NZ762863A - Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors - Google Patents

Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors Download PDF

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NZ762863A
NZ762863A NZ762863A NZ76286306A NZ762863A NZ 762863 A NZ762863 A NZ 762863A NZ 762863 A NZ762863 A NZ 762863A NZ 76286306 A NZ76286306 A NZ 76286306A NZ 762863 A NZ762863 A NZ 762863A
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pyrrolo
mol
alkyl
compound
methyl
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James D Rodgers
Stacey Shepard
Thomas P Maduskuie
Haisheng Wang
Nikoo Falahatpisheh
Maria Rafalski
Argyrios G Arvanitis
Louis Storace
Ravi Kumar Jalluri
Jordan S Fridman
Krishna Vaddi
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Incyte Holdings Corp
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Abstract

Disclosed are compositions of Ruxolitinib, more particularly a pharmaceutical composition comprising a compound, which is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein said composition is to be orally administered and provides sustained release.

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S FORM NO. 5PATENTS FORM NO. 5 Complete SpecificationComplete Specification New Zealand Patents Act 1953 New Zealand Patents Act 1953 Divisional application out of NZ 748000Divisional application out of NZ 748000 In turn a divisional application out of NZ In turn a divisional application out of NZ 733104 In turn a divisional application out of NZ 715022In turn a divisional ation out of NZ 715022 In turn a divisional application out of NZ 625189In turn a divisional application out of NZ 625189 In turn a divisional application out of NZ 603809In turn a divisional application out of NZ 603809 In turn a divisional application out of NZ 593031In turn a divisional application out of NZ 593031 In turn a divisional application out of NZ 569015In turn a divisional application out of NZ 569015 Title:Title: Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b] pyrimidines as janus kinase tors pyrimidines as janus kinase inhibitors Applicant: Incyte Holdings CorporationApplicant: Incyte gs Corporation Address: 1801 ine Cut-Off, Wilmington, 19803, DelawaAddress: 1801 Augustine Cut-Off, Wilmington, 19803, rere United States of AmericaUnited States of America ality: USNationality: US We, Incyte Holdings Corporation, hereby declare the invention, for which we pray that aWe, Incyte Holdings Corporation, hereby declare the ion, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularlypatent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the ing statement:described in and by the following statement: - l - (next page is page 1a)(next page is page la) Street Address for Service:Srreer Arlrlressfor .S‘eri‘ice.‘ Post Office Box s for ServicePosr Office Box Arlzlressfbr Se ri‘ice All Correspondence T0:All Correspondence To: Houlihan2Houlihanl Houlihan2Houlihanl Houlihan2Houlihanl Rapid 31Rapid 31 PO Box 722PO Box 722 PO Box 611PO Box 611 Mountain View RoadMountain View Road QueenstownQueenstown Balwyn North VICBalwyn North VIC 31043104 DalefieldDalefield New ZealandNew Zealand Australia Australia New ZealandNew Zealand HETEROARYL TUTED PYRROLO[2,3—b1PYRIDlNES AND PYRROLO[2,3—b]PYRIlVIIDINES AS JANUS KINASE INHIBITORS FIELD OF THE lNVENTION The present invention provides heteroaryl substituted pyrrolo[2,3-b]pyridines and heteroaryl substituted pyrrolo[2,3-b]pyrimidines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.
BACKGROUND OF THE INVENTION n kinases (PKs) are a group of enzymes that regulate e, important biological processes including cell growth, survival and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and "regeneration, among . Protein kinases exert their physiological fiinctions through catalyzing the phosphorylation of proteins (or ates) and thereby modulating the cellular activities of the substrates in various ical contexts. In on to the ons in normal tissues/organs, many protein kinases also play more specialized roles in a host of human diseases including cancer. A subset of n kinases (also referred to as oncogenic protein kinases), when dysregulated, can cause tumor formation and growth, and further contribute to tumor maintenance and progression (Blume-Jensen P et al, Nature 200], 411(6835):355—365). Thus far, oncogenic protein kinases represent one of the largest and most attractive groups of n targets for cancer intervention and drug development.
Protein s can be rized as receptor type and non—receptor type. Receptor tyrosine kinases (RTKs) have an extracellular portion, a transmembrane domain, and an ellular portion, while non—receptor tyrosine kinases are entirely intracellular. RTK mediated signal transduction is typically initiated by extracellular interaction with a specific growth factor (ligand), typically ed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity, and receptor transphosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response such as cell division, differentiation, lic s, and changes in the extracellular microenvironment At present, at least nineteen (19) distinct RTK subfamilies have been identified. One RTK subfamily, designated the HER subfamily, includes EGFR, HERZ, HERE and HER4, and bind such ligands as epithelial growth factor (EGF), TGF-OL, amphiregulin, I-IB-EGF, llulin and heregulin. la (next page is page 2‘) WO 70514 A second family of RTKs, designated the insulin subfamily, includes the INS-R, the IGF-lR and the IR—R. A third family, the "PDGF" subfamily, es the PDGF alpha and beta receptors, CSFIR, c- kit and FLK-II. Another ily of RTKs, referred to as the FLK subfamily, encompasses the Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-l), the fetal liver kinase 4 (FLK-4) and the fins-like ne kinase 1 . Two other subfamilies ofRTKs have been designated as the FGF receptor family (FGFRI, FGFRZ, FGFR3 and FGFR4) and the Met subfamily (c-Met, Ron and Sea). For a detailed discussion of protein kinases, see for e, Blume-Jensen, P. et al., Nature. 2001, 411(6835):355-365, and g, G. et al., Science. 2002, 298(5600):1912-l934.
The non—receptor type of tyrosine kinases is also composed of numerous subfamilies, including Src, Btk, Abl, Fak, and Jak. Each of these subfamilies can be r subdivided into multiple s that have been frequently linked to oncogenesis. The Src family, for example, is the largest and includes Src, Fyn, Lck and Fgr among others. For a detailed discussion of these kinases, see Bolen JB. Nonreceptor tyrosine protein kinases. Oncogene. 1993, 8(8):2025-31.
A significant number of tyrosine kinases tboth receptor and nonreceptor) are associated with cancer (see Madhusudan S, Ganesan TS. Tyrosine kinase inhibitors in cancer therapy. Clin Biochem. 2004, 618~35.). Clinical studies suggest that overexpression or ulation of tyrosine kinases may also be of prognostic value. For example, members of the HER family of RTKs have been associated with poor prognosis in breast, colorectal, head and neck and lung cancer. Mutation of c-Kit tyrosine kinase is associated with decreased survival in intestinal stromal tumors. In acute enous leukemia, Flt-3 mutation predicts r disease free survival. VEGFR sion, which is important for tumor angiogenesis, is associated with a lower survival rate in lung cancer.
Tie—1 kinase expression inversely correlates with survival in gastric cancer. l expression is an important predictor of response in chronic myelogenous leukemia and Src tyrosine kinase is an indicator ofpoor prognosis in all stages of colorectal cancer.
The immune system responds to injury and threats fiom pathogens. Qytokines are low- molecular weight polypeptides or glycoproteins that stimulate biological ses in Virtually all cell types. .For example, cytokines regulate many of the pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and they can modulate both proinflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens.
Binding of a cytokine to its cell surface receptor initiates intracellular signaling cascades that transduce the extracellular signal to the nucleus, ultimately leading to changes in gene expression. The pathway involving the Janus kinase family of protein tyrosine kinases (JAKS) and Signal Transducers and Activators of Transcription ) is engaged in the ing of a wide range of nes.
Generally, cytokine receptors do not have intrinsic tyrosine kinase activity, and thus require receptor- associated kinases to propagate a phosphorylation cascade. JAKs fulfill this function. Cytokines bind to their receptors, causing receptor dimerization, and this enables JAKs to phosphorylate each other as well as specific tyrosine motifs within the cytokine receptors. STATS that recognize these phosphotyrosine motifs are recruited to the receptor, and are then themselves activated by a JAK- ent tyrosine phosphorylation event. Upon tion, STATS dissociate from the receptors, dimerize, and translocate to the nucleus to bind to specific DNA sites and alter transcription (Scott, M. 1., C. J. Godshall, et a1. (2002). "Jaks, STATS, Cytokines, and Sepsis." Clz'n Diagn Lab Immunol 9(6): 1153-9). ‘ The JAK family plays a role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response. tly, there are four known mammalian JAK family s: JAKl (also known as Janus kinase-1), JAK2 (also known as Janus -2), JAK3 (also known as Janus kinase, leukocyterJAKL; L—JAK and Janus kinase-3) and TYK2 (also known as protein-tyrosine kinase 2). The JAK proteins range in size from 120 to 140 kDa and comprise seven conserved JAK homology (JH) domains; one of these is a functional catalytic kinase domain, and another is a pseudokinase domain potentially serving a regulatory function and/or serving as a docking site for STATS (Scott, Godshall et al. 2002, supra).
While JAK], JAK2 and TYK2 are ubiquitously sed, JAK3 is reported to be entially expressed in natural killer (NK) cells and not resting T cells, ting a role in lymphoid activation ura, M., D. W. McVicar, et al. (1994). "Molecular cloning of L—JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated ytes." Proc Natl Acad Sci U S A 91(14): 6374—8).
Not only do the cytokine-stimulated immune and inflammatory responses contribute to normal host defense, they also play roles in the pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from hypoactivity and ssion of the immune system, and a hyperactive or inappropriate immune / atory response contributes to the pathology of autoimmune diseases such as rheumatoid and psoriatic arthritis, asthma and systemic lupus erythematosus, matory bowel disease, multiple sclerosis, type I diabetes mellitus, myasthenia gravis, thyroiditis, immunoglobulin nephropathies, myocarditis as well as illnesses such as scleroderma and osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000). "Janus kinases and signal transducers and activators of transcription: their roles in cytokine signaling, development and immunoregulation." Arthritis Res 2(1): 16-32). Furthermore, syndromes with a mixed tation of autoimmune and immunodeficiency disease are quite common (Candotti, F., L. Notarangelo, et al. (2002). "Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways." J Clin Invest ): 1261-9). Thus, therapeutic agents are typically aimed at augmentation or suppression of the immune and inflammatory pathways, accordingly.
Deficiencies in expression of JAK family members are associated with e states. Jakl —/- mice are runted at birth, fail to nurse, and die perinatally (Rodig, S.
J., M. A. Meraz, et al. (1998).
"Disruption of the Jakl gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine- induced ic ses." Cell 93(3): 373-83). Jak2-/- mouse embryos are anemic and die around day 12.5 postcoitum due to the absence of definitive poiesis. JAKZ—deficient fibroblasts do not respond to [EN gamma, although responses to IFNalpha/beta and IL-6 are unaffected. JAK2 functions in signal transduction of a specific group of cytokine receptors required in definitive erythropoiesis (Neubauer, H., A. , et a1. (1998). Cell 93(3): 397—409; Parganas, 13., D. Wang, et al. (1998).
Cell 93(3): 385-95.). JAK3 appears to play a role in normal development and function of B and T lymphocytes. Mutations of JAK3 are reported to be responsible for autosomal recessive severe ed immunodeficiency (SCID) in humans tti, F., S. A. Cakes, et al. (1997). "Structural and functional basis for JAK3-deficient severe combined immunodeficiency." Blood 90(10): 3996- 4003).
The JAK/STAT pathway, and in particular all four members of the JAK , are believed to play a role in the pathogenesis of the asthmatic response, c obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. For instance, the inappropriate immune responses that characterize asthma are orchestrated by a subset of CD4+ T helper cells termed T helper 2 (Th2) cells. Signaling through the cytokine receptor IL-4 stimulates JAKI and JAK3 to te STAT6, and signaling through IL—12 stimulates activation of JAK2 and TYK2, and subsequent phosphorylation of STAT4. STAT4 and STAT6 l multiple aspects of CD4+ T helper cell differentiation (Pemis, A. B. and P. B. Rothman (2002). "JAK-STAT signaling in asthma." J Clin Invest 109(10): 1279-83). Furthermore, TYKZ-deficient mice were found to have enhanced Th2 cell-mediated allergic airway inflammation (Seto, Y., H. Nakajima, et a1. (2003).
"Enhanced Th2 cell—mediated allergic inflammation in Tyk2-deficient mice." J Immunol 170(2): 1077-83). er, multiple cytokines that signal through JAK kinases have been linked to inflammatory es or ions of the upper respiratory tract such as those affecting the nose and sinuses (e.g. rhinitis, sinusitis) whether classically allergic reactions or not.
The JAK/STAT pathway has also been implicated to play a role in inflammatory £5 diseases/conditions of the eye including, but not limited to, iritis, uveitis, scleritis, conjunctivitis, as well as chronic allergic responses. Therefore, inhibition of JAK kinases may have a beneficial role in the therapeutic treatment of these diseases.
The AT pathway, and in particular, JAK3, also plays a role in cancers of the immune system. In adult T cell ia/lymphoma (ATLL), human CD4+ T cells acquire a transformed 50 phenotype, an event that correlates with ition of constitutive phosphorylation of JAKs and STATS. Furthermore, an association n JAK3 and STAT—1, STAT—3, and STAT—5 activation and ycle progression was demonstrated by both propidium iodide staining and bromodeoxyuridine incorporation in cells of four ATLL patients tested. These results imply that JAK/STAT activation is associated with ation of ic cells and that therapeutic ches 55 aimed at JAK/STAT inhibition may be considered to halt neoplastic growth (Takemoto, S., J. C.
Mulloy, et al. (1997). "Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation ofJAK]STAT proteins." Proc Natl Acad Sci U S A 94(25): 13897-902).
Blocking signal transduction at the level of the JAK kinases holds e for developing treatments for human cancers. Cytokines of the interleukin 6 (IL-6) family, which activate the signal transducer gpl30, are major survival and growth factors for human le myeloma (MM) cells.
The signal transduction of gpl30 is believed to involve JAKl, JAK2 and Tyk2 and the ream effectors STAT3 and the mitogen-activated protein kinase (MAPK) pathways. In IL—6-dependent MM cell lines treated with the JAK2 inhibitor tyrphostin AG490, JAK2 kinase activity and ERK2 and STAT3 phosphorylation were inhibited. Furthermore, cell proliferation was suppressed and apoptosis was induced (De V03, 1, M. Jourdan, et al. (2000). "JAKZ ne kinase inhibitor tyrphostin A0490 downregulates the mitogen-activated n kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces sis in myeloma cells." Br J Haematol 109(4): 823- 8). However, in some cases, AG490 can induce dormancy of tumor cells and ly then protect them from death.
Activation of JAK/STAT in cancers may occur by multiple mechanisms including cytokine stimulation (e.g. IL—6 or GM—CSF) or by a reduction in the endogenous suppressors of JAK signaling such as SOCS (suppressor or cytokine signaling) or PIAS (protein inhibitor of activated STAT) (Boudny, V., and Kovarik, J., Neoplasm.-49:349-355, 2002). Importantly, activation of STAT ing, as well as other pathways downstream of JAKs (e.g. Akt), has been correlated with poor prognosis in many cancer types (Bowman, T., et al. Oncogene 19:2474-2488, 2000). Moreover, elevated levels of circulating cytokines that signal through JAK/STAT may adversely impact patient health as they are thought to play a causal role in ia and/or chronic fatigue. As such, JAK inhibition may be therapeutic for the treatment of cancer patients for reasons that extend beyond potential anti-tumor activity. The cachexia indication may gain further mechanistic support with realization that the satiety factor leptin signals through JAKs.
Pharmacological targeting of Janus kinase 3 (JAK3) has been employed successfully to l allograft rejection and graft versus host disease (GVHD). In addition to its involvement in signaling of cytokine receptors, JAK3 is also engaged in the CD40 ing pathway of peripheral blood monocytes. During CD40—induced maturation of myeloid dendritic cells (DCS), JAK3 activity is induced, and increases in costimulatory molecule expression, IL—lZ production, and potent neic atory capacity are observed. A rationally designed JAK3 inhibitor WHI-P-154 prevented these effects arresting the DCs at an immature level, suggesting that immunosuppressive therapies ing the tyrosine kinase JAK3 may also affect the function of d cells (Saemann, M. D., C. Diakos, et al. (2003). "Prevention of CD40-triggered dendritic cell maturation and induction of T-cell hyporeactivity by ing of Janus kinase 3." Am J Transplant 3(11): 1341-9). In the mouse model system, JAK3 was also shown to be an important lar target for ent of autoimmune insulin-dependent (type 1) diabetes mellitus. The rationally designed JAK3 inhibitor JANEX-l exhibited potent modulatory activity and delayed the onset of diabetes in the NOD mouse model of autoimmune type 1 diabetes (Cetkovic-Cvrlje, M., A. L. Dragt, et al. (2003).
"Targeting JAK3 with JANEX—l for tion of autoimmune type 1 es in NOD mice." Clin l 106(3): 213-25).
It has been suggested that inhibition of JAK2 tyrosine kinase can be beneficial for patients with myeloproliferative disorder. (Levin, et al., Cancer Cell, vol. 7, 2005: 387-397) Myeloproliferative disorder (MPD) includes polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous ia (CML), c myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES) and ic mast cell disease (SMCD). Although the roliferative disorder (such as PV, ET and MMM) are thought to be caused by acquired somatic on in hematopoietic progenitors, the genetic basis for [0 these diseases has not been known. However, it has been reported that poietic cells from a majority of patients with PV and a significant number of patients with ET and MMM possess a ent somatic activating mutation in the JAKZ tyrosine kinase. It has also been reported that inhibition of the JAK2V617F kinase with a small molecule inhibitor leads to inhibition of proliferation of hematopoietic cells, suggesting that the JAK2 tyrosine kinase is a potential target for phannacologic inhibition in patients with PV, ET and MMM.
Inhibition of the JAK kinases is also envisioned to have therapeutic benefits in patients suffering from skin immune disorders such as psoriasis, and skin sensitization. In psoriasis vulgaris, the most common form of psoriasis, it has been generally accepted that activated T lymphocytes are important for the maintenance of the disease and its associated psoriatic plaques (Gottlieb, A.B., et al, Nat Rev Drug Disc, 4:19-34). Psoriatic plaques contain a significant immune infiltrate, including leukocytes and monocytes, as well as multiple mal layers with increased keratinocyte proliferation. While the initial activation of immune cells in psoriasis occurs by an ill defined mechanism, the maintenance is believed to be dependent on a number of inflammatory cytokines, in addition to various chemokines and growth factors (JCI, 113:1664-1675). Many of these, including interleukins -2, ~4, -6, -7, -12, -15, -18, and -23 as well as GM-CSF and IFNg, signal through the Janus (JAK) kinases (Adv Pharmacol. 2000;47:113-74). As such, blocking signal transduction at the level of JAK s may result in therapeutic benefits in patients suffering from psoriasis or other immune disorders of the skin.
It has been known that certain therapeutics can cause immune reactions such as skin rash or diarrhea in some patients. For instance, administration of some of the new targeted anti-cancer agents such as Iressa, Erbitux, and Tarceva has d acneiform rash with some ts. Another example is that some therapeutics used topically induce skin imitation, skin rash, contact dermatitis or allergic t sensitization. For some ts, these immune ons may be bothersome, but for others, the immune reactions such as rash or diarrhea may result in inability to continue the treatment.
Although the driving force behind these immune reactions has not been elucidated completely at the present time, these immune reactions are likely linked to immune infiltrate.
Inhibitors of Janus kinases or related kinases are widely sought and several publications report effective classes of compounds. For example, n inhibitors are reported in WO 99/65909, US 2004/0198737; ; ; and WO 01/42246. Heteroaryl substituted es and other compounds are reported in W0 2004/72063 and WO 99/62908.
Thus, new or improved agents which inhibit kinases such as Janus kinases are continually needed that act as suppressive agents for organ transplants, as well as agents for the prevention and treatment of autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, asthma, type I diabetes, inflammatory bowel e, Crohn’s disease, autoimmune thyroid disorders, mer’s disease), diseases involving a hyperactive inflammatory se (e.g., eczema), allergies, cancer (e.g., prostate, leukemia, multiple myeloma), and some immune ons (e.g., skin rash or contact dermatitis or ea) caused by other therapeutics, to name a few. The compounds, compositions and methods described herein are directed toward these needs and other ends.
SUMMARY OF THE ION The present invention provides compounds ofFormula I: (Y)n‘"z T:A2 I \\ U\\ 19V or pharmaceutically acceptable salt forms or prodrugs thereof, wherein constituent members are defined herein.
The present invention further provides compositions comprising a compound of Formula I, or phannaceutically acceptable salt f, and a pharrnaceutically acceptable carrier.
The present invention further provides methods of modulating an activity of JAK comprising contacting JAK with a nd ofFormula I, or pharmaceutically acceptable salt thereof.
The present invention further provides methods of treating a disease in a patient, wherein the disease is associated with JAK ty, comprising administering to the patient a therapeutically effective amount of a compound ofFormula I, or pharmaceutically acceptable salt thereof.
The present ion r provides compounds of Formula I for use in therapy.
The present invention further provides compounds of Formula I for the preparation of a medicament for use in therapy.
DETAILED DESCRIPTION The t invention provides, inter alia, compounds that modulate the activity of one or more JAKs and are useful, for example, in the treatment of es associated with JAK expression or activity. The compounds ofthe invention have Formula I: (/Y)n—-Z I, \‘ UK~ 19V including ceutically acceptable salt forms or prodrugs thereof, wherein: Al and A2 are independently selected from C and N; T, U, and V are ndently selected from O, S, N, CR5, and NR6; wherein the 5-membered ring formed by Al, A2, U, T, and V is ic; X is N or CR4; Y is CH; alkylene, 02.8 alkenylene, Cu alkynylene, (CR'IR‘2)p—(Cg_w cycloalkylene)— (CR' ‘R'2),, (CR1 ‘R‘2),-(ary1ene)-(CR' ‘R‘2)q, ((21:<"R‘2),,-(c...0 heterocycloalkylene)—(CR"R'2)q, (CRl lR12)l,,-(heteroarylene)-(CRI 'R12)q, (CRI l1{'2),,O(CRl lRn)q, (CRl 1R12),,S(CRl I182),], (CR' ‘R‘2)pC(O)(CR' ‘11"), (CR1 IR"),,C(0)1\1R°(CR‘ 1R"), (CR' ‘R12)pC(O)O(CR"R‘2)q, (CR1'R12)pOC(0)(CR"R'2)q, (CR"R"),0C(0)NR°(CR"R‘2),, (CR"R'2),,NR°(CR"R"),, (CR‘ 'R'2)pNR°C(O)NRd(CR‘ '12"), (CR' 1R"),S(0)(CR‘ '11"), (CR‘ 'R"),S(0)NR°(CR' 1R"), (CR"R'2)pS(O)2(CR"R")q, or(CR!1R12)pS(O)2NR°(CR"R12)q, n said CH, alkylene, CM alkenylene, Cm alkynylene, cycloalkylene, arylene, heterocycloalkylene, or arylene, is 50 optionally substituted with 1, 2, or 3 tuents independently selected from —D3—D4; Z is H, halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, =C—Ri, =N-Ri, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NRcRd, C(O)OR"‘, OC(O)Rb, OC(O)NR°Rd, NRCR", )R", NR°C(O)NR°R", NR°C(O)OR", C(=NRi)NR°R", NR°C(=NR‘)NRCR", S(O)R", S(O)NR°R", S(O)2R", NR°S(O)2R", C(=NOH)R", C(=NO(C1-5 alkyl)Rb, and S(O)2NR°Rd, wherein said CH; alkyl, C24; alkenyl, or CH alkynyl, is optionally substituted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", , C(O)NR°R", C(O)OR", OC(O)R", OC(O)NR°Rd, NR°Rd, NR°C(O)R", NR°C(O)NR°Rd, NR°C(O)OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2R", NR°S(O)2Rb, )R", C(=NO(C1_6 alkyl))Rb, and S(O)2NR°R"; wherein when Z is H, n is 1; or the —(Y)n—Z moiety is taken together with i) A2 to which the moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which the R5 or R6 of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaiyl, or cycloalkyl ring fused to the 5-membered ring formed by A], A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, aryl, or heterocycloalkyl ring is optionally substituted by l, 2, 3, 4, or 5 substituents ndently selected from —(W)m—Q; W is CH; nyl, 02-8 alkenylenyl, 02.3 alkynylenyl, 0, S, C(O), C(O)NR°', C(O)O, 00(0), OC(0)NR°', NR", NR°’C(0)NR"’, 3(0), S(O)NRC', 5(0),, or S(O)2NR°'; Q is H, halo, CN, N02, 01-8 alkyl, Cm alkenyl, 02.3 alkynyl, Cm haloalkyl, halosulfanyl, aryl, cycloalkyl, aryl, or heterocycloalkyl, wherein said CH; alkyl, C" alkenyl, CM alkynyl, CH; haloalkyl, ar‘y], cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with l, 2, 3 or 4 substituents independently selected from halo, CM alkyl, 02-4 alkenyl, C24 l, CM haloalkyl, halosulfanyl, c._4 hydroxyalkyl, cM cyanoalkyl, Cyz, CN, N02, OR‘", SRa', C(O)Rb', C(0)NR°’R"', C(0)0R"’, OC(0)R"', R°'R"‘, NR°'Rd’, NR°’C(0)R"', NR°'C(0)NR‘=‘R"‘, NR°’C(O)0R"', [5 S(O)Rb', S(O)NR°'R"', S(O)2Rb’, NR°’S(0)2R"', and 3(0)2NR°’R°"; Cyl and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally tuted by 1, 2, 3, 4 or 5 substituents independently selected from halo, CM alkyl, C" alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, CN, N02, 0R8", SR", C(0)Rb", C(O)NR°"R"", C(0)0Ra", OC(O)R"", 0C(0)NR°"R"", NR°"Rd", NR°"C(O)R"", NR°"C(O)OR"", NR°"S(0)R"", NR°"S(0)2R"", ", S(0)NR°"R‘*", S(O)2R"", and S(O)2NR°"R""; R‘, R2, R3, and R4 are independently selected from H, halo, CM alkyl, CH alkenyl, 02.4 alkynyl, CM haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0R7, SR7, C(O)R3, C(0)NR9R‘°, 7 OC(O)R8, 0C(0)NR9R‘°, NR9R‘°, NR9C(0)R8, )OR7, S(O)R8, S(O)NR9R'°, 5(0),,118, NR98(O)2R8, and S(O)2NR9R‘°; R5 is H, halo, CM alkyl, CM alkenyl, C2-4 alkynyl, CM kyl, halosulfanyl, CN, N02, 0R7, SR7, C(O)R8, C(0)NR9R‘°, C(O)OR7, OC(O)R8, OC(O)NR9R‘°, NR9R‘°, NR90(O)R8, NR°C(O)0R7, S(O)R8, 9R‘°, S(O)2RB, NR9S(O)2R8, or S(O)2NR9R'°; R6 is H, (3..., alkyl, (32‘1 alkenyl, 02., alkynyl, cM haloalkyl, 0R7, C(O)R8, C(O)NR9R'°, C(O)OR7, , S(O)NR9R'°, S(O)2Rs, or S(O)2NR ‘0; R7 is H, CM alkyl, CM haloalkyl, CM alkenyl, CM alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, arylalkyl, cycloalkylallcyl or heterocycloalkylalkyl; R8 is H, CM alkyl, 01-5 haloalkyl, 02-5 alkenyl, CM, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, lkylalkyl or cycloalkylalkyl; R9 and R'° are independently selected from H, cHO alkyl, 01-, haloalkyl, 02.5 alkenyl, 02., alkynyl, C1_5 alkylcarbonyl, arylcarbonyl, C1-6 alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; or R9 and R'0 together with the N atom to which they are attached form a 4-, 5—, 6- or 7— membered heterocycloalkyl group; Ru and R'2 are independently selected from H and -El-E2—E3-E4; D1 and El are independently absent or independently selected from CW alkylene, CM alkenylene, CM alkynylene, arylene, cycloalkylene, heteroarylene, and cycloalkylene, wherein each of the CH; alkylene, CM alkenylene, CM alkynylene, arylene, lkylene, heteroarylene, and heterocycloalkylene is optionally substituted by l, 2 or 3 substituents independently selected from halo, CN, N02, N3, SCN, OH, Cm alkyl, C1.6haloalkyl, Cm alkoxyalkyl, CH, , C1_5haloalkoxy, amino, CH; alkylamino, and C24; dialkylamino; D2 and E2 are independently absent or independently selected from C", alkylene, alkenylene, CM lene, (CH; alkylene),-O-( CH; alkylene)s, (Cm alkylene),—S-(C,_5 alkylene)5, (CM alkylene),-NR‘-(C._6 alkylene)" (C 1.6 ne),—CO—(Cl_5 alkylene)s, (CH; alkylene),-COO—(C,.6 alkylene)s, (01.5 alkylene),-CONRc-(C1-6 alkylene)s, (CH; alkylene),-SO-(C1-(, alkylene)s, (CM alkylene),-SOz-(C1.5 alkylene),, (C 1.6 alkylene),-SONR‘-(C 1-5 ne)5, and (CM alkylene),- NRCCONRf-(Cm alkylene)s, wherein each of the CH; alkylene, C2_5 alkenylene, and (32-6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, N02, N3, SCN, OH, C 1-5 alkyl, CM haloalkyl, CM alkoxyalkyl, CH; alkoxy, CH; haloalkoxy, amino, CH; alkylamino, and Cm dialkylamino; D3 and E3 are independently absent or independently selected from CH; ne, CM alkenylene, CM alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the CM alkylene, CM alkenylene, CM alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, N02, N3, SCN, OH, C1_6alkyl, C1.5haloalkyl, Cm alkoxyalkyl, Cm alkoxy, CH haloalkoxy, amino, CH; alkylamino, and CM dialkylamino; D4 and E4 are independently selected from H, halo, CH alkyl, C24 alkenyl, C24 l, haloalkyl, halosulfanyl, CM yalkyl, C14 cyanoalkyl, Cy', CN, N02, 0R8, SR3, C(O)Rb, C(0)NR°R", C(O)OR°, OC(O)Rb, OC(O)NR°Rd, NR°Rd, NR°C(0)R", NR°C(0)NR°R", NR°C(O)OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R°, S(O)2R", )2Rb, C(=NOH)R", C(=NO(C.-5 Rb, and R°Rd, wherein said CH; alkyl, C" alkenyl, or CH l, is Optionally tuted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, C" alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NR°R", 3, OC(O)R", OC(O)N'R°Rd, NR°Rd, NR°C(0)R", NR°C(O)NR°R", NR°C(O)OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(0)2R", C(=NOH)R", C(=N0(c..6 )Rb, and S(O)2NR°R"; R3 is H, Cy', -(C._5 alkyl)-Cy', CH; alkyl, CM haloalkyl, CH alkenyl, CM l, wherein said CH, alkyl, CM haloalkyl, CM alkenyl, or CM alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C145 alkyl, CH; haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Rb is H, Cy', -(C1_5 alkyl)-Cy', CH, alkyl, CM haloalkyl, CM alkenyl, CM alkynyl, n said CH; alkyl, CH; haloalkyl, 02.5 alkenyl, or C24; l is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CM alkyl, CM haloalkyl, 01.5 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; RB’ and R8" are independently ed from H, 0,.6 alkyl, (3..6 haloalkyl, (32.5 l, 02.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, lkylalkyl and heterocycloalkylalkyl, wherein said CM alkyl, C16 haloalkyl, Cm alkenyl, C245 alkynyl, aryl, lO cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, CM alkyl, CM haloalkyl, halosulfanyl, aryl, kyl, heteroaryl, heteroarylalkyl, lkyl and heterocycloalkyl; R‘" and R"" are independently selected from H, CM alkyl, CH5 kyl, c2.6 alkenyl, [5 CM alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C._5 alkyl, C", haloalkyl, CM alkenyl, CM l, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, kyl, heteroarylalkyl, cycloalkylalkyl or cycloalkylalkyl is ally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, C,.5haloa1ky1, Cm haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, R° and R" are independently selected from H, Cy‘, -(c,_6 alkyl)—Cy', cHo alkyl, c._6 haloalkyl, CM alkenyl, 02.6 alkynyl, wherein said C140 alkyl, C1_5 haloalkyl, CM alkenyl, or C24; alkynyl, is optionally substituted with l, 2, or 3 substituents independently selected from Cy', —(Cl.6 —Cy', OH, CN, amino, halo, C1-5alkyl, C._5haloalky1, C1_5 haloalkyl,and halosulfanyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7- ed heterocycloalkyl group optionally substituted with 1, 2, or 3 tuents independently selected from Cy', -(c._6 alkyl)—Cy', OH, CN, amino, halo, C1_6allcyl, c,_,haloalkyl, C1_5haloalky1, and halosulfanyl; R6 and Rd. are independently selected from H, CHO alkyl, CH; haloalkyl, CM alkenyl, CM 50 alkynyl, aryl, aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said CHO alkyl, CH; haloalkyl, CM alkenyl, (32.6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH. alkyl, 01-6 haloalkyl, (31.5 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, 55 arylalkyl, cycloalkyl and heterocycloalkyl; or R". and RP together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently WO 70514 selected from OH, CN, amino, halo, CH; alkyl, CH; haloalkyl, CH, kyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R°" and R"" are independently selected from H, cHo alkyl, on, haloalkyl, 02., alkenyl, (32-, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said €1.10 alkyl, 01.5 haloalkyl, 02.6 alkenyl, CM alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkyl, cycloalkylallcyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected fiom OH, CN, amino, halo, Cm alkyl, loa1kyl, halosulfanyl, CH, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and cycloalkyl; O or RC" and Rd" together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group optionally substituted with I, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH alkyl, C1_6haloa1ky], C1_6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Ri is H, CN, N02, or CH; alkyl; Re and Rf are independently selected from H and C16 alkyl; R‘ is H, CN, or N02; m is 0 or 1; n is O or 1; p is 0,1, 2, 3, 4, 5, or 6; ;0 qisO,l,2,3,4,50r6; r is O or 1; and s is 0 or 1.
In some embodiments, when X is N, n is 1, and the moiety formed by A', A2, U, T, V, and —(Y)n-Z has the formula: (Y)n—Z ww then Y is other than (CR' ‘R‘Z)pC(O)NR°(CR‘ 'R'2)q.
In some embodiments, when X is N, the ered ring formed by Al, A2, U, T, and V is other than pyrrolyl.
In some embodiments, when X is CH, 11 is l, and the moiety formed by A1, A2, U, T, V, and 0 —(Y)..-Z has the formula: (Y)n~z then —(Y)n-Z is other than COOH.
In some ments, when X is CH or C-halo, R', R2, and R3 are each H, n is 1, and the moiety formed by A1, A2, U, T, V, and —(Y)n-Z has the formula: (Yb—Z (Y)n_z (Y)n—Z __ S S / \ \ S \ IWV’ WW ’ or M then Y is other than (CR' ‘R‘2),,C(O)NR°(CR"R‘2)q or (CR'1R12)pC(O)(CR"R'2)q.
In some embodiments, when X is CH or C-halo, R', R2, and R3 are each H, n is O, and the moiety formed by A', A2, U, T, V, and —(Y)n-Z has the formula: (Y)n-Z (Y)n-Z (Y)n-Z __ S S / \ \ S \ AMP ml or NVV‘ 7 ’ then Z is other than CN, halo, or CH alkyl.
In some embodiments, when X is CH or C—halo, R', R2, and R3 are each H, n is 1, and the moiety formed by A', A2, U, T, V, and —(Y)n—Z has the formula: (Y)n-Z (Y)n-Z at a %/N' SIN then Y is other than (CR1 ‘R‘2)pC(O)NR°(CR"R‘2 , or(CR1'R'2)pC(O)(CR"R12)q.
