(e)-2-(benzylamino)-n-(3-(methylsulfonyl)allyl)-benzamide derivatives and similar compounds as JAK1 inhibitors for the treatment of inflammatory diseases, autoimmune diseases or cancer

Abstract

The present invention relates to compounds of formula (I) as Janus kinase 1 (JAK1) inhibitors for the treatment of an inflammatory disease, an autoimmune disease or cancer, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis (RA), Crohn's disease, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), diabetic nephropathy, dry eye syndrome, Sjogren's Syndrome, alopecia areata, vitiligo and atopic dermatitis

Description

Dkt. Nos.184200.00053(VVID-744PC) JAK1 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application serial no. 63 / 579,527 filed August 30, 2023, the contents of which is incorporated by reference in its entirety. FIELD OF THE DISCLOSURE

[0002] The disclosure relates to compounds that inhibit JAK1 and to uses thereof.   BACKGROUND OF THE DISCLOSURE

[0003] Protein kinases are enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified into tyrosine and serine / threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dysregulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been implicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders.

[0004] The JAK (Janus-associated kinase) family includes four non-receptor tyrosine kinases, JAK1, JAK2, JAK3 and Tyk2, which play a critical role in cytokine signaling and growth factor mediated signal transduction. Upon binding to their receptors, cytokines activate JAK, which then phosphorylates the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the Signal Transducer and Activator of Transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family.

[0005] JAK1 kinase interacts with, among others, type I interferon receptors (e.g., IFN alpha), type II interferon receptors (e.g., IFN gamma), the common gamma chain yc (e.g., IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), and the interleukin-6 family (IL-10, IL- 13 and IL-22). After these cytokines bind to their receptors, receptor oligomerization occurs, resulting in the cytoplasmic tails of associated JAK kinases moving into proximity and facilitating the trans-phosphorylation and activation of tyrosine residues on the JAK kinase. Phosphorylated JAK kinases bind and activate various STAT proteins. These STAT proteins then dimerize and translocate to the nucleus where they function as both signaling molecules and transcription factors and ultimately bind to specific DNA sequences present in the promoters of cytokine- 1 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) responsive genes. Various immunodeficiency and autoimmune diseases, such as allergies, asthma, alopecia areata, transplant (allograft) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid and hematologic cancers result from signaling disruption in the JAK / STAT pathway.

[0006] A notable aspect of JAK1 is its ability to pair with other JAK kinases at the intracellular domains of different subunits of the receptor. It has been indicated that selective inhibition of JAK1 may be sufficient to treat a number of inflammatory and autoimmune diseases associated with cytokine signaling via the JAK-STAT pathway.

[0007] There exists a need for inhibitors of the JAK-STAT signaling pathway and for treatment of JAK1- related disorders, including allergic, inflammatory, and autoimmune disorders. SUMMARY

[0008] Disclosed herein, in some aspects, are inhibitors of the tyrosine kinase JAK1 and uses of those inhibitors in the treatment of medical disorders.

[0009] The present disclosure further provides for compounds having the general formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: wherein:G1is phenyl, a 5 to 6-membered heteroaryl ring comprising one, two or three heteroatoms independently selected from N, O and S, or a 9 to 10-membered fused heterocycle comprising a 6- membered aromatic or heteroaromatic ring and one, two or three heteroatoms independently selected from N, O and S; each R1is independently -OH, halogen, C1-6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, OC1C6haloalkyl, OC1C3deuteroalkyl, or -NR6R7; x is 0, 1, 2, or 3; G2is a six-membered aromatic ring comprising 0, 1 or 2 nitrogen atoms; each R2is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with halogen, C1-C3alkyl or C1-C3haloalkyl, -O-C1-6alkyl or OC1C6haloalkyl; 2 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) y is 0, 1, or 2; Z is -CH2- or -CD2-; R3is -H, -D, C1-C6alkyl, C1-C6alkyl substituted with -O-C1-C6alkyl, or C3-C6cycloalkyl; each of R4, R5and R6is independently -H or C1-C6alkyl; R7is -H, C1-C6alkyl or -C(O)R8; and R8is C1-C6alkyl.

[0010] In some embodiments, G1is phenyl, pyridyl or pyrimidinyl.

[0011] In some embodiments, G1is benzodioxolo, benzothiazolo, pyrazolopyridinyl, benzooxazolo, dihydrobenzofuranyl or dihydrobenzodioxinyl.

[0012] In some embodiments, G2is phenyl, pyridyl, pyrazinyl,or pyrimidinyl.

[0013] In some embodiments, each R1is independently halogen, C1-C6alkyl, C1-C6haloalkyl, -O-C1-6alkyl, or OC1C6haloalkyl.

[0014] The compound of claim 1, wherein x is 0, 1 or 2.

[0015] In some embodiments, each R2is independently halogen, C1-C6alkyl, C1-C6haloalkyl, -O-C1-6alkyl, OC1C6haloalkyl.

[0016] In some embodiments, y is 0, 1 or 2.

[0017] In some embodiments, Z is -CH2-.

[0018] In some embodiments, R2is selected from the group consisting of -CF3, -CH2CF3, -OCF3, or - OCHF2.

[0019] In some embodiments, R1is F.

[0020] In some embodiments, R3is -H, C1-C6alkyl or C3-C6cycloalkyl.

[0021] In some embodiments, R3is -H, methyl or cyclopropyl.

[0022] In some embodiments, R4is C1-C6alkyl.

[0023] In some embodiments, R4is methyl.

[0024] In some embodiments, R5is -H or methyl.

[0025] In some embodiments, R5is -H.

[0026] In some embodiments, R6is -H.

[0027] In some embodiments, R7is -H or -C(O)R8. 3 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0028] In some embodiments, R8is methyl or ethyl.

[0029] The present disclosure further provides for compounds having the general formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   1where R , R2, R3, R4,

[0030] The present disclosure further provides for compounds having the general formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: (R1)xwhere R1, R2, R3, R4, R5, x, and y are as defined above.

[0031] The present disclosure further provides for compounds having the general formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 4 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (R1)x where R1, R2, R3, R4, R5, x, and y are as defined above.

[0032] The present disclosure further provides for compounds having the general formula (V) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: (R1)x where R1, R2, R3, R4, R5, x, and y are as defined above.

[0033] The present disclosure further provides for compounds having the general formula (VI) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   1 R2, R3where R , , R4, x, y are as 5 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0034] The present disclosure further provides for compounds having the general formula (VII) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   where R1, R2, R3, R4, R5, x,

[0035] The present disclosure further provides for compounds having the general formula (VIII) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   where R1, R2, R3, R4, R5,

[0036] The present disclosure further provides for compounds having the general formula (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   where R1, R2, R3, R4, R5, x,

[0037] In some aspects, the present disclosure provides a method of inhibiting Janus kinase 1 (JAK1) in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective 6 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) amount of at least one compound as described above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0038] In some aspects, the present disclosure provides a method of treating an inflammatory disease, an autoimmune disease, or cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of at least one compound as described above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0039] In some embodiments, the present disclosure provides for use of the compounds of the present disclosure for the manufacture of a medicament useful for the treatment of an inflammatory disease, an auto-immune disease, or cancer.

[0040] In some embodiments, the present disclosure provides for the use of the compounds of the present disclosure in a medicament for the treatment of an inflammatory disease, an auto-immune disease, or cancer.

[0041] In some embodiments, the present disclosure provides use of the compounds of the present disclosure to treat an inflammatory or autoimmune disease.

[0042] In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of Rheumatoid Arthritis (RA), Crohn’s disease, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), diabetic nephropathy, dry eye syndrome, Sjogren’s Syndrome, alopecia areata, vitiligo, and atopic dermatitis.

[0043] In some embodiments, the cancer is a lymphoma, leukemia or myeloma. DETAILED DESCRIPTION

[0044] Protein kinases are a broad and diverse class, of over 500 enzymes, that include oncogenes, growth factors receptors, signal transduction intermediates, apoptosis related kinases and cyclin dependent kinases. They are responsible for the transfer of a phosphate group to specific tyrosine, serine or threonine amino acid residues, and are broadly classified as tyrosine and serine / threonine kinases as a result of their substrate specificity.

[0045] The Janus family kinases (JAK1, JAK2, JAK3 and TYK2) are cytoplasmic tyrosine kinases that associate with membrane bound cytokine receptors. Cytokine binding to their receptor initiates Janus kinase activation via trans and autophosphorylation processes. The activated JAK phosphorylates residues on the cytokine receptors creating phosphotyrosine binding sites for SH2 domain containing proteins such as Signal Transduction Activators of Transcript (STAT) factors and other signal regulators transduction such 7 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) as suppressor of cytokine signaling (SOCS) proteins and SH2 domain-containing inositol 5'-phosphatases (SHIP). Activation of STAT factors via this process leads to their dimerization, nuclear translocation and new mRNA transcription resulting in expression of immunocyte proliferation and survival factors as well as additional cytokines, chemokines and molecules that facilitate cellular trafficking (see Journal of Immunology, 2007, 178, p. 2623). Jak kinases transduce signals for many different cytokine families and hence potentially play roles in diseases with widely different pathologies including but not limited to the following examples. Both JAK1 and JAK3 control signaling of the so-called common gamma chain cytokines (IL2, IL4, IL7, IL9, IL15 and IL21), hence simultaneous inhibition of either JAK1 or JAK3 could be predicted to impact Th1 mediated diseases such as rheumatoid arthritis via blockade of IL2, IL7 and IL15 signaling. On the other hand, IL2 signaling has recently been shown to be essential for development and homeostasis of T-regulatory cells (Malek T R et al., Immunity, 2002, 17(2), p.167-78). Thus, based on genetic data, blockade of IL2 signaling alone is predicted to result in autoimmunity (Yamanouchi J et al., Nat Genet., 2007, 39(3), p. 329-37, and Willerford D M et al., Immunity, 1995, 3(4), p. 521-30). Th2 mediated diseases such as asthma or atopic dermatitis via IL4 and IL9 signaling blockade. JAK1 and TYK2 mediate signaling of IL13 (see Int. Immunity, 2000, 12, p. 1499). Hence, blockade of these may also be predicted to have a therapeutic effect in asthma. These two kinases are also thought to mediate Type I interferon signaling; their blockade could therefore be predicted to reduce the severity of systemic lupus erythematosus (SLE). TYK2 and JAK2 mediate signaling of IL12 and IL23. In fact, blockade of these cytokines using monoclonal antibodies has been effective in treating psoriasis.

[0046] Allosteric kinase inhibitors (type III and type IV, Pharmacol Res., 2016, 103, p.26) offer many potential advantages over ATP competitive kinase inhibitors (Angew Chem Int Ed Engl, 2020, 59(33), p. 13764). Conservation of protein sequences surrounding the kinase active site can lead to selectivity challenges and poor cellular efficacy due to competition with endogenous ATP. In some embodiments the present disclosure provides methods of inhibiting JAK1 with one or more non-synonymous single- nucleotide polymorphisms [nsSNPs, ~0.9% human JAK1, Pharmacol Res., 2016, 103, p.26] comprising administering a compound of the present disclosure.

[0047] Several pathologically significant cytokines signal via JAK1 alone (Guschin D, et al., EMBO J. 1995 Apr.3; 14(7):1421-9; Parganas E, et al., Cell.1998 May 1; 93(3):385-95; Rodig S.J., et al., Cell.1998 May 1; 93(3):373-83). Blockade of one of these, IL6, using an IL6R neutralizing antibody, has been shown to significantly improve disease scores in human rheumatoid arthritis patients (Nishimoto N. et al., Ann Rheum Dis., 2007, 66(9), p. 1162-7). Similarly, blockaded of GCSF signaling, which is also mediated by Jak1 alone, using neutralizing monoclonal antibodies or target gene deletion protects mice from experimental arthritis (Lawlor K.E. et al., Proc Natl Acad Sci U.S.A., 2004, 101(31), p. 11398-403). 8 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Accordingly, the identification of small-molecule compounds that inhibit, regulate and / or modulate the signal transduction of kinases, such as JAK1, is a desirable means to prevent or treat autoimmune diseases or other diseases related to aberrant JAK1 function.

[0048] JAK2 is also activated in a wide variety of human cancers such as prostate, colon, ovarian and breast cancers, melanoma, leukemia and other haematopoietic malignancies. In addition, somatic point mutation of the JAK2 gene has been identified to be highly associated with classic myeloproliferative disorders (MPD) and infrequently in other myeloid disorders. Constitutive activation of JAK2 activity is also caused by chromosomal translocation in haematopoeitic malignancies. It has also been shown that inhibition of the JAK / STAT pathway, and in particular inhibition of JAK2 activity, results in anti- proliferative and pro-apoptotic effects largely due to inhibition of phosphorylation of STAT. Furthermore, pharmacological modulation or inhibition of JAK2 activity could effectively block tumor growth and induce apoptosis by reducing the STAT phosphorylation in cell culture and human tumor xenografts in vivo. Accordingly, the identification of small-molecule compounds that inhibit, regulate and / or modulate the signal transduction of kinases, particularly JAK2, is desirable as a means to treat or prevent diseases and conditions associated with cancers.

[0049] Jak kinases also transmit signals regulating essential physiological processes whose inhibition could be undesirable. For example, JAK2 mediates the signaling of Erythropoetin (Epo) and Granulocyte / Monocyte-Colony Stimulating Factor (GM-CSF). Individuals with genetic, congenital or acquired defects in these signaling pathways can develop potentially life-threatening complications such as anemia and neutrophil dysfunction. Accordingly, one non-limiting aspect of this disclosure also relates to a method to identify compounds that may have a favorable safety profile as a result of them selectively avoiding inhibition of JAK2.

[0050] The protein kinase C family is a group of serine / threonine kinases that comprises twelve related isoenzymes. Its members are encoded by different genes and are sub-classified according to their requirements for activation. The classical enzymes (cPKC) require diacylglycerol (DAG), phosphatidylserine (PS) and calcium for activation. The novel PKC’s (nPKC) require DAG and PS but are calcium independent. The atypical PKC’s (aPKC) do not require calcium or DAG.

[0051] PKCtheta is a member of the nPKC sub-family (Baier, G., et al., J. Biol. Chem., 1993, 268, 4997). It has a restricted expression pattern, found predominantly in T cells and skeletal muscle (Mischak, H. et al., FEBS Lett., 1993, 326, p. 51), with some expression reported in mast cells (Liu, Y. et al., J. Leukoc. Biol., 2001, 69, p.831) and endothelial cells (Mattila, P. et al., Life Sci., 1994, 55, p.1253). 9 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0052] Upon T cell activation, a supramolecular activation complex (SMAC) forms at the site of contact between the T cell and the antigen presenting cell (APC). PKCtheta is the only PKC isoform found to localize at the SMAC (Monks, C. et al., Nature, 1997, 385, 83), placing it in proximity with other signaling enzymes that mediate T cell activation processes.

[0053] In another study (Baier-Bitterlich, G. et al., Mol. Cell. Biol., 1996, 16, 842) the role of PKCtheta in the activation of AP-1, a transcription factor important in the activation of the IL-2 gene, was confirmed. In unstimulated T cells, constitutively active PKCtheta stimulated AP-1 activity while in cells with dominant negative PKCtheta, AP-1 activity was not induced upon activation by PMA.

[0054] Other studies showed that PKCtheta, via activation of icB kinase beta, mediates activation of NF- icB induced by T cell receptor / CD28 co-stimulation (N. Coudronniere et al., Proc. Nat. Acad. Sci. U.S.A., 2000, 97, p.3394; and Lin, X. et al., Mol. Cell. Biol., 2000, 20, p.2933).

[0055] Proliferation of peripheral T cells from PKCtheta knockout mice, in response to T cell receptor (TCR) / CD28 stimulation was greatly diminished compared to T cells from wild type mice. In addition, the amount of IL-2 released from the T cells was also greatly reduced (Sun, Z. et al., Nature, 2000, 404, p.402). It has also been shown that PKCtheta-deficient mice show impaired pulmonary inflammation and airway hyperresponsiveness (AHR) in a Th2-dependent murine asthma model, with no defects in viral clearance and Th1-dependent cytotoxic T cell function (Berg-Brown, N. N. et al., J. Exp. Med., 2004, 199, p. 743; Marsland, B. J. et al., J. Exp. Med., 2004, 200, p. 181). The impaired Th2 cell response results in reduced levels of IL-4 and immunoglobulin E (IgE), contributing to the AHR and inflammatory pathophysiology. Otherwise, the PKCtheta knockout mice seemed normal and fertile.

[0056] Evidence exists that PKCtheta participates in the IgE receptor (FceRI)-mediated response of mast cells (Liu, Y. et al., J. Leukoc. Biol., 2001, 69, p.831). In human-cultured mast cells (HCMC), it has been demonstrated that PKC kinase activity rapidly localizes to the membrane following FceRI cross-linking (Kimata, M. et al., Biochem. Biophys. Res. Commun., 1999, 257(3), p.895). A recent study examining in vitro activity of bone marrow mast cells (BMMC) derived from wild-type and PKCtheta-deficient mice shows that upon FceRI cross linking, BMMCs from PKCtheta-deficient mice reduced levels of IL-6, tumor necrosis factor-alpha (TNF alpha) and IL-13 in comparison with BMMCs from wild-type mice, suggesting a potential role for PKCtheta in mast cell cytokine production in addition to T cell activation (Ciarletta, A. B. et al., poster presentation at the 2005 American Thoracic Society International Conference).

[0057] Many of the kinases, whether a receptor or non-receptor tyrosine kinase or a S / T kinase have been found to be involved in cellular signaling pathways involved in numerous pathogenic conditions, including immunomodulation, inflammation, or proliferative disorders such as cancer. 10 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0058] Many autoimmune diseases and disease associated with chronic inflammation, as well as acute responses, have been linked to excessive or unregulated production or activity of one or more cytokines.   Compounds of the Disclosure

[0059] In some aspects, the present disclosure provides compounds having the general formula shown below as Formula (I), in addition to pharmaceutically acceptable salts, solvates, and stereoisomers thereof.   wherein:G1is phenyl, a 5 to 6-membered heteroaryl ring comprising one, two or three heteroatoms independently selected from N, O and S, or a 9 to 10-membered fused heterocycle comprising a 6- membered aromatic or heteroaromatic ring and one, two or three heteroatoms independently selected from N, O and S; each R1is independently -OH, halogen, C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, O-C1-C3deuteroalkyl, or -NR6R7; x is 0, 1, 2, or 3; G2is a six-membered aromatic ring comprising 0, 1 or 2 nitrogen atoms; each R2is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with halogen, C1-C3alkyl or C1-C3haloalkyl, -O-C1-C6alkyl or -O-C1-C6haloalkyl; y is 0, 1, or 2; Z is -CH2- or -CD2-; R3is -H, -D, C1-C6alkyl, C1-C6alkyl substituted with -O-C1-C6alkyl, or C3-C6cycloalkyl; 11 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) each of R4, R5and R6is independently -H or C1-C6alkyl; R7is -H, C1-C6alkyl or -C(O)R8; and R8is C1-C6alkyl.

[0060] In some embodiments, G1is phenyl, pyridyl or pyrimidinyl.

[0061] In some embodiments, G1 is benzodioxolo, benzothiazolo, pyrazolopyridine, benzooxazolo, dihydrobenzofuran or dihydrobenzodioxine.

[0062] In some embodiments, G2 is phenyl, pyridyl or pyrimidinyl.

[0063] In some embodiments, each R1is independently halogen, C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, or -O-C1-C6haloalkyl.

[0064] The compound of claim 1, wherein x is 0, 1 or 2.

[0065] In some embodiments, each R2is independently halogen, C1-C6alkyl, C1-C6haloalkyl, -O-C1-6alkyl, -O-C1-C6 haloalkyl.

[0066] In some embodiments, y is 0, 1 or 2.

[0067] In some embodiments, Z is -CH2-.

[0068] In some embodiments, R2is selected from the group consisting of -CF3, -CH2CF3, -OCF3, or -OCHF2.

[0069] In some embodiments, R1is F.

[0070] In some embodiments, R3is -H, C1-C6alkyl or C3-C6cycloalkyl.

[0071] In some embodiments, R3is -H, methyl or cyclopropyl.

[0072] In some embodiments, R4is C1-C6alkyl.

[0073] In some embodiments, R4is methyl.

[0074] In some embodiments, R5is -H or methyl.

[0075] In some embodiments, R5is -H.

[0076] In some embodiments, R6is -H.

[0077] In some embodiments, R7is -H or -C(O)R8.

[0078] In some embodiments, R8is methyl or ethyl. 12 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0079] In some embodiments, the compound of Formula (I) has the structure of Formula (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: (R1)x wherein: each R1is independently -OH, halogen, C1-C3alkyl, or -O-C1-C3alkyl; x is 0, 1, or 2; each R2is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl optionally substituted with C1-C3alkyl; y is 1 or 2; R3is -H, C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; and R5is -H or C1-C3alkyl.

[0080] In some embodiments, the compound of Formula (I) has the structure of Formula (III), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:   wherein:13 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) each R1is independently halogen, C1-C3alkyl, C1-C3haloalkyl, -O-C1-C3alkyl, -O-C1-C3haloalkyl or -NR6R7; x is 0, 1, 2, or 3; R2is C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl optionally substituted with C1-C3alkyl; y is 1; R3is -H, C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; R5is -H or C1-C3alkyl;  R6is -H or C1-C3alkyl;  R7is C1-C3alkyl or -C(O)R8; and  R8is C1-C3alkyl.

[0081] In some embodiments, the compound of Formula (I) has the structure of Formula (IV), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: (R1)x  wherein:each R1is independently halogen, -O-C1-C3alkyl, -O-C1-C3haloalkyl, or -O-C1-C3deuteroalkyl; x is 0, 1, 2 or 3; each R2is independently halogen, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl optionally substituted with halogen, C1-C3alkyl or C1-C3haloalkyl; y is 1 or 2; R3is -H, C1-C3alkyl, C1-C3alkyl substituted with -O-C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; and 14 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) R5is -H or C1-C3alkyl.

[0082] In some embodiments, the compound of Formula (I) has the structure of Formula (V), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:   wherein: each R1is independently halogen or C1-C3alkyl; x is 0, 1, or 2; R2is C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl optionally substituted with halogen, C1-C3alkyl or C1-C3haloalkyl; y is 1; R3is -H, C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; and R5is -H.

[0083] In some embodiments, the compound of Formula (I) has the structure of Formula (VI), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:   wherein:R1is C1-C3alkyl, -O-C1-C3alkyl, -O-C1-C3deuteroalkyl, or -NR6R7; 15 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) x is 1; R2is C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl optionally substituted with halogen, C1-C3alkyl or C1-C3haloalkyl; y is 1; R3is -H, C1-C3alkyl, C1-C3alkyl substituted with -O-C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; R5is -H; and each of R6and R7is independently -H or C1-C3alkyl.

