), 6-amino-2-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.730 g, 2.99 mmol), Pd2(dba)3 (0.137 g, 0.149 mmol), xantphos (0.173 g, 0.299 mmol), and cesium carbonate (3.41 g, 10.5 mmol). The vial was capped with a septum and pump / purged 3x with nitrogen gas. Dioxane (8 mL) was introduced, and the suspension was purged with nitrogen gas for 5 minutes and then heated at 90 °C overnight. The reaction was cooled to room temperature, and the volatiles were removed. The residue was purified by preparative, reverse-phase HPLC to give 6-((5-chloro-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile as a white solid. LC / MS (M+H)+: 399.2.

[0512] Intermediate 43. 6-((5-Chloro-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0513]

[0514] 2,4,5-Trichloropyridine (500 mg, 2.74 mmol) was suspended in a mixture of DMA (4568 pL) and DIPEA (1436 pL, 8.22 mmol). Methanamine (40 wt% in wate, (474 pl, 5.48 mmol) was added in a single portion. The reaction was sealed and heated to 50 °C. (The reaction run in triplicate in parallel.) The materials from all 3 reactions were combined, diluted with DCM and water, and the layers were separated. The DCM layer was washed 2x with water, and the organic layer was dried over sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified by silica gel chromatography, eluting with 0-35% Hex / EtOAc, to afford 1.1 g of the desired product as a white solid in 76 % yield per reaction. LC / MS (M+H)+: 177.1, 179.1.1HNMR (499 MHz, CHLOROFORM-d) 88.02 (s, 1H), 6.51 (s, 1H), 4.94 (br s, 1H), 2.95 (d, J=5.1 Hz, 3H).

[0515] In a 20 mL pressure vial was added 2,5-dichloro-N-methylpyridin-4-amine (0.582 g, 3.29 mmol), 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.500 g, 1.936 mmol),Pd2(dba)3 (0.089 g, 0.097 mmol), xantphos (0.112 g, 0.194 mmol) and cesium carbonate (2.21 g, 6.77 mmol). The vial was capped with a septum and pump / purged 3x with nitrogen gas. Dioxane (8 ml) was introduced, and the suspension was purged with nitrogen gas for 5 minutes, then set to heat at 90 °C overnight. The reaction was cooled to room temperature, diluted with 10:1 DCM: MeOH and filtered. The filtrates were concentrated and diluted with DCM: MeOH and purified by silica gel chromatography (24G Isco column eluting with 0-100% ethyl acetate-hexane). The product was collected as an off-white solid (400mg) in 52 % yield. LC / MS (M+H)+: 399.2.1H NMR (499 MHz, DMSO-d6) 89.69 (s, 1H), 7.86 (s, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.53 (s, 1H), 6.50 (d, J=8.6 Hz, 1H), 6.36 (q, J=4.6 Hz, 1H), 4.47 (br s, 1H), 3.99 - 3.94 (m, 2H), 3.76 (dd, J=10.5, 3.9 Hz, 2H), 2.83 (d, J=4.8 Hz, 3H), 2.76 (br s, 2H), 1.82 (br dd, J=13.2, 8.0 Hz, 2H), 1.61 (dd, J=13.1, 4.8 Hz, 2H), 1.21 (s, 3H).

[0516] Intermediate 44. 6-((5-Bromo-4,6-dimethylpyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0517]

[0518] To a stirred solution of 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (1000 mg, 3.87 mmol) in 1,4-dioxane (20 mL) were added 3-bromo-6-chloro-2,4-dimethylpyridine (1195 mg, 5.42 mmol) and CS2CO3 (3153 mg, 9.68 mmol). The reaction mixture was purged with argon for 5 minutes, and then Pd2(dba)3 (248 mg, 0.271 mmol) and xantphos (336 mg, 0.581 mmol) were added. The reaction mixture was heated to 100 °C for 4h. The reaction mixture was diluted with DCM and concentrated under reduced pressure to afford the crude product, which was purified by silica gel chromatography (80g Silica gel, 50% Ethyl Acetate: Pet Ether and 20%Methanol: DCM) to afford 6-((5-bromo-4,6-dimethylpyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (1.2 g, 2.71 mmol, 70 %yield) as off white solid. LC / MS (M+H)+= 442.3. ’H-NMR (300 MHz, DMSO-d6) 6 ppm 1.22 (s, 3 H), 1.65 (br dd, J=12.84, 4.53 Hz, 2 H), 1.81 - 1.89 (m, 2 H), 2.22 - 2.30 (m, 2 H), 2.34 (s, 3 H) 2.71 - 2.83 (m, 3 H), 3.74 (br dd, J=10.58, 3.02 Hz, 2 H), 3.90 -3.98 (m, 2 H), 4.49 - 4.55 (m, 1 H), 6.46 - 6.59 (m, 1 H), 7.58 - 7.69 (m, 1 H), 8.11 - 8.18 (m, 1 H), 10.00 - 10.07 (m, 1 H).

[0519] Intermediate 45. Methyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinate

[0520]

[0521] A mixture of cesium carbonate (0.351 g, 1.08 mmol), xantphos (0.062 g, 0.108 mmol), Pd2(dba)3 (0.049 g, 0.054 mmol), methyl 6-chloro-4-(methylamino)nicotinate (0.108 g, 0.539 mmol) (J. Med. Chem, (2012), 55, 10229), 6-amino-2-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.132 g, 0.539 mmol) in dioxane (5 mL) was purged with a vacuum / N2 fill cycle (3x) and then heated at 95 °C for 3.5 hours. The reaction was diluted with ethyl acetate and washed with water (3x). (Be careful not discard the insoluble suspension, which is the desired product). The ethyl acetate layer was separated, (collected the insoluble solid and later analysis turned out to be the desired product - 100 mg), dried (ISfeSC ), filtered and concentrated. The product was purified by flash silica gel chromatogrphy, eluting with ethyl acetate in hexane from 0 to 50% to 100%, to give the desired product (156 mg, 68 % yield). 'H NMR (499 MHz, DMSO-d6) 8 10.01 (s, 1H), 8.52 (s, 1H), 7.95 (br d, J=5.0 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.58 (s, 1H), 6.52 (d, J=8.6 Hz, 1H), 4.67 (d,. / =4,3 Hz, 1H), 4.23 - 4.16 (m, 1H), 4.00 (br dd, J=10.6, 8.0 Hz, 2H), 3.82 - 3.74 (m, 5H), 2.92 (d, J=5.0 Hz, 3H), 2.70 (br s, 2H), 2.13 - 2.04 (m, 2H), 1.43 (dt, J=13.3, 5.4 Hz, 2H); were added 409.5; ret. time = 1.75 min. (Method C).Intermediate 46. Methyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinate

[0522]

[0523] Following the procedure outlined for intermdiate 45, obtained 100 mg solid as desired product from filtration, 64% yield; 'H NMR (499 MHz, DMSO-de) 6 10.00 (s, 1H), 8.52 (s, 1H), 7.95 (q, J=4.8 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.57 (s, 1H), 6.52 (d, J=8.6 Hz, 1H), 4.48 (s, 1H), 4.00 (br dd, J=10.5, 8.2 Hz, 2H), 3.80 (s, 3H), 3.77 (d, J=3.9 Hz, 1H), 3.18 (d, J=5.2 Hz, 1H), 2.92 (d,. / =4,9 Hz, 3H), 2.78 (br d, J=3.7 Hz, 2H), 1.83 (brdd, J=13.1, 8.1 Hz, 2H), 1.63 (dd, J=13.2, 4.6 Hz, 2H), 1.22 (s, 3H). LC / MS (M+H)+: 423.2; ret. time = 0.69 min. (method A).

[0524] Intermediate 47. 6-((5-Cyano-6-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinic acid

[0525]

[0526] A suspension of lithium hydroxide hydrate (0.050 g, 1.199 mmol), methyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinate (0.159 g, 0.389 mmol) in MeOH (4 mL) / THF (4 mL) / Water (1 mL) / lN NaOH (ImL) was stirred at room temperature until the starting material was consumed. The volatiles were removed under vacuum, and to the crude was added 2.2 mL IN HC1. The solid was filtered and washed with water, dried under vacuum overnight and used as it is. (0.116 g, 66 % yield); 'H NMR (500 MHz, DMSO-d6) 68.48 - 8.33 (m, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.37 (br s, 1H), 6.50 (br d, J=9.5 Hz, 1H), 4.24 - 4.13 (m, 1H), 4.04 - 3.91 (m, 2H), 3.78 (br dd, J=10.7, 3.1 Hz, 2H), 3.41 (br s, 1H), 2.84 (br d,. / =4,6 Hz, 3H), 2.73 - 2.64 (m, 2H), 2.15 - 2.04 (m, 2H), 1.90 (s, 2H), 1.42 (br dd, J=12.4, 6.3 Hz, 2H) (OH was suppressed by water suppression.). LC / MS (M+H)+: 395.2; ret. time= 1.16 min. (Method C).

[0527] Intermediate 48. 6-((5-Cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinic acid

[0528]

[0529] Following the procedure outlined for intermediate 47, (0.583 g, 88 % yied);

[0530] LC / MS (M+H)+: 409.2; ret. time = 0.61 min. (Method A).

[0531] Intermeidate 49. Methyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4- (cyclobutylamino)nicotinate

[0532]

[0533] Following the procedure outlined for intermediate 45, obtained 0.355g, 48 % desired product. 'H NMR (500 MHz, DMSO-de) 69.99 - 9.88 (m, 1H), 8.54 (br s, 1H), 8.18 (br d, J=6.7 Hz, 1H), 7.66 (br d, J=8.2 Hz, 1H), 7.37 (br s, 1H), 6.59 (br d, J=8.2 Hz, 1H), 4.58 (s, 1H), 4.11 - 3.96 (m, 3H), 3.86 - 3.77 (m, 4H), 2.84 (br d, J=1.5 Hz, 2H),2.41 (br d, J=6.7 Hz, 2H), 1.98 - 1.64 (m, 9H), 1.24 (s, 3H). LC / MS (M+H)+: 483.8 [(M+H)+; ret. time= 0.89 min. (Method D).

[0534] Intermediate 50. Methyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-((3,3-difluorocyclobutyl)amino)nicotinate

[0535]

[0536] Following the procedure outlined for intermediate 45, obtained 0.101g, 48% desired product. 'H NMR (500 MHz, DMSO-de) 69.99 (br s, 1H), 8.58 (s, 1H), 8.23 (br d,. / =6,7 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.24 (s, 1H), 6.71 (br d, J=8.2 Hz, 1H), 4.05 -3.91 (m, 3H), 3.87 - 3.75 (m, 4H), 3.47 - 3.32 (m, 1H), 3.17 - 3.03 (m, 2H), 2.80 (br s, 2H), 2.68 (br dd, J=13.6, 4.1 Hz, 2H), 1.86 (br dd, J=13.1, 7.6 Hz, 2H), 1.66 (br dd, J=12.8, 4.3 Hz, 2H), 1.23 (s, 3H) (-OH was suppressed by water suppression); LC / MS (M+H)+: 499.7; ret. time = 0.87 min. (Method D).

[0537] Intermediate 51. 6-((5-Cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(cyclobutylamino)nicotinic acid

[0538]

[0539] Following the procedure outlined for intermediate 47, the crude product was used as it is (assuming 100% conversion, 248 mg). LC / MS (M+H)+: 449.7; ret. time = 0.81 (Method D).Intermediate 52. 6-((5-Cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-((3,3-difluorocyclobutyl)amino)nicotinic acid

[0540]

[0541] Following the procedure outlined for intermediate 47, the crude product was used as it is (assuming 100% conversion, 80 mg). LC / MS (M+H)+: 485.6; ret. time (Method D).

[0542] Example 1. Preparation of l-[5-cyano-6-(4-hydroxypiperidin-l-yl)pyridin-2-yl]-3-(3-ethoxyphenyl)urea

[0543]

[0544] 1A. Methyl 6-chloro-4-(methylamino)nicotinate

[0545]

[0546] Methylamine (40% aqueous solution) (10.6 mL, 121 mmol) was added dropwise over 15 min to a stirred solution of methyl 4, 6-di chloronicotinate (5.00 g, 24.3 mmol) in acetonitrile (80 mL) at 0 °C. The reaction was allowed to warm to rt and stirred for 2 hours. The mixture was concentrated and dry loaded for silica gel chromatography whichafforded methyl 6-chloro-4-(methylamino)nicotinate as a white solid (3.72 g) in 76 % yield. 'H NMR (400 MHz, CHLOROFORM-d) 68.66 (s, 1H), 8.08 (br s, 1H), 6.54 (s, 1H), 3.88 (s, 3H), 2.93 (d, J=5.2 Hz, 3H). Mass spectrum m / z 201 (M+H)+.

[0547] IB. 6-Chloro-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide

[0548]

[0549] Sodium hydroxide (1 M solution) (4.98 mL, 4.98 mmol) was added to a mixture of methyl 6-chloro-4-(methylamino)nicotinate (0.500 g, 2.49 mmol) in MeOH (5 mL) and THF (3 mL). After stirring for 2h, the mixture was neutralized with 1 M HC1 (7.47 mL) and the mixture was concentrated to dryness and dried under vacuum. The crude product was dissolved in DMF (20 mL), then 2-(methylsulfonyl)benzylamine (0.554 g, 2.99 mmol), BOP (1.323 g, 2.99 mmol) and triethylamine (0.868 mL, 6.23 mmol) were added to the reaction mixture. After stirring for 2 h, the mixture was diluted with EtOAc (150 mL), washed with water (3x50 mL), brine (10 mL), dried (MgSO4) and concentrated. Silica gel chromatography afforded 6-chloro-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide as white solid (795 mg) in 90% yield. 1H NMR (400 MHz, CHLOROFORM-d) 88.23 (br s, 1H), 8.20 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 6.48 (s, 1H), 4.85 (d, J=6.4 Hz, 2H), 3.17 (s, 3H), 2.85 (d, J=5.1 Hz, 3H). LCMS (M+H)+: 354.

[0550] Example 1. l-[5-Cyano-6-(4-hydroxypiperidin-l-yl)pyridin-2-yl]-3-(3-ethoxyphenyl)urea

[0551]

[0552] A mixture of 6-chloro-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (18.5 mg, 0.052 mmol), 6-amino-2-((3aR,5r,6aS)-5-(ethoxymethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (15.8 mg, 0.052 mmol), xantphos (6.05 mg, 10.5 pmol), Pd2(dba)3 (4.78 mg, 5.23 pmol) and cesium carbonate (51.1 mg, 0.157 mmol) was evacuated and backfilled with nitrogen three times. 1,4-Dioxane (2 mL) was quickly added, and the mixture was immediately evacuated and backfilled with nitrogen three times. The vial was sealed and stirred at 110 °C overnight. After 15 h at 110 °C, the dioxane solvent was evaporated. The residue was dissolved with DMSO (2 mL), filtered and purified by preparative, reverse-phase HPLC to give 6-((5-cyano-6-((3aR,5r,6aS)-5-(ethoxymethyl)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (7.7 mg) in 23% yield. 'H NMR (500 MHz, DMSO-d6) 89.10 (br s, 1H), 8.53 (s, 1H), 8.44 -8.31 (m, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.66 (br d, J=8.5 Hz, 1H), 7.62 (br d, J=7.9 Hz, 1H), 7.55 (br t, J=7.6 Hz, 1H), 7.48 - 7.42 (m, 1H), 6.52 (br d, J=8.2 Hz, 1H), 4.84 (br d, J=5.5 Hz, 2H), 4.13 - 3.95 (m, 2H), 3.80 (br dd, J=10.4, 3.7 Hz, 2H), 3.48 (q, J=6.9 Hz, 1H), 3.24 (s, 1H), 2.86 (br d, J=4.9 Hz, 3H), 2.75 (br s, 2H), 2.56 (s, 3H), 2.03 (br dd, J=13.3, 7.5 Hz, 3H), 1.93 (s, 2H), 1.53 (br dd, J=13.4, 3.4 Hz, 2H), 1.13 (t, J=6.9 Hz, 3H).