In some embodiments, when X is CH or , R], R2, and R3 are each H, n is 1, and the moiety formed by A}, A2, U, T, V, and —(Y)n-Z has the formula: (Y)n_Z then Y is other than (CR‘‘R'2),,I~IR°(CR"R12 In some embodiments, when X is CH or C-halo and R‘, R2, and R3 are each H, then the moiety formed by A', A2, U, T, V, and ~(Y)n-Z has a formula other than: 0/ S/ / NW, NVV‘,OI‘ uvvv In some embodiments: Z is H, halo, CN, N02, CH; alkyl, C" alkenyl, C24; alkynyl, CH; haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, n said C 1-3 alkyl, C24; alkenyl, (32.8 alkynyl, CH; haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally tuted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, 02-4 l, CM haloalkyl, CM hydroxyalkyl, C._4 cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, C(O)NR°R", C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, NR°C(O)Rb, NR°C(O)NR°Rd, NR°C(O)OR", )NR°Rd, NR‘)NR¢R", S(O)R", S(O)NR°R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°R"; Q is H, halo, CN, N02, CH; alkyl, C24; alkenyl, C24; alkynyl, CH; kyl, aryl, cycloalkyl, heteroaryl, or cycloalkyl, wherein said C1_g alkyl, Cm alkenyl, CH alkynyl, CH; haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently ed from halo, CM alkyl, 02-4 l, CM alkynyl, CM haloalkyl, CM hydroxy— alkyl, cM lkyl, Cyz, CN, N02, 0R"; SR") C(0)R'°’, C(0)NR°'R‘*’, C(0)0R"’, OC(O)R"’, OC(O)NR°'R"', ", NR°’C(0)R"', NR°’C(0)NR"R"‘, NR°'C(O)OR3', S(0)Rb’, S(O)NRC'R"', S(O)2Rb', 0)2R"’, and S(O)ZNRC‘R"’; Cyl and Cy2 are ndently selected from aryl, heteroaryl, cycloalkyl, and heterocyclo- alkyl, each optionally tuted by l, 2, 3, 4 or 5 substituents independently selected from halo, alkyl, C24 alkenyl, CM alkynyl, CM haloalkyl, CM hydroxyallcyl, CM cyanoalkyl, CN, N02, 0R6", SR3", C(0)R"", C(0)NR°"R"", C(O)OR"", OC(O)R"", OC(O)NRC"R"", NR°"R"", NR°"C(0)R"", O)ORB", NR°"S(0)R"", O)2R"", S(O)R"", S(O)NR°"R"", S(O)2Rb", and S(O)2NR°"R""; R1, R2, R3, and R4 are independently selected from'H, halo, CM alkyl, 02-4 alkenyl, C24 alkynyl, CM haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0R7, SR7, C(O)R8, C(O)NR9R'°, C(O)OR7 00(0)}?3‘, OC(O)NR9R'°, NR9R‘°, NRQC(O)R8, NRCC(O)OR7, S(O)R8, S(O)NR9R-'°, S(O)2R8, NR98(O)2R8, and S(O)2NR9R'°; R5 is H, halo, CM alkyl, 02.4 alkenyl, (32.4 alkynyl, C._4 haloalkyl, CN, N02, 0R7, SR7, C(O)R8, C(0)NR9R‘°, 7, OC(O)R8, 0C(0)NR9R‘°, NR9R‘°, NR9C(O)R8, NR9C(0)0R7, S(O)R8, S(O)NR9R‘°, S(O)2R8, NR93(0)2R8, or S(O)2NR9R'°; R6 is H, cM alkyl, CM alkenyl, C24 alkynyl, CM haloalkyl, 0R7, , C(0)NR9R‘°, C(O)OR7, S(O)R8, S(O)NR9R‘°, S(O)2R8, or S(O)2NR9R‘°; R7 is H, Cm alkyl, CM haloalkyl, CM alkenyl, CM alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R8 is H, C._5 alkyl, CH; haloalkyl, CN, alkenyl, C245 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; R9 and R10 are independently selected from H, C140 alkyl, CW haloalkyl, CM l, CM alkynyl, CM alkylcarbonyl, arylcarbonyl, Cm alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl; or R9 and Rl0 together with the N atom to which they are attached form a 4-, 5-, 6- or 7— membered heterocycloalkyl group; R" and R'2 are ndently selected from H, halo, OH, CN, CM alkyl, CM haloalkyl, C2... l, C24 alkynyl, CH hydroxyalkyl, CM cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R", R8,, and R8" are independently selected from H, CM alkyl, C"; haloalkyl, CH alkenyl, C245 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said CH; alkyl, CH, haloalkyl, CM alkenyl, CM l, aryl, cyclo— alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, C._6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R", R" and Rb" are independently selected from H, (31-5 alkyl, C", haloalkyl, CM alkenyl, C245 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, kyl, heteroarylallcyl, cycloalkylalkyl and theterocycloalkylallcyl, wherein said Cm alkyl, (31.5 haloalkyl, CM alkenyl, C24; alkynyl, aryl, cyclo- alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with l, 2, or 3 substituents independently selected fi‘om OH, CN, amino, halo, Cm alkyl, 01-5 haloalkyl, CH; haloalkyl, aryl, arylalkyl, heteroaryl, arylalkyl, cycloalkyl and heterocycloalkyl; R° and Rd are ndently selected from H, C140 alkyl, CH; haloalkyl, CM alkenyl, CM alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said CHO alkyl, CH; haloalkyl, CM alkenyl, C2_6 alkynyl, aryl, hetero- aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, CM haloalkyl, Cm haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylallcyl, cycloalkyl or heterocycloalkyl; or R‘2 and Rd er with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group ally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, Cm haloalkyl, CM haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; R°' and Rd' are independently selected from H, C 1-10 alkyl, C ._6 kyl, 02-6 alkenyl, CM alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1. ,0 alkyl, CM haloalkyl, CM l, CM alkynyl, aryl, hetero- aryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, C._5 kyl, loalkyl, aryl, arylalkyl, heteroaryl, arylalkyl, cycloalkyl and heterocycloalkyl; or Rc’ and Rd, together with the N atom to which they are attached form a 4-, 5—, 6- or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alky], CH haloalkyl, CH; haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylallcyl, lkyl and heterocycloalkyl; R"" and RC" are independently selected from H, cHo alkyl, c1.6 haloalkyl, 02.6 alkenyl, 02.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C1,") alkyl, Cm haloalkyl, C24; l, C26 alkynyl, aryl, hetero- aryl, lkyl, heterocycloalkyl, arylallcyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally tuted with l, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-5 alkyl, CM kyl, CM haloalkyl, aryl, arylalkyl, heteroaryl, arylalkyl, cycloalkyl and heterocycloalkyl; and or RC" and Rd" together with the N atom to which they are ed form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, CH; alkyl, C1_6haloalkyl, CH3 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl.
In some embodiments, X is N.
In some embodiments, X is CR4.
In some embodiments, Al is C.
In some embodiments, A1 is N.
In some embodiments, A2 is C.
In some embodiments, A2 is N.
In some embodiments, at least one of A], A2, U, T, and V is N.
In some embodiments, the 5-membered ring fonned by A], A2, U, T, and V is pyrrolyl, lyl, imidazolyl, oxazolyl, thiazolyl, or oxadiazolyl.
Ul In some embodiments, the 5-membered ring formed by A', A2, U, T, and V is selected from: "‘63.. ""53, ME "'51 6 "‘43, N/ \ / \ 7wN/ N [KN—i N / / \ \N uJ." «L, W b ,Jw m, b b b b ""5" ,"5" ’"3", 0' weak ms. at m — N S / [L "r if" "8" "EM and? ; wherein: a designates the site of attachment of moiety —(Y)n-Z; b designates the site of attachment to the core moiety: it \ R2 R3 N IN! ; and ’ designate the two sites of attachment of the fused 4— to 20-membered aryl, cycloalkyl, c and c heteroaryl, or heterocycloalkyl ring.
In some embodiments, the 5-membered ormed by Al, A2, U, T, and V is ed from: Ug— 0% b b b b , ’ 5 S ’ C' "at 0' "~55, "a"; I \ — [i "BM 4‘8" and "‘3" ’ ; wherein: a designates the site of attachment ofmoiety —(Y)n-Z; b designates the site of attachment to the core moiety: XI \ \ R3J\N/ R2 H ; and ’ designate the two sites of attachment of the fused 4— c and c to 20—membered aryl, lkyl, heteroaryl, or heterocycloalky] ring.
In some embodiments, the 5—membered ring formed by Al, A2, U, T, and V is selected from: Km?3%?"MERE "’3, ,and b ; wherein: a designates the site of attachment of moiety —(Y),.—Z; [O b designates the site of attachment to the core moiety: x \ \ A / R2 R3 N N H ; and ’ designate the two sites of attachment of the fused 4- c and c to ZO-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring. [5 In some embodiments, the 5-membered ring formed by A', A2, U, T, and V is selected from: NW8 mi "vi "mi "‘49: "6?, "'3 N—N/ R6 2 N—< s—<\ N::< _ \ \ Io—< %/N \ \ N \ S \ S N \ N N Y 1) I "3", w JVVV ww MN uvw W b b b b b b b , , ’ , , and , ’ , wherein: a designates the site of ment of moiety —(Y)n-Z; b designates the site of attachment to the core moiety: fi\ \ ’R2 R3 N/ y, In some embodiments, the 5—membered ring formed by Al, A2, U, T, and V is selected from: 7‘2 ""3. R? "‘42. a "‘44..
N—N Nj N—‘\< N.— w "JVV vvw W b b b b , , , and , wherein: a designates the site of attachment of moiety —(Y)n-Z; b designates the site of attachment to the core moiety: JXL \ \ R2 R3 N/ :3 In some embodiments, the 5-membered ring formed by A1, A2, U, T, and V is selected from: 7‘4, "‘8" wherein: a designates the site of attachment of moiety —(Y)n-Z; b designates the site of attachment to the core moiety: 1 \ \ R2 R3 N/ fl In some embodiments, n is O.
In some embodiments, n is 1.
In some embodiments, n is 1 and Y is CH; ne, C2.3 alkenylene, 50 (CR‘ 'R'2)pC(O)(CR' ‘R")q, (CR' 'R'2)pC(O)NR°(CR‘ 'R'2)q, (CR‘ 'R'2)pC(O)O(CR' ‘R‘2)q, (CRl OC(O)(CR"Rn)q, n said CM; alkylene or CH alkenylene, is optionally substituted with 1, 2, or 3 halo, OH, CN, amino, CH mino, or CH dialkylamino.
In some embodiments, n is l and Y is C]_g alkylene, (CR"R"),,C(O)(CR"R12 (CR"R‘2),C(0)NR°(CR1'R"),, (CR‘ ‘R‘2)pC(O)O(CR"R‘2)q, n said c,_8 alkylene is optionally tuted with 1, 2, or 3 halo, OH, CN, amino, CM alkylamino, or CH dialkylamino.
In some embodiments, n is 1 and Y is CH; ne optionally substituted with l, 2, or 3 halo, OH, CN, amino, CM alkylamino, or C" dialkylamino.
In some embodiments, n is 1 and Y is ethylene ally substituted with l, 2, or 3 halo, OH, CN, amino, CM alkylamino, or 02-3 dialkylamino.
In some embodiments, n is 1 and Y is (CRHR'Z),,C(O)(CR"R'2)q (CRl lR"),,C(O)NR‘3- (CRl lR'2)q, or (CRl lR"),,C(O)O(CRl .
In some ments, Y is CH; alkylene, C24; alkenylene, C24; alkynylene, (CR"R‘2)p-(C3_m cycloalkylene)—(CR‘1R'2)q, (CR1 ‘R‘2),-(ary1ene)-(CR‘ 'R'2)q, (CR'1R‘2)p-(C1_lo heterocycloalkylene)- (CR"R'2)q, (CR' lR12)p—(heteroarylene)-(CRI '11"), (CR' (CR‘ 'R'2)q, or (CR"R"),S(CR1 ‘11"), wherein said C |.g alkylene, C24; alkenylene, CM alkynylene, cycloalkylene, e, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 tuents l 5 independently selected from -—D'-D2-D3-D4.
In some embodiments, Y is CH; alkylene, C24; alkenylene, Cu alkynylene, (CR"R'2)p-(C3_w cycloalkylene)—(CR‘1R12)q, (CRl lR'2)},—(arylene)-(CRI lRn)q, (CRI lR12),,-(C1.10 heterocycloalkylene)— (CR1 '11"), (CR' 'R'2)p—(heteroarylene)—(CR' ‘11"), (CR‘ ‘R‘2)pO(CR] ‘R'2).,, or (CRl 'R")pS(CR' 'R"),, wherein said CH; alkylene, C243 alkenylene, 02-8 alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is ally substituted with 1, 2, or 3 substituents independently selected from D".
In some embodiments, Y is CH; alkylene, C24; alkenylene, CH alkynylene, or (CRHR'2)p—(C3_ .0 cycloalkylene)-(CR"R'2)q, wherein said CH; alkylene, CH alkenylene, CM alkynylene, or cycloalkylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -—D'- DZ-D3-D".
In some embodiments, Y is CH; alkylene, CH alkenylene, C24; alkynylene, or (CR'IR'2)p-(C3- IO cycloalkylene)-(CR1'R'2)q, wherein said CH, alkylene, CM alkenylene, CH alkynylene, or cycloalkylene, is optionally substituted with 1, 2, or 3 substituents independently selected from D".
In some embodiments, Y is CH; alkylene, C24; alkenylene, or CH alkynylene, each optionally 50 substituted with 1, 2, or 3 substituents independently selected from —D'-D2-D3-D4.
In some embodiments, Y is CH; alkylene optionally substituted with l, 2, or 3 substituents independently selected from ——D'-D2-D3-D4.
In some embodiments, Y is C..3 ne optionally substituted with l, 2, or 3 substituents independently selected fi'om D". 55 In some embodiments, Y is C|.3 alkylene, CM lene, Cm alkynylene, (CRI'R‘2)pO- (CRHR'2)q, (CRHR‘Z)pS(CR"R‘2)q, 2)pC(O)(CR"R]2)q, (CR"R'2)pC(O)NR°(CR"R'2)q, 12)pC(O)O(CR"RIZ)q, (CR1 lR'z)pOC(O)(CRI 1R12)q, (CR1 'R'2)pOC(O)NR°(CR} 1R12)q, (CR"R'2)P °(CR"R12)q, (CR"R12)pNR°C(O)NRd(CR"R'2)q, (CR' 1R‘2)pS(O)(CR"R'2)q, (CR"R'2)pS(O)NR°(CR"R'2)q, 'Z),,S(0)2(CR"R‘2 or (CR"R'2)pS(O)2NR°(CR"R'2)q, wherein said 01-3 alkylene, 02.3 alkenylene, Cm alkynylene is optionally substituted with l, 2, or 3 tuents independently selected from halo, OH, CN, amino, CM alkylamino, and CH dialkylamino.
In some embodiments, Y is CH, alkylene, CM alkenylene, CM alkynylene, (CRl lR'z),,—(C3,..o cycloalkylene)-(CR1'R'2)q, (CRIIR'2)p-(arylene)-(CRl'R'2)q, (CR"R'2)p—(C1_loheterocycloalkylene)— (CR"R‘2),, (CR"R'2)p-(heteroarylene)-(CR‘ , (CR1 'R")p0(CR"R‘2)q, (CR"R‘2)pS(CR"R’2)q, (CR' 'R‘2)pC(O)(CR' ‘18:), (CR‘ ’R")PC(O)NR°(CR"R'2)Q, (CR‘ ‘R‘z)pC(O)O(CR"R’2)q, [0 (CR"R‘2)pOC(O)(CR"R12)q, (CR'IR‘Z),,OC(O)NR°(CR"R12)q, '2)p °(CR"R")q, (CR‘ IR12)pN-RCC(O)N'Rd(CRl IR'2)q, 12)pS(O)(CR' 1R12)q, (CR‘ 'R'2)pS(O)NR°(CRl 'R'2)q, (CR' 'R'2)pS(0)2(CR‘ 'R'2)q, or (CR1‘R‘2),,S(0)2NR°(CRl 'R").,, wherein said (3,.3 alkylene, cl.8 alkenylene, C" lene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, amino, CM alkylamino, and C2_g dialkylamino.
In some embodiments, p is 0.
In some embodiments, p is 1.
In some embodiments, p is 2.
In some embodiments, q is 0.
In some embodiments, q is 1.
In some embodiments, q is 2.
In some embodiments, one of p and q is 0 and the other of p and q is 1, 2, or 3.
In some embodiments, Z is H, halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy], CN, N02, OR", SR", C(O)Rb, C(O)NR°Rd, C(O)OR°, OC(O)R", OC(O)NR°R", NR°Rd, NR°C(0)R", NR°C(O)NR°R", )OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2Rb, C(=NOH)Rb, C(=NO(C,_6 alkyl)Rb, and R°Rd, wherein said C1.g alkyl, CM alkenyl, or C" alkynyl, is optionally substituted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, CM alkenyl, CM alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy], CN, N02, OR", SR3, C(O)R", C(O)NR"R", C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, NR°C(O)R", NR°C(0)NR°R", NR°C(O)OR", )NR°R", NR°C(=NR‘)NR°R", scomb, °R", S(O)2R", NR"S(O)2R", C(=NOH)R", C(=N0(C,_6 alkyl))Rb, and S(O)2NR°Rd.
In some embodiments, Z is aryl, llcyl, heteroaryl, or heterocycloallcyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents ed from halo, CM alkyl, 02.4 alkenyl, CM alkynyl 55 CM haloalkyl, halosulfanyl, CM yalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NR°R", 3, OC(O)R", OC(O)NR°R", mend, NR°C(O)R", NR°C(O)NR°R", NR°C(O)OR°, C(=NR‘)NRCR", NR°C(=NR‘)NR°R", , S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°Rd.
In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or cycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 tuents selected fiom halo, CM alkyl, C24 alkenyl, C24 alkynyl, C1.4 haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NR°Rd, C(O)OR", OC(O)R", OC(O)NR°Rd, NR°Rd, )R", NR°C(O)NR°R", NR°C(O)OR3, C(=NR‘)NR°R", NR‘)NR°R", S(O)R", S(O)NR"R‘1, S(O)2Rb, NR°S(O)2Rb, and S(O)2NR°R".
In some embodiments, Z is aryl or heteroaryl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, 02.4 alkenyl, 02.4 alkynyl, CM haloalkyl, halosulfanyl, cM hydroxyalkyl, (3,.4 cyanoalkyl, cy', CN, N02, OR", SR3, C(O)R", C(O)NR°R", C(O)OR", OC(O)R", OC(O)NR"R", NR°R‘*, )R", NR°C(O)NR"R", NR°C(O)OR", C(=NR‘)NR°R", lO NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2Rb, and S(O)2NR°R".
In some embodiments, Z is aryl or heteroaryl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, CM hydroxyalkyl, (3..4 cyanoalkyl, Cy', CN, N02, OR", SR", C(O)R", C(0)NR°R", C(O)OR", OC(O)R", R°R", NRcRd, NR°C(O)Rb, NR°C(O)NR°Rd, NR°C(O)OR3, C(=NRi)NR°Rd, [5 NRi)NRCRd, S(O)R", S(O)NR°R", S(O)2R", NRCS(O)sz, and S(O)2NRCR°‘.
In some embodiments, Z is phenyl or 5— or 6-membered heteroaryl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents selected from halo, CH alkyl, C24 l, C24 alkynyl CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, °R°, C(O)OR", 00mm", OC(O)NR°Rd, NRcRd, NR°C(0)R", NR"C(O)NR°Rd, NR°C(0)0R", C(=NR‘)NR°R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2R", NR"S(O)2R", and S(O)2NR°R".
In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C24 alkenyl, C2... alkynyl, (3..4 haloalkyl, C._4 hydroxyalkyl, cM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)R", C(O)NR°Rd, C(O)OR", ", OC(O)NR°R", NR°R", NR°C(O)Rb, NR"C(O)NR°R", NR°C(O)OR3, £5 C(=NR‘)NR°Rd, NR°C(=NR‘)NR°Rd, S(O)Rb, S(O)NR°Rd, S(O)2R", NR°S(O)2Rb, and S(O)2NR°R".
In some ments, Z is phenyl optionally substituted with l, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, C M hydroxy- alkyl, CM cyanoalkyl, Cy‘, CN, N02, 0R3, SR", C(O)R", C(O)NR°Rd, C(O)OR", OC(O)R", R°R", NR°Rd, NR°C(O)Rb, NR°C(O)NR°Rd, NR°C(O)OR", )NR°R", 50 NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2R", and R°R".
In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, C(O)NR°Rd, C(O)OR", OC(O)R", OC(O)NR°Rd, NRCR", NR°C(O)R", NR°C(O)NR°Rd, NR°C(O)OR", )NR°R", NR°C(=N‘Ri)NR°R", S(O)Rb, ;5, S(O)NR°R", ", NR°S(O)2R", and S(O)2NR°Rd.
In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents ed from halo, CM alkyl, C24 alkenyl, 02.4 alkynyl, CM haloalkyl, halosulfanyl, c._, yalkyl, c._4 cyanoalkyl, Cy’, CN, N02, OR", SR", C(O)Rb, C(0)NR°R", C(O)OR3, OC(O)R", OC(O)NR"R", NR°Rd, NR°C(O)R", NR°C(0)NR°R", NR"C(O)OR3, C(=NR‘)NR°R", NR"C(=NR‘)NR°R", S(O)Rb, S(O)NR°Rd, S(O)2Rb, NR°S(O)2R", and S(O)2NR°R".
In some embodiments, Z is cycloalkyl or heteroeycloalkyl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, C 1.4 hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(om", C(0)NR°R", C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, NR°C(O)Rb, )NR°R", NR°C(O)OR", C(=NR‘)NR°Rd, NR°C(=NRi)NR°Rd, S(O)Rb, S(O)NR°R", S(O)2R", NR"S(O)2R", and S(O)2NR°R".
In some embodiments, Z is ropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with l, 2, 3, 4, 5, or 6 tuents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM yalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, C(O)NR"Rd, C(O)OR", OC(O)R", OC(O)NR°R°, NR°Rd, NR"C(O)R", NR°C(O)NR°R", NR°C(O)OR3, C(=NRi)NR°Rd, NR"C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°Rd. ' In some ments, Z is CH; alkyl, CM alkenyl, or Cm alkynyl, each optionally substituted with l, 2, 3, 4, 5, or 6 tuents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, C1.4.cyanoalkyl, Cy', CN, N02, OR", SR3, C(O)Rb, C(O)NR°R", C(O)ORB, OC(O)R", OC(O)NR°Rd, NRCR", NR°C(O)Rb, )NR°R", NR°C(O)OR", C(=NRi)NR°Rd, NR"C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°R".
In some embodiments, Z is CH; alkyl, C24; alkenyl, or C" alkynyl, each ally substituted with 1, 2, 3, 4, 5, or 6 substituents ed from halo, CM alkyl, C" alkenyl, C24 alkynyl, C haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cyl, CN, N02, OR", SR", C(O)Rb, C(O)NR°Rd, ", ", OC(O)NR°R", NR°Rd, NR°C(O)R", NR"C(O)NR°R", NRcC(O)OR", C(=NR‘)NR°R", NR°C(=NR‘)NR°R‘1, S(O)R", S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°R".
In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoallcyl, Cy‘, CN, N02, 0R9, SR", C(O)Rb, C(O)NR"R", C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, )R", NR°C(O)NR°Rd, NR°C(O)OR", S(O)R", S(O)NR°Rd, b,NRcS(O)1Rb, and S(O)2NR°Rd. 3O In some embodiments, Z is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally tuted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, CM alkenyl, C24 alkynyl, CM kyl, CM hydroxyallcyl, CM cyanoalkyl, Cyl, CN, N02, OR", SR", C(O)Rb, °R", C(O)OR", occom", R°R", NR°Rd, NR°C(O)R", NR°C(O)NR°R", NR°C(O)OR", S(O)Rb, S(O)NR°R", S(O)2Rb, NR"S(O)2R", and R°Rd.
In some embodiments, Z is aryl or heteroaryl, each optionally substituted with 1, 2, 3, 4, S, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, c,_4 cyanoalkyl, Cy’, CN, N02, OR", SR", C(0)R", C(0)NR°R", C(O)OR", OC(O)Rb, OC(O)NR°R", Mend, NR°C(Q)R", NR°C(0)NR°R", NR°C(O)OR", S(O)R", S(O)NR°Rd, S(O)2Rb, NR°S(O)2R", and S(O)2NR°R".
In some embodiments, Z is aryl or heteroaryl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 l, C24 alkynyl, CM haloalkyl, CM hydroxyalkyl, cM cyanoalky1,Cy', CN, N02, OR", SR", C(O)R", C(O)NR°Rd, C(O)OR", OC(O)R", R°R", NR°R", NR°C(O)R", NR°C(O)NR°R", NR°C(O)OR", , S(O)NR°R", S(O)2R", NR°S(O)2R", and R°R".
In some embodiments, Z is phenyl or 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, S, or 6 tuents independently selected fiom halo, CM alkyl, C24 [0 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM yalkyl, CM cyanoalkyl, Cy], CN, N02, OR", SR", C(O)Rb, C(0)NR°R", C(O)OR3, OC(O)R", OC(O)NR°R", NRCR", NR°C(0)R", NR°C(O)NR"R", NR"C(O)OR", , °R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°R".
In some embodiments, Z is phenyl or 5- or 6-membered heteroa'ryl, each optionally substituted with l, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 [5 alkenyl, CM alkynyl, CM haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NR°R", C(O)0Ra, OC(O)R", OC(O)NR°Rd, NR°Rd, NR°C(O)Rb, NR°C(O)NR°R", NR°C(O)OR'°‘, S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2Rb, and S(O)2NR°Rd.
In some embodiments, Z is phenyl optionally substituted with l, 2, 3, 4, 5, or 6 substituents independently ed from halo, CM alkyl, C24 alkenyl, CM alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, cl.4 lkyl, Cy‘, CN, N02, 0R3, SR", C(O)Rb, C(O)NR°Rd, C(O)OR", OC(O)R", OC(O)NR°R", NR‘R", NR°C(O)R", NR°C(O)NR°R", )ORa, S(O)Rb, °R", S(O)2Rb, NR°S(O)2R*’, and S(O)2NR°Rd.
In some embodiments, Z is phenyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently ed from halo, CM alkyl, C24 alkenyl, 02-4 alkynyl, CM haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, ORa, SR", C(O)Rb, C(O)NR°Rd, C(O)OR", b, OC(O)NR°R", NR°Rd, NR°C(O)R", NR°C(O)NR°R", NR°C(O)OR3, S(O)R", S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°R".
In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently ed from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM 50 haloalkyl, lfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR8, , C(O)NR°R", C(O)OR", 0C(O)Rb, OC(O)NR°R", NRcRd, NR°C(O)R", NR°C(0)NR°R", NR°C(O)OR", S(O)R", S(O)NR"R", S(O)2Rb, NR°S(O)2R", and S(O)2NR°R".
In some embodiments, Z is cycloalkyl or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 tuents independently selected from halo, CM alkyl, C2", alkenyl, 02.4 alkynyl, CM $5 haloalkyl, c,_4 hydroxyallcyl, c1.4 cyanoalkyl, Cy‘, CN, N02, OR", SR", C(O)Rb, C(0)NR"R", C(O)OR", OC(O)R", R°R", NR°R°, NR°C(0)R", NR°C(O)NR°R", NR°C(O)OR", S(O)R", S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°R".
In some embodiments, Z is CH; alkyl, C24; alkenyl, or CH alkynyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CH hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR3, C(O)Rb, C(O)NR°Rd, C(O)OR", ", OC(O)NR°R", NR°Rd, )R", NR°C(O)NR°R", NR°C(O)OR", , S(O)NR°R", S(O)2R", NR°S(O)2R", and S(O)2NR°R".
In some embodiments, Z is C]_g alkyl, Cm alkenyl, or CH alkynyl, each optionally tuted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, 02-4 alkenyl, C24 alkynyl, CM haloalkyl, CH hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR3, C(O)Rb, C(O)NR°R", C(O)OR", OC(O)R", 0C(O)NR°R", NRcRd, NR°C(O)Rb, NR°C(O)NR"R", NR°C(O)OR", S(O)R", S(O)NR°R", S(O)2Rb, NR°S(O)2R", and' S(O)2NR°Rd.
In some embodiments, Z is C,_3 alkyl, Cm alkenyl, C" alkynyl, aryl, cycloalkyl, heteroaryl, or cycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents ndently selected from halo, CH alkyl, C14 haloalkyl, halosulfanyl, CM yalky], CM cyanoallcyl, Cy', CN, N02, OR", C(O)NR°R", C(O)OR", NR°Rd, NR°C(O)R", and b.
In some embodiments, Z is CH; alkyl, CH alkenyl, CH alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, CM alkyl, CM haloalkyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, 0R3, °R", C(O)ORa, NR°Rd, NR°C(0)R", and S(O)2Rb. .
In some embodiments, Z is CH; alkyl, 02-3 alkenyl, C242 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with l, 2, or 3 substituents independently selected from halo, CM alkyl, CM haloalkyl, halosulfanyl, CM yalkyl, CH cyanoalkyl, Cy', CN, N02, 018‘, C(O)NR°Rd, C(O)OR", NRcR", NR°C(0)R", and S(O)2R".
In some embodiments, Z is CH; alkyl, C24; alkenyl, CH alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each optionally substituted with I, 2, or 3 substituents independently ed from halo, CM alkyl, CM haloalkyl, CM yalkyl, CM cyanoalkyl, Cy], CN, N02, OR", C(0)NR°R°, C(O)OR", NR°R", NR°C(O)R", and S(O)2Rb.
In some embodiments, Z is substituted with at least one tuent sing at least one CN group.
In some embodiments, Z is CH; alkyl, C243 alkenyl, CH alkynyl, aryl, lkyl, heteroaryl, or heterocycloalkyl, each substituted with at least one ON or CH cyanoalkyl and optionally substituted with 1, 2, 3, 4, or 5 r substituents selected from halo, CM alkyl, 02.4 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(O)NR°R", C(O)OR", OC(O)R", OC(O)NR°Rd, NR°Rd, NRCC(O)Rb, NR°C(0)NR°R°, NR°C(O)OR", S(O)R", S(O)NR°R", S(O)2Rb, NR°S(O)7_R", and S(O)2NR°R".
In some embodiments, Z is CH; alkyl, Cm alkenyl, CM alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted with at least one ON or CH cyanoalkyl and optionally substituted with 1, 2, 3, 4, or 5 further substituents selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, CM hydroxyalkyl, CM lkyl, Cy', CN, N02, OR", SR", C(O)Rb, C(0)NR°R", C(O)OR", OC(O)R", OC(O)NR°R", NR°Rd, NR°C(0)R", NR°C(O)NR°R", NR°C(0)0R°, , S(O)NR°R", S(O)2R", NR°S(O)2Rb, and S(O)2NR°Rd.
In some ments, wherein the —(Y)n-Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R5 or R6 of either T or V is attached to form a 4— to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5—membered ring formed by A', A2, U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from —(W)m-Q.
In some embodiments, wherein the —(Y)n—Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R5 or R6 of either T or V is attached to form a 4— to 8-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A', A2, U, T, and V, n said 4— to 8-membered aryl, cycloalkyl, aryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently ed from —(W)m-Q.
In some embodiments, the —(Y).,—Z moiety is taken together with i) A2 to which said moiety is attached, ii) R5 or R6 of either T or V, and iii) the C or N atom to which said R5 or R6 of either T or V is attached to form a 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5- membered ring formed by A', A2, U, T, and V, n said 6-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, N02, CH; alkyl, C24; alkenyl, CM alkynyl, CH; haloalkyl, aryl, lkyl, heteroaryl, or heterocycloalkyl wherein said CH; alkyl, 02.3 alkenyl, Cm alkynyl, C]_g kyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted by l, 2 or 3 CN.
In some embodiments, Cy1 and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and cycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, CM alkyl, C24 alkenyl, CM alkynyl, CM haloalkyl, CM hydroxyalkyl, Ct, cyanoalkyl, CN, N02, on", SR8", C(0)R"", C(0)NR°"R"", C(O)OR"", 00(0)Rb", 00(0)NR°"R"", NR""R°‘", NR°"C(0)R"", NR°"C(O)OR"", S(O)Rb", 5(0)NR°"R"", S(0)2R"", and S(O)2NR°"R°‘".
In some embodiments, Cyl and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, CN, N02, OR", SRn", C(O)Rb", C(O)NR°"Rd", C(O)OR3", OC(O)Rb", R°"R"", NR°"R"", NR°"C(0)R"", NR°"C(0)0R8", ", °"R"", b", and 3(0)2NR°"R"".
In some embodiments, Cyl and Cf are independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, cm alkyl, cu l, 02.4 alkynyl, CM haloalkyl, CN, N02, OR", SR", C(O)R"", °"R"", C(O)OR"", "", OC(O)NR¢"R"", NR""R"", NR°"C(0)R"", NR°"C(O)OR°", S(O)R"", S(O)NR°"R"", S(O)2Rb", and S(O)ZNR°"R"".
In some ments, CyI and Cf are independently ed fi'om cycloalkyl Optionally substituted by l, 2, 3, 4 or 5 substituents independently selected from halo, CM alkyl, C24 alkenyl, 0;. 4 alkynyl, c._4 haloalkyl, CN, N02, 011"", SR"", C(0)R"", °"R"", C(O)OR"", OC(O)R°", OC(0)NR°"R"", NR°"R"", NR°"C(0)R"", O)OR"", S(O)R‘°", S(O)NR°"R"", S(O)2R"", and S(O)2NR°"R"".
In some embodiments, R1, R2, R3, and R4 are independently selected from H, halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, N02, 0R7, SR7, C(O)R8, C(O)NR9R'°, C(O)OR7 OC(O)R8, OC(O)NR9R'°, NRgR'o, NR9C(O)R8, NR°C(0)0R7, S(O)R8, S(O)NR9R'°, S(O)2R8, NR9S(O)2R8, and S(O)2NR9R‘°.
In some embodiments, R', R2, R3, and R4 are independently selected from H, halo, and CM alkyl.
In some embodiments, R1, R2, R3, and R4 are each H.
In some embodiments, R1 is H, halo, or CH alkyl.
In some embodiments, R5 is H, halo, CH alkyl, CH alkenyl, C24 alkynyl, CM haloalkyl, CN, N02, 0R7, SR7, , C(0)NR°R'°, C(O)OR7, OC(O)R8, OC(O)NR9R'°, , NRQC(O)R8, NR9C(0)0R7, , S(O)NR9R'°, S(O)2R8, NR93(0)2R3, or S(O)2NR9R'°.
In some embodiments, R5 is H, halo, (3..4 alkyl, cM haloalkyl, halosulfanyl, CN, or .
In some embodiments, R5 is H, halo, CM alkyl, CM kyl, CN, or NRgRlo.
In some embodiments, R5 is H.
In some embodiments, R6 is H or CH alkyl.
In some embodiments, R6 is H.
In some embodiments, R1’ and R12 are independently selected from H, halo, Cl-.. alkyl, 02.4 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", , C(O)NR°R", C(O)OR", b, OC(O)NR°R", NRCR", NR°C(O)Rb, NR°C(O)NR°R", NR°C(O)OR°, C(=NR‘)NR°R", NR°C(=NR‘)NR°R", scom", S(O)NR°R", S(O)2Rb, NR°S(O)2R", C(=NOH)Rb, C(=N0(c,.6 alkyl)Rb, and S(O)2NR°R", wherein said cl.8 alkyl, 02., l, or CH alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected fiom halo, CM alkyl, C24 alkenyl, C24 alkynyl, CM haloalkyl, halosulfanyl, CM hydroxyalkyl, CM cyanoalkyl, Cy‘, CN, N02, OR", SR", , C(O)NR°R", C(O)OR", OC(O)R", OC(O)NR"R", NR°Rd, NR°C(0)R", NR°C(O)NR°R", NR°C(O)OR", C(=NR‘)NR"R", NR°C(=NR‘)NR°R", S(O)Rb, S(O)NR°R", S(O)2Rb, NR°S(O)2R", C(=NOI—I)Rb, C(=NO(C,.6 alkyl))Rb, and S(O)2NR°Rd.
In some embodiments, RH and R12 are independently selected from H, halo, OH, CN, CM alkyl, CM haloalkyl, halosulfanyl, SCN, CM alkenyl, 02.4 alkynyl, CM hydroxyalkyl, CM cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.
In some embodiments, R" and R12 are independently selected from H, halo, OH, CN, CM alkyl, CM kyl, C24 alkenyl, CM alkynyl, CM hydroxyalkyl, C 1.4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.
In some embodiments, the compound has Formula Ia or Ib: (Y)n"z (Y)n—Z / / _—_A2 'I'.—:A2 d:x 9\\V d:x 9\\V \A1 \A1 R1 R1 \ \ N \ I \ R2 R2 / AL / R3 N 3 N N N R H H Ia Ib.
In some embodiments, the compound has Formula II: (Y)n_z 71—h! JXL /\ \ R2 R3 N g In some embodiments, the compound has Formula IIIa or IIIb: (Y)n-—Z (Y)n-Z / / I Dl—N / / R1 R1 \ \ I \ R2 1 / \ R2 R3 N {1" R3 N fl IIIa IIIb.
In some embodiments, the nd has Formula IV: (Y)n—Z r;l—N "t \ \ N N In some embodiments, the compound has Formula Va: R3 N u In some embodiments, the compound has Formula Vb: N\\K In some embodiments, the nd has Formula VIa: Y__/ l \ R2 R3 N N H VIa.
In some embodiments, the compound has Formula VIb: |\ \ N H VIb- At s places in the present specification, substituents of compounds of the invention are disclosed in groups or in . It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "Cm alkyl" is specifically ed to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and 05 alkyl.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment.
Conversely, various features of the ion which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
At various places in the present specification, g substituents are described. It is specifically intended that each linking substituent include both the forward and backward forms of the g substituent. For e, -NR(CR‘R"),,- includes both NR(CR’R")n and —(CR’R")n -.
Where the structure clearly es a linking group, the h variables listed for that group are understood to be linking . For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or mylene group, respectively.
The term "n—membered" where n is an integer typically describes the number of orming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
As used , the term "alkyl" is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n— propyl and isopropyl), butyl (e. g., n-butyl, isobutyl, t—butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
A linking alkyl group is referred to herein as "alkylene." As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like. A linking alkenyl group is referred to herein as "alkenylene." As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like. A linking alkynyl group is referred to herein as ylene." As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents.
Example haloalkyl groups include CF3, CZFS, CHFg, C013, CHClz, C2C15, and the like.
As used herein, "halosulfanyl" refers to a sulfur group having one or more halogen substituents. Example halosulfanyl groups include pentahalosulfanyl groups such as SF5.
As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fiised rings) ic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. A linking aryl group is referred to herein as "arylene." As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Cycloalkyl groups also include cycloalkylidenes. e cycloalkyl groups include ropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcarnyl, adamantyl, and the like. Also ed in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for e, benzo or thienyl derivatives of pentane, pentene, hexane, and the like. A cycloalkyl group containing a fiised aromatic ring can be attached through any ring—forming atom including a ring-forming atom of the fused aromatic ring. A linking cycloalkyl group is referred to herein as "cycloalkylene." As used herein, "heteroaryl" refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups e monocyclic and clic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, 3O imidazolyl, lyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, olyl, indazolyl, 1,2,4-thiadiazolyl, azolyl, benzothienyl, purinyl, carbazolyl, idazolyl, nyl, and the like. In some embodiments, the aryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms.