[0084] In some embodiments, the compound of Formula (I) has the structure of Formula (VII), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:    wherein:R1is -O-C1-C3alkyl or -O-C1-C3haloalkyl; x is 1; R2is C1-C3alkyl or C1-C3haloalkyl; y is 1; R3is C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; and R5is -H.

[0085] In some embodiments, the compound of Formula (I) has the structure of Formula (VIII), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: 16 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)   wherein:R1is C1-C3alkyl, -O-C1-C3alkyl, or -O-C1-C3deuteroalkyl; x is 1; R2is C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl; y is 1; R3is C1-C3alkyl or C3-C6cycloalkyl; R4is C1-C3alkyl; and R5is -H.

[0086] In some embodiments, the compound of Formula (I) has the structure of Formula (IX), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: wherein:X1is -O- or -CH2-; X2is -CH2- or -CH2CH2-; X3is -O-; -S- or -CH2-; or 17 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) X1, X2and X3, together with the phenyl ring to which they are attached form a bicyclic ring selected from the group of O O R2isy is 1; R3is C1-C3alkyl or C3-C6cycloalkyl; R4is C1-C3alkyl; and R5is -H.

[0087] In some aspects, the present disclosure provides a method of inhibiting Janus kinase 1 (JAK1) in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective amount of at least one compound as described above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0088] In some aspects, the present disclosure provides a method of treating an inflammatory disease, an autoimmune disease, or cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of at least one compound as described above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 18 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0089] In some embodiments, the inflammatory or autoimmune disease is selected from the group consisting of Rheumatoid Arthritis (RA), Crohn’s disease, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), diabetic nephropathy, dry eye syndrome, Sjogren’s Syndrome, alopecia areata, vitiligo, and atopic dermatitis.

[0090] In some embodiments, the cancer is a lymphoma, leukemia or myeloma. Pharmaceutical Formulations

[0091] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein (including corresponding to a compound of any one of Formulas (I) through (IX)) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.

[0092] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added.

[0093] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0094] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as 19 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0095] Pharmaceutically acceptable compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0096] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0097] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0098] Pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. 20 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0099] In some embodiments pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

[0100] The amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0101] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition. Combinations

[0102] In an additional embodiment, the disclosure provides a pharmaceutical composition comprising a compound any one of Formulas (I) through (IX) as defined in any of the foregoing embodiments, a pharmaceutically acceptable carrier, and a second therapeutic agent. In some embodiments, the second therapeutic agent may be selected from the group consisting of cytokine suppressive anti-inflammatory drugs, antibodies to or antagonists of other human cytokines or growth factors, IL-1, IL-2, IL-3, IL-4, IL- 5, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, PDGF, CTLA or their ligands including CD154, HUMIRA®, REMICADE®, SIMPONI®(golimumab), CIMZIA®, ACTEMRA®, CDP 571, soluble p55 or p75 TNF receptors, ENBREL®, Lenercept, TNFα converting enzyme inhibitors, IL-1 inhibitors, Interleukin 11, IL-18 antagonists, IL-12 antagonists, IL-12 antibodies, soluble IL-12 receptors, IL-12 binding proteins, non-depleting anti-CD4 inhibitors FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, ibuprofen, corticosteroids, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, IL-1β converting enzyme inhibitors, T-cell signaling kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6- mercaptopurines, derivatives p75TNFRIgG, sIL-1RI, sIL-1RII, sIL-6R, celecoxib, hydroxychloroquine sulfate, rofecoxib, infliximab, naproxen, valdecoxib, sulfasalazine, meloxicam, acetate, gold sodium 21 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate / apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate / apap, diclofenac sodium / misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulindac, cyanocobalamin / fa / pyridoxine, acetaminophen, alendronate sodium, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf / chondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCl / acetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, anti-IL15, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists, FTY720, PKC family inhibitors, Ruboxistaurin, AEB-071, Mesopram, methotrexate, leflunomide, corticosteroids, budenoside, dexamethasone, sulfasalazine, 5-aminosalicylic acid, olsalazine, IL-1β converting enzyme inhibitors, IL-1ra, T cell signaling inhibitors, tyrosine kinase inhibitors, 6-mercaptopurines, IL-11, mesalamine, prednisone, azathioprine, mercaptopurine, infliximab, methylprednisolone sodium succinate, diphenoxylate / atrop sulfate, loperamide hydrochloride, omeprazole, folate, ciprofloxacin / dextrose-water, hydrocodone, bitartrate / apap, tetracycline hydrochloride, fluocinonide, metronidazole, thimerosal / boric acid, cholestyramine / sucrose, ciprofloxacin hydrochloride, hyoscyamine sulfate, meperidine hydrochloride, midazolam hydrochloride, oxycodone HCl / acetaminophen, promethazine hydrochloride, sodium phosphate, sulfamethoxazole / trimethoprim, polycarbophil, propoxyphene napsylate, hydrocortisone, multivitamins, balsalazide disodium, codeine phosphate / apap, colesevelam HCl, cyanocobalamin, folic acid, levofloxacin, natalizumab, interferon- gamma, methylprednisolone, azathioprine, cyclophosphamide, cyclosporine, methotrexate, 4- aminopyridine, tizanidine, interferon-β1a, AVONEX®, interferon-(31b, BETASERON®, interferon .alpha.- n3, interferon-.alpha., interferon β1A-IF, Peginterferon-α2b, Copolymer 1, COPAXONE®, hyperbaric oxygen, intravenous immunoglobulin, cladribine, cyclosporine, FK506, mycophenolate mofetil, leflunomide, NSAIDs, corticosteroids, prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, anti-inflammatory cytokines, interferon- β, IFNβ1a, IFNβ1b, copaxone, corticosteroids, caspase inhibitors, inhibitors of caspase-1, antibodies to CD40 ligand and CD80, alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, .alpha.-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, liposome encapsulated mitoxantrone, THC, CBD, cannabinoid agonists, MBP-8298, mesopram, MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF- beta2, tiplimotide, VLA-4 antagonists, interferon gamma antagonists, IL-4 agonists, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, methotrexate, azathioprine, minocyclin, prednisone, etanercept, rofecoxib, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, 22 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium / misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate / apap, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, and efalizumab, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin, COX2 inhibitors, rofecoxib, valdecoxib, hydroxychloroquine, steroids, prednisolone, budenoside, dexamethasone, cytotoxics, azathioprine, cyclophosphamide, mycophenolate mofetil, inhibitors of PDE4, purine synthesis inhibitor, sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®™, CTLA-4-IgG, anti-B7 family antibodies, anti-PD-1 family antibodies, anti-cytokine antibodies, fonotolizumab, anti-IFNg antibody, anti- receptor receptor antibodies, anti-IL-6 receptor antibody, antibodies to B-cell surface molecules, LJP 394, Rituximab, anti-CD20 antibody and lymphostat-B.

[0103] The compounds of the disclosure are also useful in the treatment of cardiovascular disorders, such as acute myocardial infarction, acute coronary syndrome, chronic heart failure, myocardial infarction, atherosclerosis, viral myocarditis, cardiac allograft rejection, and sepsis-associated cardiac dysfunction. Furthermore, the compounds of the present disclosure are also useful for the treatment of central nervous system disorders such as meningococcal meningitis, Alzheimer’s disease and Parkinson’s disease.

[0104] In one aspect, the present disclosure provides a method of selectively inhibiting JAK1 in a human subject, comprising administering to the human an effective amount of a compound of any one of Formulas (I) through (IX) in a pharmaceutically acceptable carrier, wherein JAK1 activity is preferentially inhibited over activity of JAK2, activity of JAK3, and activity of TYK2, and less than 50%, 40%, 30%, 20%, 10%, or 5% of JAK2 and / or JAK3 activity is inhibited in the subject.

[0105] In another aspect, the disclosure provides a method of treating in a subject (such as an animal, or mammal, e.g., a dog, cat, or human) an autoimmune disease or disorder, or an inflammatory disease or disorder, the method comprising administering to the subject an effective amount of a compound of any one of Formulas (I) through (IX) and a pharmaceutically acceptable carrier or excipient, wherein the effective amount reduces reticulocyte, NK cell, NKT cell, iNKT cell, or CD8+cell count by no more than 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5% relative to a pre-treatment level. In certain embodiments, more than 50%, 60%, 70%, 80%, 90%, 95%, 99% of JAK1 activity is inhibited in the subject.

[0106] In certain embodiments, the subject is in need of treatment for a condition treatable by inhibition of JAK1 activity. For example, the condition may be an inflammatory disease / disorder, or an autoimmune disease / disorder, such as Rheumatoid Arthritis (RA), Crohn’s disease, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), diabetic nephropathy, dry eye syndrome, Sjogren’s Syndrome, alopecia areata, vitiligo, or atopic dermatitis. 23 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0107] The compounds of the disclosure are also useful in the treatment of an ocular condition, a cancer, a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, hypersensitivity reactions, hyperkinetic movement disorders, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, aordic and peripheral aneuryisms, hypothalamic-pituitary-adrenal axis evaluation, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, spinocerebellar degenerations, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphalaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, transplants, trauma / hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis / aseptic meningitis, vital-associated hemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson’s disease, xenograft rejection of any organ or tissue, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome / thrombolytic thrombocytopenic purpura, hemorrhage, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza A, ionizing radiation exposure, iridocyclitis / uveitis / optic neuritis, juvenile spinal muscular atrophy, lymphoma, myeloma, leukemia, malignant ascites, hematopoietic cancers, a diabetic condition such as insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy or microangiopathy, sickle cell anemia, chronic inflammation, glomerulonephritis, graft rejection, Lyme disease, von Hippel Lindau disease, pemphigoid, Paget’s disease, fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma or edema following burns, trauma, radiation, stroke, hypoxia, ischemia, ovarian hyperstimulation syndrome, post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, menometrorrhagia, endometriosis, pulmonary hypertension, infantile hemangioma, or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa or toxoplasmosis, progressive supranucleo palsy, primary pulmonary hypertension, radiation therapy, Raynaud’s phenomenon, Raynaud’s disease, Refsum’s disease, regular narrow QRS tachycardia, renovascular hypertension, restrictive cardiomyopathy, sarcoma, senile chorea, senile dementia of Lewy body type, shock, skin allograft, skin changes syndrome, ocular or macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser treatment complications, conjunctivitis, Stargardt’s disease, Eales disease, retinopathy, macular degeneration, restenosis, ischemia / reperfusion injury, ischemic stroke, vascular occlusion, carotid obstructive disease, ulcerative colitis, inflammatory bowel disease, diabetes, diabetes mellitus, insulin dependent diabetes mellitus, allergic diseases, dermatitis scleroderma, graft versus host 24 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) disease, organ transplant rejection (including but not limited to bone marrow and solid organ rejection), acute or chronic immune disease associated with organ transplantation, sarcoidosis, disseminated intravascular coagulation, Kawasaki’s disease, nephrotic syndrome, chronic fatigue syndrome, Wegener’s granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington’s chorea, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, Addison’s disease, idiopathic Addison’s disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt’s syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthopathy, arthropathy, Reiter’s disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, atheromatous disease / arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs positive hemolytic anemia, acquired pernicious anemia, juvenile pernicious anemia, peripheral vascular disorders, peritonitis, pernicious anemia, myalgic encephalitis / Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related Diseases, His bundle arrythmias, HIV infection / HIV neuropathy, common varied immunodeficiency (common variable hypogammaglobulinaemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, chronic wound healing, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, Pneumocystis carinii pneumonia, pneumonia, connective tissue disease associated interstitial lung disease, mixed connective tissue disease, associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis / polymyositis associated lung disease, Sjogren’s disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, hemosiderosis associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycemia, type B insulin resistance with Acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthritis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia, autoimmune neutropenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm 25 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, acute and chronic pain (different forms of pain), Goodpasture’s syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjogren’s syndrome, Takayasu’s disease / arteritis, autoimmune thrombocytopenia, toxicity, transplants, and diseases involving inappropriate vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings. In addition, such compounds may be useful in the treatment of disorders such as ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome (ARDS), proliferative disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, and glomerulopathies, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia / reperfusion injury, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity, or age- related macular degeneration. In addition, these compounds can be used as active agents against hyperproliferative disorders such as thyroid hyperplasia (especially Grave’s disease), and cysts (such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and / or metastasis.

[0108] Compounds of Formula (I) can be used alone or in combination with an additional agent, e.g., a therapeutic agent, said additional agent being selected by the skilled artisan for its intended purpose. For example, the additional agent can be a therapeutic agent art-recognized as being useful to treat the disease or condition being treated by the compound of the present disclosure. The additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition e.g., an agent that affects the viscosity of the composition.

[0109] It should further be understood that the combinations which are to be included within this disclosure are those combinations useful for their intended purpose. The agents set forth below are illustrative for purposes and not intended to be limited. The combinations, which are part of this disclosure, can be the compounds of the present disclosure and at least one additional agent selected from the lists below. The combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function. 26 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0110] Preferred combinations are non-steroidal anti-inflammatory drug(s) also referred to as NSAIDS which include drugs like ibuprofen. Other preferred combinations are corticosteroids including prednisolone; the well-known side-effects of steroid use can be reduced or even eliminated by tapering the steroid dose required when treating patients in combination with the compounds of this disclosure. Non- limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of any one of Formulas (I) through (IX) can be combined include the following: cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF. Compounds of the disclosure can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L).

[0111] Preferred combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include TNF antagonists like chimeric, humanized or human TNF antibodies, D2E7 (U.S. Patent No. 6,090,382, HUMIRA®), CA2 (REMICADE®), SIMPONI®(golimumab), CIMZIA®, ACTEMRA®, CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof, (p75TNFR1gG (ENBREL®) or p55TNFR1gG (Lenercept), and also TNF.alpha. converting enzyme (TACE) inhibitors; similarly, IL-1 inhibitors (Interleukin-1-converting enzyme inhibitors, IL-1RA etc.) may be effective for the same reason. Other preferred combinations include Interleukin 11. Yet other preferred combinations are the other key players of the autoimmune response which may act parallel to, dependent on or in concert with IL-18 function; especially preferred are IL-12 antagonists including IL-12 antibodies or soluble IL-12 receptors, or IL-12 binding proteins. It has been shown that IL-12 and IL-18 have overlapping but distinct functions and a combination of antagonists to both may be most effective. Yet another preferred combination is non-depleting anti-CD4 inhibitors. Yet other preferred combinations include antagonists of the co-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors or antagonistic ligands.

[0112] A compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof may also be combined with agents, such as methotrexate, 6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine / hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement 27 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) inhibitors, adrenergic agents, agents which interfere with signaling by proinflammatory cytokines such as TNF alpha, quadrature, or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzyme inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (ENBREL®) and p55TNFRIgG (Lenercept), sIL-1RI, sIL-1RII, sIL-6R), anti-inflammatory cytokines (e.g., IL-4, IL-10, IL- 11, IL-13 and TGFβ), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate / apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate / apap, diclofenac sodium / misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulindac, cyanocobalamin / fa / pyridoxine, acetaminophen, alendronate sodium, prednisolone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf / chondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCl / acetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists (such as FTY720), PKC family inhibitors (such as Ruboxistaurin or AEB-071) and Mesopram. Preferred combinations include methotrexate or leflunomide and in moderate or severe rheumatoid arthritis cases, cyclosporine and anti- TNF antibodies as noted above.

[0113] Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-1β monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL- 16, IL-23, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; complement inhibitors; adrenergic agents; agents which interfere with signaling by proinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, or MAP kinase inhibitors); IL-1β converting enzyme inhibitors; TNFα converting enzyme inhibitors; T-cell signaling inhibitors such as kinase inhibitors; metalloproteinase 28 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNF receptors, sIL-1RI, sIL- 1RII, sIL-6R) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-1β and TGFβ). Preferred examples of therapeutic agents for Crohn’s disease with which a compound of any one of Formulas (I) through (IX) can be combined include the following: TNF antagonists, for example, anti-TNF antibodies, D2E7 (U.S. Patent No. 6,090,382, HUMIRA®), CA2 (REMICADE®), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (Lenercept) inhibitors and PDE4 inhibitors. A compound of any one of Formulas (I) through (IX) can be combined with corticosteroids, for example, budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents which interfere with synthesis or action of proinflammatory cytokines such as IL-1, for example, IL-1β converting enzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example, tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate; diphenoxylate / atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; ciprofloxacin / dextrose-water; hydrocodone bitartrate / apap; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal / boric acid; cholestyramine / sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodone HCl / acetaminophen; promethazine hydrochloride; sodium phosphate; sulfamethoxazole / trimethoprim; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide disodium; codeine phosphate / apap; colesevelam HCl; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

[0114] Non-limiting examples of therapeutic agents for multiple sclerosis with which a compound of any one of Formulas (I) through (IX) can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-3β1a (AVONEX®; Biogen); interferon-β1b (BETASERON®; Chiron / Berlex); interferon .alpha.-n3) (Interferon Sciences / Fujimoto), interferon-a (Alfa Wassermann / J&J), interferon β1A-IF (Serono / Inhale Therapeutics), Peginterferon .alpha. 2b (Enzon / Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; cladribine; antibodies to or antagonists of other human cytokines or growth factors and their receptors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. A compound of any one of Formulas (I) through (IX) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A compound of any one of Formulas (I) through (IX) may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen, corticosteroids 29 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signaling by proinflammatory cytokines such as TNF.alpha.quadrature. or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACE inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-1β and TGFβ).

[0115] A compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, may also be combined with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, α- immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler, Antegran-ELAN / Biogen), interferon gamma antagonists and IL-4 agonists.

[0116] Non-limiting examples of therapeutic agents for ankylosing spondylitis with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, and anti-TNF antibodies, D2E7 (U.S. Patent No. 6,090,382; HUMIRA®), CA2 (REMICADE®), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (Lenercept).

[0117] Non-limiting examples of therapeutic agents for asthma with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: albuterol, salmeterol / fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl, albuterol sulfate / ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous, methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium, fexofenadine hydrochloride, flunisolide / menthol, amoxicillin / clavulanate, levofloxacin, inhaler assist device, guaifenesin, 30 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline hyclate, guaifenesin / d-methorphan, p- ephedrine / cod / chlorphenir, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin, pe / hydrocodone / chlorphenir, cetirizine HCl / pseudoephed, phenylephrine / cod / promethazine, codeine / promethazine, cefprozil, dexamethasone, guaifenesin / pseudoephedrine, chlorpheniramine / hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone, anti-IL-1β antibody, and metaproterenol sulfate.

[0118] Non-limiting examples of therapeutic agents for COPD with which a compound of any one of Formulas (I) through (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: albuterol sulfate / ipratropium, ipratropium bromide, salmeterol / fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin / clavulanate, flunisolide / menthol, chlorpheniramine / hydrocodone, metaproterenol sulfate, methylprednisolone, mometasone furoate, p-ephedrine / cod / chlorphenir, pirbuterol acetate, p- ephedrine / loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

[0119] Non-limiting examples of therapeutic agents for HCV with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: Interferon-alpha-2.alpha., Interferon-alpha-2β, Interferon-alpha con1, Interferon-alpha-n1, pegylated interferon-alpha-2.alpha., pegylated interferon-alpha-2β, ribavirin, peginterferon alfa-2b+ribavirin, ursodeoxycholic acid, glycyrrhizic acid, thymalfasin, Maxamine, VX-497 and any compounds that are used to treat HCV through intervention with the following targets: HCV polymerase, HCV protease, HCV helicase, and HCV IRES (internal ribosome entry site).

[0120] Non-limiting examples of therapeutic agents for Idiopathic Pulmonary Fibrosis with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: prednisone, azathioprine, albuterol, colchicine, albuterol sulfate, digoxin, gamma interferon, methylprednisolone sodium succinate, lorazepam, furosemide, lisinopril, nitroglycerin, spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d, alteplase, fluticasone propionate, levofloxacin, metaproterenol sulfate, morphine sulfate, oxycodone HCl, potassium chloride, triamcinolone acetonide, tacrolimus anhydrous, calcium, interferon-alpha, methotrexate, mycophenolate mofetil and interferon-gamma-1β. 31 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0121] Non-limiting examples of therapeutic agents for myocardial infarction with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: aspirin, nitroglycerin, metoprolol tartrate, enoxaparin sodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartan potassium, quinapril hydrochloride / magnesium carbonate, bumetanide, alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HCl m-hydrate, diltiazem hydrochloride, captopril, irbesartan, valsartan, propranolol hydrochloride, fosinopril sodium, lidocaine hydrochloride, eptifibatide, cefazolin sodium, atropine sulfate, aminocaproic acid, spironolactone, interferon, sotalol hydrochloride, potassium chloride, docusate sodium, dobutamine HCl, alprazolam, pravastatin sodium, atorvastatin calcium, midazolam hydrochloride, meperidine hydrochloride, isosorbide dinitrate, epinephrine, dopamine hydrochloride, bivalirudin, rosuvastatin, ezetimibe / simvastatin, avasimibe, and cariporide.

[0122] Non-limiting examples of therapeutic agents for psoriasis with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine / fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate / emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, hc / bismuth subgal / znox / resor, methylprednisolone acetate, prednisone, sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate, coal extract, coal tar / salicylic acid, coal tar / salicylic acid / sulfur, desoximetasone, diazepam, emollient, fluocinonide / emollient, mineral oil / castor oil / na lact, mineral oil / peanut oil, petroleum / isopropyl myristate, psoralen, salicylic acid, soap / tribromsalan, thimerosal / boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab.

[0123] Non-limiting examples of therapeutic agents for psoriatic arthritis with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, 32 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium / misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate / apap, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (U.S. Patent No.6,090,382, HUMIRA™), and efalizumab.

[0124] Non-limiting examples of therapeutic agents for restenosis with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, and acetaminophen.

[0125] Non-limiting examples of therapeutic agents for sciatica with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: hydrocodone bitartrate / apap, rofecoxib, cyclobenzaprine HCl, methylprednisolone, naproxen, ibuprofen, oxycodone HCl / acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeine phosphate / apap, tramadol hcl / acetaminophen, metaxalone, meloxicam, methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin, dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin, acetaminophen, diazepam, nabumetone, oxycodone HCl, tizanidine HCl, diclofenac sodium / misoprostol, propoxyphene n-pap, asa / oxycod / oxycodone ter, ibuprofen / hydrocodone bit, tramadol HCl, etodolac, propoxyphene HCl, amitriptyline HCl, carisoprodol / codeine phos / asa, morphine sulfate, multivitamins, naproxen sodium, orphenadrine citrate, and temazepam.