[0553] Example 2. Preparation of 6-((5-cyano-6-((2s,3aR,6aS)-2-oxidotetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)pyri din-2 -yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide

[0554]

[0555] A suspension of 6-((5-cyano-6-((3aR,6aS)-tetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)pyridin-2-yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (100 mg, 0.177 mmol) in methanol (2 mL) was treated with a solution of sodium periodate (38 mg, 0.177 mmol) in water (0.5 mL) andstirred at room temperature. After stirring for 20h, the mixture was diluted with water, and the precipitate was collected by filtration, washed with water and air-dried to provide a pale tan solid. The crude material was purified via preparative, reverse-phase HPLC chromatography with the following conditions Column XBridge C 200 mm x 19mm 5-pm particles; Mobile Phase A-5:95 acetonitrile / water with ammonium acetate; Mobile Phase B 95:5 acetonitrile / water with ammonium acetate; Gradient; a 0-minute hold at 13% B,13-53%B over 23 minutes then a 0-minute hold at 100%B; Flow Rate:20 mL / min; Column Temperature:25 °C.

[0556] Isomer 1: 6-((5-cyano-6-((2s,3aR,6aS)-2-oxidotetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)pyridin-2-yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide, TFA (5.7mg).1H NMR (499 MHz, DMSO-d6) 6 8.56 (s, 1H), 7.97 (dd, J=8.0, 1.1 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.59 - 7.53 (m, 1H), 6.82 - 6.60 (m, 1H), 6.39 (d, J=8.3 Hz, 1H), 4.94. 4.85 (m, 2H), 4.13 (br dd, J=10.8, 7.6 Hz, 2H), 3.75 (dd, J=11.1, 4.2 Hz, 2H), 3.61 - 3.51 (m, 2H), 3.36 (s, 3H), 3.05 (brt, J=6.3 Hz, 4H), 2.93 (s, 3H)

[0557] Example 3. Preparation of 6-((5-cyano-6-((2r,3aA,6a5)-2-oxidotetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)pyri din-2 -yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide

[0558]

[0559] A suspension of 6-((5-cyano-6-((3aR,6aS)-tetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)pyridin-2-yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (100 mg, 0.177 mmol) in methanol (2 mL) was treated with a solution of sodium periodate (37.9 mg, 0.177 mmol) in water (0.5 mL) and stirred at room temperature. After stirring for 20h, the mixture was diluted with water, and the precipitate was collected by filtration, washed with water, and air-dried to provide a pale tan solid. The crude material was purified via reverse-phasea, preparative HPLCchromatography with the following conditions Column XBridge C 200 mm x 19mm 5-pm particles; Mobile Phase A-5:95 acetonitrile / water with ammonium acetate; Mobile Phase B 95:5 acetonitrile / water with ammonium acetate; Gradient; a 0-minute hold at 13% B,13-53%B over 23 minutes then a 0-minute hold at 100%B; Flow Rate:20 mL / min; Column Temperature:25 °C.

[0560] Isomer 2: 6-((5-cyano-6-((2r,3aA,6a5)-2-oxidotetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)pyridin-2-yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide, TFA (7.9 mg). 'H-NMR (499 MHz, DMSO-d6) 6 8.57 (s, 1H), 7.97 (dd, J=7.9, 1.2 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.60 - 7.54 (m, 1H), 6.78 (br s, 1H), 6.39 (d, J=8.5 Hz, 1H), 4.89 (s, 2H), 4.21 (br dd, J=10.4, 7.3 Hz, 2H), 4.12 (br d, J=4.5 Hz, 3H), 3.42 - 3.28 (m, 6H), 2.99 (br d, J=11.8 Hz, 2H), 2.94 (s, 3H)

[0561] Example 4. Preparation of 6-((6-((lA,4A,5S)-5-amino-2-azabicyclo[2.2.1]heptan-2-yl)-5-cyanopyri din-2 -yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide

[0562]

[0563] 4A. tert-Butyl (lA,4A,55)-5-(l,3-dioxoisoindolin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carb oxy late

[0564]

[0565] In a 250 mL 2-necked round bottom flask, triphenylphosphane (1.85 g, 7.03 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL) and toluene (10 mL) at 0 °C under nitrogen flow, followed by addition of DIAL) (1.37 mL, 7.03 mmol) in a drop-wise manner over 1 minute. The reaction mixture was stirred at room temperature for 5 minutes under nitrogen, and then t-butyl (lA,4A,5A)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 4.69 mmol) was added. The reaction mixture was stirred for 10 minutes at 0 °C. To the reaction mixture were added isoindoline-1, 3-dione (1.04 g, 7.03 mmol) and potassium l,3-dioxoisoindolin-2-ide (1.30 g, 7.03 mmol), and stirring was continued overnight at room temperature. The reaction mixture was concentrated under reduced pressure to afford crude material. The crude material was purified by flash silica gel chromatography (80 g silica gel cartridge; A = Hex, B = EtOAc; 60 min grad.; 0% B to 80% B) to afford tert-butyl (lA,4A,55)-5-(l,3-dioxoisoindolin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.5 g, 93% yield) as a off white solid. 'H NMR (300 MHz, DMSO-d6) 87.71 - 7.92 (m, 5H), 4.08 - 4.34 (m, 2H), 3.11-3.24 (m, 2H), 2.93-3.04 (m, 1H), 2.78 (br s, 1H), 2.25-2.39 (m, 2H), 1.96 -2.10 (m, 1H), 1.52-1.70 (m, 1H), 1.35-1.48 (m, 9H), 1.22 (br d, J=3.78 Hz, 2H).

[0566] 4B. 6-Amino-2-((lA,4A,55)-5-(l,3-dioxoisoindolin-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)nicotinonitrile

[0567]

[0568] To a stirred solution of ter / -butyl(lA,4A,55)-5-(l,3-dioxoisoindolin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.40 g, 4.09 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (3.15 mL, 40.9 mmol). After stirring for 2 hrs at room temperature, the reaction mixture was concentrated under reduced pressure to afford crude material. In a 20 mL vial was placed 2-((lR,4R,5S)-2-azabicyclo[2.2.1]heptan-5-yl)isoindoline-l, 3-dione, TFA (1.3 g, 3.65 mmol), K2CO3 (1.51 g, 11.0 mmol) in dioxane (5 mL), and the reaction mixture was stirred at room temperature for 1 min under nitrogen. To the solution was added 6-amino-2-chloronicotinonitrile (0.448 g, 2.92 mmol). The reaction mixture was heated at 110 °C for 10 hrs. The reaction mixture wascooled and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (80 g silica gel cartridge; A = Hex, B = EtOAc; 90 min grad.; 0% B to 60% B) to afford 6-amino-2-((lA,4A,55)-5-(l,3-dioxoisoindolin-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)nicotinonitrile (450 mg, 1.25 mmol, 34 % yield) as off white solid. 'H NMR (300 MHz, DMSO-d6) 87.59 - 7.93 (m, 4H), 7.29 - 7.41 (m, 1H), 6.43 - 6.78 (m, 1H), 5.62 - 6.03 (m, 1H), 4.78-4.96 (m, 1H), 4.37 (br d, J=14.73 Hz, 1H), 3.80-3.91 (m, 1H), 3.68(br dd, >9.78,3.21 Hz, 1H), 2.31 -2.44 (m, 2H), 2.16-2.25 (m, 1H), 1.65-1.77 (m, 1H).

[0569] 4C. 6-((5-Cyano-6-((lA,4A,55)-5-(l,3-dioxoisoindolin-2-yl)-2-azabicyclo[2.2.1]heptan- 2-yl)pyridin-2-yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide

[0570]

[0571] To a stirred solution of 6-chloro-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (89 mg, 0.250 mmol) in 1,4-Dioxane (3 mL) was added 6-amino-2-((lA,4A,55)-5-(l,3-dioxoisoindolin-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)nicotinonitrile (60 mg, 0.167 mmol), and cesium carbonate (190 mg, 0.584 mmol)). Argon gas was bubbled through the solution for 1 min, and then xantphos (19.3 mg, 0.033 mmol) and Pd2(dba)3 (15.3 mg, 0.017 mmol) were added. The reaction mixture was heated to 110 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (12 g silica gel cartridge; A = Hex, B = EtOAc; 20 min grad.; 0% B to 100% B) to afford 6-((5-cyano-6-((lA,4A,55)-5-(l,3-dioxoisoindolin-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (55 mg, 0.081 mmol, 49 % yield) as a yellowish solid. LC / MS (M+H)+: 677.3; ret. time = 1.78 min (Method C).Example 4. l-[5-Cyano-6-(4-hydroxypiperidin-l-yl)pyridin-2-yl]-3-(3-ethoxyphenyl)urea

[0572]

[0573] To a stirred solution of 6-((5-cyano-6-((lR,4R,5S)-5-(l,3-dioxoisoindolin-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (50 mg, 0.074 mmol) in ethanol (3 mL) was added hydrazine hydrate (0.017 mL, 0.369 mmol), and the reaction mixture was heated at 80 °C for 2 h.. The crude material was purified via preparative, reverse-phase HPLC with the following conditions: Column: Waters XB ridge Cl 8, 19 x 150 mm, 5-pm particles;

[0574] Mobile Phase A: 10-mM ammonium acetate; Mobile Phase B: acetonitrile; Gradient: 10-30% B over 22 minutes, then a 5- minute hold at 100% B; Flow: 20 mL / min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 6-((6-((lA,4A,55)-5-amino-2-azabicyclo[2.2.1]heptan-2-yl)-5-cyanopyridin-2-yl)amino)-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (16.8 mg, 42 % yield). 'H NMR (400 MHz, DMSO-d6) 8 = 9.84 (s, 1H), 9.08 (t, J = 5.9 Hz, 1H), 8.52 (s, 1H), 8.43 - 8.29 (m, 1H), 7.94 (dd, J = 1.1, 7.9 Hz, 1H), 7.79 -7.68 (m, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.57 - 7.48 (m, 1H), 7.37 (s, 1H), 6.56 (d, J = 8.5 Hz, 1H), 4.90 - 4.76 (m, 3H), 3.38 (s, 3H), 3.27 (br d, J =9.6 Hz, 1H), 3.09 (br dd, J = 2.9, 7.1 Hz, 1H), 2.84 (d, J = 5.0 Hz, 3H), 2.39 (br s, 1H), 2.12 - 2.01 (m, 1H), 1.93 (br d, J = 9.8 Hz, 1H), 1.88 (s, 3H), 1.59 (br d, J = 9.9 Hz, 1H), 1.31 (br d, J = 13.1 Hz, 1H).

[0575] Example 5. Preparation of 6-((5-cyano-6-(pyrrolidin-l-yl)pyridin-2-yl)amino)-4-((2-hydroxyethyl)amino)-N-(2-(methylsulfonyl)benzyl)nicotinamide

[0576]

[0577] 5 A. 6-Chloro-4-(methylamino)-N-(2-(methylsulfonyl)benzyl)nicotinamide

[0578]

[0579] In a 40 ml reaction vial was added 4,6-dichloronicotinic acid (0.500 g, 2.60 mmol), acetonitrile (5 ml), TEA (1.089 ml, 7.81 mmol) and 2-aminoethan-l-ol (0.159 g, 2.60 mmol). The reaction was stirred at 70C overnight. To this was added (2-(methylsulfonyl)phenyl)methanamine (0.482 g, 2.60 mmol) and TEA (1.09 ml, 7.81 mmol). With stirring at rt, BOP (1.73 g, 3.91 mmol) was added, and the reaction was stirred for 1 hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography using 0-100% ethyl acetate / hexane to afford 6-chloro-4-((2-hydroxyethyl)amino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (450 mg, 1.172 mmol, 45.0 % yield) as a yellowish oil. LC / MS (M+H)+: 384.1; ret. time = 0.58 min (Method I).

[0580] Example 5. 6-((5-Cyano-6-(pyrrolidin-l-yl)pyridin-2-yl)amino)-4-((2-hydroxyethyl)amino)-N-(2-(methylsulfonyl)benzyl)nicotinamide

[0581]

[0582] In a 2 dram vial was added 6-chloro-4-((2-hydroxyethyl)amino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (0.035 g, 0.091 mmol), 6-amino-2-(pyrrolidin-l-yl)nicotinonitrile (0.038 g, 0.202 mmol), Pd2(dba)3 (4.17 mg, 4.56 pmol), xantphos (5.28 mg, 9.12 pmol) and cesium carbonate (0.104 g, 0.319 mmol). The flask was capped with a septum and pump / purged 3x with nitrogen. Dioxane (1 mL) was introduced, and the suspension was purged with nitrogen for 5 minutes and then heated at 90 °C overnight. The reaction was cooled to room temperature, and the volatiles were removed. The residue was purified by HPLC to afford 6-((5-cyano-6-(pyrrolidin-l-yl)pyridin-2-yl)amino)-4-((2-hydroxyethyl)amino)-N-(2-(methylsulfonyl)benzyl)nicotinamide (8.6 mg, 17.3% yield). 'H NMR (500 MHz, DMSO-d6) 89.83 (s, 1H), 9.04 (br t, J=5.8 Hz, 1H), 8.59 (br t, J=4.9 Hz, 1H), 8.53 (s, 1H), 7.95 (d, J=7.3 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.66 - 7.59 (m, 2H), 7.57 - 7.52 (m, 2H), 6.55 (d, J=8.5 Hz, 1H), 4.85 (br d, J=5.5 Hz, 2H), 3.73 (br t, J=6.0 Hz, 4H), 3.60 (q, J=5.3 Hz, 1H), 3.37 (s, 1H), 3.23 (q, J=5.3 Hz, 2H), 2.52 (s, 3H), 2.52 (br s, 2H).

[0583] Example 6. Preparation of 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)-N-((3-(methylsulfonyl)pyridin-2-yl)methyl)nicotinamide

[0584]

[0585] 6A. 6-((5-Cyano-6-((3o7?,5r,6a5)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinic acid

[0586]

[0587] In a 40 mL vial was added methyl 6-chloro-4-(methylamino)nicotinate (0.120 g, 0.599 mmol), 6-amino-2-(5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.122 g, 0.499 mmol), Pd2(dba)3 (0.023 g, 0.025 mmol), xantphos (0.029 g, 0.050 mmol) and cesium carbonate (0.569 g, 1.748 mmol). The flask was capped with a septum and pump / purged 3x with nitrogen. Dioxane (2 mL) was introduced, and the suspension was purged with nitrogen for 5 minutes and then heated at 100 °C overnight. The reaction was cooled to room temperature, and the volatiles were removed. The residue was diluted with THF (5 mL), lOOuL of MeOH and sodium hydroxide (1.25 mL, 1.25 mmol) and stirred at 50 °C for 3 hours. The volatiles were removed under a stream of nitrogen overnight, and the residue was diluted with water (5mL). A IN aqueous solution of HC1 was added until the pH = 4. The mixture was stirred for 30 minutes at room temperature. The precipitated solid was collected by filtration and rinsed with water followed by ether. The residue was dried overnight to afford 6-((5-cyano-6-((3aA,5r,6a5)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinic acid (95 mg; 48 % yield. LC / MS (M+H)+: 395.3; ret. time = 0.61 min (Method I).

[0588] Example 6. 6-((5-Cyano-6-((3aA,5r,6a5)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)-N-((3-(methylsulfonyl)pyridin-2-yl)methyl)nicotinamide

[0589] To a 2 dram reaction vial was added 6-((5-cyano-6-(5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinic acid (0.040 g, 0.101 mmol), (3 -(methyl sulfonyl)pyri din-2-yl)methanamine hydrochloride (0.023 g, 0.101 mmol), DMF (1 ml), TEA (0.071 ml, 0.507 mmol) and HATU (0.058 g, 0.152 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and purified by preparative, reverse-phase HPLC to afford 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)-N-((3-(methylsulfonyl)pyridin-2-yl)methyl)nicotinamide (7 mg, 12 % yield). 'H NMR (500 MHz, DMSO-d6) 89.90 (br s, 1H), 9.10 - 8.97 (m, 1H), 8.85 (br d, J=4.0 Hz, 1H), 8.52 (s, 1H), 8.39 - 8.25 (m, 2H), 7.74 - 7.56 (m, 2H), 7.49 (br s, 1H), 6.53 (br d, J=8.5 Hz, 1H), 4.91 (br d, J=5.2 Hz, 2H), 4.20 (br s, 1H), 4.08 - 3.91 (m, 2H), 3.78 (br dd, J=10.5, 2.9 Hz, 2H), 2.85 (br d, J=4.9 Hz, 3H), 2.70 (br s, 2H), 2.57 (s, 3H), 2.16 - 2.02 (m, 2H), 1.54 - 1.34 (m, 2H).