In some ments, the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring—forming atoms. In some embodiments, the aryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. A linking heteroaryl group is referred to herein as "heteroarylene." 2006/047369 As used herein, "heterocycloalkyl" refers to omatic heterocycles including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. cycloalkyl groups include monocyclic and polycyclic (cg, having 2, 3 or 4 fiised rings) s as well as spirocycles. Example "heterocycloalkyl" groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, ydrothienyl, 2,3- obenzofuryl, 1,3—benzodioxole, benzo-l,4—dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido. Also included in the definition of hete‘rocycloalkyl are moieties that have one or more ic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example imidyl, naphthalimidyl, and benzo derivatives of heterocycles. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. The heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring—forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in filrther embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalky] group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring—forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, l to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double or triple bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double or triple bonds. A linking heterocycloallcyl group is referred to herein as "heterocycloalkylene." As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo.
As used herein, lkyl" refers to alkyl substituted by aryl and "cycloalkylalkyl" refers to alkyl substituted by lkyl. An example arylalkyl group is benzyl.
As used herein, "heteroarylalkyl" refers to alkyl substituted by heteroaryl and "heterocycloalkylalkyl" refers to alkyl substituted by heterocycloalkyl.
As used herein, "amino" refers to NH;.
As used herein, "alkylamino" refers to an amino group substituted by an alkyl group.
As used herein, "dialkylamino" refers to an amino group substituted by two alkyl groups. 3O As used herein, "hydroxylalkyl" refers to an alkyl group substituted by hydroxyl.
As used herein, "cyanoallcyl" refers to an alkyl group substituted by cyano. The carbon of the cyano group is typically not counted if a carbon count precedes the term. For e, ethyl is ered herein to be a Cl cyanoalkyl group.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters).
All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
Compounds of the present invention that n asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds bed herein, and all such stable isomers are contemplated in the present invention. Cis and trans ric isomers of the nds of the present invention are described and may be isolated as a mixture of s or as separated isomeric forms.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral ing acid which is an optically active, salt—forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for e, optically active acids, such as the D and L forms of ic acid, diacetyltartaric acid, dibenzoyltartan'c acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfom‘c acids such as B-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of (Jr-methyl— amine (e.g., S and R forms, or reomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, ylephedrine, cyclohexylethylamine, 1,2—diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by n on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
Compounds of the invention also include tautomeric forms. Tautomeric forms result from the ng of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric fonns include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone — enol pairs, amide — imidic acid pairs, lactam — lactim pairs, amide - imidic acid pairs, enamine — imine pairs, and annular forms Where a proton can occupy two or more positions of a heterocyclic system, for example, ll-l- and 3H-imidazole, lH-, 2H— and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or ally locked into one form by appropriate substitution.
Compounds of the invention further include hydrates and solvates, as well as anhydrous and non~solvated forms.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes ofhydrogen include tritium and deuterium.
In some ments, the compounds of the invention, and salts thereof, are substantially isolated. By antially isolated" is meant that the compound is at least partially or substantially separated from the environment in which is was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can e compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about °C to about 30 °C.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic se, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The t invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts e, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the t invention include the conventional non-toxic salts of the parent compound , for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (MeCN) are preferred. Lists of le salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack'Publishing Company, , Pa., 1985, p. 1418 and Journal maceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
The t invention also includes prodrugs of the compounds described herein. As used herein, "prodrugs" refer to any covalently bonded carriers which e the active parent drug when administered to a mammalian subject. gs can be prepared by ing functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs e nds wherein hydroxyl, amino, sulfhydryl, or yl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free yl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate tives of alcohol and amine nal groups in the compounds of the invention. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Sympositlm , and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
Synthesis Compounds of the invention, including salts thereof, can be prepared using lmown organic synthesis techniques and can be sized according to any of numerous possible synthetic .
The reactions for ing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially ctive with the starting materials ants), the intermediates, or products at the atures at which the reactions are d out, e.g., temperatures which can range from the t's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular on step, suitable solvents for a particular reaction step can be ed by the skilled artisan.
Preparation of compounds of the invention can involve the protection and deprotection of various al groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is orated herein by reference in its entirety.
Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as r magnetic resonance spectroscopy (e.g., 1H or 13C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. nds of the invention can be prepared according to numerous preparatory routes known in the literature. e synthetic methods for preparing compounds of the invention are provided in the Schemes below.
As shown in Scheme 1, pyrazole—containing cores 1-9 and 1-6 can be synthesized starting with o[2,3-b]pyridine or pyrrolo[2,3—b]pyrimidine 1-1. The compound 1-1 can be converted to an active species such as an N-oxide analog (1-2) by using an oxidant such as m-CPBA. The N—oxide 1—2 can be halogenated with a halogenating agent such as a combination of tetramethylammonium bromide and methanesulfonic ide to form a 4-halo compound 1-3 such as a 4-brorno compound while the N—oxide is reduced at the same time. The amine group of the compound 1-3 can be protected by a suitable amine protecting group to afford the protected compound 1—7, which subsequently undergoes a Suzuki coupling with a boric acid 1-8 to afford the pyrazole-containing cores 1-9a which can be further reacted with reagent L—(Y)n~Z (where L is a leaving group) to give compounds of the ion 1-9b. Alternatively, the N—oxide 1-2 can be halogenated with a halogenating agent such as MeSOZCI to form a 4—halo compound 1-4 such as a ro compound while the N—oxide is reduced at the same time. The 4-halo compound 1-4 can be coupled to a bromo- substituted pyrazole compound 1-5 under suitable conditions such as heating to afford the pyrazole- containing core 1-6, which may contain some functional groups such as bromo or cyano le for flirther chemical modification.
Similarly, an imidazole core 1-11 can be synthesized by coupling of the 4-halo compound 1-4 to an imidazole derivative 1-10 under suitable conditions such as heating to afford the imidazole— containing core 1-11, which may contain some fimctional groups such as bromo or cyano le for fithhcr al modification.
Scheme‘l l)mCPBA, EtOAc R1 3:337 Br R1 aim\ N\ 2) N33003 R2 \ DMF """""1 R2 x \ \ R2 1-1 N\ r / T12 R3 N u 1-3 MesozCl protection of DMF amine group Br R1 R3 N/ 'f 1-7 P N—NH Ll, /\V Suzuki Y coupling B(OH)2 1-8 MH U /V JXL\ \ R2 R3 N/ '3 1-9a L-(Y)n-Z (Y)n'z U /V 1—11 R1 JXL\ \ R2 R3 N/ '3 As shown in §cheme 2, pyrazole-containing cores 2—3, 2-5 and 2-6 can be synthesized starting with a bromo—substituted pyrazole derivative 2-1 (a compound 1—6 in Scheme 1 wherein one of R5 is Br). The bromo-substituted pyrazole derivative 2—1 can be coupled to boron—containing aromatic species such as an aromatic boric acid 2—2 using Suzuki coupling wherein Ar is aryl or aryl, each ofwhich can be optionally substituted by one or more substituents such as alky, aryl, CN, nitro, alkoxy, etc. Alternatively, an alkene- or alkyne—containing compound such as an alkene—containing 2- unsaturated can be obtained by coupling the bromo-substituted pyrazole tive 2-1 to an compound such as an alkene 2—4 in the presence of a metal catalyst such as bis(triphenylphos- phine)palladium (II) chloride n t can be 0, 1, 2, and the like; and-R can be a substituent such as alkyl, aryl, CN, nitro, alkoxy, etc. The alkene group of compound 2-5 can be reduced by hydrogenation to afford the corresponding compound 2-6.
Scheme2 R5 Ar Ar B(OH)' 22 \ 2 ' N\ R5 Suzuki coupling X \ \ 2 JL / R R3 N N R5 __ R R5 t / \ N\ R5 N/ \ N —-——> x R5 catalyst R1 reduction R1 Xi \ \ R2 X \ 3k / \ 2 R N N JL / R R3 N N As shown in Scheme 3, ole-containing cores 3-7 can be synthesized starting with an N- protected o-pyrrolo[2,3—b]pyridine or an ected 4-bromo-pyrrolo[2,3—b]pyrimidine .3-1 wherein P is a suitable amine protecting group such as {[2-(trimethylsilyl)ethoxy]methyl} (SEM).
Compound 3-1 can be reacted with a Grignard t such as isopropyl magnesium chloride to generate an ic anion through ion exchange. The subsequent addition of a chloroacetyl— containing compound such as 2-chloro-N-methoxy-N-methylacetamide 3-2 to the anion will typically afford the chloroacetyl derivative 3-3. The derivative 3-3 can be reacted with an organic acid salt ’0 such as a cesium salt RSCOZCs to afford a compound 3-4. In the presence of a suitable a source such as ammonium acetate, the compound 3—4 can react with ammonia under suitable conditions such as at a high temperature to form the imidazole ring of the compound 3—5. The free amine nitrogen of the imidazole derivative 3-5 can undergo further modification such as reacting with a nd X-(Y),,-Z where X is a leaving group such as chloro, bromo or iodo so as to afford nd 3—6. The protecting group of compound 3—6 can be removed by an appropriate method according to the nature of the protecting group to yield compound 3-7. It should be noted that if there are functional groups present within the R, R5, and ——(Y)n—Z group, fijrther modification can be made.
For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be ted to a ester, which in turn can be further reduced to an alcohol, which in turn can be further modified. One d in the art will recognize appropriate further modifications.
Scheme 3 O/U\R5 Br O 'PngCl R1 R1 R5—-CO 0 x/ 2 s | \ THF, 0°C tort R 1 x/ x/ \ NH40Ac | R2 a1K N J\\ Cl\/U\ NCH3(OCH3) Ht. Moon—z >‘N(Y)n‘z R1 R1 1/ X-(Y)n-Z X/ I \ R2 \ deprotection R2 R2 \ \ X\/ R3 N \N E N N 3-5 3-6 W As shown in Scheme 4, thiazole-containing cores 4-3 can be synthesized staning with an N- protected acetyl derivative 4-1 wherein P is a le amine protecting group such as SEM.
Compound 4-] can be reacted with a thioamide 4—2 to form the thiazole ring, followed by deprotection of the amine nitrogen of the pyrrole ring by removal of the P group to afford the nd 4-3. Various thioureas 4—5 (equivalent to compound 4-2 wherein ~(Y)n-Z is NR’R"; and R’ and R" are H, alkyl, aryl or the like; or R’ and R" together with the N atom to which they are attached form a heterocycloalkyl) useful in preparing the thiazole compounds 4-3 can be made from secondary amines 4-4. A secondary amine 4-4 can be reacted with 1,1 ’~thiocarbonyldiimidazole; and the resulting intermediate can fiirther be d with ammonia to afford a thiourea 4-5.
Scheme4 (Y)n—Z O \ N R2 Z—(Y)n)LNH2 R2 j;/ l \ R1 \ R1 - 1/ I R3 N I?! 2) deprotection R3 \N a 4-1 4-3 ‘ S 1)Im2CS H R'\ J‘L Rv/ ‘Rn . II" NH2 2) NH3/MeOH R 44 4_5 As shown in Scheme 5, thiazole—containing cores 5-5 can be synthesized starting with a thiazole compound 5—1. The compound 5-1 can be reacted with a metal alkyl such as n-butyl lithium via ion exchange to te an aromatic anion in situ. The subsequent addition of boric acid trimethyl ester followed by hydrolysis will typically afford the boric acid 5—2. The boric acid 5—2 can undergo Suzuki ng with an N—protected 4-bromo—pyrrolo[2,3—b]pyridine or an N—protected 4— bromo-pyrrolo[2,3-b]pyrimidine 5—3 wherein P is a suitable amine ting group such as SEM.
The ting group P of the coupling product 5—4 can be removed by an appropriate method according to the nature of the protecting group to yield the nd of the invention 5—5.
Scheme 5 Br R2 X/ \ 1 R /Z z J\\ I (Y)n (Y): R3 N K" /I\ 1. nBuLi, Hexanes )\ P \_—../ 2. B(0Me)a \=< B(OH)2 Pd(Ph3P)4 HZOIDMF '2 heat (Y)n-Z (Y),,—z N:( N_ \ S deprotection \ S _________ R2 X/ \ 1 x/ R3J§N I R J\\ I \ R1 \ R3 N n -4 5.5 As shown in Scheme 6, pyrazole-containing compounds 6-1 can further be modified by substitution on the pyrazole NH group with appropriate reagents. For e, a compound 6-1 wherein P is a le amine protecting group such as SEM can be reacted with L-mn—Z where L represents a leaving group such as halo, triflate or the like to afford nd 6-2 under basic condition. If there are some functional groups present within the Y and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further d to alcohol. One skilled in the art will recognize the further modifications if appropriate.
Additionally, compound 6-1 can be reacted with alkene 6-3 (wherein R’ and R" can be H, alkyl, cycloalkyl and the like; and 2’ can be an electron withdrawing group such as an ester or CN) to afford the compound 6-4. Further, substitution can be made on alkene 6-3 at the alpha position (alpha to Z’) to generate a substituted derivatives of product, 6-4 (see, e.g., Example 68). nds 6-2 and 6-4 can be deprotected by appropriate methods according to the nature of the protecting group used to afford their corresponding de-protected counterpart.
Scheme 6 L-(Y)n-Z As shown in Scheme 7, bromo pyrazole containing compounds 7—1 can be further modified by metallation with reagents like butyl lithium and reaction with electrophiles like aldehydes to give the alcohol containing compounds 7-2 which can be ected to yield nds of the invention having formula 7-3. One skilled in the art will recognize the further ations where appropriate.
Scheme 7 R5 Br R5 R N;{ \; \ BuLl TFA Ni N NH4OH N R1 THF R1 R1 JXL \ aldehyde \ RaiN/\ R2 ketone etc. |\\| / mRZN 3 N NSEM R3 R N N \ H 74 7_2 7-3 As shown in Scheme 8, pyrazole—containing compounds 8-4 and 8—5 can be prepared by on of the N—protected bromo compound 8-1 with hydrazine in an appropriate solvent such as MN-dimethylformamide (DMF) to give the hydrazine intermediate 8-2. The hydrazino intermediate 8-2 is d with an appropriately substituted 1,3 bis-aldehyde like 8-3 to give the pyrazole ning compound 8-4. If there are some functional groups present within the Y and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to afford an amide in turn can be further reduced to alcohol. group; a carboxylic acid can be converted to a ester, which One skilled in the art will recognize further potential modifications.
Scheme 8 mn—z Z Br / R‘ _ HgNtNH R200" \ N‘NS \ NHZNHZ R1 {IZAOH R1 \ HH8-3 4 R3J\N/ R2 _, \ NSEM RaiN/\ R10 RaiN/\ I: R21 JXL \ \ R2 NSEM NSEM R3 ,( INl 8-1 8-2 3.4 8-5 As shown in Scheme 9, the 1,2,4-oxadiazole compound 9-6 can prepared from the N- ted bromo compound 9-1 by treatment with zinc cyanide in DMF in the presence of a catalyst like bis(tributyl) palladium to give the N—protected cyano compound 9-2. The N—hydroxy carbox- with imidamide nd 9-3 can be prepared by heating the N-protected cyano compound 9-2 hydroxylamine hydrochloride in an appropriate solvent like ethanol and a base like potassium carbonate at a temperature below the boiling point of the solvent. The N—protected 1,2,4-oxadiazole compound can be ed by treating the N—hydroxy carboximidamide compound 9-3 with an riately substituted acid chloride compound 9-4 in a solvent like pyridine at a sufficient temperature to complete the ring e. If there are some functional groups present within the Y and/or Z group, further modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to an ester, which in turn can be further reduced to alcohol. One skilled in the art will recognize further modifications where appropriate.
Schemes) Br R1 CN R1 DMF R 310W"z N NH OH-HCI thz fw R3 N/ N (BUaP)2Pd N EtOH R3J\ / N N R3 N/ ‘SEM ‘ K2003 SEM ‘SEM reflux 94 9.2 9_3 ("n—z mn-z Z(Y)n—<_ ,0 \ [0—K N\ N N\ N Cl TFA R1 R1 9-4 NH4OH As shown in Scheme 10, the 3— and 4-arylpyrazolo compounds 10—9 can be prepared by reaction of the respective 3-arylpyrazolo compound 10-4 or 4-aryl pyrazolo compound 10-7 with an appropriately substituted bromo compound 10-8 as previously described. The 3-aryl lo compound 10-4 can be prepared by ng an appropriately substituted aryl group ning a halogen like bromo or a e with the N-protected boronic acid or boronic acid ester pyrazole compound 10-2 under Suzuki—like conditions known in the literature. The N—protecting group of 10-3 can be removed by conditions previously described and known in the literature for removing groups like SEM.
The 4-arylpyrazolo compounds 10-7 can be prepared by reacting the appropriately substituted acetophenone compound 10-5 with DMF acetal in DMF at elevated temperatures to give the dimethylamino nd 10-6. The 4—arylpyrazolo compounds 10-7 can be prepared by treating the ylamino compound 10-6 with hydrazine in a solvent such as ethanol.
Scheme 1 0 0\ DMF ‘1 ’0 Ar Ar B TFA __ Ar-L (S (S / / / ,N—N _. HN—N HN N— ,N—N SEM SEM SUZUKI. 10-4 \ A, -1 conditions 10-3 104 "-1 \ Br R1 N‘N R1 N Jitg‘Rz\ R3JLN/ H R3 N u -8 -9 DMF-acetal | NH2NH2 _. Arm /‘ \ 1 0-5 1 0-6 As shown in Scheme 11 the tuted pyrazole compound 11-5 can be prepared by a variety of methods, such as by removing the protecting group e.g., SEM from compound 11-4 under conditions previously described. For example the substituted pyrazole N-protected compound 11-4 can be prepared by on of the ediate pyrazole N—protected compound 11-3 with an riately substituted alkyl halide, benzyl halide, alkyl sulfonates, e. g., mesylate or tosylate, or other suitable leaving group L, in an appropriate solvent such as MeCN, DMF or tetrahydrofuran (TI-IF), in the ce of a base such a sodium hydride or cesium carbonate. The N—aryl pyrazole 11— 4 (wherein Y is aromatic) may be prepared by reacting the intermediate pyrazole 11-3 with an appropriately substituted aryl boronic acid in a solvent such as dichloromethane (DCM) with copper acetate and pyridine. Alternatively the N-aryl pyrazole 11-4 (wherein Y is aromatic) can be ed by reacting the intermediate pyrazole 11-3 with an appropriately substituted aryl-fluoride in a solvent such as DMF at ed temperature. Or, the tuted pyrazole compounds 11-4 (wherein Z is a group such as nitrile or ester and Y is at least two carbons) can be prepared by the reaction of intermediate pyrazole 11-3 with an appropriately substituted te, acrylonitrile or other Michael- like acceptors in a solvent such as DMF in the presence of a base such as 1,8- diazabicyclo[5.4.0]undecene (DBU) or triethylamine (TEA) and at a temperature below the boiling point of the solvent. If there are some functional groups present within the Y and/or Z group, fiirther modification can be made. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to a ester, which in turn can be further d to alcohol. One skilled in the art will recognize the filrther modifications if appropriate.
Scheme 11 Z-(Y)n-Br NaH/DMF ,(Y)n-Z OR N—N CszcoalAcCN / K8I DMF / .
/ / ' \ K2003/H20 1 Ph-B(OH) xI 2 \ R X \ J\ / R2 7-10%TetraKis CU(OAC)2 + I ,B\ —————> R3 N N 0 0 -—‘—* X \ N/ ‘ \ er R3 11-1 M heat R3J\N/I N 11-4 SEM Ph-F 11.2 DMF 11_3 heat (Y)n' 7- "Michael" Addition / —-——> DBU/ DMF As shown in Scheme 12, pyrazole 12-1 n P is a suitable amine protecting group such as SEM can be d with an alkyne-containing conjugate acceptor such as 12—2, wherein Z is an electron-withdrawing group (for example, -CN) optionally in the presence of a base (DBU or K2C03 and the like) in a solvent such as DMF or MeCN for variable lengths of time to provide olefin- containing adducts 12-3. Compounds represented by the formula 12-3 can be deprotected by appropriate methods according to the nature of the protecting group used to afford compounds of the ion 12-4.
Scheme 12 N—NH _ / : z [)1 N Z . / R1 12-2 deprotectton R1 JNL /\ \ R2 \ R2 \ R2 R3 N N 1 \ R3 N/ N p H 12-1 12-4 As shown in Scheme 13, oxazole- or thiazole-containing compounds 13—6 can be prepared starting with N—protected 4-chloro-pyrroloI2,3—b]pyrimidine 13-1 n P is a suitable amine protecting group such as SEM. Oxazole- or thiazole-containing products of formula 13—2 can be prepared by palladium-catalyzed ng of 13-1 with oxazole or le. The compound 13-2 can be reacted with a metal alkyl such as n-butyllithium to generate the aromatic anion in situ to which can be added at low temperatures (preferably between —78°C and 0°C) derivatives of carboxylic acids 13-3 (wherein W = N(Me)(OMe) when X'=S; and W = Cl when X1=O), in the presence of other additives such as zinc chloride and copper(l) iodide when X'=O, in a suitable solvent such as THF to generate a variety of ketones 13-4. Ketones 13-4 can be caused to react with a variety of reagents such as diethyl (cyanomethyl)phosphonate or triethylphosphonoacetate in the presence of a base like potassium tert-butoxide followed by reduction (including hydrogenation or a copper—hydride catalyzed conjugate reduction), or with reagents such as tosylmethyl isocyanide to e ts of formula 13-5 wherein Z is an electron-withdrawing group such as ester or -—CN. If there are onal be made, groups present within the R group or encompassed by the Z group, further modification can and such appropriate finther modifications will be recognized by one skilled in the art. Compounds 13-5 can be deprotected by appropriate methods according to the nature of the protecting group used to afford their corresponding ected counterparts 13-6.
Scheme 13 \=\X‘ \x1 C' R1 R1 base. additives R1 \ Pd PPh NP KOAC *N/ N DMA \ heat R-133W P 13-1 13-2 13-4 /2 Z (Y)n (Y) R R N— N 1 1 \ X \ X R1 deprotectlon /N‘k : \ R2 JNL \ \ R2 R3 N "t R3 N/ N 13-5 13-6 As shown in Scheme 14, aminothiazole-containing cores 14-5 can be synthesized starting with thiazole-containing core 14-1 wherein P is a suitable amine protecting group such as SEM. The compound 14-1 can be treated with a metal alkyl such as llithium to generate the aromatic anion in situ to which can be added a suitable source of ophilic halogen such as carbon tetrabromide to afford the halogenated derivative 14-2. The protecting group P of 14-2 can be d by an appropriate method according to the nature of the protecting group to yield product 14—3. The compound 14-3 can be reacted with amines 14—4 at elevated temperatures in a le t such as DMF to afford the compound of the invention, 14-5.
Scheme 14 N=\ N_ nBuLI \ S R1 R1 deprotectnon_ CBr4 JNL /\ \ \ _.
R2 THF \ R2 N JNL R3 N -78°C Ra N In P P 144 14-2 Br N\Ru N— N— \ S R\N,R" \ S H R1 ji ,\ \ 14-4 JNL /\ R2 \ R2 R3 N g heat R3 N N 14-3 14—5 As shown in Scheme 15, pyrrole-containing cores 15-4 can be synthesized starting with N— protected 4-chloro—pyrrolo[2,3-b]pyrimidine 15-1 wherein P is a suitable amine protecting group such as DEM oxymethyl). The compound 15-1 can be reacted with isopropylsilyl)pyrrole boronic acid under Suzuki coupling conditions to afford the simultaneously pyrrole-deprotected core —2. Pyrrole-containing compounds 15-2 can be reacted with alkenes 153 containing an electron- withdrawing group Z (such as ~CN) in the presence of an appropriate base (such as DBU) at various temperatures (e.g., between room temperature and 40° C) followed by an in situ or separate deprotection step that is le for the selected protecting group to afford compounds of the invention 15—4.
Scheme 15 TIPS R / z // NH NW Cl R1 / Z / 1' RN / N \ B(OH)2 R‘ 15-3 \ R1 JL R2 N \ DBU MeCN R3 N/ N Pd(PPh3)4 \ R2 ' N \ JL / \ J'x R2 P Na2003 R3 N N / 2. TFA R3 N DME/HQO i: N heat -1 15-2 15-4 As shown in Scheme 16, a substituted pyrazole compound containing a sulfone or sulfoxide functionality as in 16-6 can be prepared by a variety of methods, such as starting with an appropriately substituted bromo thiophenyl ether 16-2. Thioether 16-2 may be readily prepared by alkylation of the thiophenol 16—1 with an alkyl halide, mesylate or the like using a base like DBU, potassium carbonate or sodium hydride. The cinnamyl nitrile 16-3 may be prepared by Heck chemistry and the like, using ium acetate and triphenylphosphine in DMF at an appropriate temperature with acrylonitrile. The SEM protected intermediate 16-4 may be prepared by methods previously described for ming the l like addition of the pyrazole core to an appropriately tuted oc—B unsaturated e like 16-3. The sulfoxide 16-5, where n=1, and sulfone 16-5, where n=2, may be prepared by methods well known in the literature for the oxidation of the thio ether 16-4 like m-chloroperbenzoic acid (MCPBA) in DCM. The final compounds 16-6, where n= 0, l or 2, may be ed by methods previously described for the removal of the SEM protecting group. Alternatively, the sulfur oxidation may be performed on compounds 16-2 or 16-3 depending on the compatibility of the substitution in the synthetic scheme.
Scheme 16 Br SH Br I Cm.» USxR s\ ——» R——» 16-1 16-2 16-3 //N 4N ( //N (o n n n ‘R ‘R g /N\N /N~N /N\N / / / R2 R2 X/ R2 X/ x/ R3’4\N / N\ Rs/QN / N\ R1 R1 R3/K / \ sEM sEM H 16-4 16-5 16-6 Also, as shown in Scheme 17, substituted pyrazole compounds ning a sulfonamide functionality, such as 17-6 can be prepared by a variety of methods. For e, one may start with an appropriately substituted bromo phenyl sulfonamide 17—2, where Re and Rd are suitable substituents. A compound 17-2 may be readily prepared by reaction of the bromo phenyl sulfonyl chloride 17-1 and an appropriately substituted amine such as an aniline, or a primary or secondary amine in a suitable solvent such as DCM, THF or pyridine. The cinnamyl nitrile 17-3 may be prepared by Heck chemistry or the like, using ium acetate and tn'phenylphosphine in DMF at an riate ature with acrylom'trile. The final compounds 17—6 where Rc and Rd are part of the sulfonamide functional group may be prepared by methods analogous to those bed in Scheme 16 ng with the cinnamyl nitrile 17-3.
Scheme 17 O O 0 O \\// Br \SLN,R°\/ Br 3020! S\N,R° O —> U e -—> an 17-1 17-2 //N 17-3 \\//0 Re S\l\\l’ /N\N Rd ———>— ————>— R2 A / \ N R1 H 17-6 Also, as shown in Scheme 18, substituted pyrazole compounds containing an alpha- allyl cyclopentylmethylene functionality, such as 18-8, can be prepared by, for example, reacting a pyrazole 18-3, wherein P is a suitable amine protecting group such as SEM and X is N or C, with a cyclopentylacrylate ester 18—4 to form the ester 18-5. The ester 18-5 may then be reduced to the corresponding aldehyde, 18—6, for example, by the two-step procedure of reducing to the alcohol and ively oxidizing the intermediate alcohol to the aldehyde, then be converted to the corresponding e.g., via a Swem oxidation. The de, 18-6, may olefin, 18—7, for example by reaction with a Wittig reagent. The olefin 18-7, may then be deprotected, as described earlier, to produce the formula 18-7 compound. The intermediate, 18—4, may be prepared, for example as shown in Scheme 18, stearting with cyclopentylaldehyde.
Scheme 18 COZH CH0 HOgCACOZH__.> I 0/ pyridine piperidine 18-1 18-2 1. (cocnzi 2. MeOHi N? CHO COzMe 002MB I)!N / 1. DIBALH / 18-4 ——-)- R1 X \ N\ 2. Swem IN R ——-> X \ \ 2 \DBU/ACN X \ \ JL R JL R2 NIB-3 " 3 N / R N R3 N N 18 6_ l3 18~5 P "IQ/Tabb l/fl‘N _N deprotection / <—-———-—-——-— I/ R1 R1 f\ 1\ \ R2 R2 R3 N/ N R3 N/ N H 13‘7 F’ 18-8 Also, as shown in Scheme 19, the cyanoguanidine derivative 19—6 can be prepared starting is a suitable protecting group from substituted pyrazole compounds such as pyrazole 18-3, wherein P such as SEM and X is N or C. A compound 18-3 may, for example, be reacted with olefin 19-1, prepared by Homer-Wadsworth Emmons reaction of the corresponding Boo-protected done, The intermediate 19—2 is the ce of a suitable basic catalyst, in a suitable solvent, to form 19—2. which then deprotected using a suitable deprotection reaction, to e the amine compound 19-3, solvent at a suitable reacts selectively with a cyanoimidocarbonate reagent such as 19-4, in a polar such as 19-5, which can then temperature, for example, about 20 °C to give a cyanoimidocarbamate be d with any of a variety of amines at elevated temperature to give product 19-6.
Scheme 19 NBoc NH NC < > NC < > N—NH R1 flu—N /N—N / / X \ \ El R1 k /I R2 deprotection 19-1 X \ \ .——>— x \ \ R3 N N\ —-> JL R2 i R2 18-3 P R3 N/ N\ R3 N/ [N1 19-2 /CN /CN /19'3I l . s s N N \ \ / T NH2 3 194 N \CN NC > NH Nc\—7C)N : 100°C / / R1 R1 x \ \ x \ \ JL / R2 JL / R2 R3 N N R3 N N H H 19-6 ) 19-5 in the The intermediate compounds 20-5 and 20-6 may be prepared by a variety of methods -3 literature, for example, s such as are ed in Scheme 20. The ediate compound —1 with an appropriately substituted Wittig may be prepared by reaction of the aldehyde compound —3. reagent or Homer Emmons reagents to give the OL-B tituted ester Alternatively, 20-3 may and an acrylic be prepared by a Heck—like reaction with an appropriately substituted aryl bromide 20-2 ester in the presence of a palladium reagent at elevated temperatures. The compound 20-4 may be prepared by methods previously described for the Michael—like addition of an appropriately 20-5 substituted pyrrole 18-3 on the OL-B unsaturated ester compound 20-3. The aldehyde compound -4 with reagents such as utyl aluminium may be prepared by ion of the ester compound hydride at low temperatures such as about -78 °C in an appropriate solvent. The aldehyde compound —5 can be further d to the ponding alcohol compound 20-6 with reagents such as sodium borohydride in methanol. Alternatively the alcohol compound 20-6 may be prepared directly by reduction of the ester 20-4 with reagents such as lithium aluminium hydride in appropriate solvent and at appropriate temperatures. 2006/047369 Scheme 20 o o/ H \ l __ NH -1:r—:32MeM6020 //7' R i R1 N_N or 1+X \\— / Br /—RN/k \ R2 —" \— R1 I / R3 N The compounds 21-2 and 21-3 may be prepared by using a variety of methods in the literature, such as, for example, methods outlined in Scheme 21. The olefin compound 21-1 may be ed by the reaction of aldehyde compound 20-5 with an appropriately substituted Wittig reagent in an or Homer Emmons reagents using a base such as sodium hydride or potassium xide riate solvent and conducted at temperature. The olefin compound compound 21-1 may be reduced to the saturated compound 21—2, for e, using hydrogenation conditions well known in the literature, e.g., hydrogen in the presence of palladium on carbon in a t such as methanol.
The acetylenic compound 21-3 may be prepared by methods previously described, or by reaction of the aldehyde 20—5 with Bestmann-Ohira reagent (E. Quesada et at, Tetrahedron, 62 (2006) 6673- 6680) as described in the literature. Alternatively the l compound 20—6 in Scheme 20 may be oxidized to the aldehyde 20-5 with methods well known in the literature, e.g., Swem oxidation conditions, followed by reaction with the Bestmann-Ohira reagent, wherein this reaction sequence reaction steps. may be carried out either as a one pot two—step reaction sequence, or in two separate Scheme 21 4R3/|\N/X. 21-3 P The compounds 22—1 and 22-3 may be prepared by using a variety of methods in the ture, for example, via methods outlined in Scheme 22. The oxygen—substituted compound 22-1 tuted alcohol 20-6 (in Scheme may be prepared, for example, by reaction of an appropriately ), wherein X is N or C, and P is a protecting group, with a base such as sodium hydride and an appropriate agent such as an alkyl iodide, carbonate, or isocyanate, carried out in a suitable solvent and at a suitable ature. atively, the alcohol group on the compound 20-6 may be converted to a leaving group LG, as in compound 22-2, where the leaving group can be, for example, bromide or mesylate. The compound 22-2 serves as a substrate for subsequent reaction with a nucleophile, such as, for example, sodium ethoxide (Nuc = ethoxy).
Scheme 22 It should noted that in all of the s described herein, if there are functional groups present on a substituent group such as Y, Z, R, R', R2, R5, etc., further ation can be made if riate and desired. For example, a CN group can be yzed to afford an amide group; a which in turn carboxylic acid can be converted to a ester, which in turn can be d to an l, can be fiirther modified. In another example, an OH group can be converted into a better leaving for nucleophilic substitution, such as by CN. One group such as mesylate, which in turn is suitable skilled in the art will recognize such further modifications.
Methods -Compounds of the invention can modulate activity of one or more Janus kinases (JAKs). term "modulate" is meant to refer to an ability to increase or decrease the activity of one or more members of the JAK family of kinases. Accordingly, compounds of the invention can be used in methods of modulating a JAK by contacting the JAK with any one or more of the compounds or compositions described herein. In some embodiments, compounds of the present invention can act as inhibitors of one or more JAKs. In some embodiments, compounds of the present invention can act to stimulate the activity of one or more JAKs. In r embodiments, the compounds of the invention in need of modulation of the or by can be used to modulate activity of a JAK in an individual administering a modulating amount of a compound ofFormula Ia, lb, or Ic. of the JAK JAKs to which the present compounds bind and/or modulate include any member family. In some embodiments, the JAK is JAKl, JAK2, JAK3 or TYK2. In some embodiments, the JAK is JAK] or JAK2. In some embodiments, the JAK is JAK2. In some embodiments, the JAK is JAK3.
The compounds of the invention can be ive. By "selective" is meant that the compound other binds to or inhibits a JAK with r affinity or potency, respectively, compared to at least one of JAKI or JAK2 IAK. In some embodiments, the compounds of the invention are selective inhibitors selective over JAK3 and/or TYK2. In some embodiments, the compounds of the invention are tors of JAK2 (e.g., over JAK], JAK3 and TYKZ). Without wishing to be bound by theory, selective for e inhibitors of JAK3 can lead to immunosuppressive effects, a compound which is JAK2 over JAK3 and which is usefiil in the treatment of cancer (such as multiple a, example) advantage fewer immunosuppressive side s. can offer the additional of having Selectivity can be at least about 5—fold, 10—fold, at least about 20—fold, at least about 50-fold, at least about IOO-fold, at least about ZOO-fold, at least about SOO—fold or at least about IOOO-fold. Selectivity can be measured by methods routine in the art. In some embodiments, selectivity can be tested at the JAK2 over Km of each enzyme. In some ments, ivity of compounds of the ion for JAK3 can be determined by the cellular ATP concentration.
Another aspect of the present invention pertains to methods of treating a JAK-associated such disease or disorder in an individual (e.g., patient) by administering to the individual in need of invention or a treatment a therapeutically effective amount or dose of a compound of the present pharmaceutical composition thereof. A JAK—associated disease can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the JAK, including over- sion and/or abnormal activity levels. A JAK—associated'disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating JAK ty. es of JAK—associated diseases include diseases involving the immune system including, for example, host organ transplant ion (e.g., allograft rejection and graft versus disease).
Further examples of JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, myasthenia gravis, immunoglobulin nephropathies, autoimmune thyroid disorders, and the like. In some embodiments, the autoimmune disease is an autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous goid (BP).
Further examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, atopic itis and rhinitis. r examples of JAK-associated es include viral diseases such as Epstein Barr Virus (EBV), tis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV). such as Further examples of JAK-associated diseases or conditions include skin disorders psoriasis (for example, psoriasis vulgaris), atopic itis, skin rash, skin irritation, skin sensitization (e.g., contact itis or ic t dermatitis). For example, certain substances including some pharmaceuticals when topically d can cause skin sensitization. In some embodiments, co-administration or tial administration of at least one JAK inhibitor of the invention together with the agent causing unwanted sensitization can be l in treating such unwanted sensitization or dermatitis. In some embodiments, the skin disorder is treated by topical administration of at least one JAK inhibitor of the invention.
In further embodiments, the JAK-associated e is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi’s leukemia such sarcoma, Castleman’s disease, melanoma etc), hematological cancers (e.g., lymphoma, cancer such as cutaneous T—cell as acute blastic leukemia, or multiple myeloma), and skin lymphoma (CTCL) and cutaneous B—cell lymphoma. Example cutaneous T—cell lymphomas include Sezary syndrome and mycosis fungoides.
JAK—associated diseases can further include those characterized by expression of a mutant JAK2 such as those having at least one mutation in the pseudo-kinase domain (e.g., JAK2V617F).
JAK—associated es can further include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), ial thrombocythemia (ET), myeloid asia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like.
Further JAK—associated diseases e inflammation and inflammatory diseases. Example inflammatory diseases include inflammatory diseases of the eye (e.g., iritis, uveitis, scleritis, conjunctivitis, tract the upper or related disease), inflammatory diseases of the respiratory (e.g., lower respiratory respiratory tract including the nose and s such as rhinitis or sinusitis or the tract ing bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory hy such as ditis, and other inflammatory diseases.