[0126] Preferred examples of therapeutic agents for SLE (Lupus) with which a compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids, for example, prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, for example Cellcept®™ A compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®™ and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL-1, for example, caspase inhibitors like IL-1β converting enzyme inhibitors and IL-1ra. A compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof may also be used with T cell signaling inhibitors, for example, tyrosine kinase inhibitors; or molecules that target T cell activation molecules, for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD-1 family antibodies. A 33 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof can be combined with IL-11 or anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg antibody), or anti-receptor receptor antibodies, for example, anti-IL-6 receptor antibody and antibodies to B-cell surface molecules. A compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof may also be used with LJP 394 (abetimus), agents that deplete or inactivate B-cells, for example, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS antibody), TNF antagonists, for example, anti-TNF antibodies, D2E7 (U.S. Patent No. 6,090,382; HUMIRA®), CA2 (REMICADE®), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (Lenercept).   Further Forms of Compounds

[0127] In one aspect, the compound of any one of Formulas (I) through (IX) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In one aspect, stereoisomers are obtained by stereoselective synthesis.

[0128] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0129] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number 34 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36Cl. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0130] Compounds described herein may be formed as, and / or used as, acceptable salts. The type of acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with an acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4- methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2- ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0131] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms, particularly solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently 35 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Kits / Article of Manufacture

[0132] Disclosed herein, in certain embodiments, are kits and articles of manufacture for use to generate JAK1 selective compounds of the present disclosure. In some embodiments, described herein is a kit for detecting protein ligand interaction. In some embodiments, such kit includes small molecule ligands described herein, small molecule fragments or libraries, compound probes described herein, and / or controls, and reagents suitable for carrying out one or more of the methods described herein. In some instances, the kit further comprises samples, such as a cell sample, and suitable solutions such as buffers or media. In some embodiments, the kit further comprises recombinant JAK1 protein for use in one or more of the methods described herein. In some embodiments, additional components of the kit comprises a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, plates, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastics.

[0133] The articles of manufacture provided herein contain packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, bags, containers, and any packaging material suitable for a selected formulation and intended mode of use.

[0134] For example, the container(s) include probes, test compounds, and one or more reagents for use in a method disclosed herein. Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.

[0135] A kit typically includes labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[0136] In some embodiments, a label is on or associated with the container. In some embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In some embodiments, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein. 36 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Synthesis of Compounds

[0137] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.

[0138] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fisher Scientific (Fisher Chemicals), and Acros Organics.

[0139] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4thEd., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rdEd., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized.

[0140] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. A detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure). Cells, Analytical Techniques, and Instrumentation

[0141] In certain embodiments, also described herein are methods for profiling a protein described above to determine a reactive or ligandable cysteine residue. In some instances, the methods comprising profiling a cell sample or a cell lysate sample. In some embodiments, the cell sample or cell lysate sample is obtained from cells of an animal. In some instances, the animal cell includes a cell from a marine invertebrate, fish, insects, amphibian, reptile, or mammal. In some instances, the mammalian cell is a primate, ape, equine, 37 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) bovine, porcine, canine, feline, or rodent. In some instances, the mammal is a primate, ape, dog, cat, rabbit, ferret, or the like. In some cases, the rodent is a mouse, rat, hamster, gerbil, hamster, chinchilla, or guinea pig. In some embodiments, the bird cell is from a canary, parakeet or parrots. In some embodiments, the reptile cell is from a turtles, lizard or snake. In some cases, the fish cell is from a tropical fish. In some cases, the fish cell is from a zebrafish (e.g., Danino rerio). In some cases, the worm cell is from a nematode (e.g., C. elegans). In some cases, the amphibian cell is from a frog. In some embodiments, the arthropod cell is from a tarantula or hermit crab.

[0142] In some embodiments, the cell sample or cell lysate sample is obtained from a mammalian cell. In some instances, the mammalian cell is an epithelial cell, connective tissue cell, hormone secreting cell, a nerve cell, a skeletal muscle cell, a blood cell, or an immune system cell.

[0143] Exemplary mammalian cells include, but are not limited to, 293A cell line, 293FT cell line, 293F cells , 293 H cells, HEK 293 cells, CHO DG44 cells, CHO-S cells, CHO-K1 cells, Expi293F™ cells, Flp- In™ T-REx™ 293 cell line, Flp-In™-293 cell line, Flp-In™-3T3 cell line, Flp-In™-BHK cell line, Flp- In™-CHO cell line, Flp-In™-CV-1 cell line, Flp-In™-Jurkat cell line, FreeStyle™ 293-F cells, FreeStyle™ CHO-S cells, GripTite™ 293 MSR cell line, GS-CHO cell line, HepaRG™ cells, T-REx™ Jurkat cell line, Per.C6 cells, T-REx™-293 cell line, T-REx™-CHO cell line, T-REx™-HeLa cell line, NC-HIMT cell line, and PC12 cell line.

[0144] In some instances, the cell sample or cell lysate sample is obtained from cells of a tumor cell line. In some instances, the cell sample or cell lysate sample is obtained from cells of a solid tumor cell line. In some instances, the solid tumor cell line is a sarcoma cell line. In some instances, the solid tumor cell line is a carcinoma cell line. In some embodiments, the sarcoma cell line is obtained from a cell line of alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, esthesioneuroblastoma, Ewing sarcoma, extrarenal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastic tumor, Kaposi sarcoma, leiomyosarcoma of bone, liposarcoma, liposarcoma of bone, malignant fibrous histiocytoma (MFH), malignant fibrous histiocytoma (MFH) of bone, malignant mesenchymoma, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxofibrosarcoma, myxoid liposarcoma, myxoinflammatory fibroblastic sarcoma, neoplasms with perivascular epitheioid cell differentiation, osteosarcoma, parosteal osteosarcoma, neoplasm with perivascular epitheioid cell differentiation, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, PNET / extraskeletal Ewing 38 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, telangiectatic osteosarcoma.

[0145] In some embodiments, the carcinoma cell line is obtained from a cell line of adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, or vulvar cancer.

[0146] In some instances, the cell sample or cell lysate sample is obtained from cells of a hematologic malignant cell line. In some instances, the hematologic malignant cell line is a T-cell cell line. In some instances, B-cell cell line. In some instances, the hematologic malignant cell line is obtained from a T-cell cell line of: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia / lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T- cell lymphoma, lymphoblastic lymphoma, nasal NK / T-cell lymphomas, or treatment-related T-cell lymphomas.

[0147] In some instances, the hematologic malignant cell line is obtained from a B-cell cell line of: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0148] In some embodiments, the cell sample or cell lysate sample is obtained from a tumor cell line. Exemplary tumor cell line includes, but is not limited to, 600MPE, AU565, BT-20, BT-474, BT-483, BT- 549, Evsa-T, Hs578T, MCF-7, MDA-MB-231, SkBr3, T-47D, HeLa, DU145, PC3, LNCaP, A549, H1299, NCI-H460, A2780, SKOV-3 / Luc, Neuro2a, RKO, RKO-AS45-1, HT-29, SW1417, SW948, DLD-1, 39 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) SW480, Capan-1, MC / 9, B72.3, B25.2, B6.2, B38.1, DMS 153, SU.86.86, SNU-182, SNU-423, SNU-449, SNU-475, SNU-387, Hs 817.T, LMH, LMH / 2A, SNU-398, PLHC-1, HepG2 / SF, OCI-Ly1, OCI-Ly2, OCI- Ly3, OCI-Ly4, OCI-Ly6, OCI-Ly7, OCI-Ly10, OCI-Ly18, OCI-Ly19, U2932, DB, HBL-1, RIVA, SUDHL2, TMD8, MEC1, MEC2, 8E5, CCRF-CEM, MOLT-3, TALL-104, AML-193, THP-1, BDCM, HL-60, Jurkat, RPMI 8226, MOLT-4, RS4, K-562, KASUMI-1, Daudi, GA-10, Raji, JeKo-1, NK-92, and Mino.

[0149] In some embodiments, the cell sample or cell lysate sample is from any tissue or fluid from an individual. Samples include, but are not limited to, tissue (e.g., connective tissue, muscle tissue, nervous tissue, or epithelial tissue), whole blood, dissociated bone marrow, bone marrow aspirate, pleural fluid, peritoneal fluid, central spinal fluid, abdominal fluid, pancreatic fluid, cerebrospinal fluid, brain fluid, ascites, pericardial fluid, urine, saliva, bronchial lavage, sweat, tears, ear flow, sputum, hydrocele fluid, semen, vaginal flow, milk, amniotic fluid, and secretions of respiratory, intestinal or genitourinary tract. In some embodiments, the cell sample or cell lysate sample is a tissue sample, such as a sample obtained from a biopsy or a tumor tissue sample. In some embodiments, the cell sample or cell lysate sample is a blood serum sample. In some embodiments, the cell sample or cell lysate sample is a blood cell sample containing one or more peripheral blood mononuclear cells (PBMCs). In some embodiments, the cell sample or cell lysate sample contains one or more circulating tumor cells (CTCs). In some embodiments, the cell sample or cell lysate sample contains one or more disseminated tumor cells (DTC, e.g., in a bone marrow aspirate sample).

[0150] In some embodiments, the cell sample or cell lysate sample is obtained from the individual by any suitable means of obtaining the sample using well-known and routine clinical methods. Procedures for obtaining tissue samples from an individual are well known. For example, procedures for drawing and processing tissue sample such as from a needle aspiration biopsy is well-known and is employed to obtain a sample for use in the methods provided. Typically, for collection of such a tissue sample, a thin hollow needle is inserted into a mass such as a tumor mass for sampling of cells that, after being stained, will be examined under a microscope.   Sample Preparation and Analysis

[0151] In some embodiments, a sample solution comprises a cell sample, a cell lysate sample, or a sample comprising isolated proteins. In some instances, the sample solution comprises a solution such as a buffer (e.g., phosphate buffered saline) or a media. In some embodiments, the media is an isotopically labeled media. In some instances, the sample solution is a cell solution. 40 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0152] In some embodiments, the solution sample (e.g., cell sample, cell lysate sample, or comprising isolated proteins) is incubated with a compound of any one of Formulas (I) through (IX) for analysis of protein-probe interactions. In some instances, the solution sample (e.g., cell sample, cell lysate sample, or comprising isolated proteins) is further incubated in the presence of an additional compound probe prior to addition of the compound of any one of Formulas (I) through (IX). In other instances, the solution sample (e.g., cell sample, cell lysate sample, or comprising isolated proteins) is further incubated with a ligand, in which the ligand does not contain a photoreactive moiety and / or an alkyne group. In such instances, the solution sample is incubated with a probe and a ligand for competitive protein profiling analysis.

[0153] In some cases, the cell sample or the cell lysate sample is compared with a control. In some cases, a difference is observed between a set of probe protein interactions between the sample and the control. In some instances, the difference correlates to the interaction between the small molecule fragment and the proteins.

[0154] In some embodiments, one or more methods are utilized for labeling a solution sample (e.g., cell sample, cell lysate sample, or comprising isolated proteins) for analysis of probe protein interactions. In some instances, a method comprises labeling the sample (e.g., cell sample, cell lysate sample, or comprising isolated proteins) with an enriched media. In some cases, the sample (e.g., cell sample, cell lysate sample, or comprising isolated proteins) is labeled with isotope-labeled amino acids, such as13C or15N-labeled amino acids. In some cases, the labeled sample is further compared with a non-labeled sample to detect differences in probe protein interactions between the two samples. In some instances, this difference is a difference of a target protein and its interaction with a small molecule ligand in the labeled sample versus the non-labeled sample. In some instances, the difference is an increase, decrease or a lack of protein-probe interaction in the two samples. In some instances, the isotope-labeled method is termed SILAC, stable isotope labeling using amino acids in cell culture.

[0155] In some embodiments, a method comprises incubating a solution sample (e.g., cell sample, cell lysate sample, or comprising isolated proteins) with a labeling group (e.g., an isotopically labeled labeling group) to tag one or more proteins of interest for further analysis. In such cases, the labeling group comprises a biotin, a streptavidin, bead, resin, a solid support, or a combination thereof, and further comprises a linker that is optionally isotopically labeled. As described above, the linker can be about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more residues in length and might further comprise a cleavage site, such as a protease cleavage site (e.g., TEV cleavage site). In some cases, the labeling group is a biotin-linker moiety, which is optionally isotopically labeled with13C and15N atoms at one or more amino acid residue positions within the linker. In some cases, the biotin-linker moiety is an isotopically-labeled TEV-tag as described in 41 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Weerapana, et al., “Quantitative reactivity profiling predicts functional cysteines in proteomes,” (Nature 468 (7325): 790-795).

[0156] In some embodiments, an isotopic reductive dimethylation (ReDi) method is utilized for processing a sample. In some cases, the ReDi labeling method involves reacting peptides with formaldehyde to form a Schiff base, which is then reduced by cyanoborohydride. This reaction dimethylates free amino groups on N-termini and lysine side chains and monomethylates N-terminal prolines. In some cases, the ReDi labeling method comprises methylating peptides from a first processed sample with a “light” label using reagents with hydrogen atoms in their natural isotopic distribution and peptides from a second processed sample with a “heavy” label using deuterated formaldehyde and cyanoborohydride. Subsequent proteomic analysis (e.g., mass spectrometry analysis) based on a relative peptide abundance between the heavy and light peptide version might be used for analysis of probe-protein interactions.

[0157] In some embodiments, isobaric tags for relative and absolute quantitation (iTRAQ) method is utilized for processing a sample. In some cases, the iTRAQ method is based on the covalent labeling of the N-terminus and side chain amines of peptides from a processed sample. In some cases, reagent such as 4- plex or 8-plex is used for labeling the peptides.

[0158] In some embodiments, the probe-protein complex is further conjugated to a chromophore, such as a fluorophore. In some instances, the probe-protein complex is separated and visualized utilizing an electrophoresis system, such as through a gel electrophoresis, or a capillary electrophoresis. Exemplary gel electrophoresis includes agarose-based gels, polyacrylamide based gels, or starch based gels. In some instances, the probe-protein is subjected to a native electrophoresis condition. In some instances, the probe- protein is subjected to a denaturing electrophoresis condition.

[0159] In some instances, the probe-protein after harvesting is further fragmentized to generate protein fragments. In some instances, fragmentation is generated through mechanical stress, pressure, or chemical means. In some instances, the protein from the probe-protein complexes is fragmented by a chemical means. In some embodiments, the chemical means is a protease. Exemplary proteases include, but are not limited to, serine proteases such as chymotrypsin A, penicillin G acylase precursor, dipeptidase E, DmpA aminopeptidase, subtilisin, prolyl oligopeptidase, D-Ala-D-Ala peptidase C, signal peptidase I, cytomegalovirus assemblin, Lon-A peptidase, peptidase Clp, Escherichia coli phage K1F endosialidase CIMCD self-cleaving protein, nucleoporin 145, lactoferrin, murein tetrapeptidase LD-carboxypeptidase, or rhomboid-1; threonine proteases such as ornithine acetyltransferase; cysteine proteases such as TEV protease, amidophosphoribosyltransferase precursor, gamma-glutamyl hydrolase (Rattus norvegicus), hedgehog protein, DmpA aminopeptidase, papain, bromelain, cathepsin K, calpain, caspase-1, separase, adenain, pyroglutamyl-peptidase I, sortase A, hepatitis C virus peptidase 2, sindbis virus-type nsP2 42 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) peptidase, dipeptidyl-peptidase VI, or DeSI-1 peptidase; aspartate proteases such as beta-secretase 1 (BACE1), beta-secretase 2 (BACE2), cathepsin D, cathepsin E, chymosin, napsin-A, nepenthesin, pepsin, plasmepsin, presenilin, or renin; glutamic acid proteases such as AfuGprA; and metalloproteases such as peptidase M48.

[0160] In some instances, the fragmentation is a random fragmentation. In some instances, the fragmentation generates specific lengths of protein fragments, or the shearing occurs at particular sequence of amino acid regions.

[0161] In some instances, the protein fragments are further analyzed by a proteomic method such as by liquid chromatography (LC) (e.g., high performance liquid chromatography), liquid chromatography-mass spectrometry (LC-MS), matrix-assisted laser desorption / ionization (MALDI-TOF), gas chromatography- mass spectrometry (GC-MS), capillary electrophoresis-mass spectrometry (CE-MS), or nuclear magnetic resonance imaging (NMR).

[0162] In some embodiments, the LC method is any suitable LC methods well known in the art, for separation of a sample into its individual parts. This separation occurs based on the interaction of the sample with the mobile and stationary phases. Since there are many stationary / mobile phase combinations that are employed when separating a mixture, there are several different types of chromatography that are classified based on the physical states of those phases. In some embodiments, the LC is further classified as normal- phase chromatography, reverse-phase chromatography, size-exclusion chromatography, ion-exchange chromatography, affinity chromatography, displacement chromatography, partition chromatography, flash chromatography, chiral chromatography, and aqueous normal-phase chromatography.

[0163] In some embodiments, the LC method is a high performance liquid chromatography (HPLC) method. In some embodiments, the HPLC method is further categorized as normal-phase chromatography, reverse-phase chromatography, size-exclusion chromatography, ion-exchange chromatography, affinity chromatography, displacement chromatography, partition chromatography, chiral chromatography, and aqueous normal-phase chromatography.

[0164] In some embodiments, the HPLC method of the present disclosure is performed by any standard techniques well known in the art. Exemplary HPLC methods include hydrophilic interaction liquid chromatography (HILIC), electrostatic repulsion-hydrophilic interaction liquid chromatography (ERLIC) and reverse phase liquid chromatography (RPLC).

[0165] In some embodiments, the LC is coupled to a mass spectroscopy as a LC-MS method. In some embodiments, the LC-MS method includes ultra-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS), ultra-performance liquid 43 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS / MS), reverse phase liquid chromatography-mass spectrometry (RPLC-MS), hydrophilic interaction liquid chromatography- mass spectrometry (HILIC-MS), hydrophilic interaction liquid chromatography-triple quadrupole tandem mass spectrometry (HILIC-QQQ), electrostatic repulsion-hydrophilic interaction liquid chromatography- mass spectrometry (ERLIC-MS), liquid chromatography time-of-flight mass spectrometry (LC-QTOF- MS), liquid chromatography-tandem mass spectrometry (LC-MS / MS), multidimensional liquid chromatography coupled with tandem mass spectrometry (LC / LC-MS / MS). In some instances, the LC-MS method is LC / LC-MS / MS. In some embodiments, the LC-MS methods of the present disclosure are performed by standard techniques well known in the art.

[0166] In some embodiments, the GC is coupled to a mass spectroscopy as a GC-MS method. In some embodiments, the GC-MS method includes two-dimensional gas chromatography time-of-flight mass spectrometry (GC*GC-TOFMS), gas chromatography time-of-flight mass spectrometry (GC-QTOF-MS) and gas chromatography-tandem mass spectrometry (GC-MS / MS).

[0167] In some embodiments, CE is coupled to a mass spectroscopy as a CE-MS method. In some embodiments, the CE-MS method includes capillary electrophoresis- negative electrospray ionization-mass spectrometry (CE-ESI-MS), capillary electrophoresis-negative electrospray ionization-quadrupole time of flight-mass spectrometry (CE-ESI-QTOF-MS) and capillary electrophoresis-quadrupole time of flight- mass spectrometry (CE-QTOF-MS).

[0168] In some embodiments, the nuclear magnetic resonance (NMR) method is any suitable method well known in the art for the detection of one or more cysteine binding proteins or protein fragments disclosed herein. In some embodiments, the NMR method includes one dimensional (1D) NMR methods, two dimensional (2D) NMR methods, solid state NMR methods and NMR chromatography. Exemplary 1D NMR methods include 1Hydrogen, 13Carbon, 15Nitrogen, 17Oxygen, 19Fluorine, 31Phosphorus, 39Potassium, 23Sodium, 33Sulfur, 87Strontium, 27Aluminium, 43Calcium, 35Chlorine, 37Chlorine, 63Copper, 65Copper, 57Iron, 25Magnesium, 199Mercury or 67Zinc NMR method, distortionless enhancement by polarization transfer (DEPT) method, attached proton test (APT) method and 1D- incredible natural abundance double quantum transition experiment (INADEQUATE) method. Exemplary 2D NMR methods include correlation spectroscopy (COSY), total correlation spectroscopy (TOCSY), 2D- INADEQUATE, 2D-adequate double quantum transfer experiment (ADEQUATE), nuclear overhauser effect spectroscopy (NOSEY), rotating-frame NOE spectroscopy (ROESY), heteronuclear multiple- quantum correlation spectroscopy (HMQC), heteronuclear single quantum coherence spectroscopy (HSQC), short range coupling and long range coupling methods. Exemplary solid state NMR method include solid state 13Carbon NMR, high resolution magic angle spinning (HR-MAS) and cross polarization 44 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) magic angle spinning (CP-MAS) NMR methods. Exemplary NMR techniques include diffusion ordered spectroscopy (DOSY), DOSY-TOCSY and DOSY-HSQC.

[0169] In some embodiments, the protein fragments are analyzed by method as described in Weerapana et al., “Quantitative reactivity profiling predicts functional cysteines in proteomes,” Nature, 468:790-795 (2010).

[0170] In some embodiments, the results from the mass spectroscopy method are analyzed by an algorithm for protein identification. In some embodiments, the algorithm combines the results from the mass spectroscopy method with a protein sequence database for protein identification. In some embodiments, the algorithm comprises ProLuCID algorithm, Probity, Scaffold, SEQUEST, or Mascot.

[0171] In some embodiments, a value is assigned to each of the protein from the probe-protein complex. In some embodiments, the value assigned to each of the protein from the probe-protein complex is obtained from the mass spectroscopy analysis. In some instances, the value is the area-under-the curve from a plot of signal intensity as a function of mass-to-charge ratio. In some instances, the value correlates with the reactivity of a Lys residue within a protein.

[0172] In some instances, a ratio between a first value obtained from a first protein sample and a second value obtained from a second protein sample is calculated. In some instances, the ratio is greater than 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some cases, the ratio is at most 20.

[0173] In some instances, the ratio is calculated based on averaged values. In some instances, the averaged value is an average of at least two, three, or four values of the protein from each cell solution, or that the protein is observed at least two, three, or four times in each cell solution and a value is assigned to each observed time. In some instances, the ratio further has a standard deviation of less than 12, 10, or 8.

[0174] In some instances, a value is not an averaged value. In some instances, the ratio is calculated based on value of a protein observed only once in a cell population. In some instances, the ratio is assigned with a value of 20.   Certain Terminology

[0175] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the 45 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0176] As used herein, ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 µL” means “about 5 µL” and also “5 µL.” Generally, the term “about” includes an amount that would be expected to be within experimental error.