[0590] Example 7. Preparation of 6-((5-cyclopropyl-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0591] OH

[0592]

[0593] H

[0594] A 1 dram vial containing 6-((5-chloro-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile(0.020 g, 0.050 mmol), cyclopropylboronic acid MIDA ester (0.015 g, 0.075 mmol) and XPHOS PD G3 (4.24 mg, 5.01 pmol) was capped and pump / purged with nitrogen (3x). Tetrahydrofuran (0.6 mL) and 2.0 M potassium phosphate, tribasic solution (0.075 mL, 0.150 mmol) were added, and the reaction was heated at 90 °C for 4 hours. Following cooling to room temperature, the volatiles were removed, and the residue was purified by preparative, reverse-phase HPLC to give 6-((5-cyclopropyl-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (2.6 mg). 'H-NMR (500 MHz, DMSO-d6) 87.57 (br d, J=8.5 Hz, 1H), 7.20 (br s, 1H), 6.47 (br s, 1H), 6.32 - 6.12 (m, 1H), 4.04 - 3.91 (m, 1H), 3.81 - 3.71 (m, 1H), 3.69 - 3.53 (m, 5H), 2.90 - 2.81 (m, 1H), 2.79 - 2.68 (m, 1H), 2.57 - 2.53 (m, 1H), 1.91 (s, 1H), 1.87 - 1.76 (m, 1H), 1.67 - 1.58 (m, 1H), 1.53 - 1.42 (m, 1H), 1.27 - 1.16 (m, 3H), 0.91 - 0.80 (m, 1H), 0.52 - 0.40 (m, 1H).

[0595] Example 8. Preparation of 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((5-((l-methyl-lH-pyrazol-3-yl)amino)-4-(methylamino)pyri din-2 -yl)amino)nicotinonitrile

[0596]

[0597] To a 2 dram vial was added 6-((5-chloro-4-(methylamino)pyri din-2 -yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.025 g, 0.063 mmol), l-methyl-lH-pyrazol-3-amine (9.13 mg, 0.094 mmol) Pd2(dba)3 (2.87 mg, 3.13 pmol), xantphos (3.63 mg, 6.27 pmol), and cesium carbonate (0.071 g, 0.219 mmol). The flask was capped with a septum and pump / purged 3x with nitrogen. Dioxane (10 mL) was introduced, and the suspension was purged with nitrogen for 5 minutes and then heated at 100 °C overnight. The solvent was removed under a stream of nitrogen, and the residue was filtered and purified by preparative, reverse-phase HPLC to give 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((5-((1 -methyl- lH-pyrazol-3-yl)amino)-4-(methylamino)pyridin-2-yl)amino)nicotinonitrile ( 2.8 mg). ‘H-NMR (500 MHz, DMSO-d6) 6 11.27 - 11.22 (m, 1H), 7.91 - 7.81 (m, 3H), 7.56 (s, 1H), 7.12 (s, 1H), 6.53 (s, 1H), 6.35 - 6.29 (m, 1H), 4.05 - 3.95 (m, 2H), 3.77 (brdd, J=10.8, 3.5 Hz, 2H), 3.71 - 3.64 (m, 4H), 3.02 - 2.98 (m, 1H), 2.90 - 2.79 (m, 4H), 1.85 (br dd, J=12.8, 7.9 Hz, 2H), 1.75 - 1.64 (m, 2H), 1.27 - 1.19 (m, 3H)

[0598] Example 9. Prepartion of 6-((5-cyano-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0599]

[0600] H

[0601] A mixture of 4-chloro-6-(methylamino)nicotinonitrile (15.6 mg, 0.093 mmol), 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (15 mg, 0.058 mmol), xantphos (16.8 mg, 0.029 mmol), Pd2(dba)3 (10.6 mg, 0.012 mmol) and cesium carbonate (37.8 mg, 0.116 mmol) in 1,4-dioxane (2 mL) was de-oxygenated by bubbling with nitrogen for 5 min. The reaction vial was sealed and stirred at 100 °C overnight. After 18 h at 100 °C, the dioxane solvent was evaporated, and the residue purified by preparative, reverse-phase HPLC to give 6-((5-cyano-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile.1H NMR (500 MHz, DMSO-d6) 8 10.22 (br s, 1H), 8.27 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.36 (s, 1H), 7.17 (br s, 1H), 6.47 (d, J=8.5 Hz, 1H), 3.96 (br dd, J=10.3, 8.4 Hz, 2H), 3.74 (br dd, J=10.5, 3.6 Hz, 2H), 2.83 (d, J=3.7 Hz, 3H), 2.77 (br s, 2H), 1.82 (br dd, J=13.2, 7.9 Hz, 2H), 1.61 (br dd, J=13.2, 4.2 Hz, 2H), 1.21 (s, 3H). The OH is missing due to water suppression.

[0602] Example 10. Preparation of 2-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol- 2(lH)-yl)-6-((4-(methylamino)-5-(pyrrolidine-l-carbonyl)pyridin-2-yl)amino)nicotinonitrile

[0603]

[0604] To a Suspension of 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxyhexahydrocyclopentafc] pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinic acid (15 mg, 0.038 mmol) in DMF (190 pL) was added pyrrolidine (9.37 pL, 0.114 mmol) and Hunig's base (26.6 pL, 0.152 mmol). BOP (18.50 mg, 0.042 mmol) was added to the slurry, and and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with EtOAc and washed with a 10% aqueous solution of LiCl. The aqueous layer was extracted with EtOAc (3x). The ethyl acetate layers were combined and washed with brine. The EtOAc layer was dried ( Na2SO4), filtered and concentrated, and the crude material was purified by preparative, reverse-phase HPLC to give -((3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((4-(methylamino)-5-(pyrrolidine-l-carbonyl)pyridin-2-yl)amino)nicotinonitrile (10.6 mg, 62 % yield). 'H NMR (500 MHz, DMSO-d6) 67.95 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.39 (br s, 1H), 6.79 (br s, 1H), 6.54 (br d, J=8.5 Hz, 1H), 4.17 (br d, J=3.7 Hz, 1H), 4.02 - 3.86 (m, 2H), 3.75 (br dd, J=10.4, 3.4 Hz, 2H), 2.80 (d, J=4.9 Hz, 3H), 2.68 (br d, J=1.2 Hz, 2H), 2.54 (s, 3H), 2.12 - 2.00 (m, 2H), 1.82 (br s, 4H), 1.45 - 1.36 (m, 2H).

[0605] Example 11. Preparation of 6-((5-(3-hydroxy-3-methylazetidine-l-carbonyl)-4-(oxetan-3-ylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0606]

[0607] 11A. (4, 6-Dichloropyri din-3 -yl)(3 -hydroxy-3 -methylazeti din- l-yl)m ethanone

[0608]

[0609] To a DMF (13 mL) mixture of Hunig's base (1.71 ml, 9.80 mmol), 4,6-dichloronicotinic acid (0.570 g, 2.97 mmol) and 3 -methylazeti din-3 -ol hydrochloride(0.303 g, 2.449 mmol) at room temperature was added BOP (1.30 g, 2.94 mmol). The reaction was stirred for 2 hours, and the reaction mixture was diluted with ethyl acetate and washed with water (3x). The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 100%, gave the desired product ( 0.101 g, 16 % yield). LC / MS (M+H)+: 261.0]; ret. time = 0.60 min. (Method C).

[0610] 11 B. (6-Chloro-4-(oxetan-3 -y lamino)pyri din-3 -y 1) (3 -hydroxy-3 -methylazetidin- 1 -yl)methanone

[0611] p°

[0612] O HN

[0613]

[0614] Me7N^CI

[0615] A mixture of (4,6-dichloropyridin-3-yl)(3-hydroxy-3-methylazetidin-l-yl)methanone (0.049 g, 0.186 mmol) and oxetan-3 -amine (0.014 g, 0.186 mmol) in dioxane (0.062 mL) was heated at 100 °C for 2 hours. The reaction was diluted with ethyl acetate and washed with brine (lx). The ethyl acetate layer was separated, dried (Na2SC>4), filtered and concentrated. The product was purified by flash silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 100%, to afford the desired product (34 mg, 62 % yield).1H NMR (499 MHz, CHLOROFORM-d) 88.53 (br d, J=3.3 Hz, 1H), 8.11 (s, 1H), 6.23 (s, 1H), 5.04 - 4.97 (m, 2H), 4.66 - 4.59 (m, 3H), 4.28 - 4.14 (m, 3H), 3.08 (br s, 1H), 1.87 - 1.73 (m, 1H), 1.60 (s, 3H). LC / MS (M+H)+: 298.1; ret. time = 0.50 min. (Method C).

[0616] Example 11. 6-((5-(3-Hydroxy-3-methylazetidine-l-carbonyl)-4-(oxetan-3-ylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0617] The mixture of cesium carbonate (0.026 g, 0.079 mmol), xantphos (2.274 mg, 3.93 pmol), Pd2(dba)3 (1.80 mg, 1.965 pmol), (6-chloro-4-(oxetan-3 -ylamino)pyri din-3 -yl)(3 -hydroxy-3 -methylazetidin- l-yl)methanone (0.012 g, 0.039 mmol), 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (10.2 mg, 0.039 mmol) in dioxane (1 mL) was evacuated under vacuum and filled with nitrogen (3x) and then heated at 95 °C for 16 hours. The reaction was purified bypreparative, reverse-phase HPLC to give 6-((5-(3-Hydroxy-3-methylazetidine-l-carbonyl)-4-(oxetan-3-ylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (11 mg, 51 % yield). 'H NMR (500 MHz, DMSO-de) 69.77 (s, 1H), 8.44 (br d,. / =6,2 Hz, 1H), 8.09 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.01 (s, 1H), 6.76 (br d, J=8.7 Hz, 1H), 4.88 (t, J=6.7 Hz, 2H), 4.71 -4.61 (m, 1H), 4.43 (t,. / =6,2 Hz, 2H), 3.98 (br dd, J=9.9, 7.9 Hz, 3H), 3.79 (br dd, J=10.5, 3.4 Hz, 2H), 2.91 - 2.75 (m, 2H), 2.52 - 2.49 (m, 3H), 1.91 (s, 2H), 1.88 (br dd, J=12.3, 8.7 Hz, 2H), 1.70 (br dd, J=13.1, 4.5 Hz, 2H), 1.40 (s, 3H), 1.24 (s, 3H).

[0618] Example 12. Preparation of 6-((4-(dimethylamino)-5-(3-hydroxy-3-(trifluoromethyl)azetidine-l-carbonyl)pyri din-2 -yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0619]

[0620] 12 A. (4, 6-Dichloropyri din-3 -yl)(3 -hydroxy-3 -(trifluoromethyl)azeti din- l-yl)m ethanone

[0621]

[0622] To a DMF (2 mL) solution of Hunig's base (2.78 ml, 15.9 mmol), 4,6-dichloronicotinic acid (0.305 g, 1.59 mmol), 3-(trifluoromethyl)azetidin-3-ol hydrochloride (2.9 g, 16.3 mmol) at room temperature was added propylphosphonic anhydride solution (3.78 ml, 6.36 mmol). The reaction was stirred for 2 hours, and the mixture was diluted with ethyl acetate and washed with a 1.5 M aqueous solution of K3PO4 (2x) and water (lx). The ethyl acetate layer was separated, dried (Na2SC>4), filtered and concentrated. Flash silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 100%, gave the desired product. (0.199 g, 40 % yield).19F NMR (470 MHz, CHLOROFORM-d) 8 -84.02 (s, 3F);1H NMR (499 MHz, CHLOROFORM-d) 68.40 (s, 1H), 7.49 (s, 1H), 4.55 - 4.49 (m, 1H), 4.31 - 4.20 (m, 2H), 4.07 (br d, J=10.0 Hz, 1H), 3.56 (br s, 1H). LC / MS (M+H)+: 315.0; ret. time = 0.86 min. (Method C).

[0623] 12B. 6-((4-Chloro-5-(3-hydroxy-3-(trifluoromethyl)azetidine-l-carbonyl)pyri din-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0624]

[0625] A mixture of (4,6-dichloropyridin-3-yl)(3-hydroxy-3-(trifluoromethyl)azetidin-l-yl)methanone (0.198 g, 0.628 mmol), 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.162 g, 0.628 mmol), Josiphos preCat Gen 3 (0.029 g, 0.031 mmol), sodium 2,2,2-trifluoroacetate (0.094 g, 0.691 mmol), DBU (0.104 mL, 0.691 mmol) in 2-methyl-THF (2.5 mL) was heated at 70 °C for 4 hours. The reaction was diluted with ethyl acetate, washed with water (3x), dried (Na2SC>4), filtered and concentrated. Flash silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 100%, gave the desired product (184 mg, 52 %). 'H NMR (500 MHz, DMSO-de) 6 10.43 (br s, 1H), 8.52 - 8.43 (m, 1H), 8.33 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 6.59 (br d, J=8.4 Hz, 1H), 4.59 - 4.47 (m, 1H), 4.28 (br dd, J=17.3, 10.9 Hz, 2H), 4.07 (br d, J=10.7 Hz, 2H), 3.99 - 3.89 (m, 2H), 3.75 (br dd, J=10.7, 3.4 Hz, 2H), 2.80 (br s, 2H), 1.85 (br dd, J=13.1, 7.8 Hz, 2H), 1.66 (br dd, J=13.0, 4.1 Hz, 2H), 1.23 (s, 3H) (OH is suppressed by water suppression);19F NMR (471 MHz, DMSO-de) 8 -82.88 (s, 3F). LC / MS (M+H)+: 537.2; ret. time = 1.65 min. (Method A).

[0626] Example 12. 6-((4-(Dimethylamino)-5-(3-hydroxy-3-(trifluoromethyl)azetidine-l-carbonyl)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0627] A mixture of Hunig's base (0.012 mL, 0.071 mmol), 6-((4-chloro-5-(3-hydroxy-3-(trifluoromethyl)azetidine-l-carbonyl)pyri din-2 -yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.019 g, 0.035 mmol),cyclopropanamine (2.02 mg, 0.035 mmol) in DMF (0.07 mL) was heated at 100 °C for 1 hour. The reaction was purified by preparative, reverse-phase HPLC to give 6-((4-(dimethylamino)-5-(3-hydroxy-3-(trifluoromethyl)azetidine-l-carbonyl)pyri din-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (7.8 mg, 40 % yield).1H NMR (500 MHz, DMSO-de) 89.78 (br s, 1H), 7.90 (s, 1H), 7.64 - 7.56 (m, 2H), 6.58 (br d, J=8.4 Hz, 1H), 4.24 (br d, J=ll.l Hz, 1H), 4.16 (br d, J=10.2 Hz, 1H), 4.03 - 3.91 (m, 4H), 3.75 (br dd, J=10.8, 2.4 Hz, 2H), 2.90 (s, 6H), 2.76 (br d, J=3.3 Hz, 2H), 1.83 (br dd, J=13.1, 7.9 Hz, 2H), 1.61 (br dd, J=13.1, 4.2 Hz, 2H), 1.21 (s, 3H) (2- OH was suppressed by water suppression).

[0628] Example 13. Preparation of 6-((5-(cy cl opropanecarbonyl)-4-(methylamino)pyri din-2 -yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0629]

[0630] 13 A. (6-Chloro-4-(methylamino)pyridin-3-yl)methanol

[0631]

[0632] To a THF (7.4 mL) suspension of methyl 6-chloro-4-(methylamino)nicotinate (0.447 g, 2.23 mmol) at 0 °C was added LAH (1.11 ml, 2.23 mmol) was added. After stirring for 2 hours, the reaction was quenched with water. The volatiles were removed under vacuum, and the crude was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 100%, provided the desired product. (0.170 g, 44 %). 'H NMR (499 MHz, CHLOROFORM-d) 87.78 (s, 1H), 6.50 (s, 1H), 4.65 (br s, 2H), 2.92 (d, J=5.0 Hz, 3H). LC / MS (M+H)+: 173.0; ret. time = 0.51 min. (Method C).13B. 6-Chloro-4-(methylamino)nicotinaldehyde

[0633]

[0634] Cl

[0635] Sulfur trioxide pyridine complex (2.12 g, 13.34 mmol) in DMSO (10 mL) was added to a DMSO (10 mL) solution of TEA (3.25 mL, 23.4 mmol) and (6-chloro-4-(methylamino)pyridin-3-yl)methanol (0.576 g, 3.34 mmol) at room temperature. After 1 hour, the reaction was diluted with ethyl acetate and washed with water (3x). The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. The crude product (0.316 g, 56 %) was used as is.1H NMR (499 MHz, CHLOROFORM-d) 69.84 (s, 1H), 8.56 (br s, 1H), 8.30 (s, 1H), 6.58 (s, 1H), 2.96 (d, J=5.1 Hz, 3H).