The JAK inhibitors described herein can further be used to treat ia reperfusion injuries as stroke or cardiac arrest. or a disease or condition related to an inflammatory ischemic event such The JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue such as that resulting from or associated with cancer. The JAK inhibitors described herein can further be used further be used to treat restenosis, sclerodermitis, or fibrosis. The JAK inhibitors described herein can diabetic retinopathy, to treat conditions ated with hypoxia or astrogliosis such as, for example, cancer, or neurodegeneration. See, e.g., Dudley, A.C. et al. Biochem. J. 2005, 390(Pt 2):427—36 and Sriram, K. et al. J. Biol. Chem. 2004, 279(19):]9936-47. Epub 2004 Mar 2.
As used herein, the term "contacting" refers to the bringing together of indicated moieties in in vitro system or an in vivo system. For example, "contacting" a JAK with a compound of the invention includes the administration of a compound of the t invention to an individual or patient, such as a human, having a JAK, as well as, for example, introducing a nd of the invention into a sample containing a cellular or purified preparation ning the JAK.
As used herein, the tenn "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other s, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) ting the disease; for example, preventing a disease, ion or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or matology), (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or ying the pathology or symptomatology of the disease, condition or disorder (lie. , reversing the pathology and/or symptomatology). ation Therapies One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti— inflarnmatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors such as, for example, those described in , or other agents can be used in combination with the compounds of the present invention for treatment of JAK-associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to t simultaneously or sequentially.
Example herapeutic include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.
Example ds include coriticosteroids such as dexamethasone or prednisone.
Example 1 inhibitors include the compounds, and ceutically acceptable salts thereof, of the genera and species disclosed in US. Pat. No. 5,521,184, W0 281, EP2005/009967, EP2005/010408, and US. Ser. No. 60/578,491.
Example le Flt—3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WC 03/037347, W0 03/099771, and W0 04/046120.
Example suitable RAF inhibitors include compounds, and their phannaceutically acceptable salts, as disclosed in WO 00/09495 and W0 05/028444.
Example suitable FAK inhibitors include compounds, and their ceutically acceptable salts, as disclosed in W0 04/080980, W0 04/056786, W0 03/024967, W0 01/064655, W0 595, and W0 01/014402.
In some embodiments, one or more JAK inhibitors of the invention can be used in combination with a chemotherapeutic in the treatment of cancer, such as multiple myeloma, and may improve the ent se as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects. Examples of additional pharmaceutical agents used in the treatment of le myeloma, for e, can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, thasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Ber-Ab], Flt—3, RAF and FAK kinase inhibitors. Additive or synergistic effects are desirable outcomes of ing a JAK tor of the present invention with an additional agent. rmore, resistance of multiple myeloma cells to agents such as dexamethasone may be reversible upon ent with a JAK inhibitor of the present invention. The agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or tially as separate dosage forms.
In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with at least one JAK inhibitor where the thasone is administered intermittently as. opposed to continuously.
In some further embodiments, combinations of one or more JAK inhibitors of the invention with other therapeutic agents can be administered to a patient prior to, during, and/or afier a bone marrow transplant or stem cell transplant.
Pharmaceutical Formulations and Dosage Forms When employed as pharmaceuticals, the nds of the invention can be stered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well 3O known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, eritoneal intramuscular or injection or infusion; or ranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
Pharmaceutical compositions and formulations for topical administration may include transdeimal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
Conventional Pharmaceutical carriers, s, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful.
This invention also includes pharmaceutical itions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers (excipients). In making the compositions of the invention, the active ingredient is lly mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the itions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for e, up to 10% by weight of the active compound, soft and hard gelatin es, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the le size can be adjusted by g to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, e, sorbitol, mannitol, starches, gum acacia, calcium phOSphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; ving agents such as methyl— and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be ated so as to provide quick, sustained or delayed release of the active ingredient after stration to the patient by employing procedures known in the art.
The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (l g), more usually about 100 to about 500 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units le as y dosages for human subjects and other s, each unit containing a predetermined quantity of active material calculated to produce the d therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be ined by a physician, according to the relevant actual circumstances, including the condition to be treated, the chosen route of stration, the compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
For ing solid compositions such as tablets, the principal active ingredient is mixed with a homogeneous a pharmaceutical excipient to form a solid preformulation composition containing mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as of the tablets, pills and es. This solid preformulation is then subdivided into unit dosage forms about 0.1 to about 1000 mg of the active type described above containing from, for example, ingredient of the t invention.
The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged . For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope resist which serves to over the former. The two ents can be separated by an enteric layer disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be d in release. A variety of materials can be used for such enteric layers or coatings, such materials ing a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the nds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored with edible oils such as seed oil, syrups, aqueous or oil suspensions, and flavored emulsions vehicles. sesame oil, t oil, or peanut oil, as well as elixirs and similar ceutical Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or c solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described the compositions are administered by the oral or nasal respiratory route supra. In some embodiments, for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the zing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be stered orally or nasally from devices which deliver the formulation in an appropriate manner.
The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the t, the manner of administration, and the like. In therapeutic applications, compositions sufficient to cure or at can be administered to a patient already suffering from a disease in an amount least partially arrest the symptoms of the disease and its complications. Effective doses will depend on clinician depending the disease condition being treated as well as by the judgment of the attending of the disease, the age, weight and l condition of the patient, upon factors such as the severity and the like.
The compositions administered to a patient can be in the form of ceutical compositions described above. These compositions can be sterilized by tional sterilization techniques, or may be e filtered. Aqueous solutions can be ed for use as is, or lyophilized, administration. The the lyophilized preparation being combined with a sterile aqueous carrier prior to from 5 to 9 and pH of the nd preparations typically will be between 3 and 11, more preferably most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
The therapeutic dosage of the compounds of the present invention can vary according to, example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical teristics (e.g., hydrophobicity), in an and the route of administration. For example, the nds of the invention can be ed about 0.1 to about 10% w/v of the nd for aqueous physiological buffer solution containing parenteral stration. Some typical dose ranges are from about 1 pig/kg to about 1 g/kg of body about 100 mg/kg weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to and extent of of body weight per day. The dosage is likely to depend on such variables as the type the relative progression of the disease or disorder, the overall health status of the particular patient, of the compound selected, formulation of the excipient, and its route of biological y from in vitro administration. Effective doses can be extrapolated from dose-response curves derived or animal model test s.
The compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti—inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
Labeled Compounds and Assay Methods Another aspect of the present invention relates to labeled compounds of the invention (radio- labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in lassays, both in vitro and in viva, for localizing and quantitating JAK in tissue samples, including human, and for identifying JAK ligands by inhibition binding of a d compound. Accordingly, the present ion includes JAK assays that contain such labeled compounds.
The present invention further includes isotopically-labeled compounds of the invention. An "isotopically" or "radio—labeled" compound is a compound of the invention where one or more atoms number different from the are replaced or substituted by an atom having an atomic mass or mass atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), llC, 13C, I4C, "N, I5N, '50, 17o, 1"o, "‘F, 35s, 3501, 82Br, 75Br, 76Br, "Br, 123I, ""1, 125I and mI. The radionuclide that is incorporated in the instant radio—labeled nds will depend on the specific application of that radio-labeled compound. For example, for in vitro metalloprotease ng and competition assays, compounds that incorporate 3I-I, MC, 82Br, I25I 1311, 3SS or will generally be most useful. For radio- imaging applications HC, 18F, "SI, 123I, ml, l3II, 75Br, 76Br or 77Br will lly be most usefill.
It is understood that a "radio-labeled " or "labeled compound" is a nd that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the 35S and 82Br. group consisting of 3H, l"C, "SI , The present invention can further include synthetic methods for incorporating radio-isotopes into compounds of the invention. Synthetic methods for incorporating isotopes into organic compounds are well known in the art, and an ry skill in the art will readily recognize the methods applicable for the compounds of invention.
A labeled compound of the invention can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (i. 2., test compound) which is labeled can be evaluated for its ability to bind a JAK by monitoring its concentration variation when contacting with the JAK, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a JAK (i.e., standard compound). Accordingly, the ability of a test compound to compete with the rd compound for binding to the JAK ly correlates to its binding affinity. sely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled.
Accordingly, the concentration of the labeled standard compound is red in order to evaluate the competition between the standard compound and the test nd, and the relative binding affinity of the test compound is thus ascertained.
Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of JAK—associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional ceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, onal containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as , ting quantities of the ents to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. 2006/047369 The invention will be bed in r detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which be changed or modified to yield ially the same s. The compounds of the Examples have been found to be JAK inhibitors according to at least one assay described herein.
EXAMPLES Example 1: 3-[3-Methyl-l-(lH—pyrrolo[2,3-b]pyridin—4—yl)—1H—pyrazol—4-yl]benzonitrile / \ N/ {3 Step 1. IH-Pyrrolo[2,3—b]pyrz'dine 7—0xide To a on of 1H-pyrrolo[2,3-b]pyridine (4.90 g, 0.0415 mol) in ethyl acetate (41 mL, 0.42 mol) was added a solution of meta-chloroperbenzoic acid (MCPBA; 9.3 g, 0.054 mol) in ethyl acetate (27 mL, 0.28 mol) at 0 °C. The reaction mixture was solidified when ~20 mL solution of MCPBA was added. An onal ~10 mL of ethyl acetate was added so that a solution resulted. The on mixture was allowed to warm to room temperature (rt) and stirred overnight, then was cooled at 0 °C, filtered and washed with ethyl acetate three times to give 10.94 g wet solid. The wet solid (8.45 g) was then suspended in water (35 mL), and to the suspension was added 13 mL of sat. Na2C03 dropwise, and the resulting mixture was stirred at room temperature overnight. The mixture was then cooled at 0° C, filtered and washed with water (x4) to give 3.55 g of pale purple solid which was dried at 40° C overnight to give the desired product (2.47 g, 44.4% yield). 1H NMR (400 MHz, CDgOD): 8 8.2 (1H, d); 7.95 (1H, d); 7.5 (1H, d); 7.2 (1H, m); 6.65 (1H, d). MS (M+H)+: 136.
Step 2. 4-Chloro-1H-pyrrolo[2, ridine To a pink solution of 1H-pyrrolo[2,3-b]pyridine 7—oxide (2.47 g, 0.0184 mol) in dimethylformamide (DMF) (13.3 mL, 0.172 mol) was added methanesulfonyl chloride (4.0 mL, 0.052 mol) at 50 °C, and the pink color changed to orange. The reaction mixture was heated at 73 °C for 2h, then cooled to 40 °C. Water (35 mL) was added, and the resulting suspension was cooled at 0 °C.
NaOH was added to adjust the pH of the mixture to about 7. The mixture was filtered and washed with water (x3) to give 3.8 g of a wet pale orange solid that was dried at 40 °C overnight to give the product (2.35 g, 82.2% yield). 1H NMR (400 MHz, CDC13): 8 10.8 (1H, br); 8.21 (1H, d); 7.41(1H, d); 7.18 (1H, d); 6.61 (1H, (1).
MS (‘M+H)+: 153.
Step 3. 4—(4—Bromo-3—methyl—IH—pyrazol-I-yl)-1H—pyrrolo[2, 3-b]pyridine I \ I \ N N A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) and 4-bromo methyl—1H-pyrazole (0.10 g, 6 mol) was heated at 130 °C ght. The reaction mixture then on silica gel) was subjected to column chromatography (eluting with 5% MeOH/DCM, 0.5% NH40H, to give 80 mg pale yellow solid which was triturated with MeOH (1.5 mL) to yield the product as a pale yellow solid (44 mg, 44% yield).
]H NMR (400 MHz, CD30D): 5 8.32 (1H, s); 8.25 (1H, d); 7.6 (1H, s); 7.45 (1H, d); 7.37 (1H, d); 6.96 (1H, d); 2.4 (3H, s). MS : 276.
Step 4. 3-[3-Methyl—1-(1H-pyrrolo[2,3—b]pyridin—4—yl)-1H—pyrazolyl]benzonitrile A mixture of 4-(4-bromomethy1-1H-pyrazol-l -y1)-1H-pyrrolo[2,3.-b]pyridine (0.032 g, 0.00012 mol), (3-cyanophenyl)boronic acid (0.027 g, 0.00018 mol), sodium carbonate (0.032 g, 0.00030 mol) and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 0.0000060 mol) in 1,2— dimethoxyethane (0.3 mL, 0.003 mol) and water (0.3 mL, 0.02 mol) was heated at 130 °C (a liquid ed, but with two layers) for 4 h. The reaction mixture then was cooled to room temperature (rt), filtered and was washed with water (x2) and dimethyl ether (DME) (x2) to give the product as a pale orange solid (15 mg, 44% yield).
'H NMR (400 MHz, CD3OD): 3 8.57 (1H, s); 8.31 (1H, d); 7.8 (2H, m); 7.75 (2H, m); 7.55 (1H, s); 7.45 (2H, m); 7.01 (1H, d); 2.6 (3H, 5). MS (M+H)+: 299.
Example 2: (2E)[3-Methyl-l-(lH-pyrrolol2,3-b]pyridinyl)-lH—pyrazolyl]acrylonitrile trifluoroacetate salt H TFA Step I. 4-Brom0-IH—pyrrolo[2,3—b]pyridz'ne To the a solution of lH-pyrrolo[2,3-b]pyridine 7—oxide (8.0 g, 0.060 mol), prepared by procedure outlined in e 1, Step 1 in DMF (100 mL, 1 mol) was added methanesulphonic anhydride (20.8 d at 0 °C for an g, 0.119 mol, in four portions) at 0 °C. The mixture was additional 20 min followed by an addition oftetramethylammonium bromide (23.0 g, 0.149 mol). The resulting mixture was stirred overnight. Water (0.1 L) was added, and a slight rm was observed. A solution of sodium hydroxide in water (12.5 M, 12 mL) was added to adjust the pH of the mixture to about 8, followed by an addition of ~O.25 L of water. The resulting mixture was stirred for additional 2 h then filtered. The solid obtained was washed with water x3 to give 6.72 g of 49% yield). a reddish solid which was dried at 50 °C over a weekend to give the product (5.75 g, 1H NMR (400 MHz, CDC13): 510.8 (1H, br); 8.2 (1H, d); 7.41(1H, d); 7.19 (1H, d); 6.61 (1H, d). MS (M+H)+: 196.
Step 2. 4—Bromo-I-[2—(trifnethylsilyDethoxyjmethyl—1H—pyrrolo[2,3—bjpyrz'dine To solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (6.2 g, 0.031 mol) and a [B— (trimethylsilyl)ethoxy]methyl chloride (6.7 mL, 0.038 mol) in DMF (62 mL, 0.80 mol) was added sodium e (1.5 g, 0.038 mol) at 0 °C, and the resulting solution turned . The mixture was stirred for additional 4 h, then diluted with methyl tert-butyl ether (MTBE). The organic layer was separated and washed with water (x2) and brine aqueous solution successively. The organic phase was dried and concentrated in vacuo to give 14.1 g of a product as a pale orange oil. The oil was purified by column chromatography eluting with 5—20% ethyl e/hexanes to give the d product as a colorless oil (9.66 g 94% yield). 1H NMR (400 MHz, CDC13): 5 8.2 (1H, d); 7.49 (1H, d); 7.19 (1H, d); 6.62 (1H, d); 5.78 (2H, s); 3.6 (2H, t); 0.98 (2H, t); 0.0 (9H, 5). MS (M+H)+: 326.
Step 3. (2E)—3-[3-Methyl-I-(IH—pyrrolo[2,3—b]pyridin—4—yl)—IH—pyrazol—4—yljacrylonitrile A solution of 2-propenenitrile (0.043 mL, 0.00065 mol), bis(triphenylphosphine)palladium(II) chloride (0.0091 g, 0.000013 mol), 4-(4-bromo—3-methy1—1H-pyrazoly1)-1H-pyrrolo[2,3-b]pyridine (0.036 g, 0.00013 mol), and thylamine (TEA) (0.15 mL, 0.0011 mol) in DMF (0.15 mL, 0.0019 mol) was microwaved at 120 °C for 2 h. The on was then diluted with ethyl acetate and washed 2006/047369 in vacuo to with water (x2) and brine successively. The organic phase was dried and concentrated to give 12 give 62 mg of the t as an orange solid. The orange solid was purified by prep-LCMS acid (TFA) salt which was triturated with MTBE (1 mL) mg of an off—white solid as a trifluoroacetic 4 h, 9 mg 28% . to provide the purified product as a pale green solid. (dried at 60 °C for , 1H NMR (400 MHz, CD30D): 2 :l of trans : cis isomers. For trans: 5 8.95 (NH,1H, s); 7.75 (olefin, 1H, d); 6.1 (olefin, 1H, d); 2.45 (Me, 3H, 5). MS (M+H)+: 249.
Example 3: 3-[3-Methyl—l-(1H-pyrrolo[2,3—b]pyridin—4-yl)—lH—pyrazol—4-yl]propanenitrile, trifluoroacetate salt N{N\ fl TFA A mixture of (2E)[3—methyl-l—(lH—pytrolo[2,3—b]pyridiny1)-lH—pyrazolyl]acrylo- nitrile, TFA salt, (0.0050 g, 0.000020 mol, prepared according to Example 2) and palladium (5.8 mg, 0.0000054 mol) in ol (1 mL, 0.02 mol) and chloroethane (1 mL, 0.01 mol) was degassed then was filtered and then was stirred under an here of hydrogen for 3 h. The reaction mixture solid. The crude and the filtrate was concentrated in vacuo to give 8 mg of the product as an off-white material was purified by prep-LCMS to give 5.1 mg of a white solid as a TFA salt which was triturated with MTB (1 mL) to give the product as a white solid (1.7 mg, 34% yield). 1H NMR (400 MHz, CD30D): 8 8.52 (1H, s); 8.35 (1H, d); 7.72(1H, d); 7.6 (1H, s); 7.38 (1H, d); 6.96 (1H, d); 2.7-2.9(4H, m); 2.4 (3H, 5). MS (M+H)+: 251.
Example 13: henyl—1H—imidazol—1-yl)—1H—pyrrolo[2,3-b]pyridinc '>'\ mN/N A melt of 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00033 mol) in 4-phenyl-1H- between imidazole (0.24 g, 0.0016 mol) was heated at 200 °C overnight. The reaction was partitioned with brine. The ethyl acetate and saturated NaHCO3, separated and the organic phase was washed organic layer was then dried and evaporated to give 250 mg of an orange oil. The oil was chromatographed with 7% MeOH/DCM, 0.7% NH40H, sample in solvent system. Collected 74 mg of the product as an orange glass. The glass was triturated with hot DCE (1.5 mL) to give 51 mg of a brown solid which was dried at 60 °C for 4 h to afford the desired product (50 mg, 59 yield). 1H NMR (400 MHz, dimethylsulxoxide (DMSO)): 8 12.5 (1H, s); 8.5 (1H, s); 8.4 (1H, s); 8.38 (1H, d); 7.8 (2H, m); 7.62 (1H, d); 7.4 (3H, m); 7.3 (1H, m); 6.81 (1H, (1). MS : 260 Example 14: [3—Methyl—l-(lH—pyrrolo ]pyridinyl)-1H-pyrazol-4—yl]-piperidin—l-yl- methanone Step 1. 3-Methyl—1-(1~[2—(trimethylsilyl)ethoxyjmethyl—1H-pyrr010[2, ridin—4—yl)-IH-pyrazole- 4-carboxylic acid To a -70 °C solution of 4-(4-bromo—3-methy1—1H—pyrazol—1-yl)[2-(trimethy1silyl)ethoxy]— methyl—1H-pyrrolo[2,3—b]pyridine (0.107 g, 0.000263 mol) in THF (1 mL, 0.01 mol), and n— butyllithium in hexane (0.23 mL of 1.6M), 0.5g of C02 solid was added. After 15 min, the reaction was quenched with NH4C1. Ethyl acetate and water were added. The c phase was washed with brine, and was evaporated to give 84 mg of an off-white glass/solid. The solid was chromatographed with 50% ethyl acetate/hexanes, 0.5% AcOH, sample on silica gel to give 40 mg of a purified product as a white solid (37% yield). 1H NMR (400 MHz, : 6 8.5 (1H, d); 7.45 (1H, d); 7.25 (1H, d); 7.02 (1H, s); 6.6 (1H, d); 5.75 (2H, s); 3.6 (2H, t); 2.48 (3H, s); 0.98 (3H, t); 0.0 (9H, 3). MS (M+H)+: 372.
Step 2. 4—[3—Methyl—4—(piperidin—I—ylcarbonyl)-1H—pyrazol—1 -yl][2—(trimethylsz'lyl)ethoxyjmethyl- IH-pyrrolo[2, 3-b]pyridine A solution of 3—methyl(l-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridiny1)- 1H-pyrazolecarboxylic acid (0.040 g, 1 mol) (1:1 of AcOH) and N,N—carbonyldiimidazole (0.035 g, 0.00021 mol) in THF (1 mL, 0.01 mol) was stirred for 1.2h, afier which time piperidine (32 uL, 0.00032 mol) was added. After another 2h, another portion of piperidine (15 14L) was added and the resulting mixture was stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water, and washed sequentially with sat. NaHCO; and brine. The organic phase was dried and evaporated to give 49 mg of the crude product as an orange ass. The crude product was chromatographed with 75-100% ethyl acetate/hexanes, sample in DCM. Collected 25 mg of the purified product as a colorless glass/oil (50% yield).
'H NMR (400 MHz, CDClg): 5 8.45 (1H, d); 8.23 (1H, s); 7.5 (1H, d); 7.4 (1H, d); 7.05 (1H, d); 5.8 (2H, s); 3.7 (4H, br); 3.6 (2H, t); 2.55 (3H, s); 1.7 (6H, br); 1.0 (3H,. t); 0.0 (9H, s). Ms (M+H)+: 439.
Step 3. 3-Methyl—I—(IH—pyrrolo[2, 3-b]pyridinyl)—1H-pyrazol—4—yU-pzperidin—1—yl—methan0ne A solution of 4—[3—methyl—4—(piperidin-1—ylcarbonyl)-1H-pyr2tzol-l-yl]~1-[2—(trimethylsily1)— ethoxy]methyl-1H—pyrrolo[2,3—b]pyridine (0.025 g, 0.000057 mol) in TFA (1 mL, 0.01 mol) was stirred for 1.5 h. The reaction mixture was then concentrated and ioned between DCM and sat.
NaHCO3 x2, and brine. The organic layer was then dried and concentrated to give 28 mg of the t as a white foam. The foam was dissolved in methanol (1 mL, 0.02 mol) and treated with ammonium hydroxide in water (8.0M, 1 mL) for 1.5h. The on was concentrated using a rotary evaporator to give 24 mg of a pale yellow glass. The glass was triturated with methyl t-butyl ether (MTBE) to give 13 mg of a white solid which was dried at It over a weekend. A total of 8 mg of the product was obtained after drying (45% yield). 1H NMR (400 MHz, CDC13): 8 9.7 (1H, s); 8.4 (1H, d); 8.2 (1H, s); 7.42 (1H, d); 7.4 (1H, d); 6.99 (1H, d); 3.4-3.8 (4H, br); 2.47 (3H, s); 1.5-1.8 (6H, br). MS (M+H)+: 309. e 15: [3-Methyl-l—(lH—pyrrolol2,3;b]pyridin—4-yl)—1H—pyrazolylmethyl]-phenyl-amine NHPh N\\/ (is’ N N Step 1. 3-Methyl-J-(J-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2, 3—b]pyridin-4—yl)—IH-pyrazole— 4—carbaldehyde To a ~70 °C solution of 4—(4-bromo—3-methy1-1H—pyrazol-l—y1)-1—[2-(trimethylsily1)ethoxy]- methyl—1H—pyrrolo[2,3-b]pyridine (0.25 g, 1 mol) in THF (2 mL, 0.03 mol), 1.6 M n- butyllithium in hexane (0.54 mL). After 10 min, DMF (120 uL, 0.0015 mol) was added. The reaction was allowed to warm to rt and stirred overnight. The reaction was then quenched with NH4C1. Ethyl acetate/water was added. The organic phase was separated and washed with brine, then dried and concentrated to give 180 mg of an orange oil. The crude product was tographed with 25% ethyl acetate/hexanes, sample in DCM. Collected 40 mg of a pale yellow oil (18% yield). 1H NMR (400 MHz, CDC13): 8 10.15 (1H, s); 8.7 (1H, s); 8.47 (1H, d); 7.58 (1H, d); 7.5 (1H, d); 7.05 (1H, d); 5.8 (2H, s); 3.63 (2H, t); 2.7 (3H, s); 0.98 (3H, t); 0.0 (9H, 3). MS (M+H)+: 356.
Step 2. N—[3—Methyl—I—(1-[2—(trimethylsilyDethoxyjmethyl—IH—pyrrolo[2,3—b]pyridinyl)—1H~ pyrazolyl]methylaniline A solution of 3-methyl-1~(l-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridinyl)- 1H-pyrazole—4-carbaldehyde (0.025 g, 0.000070 mol) and aniline (1M in DCM, 0.070 mL), in DCM (1 mL, 0.02 mol) was stirred for l min. Acetic acid (20 pL, 0.0004 mol), aniline (1M in DCM, 140 0L) and sodium triacetoxyborohydride (0.022 g, 0.00010 mol) were added. The reaction was stirred overnight and partitioned n DCM and sat. NaHCO3, washed with brine. The organic phase was .dried and ated to give 21 mg of a product as a pale orange glass (70% yield). 1H NMR (400 MHz, CD013): 5 8.4 (1H, d); 8.15 (1H, s); 7.65 (1H, d); 7.35 (3H, m); 7.09 (1H, d); 6.82 (1H, m); 6.89 (2H, m); 5.8 (2H, s); 4.35 (2H, s); 3.6 (2H, t); 2.5 (3H, s); 0.99 (3H, t); 0.0 (9H, 3).
MS (M+H)+: 433.
Step 3. [3-Methyl—I-(1H—pyrrolo[2, 3-b]pyridin-4—yl)-IH-pyrazol—4-ylmethyIJ-phenyl-amine Deprotection of N—[3 -methy1-1 —(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3~b]pyridin~ 2O 4-yl)-lH—pyrazolyl]methylaniline was d out according to the procedures of Example 14, Step 3 to give the desired product (58% yield).
‘H NMR (400 MHz, (31301.): 5 9.9 (1H, s); 8.38 (1H, d); 8.1 (1H, s); 7.4 (1H, d); 7.35 (1H, d); 7.3 (2H, m); 7.0 (1H, d); 6.79 (1H, m); 6.77 (2H, m); 4.25 (2H, s); 3.81 (1H, s); 2.41 (3H, s). MS : 303.
Example 25: 3-[3-Methyl-l-(lH-pyrrolo[2,3-b]pyridin—4-yl)—1H—pyrazolyll-cyclohexanol N\\/ N N Step 1. 3—Ethoxy-1—[3-methyl—I—(1-[2—(trimethylsilyl)ethoxyjmethyl—IH-pyrrolo[2,3-b]pyridinyl)— 1H—pyrazol-4—yl]cyclohex—Z-en-I -01 / \ CH20(CH2)2Si(CH3)3 To a -75 °C solution of 4-(4-bromomethyl-1H-pyrazol-l—y1)-1—[2~(trimethylsilyl)ethoxy]- methyl-1H—pyrrolo[2,3-b]pyridine (0.11 g, 7 mol) in THF (1.5 mL, 0.018 mol) was added 1.6 M n-butyllithium in hexane (0.22 mL). The reaction mixture turned dark orange. Afier ~10 min, 1.0 M magnesium dibromide in ether (0.35 mL) was added. After another 50 min, a solution of 3-ethoxy— 2-cyclohexenone (41.5 uL, 0.000308 mol) in THF (~0.3 mL) was added. The resulting mixture was warmed to —40 °C over ~1h and quenched with NH4CL Then ethyl acetate/water was added. The organic phase was washed with brine, and concentrated to give 145 mg of an orange oil. The crude product was chromatographed with 0-50% ethyl acetate/hexane gradient, sample in DCM. Collected 35 mg of the produce as an oil (30% yield).
IH NMR (400 MHz, CDC13): 8 8.49 (1H, d); 8.38 (1H, s); 7.55 (1H, d); 7.4 (1H, d); 7.1 (1H, d); 6.0 (2H, s); 3.6 (2H, t); 2.81 (2H, m); 2.62 (3H, s); 2.58 (2H, m); 2.27 (2H, m); 1.0 (3H, t); 0.0 (9H, 5).
MS (M+H)+: 422.
Step 2. 3—[3-Methyl—1-(1—[2—(trimethylsiéyDethoxyjmethyl-IH-pyrrola[2, 3—b]pyridin-4~yl)-1H- pyrazolyl]cyclohexanol A mixture of 3-[3-methy1-l-(1-[2-(tn'methylsilyl)ethoxy]methyl—lH-pyrrolo[2,3-b]pyridin—4~ yl)-1H-pyrazol-4—yl]cyclohex-Z-en-1—one (0.019 g, 0.000045 mol) and palladium on carbon (Pd/C) (0.018 g, 0.000017 mol) in methanol (2 mL, 0.05 mol) was degassed and was d under a hydrogen atmosphere overnight. An additional 48 mg of 10% Pd/C was added and stirred under a hydrogen atmosphere for 8h. The palladium was filtered and the filtrate was stirred with sodium tetrahydroborate (0.032 g, 0.00084 mol) for 5h. The reaction was d by prep-HPLC to give 5 of the desired product. MS (M+H)+: 426.
Step 3. 3—[3-Methyl(1H-pyrrolo[2,3-b]pyridin-4—y1)—IH-pyrazoIyl]-cyclohexanol Deprotection of 3-[3-methyl(1-[2-(tiimethylsily1)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin- 4—yl)—1H-pyrazolyl]cyclohexanol was carried out ing to the ures of Example 14, Step 3 to give the desired product (40% .
'H NMR (400 MHz, CDClg): 8 9.72 (1H, s); 8.35 (1H, d); 7.95 (1H, s); 7.41 (1H, d); 7.35 (1H, d); 7.02 (1H, d); 3.78 (1H, m); 2.6 (1H, m); 2.4 (3H, s); 1.2—2.4 (8H, m). MS (M+H)+: 296.
Example 40: 4—[1-(3-Methoxy—l-methyl-propyl)-1H—pyrazol—4-yl]-1H—pyrrolo[2,3-b]pyridine O..— | t \ N Ll Step 1. 3-Methoxymethylpropr-1H—pyrazol—4-yU—I-[2-(trimethylsilyDethoxyj-methyl—1H- pyrrolo[2,3-b]pyridine To a 0 °C solution of 3-[4-(1-[2-(trimethylsi1yl)ethoxy]methyl-1H—pyrrolo[2,3-b]pyridin yl)—1H-pyrazol-l—yl]butanol (the alcohol was made by DIBAL reduction of the ester in Example 58) (0.056 g, 0.00014 mol)) in DMF (1 mL, 0.01 mol), was added sodium e (0.0107 g, 0.000268 mol). After 5 min, methyl iodide (18 "L, 0.00029 mol) was added and the resulting mixture was stirred over a weekend. The mixture was then ioned between ethyl acetate and water, separated and the organic phase was washed with brine. The organic phase was concentrated to give a pale orange oil.
'H NMR (400 MHz, CDCl3): 5 8.4 (1H, d); 8.3 (1H, s); 8.0 (1H, s); 7.65 (1H, d); 7.27 (1H, d); 6.8 (1H, d); 5.8 (2H, s); 4.7 (1H, m); 3.63 (2H, t); 3.2—3.4 (2H, m); 3.38 (3H, s); 2.1-2.3 (2H, m); 1.7 (3H, d); 1.0 (2H, t); 0.0 (9H, 8). MS (M+H)+: 400.
Step 2. 4-[1-(3—Methoxy-I-methyl-propyl)— IH-pyrazol—4—yl]—JH-pyrrolo[2, 3-b]pyridine Deprotection of 4—[1 —(3—methoxy-1 —methy1propyl)— 1 H—pyrazoly1]-1 -[2—(trimethylsilyl)- ethoxy]—methy1-1H-pyrrolo[2,3-b]pyridine was carried out according to the procedures of Example 14, Step 3 to give the desired product (25% yield). 1H NMR (400 MHz, : 5 10.0 (1H, s); 8.35 (1H, d); 8.18 (1H, s); 7.95 (1H, s); 7.41 (1H, d); 7.21 (1H, d); 6.75 (1H, d); 4.63 (1H, m); .4 (2H, m); 3.35 (3H, s); 2.21-2.05 (2H, m); 1.6 (3H, d). MS (M+H)+: 270.
Example 42: 4—[1—(l-Methylpyrazolyl-propyl)—1H-pyrazolyl]-1H-pyrrolo[2,3-b]pyridine Step 1 . 4—1-[1-Methyl—3-(IH-pyrazol—I -yI)propyl]-1H—pyrazolyl—1-[2-(trimethylsilyDethoxyjmethyl— IH-pyrrolo[2,3-b]pyridine To a 0 °C solution of 3—[4—(1 -[2-(trimethylsi1yl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin yl)—1H-pyrazolyl]butyl methanesulfonate (prepared by mesylation of the alcohol as in Example 59, Step 1) (0.055 g, 0.00012 mol) and lH-pyrazole (0.025 g, 0.00036 mol) in DMF (1 mL, 0.01 mol) was added sodium hydride (0.014 g, 0.00036 mol). The resulting solution was stirred overnight and then partitioned between ethyl acetate and 0.1 N HCl, water. the organic phase was ted and washed with brine. The organic layer was then concentrated to give 49 mg of a pale orange glass (87% yield).
‘H NMR (400 MHz, CDC13): 8 8.4 (1H, d); 8.18 (1H, s); 7.99 (1H, s); 7.6 (1H, t); 7.5 (1H, d); 7.4 (1H, t); 7.27 (1H, d); 6.8 (1H, d); 6.3 (1H, m); 5.8 (2H, s); 4.2 (1H, m); 4.0-4.2 (2H, m); 3.61 (2H, t); 2.58 (2H, m); 1.65 (3H, d); 1.0 (2H, t); 0.0 (9H, 5). MS (M+H)+: 436.
Step 2. 4-[1—(1 -Methyl-3—pyrazol—l—yl—pr0pyl)~1H—pyrazol—4—yl]—1H—pyrrolo[2, 3~b]pyridine Deprotection of 4-1 -[1 -methyl-3—(lH-pyrazol-1—y1)propyl]-lH-pyrazoly1-1 -[2-(trimethyl- .silyl)ethoxy]methyl—1H-pyrrolo[2,3-b]pyridine was carried out according to the ures of Example 14, Step 3 to give the desired product (38% yield). lH NMR (400 MHz, CDC13): 5 9.7 (1H, s); 8.38 (1H, d); 8.1 (1H, s); 7.7(1H, s); 7.59 (1H, t); 7.4 (1H, d); 7.35 (1H, t); 7.21 (1H, d); 6.75 (1H, d); 6.25 (1H, rn); 4.4 (1H, m);3.9—4.15(2H, m); 2.55 (2H, m); 1.63 (3H, (1). MS (M+H)+: 306.
The following compounds in Table 1 were made by methods analogous to the procedures above as indicated. "Purification A" indicates that the product ing deprotection was purified by preparative-HPLC under the following conditions: C18 g with a gradient of zo ning 0.15% NH40H. 1-(1H-Pyrrolo[2,3-b]pyridin—4- yl)—1H-pyrazolecarboxylic acid ethyl ester 2006/047369 4-(3—Methy1—4-phenyl—pyrazol-1 - yl)-1H—pyrrolo[2,3-b]pyridine 4-(3 -Phcnyl-pyrazoly1)-lH- pynolo[2,3-b]pyridine 4-(4-Brom0-imidazol-l -yl)—1H- pyrrolo[2,3-b]pyridine 4—(4—Bromo—3—methyl—pyrazol—1 — yl)-1H-pyrrolo[2,3-b]pyn'dine 3-[3-Methy1(1H-pyrrolo[2,3- b1PyTidin-4—yl)-1H—pyrazol—4—yl]— benzonitrile 4-![3-Methyl(1H-pyrrolo[2,3- b]pyridin—4—yl)-lH-pyrazol—4-y1]- benzonitrile 4-[4—(3—F1uoro-phenyl)methyl- pyrazol-l -y1]—1H-pyrrolo[2,3- b]pyridine 4-[4-(3,5-Bis-trifluoromethyl- phenyl)methyl-pyrazol-1 —y1]- 1 H-pyrrolo[2,3-b]pyridine 4-[443,5-Difluoro-pheny1) methyl-pyraZOI-l H‘ pynolo[2,3-b]pyridine {3 -[3 -Methyl-1 -(1H—pyrrolo[2,3 - b1PWidinyl)-l H—pyrazolyl] - }—methanol 4-(3-Methyl-4—pyrimidin-5—yl- pyrazol—l—yl)—1H—pyrrolo[2,3-b]— pyridine WO 70514 4-[3-Methyl—4-(1 -methyl-1H- indol-S—yl)-pyrazol-1 -yl]-1 H- pyrrolo[2,3-b]pyridine 4-(3-Methy1~4-thiophen—3-yl— pyrazol-l —yl)-1H-pyrrolo[2,3—b]~ pyridine N,N-Dimethyl—4-[3-methy1—1 — (1 H—pyrrolo[2,3-b]pyridinyl)- 1H-pyrazolyl]- esulfonamide N— {4-[3-Methyl—l -(1H- pyrrolo[2,3—b]pyridin—4-yl)-I H— pyrazol-4—yl]-phenyl} —acetamide 3-tert-Butyl-l -( l H-pyrrolo[2,3— b]pyridinyl)~1 H—pyrazole—4— carbonitrile WO 70514 4-Bromo-1—(1H-pyrrolo[2,3‘-b]- n—4—yl)~1H—pyrazole—3— carbonitrile 4-(3—Cyano-phenyl)-1 -(1H- pyrrolo[2,3—b]pyridiny1)—1 H- pyrazolecarbonitrile 3—[1-(lH-Pyrrolo[2,3-b]pyridin yl)trifluoromethyl—1 H-pyrazol — 4—yl]—propan-1 -ol 3—[3—Methyl(lH-pyrrolo[2,3- b]pyridin—4-y1)—1 H-pyrazol—4-yl]- prop-Z-en—l —ol 2-[4-Bromo-l -(1H—pyrrolo[2,3- b]pyridin-4—y1)— 1 H—pyrazoly1] — isoindole-l ,3-dione 4-[4-(2,6-Dimethyl-phenyl)'3‘ methyl-pyrazol-l -y1]-1H' pyrrolo[2,3-b]pyridinc 3—[3-Amino—1 -(l H—pyn'olo[2,3- b]pyridin—4-yl)—1H—pyrazolyl]— benzonitrile 3-[3—Benzylamino—1 -(1H— pyrrolo[2,3—b]pyridin—4-yl)—1 H- pyrazol-4—y1]-benzonitfile N-[4-(3-Cyano-phenyl)-1 -(1H— o[2,3—b]pyridinyl)-l H- pyrazolyl]-acetamide 3 -[4-(1H-Pyrrolo[2,3-b]pyridin—4— . razol—1 —yl]-propan—l -01 Purification A 3—[4-(1H-Pyrrolo[2,3-b]pyridin 58 yl)-pyrazol-1 -y1]-butan-1 —ol Purification A 4—[4—(1H-Pyrrolo[2,3-b]pyridin-4— 59 razol-1 -yl]-pentanenitrile Purification A 4-[4—(1H-Pyrrolo[2,3-b]pyridin 60 yl)-pyrazol-1 -y1] -pcntanoic acid Purification A amide 4-D idazol-1 -ylmcthyl- propyl)—1H—pyrazol—4—yl]-1 H— pyrrolo[2,3-b]pyridine 4-Cyclopentyl—4-[4-(1H- 59 pyrrolo[2,3—b]pyridin—4-yl)- Punficatlon A. . pyrazol—l-yn-butyronitrile 4-Cyclopentyl—4—[4-(1 H— 60 pyrrolo[2,3-b]pyridin—4-yl)— Purification A pyrazol-l -y1]-butyramide 3—Cyclopropyl—3 —[4—(7H— o[2,3-d]py1imidin-4—yl)- 61 pyrazol-l -y1]-pr0pionitrile Purification A Example 46: 4-(2-tert—Butylmethyl-lH—imidazol-4—yl)—lH—pyrrolo[2,3-b]pyridine trifluoro— acetate salt KN// OTFA |\ \ N N Step I. 4—(2—tert—butyl—1H—imidazol—5—y0-1—[2—(trimethylsilyl)ethoxyjmethyl—1H—pyrrolo[2,3— bjpyridine To a solution of trimethylacetic acid (0.169 mL, 0.00147 mol) in ethanol (6 mL, 0.1 mol) was added cesium carbonate (0.24 g, 0.00073 mol), and the resulting mixture was d for 2 hours. The solvent was removed in vacuo to afford cesium pivalate.