[0177] “Alkyl” refers to a straight or branched hydrocarbon chain radical, having from one to twenty carbon atoms, and which is attached to the rest of the molecule by a single bond. An alkyl comprising up to 10 carbon atoms is referred to as a C1-C10alkyl, likewise, for example, an alkyl comprising up to 6 carbon atoms is a C1-C6alkyl. Alkyls (and other moieties defined herein) comprising other numbers of carbon atoms are represented similarly. Alkyl groups include, but are not limited to, C1-C10alkyl, C1-C9alkyl, C1- C8alkyl, C1-C7alkyl, C1-C6alkyl, C1-C5alkyl, C1-C4alkyl, C1-C3alkyl, C1-C2alkyl, C2-C8alkyl, C3-C8alkyl and C4-C8alkyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, npropyl, 1methylethyl (ipropyl), nbutyl, i-butyl, s-butyl, npentyl, 1,1dimethylethyl (tbutyl), 3methylhexyl, 2methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. In some embodiments, the alkyl is –CH(CH3)2or –C(CH3)3. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below. “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group. In some embodiments, the alkylene is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, the alkylene is –CH2-. In some embodiments, the alkylene is –CH2CH2-. In some embodiments, the alkylene is – CH2CH2CH2-.

[0178] “Alkoxy” refers to a radical of the formula OR where R is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy.

[0179] “Heteroalkylene” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is replaced with a O, N or S atom. “Heteroalkylene” or “heteroalkylene chain” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to a radical group. Unless stated otherwise specifically in the specification, the heteroalkyl or heteroalkylene group may be optionally substituted as described below. Representative heteroalkyl groups include, but are not limited to - OCH2OMe, -OCH2CH2OMe, or –OCH2CH2OCH2CH2NH2. Representative heteroalkylene groups include, but are not limited to -OCH2CH2O-, –OCH2CH2OCH2CH2O-, or –OCH2CH2OCH2CH2OCH2CH2O-. 46 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0180] “Alkylamino” refers to a radical of the formula -NHR or -NRR where each R is, independently, an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted as described below.

[0181] The term “aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0182] “Aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar“ (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.

[0183] “Carboxy” refers to –CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to: ,atoms forming the ring (i.e., skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon 47 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) atoms. Monocyclic cyclcoalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the monocyclic cyclcoalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, the monocyclic cyclcoalkyl is cyclopentyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and 3,4-dihydronaphthalen- 1(2H)-one. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.

[0185] “Fused” refers to any ring structure described herein which is fused to an existing ring structure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.

[0186] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

[0187] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0188] “Haloalkoxy” refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, and the like. Unless stated otherwise specifically in the specification, a haloalkoxy group may be optionally substituted.

[0189] “Heterocycloalkyl” or “heterocyclyl” or “heterocyclic ring” refers to a stable 3 to 14membered nonaromatic ring radical comprising 2 to 10 carbon atoms and from one to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1oxothiomorpholinyl, 1,1dioxothiomorpholinyl. The term heterocycloalkyl also includes all ring forms of 48 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring. In some embodiments, heterocycloalkyls have from 2 to 8 carbons in the ring and 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2 to 10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. In some embodiments, heterocycloalkyls have from 2 to 10 carbons, 1-2 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.

[0190] “Heteroaryl” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl is monocyclic or bicyclic. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. Illustrative examples of monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Illustrative examples of bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6- C9heteroaryl.

[0191] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6alkylalkyne, halogen, acyl, 49 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) acyloxy, -CO2H, -CO2alkyl, nitro, and amino, including mono and disubstituted amino groups (e.g., –NH2, -NHR, -N(R)2), and the protected derivatives thereof. In some embodiments, optional substituents are independently selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, -CN, -NH2, -NH(CH3), - N(CH3)2, -OH, -CO2H, and -CO2alkyl. In some embodiments, optional substituents are independently selected from fluoro, chloro, bromo, iodo, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic, saturated or unsaturated carbon atoms, excluding aromatic carbon atoms) includes oxo (=O).

[0192] “Electrophile” is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Such electrophiles are often involved in Michael addition reactions which involve the nucleophilic addition of a nucleophile to an α,β-unsaturated carbonyl compound containing an electron withdrawing group. It belongs to the larger class of conjugate additions and is widely used for the mild formation of C– C bonds. The term “Michael acceptor moiety” refers to a functional group that can participate in a Michael reaction, wherein a new covalent bond is formed between a portion of the Michael acceptor moiety and the donor moiety. The Michael acceptor moiety is an electrophile and the “donor moiety” is a nucleophile.

[0193] Non-limiting examples of compounds disclosed herein that are selective for JAK1 and with measurements of the micromolar quantities required for fifty percent target engagement of JAK1 and TYK2 are provided in Table 1. Table 1. Exemplary Compounds of the Disclosure Cmpd No.Structure IUPAC Name Stereochem.50 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.51 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.52 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.53 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.54 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.55 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.56 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.57 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.58 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.59 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.60 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.61 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.62 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.63 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.64 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.65 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.66 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.67 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.68 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.69 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.70 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.71 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.72 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.73 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.74 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.75 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.76 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.77 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.78 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.79 91894028.1Dkt. Nos.184200.00053(VVID-744PC) Cmpd No.Structure IUPAC Name Stereochem.

[0194] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.   EXAMPLES

[0195] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.   Abbreviations

[0196] aq: aqueous 80 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0197] dba: Dibenzylideneacetone

[0198] Boc: tert-Butoxycarbonyl

[0199] DCM: Dichloromethane

[0200] DMAP: N,N-dimethylpyridin-4-amine

[0201] DMF: Dimethyl formamide

[0202] dppf: 1,1’-Bis(diphenylphosphino)ferrocene

[0203] EA: Ethyl acetate

[0204] eq.: Equivalent

[0205] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0206] hr: Hour(s)

[0207] LDA: Lithium diisopropylamide

[0208] LiHMDS: Lithium bis(trimethylsilyl)amide

[0209] min: Minute(s)

[0210] MTBE: Methyl tert-butyl ether

[0211] NMR: Nuclear magnetic resonance

[0212] PE: Petroleum ether

[0213] Prep-HPLC: Preparative high performance liquid chromatography

[0214] Psi: Pound per square inch

[0215] Rf: Retardation factor

[0216] rt: Room temperature

[0217] TEA: Triethylamine

[0218] TFA: Trifluoroacetic acid

[0219] THF: Tetrahydrofuran

[0220] TLC: Thin-layer chromatography

[0221] TMS: Trimethylsilyl

[0222] V / V: Volume per volume Example 1. Synthesis of common intermediate (E)-3-(methylsulfonyl)prop-2-en-1-amine

[0223] Scheme A.cooled to 0°C, and diethyl ((methylsulfonyl)methyl)phosphonate (39.2 g, 170.3 mmol, 1 eq.) was added slowly. The 81 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) reaction mixture was stirred at 0°C for 30 min, then tert-butyl (2-oxoethyl)carbamate (29.81 g, 187.3 mmol, 1.1 eq.) in 30 mL of THF was added. The reaction mixture was allowed to warm to 10°C and was stirred for 1 hr. Once TLC (PE:EtOAc = 1:1, Rf(product) = 0.3) indicated reaction completion, the mixture was quenched with water (200 mL). The mixture was concentrated under reduced pressure, and the residue was extracted with EtOAc (300 mL). The organic layers were separated, and the aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layer was then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford tert-butyl (E)- (3-(methylsulfonyl)allyl)carbamate (17.1 g, 72.6 mmol, 42.8 % yield), separated from Z isomer (5.5 g, 23.4 mmol, 13.7% yield).

[0225] Step 2. To a solution of tert-butyl (E)-(3-(methylsulfonyl)allyl)carbamate (17.1 g, 72.6 mmol, 1 eq.) and p-toluenesulfonic acid monohydrate (16.59 mg, 87.2 mmol, 1.2 eq.) in MeCN (170 mL, 0.428 M) was stirred at 50°C for 1 hr. Then the mixture was cooled to 10°C slowly and stirred at 10°C for 1 hr. The formed precipitate was filtered, and the filter cake was dried under reduced pressure to afford (E)-3- (methylsulfonyl)prop-2-en-1-amine p-toluenesulfonic acid salt (19.5 g, 63.4 mmol, 87.3% yield) as a white solid.

[0226] Intermediate amines listed below were synthesized via the same procedure as (E)-3- (methylsulfonyl)prop-2-en-1-amine (Example 1) starting with the appropriate aldehyde at Step 1. (E)-N-methyl-3-(methylsulfonyl)prop-2-en-1-amine82 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Example 2. Synthesis of 3-(ethylsulfonyl)prop-2-en-1-amine

[0227] Scheme B. THF (30mL, 0.512M) was added 1M LiHMDS (18 mL, 18 mmol, 1.2 eq.) dropwise at -78°C under N2. The mixture was stirred at -78°C for 40 min, then added diphenyl phosphorochloridate (4.54 g, 16.88 mmol, 1.1 eq.) at - 78°C. After stirred for 40 min, N-Boc-2-aminoacetaldehyde (2.69 g, 16.88 mmol, 1.1 eq.) in THF was added dropwise at -78°C and stirred for 1 hr. The mixture was quenched by saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE:EtOAc=20:1 to 7:3) to afford tert- butyl (3-(ethylsulfonyl)allyl)carbamate (150 mg, 0.60 mmol, 3.9% yield) as a yellow oil.

[0229] Step 2. A solution of tert-butyl (3-(ethylsulfonyl)allyl)carbamate (150 mg, 0.60 mmol, 1 eq) in DCM (5 mL, 0.086 M) and trifluoroacetic acid (2 mL, 0.086 M) was stirred at 25°C for 30 min. TLC (PE:EtOAc=1:1, Rf(starting material)=0.8, Rf(product)=0.4) indicated the reaction was completed. The mixture was concentrated under reduced pressure to afford 3-(ethylsulfonyl)prop-2-en-1-amine (100 mg, 0.44 mmol, 72.4% yield) as a colorless oil. Example 3. Synthesis of common intermediate methyl 2-amino-4-cyclopropylbenzoate

[0230] Scheme C.2-amino-4-bromobenzoate (3 g, 13.04 mmol, 1 eq.), cyclopropylboronic acid (2.91 g, 33.90 mmol, 2.6 eq.), tricyclohexylphosphine (0.73 g, 2.61mmol, 0.2 eq.) and K2CO3(5.39 g, 39.12 mmol, 3 eq.) in toluene (100 mL, 0.10 M) and water (30 mL, 0.10 M) was added Pd(dppf)Cl2(300 mg) at rt. The mixture was heated at 100°C for 16 hr. After cooled to rt, the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (30 mL) and 83 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) concentrated under reduce pressure to afford crude methyl 2-amino-4-cyclopropylbenzoate (2.1 g, 10.98 mmol, 84.2 % yield) as a brown solid.

[0232] Intermediate anilines listed below were synthesized via the same procedure as methyl 2-amino-4- cyclopropylbenzoate (Example 3) starting with the appropriate aryl bromide and boron reagent at Step 1. methyl 2-amino-4-vinylbenzoate methyl 2-amino-4-(prop-1-en-2-yl)benzoate

[0233] Scheme D.amino-4-cyclopropylbenzoate (100 mg, 0.52 mmol, 1 eq.) in isopropanol (5 ml) was added N-chlorosuccinimide (69.83 mg, 0.52 mmol, 1 eq.) at rt. The mixture was heated at 90°C for 12 hr. After cooled to rt, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE: EtOAc=5:1, Rf(product)=0.5) to afford methyl 2-amino-5-chloro-4-cyclopropylbenzoate (70 mg, 0.31 mmol, 59.3% yield) as a yellow oil. Example 5. Synthesis of methyl 2-amino-4-ethylbenzoate

[0235] Scheme E.2-amino-4-vinylbenzoate (138.99 mg, 0.78 mmol, 1 eq.) in the ethyl acetate (3 mL, 0.26 M) was added Pd / C (15 mg) and the mixture was stirred at 25°C for 2 hr under 15 psi H2atmosphere. TLC (PE : Ethyl acetate= 3:1, Rf (reactant) = 0.60, Rf (product) = 0.65) indicated reaction completion. The mixture was filtered and concentrated under reduce pressure to afford methyl 2- amino-4-ethylbenzoate (120 mg, 0.67 mmol, 85.4% yield) as a yellow oil.

[0237] Intermediate aniline listed below was synthesized via the same procedure as methyl 2-amino-4- ethylbenzoate (Example 5) starting with the appropriate ester at Step 1. methyl 2-amino-4-isopropylbenzoate 84 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Example 6. Synthesis of methyl 2-amino-4-(1-methylcyclopropyl)benzoate

[0238] Scheme F. 18.83 mL, 18.83 mmol, 6 eq.) in DCM (30 mL, 0.10 M) underN2at 0°C and TFA (8.18 mL, 12.55 mmol, 4eq.) was added dropwise. The mixture was stirred at 0°C for 15 min, and diiodomethane (5.04 g, 18.83mmol, 6 eq.) was added. After stirred at 0°C for 30 min, the mixture was added methyl 2-amino-4-(prop-1-en-2-yl)benzoate (600 mg, 3.14mmol, 1 eq.) in DCM (5 mL). The mixture was stirred at -25°C for 48 hr. The mixture was quenched by HCl (1N, 10 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford methyl 2-amino-4-(1- methylcyclopropyl)benzoate (400 mg, 1.95 mmol, 62.1% yield) as a yellow oil. Example 7. Synthesis of methyl 2-amino-4-(2,2,2-trifluoroethyl)benzoate

[0240] Scheme G., di-tert-butyl dicarbonate (2.28 g, 10.43 mmol, 1.2 eq.), 4-(dimethylamino)pyridine (1.06 g, 8.69 mmol, 1 eq.) in DCM (100 mL, 0.087 M) was added triethylamine (2.64 g, 26.08 mmol, 3 eq.) at 0°C. The mixture was allowed to warm to 25°C and stirred at the temperature for 16 hr. TLC (PE:EtOAc = 5:1, Rf (STM = 0.5, Rf (product)= 0.7) indicated reaction completion. The mixture was extracted with DCM (3 × 20 mL) and water (30 mL). The combined organic layers were washed with brine (15 mL) and concentrated under reduce pressure. The residue was purified by silica gel column (PE:EtOAc = 30:1) to afford methyl 4-bromo-2- ((tert-butoxycarbonyl)amino)benzoate (1.5 g, 2.87 mmol, 52.3% yield) as a white solid.

[0242] Step 2. To a solution of methyl 4-bromo-2-((tert-butoxycarbonyl)amino)benzoate (500 mg, 1.51 mmol, 1 eq.), bis(pinacolato)diboron (423.0 mg, 1.67 mmol, 1.1 eq.) and KOAc (450 mg, 4.59 mmol, 3 85 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) eq.) in DMF (20 mL, 0.0757 M) was added Pd(dppf)Cl2(150 mg). The mixture was heated at 95°C for 16 hr. After cooled to rt, the mixture was extracted with MTBE (3 × 30 mL) and water (20 mL). The combined organic layers were washed with brine (20 mL) and concentrated under reduce pressure. The residue was purified by silica gel column (PE:EtOAc = 30:1) to afford methyl 2-((tert-butoxycarbonyl)amino)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (320 mg, 0.848 mmol, 56.0% yield) as a white solid.

[0243] Step 3. To a solution of methyl 2-((tert-butoxycarbonyl)amino)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate (320 mg, 0.848 mmol, 1 eq.), 2-iodo-1,1,1-trifluoroethane (534.3 mg, 2.54 mmol, 3 eq.), xantphos (343.6 mg, 0.594 mmol, 0.7 eq.) and Cs2CO3(707 mg, 2.168 mmol, 2.5 eq.) in 1,4- dioxane (100 mL, 0.0085 M) was added Pd2(dba)3(200 mg). The mixture was heated at 90°C for 16 hr. After cooled to rt, the mixture was extracted with EtOAc (3 × 30 mL) and water (20 mL). The combined organic layers were washed with brine (20 mL) and concentrated under reduce pressure. The residue was purified by prep-TLC (PE:EtOAc = 5:1) to afford methyl 2-((tert-butoxycarbonyl)amino)-4-(2,2,2- trifluoroethyl)benzoate (220 mg, 0.66 mmol, 77.8% yield) as a yellow oil.

[0244] Step 4. A solution of methyl 2-((tert-butoxycarbonyl)amino)-4-(2,2,2-trifluoroethyl)benzoate (220 mg, 0.660 mmol, 1 eq.) in HCl / MeOH (V / V, 4 mol, 20 mL) was stirred at 25°C for 16 hr. TLC (PE:EtOAc = 5:1) indicated reaction completion. The mixture was concentrated under reduce pressure to afford methyl 2-amino-4-(2,2,2-trifluoroethyl)benzoate (150 mg, 0.643 mmol, 97.5% yield) as a yellow solid. Example 8. Synthesis of common intermediate 2-(benzylamino)-4-cyclopropylbenzoic acid

[0245] Scheme H.(300 mg, 1.57 mmol, 1 eq.), benzaldehyde (249.72 g, 2.35 mmol, 1.5 eq) and HOAc (0.05 mL) in DCM (15 mL, 0.10 M) was stirred at 0°C for 0.5 hr. The mixture was added NaBH(OAc)3(665.68 mg, 3.14 mmol, 2 eq.) and stirred at 25°C for 16 hr. The mixture was extracted with EtOAc (3 × 30 mL) and the combined organic layers were washed with brine (15 mL) and concentrated under reduce pressure to afford methyl 2-(benzylamino)-4- cyclopropylbenzoate (200 mg, 0.71 mmol, 45.3% yield) as a yellow oil.

[0247] Step 2. To a solution of methyl 2-(benzylamino)-4-cyclopropylbenzoate (360 mg, 1.28 mmol, 1 eq.) in THF (5 mL, 0.19 M) and water (1.67 mL, 0.19 M) was added LiOH (153.6 mg, 6.4 mmol, 5 eq.). 86 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) The mixture was heated at 60°C for 16 hr. TLC (PE : Ethyl acetate= 5:1, Rf (reactant) = 0.70, Rf (product) = 0.30) indicated reaction completion. The reaction mixture was washed with MTBE (10 mL) and the aqueous phase was adjusted to pH=3~4 with HClaq (1 N, 15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-(benzylamino)-4-cyclopropylbenzoic acid (250 mg, 0.94 mmol, 73.1% yield) as a yellow oil.

[0248] Intermediate acids listed below were synthesized via the same procedure as 2-(benzylamino)-4- cyclopropylbenzoic acid (Example 8) starting with the appropriate aniline and aldehyde at Step 1. 4-cyclopropyl-2-((2-fluoro-5-hydroxybenzyl)amino)benzoic acid 4-cyclopropyl-2-((thiazol-5-ylmethyl)amino)benzoic acid87 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Example 9. Synthesis of 2-(benzylamino)-4-(trifluoromethyl)benzoic acid

[0249] Scheme I. 4-(trifluoromethyl)benzoic acid (100 mg, 0.488 mmol, 1 eq.)and benzaldehyde (62.1 mg, 0.585 mmol, 1.2 eq.) in DCM (3 mL, 0.163 M) was added HOAc (0.05 ml) followed by NaBH(OAc)3(206.8 mg, 0.976 mmol, 2 eq) at 0°C. The mixture was stirred at 15°C for 12 hr. The reaction mixture was quenched by MeOH (2 ml) and water (10 ml), then extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2-(benzylamino)-4-(trifluoromethyl)benzoic acid (150 mg, 0.508 mmol, 100% yield) as a yellow solid.

[0251] Intermediate acids listed below were synthesized via the same procedure as 2-(benzylamino)-4- (trifluoromethyl)benzoic acid (Example 9) starting with the appropriate aniline and aldehyde at Step 1. 2-(benzylamino)-4-(tert-butyl)benzoic acid88 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) 2-(((2-nitropyridin-3-yl)methyl)amino)-6-(trifluoromethyl)nicotinic acid 2-((benzo[d]oxazol-4-ylmethyl)amino)-6-(trifluoromethyl)nicotinic acid

[0252] Scheme J.3-yl)methyl)amino)-6-(trifluoromethyl)nicotinic acid (701 mg, 2.05 mmol, 1 eq.), tin(II) chloride (776.8 mg, 4.10 mmol, 2 eq.) and HClaq (1N, 2.05 mL, 2.05 mmol, 1 eq.) in ethanol (4 mL, 0.34 M) was stirred at rt for 16 hr. The reaction mixture was concentrated under reduced pressure and directly purified by reverse phase column chromatography to afford 2-(((2- aminopyridin-3-yl)methyl)amino)-6-(trifluoromethyl)nicotinic acid (65 mg, 0.208 mmol, 10.2% yield). Example 11. Synthesis of 2-(benzylamino)-4-cyclopropyl-5-fluorobenzoic acid

[0254] Scheme K.mmol, 1 eq.), benzaldehyde (102.7 mg, 0.968 mmol, 1.2 eq) and HOAc (0.1 ml) in DCM (5 mL, 0.161 M) was added NaBH(OAc)3(370 mg, 1.74 mmol, 2 eq.) at 0°C. The mixture was stirred at 15°C for 12 hr. TLC (PE: EtOAc=5:1, Rf(product)= 0.5) indicated reaction completion. The reaction mixture was quenched by MeOH (2 ml) and water (10 ml), then extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE: EtOAc=5:1, Rf(product)= 0.5) to afford methyl 2- (benzylamino)-4-bromo-5-fluorobenzoate (190 mg, 0.562 mmol, 69.7% yield) as a white solid. 89 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0256] Step 2. To the solution of methyl 2-(benzylamino)-4-bromo-5-fluorobenzoate (190 mg, 0.562 mmol, 1 eq.) and cyclopropylboronic acid (96.5 mg, 1.12 mmol, 2 eq.) in toluene (6 mL, 0.0468 M), THF (4 mL, 0.0468 M) and water (2 mL, 0.0468 M) was added K3PO4(3 eq) and Pd(dppf)Cl2(50 mg). The mixture was stirred at 90°C for 12 hr under N2. The reaction mixture was quenched by water (10 ml) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude methyl 2- (benzylamino)-4-cyclopropyl-5-fluorobenzoate (300 mg) as a yellow oil, which was used in Step 3 without further purification.