[0636] 13C. (6-Chloro-4-(methylamino)pyridin-3-yl)(cyclopropyl)methanol

[0637] OH HN'Me

[0638]

[0639] Cl

[0640] Cyclopropylmagnesium bromide (10.1 mL, 5.03 mmol) was added to a THF (5 mL) solution of 6-chloro-4-(methylamino)nicotinaldehyde (0.286 g, 1.68 mmol) at 0 °C. After 1 hour, the reaction was quenched with NH4Q (sat.). The reaction was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed (2x) with water, dried (Na2SO4), filtered and concentrated. Flash silica gel chromatography, eluting with ethyl acetate in hexane from 0 to 100%, gave the desired product was a white solid. (0.28 g, 78 %). 'HNMR (499 MHz, CHLOROFORM-d) 87.83 (s, 1H), 6.48 (s, 1H), 6.06 (br d, J=3.5 Hz, 1H), 3.86 (d, J=8.9 Hz, 1H), 2.88 (d, J=5.0 Hz, 3H), 2.41 (br s, 1H), 1.53 - 1.43 (m, 1H), 0.75 (dddd, J=8.9, 7.9, 5.8, 4.5 Hz, 1H), 0.69 - 0.60 (m, 1H), 0.47 (dd, J=9.9, 5.1 Hz, 1H), 0.35 - 0.26 (m, 1H)

[0641] 13D. 6-((5-(Cy cl opropyl(hydroxy)methyl)-4-(methylamino)pyri din-2 -yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0642]

[0643] A mixture of cesium carbonate (0.072 g, 0.222 mmol), xantphos (0.013 g, 0.022 mmol), Pd2(dba)3 (10.2 mg, 0.011 mmol), (6-chloro-4-(methylamino)pyridin-3-yl)(cyclopropyl)methanol (0.024 g, 0.111 mmol), 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.029 g, 0.111 mmol) in dioxane (0.8 ml) was evacuated under vacuum and filled with nitrogen (3x) and then heated at 95 °C for 2 hours. The reaction was purified by preparative, reverse-phase HPLC to give -((5-(cyclopropyl(hydroxy)methyl)-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (9.4 mg, 20% yield). 'H NMR (500 MHz, DMSO-d6) 87.54 (s, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.17 (br s, 1H), 6.35 (br d, J=8.2 Hz, 1H), 5.96 (br d, J=4.6 Hz, 1H), 3.82 - 3.73 (m, 2H), 3.70 (br d, J=7.6 Hz, 1H), 3.60 - 3.52 (m, 1H), 2.62 (d, J=4.9 Hz, 3H), 2.60 - 2.51 (m, 2H), 1.70 (s, 3H), 1.64 (br dd, J=13.1, 7.6 Hz, 2H), 1.42 (br dd, J=13.0, 4.4 Hz, 2H), 1.18 - 1.05 (m, 1H), 1.02 (s, 3H), 0.37 - 0.28 (m, 1H), 0.18 (ddd, J=16.6, 8.7, 4.3 Hz, 2H), 0.01 (br dd, J=8.4, 3.5 Hz, 1H) (OH was suppressed by water suppression)

[0644] Example 13. 6-((5-(Cy cl opropanecarbonyl)-4-(methylamino)pyri din-2 -yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile Dess-Martin periodinane (0.034 g, 0.080 mmol) was added to a CH2CI2 (1 mL) solution of 6-((5-(cyclopropyl(hydroxy)methyl)-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.023 g, 0.054 mmol) at room temperature. After 2 hours, the reaction was diluted with DCM and washed with IN NaOH. The DCM layer was separated, dried (Na2SO4), filtered and concentrated. The crude was purified by preparative, reverse-phase HPLC to give 6-((5-(cyclopropanecarbonyl)-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (1.8 mg, 7 %) 'HNMR (500 MHz, DMSO-d6) 6 10.06 (br s, 1H), 9.09 (br d, J=4.6 Hz, 1H), 8.91 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.53 (s, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.05 - 3.95 (m, 2H), 3.78 (br dd, J=10.6, 3.5 Hz, 2H), 2.89 (d, J=4.9 Hz, 3H), 2.85 (br d, J=4.4 Hz, 1H), 2.77 (br s, 2H), 1.83 (br dd, J=13.1, 7.3 Hz, 2H), 1.62 (br dd, J=12.8, 4.0 Hz, 2H), 1.22 (s, 3H), 1.01 - 0.91 (m, 4H) (OH was suppressed by water suppression).Example 14. Preparation of 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((4-(methylamino)-5-phenylpyridin-2-yl)amino)nicotinonitrile

[0645]

[0646] To a 2 dram vial was added 6-((5-chloro-4-(methylamino)pyri din-2 -yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.020 g, 0.050 mmol), phenylboronic acid (8.25 mg, 0.068 mmol), and XPHOS PD G3 (4.24 mg, 5.01 pmol). The vial was capped and pump / purged with nitrogen (3x). THF (0.6 mL) and a 2M aqueous solution of potassium phosphate, tribasic (0.075 mL, 0.150 mmol) were added, and the reaction was heated at 80 °C overnight. Following cooling to room temperature, the volatiles were removed, and the residue was diluted with 2 mL of DMF, filtered, and purified by preparative, reverse-phase HPLC to give 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((4-(methylamino)-5-phenylpyridin-2-yl)amino)nicotinonitrile (7.2 mg). 'H NMR (500 MHz, DMSO-d6) 6 9.74 (br s, 1H), 7.99 (s, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.49 (s, 1H), 7.22 (s, 1H), 6.52 (br d, J=8.2 Hz, 1H), 6.04 (br d, J=4.6 Hz, 1H), 4.02 - 3.92 (m, 2H), 3.76 (br dd, J=10.5, 2.9 Hz, 2H), 2.83 (br d, J=4.6 Hz, 3H), 2.76 (br d, J=1.8 Hz, 2H), 2.45 (s, 3H), 1.83 (br dd, J=12.7, 7.8 Hz, 2H), 1.61 (br dd, J=13.0, 3.8 Hz, 2H), 1.21 (s, 3H). The OH is missing due to water suppression.

[0647] Example 15. 6-((5-(4,5-dimethylisoxazol-3-yl)-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0648]

[0649] To 2 dram vial was added 2-chloro-5-(4,5-dimethylisoxazol-3-yl)-N-methylpyridin-4-amine (0.020 g, 0.084 mmol), 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.022 g, 0.084 mmol), Pd2(dba)3 (3.85 mg, 4.21 pmol), xantphos (4.87 mg, 8.41 pmol), and cesium carbonate (0.096 g, 0.295 mmol). The flask was capped with a septum and pump / purged 3x with nitrogen. Dioxane (1 mL) was introduced, and the suspension was purged with nitrogen for 5 minutes and then heated at 95 °C overnight. The reaction was cooled to room temperature and concentrated. The resulting residue was purified by preparative, reversephase HPLC to give 6-((5-(4,5-dimethylisoxazol-3-yl)-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (2.1 mg). 'H NMR (500 MHz, DMSO-d6) 88.07 (br s, 1H), 7.79 (br d, J=7.9 Hz, 1H), 6.94 (br s, 1H), 6.42 (br d, J=7.9 Hz, 1H), 4.04 - 3.95 (m, 2H), 3.81 - 3.72 (m, 2H), 2.84 (br d, J=4.6 Hz, 3H), 2.79 (br s, 2H), 2.25 (s, 3H), 1.91 (s, 3H), 1.83 (br dd, J=13.1, 7.6 Hz, 2H), 1.66 (br dd, J=12.8, 3.4 Hz, 2H), 1.21 (s, 3H). The OH andtwoNHs are missing due to water suppression.

[0650] Example 16. 6-((5-(l,4-dimethyl-lH-pyrazol-3-yl)-4-(methylamino)pyri din-2 -yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0651]

[0652] To a 2 dram vial was added 6-chloro-3-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)-2,4-dimethylpyridine (0.050 g, 0.188 mmol), 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (0.024 g, 0.094 mmol), Pd2(dba)3 (4.31 mg, 4.70 pmol), xantphos (5.44 mg, 9.41 pmol), and cesium carbonate (0.107 g, 0.329 mmol). The vial was capped with a septum and pump / purged 3x with nitrogen. Dioxane (1 mL) was introduced, and the suspension was purged with nitrogen for 5 minutes and then heated at 100 °C overnight. The reaction was concentrated andpurified by preparative, reverse-phase HPLC to give 6-((5-(l,4-dimethyl-lH-pyrazol-3-yl)-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (38 mg).1HNMR(500 MHz, DMSO-d6) 67.86 (br s, 1H), 7.77 (s, 1H), 7.67 (br d, J=8.5 Hz, 1H), 7.47 (s, 1H), 6.51 (br d, J=9.2 Hz, 1H), 4.30 (t, J=5.3 Hz, 2H), 3.99 - 3.89 (m, 2H), 3.79 - 3.69 (m, 4H), 3.23 (s, 3H), 2.78 (br d, J=2.4 Hz, 2H), 2.30 (s, 3H), 2.15 (s, 3H), 1.88 - 1.80 (m, 2H), 1.64 (br dd, J=13.1, 4.0 Hz, 2H), 1.21 (s, 3H). The OH and one NH are missing due to water suppression.

[0653] Example 17. Preparation of 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((5-(5-(l-methyl-lH-pyrazol-4-yl)-l,2,4-oxadiazol-3-yl)-4-(methylamino)pyridin-2-yl)amino)nicotinonitrile

[0654]

[0655] 17 A. 6-Chloro-4-(methylamino)nicotinonitrile

[0656]

[0657] To a stirred solution of 4,6-dichloronicotinonitrile (250 mg, 1.45 mmol) in DMA (5 mL) was added methylamine hydrochloride (107 mg, 1.59 mmol) followed by DIPEA (0.757 mL, 4.34 mmol). The reaction mixture was heated to 50 °C for 2 h. The reaction was quenched with ice cold water and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude mixture was purified by flash silica gel chromatography (20 % EA: Hexane; 12 g silica gel column) to afford 6-chloro-4-(methylamino)nicotinonitrile (120 mg, 0.716 mmol, 49.5 % yield) as a white solid. LC / MS (M+H)+: 168.2; ret. time = 0.46 min.17B. 6-((5-Cyano-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0658]

[0659] To a degassed solution of 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (1.00 g, 3.87 mmol) in 1,4-dioxane (1.5 mL) was added 6-chloro-4-(methylamino)nicotinonitrile (0.973 g, 5.81 mmol), cesium carbonate (3.15 g, 9.68 mmol), xantphos (0.448 g, 0.774 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.354 g, 0.387 mmol). The reaction mixture was stirred at 115 °C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude mixture was purified by flash silica gel chromatography (40-60% EtOAc-Pet Ether) to afford 6-((5-cyano-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (1.2 g, 3.08 mmol, 80 % yield) as a brown solid. LC / MS (M+H)+: 390.3; ret. time = 1.39 min.

[0660] 17C. 6-((5-Cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol- 2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinohydrazonamide

[0661]

[0662] To a stirred solution of 6-((5-cyano-4-(methylamino)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (1.00 g, 2.57 mmol) in ethanol (40 mL) was added a hydroxylamine solution, 50 wt. % in H2O (0.337 mL, 5.14 mmol). The reaction mixture was heated to 80 °C overnight. The reaction mixture was cooled to room temperature, and the solids were filtered, washed with ethanol (5 mL) and dried over vacuum to afford 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-N'-hydroxy-4-(methylamino)nicotinimidamide (600 mg, 1.42 mmol, 55 % yield) as a brown solid. LC / MS (M+H)+: 423.4; ret. time = 1.08 min.

[0663] Example 17. 2-((3aR,5r,6aS)-5-Hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((5-(5-(l-methyl-lH-pyrazol-4-yl)-l,2,4-oxadiazol-3-yl)-4-(methylamino)pyridin-2-yl)amino)nicotinonitrile

[0664] To a stirred solution of 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-N'-hydroxy-4-(methylamino)nicotinimidamide (30 mg, 0.071 mmol) in THF (2 mL) was added 1-methyl-lH-pyrazole-4-carboxylic acid (13.4 mg, 0.107 mmol), TEA (0.030 mL, 0.213 mmol) followed by Benzotriazol- l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (31.4 mg, 0.071 mmol). The reaction mixture was stirred at room temperature for 2 h. To the reaction mixture was added TBAF (0.355 mL, 0.355 mmol), and the reaction was heated to 70 °C overnight. TBAF (0.592 mL, 0.592 mmol) was added to the reaction mixture, and the reaction was heated at 70 °C overnight. The reaction mixture was concentrated under vacuum and purified by prep-HPLC to obtain 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((5-(5-(l-methyl-lH-pyrazol-4-yl)-l,2,4-oxadiazol-3-yl)-4-(methylamino)pyridin-2-yl)amino)nicotinonitrile (1.7 mg, 3.32 pmol, 4.7 % yield). ’H NMR (400 MHz, DMSO-d6) 8 = 10.65 (br s, 1H), 8.73 (d, J = 11.1 Hz, 1H), 8.22 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.71 - 7.51 (m, 1H), 7.23 (brs, 1H), 6.44 (d, J = 8.6 Hz, 1H), 4.06 - 4.00 (m, 2H), 3.98 (s, 3H), 3.81 (br dd, J = 3.4, 10.5 Hz, 2H), 3.05 (br d, J = 4.6 Hz, 3H), 2.84 - 2.78 (m,2H), 1.86 (br dd, J = 7.3, 13.3 Hz, 2H), 1.68 (br dd, J = 4.3, 13.2 Hz, 2H), 1.24 (s, 3H).

[0665] Example 18. Preparation of 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((5-(3-(2-hydroxypropan-2-yl)-l,2,4-oxadiazol-5-yl)-4-(methylamino)pyridin-2-yl)amino)nicotinonitrile

[0666]

[0667] 18 A. 6-Chloro-4-(methylamino)nicotinate

[0668] O ^NH

[0669]

[0670] A stirred solution of methyl 4, 6-di chloronicotinate (2 g, 9.71 mmol) in acetonitrile (30 mL) was cooled to 0 °C. A methylamine solution, 40 wt. % in H2O (3.77 g, 48.5 mmol) was added over a period of 10 minutes. The reaction mixture was stirred at 0 °C for 30 minutes, and the reaction mixture was gradually warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under vacuum. The crude mixture was purified by flash silica gel chromatography (20 %EA: Hexane; 40 g silica gel column) to afford methyl 6-chloro-4-(methylamino)nicotinate (1.5 g, 7.48 mmol, 77 % yield) as a white solid.

[0671] 'HNMR (400 MHz, DMSO-d6) 6 ppm 2.88 (d, J=5.00 Hz, 3 H) 3.83 (s, 3 H) 6.73 (s, 1 H) 8.03 (br d, J=3.75 Hz, 1 H) 8.49 (s, 1 H). LC / MS (M+H)+: 201.3; ret. time = 0.54 mm.

[0672] 18B. Methyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinate

[0673]

[0674] To a stirred solution of methyl 6-chloro-4-(methylamino)nicotinate (408 mg, 2.03 mmol) and 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (350 mg, 1.36 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (1324 mg, 4.06 mmol). The reaction mixture was purged argon for 5 minutes, and then xantphos (157 mg, 0.271 mmol) and Pd2(dba)s (124 mg, 0.135 mmol) were added. The reaction mixture was heated to 125 °C overnight, filtered through celite, andthe filtrate was concentrated under reduced pressure. The crude mixture was purified by flash silica gel chromatography to afford methyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinate (300 mg, 0.710 mmol, 52 % yield) as a brown solid. LC / MS (M+H)+: 423.3; ret. time = 1.49 min.

[0675] 18C. 6-((5-Cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinic acid.