To a solution of 2—chloro—1—(1-[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin—4- yl)ethanone red, e.g., as in Ex. 50, Step 1) (0.054 g, 0.00017 mol) in DMF (1.8 mL, 0.023 mol) was added cesium te 9 g, 0.000166 mol) and the reaction was stirred at room temperature for 16 hours. Ammonium acetate (0.45 g, 0.0058 mol) was added, and the reaction was heated in the microwave to 170 °C for 5 minutes. Water was added and the product was extracted with MTBE. The combined organic extracts were dried over sodium sulfate, then filtered and concentrated. The crude residue was purified by flash column chromatography (2.5% MeOI—I/DCM) to yield ert-buty1— lH—imidazol—S-yl)[2—(trimethy1silyl)ethoxy]methyl-lH—pyrrolo[2,3-b]pyridine (32 mg, 52%). lH NMR (400 MHz, CDC13): 5 8.31 (d, 1H), 7.50 (s, 1H), 7.40 (d, 1H), 7.37 (d, 1H), 6.94 (d, 1H), 5.69 (s, 2H), 3.52 (dd, 2H), 1.46 (s, 9H), 0.90 (dd, 2H), -0.08 (s, 9H); MS(ES):371(M+1).
Step 2. ert—butyl—1-methyl-1H-imidazol—4-yD-1 -[2-(trimethylsilyl)ethoagzjmethyl-IH-pyrrolo— [2,3-bjpyridine To a mixture of ert-butyl—1H—imidazol-S-yl)[2-(trimethylsi1y1)ethoxy]methyl-1H- pyrrolo[2,3—b]pyridine (0.019 g, 0.000051 mol) and ium carbonate (0.15 g, 0.0011 mol) in DMF (3 mL, 0.04 mol) was added methyl iodide (0.01 mL, 0.00015 mol) in two portions over 48 hours. Water was then added and the product was extracted with MTBE. The combined extracts were dried with sodium sulfate, filtered, and concentrated in vacuo, then purified by silica gel chromatography (20% ethyl acetate/hexanes) to afford ert—butylmethyl—1H-imidazolyl)—1- [2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (10 mg, 51%). 1H NMR (400 MHz, CDCl;): 5, 8.37 (d, 1H), 7.54 (d, 1H), 7.44-7.22 (m, 2H), 7.19 (d, 1H), 5.78 (s, 2H), 3.93 (s, 3H),.3.60 (dd, 2H), 1.61 (s, 9H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):385(M+1).
Step 3.
A solution of ‘ 4—(2-tert-butylmethyl-1H—imidazol-4—yl)-l-[2—(trimethylsi1y1)-ethoxy]- methyl-1H—pyrrolo[2,3—b]pyridine (0.010 g, 0.000026 mol) in TFA (3 mL, 0.04 mol) was stirred for 2 hours. Then the excess TFA was evaporated and the residue was d in methanol (3 mL, 0.07 mol) and NI-LOH (1 mL) for 16 hours. The solvents were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/HgO containing 0.1% TFA) to afford 4-(2— tert-butyl-l~methyl-1H—imidazoly1)-1H-pyrrolo[2,3-b]pyridine, tn'fluoroacetate salt (9 mg, 90%). 1H NMR (400 MHz, d5-DMSO): 6, 12.24 (s, 1H), 8.38 (br s, 1H), 8.24 (s, 1H), 7.70-7.63 (m, 2H), 7.08 (br s, 1H), 2.55 (s, 3H), 1.51 (s, 9H); MS(ES):255(M+1).
Additional analogs were prepared as shown in Table 2 using analogous ures to those described in Example 46 with different starting materials such as ative carboxylic acids in Step 1. When the analogs were obtained as the free base, the product was obtained by preparative—HPLC (C18 eluting with a gradient of ACN/Hzo containing 0.15% NH40H). The results are summarized in Table 2 according to the following structure: 4-(2—phenyl-1H-imidazol—5-yl)-1H- pyrrolo[2,3—b]pyridine 4-(2-benzyl-lH-imidazol-S-yl)— 3L 1H—pyrrolo[2,3—b]pyridine /\© trifluoroacetate salt 4-[2—(1-pheny1ethyl)-1H—imidazol-S- (racemic) y1]-l H-pyrrolo[2,3-b]pyridine trifluoroacetate salt Example 50: 4—(2—Phenyl-l,3~thiazol—4-yl)—1H—pyrrolo[2,3-b]pyridine trifluoroacetate salt H'TFA Step 1. 2-Chloro-1—(1-[2-(trimethylsilyDethoxyjmethyl—IH-pyrrolo[2,3-b]pyridinyl)ethanone To a solution of 4-bromo—1 —[2—(trimethy1silyl)ethoxy]methy1—1H-pyrrolo[2,3—b]pyridine (2.05 g, 0.00626 mol) in THF (10 mL, 0.123 mol) at 0 "C was added dropwise a on of isopropylmagnesium chloride in ether (2.0 M, 9.4 mL). The e was allowed to warm to room temperature and stirred for 4 hours. This mixture was then transferred via cannula to a solution of 2— chloro-N-methoxy—N-methylacetamide (2.84 g, 0.0207 mol) in THF (10 ml). Afier 30 minutes reaction time, the solution was ed by the addition of saturated ammonium chloride aqueous solution. The product was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over Na2304, filtered and concentrated. The crude residue was d by flash column chromatography (0-20% ethyl acetate/hexanes) to afford 2—chloro(1-[2-(trimethylsilyl)- ethoxy]methyl-lH—pyrrolo[2,3-b]py1idin—4-yl)ethanone (711 mg, 35%). ‘H NMR (400 MHz, CDC13): 5_ 8.56 (d, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.23 (d, 1H), 5.80 (s, 2H), 4.91 (s, 2H), 3.60 (dd, 2H), 0.98 (dd, 2H), 0.01 (s, 9H); MS(ES):325(M+1).
Step 2. 4—(2-Phenyl—1,3-thiazol—4—yD-1H-pyrrolo[2,3-b]pyridine trifluoroacetate salt A on of 2—chloro-l-(1—[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridiny1)— ethanone (0.050 g, 0.00015 mol) and benzenecarbothioamide (0.031 g, 0.00022 mol) in ethanol (2 mL, 0.03 mol) was heated to reflux for 1 hour. The solvent was removed in vacuo. Ethyl acetate was added, and the resulting solid was isolated by ion. The crude solid was stirred with TFA for 1 hour, then excess TFA was removed in vacuo. The crude residue was then stirred with aq. NH40H and MeOH for 16 hours. The solvent was removed and the product was purified by ative-HPLC (C18 eluting with a gradient of O containing 0.1% TFA) to afford 4—(2—pheny1—1,3-thiazol yl)-lH—pyrrolo[2,3-b]pyridine as the trifluoroacetate salt (11 mg, 18%). 1H NMR (400 MHz, d5- DMSO): 5, 12.01 (s, 1H), 8.58 (s, 1H), 8.39 (br s, 1H), 8.13-8.07 (m, 2H), 7.81 (d, 1H), 7.67-7.64 (m, 1H), 7.62—7.52 (m, 3H), 7.22 (d, 1H); MS(ES):278(NI+1). e 51: N—Methyl-N-propyl(lH-pyrrolo[2,3-b]pyridin—4—yl)-1,3-thiazol—2-amine, oroacetate salt Step I. N—Methyl—N—propylthiourea N—Methyl—N-propylamine (0.501 mL, 0.00488 mol) was added to a solution of 1,1'- thiocarbonyldiimidazole (0.957 g, 0.00537 mol) in THF (9 mL, 0.1 mol), and the resulting solution was stirred for 16 hours. The intermediate from the on mixture was isolated by silica gel chromatography (5% MeOH in DCM) and this intermediate was stirred with ammonia (7M on in MeOH) (6 mL) for 48 hours. The solvent was removed in vacuo. N-methyl~N—propylthiourea was obtained after flash column chromatography (4% MeOH in DCM).
Step 2.
A solution of 2-chloro-l-(1-[2—(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin—4—yl)- ethanone (0.050 g, 0.00015 mol) and N—methyl—N-propylthiourea (0.030 g, 0.00022 mol) in ethanol (2 mL, 0.03 mol) was heated to reflux for 2 hours. Then, the l was removed in vacuo and the residue was ved in 2 mL TFA and d for 40 minutes. The excess TFA was d in vacuo and the residue was dissolved in 3 mL ofMeOH. To this was added 0.5 mL ofNI-LOH and 100 uL of ethylenediamine, and the resulting solution was stirred for 16 hours. Solvent was d, then water was added to give a white precipitate which was purified by preparative-HPLC (C18 eluting with a gradient of ACN/HzO containing 0.1% TFA) to afford N—methyl-N-propyl(1H-py1rolo[2,3— b]pyridin—4-yl)—1,3-thiazolamine as the trifluoroacetate salt (39 mg, 67%). 1H NMR (300 MHz, CD30D): 5, 8.46-8.12 (br s, 1H), 7.92 (br s, 1H), 7.72 (s, 1H), 7.63 (d, 1H), 7.45 (br s, 1H), 3.56 (t, 2H), 3.20 (s, 3H), 1.78 (dq, 2H), 1.00 (t, 3H); MS(ES):273(M+1).
Additional aminothiazole analogs were prepared by procedures analogous to those described in Example 51, using different starting materials such as alternative thioureas in Step 2. In Examples 52 and 53, the white precipitate obtained by the procedure of Example 51 was isolated by filtration, washed with water and dried under high vacuum to afford the analogs as the free amine. The results are summarized in Table 3 according to the following structure: (Y)n—Z N—phenyl—4—( 1H—pyrrolo[2,3-b]pyridin—4— yl)-l ,3-thiazol—2—amine N—methyl-N—phenyl—4-(lH-pyrrolo[2,3- b]pyridinyl)-1 ,3—thiazol-2—amine Example 54: 4-(2-Phenyl—1,3-thiazol—S-yl)-1H-pyrrolo[2,3-blpyridine trifluoroacetate salt N...
I t \ N E TFA Step I. (2-Phenyl—1,3-thiazol—5—y0boronic acid To a solution of n-butyllithium in hexane (1.6 M, 2.1 mL) in ether (20 mL) at -78 °C, a solution of 2-phenyl—1,3—thiazole (449 mg, 0.00278 mol) in ether (5 mL) was added dropwise. The mixture was stirred for one hour at -78 °C followed by the addition of boric acid trimethyl ester (0.949 mL, 0.00835 mol). The mixture was stirred at ~78 °C for 15 minutes, then was allowed to warm to room temperature and stirred for an additional 40 minutes. ted NH4CI aqueous solution was added, followed by 1.0 N aqueous HCl. The acidified mixture was stirred for 15 minutes, and the desired product was extracted with four portions of DCM containing 15% isopropanol. The combined c extracts were dried over sodium e and concentrated to give 566 mg of a white solid containing the desired ny1—1,3-thiazol-5—y1)boronic acid as a mixture with 2-phenyl-1,3- thiazole. This e was used in Step 2 t finther purification. MS(ES):206(M+1).
Step 2. and 4- To a mixture of (2—pheny1-1,3-thiazol—5-yl)boronic acid (75.0 mg, 0.000366 mol) bromo—l-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.000244 mol) in DMF in water (1 (4 mL, 0.0516 mol) was added a solution of potassium carbonate (101 mg, 0.000732 mol) minutes. mL, 0.0555 mol). The mixture was purged with a steady stream of nitrogen for Tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.000018 mol) was added and the resulting mixture was heated to 125 °C for 30 minutes. The product was purified by preparative—HPLC (C18 eluting with a gradient of ACN/I-IZO containing 0.1% TFA) to afford 12 mg of a yellow solid for 1 ning the desired product as the major component. The mixture was stirred in TFA (1 ml.) 2 mL MeOH, hour. Then excess TFA was removed in vacuo and the resulting residue was stirred with 0.5 mL NH40H and 100 uL ethylenediamine for 16 hours. The product was isolated by preparative— HPLC (€18 eluting with a gradient of ACN/HgO containing 0.1% TFA) to afford 4—(2-phenyl-1,3- thiazol-S-yl)-lH—pyrrolo[2,3-b]pyridine roacetate salt (5 mg, 5%). 1H NMR (400 MHz, CD30D): 5 8.64 (s, 1H), 8.34 (d, 1H), 8.10-8.04 (m, 2H), 7.73 (d, 1H), 7.71 (d, 1H), 7.56-7.51 (m, 3H), 7.14 (d, 1H); MS(ES):278(M+1).
Example 55: Ethyl yl—2-[4-(1H—pyrrolo[2,3-b]pyridin—4-yl)—lH-pyrazol-l-yl]propanoate trifluoroacetate salt (55a) 2-Methyl—2—[4-(1H—pyrrolo[2,3-b]pyridin-4—yl)—1H—pyrazol—l-yl]propanoic acid (55b) 7 Example 56: 2—Methyl-2—[4-(1H-pyrrolo[2,3-blpyridinyl)-lH—pyrazolyl]propanamide A mixture of 2-methyl[4-(lH-pyrrolo[2,3-b]pyridinyl)-lH—pyrazol-l~yl]propanoic acid (23 mg, 85 mol) and N,N-carbonyldiimidazole (CD1) (21 mg, 0.00013 mol) in 2 mL of DMF and this was was stirred for 3 hours. An excess of solid NH4C1 and TEA was added to the mixture stirred for 3 hours. The majority of solvent was removed in vacuo, and the crude residue was purified by preparative-HPLC (C18 eluting with a gradient of ACN/HZO containing 0.1% TFA) ed by re—purification via preparative-HPLC (C18 eluting with a gradient of ACN/I-Izo containing 0.15% NH40H) to afford 2-methyl[4-(lH-pyrrolo[2,3-b]pyridinyl)-lH—pyrazol-l-yl]propanamide (6 mg, 26%). 1H NMR (400 MHz, d5-DMSO): 5 11.63 (s, 1H), 8.44 (55 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.21 (s, 1H), 6.93 (s, 1H), 6.80 (dd, 1H), 1.77 (s, 6H); MS(ES):270(M+1). e 57: Ethyl 3—methyl—3-[4-(lH-pyrrolo[2,3—b]pyridin—4-yl)-1H—pyrazol—l-yl]butanoate trifluoroacetate salt l\ \ N N H -TFA Step 1. Ethyl 3-methyl—3—[4—(I-[2-(trimethylsilyl)ethoxyjmethyl—IH—pyrrolo[2,3-b]pyridin-4—yl)~1H- Pyrazol-1 -yl]butanoate 4-(1H-Pyrazol—4—yl)—1—[2—(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (220 mg, dissolved in 996 mol) and 3-methylbutenoic acid ethyl ester (292 uL, 0.00210 mol) were mixture was DMF (10 mL). Cesium carbonate (912 mg, 0.00280 mol) was added and the ing and the product stirred at room temperature for 3 hours. The reaction mixture was diluted with water, extracts were dried over sodium sulfate and was extracted with MTBE several times. The combined concentrated. The crude residue was purified by flash column chromatography (0-60% EtOAc/Hexanes) to afford ethyl 3-methyl[4-(1—[2-(trimethylsilyl)ethoxy]methyl—1H-pyrrolo[2,3- b]pyridin—4—yl)-1H-pyrazol—l-yl]butanoate (244 mg, 79%). 1H NMR (300 MHz, CDCl3): 5, 8.37 (d, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.45 (d, 1H), 7.24 (d, 1H), 6.79 (d, 1H), 5.77 (s, 2H), 4.10 (q, 2H), 3.62 (dd, 2H), 3.04 (s, 2H), 1.88 (s, 6H), 1.20 (t, 3H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):443(M+1).
Step 2.
Ethyl 3-methy1[4-(l -[2-(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3-b]pyridiny1)—1H- pyrazol—l —y1]butanoate (20 mg, 0.0000452 mol) was d in 1 mL TFA for 1 hour. Then excess 0.5 mL TFA was removed in vacuo. The residue was stirred for 16 hours in 2 mL MeOH containing NH40H. Evaporation of the volatiles was ed by purification by preparative—HPLC (C18 eluting with a gradient of ACN/HZO ning 0.1% TFA) to afford ethyl 3-methy1-3—[4-(1H-pyrrolo[2,3—b]— n-4—y1)—lH—pyrazol—1—yl]butanoate, tn'fluoroacetate salt (5 mg, 26%). 1H NMR (400 MHz, d5- 7.02 DMSO): 6 12.19 (s, 1H), 8.61 (br s, 1H), 8.34—8.22 (br m, 2H), 7.62 (br s, 1H), 7.51 (br d, 1H), (br s, 1H), 3.91 (q, 2H), 2.96 (s, 2H), 1.70 (s, 6H), 1.02 (t, 3H); MS(ES):313(M+1).
Example 58: 3-Methy1[4-(1H-pyrrolo[2,3-b]pyridin—4-yl)-IH-pyrazol-l-yl]butan-l-ol trifluoroacetate salt l \ N H ~TFA To a solution of ethyl 3-methyl—3-[4-(1-[2—(trimethylsilyl)ethoxy]methyl—lH-pyrrolo[2,3-b]— pyridinyl)-1H-pyrazol-l-yl]butanoate (213 mg, 0.000481 mol) in THF (5 mL, 0.0616 mol) at -78 °C was added diisobutylaluminurn hydride in DCM (1.00 M, 1.1 mL) dropwise. The reaction mixture was stirred for 3 hours during which time the reaction slowly warmed to -10 0C. To the mixture at -10 °C was carefully added K/Na taitrate tetrahydrate in water. The mixture was stirred for 2 hours, then was ted with three portions of ethyl acetate. The ed organic extracts were washed with two portions of water and one portion of brine, then dried over sodium sulfate, filtered and concentrated to afford 3-methy1-3—[4-(1-[2-(trimethylsilyl)ethoxy]methyl-lH—pyrrolo[2,3-b]- (185 without further pyridiny1)-lH-pyrazol—1 —yl]butan—1-ol mg, 95%), which was used stirred in TFA (1 mL) ation. A portion of the alcohol so obtained (15 mg, 0.000037 mol) was with 2 mL MeOH containing for 2 hours. The TFA was removed in vacuo and the residue was stirred 0.5 mL NH40H for 16 hours. Volatiles were removed and the product was purified by preparative- afford yl[4-(1H- HPLC (C18 eluting with a nt of ACN/HZO containing 0.1% TFA) to o[2,3-b]pyridiny1)-1H-pyrazol-l —yl]butanol as the trifluoroacetate salt (8.0 mg, 57%).
NMR (300 MHz, dé-DMSO): 5 12.17 (s, 1H), 8.58 (br s, 1H), 8.32-8.22 (br m, 2H), 7.62 (br s, 1H), 7.53 (br (1, 1H), 7.03 (br s, 1H), 3.25 (t, 2H), 2.07 (t, 2H), 1.62 (s, 6H); MS(ES):271(M+1).
Example 59: 4-Methyl[4-(lH-pyrrolo[2,3—b]pyridin—4-yl)-lH—pyrazol—l-yl]pentanenitrile trifluoroacetate salt I \ N iii -TFA Step I. 4—Methyl-4—[4-(1—[2—(trimethylsilyl)ethoxy]methyl—1H—pyrrolo[2,3—b]pyridin—4-yl)—1H— pyrazol—I-yl]pentanenitrile TEA (38.0 tLL, 0.000273 mol) and methanesulfonyl chloride (21.1 uL, 0.000273 mol) were added sequentially to a solution of 3-methyl—3—[4—(l -[2-(trimethylsilyl)ethoxy]methyl—lI-I—pyrrolo[2,3— dinyl)—lH—pyrazolyl]butan-l-ol (prepared as in Example 58) (81 mg, 0.00020 mol) in for 1.5 hours, then DCM (4 mL, 0.05 mol) at 0° C. The reaction mixture was held at this temperature mixture was extracted with DCM four times. The was quenched by the on of water. The reaction afford crude 3—methylcombined extracts were dried over sodium sulfate, filtered and concentrated to 3-[4-(1 -[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridiny1)-1H—pyrazoi-l -yl]butyl methanesulfonate (87 mg). MS(ES):479(M+1).
A mixture of 3—methyl[4-(l-[2—(trimethylsilyl)ethoxy]methyl-lH—pyrrolo[2,3-b]pyridin yl)-lH—pyrazol-l-y1]butyl esulfonate (42 mg, 0.000088 mol) and potassium cyanide (46 mg, "C followed by 0.000702 mol) in DMF (1 mL) was heated in the microwave reactor for 30 min at 125 extracted additional 30 min at 135 0C. The e was then diluted with water, and the product was with three portions of MTBE. The combined ts were dried over sodium sulfate, filtered concentrated to give 61 mg of crude 4-methy1—4-[4—(l-[2-(trimethy1silyl)ethoxy]methyl-lH-pyrrolo- [2,3-b]pyridin—4—yl)-lH-pyrazol—l—yl]pentanenitrile, which was used without further purification.
MS(ES):410(M+1).
WO 70514 Step 2. 4-Methy1—4-[4-(1 -[2~(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3-b]pyridinyl)-1H- pyrazol-l-yl]pentanenitrile (57 mg, 0.00014 mol) was stirred in DCM (4 m1) and TFA (1 mL) for 2 hours. The ts were removed in vacuo and the e was stirred in 2 mL MeOH containing 0.2 from mL nediamine for 16 hours. The volatiles were evaporated and the product was ed the reaction mixture by preparative-HPLC (C18 eluting with a gradient of ACN/Hzo containing 0.1% TFA) affording 4-methyl-4—[4-(lH-pyrrolo[2,3-b]pyridinyl)-lH—pyrazol-l—yl]pentanenjtrile as the trifluoroacetate salt (10 mg, 18%). 1H NMR (400 MHz, d5-DMSO): 6, 12.09 (s, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 8.25 (d, 1H), 7.60 (t, 1H), 7.48 (d, 1H), 7.00 (br s, 1H), 2.33-2.21 (m, 4H), 1.61 (s, 6H); MS(ES):280(M+1).
Example 60: 4-Methyl—4-[4-(1H-pyrrolo[2,3-b]pyridinyl)—1H—pyrazol—1-yl]pentanamide trifluoroacetate salt l \ N N H -TFA The crude 4-methyl[4-(1-[2-(trimethy1silyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridinyl)- azol-l-y1]pentanenitrile (36 mg, 0.000088 moi, see preparation in Example 59), was stirred in TFA (2 mL) for 1 hour. The mixture was concentrated to remove excess TFA, and the resulting residue was stirred in 2 mL methanol containing 0.5 mL NI-LOH for 16 hours. The product was purified by preparative—HPLC (C18 eluting with a gradient of ACN/HZO containing 0.1% TFA) to afford 4-methy1—4—[4—(1H—pyrrolo[2,3—b]pyridin-4—yl)-1H—pyrazol-l—yl]pentanarriide as the tn'fluoro— acetate salt (21 mg, 58%). 1H NMR (400 MHz, d5-DMSO): 5 12.18 (s, 1H), 8.60 (s, 1H), 8.33—8.21 (m, 2H), 7.62 (br s, 1H), 7.53 (d, 1H), 7.22 (br s, 1H), 7.04 (br s, 1H), 6.71 (br s, 1H), 2.14-2.07 (m, 2H), 1.86-1.79 (m, 2H), 1.58 (s, 6H); MS(ES):298(M+1).
Example 61: (SS)[4-(1H-Pyrrolo[2,3-b]pyridinyl)-lH—pyrazol-l-yl]butanenitrile trifluoro- acetate salt , (3R)[4-(1H—Pyrrolo[2,3-b]pyridin-4—yl)—lH—pyrazol—l-yl]butanenitrile trifluoroacetate salt To a solution of 4—(1H—pyrazol—4—yl)-1—[2—(trimethylsilyl)ethoxy]methy1-lH-pyrrolo[2,3— b]pyridine (0.050 g, 0.00016 mol) in ACN were added 2—butenenitrile (0.014 mL, 0.00017 mol) and DBU (0.029 mL, 0.00020 mol). The resulting mixture was stirred for 16 hours. Then the les were ated and the residue was dissolved in ethyl acetate. The resulting solution was washed successively with 1.0 N HCl, water, and brine, then was dried over sodium sulfate, filtered and concentrated. To obtain the enantiomers in substantially pure form, Method A (vide infra) was used.
The crude residue was dissolved in TFA (7 mL, 0.09 mol) and the solution was stirred for 1 ‘10 hour. Then excess TFA was evaporated and the residue was then stirred with ethylenediamine (0.1 mL, 0.001 mol) in methanol (4 mL, 0.09 mol) for 16 hours. The mixture was concentrated, and the t was purified by preparative—HPLC (C18 eluting with a gradient of 0 containing 0.1% TFA) to afford 3-[4—(1H—pyrrolo[2,3—b]pyridin-4—yl)-1H-pyrazol-l—yl]butanenitri1e roacetate salt (35 mg, 61%). lH NMR (300 MHz, dG—DMSO): 5 12.16 (s, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 8.28 (d, 1H), 7.65—7.61 (m, 1H), 7.48 (d, 1H), 6.99 (d, 1H), 4.86 (q, 1H), 3.17 (d, 2H), 1.57 (d, 3H); MS(ES):252(M+1).
Additional analogs were prepared by procedures analogous to those described in Example 61 using different starting materials for alkylation of the pyrazole ring. For example, the unsaturated nitriles were prepared by pro'cedures analogous to the following, illustrated for (2E)- and (2Z)- hexenenitrile: To a solution of 1.00 M ium tert-butoxide in THF at 0 °C (24.2 mL) was added a solution of diethyl cyanomethylphosphonate (4.10 mL, 0.025 mol) in THF (30 mL) dropwise. The bath was removed and the solution was allowed to warm to room temperature. After reaching room temperature, the solution was re-cooled to 0°C and a on of butanal (2.00 mL, 0.023 mol) in THF (7 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The mixture was diluted with ethyl e and water. The layers were separated and the s layer was extracted with three portions of ethyl e. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. This afforded 1.6 g of a crude mixture containing both (2E)— and (ZZ)-hexenenitrile, which was used without further purification in the subsequent alkylation step. 1H NMR (400 MHz, CDClg): 8, 6.72 (dt, 1H trans olefin), 6.48 (dt, 1H cis olefin), 5.34 (dt, 1H trans , 5.31-5.30 (m, 1H cis olefin).
Where it was desirable to obtain the enantiomers in substantially pure form, chiral separation was performed by one of the following methods: A) The separation was performed on the rotected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H , eluting with % ethanol in hexanes); B) The separation was performed on the deprotected free base by ative chiral HPLC (OD—H column, eluting with 15% ethanol in hexanes); C) The separation was performed on the SEM-protected intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H column, eluting with % ethanol in hexanes); D) The tion was performed on the SEM—protected ediate afler silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (AD-H , eluting with % ethanol in hexanes); E) The separation was performed on the SEM—protected intermediate alter silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD-H column, eluting with % ethanol in hexanes; or F) The separation was performed on the SEM-protectcd intermediate after silica gel chromatography (ethyl acetate/hexanes) by preparative chiral HPLC (OD—H , eluting with % ethanol in hexanes. An OD-H column refers to Chiralcel QD-H from Chiral Technologies, Inc 3x25 cm, 5 um. An AD-H column refers to ChiralPak AD-H from Chiral Technologies, Inc. 2x25 cm, 5 pm. The results are summarized for compounds in Table 4 below.
RHCN I \ N N H Table4 Method of preparation and chiral separation 3-[4—(lH-pyrrolo[2,3-b]pyridinyl)-1H- pyrazol-l -yl]propanenitrile trifluoroacetate salt (3 S)—3-[4—(lH-pyrrolo[2,3-b]pyridin-4— yl)-1 H—pyrazol- 1 —yl]hexanenitrile trifluroracetate salt Ex. 61 Method B -[4-(lH—pyrrolo[2,3-b]pyridin yl)-lH-pyrazolyl]hexanenitrile trifluroracetate salt (3S)-3—cyclopenty1[4-(1 olo[2,3- b]pyridinyl)- l H—pyrazol-l -yl]- propanenitrilc trifluoroacetate salt Ex. 61 MathOd C (3R)cyclopentyl[4-(1H-pyrrolo[2,3- dinyl)—1H-pyrazol-l -yl]- propanenitrile trifluoroacetate salt (3 S)cyclohexyl-3—[4-(1H-pyrrolo[2,3 - b]pyridinyl)— l H-pyrazol-l -yl]- propanenitrile Ex. 61 (3R)cyclohexyl—3-[4—( 1 H-pyrrolo[2,3- b]pyridin—4~yl)—1H—pyrazol—1 ~yl] ~ propanenitrile Example 65: (3R)[4-(7H-Pyrrolo[2,3-d]pyrimidinyl)—1H—pyrazol-1—yl]hexanenitrile trifluoroacetate salt (SS)[4—(7H-Pyrrolo[2,3-d]pyrimidinyl)—lH—pyrazol-l-yl]hexanenitrile trifluoroacetate salt ON ON N-N N—N // TFA // TFA N\r/b} N\ N {/3 H andN H Step 1 . 4—Chloro—7—[2—(trimethylsilyDethoxy]methyl— 7H—pyrrolo[2,3-d]pyrimidine To a solution of 4-chloropyrrolo[2,3-d]pyrimidinc (0.86 g, 0.0056 mol) in DMF (20 mL, 0.2 mol) at 0 °C was added sodium e (0.27 g, 0.0067 mol) in several portions. The reaction mixture was stirred for an additional 45 minutes followed by a dropwise addition of methylsilyl)ethoxy]— methyl chloride (1.2 mL, 0.0067 mol). The resulting reaction mixture was stirred at 0 °C for 45 min, then was quenched with water and extracted with ethyl acetate. The organic extract was washed with water, brine, dried over sodium sulfate, d and concentrated to give an oil. The crude residue was purified by flash column chromatography (0-15% ethyl acetate/hexanes) to yield 4—chloro[2— (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (1.40 g, 88%). 1H NMR (400 MHz, CDCl3): 8, 8.71 (s, 1H), 7.46 (d, 1H), 6.72 (d, 1H), 5.71 (s, 2H), 3.59 (dd, 2H), 0.97 (dd, 2H), 0.00 (s, 9H); :284(M+1).
Step 2. 4-(1H-Pyrazol—4-y0[2-(trimetlzylsiéyvethoxyjmethyl-7H-pyrrolo[2,3-djpyrimidine To a mixture of 4-chloro[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (1.4 g, 0.0049 mol) and 4-(4,4,5,5-tetramethyl~l,3,2-dioxaborolan—2—yl)—lH-pyrazole (1.4 g, 0.0074 mol) in DMF (40 mL, 0.5 mol) was added potassium carbonate (2.0 g, 0.015 mol) in 15 mL of water.
The mixture was purged with a steady stream of en for 15 minutes. Tetrakis(triphenyl- phosphine)palladium(0) (0.41 g, 0.00036 mol) was added and the reaction was heated to 125 °C for 30 min. The mixture was allowed to cool then diluted with ethyl e. The diluted reaction e was washed with water, brine, dried over NaZSO4 and concentrated to give a solution in a small volume ofDMF (about 2-3 mL). Water was added, causing the al to form a gum on the walls of the flask. Then water was decanted, and the solids were dissolved in ethyl acetate. The solution was dried over Na2S04, and concentrated in vacuo to afford a yellow solid. The product was triturated with ethyl ether to yield 4-(1H-pyrazol-4—yl)[2-(trimethylsily1)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidine as a white powder which was dried under vacuum (1 g, 60%). 1H NMR (300 MHZ, CDC13): 8 10.80 (br s, 1H), 8.93 (s, 1H), 8.46 (s, 2H), 7.46 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 3.61 (dd, 2H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES):316(M+1).
Step 3.
To a solution of 4—(1H-pyrazol-4—yl)—7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidine (0.050 g, 0.00016 mol) in ACN (1 mL, 0.02 mol) was added hex-Z-enenitrile (0.100 g, 0.00105 mol) (as a mixture of cis and trans isomers), followed by DBU(60 uL, 0.0004 mol). The resulting e was stirred at room temperature for 16 hours. The ACN was removed in vacuo. The crude residue was dissolved in ethyl acetate, and was washed with 1.0 N HCl, brine, dried over NaZSO4 and concentrated. The crude residue was purified by flash column chromatography (0-70% Hexane) to afford 56 mg of product, which was stirred with 1:1 M for 1 hour and the ts were evaporated. The resulting product was stirred with methanol (4 mL, 0.1 mol) containing ethylenediamine (0.1 mL, 0.001 mol) overnight. The solvent was evaporated and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H20 containing 0.1% TFA) to afford 3-[4-(7H—pyrrolo[2,3-d]pyrimidin—4—yl)—lH—pyrazol—1—yl]hexanenitrile as the trifluroacetate salt. Where desired, the enantiomers were isolated in substantially pure form by Method A described above for Example 61. 1H NMR (300 MHz, CD30D): 6_ 8.93 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 7.85 (d, 1H), 7.28 (d, 1H), 4.87-4.77 (m, 1H), 3.26-3.05 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.86 (m, 1H), 1.40-1.10 (m, 2H), 0.95 (t, 3H); MS(ES):281(M+1).
Example 67: (3R)- and -Cyclopentyl—3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4—yl)—IH-pyrazol- 1—yl]propanenitrile r0CN E CN ‘2IZ N—Z \ and N / / N t \ t \/\ N 3:2 N 3:2 Step 1. (2E)- and (2Z)—3—Cyclopentflacrylonitrile To a solution of 1.0 M potassium tert—butoxide in THF (235 mL) at 0 0C was added dropwise a solution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in THF (300 mL). The cold bath was removed and the reaction was warmed to room ature followed by recooling to 0 0C, at which time a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was added dropwise. The bath was removed and the reaction warmed to ambient temperature and stirred for 64 hours. The e was partitioned between diethyl ether and water, the aqueous was extracted with three portions of ether, followed by two portions of ethyl acetate. The ed extracts were washed with brine, then dried over sodium sulfate, filtered and trated in vacuo to afford a e containing 24.4 g of olefin isomers which was used without further purification (89%). 1H NMR (400 MHz, CDC13): 5 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5.20 (d, 1H, cis olefin), 3.07—2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product), 1.98- 1.26 (m, 16H).
Step 2. (3R)- and (35)-3—Cyclopentyl—3-[4-(7-[2-(trimethylsilyDethoxy]methyl—7H-pyrrolo[2,3-d]- pyrimidinyl)-1H-pyrazol—1-yl]propanenitrile To a solution of 4—(1H-pyrazol-4—yl)—7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]~ pyrimidine (15.0 g, 0.0476 mol) in ACN (300 mL) was added 3-cyclopentylacrylonitrile (15 g, 0.12 mol) (as a mixture of cis and trans isomers), followed by DBU (15 mL, 0.10 mol). The resulting mixture was stirred at room temperature overnight. The ACN was evaporated. The mixture was diluted with ethyl e, and the solution was washed with 1.0 N HCl. The organic layer was back- extracted with three portions of ethyl acetate. The combined c extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (gradient of ethyl acetate/hexanes) to yield a s clear syrup, which was dissolved in ethanol and evaporated several times to remove ethyl acetate, to afford 19.4 g of racemic adduct (93%). The omers were separated by preparative-HPLC, (OD~H, 15% ethanol/hexanes) and used separately in the next step to generate their corresponding final product. The final products (see Step 3) stemming from each of the separated enantiomers were found to be active JAK inhibitors; r, the final product stemming from the second peak to elute from the ative-HPLC was more active than its enantiomer. 1H NMR (300 MHz, CD013): 8 8.85 (s, 1H), 8.32 (s, 2H), 7.39 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 1.80— 4.26 (dt, 1H), 3.54 (t, 2H), 3.14 (dd, 1H), 2.95 (dd, 1H), 2.67—2.50 (m, 1H), 2.03—1.88 (m, 1H), 1.15 (m, 7H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):437 (M+1).