[0257] Step 3. To a solution of crude methyl 2-(benzylamino)-4-cyclopropyl-5-fluorobenzoate (100 mg, 0.334 mmol, 1 eq.) in methanol (3 mL, 0.0835 M) and water (1.0 mL, 0.0835 M) was added LiOH (7 eq.). The mixture was heated at 60°C for 12 hr until TLC (PE:EA= 5:1, Rf(product)= 0) indicated reaction completion. The reaction mixture was adjusted to pH = 3 by HClaq (1 M) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-(benzylamino)-4-cyclopropyl-5-fluorobenzoic acid (70 mg, 0.245 mmol, 73.4% yield) as a yellow solid. Example 12. Synthesis of 2-fluoro-6-(trifluoromethoxy)benzoic acid

[0258] Scheme L.(6.7 ml, 2M, 13.3 mmol, 1.2 eq.) in THF (20 mL, 0.555 M) was added 1-fluoro-3-(trifluoromethoxy)benzene (2.0 g, 11.105 mmol, 1 eq.) at -78°C under N2. After 2 hr, CO2(10 g) was added at -78°C. The reaction was allowed to warm to 25°C and stirred for 2 hr. TLC (PE: Ethyl acetate=1:1, Rf (reactant) =0.5, Rf (product) =0.3) indicated reaction completion. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 2-fluoro- 6-(trifluoromethoxy)benzoic acid (1.0 g, 4.46 mmol, 40.2% yield).1H NMR (400 MHz, DMSO-d6) δ = 3.97 - 4.09 (m, 1H), 7.24 - 7.47 (m, 2H), 7.55 - 7.69 (m, 1H). 90 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Example 13. Synthesis of common intermediate (5-fluoro-2-(trifluoromethoxy)phenyl)methanamine

[0260] Scheme M. mmol, 1 eq.) inDCM (5 mL, 0.0148 M) was added oxalyl chloride (424.8 mg, 3.347 mmol, 1.5 eq.) and DMF (0.50 uL) at 0°C. The reaction mixture was stirred at 25°C for 2 hr. TLC (PE : Ethyl acetate= 3:1, Rf (reactant) = 0.2, Rf (product) = 0.6) showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to afford 5-fluoro-2-(trifluoromethoxy)benzoyl chloride (500 mg, 2.06 mmol, 92.4% yield) as a yellow solid.

[0262] Step 2. To a solution of 5-fluoro-2-(trifluoromethoxy)benzoyl chloride (500 mg, 2.06 mmol, 1 eq.) in DCM (5 mL, 0.0148 M) was added ammonium hydroxide (20.6 mmol, 10 eq.) in DCM (4 mL, 0.2290 M) at 0°C. The reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to afford 5-fluoro-2-(trifluoromethoxy)benzamide (400 mg, 70% purity, 1.25 mmol, 60.9% yield) as a yellow solid, which was used without further purification.

[0263] Step 3. To a mixture of 5-fluoro-2-(trifluoromethoxy)benzamide (400 mg, 1.79 mmol, 1 eq.) in THF (2 mL, 0.896 M) was added borane (35.85 mL, 35.85 mmol, 20 eq.) at 0°C and then heated at 60°C for 12 hr. The reaction mixture was quenched by MeOH (50 mL) at 0°C and stirred for 0.5 hr, then warmed up to rt and stirred for 1 hr. The mixture was concentrated under reduced pressure to afford (5-fluoro-2- (trifluoromethoxy)phenyl)methanamine (300 mg, 1.43 mmol, 80.0% yield) as a white solid, which was used without further purification.

[0264] Intermediate amines listed below were synthesized via the same procedure as (5-fluoro-2- (trifluoromethoxy)phenyl)methanamine (Example 13) starting with the appropriate acid at Step 1. (2-fluoro-6-(trifluoromethoxy)phenyl)methanamineExample 14. Synthesis of 3,6-difluoro-2-methoxybenzonitrile

[0265] Scheme N.Dkt. Nos.184200.00053(VVID-744PC)

[0266] Step 1. To a solution of 2,3,6-trifluorobenzonitrile (4.0 g, 25.46 mmol, 1 eq.) in methanol (40 mL, 0.637 M) was added MeONa (1.37 g, 25.46 mmol, 1 eq.) at 25°C. The reaction mixture was stirred at 25°C for 16 hr. TLC (PE: Ethyl acetate=3:1, Rf (reactant) =0.5, Rf (product) =0.3) indicated reaction completion. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ethyl acetate / petroleum ether = 0~30%) to afford 33,6-difluoro-2- methoxybenzonitrile (3.7 g, 21.9 mmol, 85.9% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 4.10 - 4.15 (m, 3H), 7.14 - 7.29 (m, 1H), 7.68 - 7.81 (m, 1H). Example 15. Synthesis of 2-(difluoromethoxy)-3-fluorobenzonitrile

[0267] Scheme O.3-fluoro-2-hydroxybenzonitrile (600 mg, 4.376 mmol, 1 eq.) in DCM (6 mL, 0.729 M) was added KOH (1.47g, aq.) at 0°C. After stirred at 0°C for 10 min under N2, the mixture was added [bromo(difluoro)methyl]-trimethyl-silane (888.8 mg, 4.376 mmol, 1 eq.) at 0°C. Then the mixture was stirred at 25°C for 16 hr. TLC (PE: Ethyl acetate=5:1, Rf (reactant) =0.4, Rf (product) =0.6) indicated the starting material consumption. The reaction mixture was extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (Ethyl acetate:PE = 0~30%) to afford 2-(difluoromethoxy)-3-fluorobenzonitrile (550 mg, 2.94 mmol, 67.2% yield) as a yellow oil.

[0269] Intermediate benzonitrile listed below was synthesized via the same procedure 2- (difluoromethoxy)-3-fluorobenzonitrile (Example 15) starting with the appropriate benzonitrile at Step 1. 2-(difluoromethoxy)-5-fluorobenzonitrile Example 16. Synthesis of 5-fluoro-2-(methoxy-d3)benzonitrile

[0270] Scheme N.fluoro-2-hydroxybenzonitrile (200 mg, 1.459 mmol, 1 eq.) in DMF (5 mL, 0.292 M) was added iodomethane-d3(0.317 g, 2.188 mmol, 1.5 eq.) at 0°C. After stirred for 1 hr, the 92 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) mixture was added sodium hydride (35 mg, 1.459 mmol, 1 eq.) portion-wise at °C and stirred for 1 hr. TLC (SiO2, PE:EA=3:1, Rf(reactant)=0.6, Rf(product)=0.4) indicated reaction completion. The reaction mixture was poured into water (10 mL) and extracted with EtOAc(10 mL × 3). The combined organic layers were washed brine (10 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (SiO2, PE:EA=20:1 to 3:1) to afford 5- fluoro-2-(methoxy-d3)benzonitrile (120 mg, 0.545 mmol, 37.4% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.33 - 7.27 (m, 2H), 6.99 - 6.92 (m, 1H).

[0272] Intermediate benzonitrile listed below was synthesized via the same procedure as 5-fluoro-2- (methoxy-d3)benzonitrile (Example 16) starting with the appropriate phenol at Step 1. 2-fluoro-6-(methoxy-d3)benzonitrile Example 17. Synthesis of 2-(methoxy-d3)nicotinonitrile

[0273] Scheme P.Pd(OAc)2(32 mg, 0.144 mmol, 0.1 eq.) and tBuXPhos (122.6 mg, 0.288 mmol, 0.2 eq.) in toluene (2 mL, 0.722 M) was added Cs2CO3(710 mg, 2.16 mmol, 1.5 eq.) at 25°C. The reaction mixture was stirred at 80°C for 5 min under N2. 2-Chloronicotinonitrile (200 mg, 1.44 mmol, 1 eq.) and methanol-d3(2 ml) was added at 25°C. The reaction was heated at 80°C for 12 hr under N2. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (Ethyl acetate / Petroleum= 0~30%) to afford 2-(methyoxy-d3)nicotinonitrile (200 mg, 1.46 mmol, 101% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.18 (dd, J=7.50, 5.00 Hz, 1 H), 8.23 - 8.30 (m, 1 H), 8.44 - 8.54 (m, 1 H). Example 18. Synthesis of common intermediate (2-(difluoromethoxy)-6-fluorophenyl)methanamine

[0275] Scheme Q.Dkt. Nos.184200.00053(VVID-744PC)

[0276] Step 1. A mixture of Raney Ni (0.05 g) in water (2 mL) was added 2-(difluoromethoxy)-6- fluorobenzonitrile (500 mg, 2.672 mmol, 1 eq.) in methanol (10 mL, 0.267 M) and NH3.MeOH (10 ml) under Ar. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(50 psi) at 25°C for 16 hr. The reaction mixture was filtered and concentrated under reduced pressure to (2-(difluoromethoxy)-6-fluorophenyl)methanamine (450 mg, 2.35 mmol, 88.1% yield).

[0277] Intermediate amines listed below were synthesized via the same procedure as (2- (difluoromethoxy)-6-fluorophenyl)methanamine (Example 18) starting with the appropriate benzonitrile at Step 1. (3,6-difluoro-2-methoxyphenyl)methanamine (2-(difluoromethoxy)-3-fluorophenyl)methanamineExample 19. Synthesis of common intermediate phenylmethan-d2-amine

[0278] Scheme R.of benzonitrile (1.0 g, 9.697 mmol, 1 eq.) in THF (20 mL, 0.485 M) was added LiAlD4(776 mg, 19.3 mmol, 2 eq.) at 0°C under N2. The mixture was stirred for 2 hr at 25°C. TLC (PE: Ethyl acetate = 3 : 1, Rf (reactant) = 0.60, Rf (product) = 0.10) indicated reaction completion. The mixture was diluted THF (20 ml) and quenched with water (1 mL). After 5 min, 10% NaOH (1 ml) was added. After another 5 min, water (1 mL) was added. The mixture was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford phenylmethan-d2-amine (1.0 g, 9.16 mmol,94.5% yield) as a white solid, which was used without further purification.1H NMR (400 MHz, CHLOROFORM- d) δ = 3.71 - 3.81 (m, 1 H), 7.15 - 7.20 (m, 1 H), 7.21 - 7.32 (m, 3 H).

[0280] Intermediate amine listed below was synthesized via the same procedure as phenylmethan-d2- amine (Example 19) starting with the appropriate nitrile at Step 1. 94 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (2-(methoxy-d3)pyridin-3-yl)methan-d2-amine Example 20. Synthesis of common intermediate (2,3-difluoro-6-methoxyphenyl)methanamine

[0281] Scheme S. (1 g, 5.810 mmol, 1 eq.), hydroxylaminehydrochloride (807.4 mg, 11.619 mmol, 2 eq.) in methanol (15 mL, 0.1937 M) and NaOH (929 mg, 4 eq.) in water (45 mL) was stirred at 25°C for 3 hr. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (200 ml). The organic layers were washed with 1 M HCl (50 mL × 2), saturated NaHCO3(100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (E)-2,3-difluoro-6-methoxybenzaldehyde oxime (1.20 g,5.77 mmol, 99.3% yield) as a white solid.

[0283] Step 2. To a mixture of (E)-2,3-difluoro-6-methoxybenzaldehyde oxime (500 mg, 2.672 mmol, 1 eq.) in methanol (5 mL, 0.5343 M) and aminomethanol (8 mL) was added Raney Ni (0.4 g) at 25°C. The mixture was stirred at 25°C for 16 hr under H2at 50 psi. TLC (PE : Ethyl acetate= 3:1, Rf (reactant) = 0.50, Rf (product) = 0.1) indicated reaction completion. The reaction mixture was filtered and concentrated under reduced pressure to afford (2,3-difluoro-6-methoxyphenyl)methanamine (350 mg, 1.41 mmol, 53.0% yield) as a brown solid.

[0284] Intermediate amine listed below was synthesized via the same procedure as (2,3-difluoro-6- methoxyphenyl)methanamine (Example 20) starting with the appropriate aldehyde at Step 1. (2-(difluoromethoxy)-3,6-difluorophenyl)methanamine Example 21. Synthesis of 3-(benzylamino)-5-cyclopropylpicolinic acid

[0285] Scheme T.mmol, 1 eq.) in DMSO (10 mL, 0.427 M) was added phenylmethanamine (686.9 mg, 6.41 mmol, 1.5 eq.) at 25°C under 95 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) N2, then the mixture was heated at 110°C for 16 hr. TLC (PE : Ethyl acetate= 3:1, Rf (reactant) = 0.50, Rf (product) = 0.40) indicated reaction completion. The reaction mixture was concentrated under reduced pressure, and then diluted with brine (15 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford methyl 3-(benzylamino)-5-bromopicolinate (1.0 g, 3.11 mmol, 72.9% yield) as a brown solid, which was used without further purification.

[0287] Step 2. To a mixture of methyl 3-(benzylamino)-5-bromopicolinate (200 mg, 0.623 mmol, 1 eq.) in toluene (4 mL, 0.125 M) and water (1 mL, 0.125 M) was added potassium cyclopropyltrifluoroborate (110.6 mg, 0.747 mmol, 1.2 eq.), cesium carbonate (405.8 mg, 1.245 mmol, 2 eq.) and RuPhos Pd G3 (52.1 mg, 0.0623 mmol, 0.1 eq.) at 25°C under N2, then the mixture was heated at 110°C for 24 hr. TLC (PE : Ethyl acetate= 1:1, Rf (reactant) = 0.60, Rf (product) = 0.40) indicated reaction completion. The reaction mixture was concentrated under reduced pressure, and then diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO2, PE:EtOAc= 1:1) to afford methyl 3-(benzylamino)-5-cyclopropylpicolinate (80 mg, 0.283 mmol, 45.5% yield) as a yellow oil.

[0288] Step 3. To a solution of methyl 3-(benzylamino)-5-cyclopropylpicolinate (80 mg, 0.283 mmol, 1 eq.) in THF (1 mL, 0.189 M) and water (0.50 mL) was added LiOH (29.7 mg, 0.708 mmol, 2.5 eq.) at rt. The mixture was stirred at 25°C for 12 hr. The mixture reaction was filtered to afford 3-(benzylamino)-5- cyclopropylpicolinic acid (80 mg, 0.298 mmol, 105% yield) as a pale-yellow solid, which was used without further purification.

[0289] Intermediate carboxylic acids listed below were synthesized via the same procedure as 3- (benzylamino)-5-cyclopropylpicolinic acid (Example 21) starting with the appropriate aryl halide and amine at Step 1. 2-(benzylamino)-6-cyclopropylnicotinic acid96 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Example 22. Synthesis of 1-methylcyclopropane-1-carboximidamide

[0290] Scheme U. 1-carboxylic acid (2.0 g, 19.976 mmol, 1 eq.) inmL, was g, 21.974 mmol, 1.1 eq.) at 0°C. The reaction was stirred at 25°C for 2 hr. The reaction mixture was added a solution of NH3(5 mL) at -40°C and stirred for 1 hr at -40°C then 12 hr at 25°C. TLC (PE : Ethyl acetate=3:1 , Rf (reactant) =0.5, Rf (product) = 0.4) showed the starting material was consumed completely. The mixture was concentrated under reduced pressure to afford crude 1-methylcyclopropane-1-carboxamide (2.0 g, 20.18 mmol, 101% yield), which was used without further purification.

[0292] Step 2. To a solution of 1-methylcyclopropane-1-carboxamide (1.5 g, 15.132 mmol, 1 eq.) in DCM (15 mL, 1.0 M) was added trimethyloxonium tetrafluoroborate (2.23 g, 15.132 mmol, 1 eq.) at 0°C. After stirred at 25°C for 12 hr, the mixture was added NH3 / MeOH (21.0 mL, 7 mmol / L, 10 eq.) at 25°C. The reaction was heated at 70°C for 12 hr. After cooled to rt, the mixture was concentrated under reduced pressure to afford crude 1-methylcyclopropane-1-carboximidamide (1.5 g, 15.28 mmol, 101% yield), which was used without further purification.

[0293] Intermediate amidines listed below were synthesized via the same procedure as 1- methylcyclopropane-1-carboximidamide (Example 22) starting with the appropriate acid at Step 1. 2,2-difluoropropanimidamideExample 23. Synthesis of common intermediate ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5- carboxylate

[0294] Scheme V.mmol, 1 eq.) and diethyl ethoxymethylenemalonate (4.37 g, 20.201 mmol, 1 eq.) in MeCN (30 mL, 0.673 M) was added potassium carbonate (2.79 g, 20.201mmol, 1 eq.) at 25°C and stirred for 3 hr at 70°C under N2. The mixture was concentrated under reduced pressure and the resultant residue was re-crystallized from MTBE (10 mL) 97 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) to afford ethyl 4-hydroxy-2-(trifluoromethyl)pyrimidine-5-carboxylate (4.50 g, 19.1 mmol, 94.3% yield) as a white solid.

[0296] Step 2. A mixture of ethyl 4-hydroxy-2-(trifluoromethyl)pyrimidine-5-carboxylate (500 mg, 2.12 mmol, 1 eq.) and POCl3(5 ml) was heated at 80°C for 3 hr under N2. The mixture was concentrated under reduced pressure to afford ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (400 mg, 1.57 mmol, 74.2% yield) as a yellow oil.

[0297] Intermediate aryl chlorides listed below were synthesized via the same procedure as ethyl 4-chloro- 2-(trifluoromethyl)pyrimidine-5-carboxylate (Example 23) starting with the appropriate amidine at Step 1. ethyl 4-chloro-2-cyclopropylpyrimidine-5-carboxylate ethyl 4-chloro-2-(1-methylcyclopropyl)pyrimidine-5-carboxylatea p e . y es s o e y -a o- -cyc op opy py a e- -ca o y a e

[0298] Scheme W.2-amine (500 mg, 2.399 mmol, 1 eq.) in toluene (9 mL, 0.240 M) and water (1 mL, 0.240 M) was added potassium cyclopropyltrifluoroborate (248.5 mg, 1.679 mmol, 0.7 eq.), cesium carbonate (2.36 g, 7.196 mmol, 3 eq.), butyl-di(1-adamantyl)phosphine (85 mg, 0.1 eq.) and palladium(II) acetate (54.3 mg, 0.240 mmol, 0.1 eq.). The mixture was heated at 100°C for 12 hr under N2. TLC (PE : Ethyl acetate= 3:1, Rf (reactant) = 0.4, Rf (product) = 0.6) indicated reaction completion. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (EtOAc / PE = 0~8%) to afford 3-chloro- 6-cyclopropylpyrazin-2-amine (300 mg, 1.77 mmol, 73.7% yield) as a brown oil.

[0300] Step 2. A mixture of Pd(dppf)Cl2(1 g) in MeOH (30 mL) was added 3-chloro-6- cyclopropylpyrazin-2-amine (2.0 g, 11.79 mmol, 1 eq.) in MeOH (50 mL, 0.236 M) and TEA (2.0 g, 1.5 eq.) under Ar. The suspension was degassed under vacuum and purged with CO several times. The mixture 98 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) was stirred under CO (50 psi) at 80°C for 24 hr. TLC (PE: Ethyl acetate= 2:1, Rf (reactant) = 0.6, Rf (product) = 0.4) indicated reaction completion. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (PE: ethyl acetate = 2: 1, Rf (product) = 0.4) to afford methyl 3-amino-5-cyclopropylpyrazine-2-carboxylate (1.8 g, 9.33 mmol, 79.1% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 0.93 - 1.10 (m, 4H), 2.02 - 2.18 (m, 1H), 3.75 - 3.86 (m, 3H), 7.13 - 7.30 (m, 2H), 7.85 - 7.94 (m, 1H). Example 25. Synthesis of methyl 3-amino-5-(1-methylcyclopropyl)pyrazine-2-carboxylate

[0301] Scheme X. 1 eq.) in DCM(10 mL, 0.096 M) was added di-tert-butyl dicarbonate (418.8 mg, 1.919 mmol, 2 eq.) and TEA (485 mg, 1.92 mmol, 2 eq.) and DMAP (29.3 mg, 0.24 mmol, 0.25 eq.) at 0°C. The mixture was stirred at 25°C for 12 hr. The reaction mixture was concentrated under reduced pressure, diluted with water (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO2, PE:EtOAc= 5:1, Rf (reactant) = 0.20, Rf (product) = 0.60) to tert-butyl (6-bromo-3- chloropyrazin-2-yl)(tert-butoxycarbonyl)carbamate (200 mg, 0.489 mmol, 51.0% yield) as a pale yellow solid.

[0303] Step 2. To a solution of tert-butyl (6-bromo-3-chloropyrazin-2-yl)(tert-butoxycarbonyl)carbamate (3.0 g, 7.341 mmol, 1 eq.) in 1,4-dioxane (30 mL, 0.204 M) and water (6mL, 0.204 M) was added 2- isopropenylboronic acid pinacol ester (863.5 mg, 5.139 mmol, 0.7 eq.), K3PO4(3.12 g, 14.76 mmol, 2 eq.) and PdCl2(dppf)(600 mg, 0.738mmol, 0.1eq.) at 25°C under N2. The reaction was stirred at 70°C for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (Ethyl acetate / PE = 0~30%) to afford tert-butyl (tert-butoxycarbonyl)(3- chloro-6-(prop-1-en-2-yl)pyrazin-2-yl)carbamate (2.2g, 5.95 mmol, 81.0% yield) as a yellow solid. 99 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0304] Step 3. To a solution of trimethylsulfoxonium iodide (3.99 g, 18.16 mmol, 5 eq.) in DMSO (15 mL, 0.242 M) was added sodium hydride (434.8 mg, 18.115 mmol, 5 eq.) at 0°C under N2. The mixture was stirred at 25°C for 30 min. Then tert-butyl (tert-butoxycarbonyl)(3-chloro-6-(prop-1-en-2-yl)pyrazin- 2-yl)carbamate (1.34 g, 3.623 mmol, 1 eq.) was added under N2. The mixture was stirred at 25°C for 2 hr. The reaction was poured into NH4Cl (aq) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (petroleum ether: ethyl acetate = 5: 1, Rf (reactant) = 0.60, Rf (product) = 0.7) to afford tert-butyl (3-chloro-6-(1-methylcyclopropyl)pyrazin-2- yl)carbamate (300 mg, 1.06 mmol, 29.2% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM- d) δ = 8.01 (s, 1H), 1.56 - 1.50 (m, 11H), 1.37 - 1.31 (m, 2H), 0.89 - 0.83 (m, 3H).

[0305] Step 4. To a solution of tert-butyl (3-chloro-6-(1-methylcyclopropyl)pyrazin-2-yl)carbamate (250 mg, 0.8810 mmol, 1 eq.) in methanol (5 mL, 0.176 M) was added triethylamine (267.5 mg, 2.643 mmol, 3 eq.) and PdCl2(dppf) (63.8 mg, 0.0881 mmol, 0.1 eq.) at 25°C under Ar. The suspension was degassed under vacuum and purged with CO several times. The mixture was heated at 80°C under CO (50 psi) for 24 hr. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (petroleum ether: ethyl acetate = 3: 1, Rf (reactant) = 0.50, Rf (product) = 0.7) to afford methyl 3-((tert-butoxycarbonyl)amino)-5-(1-methylcyclopropyl)pyrazine-2-carboxylate (200 mg,0.651 mmol, 73.9% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 9.91 (s, 1H), 8.28 (br s, 1H), 4.02 (s, 3H), 1.59 (s, 3H), 1.54 (s, 9H), 1.52 - 1.47 (m, 2H), 1.00 - 0.95 (m, 2H).