[0676]

[0677] To a stirred solution of methyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinate (150 mg, 0.355 mmol) in 1,4-dioxane (1.5 mL), MeOH (1.5 mL) and Water (0.1 mL), was added LiOH. H2O (74.5 mg, 1.78 mmol). The reaction mixture was heated to 55 °C for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (10 mL) and acidified with 1.5 N aqueous HC1, and the solids were dried uncer vacum to afford 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinic acid (100 mg, 0.245 mmol, 69 % yield) as a white solid. LC / MS (M+H)+: 409.3; ret. time = 0.72 min.

[0678] Example 18. 2-((3aR,5r,6aS)-5-Hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((5-(3-(2-hydroxypropan-2-yl)-l,2,4-oxadiazol-5-yl)-4-(methylamino)pyridin-2-yl)amino)nicotinonitrile

[0679] To a stirred solution of 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-4-(methylamino)nicotinic acid (40 mg, 0.098 mmol) in DMF (2 mL) were added N',2-dihydroxy-2-methylpropanimidamide (17.4 mg, 0.147 mmol), TEA (0.041 mL, 0.294 mmol) followed by Benzotriazol- l-yloxytris(dimethylamino)phosphoniumhexafluorophosphate(BOP) (52.0 mg, 0.118 mmol). The reaction mixture was stirred at room temperature overnight and then heated to 100 °C for an additional night. The reaction mixture was concentrated under vacuum and purified by prep-HPLC to obtain 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((5-(3-(2-hydroxypropan-2-yl)-l,2,4-oxadiazol-5-yl)-4-(methylamino)pyridin-2-yl)amino)nicotinonitrile (2.2 mg, 4.48 μmol, 4.6 % yield). 'H NMR. (400 MHz, DMSO-d6) 8 = 10.10 (s, 1H), 8.62 (s, 1H), 8.06 (br d, J = 5.3 Hz, 1H), 7.71 - 7.63 (m, 2H), 6.57 (d, J = 8.3 Hz, 1H), 5.65 (s,lH), 4.50 (s, 1H), 4.06 - 3.95 (m, 2H), 3.81 (dd, J = 3.5, 10.8 Hz, 2H), 3.03 (d, J = 4.8 Hz, 3H), 2.83 - 2.75 (m, 2H), 1.85 (br dd, J = 7.5, 13.0 Hz,2H), 1.64 (dd, J = 4.1, 13.4 Hz, 2H), 1.56 (s, 6H), 1.23 (s, 3H).

[0680] Example 19. Preparation of 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((4-(methylamino)-5-(2,7-dioxa-5-azaspiro[3.4]oct-5-en-6-yl)pyridin-2-yl)amino)nicotinonitrile

[0681]

[0682] 19 A. Methyl 6-chloro-4-(methylamino)nicotinate

[0683]

[0684] A stirred solution of methyl 4, 6-di chloronicotinate (2 g, 9.71 mmol) in acetonitrile (30 mL) was cooled to 0 °C. Methylamine solution, 40 wt. % in H2O (3.77 g, 48.5 mmol) was added over a period of 10 minutes. The reaction mixture was stirred at 0 °C for 30 minutes, and the reaction mixture was gradually warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under vacuum, and the crude mixture was purified by flash silica gel chromatography (20 % EA: Hexane; 40 g silica gel column) to afford methyl 6-chloro-4-(methylamino)nicotinate (1.5 g, 7.48 mmol, 77 % yield) as a white solid. 'H NMR (400 MHz, DMSO-d6) 6 ppm 2.88 (d, J=5.00 Hz, 3 H) 3.83 (s, 3 H)6.73 (s, 1 H) 8.03 (br d, J=3.75 Hz, 1 H) 8.49 (s, 1 H). LC / MS (M+H)+: 201.3; ret. time = 0.54 min.

[0685] 19B. 6-Chloro-4-(methylamino)nicotinic acid

[0686] O ^NH

[0687]

[0688] To a stirred solution of methyl 6-chloro-4-(methylamino)nicotinate (1920 mg, 9.57 mmol) in methanol (20 mL). Lithium hydroxide monohydrate (1205 mg, 28.7 mmol) dissolved in water (6.67 mL) was added to the reaction mixture in one portion. The mixture was stirred overnight at room temperature. The solvents were evaporated under vacuum, and the residue was suspended in 50 mL of 1.5 N HC1. A10% aqueous NaOH solution was used to bring the solution to pH 7. The aqueous layer was extracted with 2x50 mL of EtOAc, and the combined organic layers were washed with 50 mL aqueous brine solution, dried over anhydrous sodium sulfate and concentrated to leave behind the desired product, 6- chloro-4-(methylamino)nicotinic acid (1480 mg, 7.93 mmol, 83 % yield) as a white solid. LC / MS (M+H)+: 187.2; ret. time = 0.29 min. 'H NMR (400MHz, DMSO-d6) 8 = 14.42 - 11.63 (bs, 1H), 8.53 - 8.43 (m, 1H), 8.39 - 8.24 (m, 1H), 6.82 -6.50 (m, 1H), 2.93 - 2.80 (m, 3H).

[0689] 19C. 6-Chloro-N-(3-(hydroxymethyl)oxetan-3-yl)-4-(methylamino)nicotinamide

[0690]

[0691] To a stirred solution of 6-chloro-4-(methylamino)nicotinic acid (100 mg, 0.536 mmol) in DMF (2 mL) was added benzotriazol- l-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) (474 mg, 1.07 mmol), DIPEA (0.281 mL, 1.61 mmol) and (3-aminooxetan-3-yl)m ethanol (66.3 mg, 0.643 mmol) at 0 °C. The reaction mixture was stirred at 25 °C. for 12 h. The reaction mixture was diluted with EtOAc ( 10 mL ). The organic layer was washed with ice cooled water ( 5 mL, washed with brine ( 5 mL ), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography (12g, 100% EtOAc in Hexane ) to afford 6-chloro-N-(3-(hydroxymethyl)oxetan-3-yl)-4-(methylamino)nicotinamide (120 mg, 0.353 mmol, 66 % yield). LC / MS (M+l)+: 272.3; ret. time = 0.72 min.19D. 2-Chloro-N-methyl-5-(2,7-dioxa-5-azaspiro[3.4]oct-5-en-6-yl)pyridin-4-amine

[0692]

[0693] To a stirred solution of 6-chloro-N-(3-(hydroxymethyl)oxetan-3-yl)-4-(methylamino)nicotinamide (70 mg, 0.258 mmol) in DCM (1 mL) at 0 °C was added DAST (0.068 mL, 0.515 mmol). The reaction mixture was stirred at 0 °C for 60 min. The reaction was quenched with aq. 10% sodium bicarbonate solution ( 2 mL ), the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-chloro-N-methyl-5-(2,7-dioxa-5-azaspiro[3.4]oct-5-en-6-yl)pyridin-4-amine (50 mg, 0.197 mmol, 77 % yield). LC / MS (M+H)+: 254.3; ret. time = 1.09 min. Example 19. 2-((3aR,5r,6aS)-5-Hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((4-(methylamino)-5-(2,7-dioxa-5-azaspiro[3.4]oct-5-en-6-yl)pyridin-2-yl)amino)nicotinonitrile

[0694] To a stirred solution of 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (20.37 mg, 0.079 mmol) and 2-chloro-N-methyl-5-(2,7-dioxa-5-azaspiro[3,4]oct-5-en-6-yl)pyridin-4-amine (20 mg, 0.079 mmol) in 1,4-dioxane (1 mL) at room temperature was added cesium carbonate (77 mg, 0.237 mmol). Argon was bubbled through the solution for 5 min and then Pd2(dba)3 (21.7 mg, 0.024 mmol) and xantphos (27.4 mg, 0.047 mmol) were added. The reaction mixture was heated at 115 °C and stirred for 12 h. The reaction mixture was diluted with DCM (20 mL) and concentrated under reduced pressure. The reaction mixture was purified by preparative, reverse-phase HPLC to obtain 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((4-(methylamino)-5-(2,7-dioxa-5-azaspiro[3.4]oct-5-en-6-yl)pyridin-2-yl)amino)nicotinonitrile (2.4 mg, 6.4%).1H NMR (400MHz, DMSO-d6) 8 = 10.11 - 10.02 (m, 1H), 8.81 - 8.71 (m, 1H), 8.33 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.48 (br s, 1H), 6.49 (d, J=8.3 Hz, 1H), 4.78 - 4.71 (m, 4H), 4.58 (s, 2H), 4.03 - 3.97 (m, 2H), 3.79 (dd, J=3.8, 10.9 Hz, 2H), 3.18 (s, 1H), 2.99 (d, J=5.1 Hz, 3H), 2.83 - 2.76 (m, 2H), 1.84 (dd, J=7.8, 13.4 Hz, 2H), 1.64 (dd, J=4.6, 13.0 Hz, 3H), 1.23 (s, 3H).Example 20. Preparation of 6-((4,6-dimethyl-5-(lH-pyrazol-4-yl)pyridin-2-yl)amino)-2- ((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0695]

[0696] 20A. 6-((5-Bromo-4,6-dimethylpyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0697]

[0698] To a stirred solution of 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (500 mg, 1.94 mmol) in 1,4-dioxane (20 mL) were added 3-bromo-6-chloro-2,4-dimethylpyridine (427 mg, 1.94 mmol) and CS2CO3 (1577 mg, 4.84 mmol). The reaction mixture was purged with argon for 5 minutes, and Pd2(dba)3 (177 mg, 0.194 mmol) and xantphos (224 mg, 0.387 mmol) were added. The reaction mixture was heated to 115 °C overnight. The reaction mixture was diluted using DCM and concentrated under reduced pressure. The crude material was purified by Combi-Flash silica gel chromatography (24g Silica gel, 50% EtOAc: Pet ether) to afford 6-((5-bromo-4,6-dimethylpyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (260 mg, 0.588 mmol, 30 % yield). LC / MS (M+H)+: 442.4.; ret. time = 1.96 min. 'H NMR (300 MHz, DMSO-d6) 8 ppm 1.22 (s, 3 H) 1.65 (br dd, J=12.84, 4.53 Hz, 2 H) 1.81 - 1.89 (m, 2 H) 2.22 - 2.30 (m, 2 H) 2.34 (s, 3 H) 2.71- 2.83 (m, 3 H) 3.74 (br dd, J=10.58, 3.02 Hz, 2 H) 3.90 - 3.98 (m, 2 H) 4.49 - 4.55 (m, 1 H) 6.46 - 6.59 (m, 1 H) 7.58 - 7.69 (m, 1 H) 8.11 - 8.18(m, 1 H) 10.00 - 10.07 (m, 1 H).Example 20. 6-((4,6-Dimethyl-5-(lH-pyrazol-4-yl)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile

[0699] To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (35.1 mg, 0.181 mmol) in 1,4-dioxane (1.6 mL) were added 6-((5-bromo-4,6-dimethylpyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (40 mg, 0.090 mmol) and potassium phosphate, tribasic, 97%, pure, anhydrous (0.136 mL, 0.271 mmol). The reaction mixture was purged with argon for 5 minutes, and XPHOS PD G3 (7.65 mg, 9.04 μmol) was added. The reaction mixture was heated to 115 °C for 16h. The reaction mixture was diluted with DCM (20 mL) and concentrated under reduced pressure. The reaction mixture was purified by preparative-reverse-phase HPLC to obtain 6-((4,6-dimethyl-5-(lH-pyrazol-4-yl)pyridin-2-yl)amino)-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (6.4 mg, 4.48 μmol, 16 % yield). 'H NMR (400 MHz, DMSO-d6) 8 = 9.92 (br s, 1H), 8.02 (br s, 1H), 7.62 (br d, J = 8.8 Hz, 3H), 6.55 (d, J = 9.0 Hz, 1H), 4.50 (s, 1H), 4.00 - 3.91(m, 2H), 3.76 (dd, J = 3.9, 10.4 Hz, 2H), 2.87 - 2.71 (m, 2H), 2.26 (s, 3H), 2.12 (s, 3H), 1.85 (dd, J= 8.1, 13.1 Hz, 2H), 1.65 (dd, J = 4.5, 13.0 Hz,2H), 1.22 (s, 3H).

[0700] Example 21. Preparation of 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((6-methyl-4-(methylamino)-5-(3-phenyl-l,2,4-oxadiazol-5-yl)pyridin-2-yl)amino)nicotinonitrile

[0701]

[0702] 21 A. 6-Chloro-2-methyl-4-(methylamino)nicotinate

[0703] O "" MH

[0704]

[0705] To a stirred solution of ethyl 4,6-dichloro-2-methylnicotinate (5 g, 21.4 mmol) in acetonitrile (75 mL) was cooled to 0 °C. Methylamine solution, 40 wt. % in H2O (8.29 g, 107 mmol) was added over a period of 10 minutes. The reaction mixture was stirred at 0 °C for 30 minutes and then gradually warmed to room temperature and stirred for 24h. The reaction mixture was concentrated under vacuum, and the crude mixture was purified by flash silica gel chromatography (20 %EA: Hexane; 40 g silica gel column) to afford ethyl 6-chloro-2-methyl-4-(methylamino)nicotinate (4.5 g, 19.7 mmol, 92 % yield) as a white solid. LC / MS (M+H)+: 229.0; ret. time = 2.28 min.

[0706] 21B. Methyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-2-methyl-4-(methylamino)nicotinate

[0707]

[0708] To a stirred solution of ethyl 6-chloro-2-methyl-4-(methylamino)nicotinate (465 mg, 2.03 mmol) and 6-amino-2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)nicotinonitrile (350 mg, 1.36 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (1324 mg, 4.06 mmol). The reaction mixture was purged with argon for 5 minutes, and xantphos (157 mg, 0.271 mmol) and Pd2(dba)3 (124 mg, 0.135 mmol) were added. The reaction mixture was heated to 125 °C overnight, diluted with water (15 mL) and extracted with ethyl acetate (2 x20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The mixture was purified by flash chromatography (silica gel, 12 g, 80% EtOAc in Hexane) to afford ethyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-2-methyl-4-(methylamino)nicotinate (400 mg, 0.888 mmol, 66 % yield) as a brown solid. LC / MS (M+H)+: 451.4; ret. time = 1.74 min.21C. 6-((5-Cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol- 2(lH)-yl)pyridin-2-yl)amino)-2-methyl-4-(methylamino)nicotinic acid

[0709]

[0710] To a stirred solution of ethyl 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-2-methyl-4-(methylamino)nicotinate (380 mg, 0.843 mmol) in ethanol (8 mL) was added LiOH·H₂O (177 mg, 4.22 mmol) in water (1 mL). The reaction mixture was heated to 55 °C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL) and acidified with a 1.5 N aqueous solution of HC1. The resulting solid was collected and dried under vacuum for 12 h to afford 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-2-methyl-4-(methylamino)nicotinic acid (155 mg, 0.367 mmol, 44 % yield) as an off white solid. LC / MS (M+H)+: 423.2; ret. time = 1.26 min.

[0711] Example 21. 2-((3aR,5r,6aS)-5-Hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((6-methyl-4-(methylamino)-5-(3-phenyl-l,2,4-oxadiazol-5-yl)pyridin-2-yl)amino)nicotinonitrile

[0712] To a stirred solution of 6-((5-cyano-6-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)pyridin-2-yl)amino)-2-methyl-4-(methylamino)nicotinic acid (25 mg, 0.059 mmol) in DMF (1 mL) were added N'-hydroxybenzimidamide (12.08 mg, 0.089 mmol), TEA (0.025 mL, 0.178 mmol) and benzotriazol- l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (28.8 mg, 0.065 mmol). The reaction mixture was stirred at room temperature for 3 h and then heated at 110 °C overnight. The reaction mixture was concentrated under vacuum and purified by prep-HPLC to obtain 2-((3aR,5r,6aS)-5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-((6-methyl-4-(methylamino)-5-(3-phenyl-l,2,4-oxadiazol-5-yl)pyridin-2-yl)amino)nicotinonitrile (6.8 mg, 0.013 mmol, 22% yield). 'H NMR (400MHz, DMSO-d6) 6 = 9.95 (s, 1H), 8.28 (q, J = 4.7 Hz, 1H), 8.15 (dd, J = 1.7, 7.8 Hz, 2H), 7.70 - 7.43 (m, 5H), 6.55 (d, J = 8.6 Hz,lH), 4.52 (s, 1H), 4.06 -3.91 (m, 2H), 3.78 (dd, J = 3.9, 10.8 Hz, 2H), 3.00 (d, J = 4.6 Hz, 3H), 2.86 - 2.70 (m, 2H), 2.64 (s, 3H), 1.83 (br dd, J =7.9, 13.1 Hz, 2H), 1.63 (dd, J = 4.3, 13.1 Hz, 2H), 1.22 (s, 3H).