Step 3.
To a solution of 3-cyclopenty1—3-[4-(7-[2—(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]- pyrimidin—4-yl)-lH-pyrazol—l—yl]propanenitrile (6.5 g, 0.015 mol, R or S enantiomer as isolated The solvent and above) in DCM (40 mL) was added TFA (16 mL) and this was stirred for 6 hours.
TFA were removed in vacuo. The residue was dissolved in DCM and concentrated using a rotary of the TFA. Following this, the residue ator two further times to remove as much as possible The solvent was was stirred with nediamine (4 mL, 0.06 mol) in ol (30 mL) overnight. of ethyl acetate. d in vacuo, water was added and the product was extracted into three portions and concentrated The combined ts were washed with brine, dried over sodium sulfate, decanted to afford the crude product which was purified by flash column chromatography (eluting with a gradient of methanol/DCM). The resulting mixture was further purified by preparative—HPLC/MS (C18 eluting with a gradient of ACN/HZO containing 0.15% NH40H) to afford t (2.68 g, 58%). 1H NMR (400 MHz, D6—dmso): 5 12.11 (br s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.98 (d, 1H), 4.53 (dt, 1H), 3.27 (dd, 1H), 3.19 (dd, 1H), .36 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.13 (m, 7H); MS(ES):307(M+1).
Additional s provided in the following Tables were prepared by procedures analogous such as to those described in, for example, Examples 61 and 65, using different starting materials different (LB—unsaturated nitriles in Step 3. Isolation of the enantiomers in substantially pure form described above (A-F) preceding Table 4. was achieved by the indicated chiral separation method Where the product was isolated as the free amine, the product following deprotection was purified by instead of preparative-HPLC (C18 eluting with a gradient of ACN/HZO containing 0.15% NILOH) referred preparative-HPLC (C18 eluting with a gradient of ACN/Hgo containing 0.1% TFA). This is to the following structure: to as "modification G". The results are ized in Table 5 according N—N R" N‘k \ \ N N Tables WO 70514 Method of preparation and chiral se - aration (3R)—3-[4-(7H—pyrrolo[2,3—d]pyrimidin— 4-yl)-l H-pyrazol—l -yl]butanenitrile trifluoroacetate salt Example 65, Method A (3 S)[4-(7H—pyrrolo[2,3-d]pyrimidin— 4-yl)-1H-pyrazol-l -yl]butanenitrile trifluoroacetate salt (3R)cyclopenty1—3-[4~(7H-pyrrolo- [2,3 -d]py1imidin—4-yl)—lH-pyrazol-l - yl]propanenitrile trifluoroacetate salt and Example 67 (3 S)—3~cyclopentyl—3—[4-(7H—pyrrolo— [2,3—d]pyrimidinyl)~ lH-pyrazol-l — ro » anenitrile trifluoroacetate salt 2-methyl[4—(7H—pyrrolo[2,3- d]pyrimidinyl)-l zol-l - r0 . anenitrile trifluoroacetate salt -[4-(7H—pyrrolo[2,3-d]pyrimidin— 4-yl)-1H-pyrazol-l -yl]pentanenitrile Example 65, and modification G, (3S)-3—[4-(7H-pyrrolo[2,3-d]pyrimidin— Method B .entanenitrile (3R)—5-methyl[4-(7H-pyrrolo[2,3- d]pyrimidin—4-yl)—l H—pyrazol— 1 — yl]hexanenitrile Example 65 , and modification G, (3 S)—5-methyl—3 —[4-(7H-pyrrolo[2,3- Method A d]pyrimidin—4—yl)—1H—pyrazol—l — 1 hexanenitrile (3R)—3-cyclohexyl[4-(7H- pyrrolo[2,3-d]pyrimidin—4-yl)—1 H- pyrazoI-l -yl]propanenitrile Example 65, and modification G, (3 yclohexyl[4-(7H- Method A o[2,3-d]pyrimidinyl)—1H- :- r0 . anenitrile (3R)—4—cyclopropyl—3—[4—(7H- pyIT'olo[2,3-d]pyrimidin—4-y1)—l H— pyrazol—l -yl]butanenitrile Example 65, and modification G, (3S)cyclopropy1—3-[4-(7H— Method F pyrrolo[2,3—d]pyrimidiny1)-1H- Example 69: 4-{1-[(1S)-l-Methylbutyl]-1H-pyrazol-4—yl}-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 4-{1-[(1R)—l-Methylbutyl]-1H-pyrazol—4—yl}-7H-pyrrolo[2,3-d1pyrimidine trifluoroacetate salt WO 70514 2006/047369 N—N N—N / I / / TFA N \ N \ m / S 'k / N N .7 H and H A solution of 4-(1H—pyrazol—4—yl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- this was pyrimidine (0.050 g, 0.00016 mol) in DMF (2 mL, 0.02 mol) was cooled in an ice bath and to added sodium hydride (0.013 stirred for 10 minutes, g, 0.00032 mol). The resulting mixture was followed by an addition of 2-bromopentane (0.030 mL, 0.00024 mol). The cooling bath was then removed and the reaction was stirred at room temperature for 3 hours, at which time a further portion of opentane (0.015 mL, 2 mol) was added. Afier 45 minutes, water was added and the reaction mixture was extracted with three portions of ethyl acetate. The combined extracts were with Washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was stirred TFA (3 mL, 0.04 mol) and DCM (3 mL, 0.05 mol) for 3.5 hours, then the solvent was removed for 16 hours. The solvent vacuo. The residue was then stirred with NI-LOH (1.5 mL) in MeOH (4 mL) with a gradient of was evaporated and the product was purified by ative-HPLC (C18 g ACN/H20 containing 0.1% TFA) to afford 4-[1-(1-methylbutyl)-1H-pyrazolyl]-7H—pyrrolo[2,3- d]pyrimidine as the trifluoroacetate salt (25 mg, 44%). 1H NMR (300 MHz, CD30D): 5 8.83 (s, 1H), 8.75 (s, 1H), 8.43 (s, 1H), 7.77 (d, 1H), 7.24 (d, 1H), 4.63-4.50 (m, 1H), 2.07-1.91 (m, 1H), 1.88-1.74 (m, 1H), 1.58 (d, 3H), 1.38-1.09 (m, 2H), 0.93 (t, 3H); :256(M+1).
Isolation of the enantiomers in substantially pure form was achieved by separation of the racemic free base (isolated by flash column chromatography afier deprotection, eluting with a MeOH/DCM gradient) using HPLC (OD-H, eIuting with 5% isopropanol/hexanes).
Example 69a: 4—Methyl—4—[4-(7H-pyrrolo[2,3—d]pyrimidinyl)-lH-pyrazol-l-yl]pentanenitrile Step 1. Ethyl 3—methy1[4-(7-[2-(trimethylsilyl)ethongzjmethyl- 7H-pyrrolo[2,3-d]pyrimidin—4—yl)—1H— pyrazolyl]butanoate A solution of 4—(1H—pyrazol—4—y1)—7—[2—(trimethy1silyl)ethoxy]methyl-7H-pyrrolo[2,3-d]— pyrimidine (12.1 0.115 mol) and g, 0.0384 mol), 2-butenoic acid, 3—methy1-, ethyl ester (16.0 mL, DBU (14.3 mL, 0.0959 mol) in ACN (100 mL) was heated at reflux for 3.5 hours. The solvent was 2006/047369 removed in vacuo. The residue was diluted with water, extracted with ethyl acetate, and the combined organic extracts were washed with saturated. ammonium chloride, dried over sodium sulfate, and concentrated. The crude residue was purified by flash column tography (ethyl acetate/hexanes) to yield the desired product (15.5 g, 91%).
'H NMR (400 MHz, CDC13): 8, 8.83 (s, 1H), 8.36 (5, 11-1), 8.27 (s, 1H), 7.37 (d, 1H), 6.80 (d, 1H), .66 (s, 2H), 4.03 (q, 2H), 3.54 (dd, 2H), 2.98 (s, 2H), 1.80 (s, 6H), 1.13 (t, 3H), 0.91 (dd, 2H), -0.07 (s, 9H); MS(ES):444(M+1).
Step 2. 3-Methyl-3—[4-(7-[2-(trz'methylsilyl)ethoxy]methyl-7H~pyrrolo[2,3-d]pyrimidinyl)—1H- pyrazolyl]butan-I~01 To a solution of ethyl 3-methy1—3-[4-(7—[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]~ pyrimidinyl)-1H-pyrazolyl]butanoate (15.4 g, 0.0347 mol) in THF (151 mL) at -78 °C was added 1.00 M diisobutylaluminum e in DCM (84.5 mL) dropwise. The reaction was stirred for 2 hours with slow warming to -10 °C. The mixture was quenched with water, then was treated with potassium sodium tartrate tetrahydrate and water. The mixture was stirred for 1 hour, then was extracted with ethyl acetate. The extracts were washed with water and brine, then dried with sodium sulfate, filtered, and concentrated in vacuo. The crude e was purified by flash column chromatography to yield the d product (13.8 g, 99%). 1H NMR (300 MHz, CD013): 8 8.83 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 7.38 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 3.65 (dd, 2H), 3.54 (dd, 2H), 2.21 (t, 2H), 1.72 (s, 6H), 0.91 (dd, 2H), -0.07 (s, 9H); MS(ES):402(M+1).
Step 3. 3-Methyl[4—(7H-pyrrolo[2,3-d]pyrimidinyl)-IH-pyrazol-I-yl]butan—1 -01 A solution of 3—methyl[4—(7—[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1H—pyrazol-l—yl]butanol (13.8 g, 0.0344 mol) in TFA (20 mL) was stirred for 1 hour. The e was then concentrated in vacuo and the residue was stirred for 2 hours in a mixture of ol (30 mL), um hydroxide (30 mL), and ethylenediamine (8 mL). The mixture was then concentrated, and the residue was diluted with water and extracted with several portions of 15% IPA/CH2C12. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give 20 g of white solid. The solid was triturated with ether and the product was isolated by ion to give the product as a white solid (7.75 g, 83%).
'H NMR (400 MHz, CD013): 5 9.99 (s, 1H), 8.83 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.38 (dd, 1H), 6.80 (dd, 1H), 3.66 (t, 2H), 2.72 (br s, 1H), 2.22 (t, 2H), 1.74 (s, 6H); MS(ES):272(M+1).
Step 4. 3-Methyl-3—[4—(7H-pyrrolo[2,3—d]pyrimidin—4—yl)-IH—pyrazol-I-yljbmfivl methanesuéfonate A solution of 3-methyl[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-lH-pyrazol-l~yl]butanol (6.61 g, 0.0244 mol) in DCM (300 mL) at 0 °C was treated with TEA (3.74 mL, 0.0268 mol), followed by methanesulfonyl chloride (2.07 mL, 0.0268 mol). The reaction was stirred for 1 hour, and was then concentrated in vacuo. The crude e was purified by flash column chrornatography to afford the desired product (4.9 g, 57%).
IH NMR (400 MHz, 0): 8_ 12.45 (s, 1H), 9.50 (s, 1H), 9.35 (s, 1H), 8.83 (s, 1H), 7.79 (dd, 1H), 7.11 (dd, 1H), 4.75 (t, 1H), 3.30 (s, 3H), 2.85 (t, 1H), 1.75 (s, 6H); MS(ES):254(M-CH3303H+1).
Step 5. 4-MethyI[4-(7H—pyrrolo[2,3—d]pyrimidinyl)-IH-pyrazol-I-yl]pentanenitrile 3—methyl[4-(7H-pyrrolo[2,3-d]pyrimidinyl)—l H-pyrazol-l -yl]butyl methanesulfonate (2.97 8.50 mmol), DMF (120 mL) and sodium cyanide (6.21 g, g, 0.127 mol) were distributed evenly into six 20 mL avable vessels, each of which was heated in the microwave reactor mL water 4000 seconds at 125 l’C. The contents of the vials were combined and were diluted with 400 and extracted with five 150 mL portions of ethyl acetate. The combined ts were dried over sodium sulfate, and the solvent was removed in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.40 g, 59%). 1H NMR (400 MHz, CDClg): (S 9.52 (br s, 1H), 8.83 (s, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 7.39 (dd, 1H), 6.81 (dd, 1H), 2.38 (dd, 2H), 2.16 (dd, 2H), 1.73 (s, 6H); MS(ES):281(M+1).
The analogs in Table Sa were prepared according to the above method described for Example 69a. For Example 69b, a conjugate acceptor was used and prepared as bed in Perkin Trans. 1, 2000, (17), 2968-2976, and Steps 4&5 were med before Step 3.
Table 53 MS (ES) 3[4-(7H-pyrrolo[2,3-d]— pyrimidinyl)-1H—pyrazol—l - 279 yl]cyclopropylpropanenitrile (4S)— and (4R)—4-[4(7H- pyirolo[2 ,3-d]pyn'midinyl)- lH—pyrazol-l -yl]pentanenitn'le Example 69d: 3-Methyl[4-(7H-pyrrolo[2,3-d]pyrimidin—4-yl)—lH—pyrazol—l-yl]butanenitrile : CN Step 1. Senecionim'le To a solution of 1.0 M potassium tert-butoxide in TI-IF (2.0 mL) at 0 "C was added a solution of diethyl cyanomethylphosphonate (0.33 mL, 2.06 mmol) in THF (4 mL) dropwise. The cold bath was removed and the reaction was warmed to room temperature. The reaction was then re~cooled to 0 °C and acetone (0.20 mL, 2.81 mmol) was added dropwise. The cooling bath was then removed and the reaction was allowed to warm to room temperature and stir overnight. The reaction was diluted with water, the layers separated, and the aqueous extracted with ethyl acetate. The extracts were washed with brine, dried over sodium e, filtered and concentrated. The product was used without further purification (339 mg, 67%).
'H NMR (300 MHz, CDCla): 8_ 5.10 (br s, 1H), 2.05 (s, 3H), 1.92 (s, 3H).
Step 2. 3—Methyl-3—[4—(7H—pyrrolo[2,3-d]pyrimidinyl)—IH—pyrazol—1~yl]butanenitrile To a solution of 4-(1H-pyrazolyl)[2-(tn'methylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]— dine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 111., 0.002 mol) and the resulting mixture was heated to 60 "C for 23 hours. The e was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium sulfate, filtered and trated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired t. 1H NMR (300 MHz, ds—dmso): 8 8.83 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H), .66 (s, 2H), 3.54 (dd, 2H), 3.08 (s, 2H), 1.84 (s, 6H), 0.91 (dd, 2H), —0.07 (s, 9H); MS(ES):397(M+1).
To a solution of this product in DCM at 0 °C was added TFA sufficient to se 20% of the total volume. The solution was stirred at this ature for 30 min, then at ambient temperature for 2 hours and 15 minutes. The ts were removed in vacuo and the residue was stirred with methanol (10 mL) and ethylenediamine (0.4 mL, 0.006 mol) overnight. The solvent was evaporated and the product was purified by preparative-HIPLC/MS (C18 column eluting with a gradient of ACN/HZO containing 0.15% NH40H) to afford the t (25 mg, 14%).
IH NMR (300 MHz, d5-dmso): 6, 12.08 (s, 1H), 8.68 (s, 2H), 8.39 (s, 1H), 7.59 (d, 1H), 7.05 (d, 1H), ' 3.32 (s, 2H), 1.73 (s, 6H); MS(ES):267(M+1).
Examples 69e and 69f in Table 5b were prepared by a method analogous to that bed above for Example 69d, with rated nitriles prepared either according to published literature procedures, or by the method in Step 1.
Table 5b MS (ES) 3-ethyl—3—[4-(7H—pyrrolo[2,3- d]pyrimidin—4-yl)—1H—pyrazol— 295 1 —y1]pentanenitrile 1—[4-(7H-pyrrolo[2,3-d]— pyrimidin-4—yl)-1H-pyrazol-l - y1]cyclopropylacetonitrile Additional analogs were prepared by procedures analogous to those described in Example 69, using different starting materials such as alternative bromide or mesylate compounds for the nucleophilic substitution step. Where the free amine was obtained as the product, the t was purified after deprotection either by silica gel chromatography ng with 5% methanol in DCM) or by preparative—HPLC (C18 eluting with a gradient of ACN/HzO containing 0.15% NH40H). The results are summarized for compounds listed in Table 6.
/(Y)n—Z 4—1 —[(2R)—pyrrolidin—2-ylmethyl]-l H- pyrazolyl-7H-pyrrolo[2,3—d]- pyrimidine 4—(1 —[(2R)-1 -(methylsulfonyl)pyrrolidin- 2—yl]methy1-lH—pyrazol72yl)-7H- pyrrolo[2,3-d]pyrimidine ethyl 2-methyl[4-(7H-pyrrolo[2,3-d]- pyrimidinyl)-1H-pyrazol-l -yl] - propanoate trifluoroacetate salt e 74: -Cyclopentyl-3—[4-(7H—pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazolyllacrylonitrile Z Z\/\ \ Step 1. 3-CyclopenWIprop—2—ynenitrz‘le To a solution of cyclopentylacetylene (0.50 g, 5.3 mmol) in TI-IF (5 mL) at -78 0C was added 2.5 M n-butyllithium in hexane (2.23 mL). The e was stirred for 15 min followed by the dropwise addition of phenyl cyanate (0.70 g, 5.8 mmol) in THF (3 mL). The reaction was warmed to room temperature. Into the reaction mixture was poured 6 N NaOH, and the mixture was stirred for 5 minutes. The product was extracted with diethyl ether. The extracts were washed with 6 N NaOH and with brine, then dried over sodium sulfate, decanted and the solvent was removed in vacuo to afford product (600 mg, 95%). ‘H NMR (300 MHz, CDC13): 5. 2.81-2.68 (m, 1H), 2.07-1.54 (m, 8H).
Step 2. (ZZ)Cyclopentyl[4-(7-[2—(trimethylsilyDethoxyjmet/Iyl— rolo[2,3-d]pyrimidin-4— 1 5 yl)-1H—pyrazol—I—y1]acrylonitrile To a mixture of 4-(1H-pyrazol—4—yl)-7~[2-(trimethylsilyl)ethonymethyl—7H-pyrrolo[2,3—d]~ pyrimidine (0.40 g, 1.2 mmol) and 3-cyclopentylprop-Z-ynenitrile (0.30 g, 2.5 mmol) in DMF (8 mL) was added ium ate (0.09 g, 0.6 mmol). The mixture was stirred for 35 min. The reaction was diluted with ethyl acetate and brine, and the aqueous portion extracted with three volumes of 2006/047369 ethyl acetate. The combined organic extracts were washed with brine again, then were dried over sodium sulfate, decanted and concentrated in vacuo. The crude residue was purified by flash column chromatography (ethyl e/hexanes) to yield the desired product (290 mg, 53%). 1H NMR (400 MHz, CDC13): 6_ 8.98 (s, 1H), 8.87 (s, 1H), 8.46 (s, 1H), 7.42 (d, 11-1), 6.84 (d, 1H), .67 (s, 2H), 5.21 ‘(s, 1H), 3.64-3.55 (m, 1H), 3.53 (t, 2H), 2.13-2.01 (m, 2H), 1.83-1.66 (m, 4H), 1.57—1.46 (m, 2H), 0.91 (t, 2H), -0.07 (s, 9H); MS(ES):435(M+1).
Step 3. (2Z)Cyclopentyl[4—(7H-pyrrolo[2,3~d]pyrimidinyD-IH-pyrazol—1~yl]acrylonitrile A solution of —cyclopentyl—3—[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3«d1- pyrimidin-4—yl)-1H—pyrazol-l-yl]acrylonitrile (0.030 g, 0.069 mol) in DCM (3 mL) and TFA (2 mL) was stirred for 1 hour. The solvents were d in vacuo and the product was stirred with TI-IF (1.5 mL), sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) for 2 hours. The reaction mixture was neutralized by the dropwise addition of cone. HCl. The product was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient ofACN/H20 containing 0.15% NH40H) to afford the desired product (16 mg, 76%). 1H NMR (400 MHz, ds-dmso): 8_ 9.08 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 7.66 (d, 1H), 7.05 (d, 1H), .82 (d, 1H), 3.62-3.54 (m, 1H), 2.00-1.90 (m, 2H), 1.76—1.48 (m, 6H); :305(M+1).
Example 75 : 3-Cyclopentylidene—3-[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol—l—yl]- propanenitrile Step I . 3—Cyclopemylt'dene-3~[4—(7—[2~(trimetlzylsilyl)ethoxy]methyl— 7H-pyrralo[2, rimidin yl)—IH—pyrazol-I ~yl]propanenitrile To a suspension of 3-cyc1opentylprop—Z-ynenitrile (0.4 g, 0.003 mol) in ACN (10 mL) was added 4-(1H-pyrazol-4—yl)-7~[2-(trimethylsily1)ethoxy]methyl—7H—pyrrolo[2,3—d]pyrimidine (0.53 g, 1.7 mmol) and DBU (0.33 mL, 2.2 mmol). This e was stirred at room temperature for 50 minutes. The on mixture was partitioned between ethyl acetate and dilute HCl. The aqueous n was separated and extracted with ethyl acetate. The combined organic extracts were washed with dilute HCl and brine, were dried over sodium sulfate, filtered and concentrated in vacuo. The crude e was purified by flash column chromatography (ethyl e/hexanes) to yield the desired t (540 mg, 74%). 1H NMR (300 MHz, CDC13): 8_ 8.85 (s, 1H), 8.36 (s, 1H), 8.35 (5, 11-1), 7.40 (d, 1H), 6.78 (d, 1H), .67 (s, 2H), 3.70 (s, 2H), 3.54 (dd, 2H), 2.55 (t, 2H), 2.45 (t, 2h), 1.85 (dddd, 2H), 1.73 (dddd, 2H), 0.91 (dd, 2H), -0.06 (s, 9H); MS(ES):435(M+1).
Step 2. 3—Cyclopentylidene—3-[4—(7H~pyrrolo[2, 3-djpyrimz'din-4—yl)—1H—pyrazol—1-yl]propanenitrile A solution of 3-cyclopentylidene—3-[4-(7-[2~(tn'methy1silyl)ethoxy]methy1-7H-pyrrolo[2,3-d]- pyrimidin—4-yl)-lH-pyrazol—1-yl]propanem'trile (0.030 g, 0.069 mmol) in DCM (3 mL) and TFA (2 mL) was stirred for 1 hour. The solvents were evaporated in vacuo and the t was stirred with sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) and THF (1.5 mL) for 2 hours. The reaction e was neutralized by dropwise addition of concentrated HCl. The product was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and trated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H20 containing 0.15% NH4OH) to afford the desired t (7 mg, 33%). lH NMR (400 MHz, ds-dmso): E; 12.23-12.01 (br s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.46 (s, 1H), 7.60 (d, 1H), 7.04 (d, 1H), 3.95 (s, 2H), 2.53 (t, 2H), 2.42 (t, 2H), 1.76 (dddd, 2H), 1.65 (dddd, 2H); MS(ES):305(M+1).
Example 76: 3—Methyl[5-(7H-pyrrolo[2,3—d]pyrimidinyl)-l,3-thiazolyl]aminopropane— nitrile trifluoroacetate salt N——<\NfCN *TFA "l \ \ I\N/ a Step 1. 4- (I, 3—Thiazol—S-yD— 7-[2—(trimethylsilyDethoxyjmethy1~ 7H-pyrrolo[2, 3—djpyrimidine ro[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3—d]pyrimidine (3.00 g, 0.0106 mol), and 1,3-thiazole (7.50 mL, 0.106 mol) were dissolved in N,N-dimethylacetamide (40.0 mL).
The solution was distributed in equal portions into four 20 mL microwavable vessels. Into each reaction vessel was then added potassium acetate (0.777 g, 7.93 mmol) followed by tetrakis(triphenyl— phosphine)palladium(0) (0.60 g, 2.1 mmol). Each reaction vessel was heated at 200 °C in the microwave reactor for 30 minutes. The reactions were combined and most of the solvent was removed in vacuo. The residue was diluted with DCM, filtered and concentrated. Purification by flash column tography (ethyl acetate/hexanes) afforded the desired product (2.25 g, 64%). 1H NMR (300 MHz, CDCl;): 5 8.99 (s, 1H), 8.90 (s, 1H), 8.72 (s, 1H), 7.49 (d, 1H), 6.91 (d, 11—1), .70 (s, 2H), 3.56 (dd, 2H), 0.93 (dd, 2H), -0.05 (s, 9H); MS(ES):333(M+1).
Step 2. 4-(2-Bromo-I,3-thiazol-5—yl)- 7-[2—(trimethylsilyDethoxyjmethyl— rolo[2,3-d]pyrimidine 2.5 M n-Butyllithium in hexane (0.860 mL) was added dropwise to a —78 °C solution of 4- (1,3-thiazol—5-yl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (550 mg, 0.0016 mol) in THF (20 mL). The mixture was stirred for 30 minutes at -78 °C, ed by the slow addition of carbon tetrabromide (658 mg, 0.00198 mol) as a solution in TI-IF (10 mL). After 30 minutes, the mixture was quenched with a small amount of saturated ammonium chloride, diluted with ether, and dried over sodium e. The residue obtained after filtration and concentration was purified by flash column chromatography (ethyl acetate/hexanes) to afford the desired t (387 mg, 57%). r'H NMR (300 MHz, cock): 6 8.85 (s, 1H), 8.33 (s, 1H), 7.49 (d, 1H), 6.83 (d, 1H), 5.69 (s, 2H), 3.55 (dd, 2H), 0.92 (dd, 2H), —0.05 (s, 9H); MS(ES):411, 413(M+1).
Step 3. romo—1,3—thiazol—5-yl)— rolo[2, 3-d]pyrimidine A solution of 4-(2—bromo-1,3—thiazol-5—yl)—7—[2—(trimethylsily1)ethoxy]methyl—7H—pyrrolo~ ]pyrimidine (370 mg, 0.90 mmol) in DCM (5.0 mL) and TFA (1.0 mL) was stirred at room temperature for 7 hours. The mixture was then concentrated, re-dissolved in methanol (2 mL), and ethylenediamine (0.5 mL) was added. The mixture was stirred for 6 hours at room temperature. The mixture was diluted with DCM (10 mL), and the precipitate was isolated by filtration and washed with a small amount ofDCM to afford desired product (182 mg, 72%). lH NMR (300 MHz, dG—dmso): 5_ 8.74 (s, 1H), 8.70 (s, 1H), 7.76 (d, 1H), 7.15 (d, 1H); MS(ES):281,283(M+1).
Step 4. 3—Methyl[5—(7H—pyrrolo[2,3—d]pyrimidin—4-yl)-1,3-thiazol—Z-yljaminopropanenitrile A solution of 4-(2—bromo-1,3-thiazoly1)—7H—pyrrolo[2,3-d]pyrimidine (31 mg, 0.11 mmol) and 3-(methylamino)propionitrile (103 uL, 0.00110 mol) in DMF (1.0 mL, 0.013 mol) was stirred at 90 °C for 2 hours. The crude reaction mixture was purified by ative—HPLC/MS (C18 column eluting with a gradient of ACN/HzO ning 0.15% NH4OH) and again by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/HZO containing 0.1% TFA) to yield the desired product as the trifluoroacetate salt (30 mg, 68%). 1H NMR (300 MHz, dG—DMSO): :3 12.25 (s, 1H), 8.60 (s, 1H), 8.31 (s, 1H), 7.60 (dd, 1H), 7.00 (dd, 1H), 3.89 (t, 2H), 3.20 (s, 3H), 2.94 (t, 2H); MS(ES):285(M+1).
Example 77: (3S)- and (3R)[5-(7H-Pyrrolol2,3-d]pyrimidin—4-yl)—1,3-thiazol—2—yl]hexane- nitrile ON ON lll|/ . N- \ S \ S ~.\ \ Nb \ kN/ N I\N/ N H H Step I. N-Methoxy—N-methylbutanamide To a mixture of butanoic acid (1.01 g, 0.0115 mol) and N,O-dimethylhydroxylamine hydro— chloride (1.12 g, 0.0115 mol) in DCM (50 mL) was added benzotriazol-l -yloxytris(dimethylamino)- phosphom'um hexafluorophosphate (5.6 g, 0.013 mol) and TEA (3.2 mL, 0.023 mol). The mixture was stirred overnight at room temperature. The solution was then washed with water and brine, dried over sodium sulfate, and trated in vacuo. The crude t was purified by flash column chromatography (ether/hexanes). The solvent was removed (235 mbar/40 °C) to afford the product (1.33g, 88%). 1H NMR (300 MHz, CDCIa): 3. 3.68 (s, 3H), 3.18 (s, 3H), 2.40 (t, 2H), 1.74-1.59 (m, 2H), 0.96 (t, 3H).
Step 2. 1—[5-(7-[2—(Trimethylsilyl)ethoxyjmethyl- 7H—pyrrolo[2, 3~d]pyrimz'diny0-1 , 3—thiazolylj- butan-I-one 2.5 M n~Butyllithium in hexane (878 uL) was added slowly dropwise to a -78 °C solution of 4-(1,3-thiazol—S—y1)~7—[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidine (501 mg, 1.37 mmol) in THF (20 mL). Afier 45 minutes, N—methoxy-N-methy1butanamide (0.360 g, 2.74 mmol) was added. The on was continued at -78 0C for 30 min, and was then allowed to reach room temperature. The on was quenched with saturated um chloride, and was extracted with ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography (ethyl acetate/hexanes) afforded the product (235 mg, 42%). 1H NMR (300 MHz, CDC13): 5_ 8.93 (s, 1H), 8.76 (5, 11-1), 7.52 (d, 1H), 6.92 (d, 1H), 5.71 (s, 2H), 3.56 (dd, 2H), 3.19 (t, 2H), 1.92-1.77 (m, 2H), 1.05 (t, 3H), 0.93 (dd, 2H), —0.05 (s, 9H); MS(ES):403(M+1).
Step 3. (2E)- and -[5—(7—[2—(Trimethylsilyl)ethoygz]methyl—7H-pyrrolo[2,3~d]pyrimidin—4—yl)~ I, 3-thiazol-Z—yUhex—Z—enenitrile To a solution of 1.0 M potassium tert-butoxide in THF (0.605 mL) in THF (4.0 mL) 0° C was added diethyl cyanomethylphosphonate (0.102 mL, 0.634 mmol) dropwise. The cooling bath was removed and the reaction was warmed to room temperature. After 30 s, a solution of 1—[5- (trimethylsilyl)ethoxy]methyl—7H~pyrrolo[2,3~d]pyrimidin—4—yl)—l ,3—thiazol~2—yl]butan-l —one (232 mg, 0.576 mmol) in THF (3.0 mL) was added dropwise. The reaction was stirred for 2 hours, and the crude mixture was then adsorbed onto silica gel'and purified by flash column chromatography (ethyl acetate/hexanes) to afford the product as a mixture of olefin isomers (225 mg, 92%). 1H NMR (300 MHz, CD013), major isomer: _5 8.89 (s, 1H), 8.65 (s, 1H), 7.52 (d, 1H), 6.89 (d, 1H), 6.35 (s, 1H), 5.70 (s, 2H), 3.56 (dd, 2H), 2.96 (t, 2H), .72 (m, 2H), 1.08 (t, 3H), 0.93 (dd, 2H), - 0.07 (s, 9H); MS(ES):426(M+1).
Step 4. (3S)- and (3R)[5—(7—[2—(Trimethylsily0ethowjmethyl- rolo[2,3-d]pyrimidinyl)— I,3—thiazol—Z—yUhexanenitrile Cupric acetate, monohydrate (0.7 mg, 0.004 mmol) and (oxydi-Z,1-phenylene)bis(diphenyl- phosphine) (2 mg, 0.004 mol) was mixed in toluene (0.24 mL). PMHS (30 uL) was added. The mixture was d for 25 minutes at room temperature followed by the addition of (2E)[5-(7-[2- (trimethylsilyl)ethoxy]methy1—7H-pyrrolo[2,3~d]pyrimidinyl)—l ,3-thiazolyl]hex~2-enenitrile (51 mg, 0.12 mol) in toluene (0.24 mL) and finally, tert-butyl alcohol (0.043 mL). The resulting mixture was stirred overnight. The crude mixture was purified directly by flash column chromatography (ethyl acetate/hexanes) to afford the desired product (39 mg, 76%). 1H NMR (300 MHz, CDC13)3 8_ 8.87 (s, 1H), 8.52 (s, 1H), 7.48 (d, 1H), 6.87 (d, 1H), 5.69 (s, 2H), 3.60-3.46 (m, 3H), 2.99-2.82 (m, 2H), 2.05—1.89 (m, 2H), 1.50-1.34 (m, 2H), 0.97 (t, 3H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):428(M+1).
Step 5. (3.59— and (3R)~3—[5-(7H—Pyrrolo[2,3—d]pyrimidin~4—yl)-1,3~thiazol—2~yl]hexanenitrile TFA (1.0 mL) was added to a solution of 3~[5~(7-[2—(trimethylsilyl)ethoxy]methyl-7H- o[2,3-d]pyrimidinyl)-1,3-thiazo1yl]hexanenitrile (36 mg, 0.084 mmol) in DCM (4.0 mL) and the mixture was d at room temperature for 3 hours.
The mixture was concentrated, and re- ved in methanol (3 mL), to which ethylenediamine (0.1 mL) was added. After 2 hours reaction time, the mixture was concentrated and directly purified by preparative-HPLC/MS (C18 column eluting with a gradient ofACN/HZO containing 0.15% :!) to afford the desired product (10 mg, 40%). 1H NMR (300 MHz, CDCI3)Z 8_ 9.96 (br 5, 11-1), 8.87 (s, 1H), 8.54 (s, 1H), 7.51-7.45 (m, 1H), 6.90-6.86 (m, 1H), 3.59-3.44 (m, 1H), 3.01 -2.82 (m, 2H), 2.06-1.87 (m, 2H), 1.51~l.34 (m, 2H), 0.98 (t, 3H); MS(ES):298(M+1).
Example 78: (3R)- and (3S)Cyclopentyl-3~[5—(7H—pyrrolo[2,3—d]pyrimidin—4~yl)-l,3-thiazol—2— yllpropanenitrile CN CN 'lll/ N— N— \ S and \ S / / N N N N H H To a on of (2E)~ and (ZZ)cyclopentyl-3—[5-(7~[2—(trimethylsi1y1)ethoxy]methyl~7H— pyrrolo[2,3—d]pyrimidinyl)—1,3—thiazolyl]acrylonitfile (199 mg, 0.440 mmol) (prepared, for example, as in Example 77, steps 1 through 3) in a mixture of ethanol (10 mL) and ethyl acetate (10 mL) was added a catalytic amount of 10% palladium on carbon. The mixture was stirred at room temperature under one atmosphere of hydrogen overnight. It was then subjected to 50 PSI H2 until the reaction was complete. tion and l of solvent afforded an oil which was dissolved in DCM (4 mL) and TFA (1. mL). The solution was stirred until starting material was consumed and the mixture was then trated and re-dissolved in methanol (3 mL), to which ethylenediamine (0.4 mL) was added. The solution was stirred at room temperature for one hour, and was concentrated in vacuo. The crude mixture was purified by preparative—HPLC/MS (C18 column eluting with a gradient ofACN/HZO containing 0.15% NH40H) to afford the desired product (36 mg, 25%). 1H NMR (400 MHz, CD013): 6_ 10.44 (br s, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 7.50 (dd, 1H), 6.89 (dd, 1H), 3.34 (dt, 1H), 2.98 (dd, 1H), 2.89 (dd, 1H), 2.44-2.31 (m, 1H), 2.07~1.96 (m, 1H), 1.80-1.52 (m, 5H), .24 (m, 2H); :324(M+1).