[0306] Step 5. To a solution of methyl 3-((tert-butoxycarbonyl)amino)-5-(1-methylcyclopropyl)pyrazine- 2-carboxylate (200 mg, 0.651 mmol, 1 eq.) in EtOAc (4 mL, 0.163 M) was added HCl / EtOAc (4 mol / L, 2 mL) at 25°C. The reaction was stirred at 25°C for 2 hr. The reaction mixture was concentrated under reduced pressure to afford crude methyl 3-amino-5-(1-methylcyclopropyl)pyrazine-2-carboxylate (180 mg ) as a yellow solid, which was used without further purification. Example 26. Synthesis of common intermediate methyl 3-chloro-5-cyclopropylpyrazine-2-carboxylate

[0307] Scheme Y.amino-5-cyclopropylpyrazine-2-carboxylate (1.5 g, 7.764 mmol, 1 eq.) in DCM (15 mL, 0.518 M) was added TMS-Cl (2.1 g, 19.4 mmol, 2.5 eq.) and t-BuNO (6.9 g, 77.6 mmol, 10 eq.) at 0°C. The reaction was stirred at 25°C for 2 hr. The mixture was diluted with water (150 mL) and extracted with DCM (150 mL × 3). The combined organic layers were washed with brine (200 100 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (Ethyl acetate / Petroleum ether = 0~30%) to afford methyl 3- chloro-5-cyclopropylpyrazine-2-carboxylate (1.2g, 5.64 mmol, 72.7% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 1.16 - 1.24 (m, 4H), 2.07 - 2.17 (m, 1H), 3.96 - 4.04 (m, 3H), 8.40 - 8.50 (m, 1H).

[0309] Intermediate aryl chloride listed below was synthesized via the same procedure as methyl 3-chloro- 5-cyclopropylpyrazine-2-carboxylate (Example 26) starting with the appropriate aniline at Step 1. methyl 3-chloro-5-(1-methylcyclopropyl)pyrazine-2-carboxylate Example 27. Synthesis of common intermediate methyl 2,5-dichloro-6-cyclopropylnicotinate

[0310] Scheme Z. 1 eq.), potassiumcyclopropyltrifluoroborate (538.7 mg, 3.640 mmol, 1.5 eq.) and potassium carbonate (1.0 g, 7.281 mmol, 3 eq.) in 1,4-dioxane (5 mL, 0.405 M) and water (1 mL, 0.405 M) was added Pd(dppf)Cl2(176.1 mg, 0.243 mmol, 0.1 eq.) under N2. The mixture was heated at 80°C for 16 hr under N2. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 30 / 1) to afford methyl 5-chloro-6-cyclopropylnicotinate (390 mg, 1.66 mmol, 68.3% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.90 - 8.84 (m, 1H), 8.15 (d, J=1.9 Hz, 1H), 3.92 (s, 3H), 2.62 - 2.52 (m, 1H), 1.22 - 1.17 (m, 2H), 1.15 - 1.08 (m, 2H).

[0312] Step 2. To a solution of methyl 5-chloro-6-cyclopropylnicotinate (390 mg, 1.843 mmol, 1 eq.) in DCM (5 mL, 0.369 M) was added 3-chloroperbenzoic acid (993.7 mg, 4.607 mmol, 2.5 eq.) in portions during a period of 10 min. The mixture was stirred at 25°C for 12 hr. Sodium thiosulfate aqueous solution (20 mL) was added and the mixture was stirred for 10 min. Saturated sodium bicarbonate aqueous solution (10 mL) was added and the mixture was stirred for another 10 min. The reaction mixture was poured into water (15 mL) and extracted with DCM (15 mL × 3), and washed by brine (10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude 3-chloro-2- cyclopropyl-5-(methoxycarbonyl)pyridine 1-oxide (290 mg, 1.02 mmol, 55.3% yield).1H NMR (400 MHz, CHLOROFORM-d) δ = 8.66 (d, J=1.4 Hz, 1H), 7.81 (d, J=1.4 Hz, 1H), 3.94 (s, 3H), 2.22 (tt, J=5.8, 8.7 Hz, 1H), 1.65 - 1.53 (m, 2H), 1.32 - 1.11 (m, 2H). 101 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0313] Step 3. To a solution of 3-chloro-2-cyclopropyl-5-(methoxycarbonyl)pyridine 1-oxide (290 mg, 1.274 mmol, 1 eq.) in toluene (5 mL, 0.255 M) was added phosphorus oxychloride (0.594 mL, 6.370 mmol, 1.645 g / ml, 5 eq.) at 0°C. The reaction was heated at 90°C for 3 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO2, PE:EtOAc= 10:1) to afford methyl 2,5-dichloro-6-cyclopropylnicotinate (170 mg, 0.691 mmol,54.2% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 1.12 - 1.18 (m, 2H), 1.19 - 1.24 (m, 2H), 2.52 (tt, J=7.97, 4.78 Hz, 1H), 3.94 (s, 3H), 8.11 (s, 1H).

[0314] Intermediate aryl chloride listed below was synthesized via the same procedure as methyl 2,5- dichloro-6-cyclopropylnicotinate (Example 27) starting with the appropriate aryl halide at Step 1. methyl 2-chloro-6-cyclopropyl-5-fluoronicotinate Example 28. Synthesis of common intermediate methyl 3-chloro-5-(trifluoromethyl)pyrazine-2- carboxylate

[0315] Scheme AA. 1 eq.) in HI(10 mL) was added NaI (1.5 g, 10.363 mmol, 2 eq.). The reaction mixture was stirred at 50°C for 4 hr. After cooled to rt, the reaction mixture was added water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford a 3:1 mixture of 3-chloro-5-iodopyrazine-2-carboxylic acid and 5-chloro-3-iodopyrazine-2-carboxylic acid (1.7 g) as a dark brown solid, which was used without further purification.

[0317] Step 2. To a 3:1 mixture of 3-chloro-5-iodopyrazine-2-carboxylic acid and 5-chloro-3- iodopyrazine-2-carboxylic acid (1.7 g, 5.977 mmol, 1 eq.) in DMF (17 mL, 0.352 M) was added NaHCO3(1.5 g, 17.928 mmol, 3 eq.) and iodomethane (4.24 g, 29.883 mmol, 5 eq.) at rt. The reaction mixture was stirred at 25°C for 2 hr. The reaction mixture was added water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PE / Ethyl acetate=1 / 0 to 3 / 1) to give a 3:1 mixture of methyl 3-chloro-5-iodopyrazine-2-carboxylate and methyl 5-chloro-3-iodopyrazine-2-carboxylate (1.1 g, 3.68 mmol, 61.6% yield) as a yellow solid.

[0318] Step 3. To a 3:1 mixture of methyl 3-chloro-5-iodopyrazine-2-carboxylate and methyl 5-chloro-3- iodopyrazine-2-carboxylate (1.0 g, 3.35 mmol, 1 eq.) in DMF (20 mL, 0.117 M) was added methyl 2,2- 102 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) difluoro-2-(fluorosulfonyl)acetate (0.901 g, 4.691 mmol, 2 eq.) and CuI (1.27 g, 6.711 mmol, 2 eq.). The reaction mixture was heated at 95°C for 2 hr. TLC (PE:EtOAc=5:1, Rf(starting material)=0.6, Rf(product)=0.7) indicated reaction completion. EtOAc (50 mL) was added to the reaction mixture and filtered. The filtrate was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (neutral condition) to afford methyl 3-chloro-5-(trifluoromethyl)pyrazine-2-carboxylate (100 mg, 0.416 mmol, 17.7% yield) as a green yellow oil, separated from the minor isomer.1H NMR (400 MHz, CHLOROFORM- d) δ = 4.09 (s, 3H), 8.92 (s, 3H). Example 29. Synthesis of methyl 4,6-dichloro-2-(1-methylcyclopropyl)pyrimidine-5-carboxylate

[0319] Scheme BB. mmol, 0.2 eq.) was added to the mixture of methyl 4,6-dichloropyrimidine-5-carboxylate (400 mg, 1.932 mmol, 1 eq.), 1-methylcyclopropanecarboxylic acid (580.4 mg, 5.797 mmol, 3 eq.) and ammonium persulfate (1.32 g, 5.797 mmol, 3 eq.) in acetone (5 mL, 0.193 M) and water (5 mL, 0.193 M). The resulting mixture was stirred at 25°C for 48 hr under N2. The reaction mixture was poured into water (10 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO2, PE:EtOAc= 3:1) to afford methyl 4,6-dichloro-2-(1-methylcyclopropyl)pyrimidine-5-carboxylate (50 mg,0.150 mmol 7.8% yield) as a white oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 3.99 (s, 3H), 1.58 - 1.49 (m, 3H), 1.49 - 1.43 (m, 2H), 1.09 - 0.98 (m, 2H). Example 30. Synthesis of methyl 2-fluoro-6-(prop-1-en-2-yl)nicotinate

[0321] Scheme CC.6-bromo-2-fluoronicotinate (1.5 g, 6.410 mmol, 1 eq.) in toluene (8 mL, 0.641 M) and water (2 mL, 0.641 M) was added potassium trifluoro(prop-1-en-2-yl)borate (1.04 g, 7.051 mmol, 1.1 eq.) and Cs2CO3(4.17 g, 12.8 mmol, 2 eq.) and RuPhos Pd G3 (534 mg, 0.64 mmol, 0.1 eq.) at 25°C under N2. The reaction was heated at 110°C for 16 hr. The mixture was diluted with water (15 103 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 3 / 1) to give methyl 2-fluoro-6-(prop-1-en-2-yl)nicotinate (1.0 g, 4.61 mmol, 71.9% yield) as a white solid.

[0323] Intermediate aryl fluoride listed below was synthesized via the same procedure as methyl 2-fluoro- 6-(prop-1-en-2-yl)nicotinate (Example 30) starting with the appropriate aryl bromide and boronate at Step 1. methyl 4-cyclopropyl-2,6-difluorobenzoate Example 31. Synthesis of methyl 6-(1,1-difluoroethyl)-2-fluoronicotinate

[0324] Scheme DD. nicotinate (1.0 g, 5.123 mmol, 1 eq.) inTHF (15 mL, 0.256 M) and water (5 mL, 0.256 M) was added potassium osmate(VI) dihydrate (180 mg, 0.51 mmol, 0.1 eq.) and NaIO4(9.86 g, 46.1 mmol, 9 eq.) at 0°C. The reaction mixture was stirred at 25°C for 2 hr. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO2, PE:EtOAc= 3:1) to afford methyl 6-acetyl-2-fluoronicotinate (515 mg, 2.48 mmol, 48.4% yield) as a white solid.

[0326] Step 2. To a solution of methyl 6-acetyl-2-fluoronicotinate (100 mg, 0.507 mmol, 1 eq.) in toluene (5 mL, 0.101 M) was added Deoxo-Fluor(R) (1.12g, 5.072 mmol, 10 eq.) dropwise at 0°C under N2. The mixture was heated at 120°C for 2 hr. The reaction mixture was poured into NaHCO3(10 mL) and extracted with EtOAc (10 mL × 3) and washed by brine (10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO2, PE:EtOAc= 3:1) to afford methyl 6-(1,1-difluoroethyl)-2-fluoronicotinate (60 mg, 0.235 mmol,46.4% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.53 - 8.37 (m, 1H), 7.69 (br dd, J=4.4, 8.6 Hz, 1H), 4.01 - 3.95 (m, 3H), 2.01 (t, J=18.6 Hz, 3H). 104 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Example 32. Synthesis of 2-(benzylamino)-5-chloro-4-(trifluoromethyl)benzoic acid

[0327] Scheme EE. 1.5 eq.) was added to THF (15 mL,n-butyl lithium (2.5 M, 4.53 mL) was added dropwise within about 45 min at a controlled temperature below 3°C. The reaction mixture was allowed to warm to 0°C for 1 hr, and then cooled to -78°C. 1-Chloro-4-fluoro-2-(trifluoromethyl)benzene (1.5 g, 7.555 mmol, 1 eq.) was added dropwise, and the reaction mixture was stirred for 3 hr. Excess dry ice was added, and the reaction mixture was allowed to warm to 0°C, followed by addition of ice water (15 mL). The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, EtOAc / PE = 0~25%) to afford 5-chloro-2-fluoro-4- (trifluoromethyl)benzoic acid (1.40 g, 5.77 mmol, 76.4% yield) as a light pink solid.1H NMR (400 MHz, DMSO-d6) δ = 7.94 (d, J=10.26 Hz, 1 H), 8.07 (d, J=6.13 Hz, 1 H), 14.06 (br s, 1 H).

[0329] Step 2. To a mixture of 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (1g, 4.123 mmol, 1 eq.) in DMSO (10 mL, 0.412 M) was added potassium carbonate (1.71 g, 12.369 mmol, 3 eq.) and phenylmethanamine (441.8 mg, 4.123 mmol, 1 eq.) at rt. The mixture was heated at 130°C for 12 hr under N2. TLC (PE / ethyl acetate= 1 / 1, Product: Rf =0.3) indicated reaction completion. After cooled to rt, the reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-(benzylamino)-5-chloro-4- (trifluoromethyl)benzoic acid (500 mg, 0.758 mmol, 18.4% yield) as a white solid. 105 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Example 33. Synthesis of common intermediate 4-(benzylamino)-2-cyclopropylpyrimidine-5-carboxylic acid

[0330] Scheme FF. 5-carboxylate (130 mg, 0.574mg, (2 mL, 0.287 M) was added potassium carbonate (237.8 mg, 1.721 mmol, 3 eq.) at 25°C. The mixture was heated at 80°C for 12 hr under N2. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (3 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was was purified by column chromatography (SiO2, PE / Ethyl acetate=1 / 0 to 3 / 1) to afford ethyl 4-(benzylamino)-2-cyclopropylpyrimidine-5-carboxylate (130 mg, 0.437 mmol, 76.2% yield) as a yellow oil.

[0332] Step 2. To a mixture of ethyl 4-(benzylamino)-2-cyclopropylpyrimidine-5-carboxylate (100 mg, 0.336 mmol, 1 eq.) in THF (1 mL, 0.168 M) and water (1 mL, 0.168 M) was added lithium hydroxide monohydrate (35.3 mg, 0.841 mmol, 2.5 eq.) at 25°C. The mixture was heated at 40°C for 2 hr under N2. TLC (PE : Ethyl acetate= 5:1, Rf (reactant) = 0.5, Rf (product) = 0.01) indicated reaction completion. After filtration, the filtrate was concentrated to afford 4-(benzylamino)-2-cyclopropylpyrimidine-5-carboxylic acid lithium salt (70 mg, 0.260 mmol 77.3% yield) as a white solid.

[0333] Intermediate carboxylic acids listed below were synthesized via the same procedure as 4- (benzylamino)-2-cyclopropylpyrimidine-5-carboxylic acid (Example 33) starting with the appropriate aryl halide and amine at Step 1. 4-(benzylamino)-2-(trifluoromethyl)pyrimidine-5-carboxylic acid106 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) 2-cyclopropyl-4-((2-fluoro-6-methoxybenzyl)amino)pyrimidine-5-carboxylic acid 2-cyclopropyl-4-((5-fluoro-2-methoxybenzyl)amino)pyrimidine-5-carboxylic acid107 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) 4-((2,5-difluorobenzyl)amino)-2-(1-fluorocyclopropyl)pyrimidine-5-carboxylic acid 4-((2,5-difluorobenzyl)amino)-2-(1-(trifluoromethyl)cyclopropyl)pyrimidine-5-carboxylic acid108 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) 2-(benzylamino)-4-cyclopropyl-6-fluorobenzoic acid 2-((2,5-difluorobenzyl)amino)-6-(1,1-difluoroethyl)nicotinic acid. (trifluoromethyl)benzamide (Compound 1)

[0334] Scheme GG.acid (50 mg, 0.169 mmol, 1 eq.) and (E)-3-(methylsulfonyl)prop-2-en-1-amine p-toluenesulfonic acid salt (52.1 mg, 0.169 mmol, 1 eq.) in DCM (3 mL, 0.0564 M) was added N,N-diisopropylethylamine (54.7 mg, 0.423 mmol, 2.5 eq.) and HATU (118 mg, 0.310 mmol, 1.8 eq.) at rt. The mixture was stirred at 15°C for 30 min. The reaction mixture was quenched by water (10 ml) and extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to afford (E)-2-(benzylamino)-N-(3- (methylsulfonyl)allyl)-4-(trifluoromethyl)benzamide (26.7 mg, 0.065 mmol, 38.1% yield) as a white solid. [M+H] calculated for C19H19F3N2O3S, 412.1; found 413.1.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.49 (d, J=8.03 Hz, 1 H) 7.37 (d, J=4.39 Hz, 4 H) 7.28 - 7.33 (m, 1 H) 7.00 (dt, J=15.21, 4.56 Hz, 1 H) 6.92 (s, 1 H) 6.86 (d, J=7.65 Hz, 1 H) 6.53 (br d, J=14.93 Hz, 1 H) 6.39 (br s, 1 H) 4.42 (s, 2 H) 4.30 (br t, J=4.27 Hz, 2 H) 2.94 (s, 3 H). 109 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0336] Starting with the appropriate carboxylic acid and amine, the following compounds were synthesized in an analogous manner to (E)-2-(benzylamino)-N-(3-(methylsulfonyl)allyl)-4- (trifluoromethyl)benzamide (Compound 1). Table 2. LCMS Cmpd. No.1H NMR [M+H] .07 d, - m, 1 (br , .26 2 , s, .00 ) 1 ,110 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 3 - .01 .05 t, 2 29 0 40 Hz, 23 3 - r 27 H) m, 7 3 59111 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 3 6 = J= , m, = 5 m, , z, .3, H), J= ,112 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] z, 6 5, z, 5 7 7 , 02 H) (br z, , , z, 1 9 0113 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] z, 2, 1 , 8 = .0 6 J= Hz,114 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] , 1 , .1, z, 4 1 , 3 .1 ,115 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] z, 8 m, 43 z, .9, .8 z, z, 1 , z, ,116 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] z, , z, , , z, , m, z, ), z, z, 8 J=117 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 71 ), ) z, , 68 88 J= 5 z, m, z, 42 7 .64 z, )118 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] .11 2 .48 z, , .06 5 - ) m, .06 4 - ) .70 9 - ) , 4 40 H), 8119 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 50 3 - 19 - .49 .79 9 .00 2 1 H) .59 06 H) .34 H) 94120 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] .8, 66 .12 r .37 .44 7 8 41 19 .12 9 - z, 76121 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] .27 ) ) .17 ) 06 .78 6 z, 96 .17 1 - ) .16 6 H) .40 1 - , 64 s,122 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] z, 00 z, 6 z, 1 41 z, 0 6 J= .75 3 50123 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 67 , 7.7 66 m, 07 m, z, , z, , 1 z, , ,124 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 46 , 45 , m, ), , 5 0 , = , , ),125 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 51 Hz, , z, , 2, 1 .21 8 - 1 z, z, .08 t,126 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 58 , 0 44 - 4 52 - .21 8 - ) .01 8 - .28 4 - ) m, H), ),127 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 95 J= 52 , J= H), 55 52 ), z, , 7.9128 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 0 - 36 ), 56 , H), 32 ) 4 2 z, ) m, .02 9 -129 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] br .03 0 - ) 01 , .4 .72 H), .99 2 - ) m, z, 0130 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] , 1.7 ), ), .42 4 - ) z, , z, , z, , z, .9 .7 s,131 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] H), 6 = z, J= ), z, z, 4 - 3 2 2 z, 9 H), z, z, H),132 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] z, ) m, .80 7 - ) m, .80 m, 87 .79 8 - ) m, .55 H)133 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] .77 4 63 br .77 ) 1 s, 0 - .79 ) ) Hz, .79 8 - ) 71 .77 5 - )134 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] .49 3 - ) m, .71 m, d, 05 .83 3 - ) d, 4 .02 H) 67 (s,135 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] .81 ) , 1 05 = ), 02 5.1 = 9 72 , 41136 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] 51 z, .81 3 (s, H) 95 (m, .77 ) , 6 ) r s, .79 5 - )137 91894028.1Dkt. Nos.184200.00053(VVID-744PC) LCMS Cmpd. No.1H NMR [M+H] .80 H) 25 H) 0 3 m, .83 4 - ) H) .81 9 - )138 91894028.1Dkt. Nos.184200.00053(VVID-744PC) BIOLOGICAL EXAMPLES Example 35. Synthesis of JAK1_C817 Fluorescent Probe 5-(4-(5-(((R)-3-(3-((S)-3-(3,4- dichlorophenyl)piperidin-1-yl)-3-oxoprop-1-yn-1-yl)pyrrolidin-1-yl)sulfonyl)pentyl)piperazine-1- carbonyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate

[0337] Scheme HHDkt. Nos.184200.00053(VVID-744PC)

[0338] Step 1. To a solution of 1-bromo-3,4-dichlorobenzene (3.0 g, 13.281 mmol, 1 eq.) in 1,4-dioxane (20 mL, 0.553 M) and water (4 mL, 0.553 M) was added 1-Boc-5,6-dihydro-2H-pyridine-3-boronic acid pinacol ester (4.1 g, 13.281 mmol, 1 eq.) and K2CO3(5.5 g, 3 eq.) and Pd(dppf)Cl2(1 g, 0.1 eq.) at 25°C under N2. The mixture was heated at 80°C for 18 hr under N2. After cooled to rt, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~30% EA / PE) to afford tert-butyl 5-(3,4-dichlorophenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (4.0 g, 12.2 mmol, 91.8% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 1.34 - 1.52 (m, 9H), 2.16 - 2.31 (m, 2H), 3.41 - 3.55 (m, 2H), 4.04 - 4.24 (m, 2H), 6.10 - 6.21 (m, 1H), 7.06 - 7.16 (m, 1H), 7.28 - 7.42 (m, 2H).

[0339] Step 2. A mixture of PtO2(400 mg) in MeOH (10 mL) was added tert-butyl 5-(3,4-dichlorophenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (2.0 g, 6.093 mmol, 1 eq.) in MeOH (50 mL, 0.122 M) under Ar. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) at 25°C for 30 min. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 3-(3,4-dichlorophenyl)piperidine-1-carboxylate (1.5 g, 4.54 mmol, 74.5% yield) as a yellow solid, which was purified by prep-SFC to afford tert-butyl (S)-3-(3,4-dichlorophenyl)piperidine- 1-carboxylate (600 mg) as the first peak in analytical SFC [Column: (S,S)-WHELK-O1, 100x4.6mm, I.D., 3.5 um, Mobile phase A: CO2, B: IPA (0.1%IPAm, v / v)].1H NMR (400 MHz, CHLOROFORM-d) δ = 1.48 (s, 9H), 1.54 - 1.65 (m, 2H), 1.69 - 1.84 (m, 1H), 1.95 - 2.06 (m, 1H), 2.58 - 2.82 (m, 3H), 3.96 - 4.33 (m, 2H), 7.07 (dd, J=8.25, 2.13 Hz, 1H), 7.31 - 7.35 (m, 1H), 7.36 - 7.41 (m, 1H).