[0713] In the table below:

[0714] Examples 22 through 56 were prepared in a similar fashion as described in the procedures for Examples 1 through 6, starting with the appropriate starting material.

[0715] Examples 57 through 80 were prepared in a similar fashion as described in the procedures for Examples 1 through 12, starting with the appropriate starting material.

[0716] Exaples 81 through 91 were prepared in a similar fashion as described in the procedure for Example 14, starting with the appropriate starting material.

[0717] Examples 92 through 102 were prepared in a similar fashion as described in the procedures for Examples 14, 15, 17, or 18 starting with the appropriate starting material.

[0718] Examples 103 through 123 were prepared in a similar fashion as described in the procedures for Example 17, starting with the appropriate starting material.

[0719] Examples 124 through 139 were prepared in a similar fashion as described in the procedures for Example 18, starting with the appropriate starting material.

[0720] Example 140 was prepared in a similar fashion as described in the procedures for Examples 14, 15, 17, or 18 starting with the appropriate starting material.

[0721] Examples 141 through 146 were prepared in a similar fashion as described in the procedures for Example 19, starting with the appropriate starting material.

[0722] Examples 147 through 148 were prepared in a similar fashion as described in the procedures for Examples 14, 15, 17, or 18 starting with the appropriate starting material.

[0723] Examples 149 through 163 were prepared in a similar fashion as described in the procedures for Examples 16 and 20, starting with the appropriate starting material.

[0724] Examples 164 through 168 were prepared in a similar fashion as described in the procedures for Example 21, starting with the appropriate starting material.Examples 169 through 176 were prepared in a similar fashion as described in the procedures for Example 19, starting with the appropriate starting material.

[0725] LCMS

[0726] [M+H]+ NIK HTRF ICso Exp.# Structure

[0727] RT min. (pM) (Method)

[0728] HQ \

[0729] 620

[0730] 1 1.58 0.003 i.

[0731] O=S=O 0 NH N (A)

[0732] (YYYr YY

[0733] H

[0734] 0

[0735] II S HH — HH

[0736] 580

[0737] 2 O=S=O 0 ^NH 1.14 0.001 (A)

[0738] 6^ Y i YY"

[0739] H

[0740] 0

[0741] II S HH — HH

[0742] 580

[0743] 3 O=S=O 0 ^NHK|\t 1.18 0.001 (A) dn Yi YY"

[0744] H NH2

[0745] 547

[0746] O=S=O 0 NH N

[0747] 4 1.19 0.004 (A)

[0748] (io YY YY

[0749]

[0750] HLCMS

[0751] [M+H]+ NIK HERE IC50 Exp.# Structure

[0752] RT min. (pM) (Method)

[0753] . OH

[0754] 1 C O 536

[0755] 5 1.63 0.004 (A)

[0756] H OH

[0757] HH — HH

[0758] 563

[0759] 6 O=S=O 0 ^NHK|\t 1.52 0.012 (B) (W r

[0760] H HOZzMe

[0761] HH — b-H

[0762] 404.9

[0763] 7AHN'MeV 1.49 0.030 MA / CN (A)

[0764] X l 1 J

[0765] H HOZ, Me

[0766] HH — b-H

[0767] 460.2

[0768] 8HHN'MeN 1.31 0.001 (A)

[0769] o N-Nr o. i J

[0770] Me H

[0771] H0ZzMe

[0772] H4 — b-H

[0773] 390.1

[0774] 9 HN'MeN 1.09 0.017 NC.k l / L / CN (A)

[0775] TI n

[0776]

[0777] HLCMS

[0778] [M+H]+ NIK HTRF IC50 Exp.# Structure

[0779] RT min. (pM) (Method)

[0780] HO H

[0781] 422.2

[0782] 10 0 HN* V 1.30 0.009 (A)

[0783] o Y i A "

[0784] VYP H HO,zMe

[0785] 0.

[0786] H-W-H 574.2

[0787] 11 0 NH ^14 1.36 0.009 (A)

[0788] “ M-Pe YNX N^ "

[0789] rl

[0790] HO,zMe

[0791] MMeH"4 — 4-H

[0792] Me-^Y V V 546.0

[0793] 12 0 NH 1.61 0.006 (A)

[0794] ” F3PC Y NX. N^V“

[0795] HOZzMe

[0796] HH — HH

[0797] 433.4

[0798] 13 0 HN'MeN 1.40 0.001MX. CN (A)

[0799] v U JU

[0800] H HO Me

[0801] 441.2

[0802] 14 HN-MeV 1.74 0.005 YJYY,K, YXCN(A)

[0803] N

[0804]

[0805] HLCMS

[0806] [M+H]+ NIK HERE IC50 Exp.# Structure

[0807] RT min. (pM) (Method)

[0808] HOZzMe

[0809] HH — HH

[0810] 460.2

[0811] 15 P'N HN'MeN 1.44 0.003 Me— X X EN (A)

[0812] / IlNtT

[0813] Me k- A A A

[0814] N N H HOZzMe

[0815] MeO \ /

[0816] \ HH — HH

[0817] 488.2

[0818] 16zN"n Me 1.37 0.004klX^CN (A)

[0819] jfl

[0820] H HOZzMe

[0821] H-^H

[0822] 513.2

[0823] 17 O-N HN'MeV 1.28 0.005 '0^ 1A A / CN (E)

[0824] Me 1 II jl 1

[0825] H HO,zMe

[0826] H-^H

[0827] 491.2

[0828] 18 Me N-o HN'MeV 1.26 0.003H07 \A A MA^CN(E)

[0829] Me'N|^ |] ’ll AT

[0830] H HOZ / Me

[0831] HH — £-H

[0832] 476.2

[0833] 19 / \A~O HN'MeN 1.55 0.0010^NAXNA¥CN (F)

[0834] L II Ji J

[0835]

[0836] HLCMS

[0837] [M+H]+ NIK HERE IC50 Exp.# Structure

[0838] RT min. (pM) (Method)

[0839] HOZzMe

[0840] o —.

[0841] H / \ 4) co — / — HH — HH

[0842] 430.0

[0843] / V / IIs

[0844] 20 ' K o — Me IT 1.10 0.001H\A IZ J\MX / CN (E)

[0845] J \O=TI n

[0846] AT / /

[0847] V Z z— H

[0848] / \ T _ HOZzMe

[0849] TZ 1x

[0850] H YL zH— / ^\-^ — b-H

[0851] V > O Z V"- 523.2

[0852] \ / T

[0853] 21 r--^ N--o HN'MeN 1.70

[0854] N\ U A r1(E)

[0855] v A ^CNz

[0856] X 1 A J

[0857] Me^N N^^

[0858] H HQ /

[0859] HH — (-H

[0860] 576

[0861] i o

[0862] 22 O=s=o 0 NH N 1.58 0.001 (A) (in V i Zf"

[0863] H

[0864] 562

[0865] 23 1.7 0.002

[0866] (B)

[0867]

[0868] LCMS

[0869] [M+H]+ NIK HERE IC50 Exp.# Structure

[0870] RT min. (pM) (Method)

[0871] HQ. CF3

[0872] HH — HH

[0873] 630

[0874] 24 0=S=0 0 ^NH N 1.87 0.050 (B) (in V i Zf"

[0875] H

[0876] z

[0877] \ X

[0878] Hx / N O^

[0879] )6 Xz z>< —

[0880] Q> 596

[0881] 25 1.59 0.005 zzT

[0882] (B)

[0883] / \ T

[0884] (\ Z z—==

[0885] /

[0886] \o=

[0887] zz

[0888] ) < O - HO ^0 Ax

[0889] <z>> < ——z x / / X II '

[0890] / \ _ II

[0891] o ' — ' 670

[0892] HH — HH

[0893] 26 1.77 0.010

[0894] 1 \ O

[0895] O=s=o 0 NH N (B)

[0896] do V i XT

[0897] H

[0898] s

[0899] H-4 — F-H

[0900] 564

[0901] 27 0=S=0 0 ^NH ^l\T 1.86 0.003 (B) dn V i / f

[0902]

[0903] H

[0904] - Ill -LCMS

[0905] [M+H]+ NIK HERE IC50 Exp.# Structure

[0906] RT min. (pM) (Method)

[0907] HQ.

[0908] H-4 — (-H 602

[0909] 28 1 \ O 1.41 0.004 0=S=0 0 NH N

[0910] (A) (ioY i AA

[0911] H

[0912] / OH

[0913] 548

[0914] 29 O=S=O 0. NHH’A N'H1.32 0.013 (A) bobb bb

[0915] H OH

[0916] 1. b 548

[0917] 30 0=S=0 0 NH N 1.61 0.004 (B) QrV A AA"

[0918] H OH

[0919] 550

[0920] 31 O=S=O 0 ^NH ^N^ 1.39 0.011 (A) ArV A AA"

[0921] H OH

[0922] i. b 536

[0923] 32 O=S=O 0 NH N 1.65 0.005 (B) bnbb bb

[0924]

[0925] HLCMS

[0926] [M+H]+ NIK HERE IC50 Exp.# Structure

[0927] RT min. (pM) (Method)

[0928] OH

[0929] i. s 536

[0930] 33 O=S=O 0 NH N 1.52 0.004 (B) dn V i ir""

[0931] H OH

[0932] 1 \ O 550

[0933] 34 O=S=O 0 NH N 1.7 0.005 (B) dn V i Zf"

[0934] H OH

[0935] 1 \ O 564

[0936] 35 O=S=O 0 NH N 1.84 0.004 (B)

[0937] H

[0938] y^-OH

[0939] 564

[0940] O=S=O 0 ''" NH N

[0941] 36 1.74 0.001 (B) (YA k #r

[0942] H KH

[0943] i. d 564

[0944] O=S=O 0 NH N

[0945] 37 1.76 0.005 (B)

[0946] ^N^N^5^

[0947]

[0948] HLCMS

[0949] [M+H]+ NIK HERE IC50 Exp.# Structure

[0950] RT min. (pM) (Method)

[0951] 0

[0952] / -NH2

[0953] 549

[0954] 38 O=S=O 0 "" NH N 1.44 0.003 (B)

[0955] (V rY l.

[0956] V't / V

[0957] H

[0958] _

[0959] HN

[0960] 577

[0961] 39 1. 1.25 0.001 O=S=O 0 NH N

[0962] (A)

[0963] dn V i Zr""

[0964] H NH,

[0965] /

[0966] 1 x b 535

[0967] 40 O=s=o 0 NH N 1.39

[0968] (A) (in V i Zf"

[0969] H

[0970] _

[0971] HN

[0972] 577

[0973] 41 1. b 1.25 0.002 O=S=O 0 NH N

[0974] (A)

[0975] (in V i

[0976] H OH

[0977] 1 x d'

[0978] O=S=O 0 NH N 536

[0979] 42 1.61 0.004 (B) bohb bb

[0980] ^N^N^5^

[0981]

[0982] HLCMS

[0983] [M+H]+ NIK HERE IC50 Exp.# Structure

[0984] RT min. (pM) (Method)

[0985] H2N"' /

[0986] 1. o 549

[0987] 0=S=0 0 NH N

[0988] 43 0.93 0.056 (A)

[0989] ^N^N^^

[0990] H

[0991] H2N— I

[0992] i. b 549

[0993] 0=S=0 0 NH N

[0994] 44 0.96 0.003 (A) dn Y i ET

[0995] H

[0996] i. b°H

[0997] 0=S=0 0 NH N 522

[0998] 45 1.54 0.006 if (B)

[0999] H NH2

[1000] I. <b 535

[1001] 46 0=S=0 0 NH N 1.11

[1002] i (B) (irA \

[1003] H f

[1004] OH

[1005] 1. 548

[1006] 47 1.46 0.000 (B)

[1007] (5r^T\

[1008]

[1009] HLCMS

[1010] [M+H]+ NIK HTRF IC50 Exp.# Structure

[1011] RT min. (pM) (Method)

[1012] o O —. <=S=O 0 ^NH 548

[1013] 48 Il / \ <) CD —\ / — 1.56 0.001 cY / / Y Il

[1014] ' < O —

[1015] TZ « Vi (B)

[1016] H

[1017] \°= QH

[1018] AT / /

[1019] x> z z—

[1020] / \ I _

[1021] i > 548

[1022] O=S=O 0 NH N

[1023] 49 1.48 0.002 dn-Yi H c YO>s"- * (B)

[1024] ,xO ^Hz

[1025] r"<- 1

[1026] O=S=O 0 ^NH 548

[1027] 50 1.26 0.007 cY « Yi Y * (A)

[1028] H OH

[1029] 548

[1030] 51 1.54 0.002 (B)

[1031] H

[1032] 548

[1033] 52 1.2 0.001

[1034] (B)

[1035]

[1036] LCMS

[1037] [M+H]+ NIK HERE IC50 Exp.# Structure

[1038] RT min. (pM) (Method)

[1039] 576

[1040] x 8,

[1041] 53 1.91 0.01

[1042] (B) dn V i xY

[1043] H OH

[1044] 1 o 550

[1045] 0=S=0 0 NH N

[1046] 54 1.7 0.002 (B)

[1047] S^N^^

[1048] H OH HO

[1049] 618

[1050] i h

[1051] 55 0=S=0 0 NHHT NT 1.31 0.006 (A)

[1052] #r*"

[1053] H

[1054] o

[1055] HQZ

[1056] \

[1057] 606

[1058] 56 i.H{ yH1.6 0.004 O=S=O 0 NH N (A)

[1059] AV"

[1060] H HO Me

[1061] H-J-}H 422.2

[1062] 57 0 HN-MeV 1.30 0.009 (A)

[1063] Me'« Y i ACN

[1064]

[1065] HLCMS

[1066] [M+H]+ NIK HERE IC50 Exp.# Structure

[1067] RT min. (pM) (Method)

[1068] HO,, Me

[1069] HH — b-H

[1070] 425.2

[1071] 58 0 HN'MeN 1.37 0.003 (A)

[1072] “■'nV i

[1073] H HOZzMe

[1074] HH — HH

[1075] 436.2

[1076] 59 0 HN'MeN 1.34 0.010 (A)

[1077] NV '

[1078] - u v

[1079] H HC\ Me

[1080] 448.3

[1081] 60A1.44 0.005 (A)

[1082] H

[1083] H06Me

[1084] HH — b-H

[1085] 448.1

[1086] 61 0 HN'MeN 1.28 0.004 (A)

[1087] c-V i A “

[1088] H

[1089] H06Me

[1090] HH — b-H

[1091] 466.2

[1092] 62 0 HN'MeN 1.34 0.004 (A)

[1093] x-A A "

[1094]

[1095] HLCMS

[1096] [M+H]+ NIK HERE ICso Exp.# Structure

[1097] RT min. (pM) (Method)

[1098] H0,zMe

[1099] HH — HH

[1100] 475.9

[1101] 63 0 HN'MeN 1.58 0.003 (A)

[1102] Me N N

[1103] rl

[1104] H0ZzMe

[1105] HH — b-H

[1106] 484.1

[1107] 64 0 HN'MeN 1.44 0.005 (A)

[1108] F N N H

[1109] H0,zMe

[1110] HH — HH

[1111] 477.9

[1112] 65 0 HN'MeN 1.24 0.004 (A)

[1113] -° M-Pe A NX N

[1114] rlA“

[1115] H0„zMe

[1116] HH — f-H

[1117] 463.9

[1118] 66 0 HN'MeN 1.22 0.004 (A)

[1119] HO X-V l A ”

[1120] H

[1121] H0Zzr~ CN

[1122] HH — h-H

[1123] 473.2

[1124] 67 0 HN'MeN 1.26 0.002 (A)

[1125] C'-'Yi A "

[1126] A^N^

[1127]

[1128] HLCMS

[1129] [M+H]+ NIK HERE IC50 Exp.# Structure

[1130] RT min. (pM) (Method)

[1131] HO,_ Me

[1132] H4 — b-H

[1133] 477.9

[1134] 68 0 HN'MeN 1.35 0.004 (A)

[1135] MeO X'-Y i Yr

[1136] H HO,zMe

[1137] H4 — b-H

[1138] 505.9

[1139] 69 0 HN'MeN 1.57 0.003 (A)