The following compounds of Table So were prepared (as racemic mixtures) as described by e 77, 78 or 86, as indicated in the following table, by using different Weinreb amides (as prepared in Example 77, Step 1): R CN "U \ / N N Table 5c EX- MS (ES) Method of S—methyl~3-[5-(7H-pyrrolo[2,3-d]— pyrimidin—4-yl)-l ,3-thiazoly1] - 3 12 nitrile :71 3-pyridin—3—yl—3—[5—(7H-pyrrolo[2,3—d]— . \ pyrimidinyl)-1,3-thiazolyl]— I 333 Ex. 78 . . N propanemtnle "a / 3-(5 -bromopyridinyl)—3—[5-(7H— pyrrolo[2,3-d]pyrimidinyl)-1,3-thiazol- 411 413 Ex. 77 2—yl]propanenitrile Ex. 77 through Step 4, ~2-cyano~1-[5-(7H-pyrrolo[2,3-d]— then Ex. 431 pyrimidin-4~yl)—1,3—thiazol~2-yl]— 358 excluding ethylnicotinonitrile purification, then Ex. 77, Ste. 5 Ex. 86, Step 3 . . . jgnéitions ofb'ected to 3-[5-(7H-pyrrolo[2,3-d]pyr1m1d1n~4-yl)- iazol-2~y1]butanenitrile Ex 77 Steps 3-pyridin—4-yl—3-[5-(7H—pyrrolo[2,3- d]pyrimidinyI)-1 ,3-thiazol-2— 333 yljpropanenitrile Ex. 77 through Step 3, then BX. 431 ' excluding 4—2—cyano-1—[5-(7H—pyrrolo[2,3-d]- lgfinfilgatlgg, pyrimidin-4—yl)-1,3-thiazolyl]- , 358 enf Xd b ethylpyridine-2—carbonitri1e pun 16 y trifluoroacetate salt Wig/RdS using containing 0.1% TFA 3~pyridin—2-y1[5-(7H-pyrrolo[2,3-d]~ pyrimidinyl)—1,3-thiazolylj- 333 Ex. 78 propanenitrile Example 84: (ZS)- and -[5-(7H—Pyrrolo[2,3-d]pyrimidinyl)—l,3-thiazol-2—yllpentane— nitrile \S and \ S N N / N N H H Step 1. (2S)- and (2R)[5-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidinyl)— I,3-thiazol-Z-yUpentanenitrile To a mixture of 1—[5-(7—[2—(trimethylsilyl)ethoxy]methyl—7H~pyrrolo[2,3-d]pyrimidin—4—yl)— l,3-thiazol~2—yl]butan~1-one (prepared as in Example 77) (101 mg, 0.251 mmol) and p-tolylsulfonyl— methyl isocyanide (147 mg, 0.753 mmol) in a mixture of DMSO (5.0 mL) and ethanol (61 uL) was added 1.0 M potassium tert-butoxide in THF (753 ML). The mixture was then heated to 45 °C for 2 hours. Upon cooling to room temperature, the mixture was quenched by the addition of ted . ammonium chloride, followed by water. The product was extracted with ether, and the extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (ethyl acetate/hexanes) ed the t (39 mg, 25%). 1H NMR (400 MHz, CD013): 6 8.88 (s, 1H), 8.52 (s, 1H), 7.50 (d, 1H), 6.87 (d, 1H), 5.70 (s, 2H), 4.32 (dd, 1H), 3.55 (dd, 2H), 2.20—2.11 (m, 2H), 1.71-1.57 (m, 2H), 1.03 (t, 3H), 0.93 (dd, 2H); MS(ES):414(M+1).
Step 2. (2S)- and -[5-(7H—Pyrr010[2,3-djpyrimidinyD-1,3-ZhiazoIyljpentanenitrile A solution of 2-[5-(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d]pyrimidin-4—yl)~l,3- thiazolyl]pentanenitrile (59 mg, 0.093 mmol) in DCM (3 mL) and TFA (0.5 mL) was d at room temperature for 4 hours. The mixture was then concentrated, and the residue was then dissolved in methanol (3 mL) to which nediamine (0.3 mL) was then added. The solution was stirred at room temperature for 40 minutes. The solvent was removed in vacuo, and the crude mixture purified by preparative-HPLC/MS (C18 column g with a gradient of ACN/HZO containing 0.15% NI-LOI-I) to afford the desired product (20 mg, 76%). 1H NMR (400 MHz, CDC13)I 6, 9.66 (br s, 1H), 8.88 (s, 1H), 8.54 (s, 1H), 7.49 (dd, 1H), 6.88 (dd, 1H), 4.33 (dd, 1H), 2.23-2.12 (m, 2H), 1.75-1.60 (m, 2H), 1.04 (t, 3H); MS(ES):284(M+1).
Example 85: (4S)- and (4R)[5-(7H—Pyrrolo[2,3-d]pyrimidin—4-yl)-l,3-thiazol-2—yllheptane- nitrile CN CN I'll’ N— N.— \ S \ S N \ \ NI \ \ H H To a solution of triethyl phosphonoacetate (188 mg, 0.838 mmol) in THF (6.0 mL) at 0 °C was added 1.0 M potassium tert—butoxide in THE (840 uL). The mixture was then allowed to warm to room temperature followed by re-cooling to 0 °C, at which time 1-[5-(7-[2-(trimethylsilyl)ethoxy]— methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1,3-thiazolyl}butanone (prepared as in Example 77) (225 mg, 0.559 mmol) in THF (4.0 mL) was added. The mixture was stirred at room temperature for 1.5 hours, at which time it was quenched with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over sodium sulfate and trated in vacuo.
Flash column chromatography afforded the product as a mixture of olefin isomers (222 mg, 84%).
MS(ES):473(M+1).
Ethyl 3-[5—(7~[2-(trimethy1silyl)ethoxy]methyl~7H-pyrrolo[2,3-d]pyrimidin—4-yl)-l,3-thiazol- 2-yl]hex—2-enoate as a mixture of (2E)- and (2Z)- isomers (222 mg, 0.470 mmol) was dissolved in ethanol (10 mL), and a catalytic amount of 10% Pd-C was added. The mixture was stirred under an atmosphere of hydrogen, provided by a balloon, for 16 hours. Filtration and concentration in vacuo ed the desired product (201 mg, 90%). MS(ES):475(M+1).
To a solution of ethyl 3—[5—(7—[2—(trimethylsilyI)ethoxy]methyl—7H—pyrrolof2,3—d]pyrimidin— 4—y1)—1,3—thiazol;2—yl]hexanoate (201 mg, 0.423 mmol) in THF (5.0 mL) at —78 °C was added 1.00 M diisobutylaluminum hydride in DCM (1.06 mL). The mixture was allowed to warm to -10 °C slowly over 1.5 hours, followed by the addition of potassium sodium tartrate tetrahydrate, water, and ether.
The e was stirred for 1 hour, then layers were separated, and the aqueous layer was extracted fiirther with ethyl acetate. The c extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to afford desired product (176 mg, 96%). MS(ES):433(M+1).
A solution of 7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3-d]pyrimidinyl)-1,3- thiazol-Z—yl]hexan—1—ol (88 mg, 0.20 mmol) in TFA (2 mL) was d for 30 minutes. The TFA was then ated and the residue was stirred in methanol (2 mL) containing ethylenediamine (0.2 and a drop of water for 30 minutes. Purification via preparative—HPLC/MS (C18 eluting with a gradient of ACN/HZO ning 0.15% NH40H) afforded the desired t (36 mg, 58%).
MS(ES):303(M+1).
To a mixture of 3-[5-(7H-pyrrolo[2,3~d]pyrimidin-4—yl)~1,3-thiazolyl]hexan-l~01 (36 0.12 mmol) and TEA (19.9 uL, 0.143 mmol) in DCM (5 mL) at 0 °C was added esulfonyl chloride (11.0 uL, 0.143 mmol). After stirring for 10 minutes, the solution was concentrated and WO 70514 dissolved in DMSO (1.6 mL) and sodium cyanide (23 mg, 0.48 mmol) was added. The mixture was then heated at 125 °C in the microwave for 30 minutes. The mixture was then purified directly using preparative—HPLC/MS (C18 eluting with a gradient ofACN/H20 containing 0.15% NH40H) to afford the desired product (10 mg, 27%). 1H NMR (400 MHz, CDClg): 5, 9.37 (br s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 7.46 (dd, 1H), 6.88 (dd, 1H), 3.34—3.25 (m, 1H), 2.47~2.30 (m, 2H), 2.22-2.12 (m, 2H), 1.95-1.71 (m, 2H), 1.44-1.31 (m, 2H), 0.94 (t, 3H); MS(ES):312(M+1).
Example 86: 3~[5-(7H—Pyrrolo[2,3-d]pyrimidin—4—yD-1,3-thiazol—2—yl]pentanedinitrile "l \ \ ti Step 1. N-Methoxy‘2«[(4-methoxybenzyl)oxyj-N—methylacetamide To a e of [(4-methoxybenzyl)oxy]acetic acid gam'c and Medicinal Chemistry Letters, 2001, pp. 2837—2841) (6.86 g, 0.0350 mol) and N,O-dimethylhydroxylamine hydrochloride (3.41 g, 0.0350 mol) in DCM (100 mL) was added benzotriazol~1—yloxytris(dimethylamino)— phosphonium hexafluorophosphate (17 g, 0.038 mol) followed by TEA (9.7 mL, 0.070 mol). The resulting mixture was stirred overnight at room temperature. The solution was then washed with water, 0.5 M HCl, saturated NaHCO3, and brine, then was dried over sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (ether/hexanes) afforded the desired product (5.75 g, 69%).
Step 2. 2—[(4—Met/toxybenzyl)oxy]—1—[5—(7—[2—(trimethylsib20ethoxyjmethyl- 7H—pyrrolo[2,3—d]- pyrimidinyU-1,3~thiazol—2-yl]ethanone To a on of 4-(1,3-thiazol-5~yl)-7—[2-(trimethylsilyl)ethoxy]methyl~7H-pyrrolo[2,3-d]— pyrimidine (2.12 g, 6.38 mmol) in THF (70 mL) at ~78 °C was added 2.5 M llithium in hexane (3.06 mL) slowly dropwise. After stirring for 30 s, N-methoxy[(4-methoxybenzyl)oxy]-N— methylacetamide (2.29 g, 9.56 mmol) was added. The on was continued for 30 minutes following the on, at -78 °C, then the cooling bath was removed and the reaction was quenched with saturated ammonium chloride and extracted with ether. The ts were dried with sodium sulfate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (ethyl acetate/hexanes) to afford desired product (2.16 g, 66%).
'H NMR (300 MHz, : a 8.93 (s, 1H), 8.72 (s, 1H), 7.53 (d, 1H), 7.37 (d, 2H), 6.91 (d, 2H), 6.89 (d, 1H), 5.70 (s, 2H), 5.00 (s, 2H), 4.70 (s, 2H), 3.81 (s, 3H), 3.56 (dd, 2h), 0.93 (dd, 2H), .0.05 (s, 9H); MS(ES):511(M+1).
Step 3. (2E)- and (2Z)[(4-Meth0xybenzy00xy]-3—[5-(7-[2-(trz'methylsily1)ethoxflmethyl-7H- pyrrolo[2, 3-d]pyrimidinyl)-1, 3-thiazol—2—yljbut-Z-enenitrile To a solution of 1 M potassium tert-butoxide in THF (4.44 mL) in TI—[F (30 mL) at 0° C was added diethyl cyanomethylphosphonate (820 mg, 0.0046 mol) dropwise. The bath was d and the reaction was warmed to room temperature. After 30 minutes, a solution of 2-[(4-methoxybenzyl)- oxy] —l -[5-(7—[2~(trimethylsilyl)ethonymethyl—7H—pyrrolo[2,3-d]pyrimidin—4—yl)—1 ,3-thiazol-2~y1] - ethanone (2.16 g, 0.00423 mol) in THF (20 mL) was added dropwise. The reaction was stirred for 1 hour, and was then quenched with a small amount of saturated ammonium chloride, d with ether, dried over sodium e and concentrated in vacuo. Purification by flash column chromatography, eluting with a gradient of 0—35% ethyl acetate/hexanes afforded the desired product as a e ofolefin isomers in nearly equal amounts (1.76 g, 78%). 1H NMR (400 MHz, CDC13): 8 8.90 (s, 1H), 8.88 (s, 1H), 8.71 (s, 1H), 8.67 (s, 1H), 7.50 (d, 2H), 7.35 (dd, 2H), 7.31 (dd, 2H), 6.92 (dd, 2H), 6.90 (dd, 2H), 6.86 (d, 2H), 6.62 (s, 1H), 6.10 (t, 1H), 5.70 (5, 41:1), 4.75 (s, 2H), 4.72 (d, 2H), 4.64 (s, 4H), 3.82 (s, 3H), 3.81 (s, 3H), 3.56 (dd, 2H), 3.55 (dd, 2H), 0.96—0.90 (m, 4H), -0.05 (s, 9H), -0.054 (s, 9H); MS(ES):534(M+1).
Step 4. Meth03qybenzyl)oxy][5—(7—[2—(trimethylsibzl)ethoag/jmethyl- 7H-pyrrolo[2,3-d]— pyrt'mz'din-4—yD-J, 3-thiazolyl]butanenitrile (2E)- and (2Z)-4—[(4—Methoxybenzyl)oxy]-3—[5—(7~[2—(trimethylsilyl)ethoxy]methyl-7H— pyrrolo[2,3—d]pyrimidin—4-yl)-l,3-thiazol-2—yl]but—2~enenitrile (880 mg, 1.6 mmol) was dissolved in a mixture of ethanol (20 mL) and ethyl acetate (20 mL). A catalytic amount of 10% Pd-C was added.
The e was shaken under 50 PSI of hydrogen. The mixture was filtered and concentrated in vacuo to afford the desired product (0.85 g, 99%). MS(ES):536(M+1).
Step 5. 3-[5-(7H~Pyrrolo[2, 3-d]pyrimidin-4—yl)—1, 3-thz'azol—2—yUpentanedim'trile 4—[(4—Methoxybenzyl)oxy][5-(7-[2-(trimethylsilyl)ethonymethy1—7H—pyrrolo[2,3—d]- pyrimidin—4—yl)-1,3~thiazoly1]butanenit1ile (251 mg, 0.468 mmol) in DCM (10 mL) was treated with dichlorodicyanoquinone (DDQ) (434 mg, 1.87 mmol), followed by water (376 uL). After 1.5 hours, saturated sodium bicarbonate and water were added, and the reaction was extracted with ethyl acetate three times. The extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product which was used without fiirther purification.
A solution of the above prepared 4-hydroxy—3—[5-(7-[2-(trimethylsily1)ethoxy]methyl-7H— pyrrolo[2,3-d]pyrimidin—4-yl)—1,3~thiazol—2—yl]hutanenitrile in DCM (12 mL) at 0 °C was treated sequentially with TEA (130 uL, 0.94 mmol) and esulfonyl chloride (73 pL, 0.94 mmol). Afier 1 hour reaction time, the mixture was diluted with water and extracted with ethyl e three times.
The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then dissolved in DMSO (5 mL) and sodium cyanide (110 mg, 2.3 mmol) was added. After 30 minutes, the mixture was diluted with water, ted with ether, washed with water, brine and dried over sodium e. Concentration and purification by flash column chromatography (ethyl acetate/hexanes) afforded the desired product (14 mg, 7%). MS(ES):425(M+1).
A solution of 3-[5—(7-[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-l,3- thiazol-Z-yl]pentanedinitn'le (14 mg, 0.033 mmol) in DCM (3 mL) containing TFA (0.6 mL) was stirred for 4 hours. The mixture was then concentrated and the residue was redissolved in methanol (2 mL) to which ethylenediamine (0.4 mL) was then added. After 1 hour reaction time, the product was purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H20 containing 0.15% NH40H) to afford the desired product (6 mg, 62%). 1H NMR (400 MHz, dG-dmso): 8, 12.27 (br s, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 7.75 (d, 1H), 7.14 (d, 1H), 4.14 (m, 1H), 3.17 (d, 4H); MS(ES):295(M+1). e 87: (3R)-3—Cyclopentyl[5-(7H—pyrrolo[2,3—d]pyrimidin-4—yl)—1,3-oxazol—2—yll— propanenitrile, (3S)—3—Cyclopentyl[5-(7H-pyrrolo [2,3-d]pyrimidin-4—yl)—1,3-oxazol—2-yllpropanenitrile ON ON 'IUI/ N— N— \ O and \ O "i\ \ \ / hi\/ N N N N H H Step 1. 4—(1,3-0xazolyl)—7—[2—(trimethylsibilkthoxyjmethyl-7H-pyrrolo[2,3-d]pyrimidine A mixture of 4—chloro[2—(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3—d]pyrimidine (0.440 g, 1.55 mmol), 1,3-oxazole (0.306 mL, 4.65 mmol), potassium acetate (0.456 g, 4.65 mmol) and tetrakis(ttiphenylphosphine)palladium(0) (0.179 g, 0.155 mmol) in N,N—dimcthylacetamide (8.0 mL) was heated to 200 °C in the microwave reactor for 30 minutes. Most of the solvent was removed in v_acuo. The resulting residue was diluted with DCM, and was d and trated. Flash column chromatography (ethyl e/hexanes) afforded the product (330 mg, 67%). lH NMR (400 MHz, : 8 8.96 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.54 (d, 1H), 7.08 (d, 1H), .76 (s, 2H), 3.60 (t, 2H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):3l7(I\/I+1).
Step 2. entyl[5—(7—[2—(trimethylsibzuethoxyjmethyl— 7H—pyrrolo[2, 3-d]pyrimidin-4—yl)~1 , 3— oxazol—Z-yljmethanone n-Butyllithium in hexane (1.6 M, 0.30 mL) was added slowly dropwise to a —78 °C solution of 4-(1,3-oxazolyl)[2—(trimethylsilyl)ethoxy]methyl-7H-pyrroloi2,3—d]pyrimidine (140.0 mg, 0.44 mmol) in THF (10.0 mL). After 20 minutes, 1.0 M zinc dichloride in ether (0.53 mL) was added. The reaction mixture was then stirred for 60 min at 0 °C. Following this, fl) iodide (84 mg, 0.44 mmol) was added, and this mixture was allowed to stir for 10 minutes. Cyclopentanecarbonyl chloride (108 uL, 0.885 mmol) was then added. The reaction was stirred at 0 °C for a further 1 hour, at which time it was allowed to warm to room ature. The reaction was quenched by the addition of saturated NH4C1 solution, and was extracted with ethyl acetate. The extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash column tography (ethyl acetate/hexanes) afforded the product (97 mg, 53%). 1H NMR (400 MHz, CDC13): 5 8.96 (s, 1H), 8.21 (s, 1H), 7.56 (d, 1H), 7.22 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 3.56 (t, 1H), 2.23-1.56 (m, 8H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):413(M+1).
Step 3. (3R)- and (3S)Cyclopenbzl[5-(7—[2-(trimethylsilyDeth0xy]methyl—7H—pyrrolo[2,3- d]pyrimz'dz‘n-4~yl)-1 , 3—0xazol-2—yljpropanenitrile To a solution of 1.0 M potassium tert—butoxide in THF (0.355 mL) and THF (3 mL) at 0° C was added diethyl cyanomethylphosphonate (66 mg, 0.37 mmol) dropwise. The cold bath was removed and the reaction was warmed to room temperature. After 30 minutes, a on of cyclopentyl[5-(7—[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidin—4-yl)-l ,3-oxazol y1]methanone (1.40E2 mg, 0.338 mmol) in THF (2.0 mL) was added dropwise. After 3 hours reaction time, the mixture was adsorbed onto silica gel, and flash column chromatography (ethyl acetate/hexanes) ed the desired product as a mixture of olefin isomers (89 mg, 60%).
MS(ES):436(M+1).
To a mixture of cupric acetate, monohydrate (4.0 mg, 0.020 mmol) and (oxydi—2,1— phenylene)bis(diphenylphosphine) (11 mg, 0.020 mmol) in toluene (0.40 mL, 0.0038 mol) was added PMHS (50 uL). The resulting mixture was stirred for 25 minutes at room temperature, followed by the addition of (2E)- and -cyclopentyl[5-(7-[2—(trimethylsilyl)ethoxy]methyl~7H—pyrrolo— [2,3-d]pyrimidin—4—yl)—l,3-oxazolyl]acrylonitrile (88 mg, 0.20 mmol) in toluene (0.40 mL), and then tert-butyl alcohol (0.072 mL). After failure to react at room temperature over 16 hours, additional cupric acetate, drate and (oxydi-2,1—phenylene)bis(diphenylphosphine) (0.10 mol equivalent each) Were added and the reaction mixture was heated at 60 °C for 16 hours. The crude mixture was ted to flash column chromatography (ethyl acetate/hexanes) to afford the desired product (21 mg, 23%).
’H NMR (400 MHz, CDCl3): 6 8.96 (s, 1H), 8.02 (s, 1H), 7.56 (d, 1H), 7.10 (d, 1H), 5.76 (s, 2H), 3.60 (t, 2H), 3.38-3.30 (m, 1H), 3.03 (dd, 1H), 2.95 (dd, 1H), 2.60—2.40 (m, 1H), 2.10-2.00 (m, 1H), 1.85-1.15 (m, 7H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):438(M+1).
Step 4. (3R)— and -Cyclopentyl—3-[5~(7H—pyrrolo[2,3-d]pyrimidin—4—yl)—1,3-oxazol~2-yl]- enitrile A solution of 3-cyclopentyl—3-[5-(7-[2~(trimethylsilyl)ethoxy]methyl~7H-pyrrolo[2,3-d]- pyrimidin—4-yl)-1,3-oxazolyl]propanenitn'le (20.0 mg, 0.0457 mmol) was stirred with TFA (0.1 mL) in DCM (0.2 mL) for 6 hours. The solvent was removed, and the resulting residue was stirred overnight with ethylenediamine (0.1 mL) in methanol (0.2 mL). The solvent was removed in vacuo.
The desired product was obtained via ative-HPLC/MS (C18 column eluting with a gradient of ACN/H20 containing 0.15% NH40H) (5.3 mg, 38%). 1H NMR (400 MHz, CDC]3)Z 5 10.25 (br s, 1H), 8.90 (s, 1H), 8.00 (s, 1H), 7.50 (d, 1H), 7.06 (d, 1H), 3.36-3.28 (m, 1H), 2.98 (dd, 1H), 2.90 (dd, 1H), 2.51—2.38 (m, 1H), 2.08~l.96 (m, 1H), .51 (m, 5H), 1.44—1.30 (m, 2H); MS(ES):308(M+1).
The following nd of Table 5d was also prepared as a racemic mixture, according to the procedure of the above Example 87.
Table 5d 3—[5—(7H—pyrrolo[2,3-d]— pyrimidin-4—yl)-l ,3-oxazoly1] - hexanenitrile Example 90: 5—(1VIethylthio)-3—[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol—l-yl]pentane- nitrile N. \ I\N" N Step 1. (2E)—5—(Methylthio)pent-2—enenitrile To a 0 °C mixture of [chloro(triphenyl)phosphoranyl]ACN (2.5 g, 0.0073 mol) in THF (10 mL, 0.1 mol) was added TEA (2.0 mL, 0.014 mol), and the resulting mixture was stirred for 30 min.
The ice bath was removed for 30 min, then the mixture was re~cooled back to 0 °C, A solution of 3— (methylthio)~pr0panol (0.68 mL, 0.0072 mol) in THF (1 mL, 0.02 mol) was added and the mixture was stirred overnight. Water was added and the mixture was filtered. The filtrate was washed with water x3 and brine. The organic phase was dried and the t was removed by rotary evaporation to give 2.1 g of an off-white solid. The solid was triturated with MTBE and was filtered. The filtrate was washed with 1N HCI, water, sat. NaHCO3 and brine. The c phase was dried and was concentrated using a rotary evaporator to give 0.62 g orange oil (44% yield, trans : cis ~ 2 : 1). 1H NMR for trans (400 MHZ, CDC13): 5 6.68 (1H, m); 5.14 (1H, d); 2.6 (2H, m); 2.55 (2H, t); 2.1 (3H, 3).
Step 2. 5—(Methylthi0)—3—[4-(7-[2-(trimethylsilyDet/zoxy]methyl— 7H-pyrrolo[2,3—d]pyrimidin-4—yl)-1H— pyrazol-1«yl]pentanenitrile A mixture of 4—(1H—pyrazo]y1)[2~(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]— pyrimidine (0.30 g, 0.00095 mol), (2E)(rnethylthio)pent-2enenitrile (0.28 g, 0.0016 mol) and DBU (45 uL, 0.00030 mol) in ACN (3 mL, 0.06 mol) was stirred at rt for 5 days. The solvent was removed by rotary evaporation to give an orange oil. The crude oil was tographed with 30-70 ethyl acetate/her to give 0.35 g of a colorless oil (83% yield).
’H NMR (400 MHz, CD013): 5 8.95 (1H, s); 8.41 (1H, s); 8.4 (1H, s); 7.48 (1H, d); 6.84 (1H, d); 5.75 (2H, s); 4.95 (1H, br); 3.6 (2H, t); 3.1 (2H, m); 2.58 (2H, m); 2.28 (2H, m); 2.1 (3H, s); 1.99 (2H, t); 0.0 (9H, 5). MS ("M-PH): 443.
Step 3. hylthio)~3—[4—(7H-pyrrolo[2,3—d]pyrimidin-4—yl)—1H-pyrazol-I—yUpentanenitrile A solution of 5-(methylthio)—3-[4—(7—[2—(trimethylsily1)ethoxy]methyl~7H~pyrrolo[2,3—d]— pyrimidinyl)—1H-pyrazol-l -yl]pentanenitrile (0.35 g, 0.00079 mol) in THF (4 mL, 0.05 mol) and 3.0 M HCI (HCl) in water (4 mL) was heated to reflux ght. The solvent was removed by rotary evaporation to give a pale orange oil. The oil was d in ethanol (3 mL, 0.05 mol) and 8.0 M ammonium hydroxide in water (1 mL) overnight. The reaction was concentrated and purified by prep LCMS (C18 column eluting with a gradient of ACN/HZO containing 0.15% NI-LOH) to give 125 mg of a white foam. The white foam was triturated with MTBE (~ 1.5 mL). The ing solid was filtered, washed and dried to give 80 mg of the t (32% yield). 1H NMR (400 MHz, : 5 10.38 (1H, s); 8.88 (1H, s); 8.39 (1H, s); 8.38 (1H, s); 7.44 (1H, d); 6.8 (1H, d); 5.75 (2H, s); 4.9 (1H, br); 3.05 (2H, m); 2.5 (2H, m); 2.23 (2H, d); 2.1 (3H, 5). MS ('M-t-H): 313.
Example 91: 5—(Methylsulfinyl)[4-(7H—pyrrolo[2,3-d]pyrimidin-4—yl)—1H—pyrazal—l-yl]- pentanenitrile NU \ / N N A solution of 5—(methylthio)-3—[4—(7H—pyrrolo[2,3—d]pyrimidin—4-yl)-1H—pyrazol-l~yl]— pentanenitrile (0.065 g, 0.00021 mol) and hydrogen peroxide (0.022 mL, 0.00023 mol) in ACN (1 mL, 0.02 mol) was stirred overnight. The reaction was concentrated and purified by HPLC to give 21 mg of a solid. The solid was triturated with MTBE (l mL)/DCM (10 drops). The solid was filtered and washed to give 13 mg of a white solid (20% yield) which was dried rt to 50 °C for 2 h.
IH NMR (400 MHz, CDC13)I 5 9.95 (1H, s); 8.85 (1H, s); 8.4 (2H, m); 7.4 (1H, d); 6.8 (1H, s); 4.9 (1 H, br); 3.15 (2H, m); 3.0 (2H, m); 2.8-2.5 (2H, m); -1, 5). MS (M+H): 329.
Example 92: 5-(Methylsulfonyl)[4-(7H-pyrrolo[2,3-d]pyrimidin—4—yl)-IH-pyrazol-l-yl]- pentanenitrile A solution of hy1thio)[4-(7H-pyrrolo[2,3~d]pyrimidin—4-yl)—1H—pyrazol-l~yl]- pentanenitn'le (0.040 g, 0.00013 mol) and hydrogen peroxide (0.5 mL, 0.005 mol) in ACN (1 mL, 0.02 mol) was refluxed overnight. The reaction was purified by HPLC to give 16 mg of a white glass/solid which was tn'turated With EtOH (~0.8 mL) to give 13 mg of a white solid (30% .
'H NMR (400 MHz, CDCl;): 8 8.75 (1H, s); 8.48 (1H, d); 8.4 (1H, d); 7.43 (1H, d); 6.8 (1H, s); 5.0 (1H, br); 3.4 (2H, In); 323.0 (2H, m); 2.8—2.5 (2H, m); 2.95 (3H, s). MS (M+H): 345. e 93: 4,4,4—Trifluoro[4-(7H-pyrrolo[2,3-d]pyrimidinyl)—pyrazol-l-yII-butyronitrile F3C’ Step 2. 4, 4, 4-Trifluoro[4—(7H—pyrrolo[2, 3-d]pyrimidinyl)-pyrazol—1~yl]—butyronitrile A solution of 4,4,4-trifluoro—3—[4—(7—[2—(trimethylsilyl)ethoxy]methy1—7H—pyrrolo[2,3-d]— pyrimidinyl)-lH-pyrazol-l-yl]butanenitrile (3.1 g, 0.007] mol) from Step 1 in THF (35 mL, 0.43 mol) and 3.0 M HCl in water (35 mL) was heated to reflux overnight. The solvent was removed by rotary evaporation to give a greenish orange oil/glass. The oil was stirred with ethyl acetate and sat.
NaHC03 (50 mL). The aqueous phase was extracted with ethyl acetate. The organic layers were washed with brine and reduced by rotary evaporation to give an oil/glass residue. The residue was stirred in ethanol (20 mL, 0.3 mol) and 8.0 M ammonium hydroxide in water (10 mL) over a weekend. The t was removed by rotary ation to give a pale orange foam/solid. The crude was chromatographed with 0-7% MeOH/DCM, 0‘:O.7% NH4OH to give 3 g of a pale orange paste/solid. The solid was recrystallized from EtOH to give 1.6 g of an ite crystals (74% yield).
‘H NMR (400 MHz, DMSO): 8 12.2 (1H, s); 8.95 (1H, s); 8.7 (1H, s); 8.5 (1H, s); 7.63 (1H, d); 6.96 (1H, d); 6.01 (1H, m); 3.7 (2H, m). MS (M+I—I): 306.
The following compounds of Table 5e were prepared as indicated in the column labeled "Prep. Ex. No." Table 5e ,5-Dimethyl[4-(7H- pyrrolo[2,3-d]pyrimidin-4—yl)- 61 l-l -yl]-hexanenitrile modification G 4—[1 —(2—Methanesu1fonyI—ethyl)- 1H—pyrazo(13:31:11]igniyrro O[2’31 6] - - - l - modification G ,5,5-Trifluoro—4-[4-(7H— pyrrolo[2,3-d]pyrimidin—4~yl)— 59 . . pyrazol-l -y]]-pentanenitrile modlficatron G Example 97: yano[4-(7H-pyrrolo[2,3-d}pyrimidinyl)-lH-pyrazolyl]ethyl)-cyclo-n" p'entane-carbonitrile trifluoroacetate / TFA "IO \ N/ 0 Step 1.‘ 3—(DimethoszmethyDcyclopentanecarbaldehyde.
Into a 3—neck round bottom flask ornene (5.500 g, 0.05841 mol) was dissolved in DCM (198.0 mL,) and methanol (38.5 mL) and was cooled at -78 °C. Ozone was passed through the reaction until it turned blue and was stirred at —78 °C for 30 minutes. Then nitrogen was passed through for 20 minutes and p-toluenesulfonic acid (0.95 g, 0.0055 mol) was added The reaction was d to warm at 20 °C and was stirred for 90 minutes. Into the reaction was added sodium bicarbonate (1.67 g, 0.0199 mol) and the resulting mixture was stirred at 20 °C for 30 s and dimethyl sulfide (9.4 mL, 0.13 mol) was added. The reaction was stirred for 16 hoursand was reduced by rotary evaporation to ~50 mL The reaction was extracted with DCM and the c extracts were washed with water and brine, dried (MgSO4), and stripped in vacuo. The on was led at 135 °C (bath temperature) at high pump vacuum to give the product (7:5! g) as‘a ~2:1 mixture of diastereomers. 'H NMR (300 MHz, CDC13): 9.64 & 9.62 (d, 1H), 4.15 ~& 412 (s, 1H), 3.35 & 3.34 (s, 6H), 2.77 m, 1H), 2.34 (m, 1H), 1.35-2.00 (m, 6H).
Step 2. (2E, Z)—3—[3-(Dimethoxymethyl)cyclopentyl]acrylonz'trile.
Into a flask ning a 0 °C solution of t-BuOK in THF (1.0 M, 6,10 mL) was added a solution of diethyl cyanomethylphosphonate (1.1 g, 6.4 mmol) in THF (8 mL). The cooling bath was removed and the reaction was warmed to ambient temperature, then a solution of 3-(dimethoxy- methyl)cyclopentanecarbaldehyde (1.00 g, 5.81 mmol) in THF (2 mL) was added dropwise. Shortly after completion of the addition orange gel-like particulates began to form, afier approximately 1 hour the reaction was gelatinous. The reaction was held with stirring at ambient temperature for 16 hours at which time tlc indicated complete reaction. The on was partitioned between water and EtOAc and the aqueous phase was washed with additional EtOAc.
The combined organic phase was washed with water, then sat'd NaCl, and then was dried over MgSO4 and reduced in vacuo, and the resulting residue was purified by column chromatography with 6:1 hexaneszEtOAc + 1% TBA to obtain the product as a 1:1 e of E/Z isomers (760 mg, 61%). 1H NMR (400 MHz, CDC13): 8 vinylic protons at 6.69 (m, 0.5H), 6.37 (m, 0.5H), 5.32 (m, 0.5H), 5.23 (m, 0.5H), acetal methine proton at 4.14 (m, 1H), methyl protons at 3.34 (s, 6H).
Step 3. 3—[3-(Dimethoxymethyl)cyclopentyU-3—[4—(7—[2-(trimethylsinDelhoxyjmethyl- 7H- pyrrolo[2,3—d]pyrimidin—4—yD-1H-pyrazol—I~yl]pr0panenitrile.
To a solution of 4—(1H—pyrazol~4-y1)[2-(trimethylsilyl)ethoxy]methyI—7H-pyrrolo[2,3- d]pyrimidine (230 mg, 0.74 mmol) in ACN (5 mL) was added (2E,Z)-3—[3-(dimethoxymethyl)cyclo- pentyl]acrylonitrile (289 mg, 1.48 mmol), followed by DBU (300 uL, 2.0 mmol). The e was d at ambient temperature for 16 hours, at which point LCMS and TLC indicated complete reaction. The reaction was reduced to dryness in vacuo, and the residue was purified by column chromatography to obtain the product as a mixture of reomers (293 mg, 77%). 1H NMR (400 MHz, CDC13): 8 8.85 (s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.28 (m, 1H), 4.11 (m, 1H), 3.54 (t, 2H), 3.36 (s, 1.5H), 3.34 (s, 1.5H), 3.30 (s, 1.5H), 3.26 (s, 1.5H), 3.12 (m, 1H), 2.94 (m, 1H), 2.65 (m, 1H), 2.34 (m, 1H), 0 (m, 6H), 0.92 (t, 2H), -0.56 (s, 9H). MS (EI) m/z = 511.3 (M+H).
Step 4. 3—(3-Formylcyclopentyl)—3—[4-(7-[2-(trimethylsilyljethoxyjmethyl- 7H-pyrrolo[2,3—d]- dinyI)-1H—pyrazol—1-yl]pr0panenitrile.
To a solution of 3-[3-(dimethoxymethyl)cyclopentyl]~3-[4-(7-[2-(trimethylsilyl)ethoxy]- methyl-7H-pyrrolo[2,3—d]pyrimidin_—4—yl)-1H-pyrazol—l—yl]propanenitrile (293 mg, 0.574 mmol) in THF (4.5 mL) was added aqueous HCl (1.0 M, 1.5 mL). The reaction was held at ambient temperature for 2.5 hours at which point TLC and LCMS indicated complete deprotection to the corresponding aldehyde. The on was partitioned between water and EtOAc and the aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with water, then sat'd NaHCO3, then sat'd NaCl, and then was dried over MgSO4 and filtered and stripped to dryness to leave the crude product as a mixture of diastereomers. 1H NMR (400 MHz, CDC13)Z 8 9.69 (d, 0.5H), 9.64 (d, 0.5H), 8.85 (s, 0.5H), 8.84 (s, 0.5H), 8.35 (s, 0.5H), 8.34 (s, 0.5H), 8.32 (s, 0.5H), 8.30 (s, 0.5H), 7.41 (d, 0.5H), 7.40 (d, 0.5H), 6.80 (d, 0.5H), 6.79 (d, 0.5H), 5.68 (s, 1H), 5.67 (s, 1H), 4.32 (m, 1H), 3.54 (m, 2H), 3.14 (m, 1H),‘2.96 (m, 2H), 2.76 (m, 1H), 2.1-1.1 (m, 6H), 0.92 (m, 2H), ~0.058 (s, 9H). MS (EI) m/z= 465.1 (M+H).
Step 5. 3—3-[(E,Z)-(Hydroxyimino)methyl]cyclopentyl—3-[4-(7—[2-(trimethylsilyl)ethoxyjmethyl— 7H— 0[2,3—d]pyrimidin—4-yD—1H—pyrazol—1—yl]propanenitrile.
To a solution of 3—(3-formylcyclopenty1)-3—[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H- pyrrolo[2,3-d]pyrimidin-4—yl)-1H—pyrazol-l-yl]propanenitrile (336 mg, 0.000723 mol) in CI-I3OH (5.0 mL, 0.12 mol) was added hydroxylamine hydrochloride (60 mg, 0.00087 mol) and KHCO3 (110 mg, 0.0011 mol) and the reaction was held at ambient temperature for 16 hours, at which point LCMS indicated complete reaction. The reaction was reduced to dryness in vacuo and the residue was partitioned between water and EtOAc, and the aqueous phase was extracted with additional EtOAc.
The combined organic phase was washed with water, then sat'd NaCl, then was dried over MgSO4 and concentrated to leave the crude product, which was cam'ed forward to the subsequent on t purification. NMR indicated disappearance ofaldehydic protonS. MS (EI) m/z = 480.2 (M+H).
Step 6. 3-(2—Cyan0—1 —[4~(7—[2-(trimethylsilyl)ethoxyjmethyl— 7H—pyrrolo[2, 3—d]pyrimidin-4—yD—1H- pyrazol-I—yljethyocyclopentanecarbonitrile.
To a solution of 3[(E,Z)-(hydroxyimino)methyl]cyclopentyl—3-[4-(7-[2—(trimethylsiIyl)- ethoxy]-methy1-7H—pyrrolo[2,3—d]pyrimidin—4—yl)-lH-pyrazol-l -y1]propanenitri1e (324 mg, 0.67 mmol) in pyridine (1.2 mL), was added methanesulfonyl chloride (210 pL, 2.7 mmol) dropwise. The reaction was heated to 60 °C for 2.5 hours, at which point LCMS indicated complete reaction. The reaction was partitioned between water and EtOAc, and the aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with water, then 0.1N HCl, then sat‘d NaCl, and then was dried over MgSO4. The crude product was purified by column chromatography to obtain the product as a mixture of diastereomers (164 mg, 52%). The diastereomers were then separated by chiral HPLC to provide four distinct diastercomers, which were taken directly on to the deprotection step. MS (EI) m/z = 462.1 (M+H).