[0340] Step 3. A solution of tert-butyl (S)-3-(3,4-dichlorophenyl)piperidine-1-carboxylate (600 mg, 1.817 mmol, 1 eq.) in HCl / dioxane (4 mol / L, 10 mL) was stirred at 25°C for 2 hr. The reaction mixture was concentrated under reduced pressure to afford (S)-3-(3,4-dichlorophenyl)piperidine HCl salt (600 mg) as a yellow solid, which was used without further purification.

[0341] Step 4. To a solution of tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (10 g, 49.685 mmol, 1 eq.) in DCM (100 mL, 0.497 M) was added Dess-Martin periodinane (3.1 g, 1.5eq.) at 0°C and the mixture was stirred at 25°C for 3 hr. TLC (PE:EtOAc=1:1; Rf(substrate)=0.2, Rf(product)=0.6) showed reaction completion. 10% Na2S2O3(20 mL) was added to the mixture and stirred at 20°C for 0.5 hr. The mixture was partitioned and the organic phase was washed with sat. NaHCO3(20 mL) and brine (20 mL), dried over anhydrous Na2SO4. The reaction mixture was filtered and concentrated under reduced pressure to afford tert-butyl (S)-3-formylpyrrolidine-1-carboxylate (9.0 g, 45.2 mmol, 90.9% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 1.41 - 1.44 (m, 9H), 2.14 - 2.34 (m, 2H), 2.94 - 3.10 (m, 1H), 3.23 - 3.55 (m, 4H), 9.65 (d, J=1.47 Hz, 1H). 140 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0342] Step 5. To a solution of tert-butyl (S)-3-formylpyrrolidine-1-carboxylate (9 g, 45.2 mmol, 1 eq.) in methanol (100 mL, 0.452 M) was added dimethyl (1-diazo-2-oxopropyl)phosphonate (11.3 g, 58.72 mmol, 1.3 eq.), followed by K2CO3(15.8 g, 2.3 eq.) at 0°C and the reaction was stirred at 25°C for 12 hr. TLC (PE:EtOAc=5:1; Rf(starting material)= 0.2; Rf(product)=0.6) showed reaction completion. The mixture was diluted with EtOAc (20 mL), filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE:EtOAc=19:1 to 9:1) to afford tert-butyl (R)-3- ethynylpyrrolidine-1-carboxylate (6.0 g, 30.7 mmol, 68.0% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 1.45 (s, 9H), 1.87 - 1.99 (m, 1H), 2.08 - 2.20 (m, 2H), 2.85 - 3.01 (m, 1H), 3.21 - 3.39 (m, 2H), 3.42 - 3.70 (m, 2H).

[0343] Step 6. To a solution of tert-butyl (R)-3-ethynylpyrrolidine-1-carboxylate (6 g, 30.728 mmol, 1 eq.) in THF (60 mL, 0.512 M) was added n-BuLi (14.75 ml, 36.87 mmol, 1.2 eq.) at -70°C. After 30 min, methyl chloroformate (3.5 g, 37.041 mmol, 1.2 eq.) was added. The reaction mixture was stirred at -70°C for 1.5 hr. TLC (Petroleum ether: Ethyl acetate=5:1, Rf (reactant) =0.5, Rf (product) =0.3) showed the starting material was consumed completely. The mixture was diluted with water (150 mL) and extracted with EtOAc (150 mL × 3). The extract was washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~30% Ethyl acetate / Petroleum ether) to afford tert-butyl (R)-3-(3-methoxy-3-oxoprop-1-yn-1-yl)pyrrolidine-1- carboxylate (7.0 g, 27.6 mmol, 89.9% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 1.41 - 1.48 (m, 9H), 2.00 - 2.03 (m, 1H), 2.12 - 2.26 (m, 1H), 3.01 - 3.15 (m, 1H), 3.36 (br s, 2H), 3.52 (br s, 1H), 3.60 - 3.72 (m, 1H), 3.73 - 3.80 (m, 3H).

[0344] Step 7. To a solution of tert-butyl (R)-3-(3-methoxy-3-oxoprop-1-yn-1-yl)pyrrolidine-1- carboxylate (7 g, 27.635 mmol, 1 eq.) in MeCN (100 mL, 0.276 M) was added TsOH (6 g, 1.1 eq.) at 25°C. The reaction mixture was stirred at 60°C for 12 hr. After cooled to rt, the reaction mixture was concentrated under reduced pressure to afford methyl (R)-3-(pyrrolidin-3-yl)propiolate TsOH salt (3.0 g) as a yellow solid, which was used without further purification.

[0345] Step 8. To a solution of methyl (R)-3-(pyrrolidin-3-yl)propiolate TsOH salt (4 g, 12.293 mmol, 1 eq.) in DCM (50 mL, 0.246 M) was added 5-bromopentane-1-sulfonyl chloride (3.0 g, 12.293 mmol, 1 eq.) and N,N-diisopropylethylamine (13 g, 5 eq.) at 0°C. After stirred at 25°C for 1 hr, the mixture was diluted with water (15 mL) and extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~30% Ethyl acetate / Petroleum ether) to afford methyl (R)-3-(1-((5-bromopentyl)sulfonyl)pyrrolidin-3-yl)propiolate (4.8 g, 13.1 mmol, 107% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 1.82 - 1.95 (m, 6H), 2.07 - 2.20 (m, 1H), 2.24 - 141 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) 2.35 (m, 1H), 2.96 - 3.08 (m, 2H), 3.15 - 3.25 (m, 1H), 3.39 - 3.45 (m, 3H), 3.47 - 3.55 (m, 2H), 3.66 - 3.73 (m, 1H), 3.78 (s, 3H).

[0346] Step 9. To a solution of methyl (R)-3-(1-((5-bromopentyl)sulfonyl)pyrrolidin-3-yl)propiolate (1.6 g, 4.368 mmol, 1 eq.) in MeCN (10 mL, 0.437 M) was added tert-butyl piperazine-1-carboxylate (813.6 mg, 4.368 mmol, 1 eq.) and K2CO3(1.8 g, 3 eq.) at 25°C. The reaction mixture was heated at 50°C for 12 hr. After cooled to rt, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford tert-butyl (R)-4-(5- ((3-(3-methoxy-3-oxoprop-1-yn-1-yl)pyrrolidin-1-yl)sulfonyl)pentyl)piperazine-1-carboxylate (1.0 g,2.12 mmol, 48.5% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 1.46 (s, 11H), 1.50 - 1.57 (m, 2H), 1.80 - 1.90 (m, 2H), 2.07 - 2.18 (m, 1H), 2.24 - 2.41 (m, 7H), 2.96 - 3.04 (m, 2H), 3.19 (quin, J=6.63 Hz, 1H), 3.36 - 3.45 (m, 5H), 3.47 - 3.54 (m, 2H), 3.67 - 3.73 (m, 1H), 3.74 - 3.82 (m, 3H).

[0347] Step 10. To a solution of tert-butyl (R)-4-(5-((3-(3-methoxy-3-oxoprop-1-yn-1-yl)pyrrolidin-1- yl)sulfonyl)pentyl)piperazine-1-carboxylate (340 mg, 0.721 mmol, 1 eq.) in THF (9 mL, 0.060 M) in water (3 mL, 0.060 M) was added LiOH (61 mg, 2 eq.) at 25°C. After stirred at 25°C for 1 hr, the reaction mixture was concentrated and then diluted with water (50 mL) and neutralized by HCl (aq, 1M) to pH= 3-4. The mixture was extracted with EtOAc (5 mL × 3) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (R)-3- (1-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pentyl)sulfonyl)pyrrolidin-3-yl)propiolic acid (400 mg) as a yellow solid, which was used without further purification.

[0348] Step 11. To a solution of (R)-3-(1-((5-(4-(tert-butoxycarbonyl)piperazin-1- yl)pentyl)sulfonyl)pyrrolidin-3-yl)propiolic acid (50 mg, 0.109 mmol, 1 eq.) in DCM (5 mL, 0.0219 M) was added (S)-3-(3,4-dichlorophenyl)piperidine HCl salt (25.1 mg, 0.109 mmol, 1 eq.) and N,N- diisopropylethylamine (0.07 ml, 5 equiv ) and T3P (205 mg, 2.5 eq., 50% in EtOAc) at 0°C. After stirred at 25°C for 1.5 hr, the mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 0: 1 Rf (product) = 0.5 UV) to afford tert-butyl 4-(5-(((R)-3-(3-((S)-3-(3,4-dichlorophenyl)piperidin-1-yl)-3- oxoprop-1-yn-1-yl)pyrrolidin-1-yl)sulfonyl)pentyl)piperazine-1-carboxylate (45 mg, 0.0672 mmol, 61.5% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 1.43 - 1.50 (m, 9H), 1.59 (br s, 10H), 2.01 - 2.50 (m, 8H), 2.60 - 2.77 (m, 2H), 2.90 - 3.29 (m, 4H), 3.33 - 3.76 (m, 8H), 4.29 - 4.41 (m, 1H), 4.53 - 4.70 (m, 1H), 7.04 - 7.14 (m, 1H), 7.31 - 7.36 (m, 1H), 7.37 - 7.47 (m, 1H).

[0349] Step 12. To a solution of tert-butyl 4-(5-(((R)-3-(3-((S)-3-(3,4-dichlorophenyl)piperidin-1-yl)-3- oxoprop-1-yn-1-yl)pyrrolidin-1-yl)sulfonyl)pentyl)piperazine-1-carboxylate (45 mg, 0.0672 mmol, 1 eq.) 142 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) in DCM (3 mL, 0.0224 M) was added TFA (1 ml) at 25°C. After stirred at 25°C for 2 hr, the reaction mixture was concentrated under reduced pressure to afford 1-((S)-3-(3,4-dichlorophenyl)piperidin-1-yl)-3- ((R)-1-((5-(piperazin-1-yl)pentyl)sulfonyl)pyrrolidin-3-yl)prop-2-yn-1-one TFA salt (36 mg) as a white solid, which was used without further purification.

[0350] Step 13. To a solution of 1-((S)-3-(3,4-dichlorophenyl)piperidin-1-yl)-3-((R)-1-((5-(piperazin-1- yl)pentyl)sulfonyl)pyrrolidin-3-yl)prop-2-yn-1-one TFA salt (5 mg, 0.0073 mmol, 1 eq.) was added 2-(6- (dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)-5-(((2,5-dioxopyrrolidin-1- yl)oxy)carbonyl)benzoate (5.8 mg, 0.011 mmol, 1.5 eq.) and N,N-diisopropylethylamine (1.4 mg, 0.011 mmol, 1.5 eq.) in DCM (2 mL, 0.0037 M) at 0°C. The reaction mixture was allowed to warm to rt and stirred at rt for 10 hr. The mixture was directly purified by prep-HPLC to afford 5-(4-(5-(((R)-3-(3-((S)-3- (3,4-dichlorophenyl)piperidin-1-yl)-3-oxoprop-1-yn-1-yl)pyrrolidin-1-yl)sulfonyl)pentyl)piperazine-1- carbonyl)-2-(6-(dimethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate (6.6 mg, 0.0067 mmol, 91.9% yield). [M+H] calculated for C52H58Cl2N6O7S, 980.4; found 981.2.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.03 (s, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.40 (dd, J=22.2, 8.3 Hz, 1H), 7.32 (dd, J=9.2, 2.1 Hz, 1H), 7.23 (s, 1H), 7.07 (td, J=9.3, 2.1 Hz, 1H), 6.69 (s, 2H), 6.57 – 6.38 (m, 3H), 4.63 – 4.53 (m, 1H), 4.34 (d, J=13.2 Hz, 1H), 3.71 – 3.62 (m, 2H), 3.57 – 3.52 (m, 1H), 3.50 – 3.39 (m, 3H), 3.26 – 3.08 (m, 3H), 3.05 – 2.94 (m, 11H), 2.90 – 2.86 (m, 1H), 2.76 – 2.55 (m, 6H), 2.29 (dt, J=18.2, 6.3 Hz, 1H), 2.13 – 2.05 (m, 2H), 1.90 (d, J=16.8 Hz, 3H), 1.25 (s, 8H), 0.90 – 0.81 (m, 2H), 0.08 (d, J=1.0 Hz, 2H). Example 36. Fluorescence Polarization Assay Protocol

[0351] Compounds binding to JAK1 was assessed with the JAK1 FP Assay using the compound as synthesized in Example 35. This is a fluorescence polarization-based assay using recombinant JAK1 and a fluorescent JAK1 probe. Table 3. Reagents Reagent Working Solutions Stock Conc End Conc143 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) Reagents Reagent Working Solutions Stock Conc End Conc 5-(4-(5-(((R)-3-(3-((S)-3-(3,4-_ ate, 20 µl / well. JAK1 was treated with serial dilutions of test compounds (0-50 µM), centrifuged (1000 rpm for 30 seconds), and incubated for 60 minutes at room temperature, final DMSO concentration of 0.5%. Following compound incubation, the fluorescent probe was added (10 nM final concentration) and the mixture was centrifuged (1000 rpm for 30 seconds) and incubated for an additional 60 minutes at room temperature. Following the probe incubation, the endpoint measurement of fluorescence polarization was performed (Ex. 535 nm, Dichroic LP 566, Em. 585 nm) on a Clariostar plate reader (BMG Labtech, Cary, NC). Compound binding was determined by blockade of the probe binding site and subsequent lack of fluorescence polarization. For each compound, the potency of inhibition (IC50) was determined using Graphpad Prism. Example 37. Targeted Tandem Mass Tag Protocol

[0353] In vitro TE50values for JAK1_C817 were obtained by treating 500 µg of cell lysate generated from Jurkat or KARPAS-299 cells with DMSO or a dose response of test compounds for 1 hour at room temperature followed by the addition of 200 µM IA-DTB (in DMSO) for one hour at room temperature. Samples were then precipitated by addition of 8x ice cold acetonitrile and incubated at -80°C for two hours, followed by centrifugation (4,200 RPM, 45 min, 4°C) to pellet the protein. The pelleted material was resuspended in 9M Urea, 50 mM ammonium bicarbonate and proteins were reduced and alkylated by the addition of DTT and iodoacetamide (10 and 30 mM, respectively). Following reduction and alkylation, samples were exchanged into 2M urea (Zeba spin desalting plates, Thermo Fisher) and digested with Trypsin. IA-DTB labeled peptides were isolated with streptavidin agarose resin. Enriched peptides were 144 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) eluted by the addition of 50% acetonitrile (ACN) 0.1% Formic Acid (FA) and dried in a SpeedVac vacuum concentrator.

[0354] Dried peptides were resuspended in 0.2 M EPPS pH 8.5 with 30% anhydrous acetonitrile and treated with 6.5 µL of 16-plex tandem mass tag (TMT; 8.3 µg / µL in anhydrous acetonitrile) for 2 hours at room temperature. Reactions were quenched by the addition of 6.5 µL of 5% Hydroxylamine. Samples were then combined and desalted on a Biotage Evolute express ABN plate (600-0010-PX01). Targeted TMT measurements were collected using an Orbitrap Lumos Tribrid Mass Spectrometer (Thermo Scientific) coupled to an UltiMate 3000 Series Rapid Separation LC system and autosampler (Thermo Scientific, Dionex). Peptides were loaded onto an Acclaim Pepmap 100 loading column (Thermo, 164535) and separated on a custom C18 capillary analytical column (75-μm inner diameter fused silica, packed with Acclaim PepMap C18 resin (Thermo Scientific)) with a flow rate of 1.0 μl / min. Data were acquired using a specific MS3-based TMT method targeting the peptide containing JAK1 C817 (CRPVTPSC(+324.2)K, +3 charge state) where MS2 peptide fragmentation is triggered upon detection of the peptide precursor ion. Subsequent MS3 analysis was then performed using pre-selected peptide fragment ions that were isolated for fragmentation using synchronous precursor selection. RAW files were converted to MZXML format and searched with the SEQUEST algorithm using the MassPike software package. TMT quantitation was performed with a filter requiring at least ten summed signal-to-noise for control channels. Dose response curves were generated using TMT quantitation and the TE50calculated as the center of the dose response curve. Example 38. ISRE Reporter Gene Assay Protocol

[0355] The goal of the HEK 293T cell IFN-stimulated Response Element (ISRE) Reporter Gene Assay is to generate IC50s (potency of inhibition) for JAK1 inhibitors based on ISRE luciferase reporter activity. In response to the type I interferon (IFN), IFNα, JAK1 is activated, leading to phosphorylation and activation of STAT1 and STAT2, which form the ISGF3 complex after interaction with IRF9. This complex binds to the ISRE promoter, allowing for gene transcription. Effective JAK1 inhibitors will prevent this signaling cascade and subsequent gene transcription from occurring.

[0356] The cell line HEK 293T is derived from human kidney cells; HEK 293T reporter gene cells (HEK 293T cells transfected with pGL4.45[luc2P / ISRE / Hygro] vector (Promega, Madison, WI)) which contain a luc2P luciferase reporter gene transcribed by engagement of the ISRE, allow for measurement of the bioluminescent luciferase signal upon activity at the ISRE binding site. Degree of bioluminescent signal, measured on a CLARIOstar Plus plate reader (BMG Labtech, Cary, NC) correlates with degree of gene transcription. 145 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)

[0357] Efficacy of JAK1 inhibitors was measured by treating HEK 293T reporter gene cells with JAK1 inhibitors in a dose response curve for 2 hours, followed by treatment with 5 ng / ml IFNα for 18 hours. Positive and negative controls for JAK1 activity and IFNα stimulation were included in the assay. Luciferase activity was measured using the Bright-Glo™ Luciferase Assay System (Promega, Madison, WI) and cell viability was measured using the CellTiter-Glo®2.0 reagent (Promega, Madison, WI). IC50s were calculated for each inhibitor using Dotmatics (Boston, MA). Example 39. Human Whole Blood CXCL10 qPCR Assay Protocol

[0358] The goal of the human whole blood CXCL10 qPCR assay is to generate IC50’s and IMAX (maximal inhibition) values for JAK1 inhibitors using human whole blood. CXCL10 mRNA is upregulated after stimulation with human IFNg. We measured CXCL10 transcription by qPCR after 2 hours treatment with JAK1 inhibitors and a subsequent 2-hour stimulation with human IFNg. JAK1 inhibitors were tested in a dose response curve in assays with multiple human whole blood donors with a diverse set of donor parameters (age, weight, ethnicity, blood type). Positive and negative controls for human IFNg stimulation were included in assay for each human whole blood donor. These assays demonstrate that the compounds of the present disclosure inhibit JAK1 with high affinity. Table 4. Test Data HEK293T ISRE hWB CXCL10 JAK1_C817 tTMT )146 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) HEK293T ISRE hWB CXCL10 JAK1_C817 tTMT Compound No.JAK1 FP IC50 (uM)Reporter Gene Assay qPCR IC50(uM)147 \91894028.1Dkt. Nos.184200.00053(VVID-744PC) HEK293T ISRE hWB CXCL10 JAK1_C817 tTMT Compound No.JAK1 FP IC50 (uM)Reporter Gene Assay qPCR IC50(uM)148 \91894028.1Dkt. Nos.184200.00053(VVID-744PC) HEK293T ISRE hWB CXCL10 JAK1_C817 tTMT Compound No.JAK1 FP IC50 (uM)Reporter Gene Assay qPCR IC50(uM)149 \91894028.1Dkt. Nos.184200.00053(VVID-744PC) HEK293T ISRE hWB CXCL10 JAK1_C817 tTMT Compound No.JAK1 FP IC50 (uM)Reporter Gene Assay qPCR IC50(uM)150 \91894028.1Dkt. Nos.184200.00053(VVID-744PC) HEK293T ISRE hWB CXCL10 JAK1_C817 tTMT Compound No.JAK1 FP IC50 (uM)Reporter Gene Assay qPCR IC50(uM)151 \91894028.1Dkt. Nos.184200.00053(VVID-744PC) HEK293T ISRE hWB CXCL10 JAK1_C817 tTMT Compound No.JAK1 FP IC50 (uM)Reporter Gene Assay qPCR IC50(uM)152 \91894028.1Dkt. Nos.184200.00053(VVID-744PC) HEK293T ISRE hWB CXCL10 JAK1_C817 tTMT Compound No.JAK1 FP IC50 (uM)Reporter Gene Assay qPCR IC50(uM)

[0359] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. 153 Q   B\91894028.1

Claims

Dkt. Nos.184200.00053(VVID-744PC) CLAIMS WHAT IS CLAIMED IS:

1. A compound of formula I, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: (R1)xG1R4wherein:G1is phenyl, a 5 to 6-membered heteroaryl ring comprising one, two or three heteroatoms independently selected from N, O and S, or a 9 to 10-membered fused heterocycle comprising a 6- membered aromatic or heteroaromatic ring and one, two or three heteroatoms independently selected from N, O and S; each R1is independently -OH, halogen, C1-6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl, -O-C1-C3deuteroalkyl, or -NR6R7; x is 0, 1, 2, or 3; G2is a six-membered aromatic ring comprising 0, 1 or 2 nitrogen atoms; each R2is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl optionally substituted with halogen, C1-C3alkyl or C1-C3haloalkyl, -O-C1-C6alkyl or -O-C1-C6haloalkyl; y is 0, 1, or 2; Z is -CH2- or -CD2-; R3is -H, -D, C1-C6alkyl, C1-C6alkyl substituted with -O-C1-C6alkyl, or C3-C6cycloalkyl; each of R4, R5and R6is independently -H or C1-C6alkyl; 154 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) R7is -H, C1-C6alkyl or -C(O)R8; and R8is C1-C6alkyl.

2. The compound of claim 1, wherein G1is phenyl, pyridyl or pyrimidinyl.

3. The compound of claim 1, wherein G1is benzodioxolo, benzothiazolo, pyrazolopyridinyl, benzooxazolo, dihydrobenzofuranyl, or dihydrobenzodioxinyl.

4. The compound of claim 1, wherein G2is phenyl, pyridyl, pyrazinyl, or pyrimidinyl.

5. The compound of claim 1, wherein each R1is independently halogen, C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, or -O-C1-C6haloalkyl.

6. The compound of claim 1, wherein R1is F.

7. The compound of claim 1, wherein x is 0, 1 or 2.

8. The compound of claim 1, wherein each R2is independently halogen, C1-C6alkyl, C1-C6haloalkyl, -O-C1-C6alkyl, -O-C1-C6haloalkyl.