[1140] L 1 1 NV J

[1141] HO-q N

[1142] Me H

[1143] HO Me

[1144] H^-}H 480.2

[1145] 70 0 HN* V 1.11 0.001 (E)

[1146] H0H N IIVCN

[1147] H HOZzMe

[1148] HH — b-H

[1149] 462.3

[1150] 71 0 HN'MeN 1.33 0.006 (A)

[1151] cYA A "

[1152]

[1153] HLCMS

[1154] [M+H]+ NIK HERE IC50 Exp.# Structure

[1155] RT min. (pM) (Method)

[1156] HC\ Me

[1157] HH — HH

[1158] 480.4

[1159] 72 0 HN'MeN 1.19 0.004 (A)

[1160] '-0V 1 A “

[1161] H

[1162] H0ZyMe

[1163] HH — HH

[1164] 498.1

[1165] 73 0 HN'MeN 1.40 0.004 (A) x#Yi A "

[1166] H HO,, Me

[1167] 478.2

[1168] 74 0 HN'MeN 1.22 0.005 HO< M NV (A)

[1169] VJAV H HO Me

[1170] H^ H

[1171] 478.1

[1172] 75 0 HN'MeV 1.19 0.005 (A)

[1173] H°<V-JJNA / SAI V AECN

[1174] H HO Me

[1175] 436.1

[1176] 76 0 HN-MeV 1.22 0.019 (A)

[1177] jdyCN

[1178] Me N N / ^xz /

[1179]

[1180] HLCMS

[1181] [M+H]+ NIK HERE IC50 Exp.# Structure

[1182] RT min. (pM) (Method)

[1183] HO„zMe

[1184] HH — HH

[1185] 462.2

[1186] 77 0 HN'Et1.36 0.004 (A)

[1187] H HC\ Me

[1188] 474.4

[1189] 78 0 HN^ N 1.24 0.004 (A) c" Y i A “

[1190] H HO,, Me

[1191] 520.2

[1192] 79 0 NH N 1.52 0.012 (A)

[1193] '-0V 1

[1194] H IYNHO, Me

[1195] 554.2

[1196] 80 0 NH 1.33 0.003 (A)

[1197] MeNN

[1198] rl

[1199] HO,zMe

[1200] CN HH — HH

[1201] 484.2

[1202] 81 HN'MeN 1.51 0.003 (A)

[1203] W i Yr

[1204]

[1205] HLCMS

[1206] [M+H]+ NIK HERE IC50 Exp.# Structure

[1207] RT min. (pM) (Method)

[1208] H0ZzMe

[1209] H{-}H

[1210] 459.1

[1211] 82 HN'MeV 1.64 0.005 (A)

[1212] NV

[1213] L 1 A J

[1214] H HC\ Me

[1215] HH — HH

[1216] 454.9

[1217] 83 AA HN'MeN 1.76 0.006 A> Jk A ^CN (A)

[1218] L II j J

[1219] H HC\ Me

[1220] HH — HH

[1221] 487.3

[1222] , Me < >

[1223] 84 N HN N 1.38 0.001 A A A A / ON (E)

[1224] Me^ N N

[1225] L H A J H HQ, Me

[1226] A

[1227] 488.9

[1228] 85 HN* V 1.49 0.001 HO. A. Ax. A / ON (A)

[1229] T r nNAr

[1230] F JL A^J

[1231] N N H HO„zMe

[1232] o o HAAH 519.2

[1233] / S., Me \?

[1234] 86 Me A^ ll HN N 1.47 0.004 AAAx MACN(A)

[1235] L l 1 J

[1236]

[1237] HLCMS

[1238] [M+H]+ NIK HERE IC50 Exp.# Structure

[1239] RT min. (pM) (Method)

[1240] HOZzMe

[1241] 460.2

[1242] 87r,. 1.42 0.007 (A) rA iir"

[1243] FH HOZzMe

[1244] HH — P-H

[1245] 459.2

[1246] 88Me0Y^N HN'MeV 1.58 0.006 HA ZTx, AcN (A)

[1247] D / (

[1248] / \=n

[1249] / I / H

[1250] HO„zMe

[1251] \\ #

[1252] z—J

[1253] H-4 — b-H

[1254] 442.1

[1255] 89 HN'MeV 1.18 0.004 N^. JL A / CN (A) ^UL 1 J

[1256] H HO,zMe

[1257] 477.1

[1258] 1

[1259] 90 A HN* 4 VT 1.81 0.006 (A)F^ JL lY

[1260] H

[1261] 442.1

[1262] 91 1.13 0.005

[1263] (A)

[1264]

[1265] LCMS

[1266] [M+H]+ NIK HERE IC50 Exp.# Structure

[1267] RT min. (pM) (Method)

[1268] HC\ Me

[1269] MeH-H-H459.1

[1270] 92 N-N HN'Me1.56 0.005 (A)

[1271] / ilNtT

[1272] Me L. JL A J

[1273] N N H HC\ Me

[1274] HH — b-H

[1275] 459.1

[1276] Me Mg 4 \

[1277] 93 N-N HN' N 1.63 0.009MEK. A^ / CN (A)

[1278] tfl I J

[1279] H HQ,zMe

[1280] MeO A\

[1281] / HH — b-H

[1282] 489.2

[1283] 94,N~-n HN'MeN 1.42 0.004K1XxCN (A)

[1284] xH 1 J

[1285] H HOZzMe

[1286] MeH-H"H459.3

[1287] 95 N-n HN'MeV 1.34 0.001NJ< XKI / UCN (A)

[1288] / IlN

[1289] Me k k 1 J

[1290] N N

[1291]

[1292] HLCMS

[1293] [M+H]+ NIK HERE IC50 Exp.# Structure

[1294] RT min. (pM) (Method)

[1295] 446.0

[1296] 96 1.29 0.002 (A)

[1297] HO„zMe

[1298] — HH

[1299] Me / \ 446.1

[1300] 97 ^0 HN'MetA4> N 1.35 0.003 ZZ

[1301] N / D <x(A)

[1302] -AE

[1303] =„X /

[1304] / \ SCN

[1305] ifl z z—

[1306] / T / I J

[1307] H HO Me

[1308] y T

[1309] z

[1310] 1

[1311] D C

[1312] MeH-H"H459.9

[1313] 98 >~O HN'MeV 1.41 0.001MX^CN(A)

[1314] / It llN

[1315] Me k A A J

[1316] N N H HO,zMe

[1317] HH — b-H

[1318] 480.9

[1319] 99 Q -0 HN'MeN 1.57 0.004 MA> / CN(A)

[1320] [fl

[1321] H HO,zMe

[1322] HH — b-H

[1323] 494.3

[1324] 100 / =\, Me 1 >

[1325] ^-~NH HN N 1.79 0.027 (A)

[1326] M^^CN

[1327] / ilNJT

[1328] Me f A A J

[1329] N N

[1330]

[1331] HLCMS

[1332] [M+H]+ NIK HERE IC50 Exp.# Structure

[1333] RT min. (pM) (Method)

[1334] HC\ Me

[1335] CD MeO \ /

[1336] \ Me HH — HH

[1337] 503.2

[1338] 101zN"n HN^ N 1.49 0.004 (A)

[1339] j; ifl

[1340] HTHC\ Me

[1341] z z y—

[1342] / ) k=

[1343] MeO 'D C \ /

[1344] \ HH v*H515.0

[1345] 102zN"n NH ^14 1.49 0.006klX^CN (A)

[1346] To

[1347] ifl I j z

[1348] H HOZ, Me

[1349] 497.0

[1350] 103 f P-N HN'MeN 2.12 0.003 MA^CN (F)

[1351] Me7 N|* |] ’ll jT

[1352] H HOZ / Me

[1353] HH — HH

[1354] 513.0

[1355] 1041^X / °''NHN'MeN 1.30 0.006 (E)

[1356] N-, / ^ N^VCN

[1357] Me

[1358] H

[1359] 530.0

[1360] 105 1.60 0.001

[1361] (F)

[1362]

[1363] LCMS

[1364] [M+H]+ NIK HERE IC50 Exp.# Structure

[1365] RT min. (pM) (Method)

[1366] HOZzMe

[1367] HH — hH

[1368] 517.0

[1369] 106 1 - ^ O'N HN'MeN 1.10 0.001 NV L ICN(E)

[1370] I Ji J

[1371] H

[1372] H0ZzMe

[1373] HH — HH

[1374] 490.0

[1375] 107 P'N HN'MeN 0.94 0.001 (E)

[1376] Me-NNf || H

[1377] Me

[1378] H HO Me

[1379] H{-}H 516.3

[1380] 108 0.996 0.001 r-\ _ / °'N HN'Me

[1381] (E)

[1382] ""vM -SA Ar™

[1383] L II Ji J

[1384] H HO Me

[1385] H^ H

[1386] 530.3

[1387] 109 / ---x Me O~NHN'MeV 1.08 0.005 (E)H\_7A\A

[1388] L II JNi#V JCN

[1389] H HOZzMe

[1390] H{-}H 517.0

[1391] 110 O-N HN'MeV 1.29 0.001 (E)

[1392] L II J NiJV JCN

[1393]

[1394] HLCMS

[1395] [M+H]+ NIK HERE IC50 Exp.# Structure

[1396] RT min. (pM) (Method)

[1397] H06Me

[1398] HH — HH

[1399] 505.0

[1400] Ill P'N HN'MeN 1.46 0.004Mexkl / L XN (E)

[1401] r°Nc l 1 J

[1402] H

[1403] 491.0

[1404] 112 ZI 1.29 0.001 D / <x

[1405] / \ S=(F)

[1406] Z G Z—

[1407] / I /

[1408] HOZzMe

[1409] Y

[1410] #o5- 0 I) H^-H

[1411] 517.0

[1412] 113... P-N HN'MeV 1.35 0.001 (E)Mex< / '1A. A A ®

[1413] H0'N^L 1L jf jT

[1414] H HOZ / Me

[1415] HH — £-H

[1416] 602.3

[1417] 114 / -xxMe /

[1418] n / — \ P" N HN N 1.33 0.001 W y-4 A I iCN (E)

[1419] Me^ / \ - ' N |1 N

[1420] HO Me It

[1421] H HQ,, Me

[1422] HH — b-H

[1423] 516.0

[1424] 115 P'N HN'MeN 1.83 0.001 (F)

[1425] r"NW 1VN

[1426]

[1427] HLCMS

[1428] [M+H]+ NIK HERE IC50 Exp.# Structure

[1429] RT min. (pM) (Method)

[1430] HOZzMe

[1431] HH — HH

[1432] 525.0

[1433] 116,°'N HN'MeN 1.64 0.001 (F)

[1434] MeO2SNjp ||

[1435] H HO„zMe

[1436] HH — HH

[1437] 488.2

[1438] 117 P'N HN'MeN 0.942 0.001 (E) " V YsA ^ CN

[1439] L II Jj J

[1440] H HOZzMe

[1441] H^-H

[1442] 493.0

[1443] 118 MeKO-NHN'MeST 1.54 0.005 (E)

[1444] Me7 N|^ |1 ’ll jT

[1445] H HOZzMe

[1446] H{-}H 523.0

[1447] 119F / K P'N HN'MeV 1.43 0.006 (E)F>^_J¥I A "

[1448] H HO,zMe

[1449] HH — HH

[1450] 528.3

[1451] 120 1.03 0.001 / \ / \___ / °'N HN'Me N

[1452] HNQKZA^A (E)

[1453] rArCN

[1454] L II Ji J

[1455]

[1456] HLCMS

[1457] [M+H]+ NIK HERE IC50 Exp.# Structure

[1458] RT min. (pM) (Method)

[1459] H0„zMe

[1460] D C HH — HH

[1461] 551.0

[1462] JL® ro

[1463] 121 I - <,°'N HN'MeN 2.09 0.011 FV A-SA (F)

[1464] L 1 A NV J

[1465] u

[1466] FAT / H

[1467] zz / ,

[1468] k ) / = H0,_ Me

[1469] fD C

[1470] TZH I1VHz— HH

[1471] A <'z n—\. 541.0

[1472] 122 F3C^ O'N HN'MeN / / NS

[1473] ' \D - C 1.66 0.010 VNAA NVTICoN(E)

[1474] z

[1475] L U H HO Me

[1476] 491.0

[1477] 123 P'N HN'Me1.49 0.004

[1478] •VNA LA (E)

[1479] NVBII Ji J

[1480] H

[1481] 489.0

[1482] 124 1.62 0.003 (F)

[1483] H0Z / Me

[1484] HH — HH

[1485] 488.2

[1486] 125 / < / N" O HN'MeN 0.967 0.002 (E)HN> AVSl

[1487] L II J NiV JCN

[1488]

[1489] HLCMS

[1490] [M+H]+ NIK HERE IC50 Exp.# Structure

[1491] RT min. (pM) (Method)

[1492] HC\ Me

[1493] HH — b-H

[1494] 531.0

[1495] 126 1.79 0.001 / —x HN Me N

[1496] (F)

[1497] ME'N\___ / NNAA ACN

[1498] L 11 Ji J

[1499] H HOZ<Me

[1500] HH — hH

[1501] 517.0

[1502] 127 1 - \ N-0HN'MeN 1.33 0.017 (E) O AAA A L II Ji J

[1503] H HOZzMe

[1504] H^ H

[1505] 473.0

[1506] 128 N-o HN'MeA 1.43 0.006 (E)

[1507] A A A L II Ji J

[1508] N N —

[1509] H HO,zMe

[1510] HH — b-H

[1511] 477.0

[1512] 129 Me-0 N-oHN'Me1.75 0.001 (F)

[1513] NA LA II J NiA JCN

[1514] H HOZ / Me

[1515] H^ H

[1516] 516.3

[1517] 130 1.24 0.006 / --x A0 HN'MeA

[1518] (F)

[1519] HNX_A<NA LA II J NiA JCN

[1520]

[1521] HLCMS

[1522] [M+H]+ NIK HERE IC50 Exp.# Structure

[1523] RT min. (pM) (Method)

[1524] HO,, Me

[1525] H4 — b-H

[1526] 497.0

[1527] 131 1.45 0.027 E N"°HN'Me N

[1528] „, A, CN (E)

[1529] MeNp |j 'll

[1530] H

[1531] 523.0

[1532] 132 ZZxX A

[1533] / D < 1.52 0.006 / \ S=(E)

[1534] Z 4 Z—

[1535] / / I

[1536] H0,zMe

[1537] H^-H

[1538] X 447.0

[1539] 133 N-0 HN'MeV 1.20 0.003 (E)

[1540] MEL II J NiV J

[1541] H HO, Me

[1542] A „

[1543] 546.0

[1544] 134MAAN-0 HN-MeV 1.53 0.0650XUNAANJL. CN (E)

[1545] / L 1 I J

[1546] Me

[1547] H HO, Me

[1548] 524.0

[1549] 135 M 1.45 0.011 (E) x^x r T ii j "iV \

[1550]

[1551] HLCMS

[1552] [M+H]+ NIK HERE IC50 Exp.# Structure

[1553] RT min. (pM) (Method)

[1554] HOZzMe

[1555] H-4 — HH

[1556] 487.0

[1557] 136 HN'MeN 1.54 0.007 (E)

[1558] N^CN

[1559] L II Jj J

[1560] H HOZzMe

[1561] HH — HH

[1562] 509.0

[1563] 137 A--^ N--O HN'MeN 1.54 0.048 (E) C / V yA N-ACN

[1564] L I U N N'^^

[1565] H HOZzMe

[1566] H^-H

[1567] 501.0

[1568] 138 N-0 HN'MeV 2.15 0.007F~V ANACN (F)

[1569] L II Jj J

[1570] H HO,zMe

[1571] F Me 11 \ / 11

[1572] Me-\H"7 493.2

[1573] 139 \, Me <?