9. The compound of claim 8, wherein R2is selected from the group consisting of -CF3, -CH2CF3, - OCF3, or -OCHF2.

10. The compound of claim 8, wherein R2is selected from the group consisting of methyl, ethyl, cyclopropyl, methylcyclopropyl, fluorocyclopropyl, and trifluoromethylcyclopropyl.

11. The compound of claim 1, wherein y is 0, 1 or 2.

12. The compound of claim 1, wherein Z is -CH2-.

13. The compound of claim 1, wherein R3is -H, C1-C6alkyl or C3-C6cycloalkyl.

14. The compound of claim 13, wherein R3is -H, methyl or cyclopropyl.

15. The compound of claim 1, wherein R4is C1-C6alkyl.

16. The compound of claim 15, wherein R4is methyl.

17. The compound of claim 1, wherein R5is -H or methyl.

18. The compound of claim 17, wherein R5is -H.

19. The compound of claim 1, wherein R6is -H.

20. The compound of claim 19, wherein R7is -H or -C(O)R8. 155 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) 21. The compound of claim 1, wherein R8is methyl or ethyl.

22. The compound of claim 1, wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:  wherein: each R1is independently -OH, halogen, C1-C3alkyl, or -O-C1-C3alkyl; x is 0, 1, or 2; each R2is independently halogen, C1-C6alkyl, C1-C6haloalkyl, or C3-C6cycloalkyl optionally substituted with C1-C3alkyl or -O-C1-C3alkyl; y is 1 or 2; R3is -H, C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; and R5is -H or C1-C3alkyl.

23. The compound of claim 1, wherein the compound is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) wherein: each R1is independently halogen, C1-C3alkyl, C1-C3haloalkyl, -O-C1-C3alkyl, -O-C1-C3haloalkyl or -NR6R7; x is 0, 1, 2, or 3; R2is halogen, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl optionally substituted with C1-C3alkyl; y is 1 or 2; R3is -H, C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; R5is -H or C1-C3alkyl;  R6is -H or C1-C3alkyl; R7is C1-C3alkyl or -C(O)R8; and R8is C1-C3alkyl.

24. The compound of claim 1, wherein the compound is a compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:     wherein:each R1is independently halogen, -O-C1-C3alkyl, -O-C1-C3haloalkyl, or -O-C1-C3deuteroalkyl; x is 0, 1, 2 or 3; 157 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) each R2is independently halogen, C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl optionally substituted with halogen, C1-C3alkyl or C1-C3haloalkyl; y is 1 or 2; R3is -H, C1-C3alkyl, C1-C3alkyl substituted with -O-C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; and R5is -H or C1-C3alkyl.

25. The compound of claim 1, wherein the compound is a compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   wherein:each R1is independently halogen or C1-C3alkyl; x is 0, 1, or 2; R2is C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl optionally substituted with halogen, C1-C3alkyl or C1-C3haloalkyl; y is 1; R3is -H, C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; and R5is -H.

26. The compound of claim 1, wherein the compound is a compound of formula (VI), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   158 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)   wherein:R1is C1-C3alkyl, -O-C1-C3alkyl, -O-C1-C3deuteroalkyl, or -NR6R7; x is 1; R2is C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl optionally substituted with halogen, C1-C3alkyl or C1-C3haloalkyl; y is 1; R3is -H, C1-C3alkyl, C1-C3alkyl substituted with -O-C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; R5is -H; and each of R6and R7is independently -H or C1-C3alkyl.

27. The compound of claim 1, wherein the compound is a compound of formula (VII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   wherein:R1is -O-C1-C3alkyl, -O-C1-C3haloalkyl, or -O-C1-C3deuteroalkyl; 159 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) x is 1; R2is C1-C3alkyl or C1-C3haloalkyl; y is 1; R3is C1-C3alkyl, or C3-C6cycloalkyl; R4is C1-C3alkyl; and R5is -H.

28. The compound of claim 1, wherein the compound is a compound of formula (VIII), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:   wherein:R1is C1-C3alkyl, -O-C1-C3alkyl, or -O-C1-C3deuteroalkyl; x is 1; R2is C1-C3alkyl, C1-C3haloalkyl, or C3-C6cycloalkyl; y is 1; R3is C1-C3alkyl or C3-C6cycloalkyl; R4is C1-C3alkyl; and R5is -H.

29. The compound of claim 1, wherein the compound is a compound of formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 160 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC)   wherein:X1is -O- or -CH2-; X2is -CH2- or -CH2CH2-; X3is -O-; -S- or -CH2-; or X1, X2and X3, together with the phenyl ring to which they are attached form a bicyclic ring selected from the group of O Oor y is 1; R3is C1-C3alkyl or C3-C6cycloalkyl; 161 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) R4is C1-C3alkyl; and R5is -H.

30. The compound of claim 1, wherein the compound is selected from the group consisting of: (E)-2-(benzylamino)-N-(3-(methylsulfonyl)allyl)-4-(trifluoromethyl)benzamide; (E)-2-(benzylamino)-4-cyclopropyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-2-(benzylamino)-4-cyclopropyl-N-(3-(ethylsulfonyl)allyl)benzamide; (E)-4-cyclopropyl-2-((2-fluoro-5-hydroxybenzyl)amino)-N-(3-(methylsulfonyl)allyl)benzamide; (E)-2-(benzylamino)-4-cyclopropyl-N-methyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-2-(benzylamino)-4-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)benzamide; (E)-2-(benzylamino)-5-chloro-4-cyclopropyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopropyl-N-(3-(methylsulfonyl)allyl)-2-((thiazol-5-ylmethyl)amino)benzamide; (E)-2-(benzylamino)-4-ethyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-2-(benzylamino)-4-isopropyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-2-(benzylamino)-4-(tert-butyl)-N-(3-(methylsulfonyl)allyl)benzamide; (E)-2-(benzylamino)-4-cyclopropyl-5-fluoro-N-(3-(methylsulfonyl)allyl)benzamide; (E)-2-(benzylamino)-N-(3-(methylsulfonyl)allyl)-4-(2,2,2-trifluoroethyl)benzamide; (E)-2-(benzylamino)-4-(1-methylcyclopropyl)-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopropyl-2-((2-fluorobenzyl)amino)-N-(3-(methylsulfonyl)allyl)benzamide; (E)-2-((2-chlorobenzyl)amino)-4-cyclopropyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-2-((3-chlorobenzyl)amino)-4-cyclopropyl-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopropyl-2-((3-fluorobenzyl)amino)-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopropyl-2-((2-methoxybenzyl)amino)-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopropyl-2-((3-methoxybenzyl)amino)-N-(3-(methylsulfonyl)allyl)benzamide; (E)-4-cyclopropyl-2-((3-methylbenzyl)amino)-N-(3-(methylsulfonyl)allyl)benzamide (E)-4-cyclopropyl-2-((2-methylbenzyl)amino)-N-(3-(methylsulfonyl)allyl)benzamide; (R,E)-2-(benzylamino)-6-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)nicotinamide; 162 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-6-cyclopropyl-2-((2-fluoro-6-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; (S,E)-6-cyclopropyl-2-((3-fluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; (S,E)-6-cyclopropyl-2-((5-fluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; (S,E)-2-((2,3-difluoro-6-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((2,3-difluoro-6-methoxybenzyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-2-((3,5-difluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((3,5-difluoro-2-methoxybenzyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((2,5-difluorobenzyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-2-((2,6-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((2,6-difluorobenzyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-2-((2-(difluoromethoxy)-5-fluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((2-(difluoromethoxy)-5-fluorobenzyl)amino)- 6-(trifluoromethyl)nicotinamide; (S,E)-2-((5-fluoro-2-(trifluoromethoxy)benzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; 163 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((5-fluoro-2-(trifluoromethoxy)benzyl)amino)- 6-(trifluoromethyl)nicotinamide; (S,E)-2-((2-methylbenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-2-((2-methylbenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-2-(((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)-6-(trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((2,3-dihydrobenzo[b][1,4]dioxin-5- yl)methyl)amino)-6-(trifluoromethyl)nicotinamide; (S,E)-2-((5-fluoro-2-(trifluoromethyl)benzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((5-fluoro-2-(trifluoromethyl)benzyl)amino)- 6-(trifluoromethyl)nicotinamide; (S,E)-2-((5-fluoro-2-methylbenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((5-fluoro-2-methylbenzyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((2-methylpyridin-3-yl)methyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((2,3-dihydrobenzofuran-7-yl)methyl)amino)- 6-(trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)- 6-(trifluoromethyl)nicotinamide; (S,E)-2-((2-acetamidobenzyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- (trifluoromethyl)nicotinamide; 164 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((2-ethylbenzyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-2-((benzo[d]thiazol-7-ylmethyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- (trifluoromethyl)nicotinamide; (S,E)-2-(((2-aminopyridin-3-yl)methyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- (trifluoromethyl)nicotinamide; (S,E)-2-((benzo[d]oxazol-4-ylmethyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((3-methoxypyrazin-2-yl)methyl)amino)-6- nicotinamide; (E)-3-(benzylamino)-5-cyclopropyl-N-(3-(methylsulfonyl)allyl)picolinamide; (E)-2-(benzylamino)-6-cyclopropyl-N-(3-(methylsulfonyl)allyl)nicotinamide; (S,E)-2-(benzylamino)-6-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; (R,E)-2-(benzylamino)-6-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)nicotinamide; (S,E)-2-(benzylamino)-6-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)nicotinamide; (E)-4-(benzylamino)-2-cyclopropyl-N-(3-(methylsulfonyl)allyl)pyrimidine-5-carboxamide; (E)-4-(benzylamino)-N-(3-(methylsulfonyl)allyl)-2-(trifluoromethyl)pyrimidine-5-carboxamide; (E)-3-(benzylamino)-5-cyclopropyl-N-(3-(methylsulfonyl)allyl)pyrazine-2-carboxamide; (S,E)-6-cyclopropyl-2-((2,5-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)nicotinamide; (S,E)-6-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((2,5- difluorobenzyl)amino)nicotinamide; (E)-2-(benzylamino)-4-cyclopropyl-6-methoxy-N-(3-(methylsulfonyl)allyl)benzamide; (E)-2-cyclopropyl-4-((2-methoxybenzyl)amino)-N-(3-(methylsulfonyl)allyl)pyrimidine-5- carboxamide; 165 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (E)-2-cyclopropyl-4-((2,6-difluorobenzyl)amino)-N-(3-(methylsulfonyl)allyl)pyrimidine-5- carboxamide; (R,E)-4-(benzylamino)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5- carboxamide; (S,E)-4-(benzylamino)-2-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine-5- carboxamide; (E)-2-cyclopropyl-4-((2-fluorobenzyl)amino)-N-(3-(methylsulfonyl)allyl)pyrimidine-5- carboxamide; (E)-2-cyclopropyl-N-(3-(methylsulfonyl)allyl)-4-((2-(trifluoromethoxy)benzyl)amino)pyrimidine- 5-carboxamide; (E)-2-cyclopropyl-4-((2,5-difluorobenzyl)amino)-N-(3-(methylsulfonyl)allyl)pyrimidine-5- carboxamide; (E)-2-cyclopropyl-4-((2,3-difluorobenzyl)amino)-N-(3-(methylsulfonyl)allyl)pyrimidine-5- carboxamide; (E)-2-cyclopropyl-4-((2-fluoro-6-methoxybenzyl)amino)-N-(3-(methylsulfonyl)allyl)pyrimidine- 5-carboxamide; (E)-2-cyclopropyl-4-((5-fluoro-2-methoxybenzyl)amino)-N-(3-(methylsulfonyl)allyl)pyrimidine- 5-carboxamide; (S,E)-4-(benzylamino)-2-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)pyrimidine-5- carboxamide; (E)-2-cyclopropyl-4-((3-fluoro-2-methoxybenzyl)amino)-N-(3-(methylsulfonyl)allyl)pyrimidine- 5-carboxamide; (S,E)-4-(benzylamino)-2-cyclopropyl-N-methyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrimidine- 5-carboxamide; (E)-2-cyclopropyl-4-((2-(difluoromethoxy)benzyl)amino)-N-(3-(methylsulfonyl)allyl)pyrimidine- 5-carboxamide; 166 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-2-cyclopropyl-4-((2,5-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (S,E)-4-((2,5-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-4-((2,6-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2,5-difluorobenzyl)amino)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2,6-difluorobenzyl)amino)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (R,E)-4-(benzylamino)-2-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)pyrimidine-5- carboxamide; (S,E)-2-cyclopropyl-4-((2,6-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2,5- difluorobenzyl)amino)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2,6- difluorobenzyl)amino)pyrimidine-5-carboxamide; (S,E)-4-(benzylamino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-(trifluoromethyl)pyrimidine-5- carboxamide; (S,E)-4-((5-fluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-4-((2-fluoro-6-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-4-(((2-methoxypyridin-3-yl)methyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; 167 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-((thiazol-5-ylmethyl)amino)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclobutyl-3-(methylsulfonyl)allyl)-2-cyclopropyl-4-((2,5- difluorobenzyl)amino)pyrimidine-5-carboxamide; (R,E)-2-cyclopropyl-4-((2,5-difluorobenzyl)amino)-N-(1-methoxy-4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2-fluoro-6- methoxybenzyl)amino)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((5-fluoro-2- methoxybenzyl)amino)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-4-((2-fluoro-6-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-4-((5-fluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (S,E)-4-((3-fluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((3-fluoro-2- methoxybenzyl)amino)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-4-((3-fluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (E)-2-cyclopropyl-4-((5-fluoro-2-methoxybenzyl)amino)-N-methyl-N-(3- (methylsulfonyl)allyl)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-(((2-methoxypyridin-3-yl)methyl)amino)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (E)-2-cyclopropyl-4-((5-fluoro-2-(trifluoromethoxy)benzyl)amino)-N-(3- (methylsulfonyl)allyl)pyrimidine-5-carboxamide; 168 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-4-((5-fluoro-2-(trifluoromethoxy)benzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-4-((2-(difluoromethoxy)-6-fluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3- en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-((2-(difluoromethoxy)-6-fluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (E)-2-cyclopropyl-4-((2-fluoro-6-(trifluoromethoxy)benzyl)amino)-N-(3- (methylsulfonyl)allyl)pyrimidine-5-carboxamide; (S,E)-4-((3,6-difluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-4-((3,6-difluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (S,E)-4-((2,3-difluoro-6-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-4-((2,3-difluoro-6-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (S,E)-4-((2-fluoro-6-(trifluoromethoxy)benzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-4-((2-(difluoromethoxy)-3-fluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3- en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-((2-(difluoromethoxy)-5-fluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-4-((2-(difluoromethoxy)-5-fluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3- en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-((2-(difluoromethoxy)-3-fluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; 169 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-2-cyclopropyl-4-((2-(difluoromethoxy)-3,6-difluorobenzyl)amino)-N-(4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-((6-(difluoromethoxy)-2,3-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-2-cyclopropyl-4-((6-(difluoromethoxy)-2,3-difluorobenzyl)amino)-N-(4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-((2-(difluoromethoxy)-3,6-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-4-((2,5-difluorobenzyl)amino)-2-(1-methylcyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (E)-4-(benzylamino)-2-(1,1-difluoroethyl)-N-(3-(methylsulfonyl)allyl)pyrimidine-5- carboxamide; (S,E)-4-(benzylamino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1- difluoroethyl)pyrimidine-5-carboxamide; (S,E)-4-((2,5-difluorobenzyl)amino)-2-(1,1-difluoroethyl)-N-methyl-N-(4-(methylsulfonyl)but-3- en-2-yl)pyrimidine-5-carboxamide; (S,E)-4-((2,5-difluorobenzyl)amino)-2-(1-fluorocyclopropyl)-N-(4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (S,E)-4-((2,5-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2-(1- (trifluoromethyl)cyclopropyl)pyrimidine-5-carboxamide; (S,E)-4-((2,5-difluorobenzyl)amino)-2-(1,1-difluoroethyl)-N-(4-(methylsulfonyl)but-3-en-2- yl)pyrimidine-5-carboxamide; (S,E)-2-(1,1-difluoroethyl)-4-((5-fluoro-2-(trifluoromethoxy)benzyl)amino)-N-(4- (methylsulfonyl)but-3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2,5-difluorobenzyl)amino)-2-(1,1- difluoroethyl)-N-methylpyrimidine-5-carboxamide; 170 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-2-((2,5-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-2-(benzylamino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6-(trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((2-fluoro-6-methoxybenzyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((5-fluoro-2-methoxybenzyl)amino)-6- (trifluoromethyl)nicotinamide; (E)-2-(benzylamino)-N-methyl-N-(3-(methylsulfonyl)allyl)-6-(trifluoromethyl)nicotinamide; (S,E)-2-((2-fluoro-6-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-2-((5-fluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-2-((3-fluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-2-(((2-methoxypyridin-3-yl)methyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((2-methoxypyridin-3-yl)methyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-(trifluoromethyl)-2-((2- (trifluoromethyl)benzyl)amino)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((3-methylpyrazin-2-yl)methyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((2-ethylpyridin-3-yl)methyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((pyrazolo[1,5-a]pyridin-7-ylmethyl)amino)- 6-(trifluoromethyl)nicotinamide; 171 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-((pyrazolo[1,5-a]pyridin-4-ylmethyl)amino)- 6-(trifluoromethyl)nicotinamide; (S,E)-2-((benzo[d][1,3]dioxol-4-ylmethyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((6-methoxypyridin-2-yl)methyl)amino)-6- (trifluoromethyl)nicotinamide; (S,E)-2-((benzo[d]thiazol-4-ylmethyl)amino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- (trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((2-(methylamino)pyridin-3- yl)methyl)amino)-6-(trifluoromethyl)nicotinamide; (S,E)-6-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((2-methoxypyridin-3- yl)methyl)amino)nicotinamide; (S,E)-5-cyclopropyl-3-((2,5-difluorobenzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrazine- 2-carboxamide; (S,E)-5-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-((2,6- difluorobenzyl)amino)pyrazine-2-carboxamide; (S,E)-5-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-(((2-methoxypyridin-3- yl)methyl)amino)pyrazine-2-carboxamide; (S,E)-5-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-(((2-methylpyridin-3- yl)methyl)amino)pyrazine-2-carboxamide; (S,E)-5-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-((5-fluoro-2- methylbenzyl)amino)pyrazine-2-carboxamide; (S,E)-3-(benzylamino)-5-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)pyrazine-2- carboxamide; (S,E)-3-(benzylamino)-5-cyclopropyl-N-(4-(methylsulfonyl)but-3-en-2-yl)pyrazine-2- carboxamide; 172 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-2-(benzylamino)-5-chloro-6-cyclopropyl-N-(1-cyclopropyl-3- (methylsulfonyl)allyl)nicotinamide; (S,E)-5-chloro-6-cyclopropyl-2-((5-fluoro-2-methoxybenzyl)amino)-N-(4-(methylsulfonyl)but-3- en-2-yl)nicotinamide; (S,E)-2-(benzylamino)-6-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5- fluoronicotinamide; (S,E)-3-(benzylamino)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(trifluoromethyl)pyrazine-2- carboxamide; (S,E)-3-(benzylamino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-5-(trifluoromethyl)pyrazine-2- carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-(((2-methoxypyridin-3-yl)methyl)amino)-5- (trifluoromethyl)pyrazine-2-carboxamide; (S,E)-4-chloro-6-((2,5-difluorobenzyl)amino)-2-(1-methylcyclopropyl)-N-(4-(methylsulfonyl)but- 3-en-2-yl)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-((2,6-difluorobenzyl)amino)-5-(1- methylcyclopropyl)pyrazine-2-carboxamide; (E)-2-(benzylamino)-4-cyclopropyl-6-fluoro-N-(3-(methylsulfonyl)allyl)benzamide; (S,E)-2-((2,5-difluorobenzyl)amino)-6-(1,1-difluoroethyl)-N-(4-(methylsulfonyl)but-3-en-2- yl)nicotinamide (E)-2-(benzylamino)-5-chloro-N-(3-(methylsulfonyl)allyl)-4-(trifluoromethyl)benzamide; (S,E)-4-((5-fluoro-2-(methoxy-d)benzyl)amino)-N-(4-(methylsulfonyl)but-3-en-2-yl)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((5-fluoro-2-(methoxy-d3)benzyl)amino)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2-fluoro-6-(methoxy-d3)benzyl)amino)-2- (trifluoromethyl)pyrimidine-5-carboxamide; 173 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) (S,E)-5-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-(((2-(methoxy-d3)pyridin-3- yl)methyl)amino)pyrazine-2-carboxamide; (S,E)-N-(4-(methylsulfonyl)but-3-en-2-yl)-4-((phenylmethyl-d2)amino)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-((phenylmethyl-d2)amino)-5- (trifluoromethyl)pyrazine-2-carboxamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-((phenylmethyl-d2)amino)-2- (trifluoromethyl)pyrimidine-5-carboxamide; (S,E)-5-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-((phenylmethyl- d2)amino)pyrazine-2-carboxamide; (S,E)-6-cyclopropyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-fluoro-2-((phenylmethyl- d2)amino)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(((2-(methoxy-d3)pyridin-3-yl)methyl- d2)amino)-6-(trifluoromethyl)nicotinamide; (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-4-(((2-(methoxy-d3)pyridin-3-yl)methyl- d2)amino)-2-(trifluoromethyl)pyrimidine-5-carboxamide; and (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-(((2-(methoxy-d3)pyridin-3-yl)methyl- d2)amino)-5-(trifluoromethyl)pyrazine-2-carboxamide.

31. A pharmaceutical composition comprising a compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and a pharmaceutically acceptable excipient or carrier.

32. A method of inhibiting Janus kinase 1 (JAK1) in a subject in need of such inhibition, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

33. A method of treating an inflammatory disease, an autoimmune disease, or cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a 174 Q   B\91894028.1Dkt. Nos.184200.00053(VVID-744PC) compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

34. The method of claim 33, wherein the inflammatory or autoimmune disease is selected from Rheumatoid Arthritis (RA), Crohn’s disease, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), diabetic nephropathy, dry eye syndrome, Sjogren’s Syndrome, alopecia areata, vitiligo, and atopic dermatitis.

35. The method of claim 33, wherein the cancer is a lymphoma, leukemia or myeloma.

36. Use of a compound according to any one of claims 1-30 for the treatment of an inflammatory disease, an autoimmune disease, or cancer.

37. The use according to claim 36, wherein the inflammatory or autoimmune disease is selected from Rheumatoid Arthritis (RA), Crohn’s disease, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), diabetic nephropathy, dry eye syndrome, Sjogren’s Syndrome, alopecia areata, vitiligo, and atopic dermatitis.

38. The use according to claim 36, wherein the cancer is a lymphoma, leukemia or myeloma. 175 Q   B\91894028.1

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