[1574] ^0 HN N 1.45 0.001 ACN (E)

[1575] L II Ji J

[1576] H HO,zMe

[1577] HH — b-H

[1578] 481.0

[1579] 140 / =\, Me < >

[1580] ^-~N HN N 1.87 0.005 (F)

[1581] s V i A

[1582]

[1583] HLCMS

[1584] [M+H]+ NIK HERE IC50 Exp.# Structure

[1585] RT min. (pM) (Method)

[1586] H0„zMe

[1587] HH — i-H

[1588] 462.0

[1589] 141, Me < J

[1590] Me^ / '-O HN N 1.98 0.010 (F)

[1591] Me N'Z^V'CN

[1592] L 1 1 J

[1593] N N'^-^

[1594] H HOZzMe

[1595] HH — b-H

[1596] 504.0

[1597] 142 / - X / '-O HN'MeN 1.71 0.001 (F) vM A N^vCN

[1598] L 1 Jj J

[1599] N N'^"^

[1600] H HOZzMe

[1601] H^-H

[1602] 502.0

[1603] 143 / "-o HN'MeN 1.95 0.007F3CNAANATCN (F)

[1604] L II Ji J

[1605] H HO„zMe

[1606] HH — b-H

[1607] 490.2

[1608] 144, Me < J

[1609] V-K N HN N 1.24 0.004 (E)

[1610] 0 |i N

[1611] L II Ji J

[1612] H HOZzMe

[1613] HH — HH

[1614] 503.2

[1615] 145 / - HN'MeN 1.24 0.001HNJNAA (F)

[1616] L II Ji J

[1617]

[1618] HLCMS

[1619] [M+H]+ NIK HERE IC50 Exp.# Structure

[1620] RT min. (pM) (Method)

[1621] HOZzMe

[1622] MMe H" H"H462.0

[1623] 146 HN'MeV 1.51 0.002 (E)

[1624] L II JNj^VJCN

[1625] H HOZzMe

[1626] HH — HH

[1627] 462.1

[1628] 147 N-n HN'Me1.51 0.001Me\ sJVX 7] M NX^CN(F)

[1629] L. 1 A J

[1630] H HO„ Me

[1631] 460.2

[1632] -4

[1633] 148, N=<MeHN-MeV 1.47 0.116 (F)

[1634] °Y*4U X ™

[1635] / iiNxr

[1636] Me L. JL JL 4

[1637] N N H HOZzMe

[1638] H4 — HH

[1639] 486.2

[1640] 149 z.,N^i Me ^14 1.60 0.003 °x / N\^\ (F)

[1641] JUL JL J H HO„zMe

[1642] H-4 — HH

[1643] 597.3

[1644] 150 _ / - <,N;=i Me \1 1.59 0.001 (F) UuU'UUxNUCN

[1645] x' L II Ji J

[1646] Me^N^N^^

[1647]

[1648] HLCMS

[1649] [M+H]+ NIK HERE IC50 Exp.# Structure

[1650] RT min. (pM) (Method)

[1651] H0,zMe

[1652] HH — b-H

[1653] 488.3

[1654] 151 Me IT 1.53 0.001 (F)

[1655] Me-\ T |1 7. T

[1656] OH A- A A A

[1657] Me^ N N ^^

[1658] H HO,zMe

[1659] HH — HH

[1660] 500.2

[1661] 152,NU Me ^14 1.68 0.001 (F) u A l ACN

[1662] JUL JL J

[1663] Me^N N"'’^^

[1664] H HO,zMe

[1665] 514.0

[1666] 153 1 —, A Me N 1.65 0.002 Ov / N\uA A. AN (F)

[1667] JUL Ju

[1668] Me^N N^^

[1669] H HO, Me

[1670] HH — b-H

[1671] 488.0

[1672] 154 JA Me 1.47 0.003

[1673] Me— < Y H M 7. AA^ (F)

[1674] T

[1675] bn A A A

[1676] Me^ N N

[1677] H HO,zMe

[1678] HH — £-H

[1679] 500.2

[1680] 155,N;=n Me ^ht 1.68 0.002 UN'A ACN(F)

[1681] JUL 1 J

[1682]

[1683] HLCMS

[1684] [M+H]+ NIK HERE IC50 Exp.# Structure

[1685] RT min. (pM) (Method)

[1686] HQ,z / ^CN

[1687] H-4 — HH

[1688] 495.2

[1689] 156 Me 1.69 0.002 zxMA / CN(F)

[1690] / z

[1691] JI J S V yQ < n

[1692] Me'^D — N N'"^^

[1693] H

[1694] C^- z— HO„zMe

[1695] / \ CD

[1696] HH — HH

[1697] 513.3

[1698] 157 / — <,N^i Me 1.31 0.003 HN / N\^\ AA4 / k / CN (F)

[1699] To

[1700] z

[1701] jfl JL J

[1702] Me^N N''^'^

[1703] H HOZzMe

[1704] H^-H

[1705] 502.3

[1706] 158,N=^ Me N 1.63 0.003

[1707] Me-A T |l N iX^CN(F)

[1708] i T

[1709] HO Me A A

[1710] Me^ N N ^^

[1711] H

[1712] 526.3

[1713] 159 1.70 0.006 (F)

[1714] HO,zMe

[1715] H^-H

[1716] 472.0

[1717] 160 Me,N;:=n Me N 1.80 0.003 kNA. A,NAC(E)

[1718] Me || N -yN

[1719] Me^N^N^^^

[1720]

[1721] HLCMS

[1722] [M+H]+ NIK HERE IC50 Exp.# Structure

[1723] RT min. (pM) (Method)

[1724] H0ZzMe

[1725] HH — HH

[1726] 470.0

[1727] 161zN=n Me IT 1.77 0.002 E'lJx,NX. CN (E)

[1728] I l

[1729] H

[1730] H0„zMe

[1731] HH — HH

[1732] 499.3

[1733] 162 Me ^14 0.948 0.002 Me-N yN\A 1klX / CN (E)

[1734] I I 1 J

[1735] Me^N N'"^^

[1736] H

[1737] H0„zMe

[1738] H4 — HH

[1739] 444.0

[1740] 163,N=n Me IE 1.58 0.002Me'N\^\ A. / CN (E)

[1741] jii n

[1742] Me^^N N^^

[1743] H

[1744] H0,zMe

[1745] H4 — r-H

[1746] 560.3

[1747] 164 % — \ N'O HN'MeN 1.56 0.028 (E) V " IIi

[1748] / 1. II J NjAJ<CN

[1749] MeMe^N N"^^

[1750] H HO„zMe

[1751] H4 — HH

[1752] 530.3

[1753] 165 / — ^ / ^'O HN'MeN 1.00 0.009HO \AANJV (E)

[1754] L II Ji JCN

[1755] Me^N N''^'^

[1756]

[1757] HLCMS

[1758] [M+H]+ NIK HERE IC50 Exp.# Structure

[1759] RT min. (pM) (Method)

[1760] HQ,, Me

[1761] HH — HH

[1762] 537.2

[1763] 166 1.57 0.044 F / K / A0 HN'Me N

[1764] (E)

[1765] H HO,, Me

[1766] HH — HH

[1767] 487.0

[1768] 167 N-o HN'MeN 2.08

[1769] (F) H AANV

[1770] X 1 A J

[1771] H HO Me

[1772] H^-H

[1773] 502.3

[1774] 168. N-0 HN'MeV 1.01 0.002HN(E)

[1775] V V\ LA II J NiV J

[1776] Me^N N^^

[1777] H HO,, Me

[1778] HH — HH

[1779] 571.3

[1780] 169 / - \ / ~'O HN'MeN 1.06 0.002 (AW NAA (E)

[1781] NAjN

[1782] L ii jj j

[1783] H HO, Me

[1784] 4A 531.3

[1785] 170 r-xro HN'MeV 1.05 0.002Me'\_A\AJx NA^CN (E)

[1786] A A A J

[1787] Me'^N^NX^'X

[1788]

[1789] HLCMS

[1790] [M+H]+ NIK HERE IC50 Exp.# Structure

[1791] RT min. (pM) (Method)

[1792] H0ZzMe

[1793] H4 — i-H

[1794] 559.3

[1795] 171, Me \ / 1.09 0.003 Me / —HN N

[1796] y-N (E)

[1797] / x 1 N VA N

[1798] Me 1 II

[1799] Me^N'^N''''^^

[1800] H

[1801] H0ZzMe

[1802] HH — HH

[1803] 476.0

[1804] 172zMe < >

[1805] Me^A~O HN' N 1.78 0.006MENAA (F)

[1806] N^VCN

[1807] L II jl J

[1808] Me^N N''''^'^

[1809] H

[1810] H0ZzMe

[1811] Me H-W-H 476.2

[1812] 173MA0HN'MeV 1.89 0.004 (F)

[1813] > AA

[1814] L II J NjAJCN

[1815] Me^N N —

[1816] H

[1817] H0„zMe

[1818] H-4 — b-H

[1819] 603.4

[1820] 174 _, Me O

[1821] 0 / — X A'O HN N 1.39 0.001 (E)u>\JSA. A

[1822] Me-7\ 1 ||N||A ICN

[1823] H0 MeMe^N^N^^

[1824] H

[1825] H0zMe

[1826] H{-}H 478.2

[1827] 175A0 HN-MeV 1.26 0.002 (E)

[1828] h° 'NA lY

[1829]

[1830] HLCMS

[1831] [M+H]+ NIK HERE ICso Exp.# Structure

[1832] RT min. (pM) (Method)

[1833] H0ZyMe

[1834] H4 — i-H

[1835] 492.2

[1836] 176Me< / ~~0 HN'MeN 1.48 0.001 (F)

[1837] Ho "NAA

[1838]

[1839] H

Claims

1. WE CLAIM:

1. A compound having the structure of formula (I):Formula (I)or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof; wherein A is selected from:each R1and R2is independently selected from hydrogen, halo, hydroxy, -NRaRb, - ORa, -SRb, Ci-6 alkyl, C2-6 alkenyl and C2-6 alkynyl; wherein each C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted with one to four R100;each R3and R4is independently selected from hydrogen, halo, hydroxy, amino, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C(O)Ra, -C(O)ORb, -C(O)NRaRband -N(Ra)C(O)Rb; wherein each C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted with one to four R100;R5is selected from hydrogen, halo, cyano, hydroxy, amino and C1-6 alkyl;R6is independently selected from hydrogen, halo, hydroxy, -NRaRband -C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one to four R100;R7is selected from hydrogen, halo, cyano, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -C(O)N(Ra)C(O)Rb, -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, C2-6 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;R8is selected from hydrogen, halo, cyano, hydroxy, amino, -C(O)Ra, -C(O)ORb, -C(O)NRaRb, -C(O)N(Ra)C(O)Rb, -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, C2-6 alkynyl, C3-8 cycloalkyl 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 and 4-10 membered heterocyclyl is optionally substituted with one to four R100; each Raand Rbis 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; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, Ce-io aryl, 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 is optionally substituted with one to four R200; alternatively, Raand Rbtogether with the atoms to which they are attached forms a C3-8 cycloalkyl, Ce-ioaryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl 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(0)NRcRd, -N(Rc)C(0)Rd, -S(O)NRcRd, -S(O)2NRcRd, -S(O)Rh, -S(O)2Rh, -NRcRd, -ORC, -SRC, 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 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; 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 R202;each R200, R201and R202is 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, -S(O)Ri, -S(O)2Ri, -NReRf, -ORe, -SRe, 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 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;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, -S(O)2Re, -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 according to claim 1, wherein R1is -OH.

3. A compound according to any of claims 1-2, wherein R2is -CH3.

4. A compound according to any of claims 1-3, wherein R3is -H and R4is -H.

5. A compound according to any of claims 1-4, wherein R6is -N(H)(CH3).

6. A compound according to any of claims 1-5, wherein R8is selected from hydrogen and -CH3.

7. A compound selected from table below, or a pharmaceutically acceptable salt, stereoisomer, or a mixture thereof:Example No. StructureNH2O=S=O 0 NH N46^X 1,^ 'H. OH1 C O O=S=O 0 NH N56^X 1,^ 'H OH HH — HH 6 O=S=O O ^NHH HO„zMeHH — HH7AHN'MeNH HOZ / Me H4 — HH 8HHN'MeNMe HExample No. StructureHQ QF324 O=s=o 0 NH NHo*,p25 O=S=O 0 NH NH HO / —Q> AxHH —26 HH O=S=O 0 ^NH W (X XKZXH SH-4 — r“H 27 O=S=O 0XNH NH HQ HH — HH 28O=S=O 0 ^NH NHExample No. Structure^OHH—y29 O=S=O 0 '"'NH WH OH1.30 O=S=O 0 NH N6^ ^H OH31 O=S=O 0 ^NHH OHi. b32 O=S=O 0 NH NH OHi. s33 O=S=O 0 NH Ndrs'Xi.ir’HExample No. StructureOH34 O=S=O 0 ^NHH OH35 O=S=O 0 ^NHH / -OH O=S=O 0 ^NH N36H VOH1. o O=S=O 0 NH N37H0 / — NH238 O=S=O 0 ^NH NHExample No. Structure0 HN39 i. 8O=S=O 0 NH N H NH2 / i. b 40 O=s=o 0 NH N y wH0 HN41 i. d O=S=O 0 NH N H OHO=S=O 0 ^NH ^N^ 42HH2N" / 1. o O=S=O 0 NH N 43HExample No. StructureH2N— Ii. b O=S=O 0 NH N44(Y YK HY" i. b°HO=S=O 0 NH N45tY Y. Y ’ H NH2I. <b46 O=S=O 0 NH NH OH1. A O=S=O 0 NH N47(Y YK HY '^CY*OHO=S=O 0XNH ^N^ 48(Y Y, Y *H OHbbl O=s=o 0 ^NH ^N^49Y SYK H-YExample No. StructurevxOH O=S=O 0 ^NH50H OH51,u 6H OH52 O=S=O 0 '''NHHi r 9 O=S=O 0 NH N53H OH1 o54 O=S=O 0 NH NH OH HO55!HftHO=S=O 0 NH NCr«\ iNir*HExample No. StructureHOZzMe61 0 HN'MeNH HO„zMeHH — HH 62 0 HN'MeNYrH HO„zMeH-4 — HH 63 0 HN'MeNMeNNnHOZMeHH — HH 64 0 HN'MeNF N N H HO,zMe65HoTa'JlxJiNji'c" Me N NnExample No. StructureHOZzMe66 0 HN'MeNHO H HOZzr~ CN HH — b-H67 0 HN'MeN ACNH HOZzMe68 0 HN* VMeO xrV lH HOZzMeHH — HH 69 0 HN'MeN pAAMe^Aj 1 1 1 N^ JYCNHOH NMe HHOZMeH-H — HH 70 0 HN'MeNMHO6> T^NAA N'V™ 7. H IIHExample No. StructureHOZMe71 0 HN'MeNovY-JiH HOZ / Me H{-}H 72 0 HN-MeV’-oY iH HOZzMeHH — HH 73 0 HN'MeNX? V 1 Xir“ H HOZzMe74 O HN-MeVH°< JNY I A ™ H HO„zMe— b-H 75 0 HN'MeN*>< M ACNHExample No. StructureHO,zMe76 0 HN'MeNMe N AVCNH HOZ / Me77 0 HN'Etc> Y i xY" H HOZzMe78 O HNZAHT NTcY l lY " H HO,_ MeX A79 0 NH NY A xY"H HQ, MeFA H4 <5— U 80 O NH“ M-Pe YNA NY3”rlExample No. StructureHO„zMeCN H4 — b-H81 A HN'MeVW "FArA^H HO Me82 Aj HN'MeVFAXX X ™L II Ji JN N^^^H HOZzMe H{-}H 83 AA HN'MeVMAA LA II J Ai JCNN N^^^H HOZzMeHH — HHzMe N J84 A N HN N / U Jk X AN Me^ N 1A n NL II JI J N N^^H HO„zMeHH — £-H 85 AAHN'MeVHO. / X J\ X. X / CN i r nNAr F C JL Jk< AN NHExample No. StructureHO Me106 / -\ P-N HN'MeSr V SA L,II JNiA J-CNH HOZ / Me HH — HH 107,°'N HN'MeNMe-NNT |1Me AN N H HO,zMe H4 — hH 108 1 — \ _ / 0'N HN'MeNHV YSA NV L II Ji J1H HO,zMe H{-}H 109 HN'MeL II J NiJV JCNH HOZzMe H{-}H 110 ^ O-NHN'MeVN^CN L ll Jj JH8. A pharmaceutical composition comprising one or more compounds according to any of the above claims and a pharmaceutically acceptable carrier or diluent.

9. A pharmaceutical composition comprising one or more compounds according to claim 8 and a pharmaceutically acceptable carrier or diluent.

10. 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 claims 1-9, wherein the disease is an autoimmune disease.

11. The method of claim 10 wherein the autoimmune disease is rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn’s Disease, Sjogren’s syndrome or scleroderma.

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