Step 7. 3-(2—Cyan0-I—[4—(7H-pyrrolo[2,3-djpyrimidinyl)-IH-pyrazol-1~yl]ethyl)-cyc10pentane- itrile trzfluoroacetate.
The four diastereomers were then separately deprotected in this representative manner. To 3— 2—cyano-1 -[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4—y1)—lH-pyrazol-l - yl]ethylcyclopentanecarbonitn'le (35 mg, 0.076 mmol) dissolved in CHZCIZ (2.0 mL) was added TFA (1.0 mL) and the reaction was stirred for 2 hours at ambient temperature at which point LCMS indicated complete cleavage to the N—hydroxymethyl intermediate. The solvent was removed and to the e was added methanol (1.0 mL) followed by ethylenediamine (40 nL, 0.61 mmol), the reaction was stirred for 16 hours at which point LCMS indicated te reaction. The t was removed and the residue was purified by preparative LCMS to provide the t as a TFA salt.
NOE experiments confirm that all isomers have cis geometry on entyl ring. Isomers 1 and 2: 1H NMR (400 MHz, CD3OD)Z 6 8.95 (s, 1H), 8.89 (s, 1H), 8.54 (s, 1H), 7.86 (d, 1H), 7.29 (d, 1H), 3O 4.72 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H), 2.95 (m, 1H), 2.72 (m, 1H), 2.2-1.9 (m, 4H), 1.67 (m, 2H).
Isomers 3 and 4: 1H NMR (400 MHz, CD3OD): 5 8.95 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 7.85 (d, 1H), 7.28 (d, 1H), 4.72 (m, 1H), 3.27 (m, 1H), 3.19 (m, 1H), 3.05 (m, 1H), 2.71 (m, 1H), 2.44 (m, 1H), 2.05 (m, 1H), 1.92 (m, 1H), 1.72 (m, 1H), 1.58 (m, 2H).MS (El) m/z = 332.2 (M+H).
Example 98: 3—[3-(Hydroxymethyl)cyclopentyl]-3—[4-(7H—pyrrolo[2,3-d]pyrimidin-4~yl)-1H- pyrazol-l-yl]propanenitrile NP \ / N N Step I.‘ 3-[3-(Hydroxymethyl)cyclopentylj[4-(7—[2-(trimethylsibiljethoxy]methyl- 7H—pyrrolo[2, 3- d]pyrimidinyl)-1H-pyrazol-I-yI]propanenitrile A solution of 3—(3~fonnylcyclopentyl)[4—(7—[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo- [2,3-d]pyrimidinyl)-1H—pyrazol—l-yl]propanenitrile (50.0 mg, 0.108 mmol) in methanol (280 uL) was cooled to 0 °C, then sodium ydroborate (14 mg, 0.37 mmol) was added. The reaction was held at 0 °C for 10 minutes, at which point LCMS and TLC indicated complete reaction.
The reaction was quenched by cautious addition of 1N HCI (3 drops) and methanol (1 mL), followed by addition of aqueous NaHCO; and CHClg. The phases were ted and the aqueous phase was washed with additional CHC13. The combined organic phase was washed with sat'd NaCl, dried over MgSO4 and reduced to dryness. The residue was purified by column chromatography to obtain the product as a mixture of diastereomers (37.4 mg, 74%). 1H NMR (400 MHz, : 5_ 8.84 (s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.29 (m, 1H), 3.53 (m, 1H), 3.53 (t, 2H), 3.14 (m, 1H), 2.95 (m, 1H), 2.68 (m, 1H), 2.2-1.0 (m, 9H), 0.92 (t, 2H), ~0.059 (s, 9H). MS (EI) m/z = 467.2 (M+H).
Step 2. 3-[3—(Hydroxymethyl)cyclopentyl]~3—[4—(7H-pyrrolo[2,3-d]pyrimidin—4—yl)—1H—pyrazol—1 - yljpropanenim'le To hydroxymethyl)cyclopentyl][4-(7-[2~(trimethylsi1yl)ethoxy]methyl-7H—pyrrolo— [2,3-d}pyrimidin~4-yl)-1H-pyrazol-l—yl]propanenitrile (60.4 mg, 0.129 mmol) ved in CHZCIZ (2.0 mL) was added TFA (1.0 mL) and the reaction was stirred for 1 hour at which point LCMS indicated complete cleavage to the N~hydroxymethyl intermediate (m/z = 367). The trifluoroacetate ester of the hydroxymethyl of the cyclopentyl ring was also observed (m/z = 463). The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (80 uL, 1.19 mmol). The resulting mixture was stirred for 16 hours at which point LCMS indicated complete reaction to the desired t. The solvent was d and the e was purified by chiral HPLC to provide four distinct diastereomers (20.2 mg total of four isomers, 46%). NOE experiments suggest that all isomers have cz's geometry on the cyclopentyl ring. Isomers l and 2: IH NMR (400 MHz, CD30D): 8 8.65 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.40 (m, 2H), 3.22 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.10 (m, 1H), 1.94 (m, 1H), 1.82 (m, 1H), 1.6—1.4 (m, 3H), 1.03 (m, 1H). Isomers 3 and 4: IH NMR (400 MHz, CD3OD): 8 8.66 (s, 1H), 8.62 (s, 1H), 8.37 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.46 (m, 2H), 3.21 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.22 (m, 1H), 2.09 (m, 1H), 1.71 (m; 1H), .25 (m, 3H); 1.04 (m, 1H). MS (EI) m/z = 337.1 (M+H).
Example 100: Pyrrolo[2,3-b]pyridin—4—yl)—lH—indazole (100a) and 2—(1H-pyrrolol2,3-b]- pyridin-4—yl)-2H—indazole (100b) 8% 2 \ ,N \ \ l \ 12 N N p: 4—Bromo-1H—pyrrolo[2,3—b]pyridine (0.078 g, 0 mol) and lH-indazole (0.283 g, 0.00240 mol) was heated neat in a sealed tube at 200 °C (an oil bath) overnight with stirring. The reaction was allowed to cool to rt and the crude product was purified by prep LC-MS on a C-18 column eluting with a water/ACN gradient containing 0.2% TFA to give the title compound (0.015 gm, 15%), as an amorphous white solid, LC /MS (M+H)* 235, 'H NMR (DMSO-dé) 5 12.01 (bs, 1H) 9.17(s, 1H), 8.31(s, 1H), 7.73(d, 1H, J=9.0), 7.67(m, 2H), 7.58(m, 1H), 7.28(m, 1H), 7.07(m, 2H).
Example 106: 3-[3-(1‘H-Pyrrolo[2,3-b]pyridinyl)—1,2,4-oxadiazolyl]benzonitrile Step 1. 1-[2—Ttrimethylsilyl)ethoxy]methyl-JH—pyrrolo[2,3-b]pyridinecarbonitrile CH20(CH2)2Si(CH3)a 4-Bromo~1-[2-(trimethylsilyl)ethoxy]methy1—lH-pyrrolo[2,3—b]pyridine (0.300 g, 0.000917 mol) was dissolved in DMF (6.5 mL, 0.084 mol) and then zinc cyanide (0.30 g, 0.0026 mol) was added. The solution was degassed with en and then bis(tri—t-buty1phosphine)pa11adium (0.1 g, WO 70514 0.0002 mol) was added. The reaction was sealed and heated in the microwave to 100 °C for 30 minutes. The reaction was allowed to cool to rt, taken up in ethyl acetate and washed with water saturated sodium ate, brine, dried over magnesium sulfate and concentrated to give an oil. The crude product was purified by flash column chromatography (FCC) on silica gel, eluting with a hexane: ethyl acetate gradient to give the product (0.25 gm) as a colorless oil. LC/M S (M+H)+ 274, lH NMR ) 8 8.22 (d, 1H), 7.53(d, 1H), 7.40(d, 1H), 6.73(d, 1H), 5.65(s, 2H), , 2H), 0.90(m, 2H), 0.0(s, 9H).
Step 2. N-Hydroxy-1 -[2-(trimethylsilyDethowjmethyl—IH—pyrrolo[2,3-b]pyrz'dine—4—carboximidamide HN NHOH | \, \ N N IO CH20(CH2)ZSi(CH3)3 Trimethylsilyl)ethoxy]methyl—1H—pyrrolo[2,3-b]pyridine—4-carbonitrile (0.05 g, 0.0002 mol) was dissolved in ethanol (2.0 mL, 0.034 mol), and then hydroxylamine hydrochloride (0.023 g, 0.00033 mol) and potassium carbonate (0.10 g, 3 mol) were added. The reaction was heated to reflux for 5 h, and the reaction was then allowed to cool to rt and filtered to remove the solids. The filtrate was concentrated to give the product 0.06 g as yellow oily residue, LC/MS (M+H)+ 307.
Step 3. 3-[3-(1«[2-(TrimethylsilyDethoxyjmethyl-IH-pyrrola[2, 3-b]pyridin-4—yl)—1,2;4—0xadiqzol—5- yljbenzom'trile N\ N l \ N/ N.
CH20(CH2)ZSi(CH3)3 The crude product N-hydroxy-l-[2-(trimethylsilyl)ethoxy]rnethyl—lH-pyrrolo[2,3-b]pyridine- 4-carboximidamide (0.06 gm, 0.0002 mol) was dissolved in pyridine (1.0 mL, 0.012 mol) and then 3- cyanobenzoyl chloride (0.040 g, 0.00024 mol) was added at rt. This mixture was stirred for 1 h and heated to 80 0C in an oil bath. After heating for 18 h the reaction was allowed to cool to it and then diluted with ACN and concentrated in vacuo to give 3-[3-(1-[2-(trimethylsilyl)ethoxy]methyl—lH- pyrrolo[2,3-b]pyridinyl)-1,2,4-oxadiazolyl]benzonitrile 0.08 gm as an off white residue, LC/M S (M+H)+ 418.
WO 70514 Step 4. 3-[3-(1H-Pyrrolo[2,3-b]pyridinyl)—1,2,4-oxadiazol-5~yl]benzonitrile The crude 3-[3-(1—[2-(trimethylsilyl)eth0xy]methyl-lH-pyrrolo[2,3-b]pyridinyl)-I,2,4-0xa- diazol—S—yljbenzonitrile (0.08 g, 0.0002 mol) was dissolved in TFA (3.0 mL, 0.039 mol) under nitrogen and then heated to 60 °C. Afier heating for 2 h the reaction was allowed to cool to rt and concentrated in vacuo. The resulting residue was taken up in methanol and concentrated to remove as much of the TFA as possible. The residue was taken up in methanol (2.0 mL, 0.049 mol) and ammonium hydroxide (1 mL). This mixture was stirred at rt for 2 h and the reaction was then complete. The reaction was concentrated in vacuo to give the crude product which was purified by prep HPLC on a C-18 column eluting with a ACNzwater gradient with 0.2% TFA to give the title compound (0.025 gm, 43%) (M+H)+ 288. 'H NMR (DMSO-ds) 5 12.1 (bs, 1H), 8.65(s, 1H), 8.48(d, 1H,J=6.4), 8.39(d, 1H, J=4.8), 8.16(d, 1H, J=6.4), 7.840;, 1H, J=6.4), 7.75(d, 1H, J=4.8), 7.68(m, 1H), 6.99 (m, 1H).
Example 107: 4-(1-Benzothien-2—yl)-lH—pyrrolo[2,3-b]pyridine Z\/\ \ Step 1. 4-(’1-Benzothienyl)-1~[2-(trimethylsilyl)ethoxy] methyl-1H—pyrrolo[2, ridine ‘CH203 othien—z—ylboronic acid (0.05 g, 0.0003 mol) and 4-bromo-l —[2-(trimethylsilyl)- ethonymethyl-lH—pyrrolo[2,3-b]pyridine (0.10 g, 0.00031 mol) were combined in toluene (3.0 mL, 0.028 mol) and l (1.0 mL, 0.017 mol).
Potassium carbonate (0.085 g, 0.00062 mol) dissolved in water (1.0 mL) then was added and the reaction was degassed with en. Then tetrakis(triphenylphosphine)palladium(0) (0.05 g, 4 mol) was added and the reaction was heated to 120 °C in a sealed tube in the microwave for 60 minutes. This was allowed to cool to rt, taken up in ethyl e and washed with water 2X, brine, dried over magnesium sulfate and trated to give enzothien—2—yl)-l-[2-(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3-b]— ne (0.10 gm) as an oil, LC /MS (M+H)+ 381.
Step 2. 4—(1-Benzothien-Z—yD-IH—pyrrolo[2,3-b]pyridine Using a procedure analogous to Example 106, Step 4, but using 4—(1-benzothien—27yl)—1-[2— (trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine, the title compound was prepared as a yellow powder (0.015 g, 18%), LC IMS (M+H)+: 251, 1H NMR (DMSO—dG) 8 11.95 (bs, 1H), 8.28(d, 1H, J=5.4), 8.15(s, 1H), 8.03(m, 1H), 7.96(m, 1H), 7.64(m, 1H), 7.42(m, 2H), 7.39(d, 1H, J=5.4), 6.95(m, 1H).
Example 120: 4-Fluoro[l-(lH—pyrrolo[2,3-b]pyridinyl)-lH—pyrazol—3-yl]phenol / \ OH N N 4—Bromo-1H-pyrrolo[2,3-b]pyridine (0.050 g, 5 mol) and 4-fluoro—2—(1H-pyrazol yl)phenol (0.150 g, 0.000842 mol) were heated neat to 160 °C for 5 h. The reaction was allowed to cool to It and the residue was purified by prep LC-MS on a C-18 column eluting with a water/ACN gradient containing 0.2% TFA to give the title compound, (0.052 g, 20%, as an amorphous white solid, LC IMS (M+H)+ 295, 'H NMR (DMSO-da) 5 12.01 (bs, 1H), 10.25(bs, 1H), 8.81(s,1H), 8.35(d, 1H, J: 5.5), 7.77(d, 1H, J=9.5), 7.64(m, 1H), 7.59(d, 1H, J=5.5), , 1H), 7.09(m, 1H), 7.05(m, 1H), 7.01(m, 1H).
Example 127 : 4[3—(Trifluoromethyl)phenyl]—1H—pyrazol-l—yl-IH-pyrrolo[2,3-b] pyridine Step 1. (2E)—3—(Dimethylamino)—1-[3—(trifluoromethprhenyljprop-Z-en—1—one 1-[5-(Trifluoromethyl)phenyl]ethanone (0.20 mL, 0.0013 mol) and l,1—dimethoxy—N,N- dimethylmethanamine (0.17 mL, 0.0013 mol) were combined in a sealed tube and heated in a ave to 120 °C for 15 minutes, the reaction was allowed to cool and was concentrated to remove the residual DMF acetal, to give (2E)—3-(dimethy1amino)[3—(trifluoromethyl)phenyl]prop- 2—en—1vone, 0.32 gm, as a red oil, LC /MS (M+H)*: 244.
Step 2: 3-[3-(Trifluoromethprhenylj-IH-pyrazole F30 ‘ \ N‘NH The (2E)(dimethylamin0)[3-(trifluoromethyl)phenyl]propen—1-one (0.32 g, 0.0013 mol) was dissolved in ethanol (10.0 mL, 0.171 mol) and hydrazine (0.24 mL, 0.0078 mol) under nitrogen and heated to reflux. The on was monitored by HPLC and was complete almost immediately. The mixture was allowed to cool to rt and concentrated to give the crude product as an oil. The product was purified by FCC on silica gel eluting with a hexane: ethyl acetate gradient to give 3~[3-(trifluoromethyl)phenyl]—1H—pyrazole as an oil (0.25 g, 89% ), LC /MS (M+H)+: 213, 1H NMR (CDC13) 5 8.06 (s, 1H), 7.99(d, 1H, J=7.5), 7.66(d, 1H, J= 2.4), 7.57(m, 1H), 7.55(d, 1H, J=7.5), 6.69(d, 1H, J= 2.4).
Step 3. 4[3—(Triflu0romethprhenyl]-1H—pyrazol-I-yl-1H-pyrrolo[2,3-b]pyridine 4-Bromo-l olo[2,3-b]pyridine (0.028 g, 0.00014 mol) and 3-[3-(trifluoromethyl)- phenyl]-1H-pyrazole (0.03 g, 0.0001 mol) were combined neat. The reaction was heated in a sealed tube in an oil bath to 175 °C for 20 to produce a crude product that was a black s gum. The crude product was purified by HPLC on a C—1 8 column eluting with a waterzACN gradient with 0.2% TFA to give the title product (0.025 gm, 50%) as a white amorphous solid, LC [MS : 329, IH NMR (DMSO—ds) 6 11.95 (bs, 1H), 8.83(d, 1H, J=2.7), , 3H), 7.75(m, 2H), , 2H), 7.35(d, 1H, J=2.7), 7.14(m, 1H).
Example 128: 3-[1-(1H-Pyrrolo[2,3-b]pyridinyl)—1H—pyrazolyl]benzonitrile {ThI,N Step 1. 3—[(2E)—3-(Dimethylamin0)prop—2—enoyl]benzonitrile 3-Acetylbenzonitrile (0.435 g, 0.00300 mol) and 1,1—dimethox‘y—N,N-dimethylmethanamine (0.400 mL, 0.00301 mol) were combined and heated in sealed tube to 120 °C in the microwave for 15 min. The reaction was then allowed to cool to rt giving the 3-[(2E)(dimethylamino)propenoyl]- benzonitrile as a red-orange crystalline material, LC IMS (M+H)+: 201.
Step 2. 3-(1H—Pyrazol—3—yl)benzonitrile The 3—[(2E)—3—(dimethylamino)prop—2—enoyl]benzonitrile (0.600 g, 0.00300 mol) was dissolved in ethanol (20.0 mL, 0.342 mol) and hydrazine (0.56 mL, 0.018 mol) under an atmosphere of en was stirred at room temperature for 1.5 h. The reaction was concentrated in vacuo to give a dark product which was d by FCC on silica gel, eluting with ethyl acetate-hexane 1:1 to give 3—(1H—pyrazol—3-y1)benzonitrile as an oil (0.430g, 84%), LC /MS (M+H)+: 170.
Step 3. 3-[1-(1H—Pyrrolo[2,3-b]pyridinyl)-IH-pyrazol—3-yl]benzonitrile 4~Bromo~1H-pyrrolo[2,3-b]pyridine (0.075 g, 0.00038 mol) and 3-(1H-pyrazolyl)benzo- nitrile (0.161 g, 52 mol) were heated in sealed tube to 160 °C for 18 h. The resulting product, dark s gum, was purified by I-IPLC on a C—18 column eluting with a waterzACN gradient with 0.2% TFA to give the title product (0.030 g, 27%) as a white amorphous solid, LC /MS (M+H)+: 286, 'H NMR (DMSO—da) 5 11.95 (bs, 1H), , 1H), , 1H), 8.29(d, 1H, J=7.5), 8.25(d, 1H, J=5.0), 7.79(d, 1H, J= 7.5), 7.62(t, 1H, J= 7.5), 7.53(m, 2H), 7.25(s, 1H), 7.11(m, 1H).
Example 153: 3-[1-(1H—Pyrrolo[2,3-b]pyridin—4-yl)—lH-pyrazol-4—yl]benzonitrile 2 12/ Step I. 4-(4,4,5,5-Tezramethyl—1,3,2-dioxaborolany0-I—[2-(trimethylsilyl)ethoxyjmethyl-1H- pyrazole A solution of ,5,5-tetramethyl—l,3,2-dioxaborolanyl)-lH—pyrazole (2.0 g, 0.010 mol) and DMF (30.0 mL, 0.387 mol) was cooled to 0 °C. Sodium hydride (320 mg, 0.013 mol) (60% in oil) was added and the mixture was stirred for 10 min. [B—(Trimethylsily1)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was added and the resulting mixture was stirred for 20 min at 0° C and 2 h at room temperature. The reaction was partitioned between water and ethyl acetate. The c layer was washed with brine, dried over Mg804 and concentrated to give 4-(4,4,5,5-tetrarnethy1—l,3,2- dioxaborolan-Z-yl)-l-[2-(trimethylsilyl)ethoxy]methyl-1H—pyrazole as a crude material. LC/MS (M+H)*: 325, 'H NMR (CDCl3) 5 7.85 (s, 1H), 7.80(s, 1H), 5.45(s, 2H), 3.55(t, 2H), 1.35(s, 12H), 0.95(t, 2H), 0.0(s, 9H).
Step 2. 3-(1-[2-(TrimethylsilyDet/onyjmethy]—IH-pyrazol—4—y0benzonitrile A mixture of 4—(4,4,5,5-tetramethyl—l,3,2—dioxaborolanyl)[2-(trimethylsilyl)ethoxy]- methyl-lH-pyrazole (150.0 mg, 0.0004625 mol) and 3-bromobenzonitrile (0.10 g, 0.00056 mol) in toluene (2.0 mL, 0.019 mol) and ethanol (0.3 mL, 0.005 mol) was treated with sodium carbonate (98 mg, 0.00092 mol) in water (0.5 mL, 0.03 mol). The mixture was degassed by bubbling nitrogen.
Tetrakis(triphenylphosphine)palladium(0) (53 mg, 46 mol) was added and nitrogen was bubbled for 3 min. The on was heated in a ave at 80 °C for 30 min, then d to cool to rt and taken up in water and ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to give a crude product, which was purified by FCC on silica gel, eluting with EtOAc/Hexanes (1:5) to give 3—(1-[2-(trimethylsi1y1)ethoxy]methyl—lH—pyrazol—4—yl)benzonitrile, as anmLLcnwsoanfl3mi Step 3. 3-(1H—Pyrazol-4—yl)benzonitrile trifluoroacetate N‘NH A on of 3-(1-[2-(tn'methylsilyl)ethoxy]methyl-lH—pyrazol—4—yl)benzonitrile (110.0 0.0003673 mol) was taken up in TFA (3.0 mL, 0.039 mol) and the mixture was heated in microwave at 120 °C for 3 min. The reaction mixture was allowed to cool to rt, and then concentrated to give a crude residue. The product was purified by I-IPLC on a C-18 column eluting with a water/ACN gradient ning 0.2% TFA to give 3-(1H-pyrazol~4-yl)benzonitrile trifluoroacetate as an amorphous white solid, LC /MS (M+H)+: 170.
Step 4. 3—[1-(1H—Pyrrolo[2,3-b]pyridin—4—yl)—IH—pyrazolyl]benzonitrile A mixture of 4-bromo;1H-pyrrolo[2,3-b]pyridine (25.0 mg, 0.000127 mol) and 3-(lH- pyrazolyl)benzonitrile trifluoroacetate (23.6 mg, 0.0000833 mol) was heated at 180 °C, neat overnight. The crude residue was purified by HPLC on a C-18 column g with a water; ACN gradient containing 0.2% TFA to give the title compound as an amorphous white solid, LC/MS (M+H)+: 286, 1H NMR (DMSO-ds) 8 11.85 (bs, 1H), , 1H), 8.42(s, 1H), 8.28(s, 1H), 8.25(d, 1H, J=5.0), 8.07(d, 1H, J=7.0), 7.64(d, 1H, J=7.0), 7.56(t, 1H, J= 7.0), 7.51(m, 1H), 7.47(d, 1H, J=5.0), 7.03(m,lH).
Example 170: 2-[1-(1H-Pyrrolo[2,3-b]pyridinyl)-1H—pyrazol-4—yl]-l,3-benzoxazole N\ ; NT;0 N fi Step 1. 4—Hydrazz'no—1—[2—(trimethylsilyDethquyjmethyl-1H-pyrrolo[2,3—bjpyrz‘dine HZN‘NH I j \ N N bH20(CH2)28i(CH3)3 To 4-bromo[2—(trimethylsilyl)ethoxy]methyl-lH—pyrrolo[2,3-b]pyridine (1.98 g, 0.00605 mol) was added hydrazine (11.0 mL, 0.350 mol) followed by addition of methanol (1.0 mL, 0.025 mol) (to improve solubility). The on e was heated in a sealed tube at 97 °C (an oil bath) for 18 h. The reaction mixture was cooled to it and formed an off-white solid itate. The solid was filtered off and rinsed with cold water and dried to give 4-hydrazino-l-[2-(trimethylsi1yl)ethoxy]- methyl-lH—pyrrolo[2,3-b]pyridine (1.55gm) as a light yellow solid, LC/MS (M+H)+:279, 1H NMR (DMSO-a'fi) 8 7.98(d, 1H), 7.91(s, 1H), 7.28(d, 1H), 6.69(s, 1H), 6.6l(d, 1H), 5.58(s, 2H), , 2H), 3.56(t, 2H), 0.90(t, 2H), 0.0(s, 9H).
Step 2. 2-[1-(1-[2-(Trimethylsilyl)eth0xy]methyl—1H—pyrrolo[2, 3—bjpyridinyl)-1H-pyrazol—4—yl]— 1, 3-benzoxazole / \ . N/ N\ CH20(CH2)23i(CH3)3 To 4—hydrazino[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.083 g, 0.00030 mol) 37821 and 1,3-benzoxazolylmalonaldehyde (0.056 g, 0.00030 mol) in toluene (1.5 mL, 0.014 mol) was added molecular . The mixture was heated in a sealed tube at 70 °C (an oil bath) with stirring for 2 h. The solvent was removed in vacuo and the crude product was d by FCC on silica using ethyl acetatezhexanes 3:7 to give 1-[2-(tn'methy1silyl)ethoxy]- methyl-1H-pyrrolo[2,3-b]pyridinyl)-—1H-pyrazol—4-yl]-1,3-benzoxazole (0.090gm) as an oil, LC/MS (M+H)+: 432.
Step 3.
Using a procedure analogous to Example 106, Step 4, but using 2-[1-(1—[2-(trimethylsilyl)- ethonymethyl—lH-pyrrolo[2,3-b]pyridinyl)-lH-pyrazol—4-yl]-1,3—benzoxazole, the title compound was prepared as a white amorphous powder (0.015 gm, 18%), LC IMS (M+H)+:302, 1H NMR (DMSO-ds) 5 11.85 (bs, 1H), 9.45(s,1H), 8.53(s, 1H), 8.36(bs, 1H), 7.7—7.6(m, 2H), 7.65(d, 1H), 7.56(bs, 1H), .34(m, 2H),7.0l(d,lH).
Example 172: Cyclohexyfll-(lH—pyrrolo[2,3-b]pyridin—4-yl)—1H—pyrazol—4-yl]methanol N N Step 1 . 4—(4-Br0mo-1H-pyrazol—I—yl)-1H-pyrrolo[2,3—b]pyridine A mixture of 4-bromo~1H-pyrrolo[2,3-b]pyridine (1.10 g, 8 mol) and 4-bromo~lH— pyrazole (1.2 g, 0.0084 mol) was heated neat to 150 °C for 2 h. DMF was added to dissolve the crude residue. This residue was taken up in EtOAc and washed with 1N NaOH. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give a crude 4-(4-bromo-1H— pyrazol—l-yl)~1H-pyrrolo[2,3-b]pyridine residue, LC [MS (M+H)+: 263,265.
Step 2. 4—(4—Bromo~1H—pyrazol~1-yl)~1—[2-(trimethylsibxl)ethoxy]methyl—1H-pyrrolo[2,3-b]pyridine the/ N N CH20(CH2)28i(CH3)3 A solution of 4-(4-br0mo-1H-pyrazol—I—ylj-I-[2-(trimethylsilyDet/zosty]methyl chloride (1.4 mL, 0.0079 mol) was added and stirred for 20 min at 0 °C. The reaction was ioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the crude material. The product was purified by FCC on silica gel (EtOAc/Hexanes, 1/10) to give 4-(4-bromo-1H—pyrazol-l~yl)—l trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-bjpyridine as a solid product, LC [MS (M+H)+: 393, 394, 1H NMR (CDC13) 8 8.47(d, 1H, J=7.0), 8.27(s, 1H), 7.88(s, 1H), , 1H, J=4.5), 7.39(d, 1H, J=7.0), 7.069(d, 1H, J=4.5), 5.80(s, 2H), 3.6(t, 2H), 1.95(t, 2H), 0.0(s, 9H).
Step 3. Cycloheaazlfl—(J-[2—(trimethylsilyl)ethoxyjmethyfl1H—pyrrolo[2, 3—b]pyridin~4—yl)—1H—pyrazol— 4uyljmethanol N‘\/ CH20(CH2)25i(CH3)3 A mixture of 4~(4~bromo~1H-pyrazol—1 —y1)-1 ~[2—(trimethylsi1y1)ethoxy]rnethyl—1 H— pyrrolo[2,3-b]pyridine (50.0 mg, 0.000127 mol) in THF (2.0 mL, 0.025 mol) under a nitrogen atmosphere was cooled to ~78 °C and 1.6 M n-butyllithium in water (1.00 mL, 0.0555 mol). The mixture was stirred for 3 min. The reaction was partitioned n water and EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give the cyclohexyl[1-(1:5) to give 4-yl)- azol-4—y1]methanol as a crude residue, LC IMS (M+H)+: 417.
Step 4. CyclohexyIfl—phenylvinyD-IH—pyrazol-4—yUmethanol Using a procedure analogous to e 106, Step 4, but using exyl[l—(1-[2- (trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine, the title compound was prepared as a white amorphous powder (0.015 gm, 18%), LC /MS : 297. ‘H NMR (DMSO-dé) 5 11.85 (bs, 1H), 8.44(s, 1H), 7.74(s, 1H), 7.50(m, 1H), 7.44(d, 1H, J=6.5.70(s, 1H), 5.37(s, 1H).
Example 173: 4-[4-(1-Phenylvinyl)—1H-pyrazol-l-yl]-lH-pyrrolo[2,3—blpyridine / \ ‘N TFA the)’N Step 1. 4—[4—(1~Phenylvz'nyl)—1H—pyrazol~1—yl]-J-[2—(trimethylsilyl)ethoxyj—methyl-IH-pyrrolo[2, 3~ bjpyridz'ne N". \E - N N N CH20(CH2)28i(CH3)3 A mixture of (l-phenylvinyl)boronic acid (24.0 mg, 0.000162 mol) and 4—(4-bromo-1H— pyrazol-l-yl)[2-(trimethylsilyl)ethoxy]methy1—lH—pyrrolo[2,3-b]pyridine (50.0 mg, 0.000127 mol) in toluene (2.00 mL, 0.0188 mol) and ethanol (0.50 mL, 0.0086 mol) was treated with potassium carbonate (35 mg, 0.00025 mol) in water (1.00 mL, 0.0555 mol). The mixture was degassed by bubbling nitrogen. Tetrakis(tfiphenylphosphine)palladium(0) (10 mg, 1 mol) was added and nitrogen was bubbled for 3 min. The reaction was heated in a sealed tube in the microwave at 100 °C for 30 min. The reaction was allowed to cool to rt and partitioned between ethyl acetate and water.
The combined organic layer was dried over MgSO4, filtered and trated to give the crude material The crude product was purified by FCC on silica gel eluting with EtOAc/Hexanes (1:5) to give 4-[4-(1—phenylvinyl)—1H—pyrazol-l -y1] -l -[2-(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3 -b]- pyridine as a solid residue, LC /MS (M+H)+: 417.
Step 2.
Using a procedure analogous to Example 106, Step 4, but using 4-[4-(1-phenylvinyl)-1H- pyrazol—l-yl]—1—[2-(trimethylsilyl)ethoxy]methyl—lH—pyrrolo[2,3-b]pyridine, the title compound was prepared as an white amorphous powder (0.015 gm, 31%), LC IMS (M+I-l)+: 287, IH NMR (DMSO- d5) 8 11.85 (bs, 1H), 8.63(s, 1H), 7.99(s, 1H), 7.55(bs, 1H), , 2H), 7.43-7.37(m, 5H), 7.01(m,lH), 5.70(s, 1H), 5.37(s, 1H). e 200: 4-(l-Benzyl-lH—pyrazolyl)—1H-pyrrolo[2,3-b]pyridine l, \ N N H Step 1 . 4-‘(1-Benzyl—IH-pyrazol—4—yl)—1—[2—(trimethylsilyl)ethoxyjmethyl—1H~pyrrolo[2, 3—b]pyridine N—N@ l \ N N CH20(CH2)ZSi(CH3)3 4—Bromo-l-[2-(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3-b]pyridine (0.100 g, 0.000306 mol) was combined with l-benzyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolan—2-yl)-lH—pyrazole (0.113 g, 0.000398 mol) in e (3.0 mL, 0.028 mol) and ethanol (0.5 mL, 0.008 mol). Potassium carbonate (0.084 g, 0.00061 mol) dissolved in water (1.0 mL, 0.056 mol) was added and the reaction mixture was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.080 g, 69 mol) was added, and again the e was degassed with nitrogen for 5 min. The reaction was heated in sealed tube to 100 °C in a microwave for 30 minutes. The reaction was partitioned n ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate and trated to give a crude residue. The product was purified by FCC on silica gel using ethyl acetatethexane 3:7, to give enzy1—lH-pyrazolyl)—1-[2-(trimethylsilyl)ethoxy]methyl—1H— pyrrolo[2,3-b]pyridine 0.092g as a semisolid residue, LC /MS (M+H)+: 405.
Step 2. 4-(1-Benzyl—1H—pyrazolyD-1H-pyrrolo[2,3-bjpyridine Using a procedure analogous to Example 106, Step 4, but using 4-(1-benzy1—lH-pyrazol yl)-l—[2-(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3—b]pyridine, the title compound was ed as a white amorphous powder (0.054 gm), LC [MS (M+H)+: 275, 1H NMR (DMSO—d5) 5 12.21 (135, 1H), 8.80(s, 1H), 8.25(vbs, 1H), 8.23(s, 1H), 7.63(s, 1H), 7.49035, 1H), 7.4—7.2(m, 5H), 6.99(s, 1H), 5.42(s, 2H).
Example 201 : 4—[1-(2-Naphthylmethyl)-1H—pyrazolyl]-1H-pyrrolo[2,3-b]pyridine N N Step 1. 1-(2-Naphthylmethyl)(4, 4,5,5-tetramethyl—1,3,2-dioxaborolan—2-yl)—1H~pyrazole The 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolanyl)-1H—pyrazole (0.10 g, 0.00052 mol) was combined with naphthalene, 2-(bromomethyl)— (0.12 g, 0.00057 mol) in ACN (3.0 mL, 0.057 mol) under nitrogen at rt. Then cesium carbonate (0.50 g, 0.0015 mol) was added and the reaction was complete after stirring for 1 h. This was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 1—(2- naphthylmethyl)(4,4,5,5-tetramethyl-1,3,2—dioxaborolan—2-yl)—lH—pyrazole 0.17 gm, as an oil, LC/MS (M+H)+: 335, 'H NMR (CDC13) 8 7.89 (s, 1H), 7.79-7.84(m, 3H), 7.69(bs, 2H), 7.49-7.4(m, 2H), 7.46-7.33(m, 1H), , 2H), l.3l(s, 12H).
Step 2. 4—[1 -(Z—Naphthylmethyl)-1H—pyrazolylj—1~[2—(trimethylsilyDethoxyjmethyl-1H—pyrrolof2, 3- dine I \ N N CH20(CH2)ZSi(CH3)3 2006/047369 4-Bromo-1—[2-(trimethylsily1)ethoxy]methyl—1H-pyrrolo[2,3-b]pyridine (0.06 g, 0.0002 mol) and 1-(2-naphthy1methyl)—4—(4,4,5,5-tetramethyl—l,3,2-dioxaborolan—2-y1)-1H—pyrazole (0.074 g, 0.00022 mol) were combined in toluene (2.0 mL, 0.019 mol) and ethanol (1.0 mL, 0.017 mol), and then potassium carbonate (0.063 g, 0.00046 mol, in 1 mL water) was added. The reaction mixture was degassed with nitrogen, then tetrakis(triphenylphosphine)palladium(0) (0.02 g, 2 mol) was added, sealed in a tube and heated to 120 °C in a microwave for 30 minutes. This was d to cool and then partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate and concentrated to give 4-[1-(2—naphthylmethyl)-lH-pyrazolyl]—l-[2- (trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine 0.08 g, as an oily residue, LC /MS (M+H)+: 455.
Step 3 Using a procedure analogous to Example 106, Step 4, but using 4-[1-(2-naphthylmethyl)-1H- pyrazol—4-y1][2-(trimethylsily1)ethoxy]methyl—1H-pyrrolo[2,3-b]pyridine, the title compound was prepared as a white amorphous powder (0.053 g, 88%), LC /MS (M+H)+: 325, lH NMR (DMSO-dg) 5 12.0(bs, 1H), 8.79(s, 1H), 8.24(s, 1H), 8.19(d, 1H, J=5.7), 7.82(m, 4H), 7.56(m, 1H), , 4H), 6.92(m, 1H), , 2H).
Example 219: 4-(1-Phenyl-lH—pyrazol—4-yl)—1H-pyrrolo[2,3-b]pyridine N N H Step 1 . 1—phenyl—4-(4, 4, 5, 5—Tetramethyl—1, 3.Z—dz'oxaborolan—Z—yD—IH-pyrazole 4—(4,4,5,5-Tetramethyl-l,3,2-dioxaborolanyl)-1I—l-pyrazole (0.07 g, 0.0003 mol) and phenylboronic acid (0.083 g, 0.00068 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then copper(II) ate (0.010 g, 0.000055 mol) and pyridine (0.069 mL, 0.00085 mol) were added. The reaction was heated in an open tube to 80 °C for 40 s. The reaction was complete by I-IPLC, allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 1-phenyl—4-(4,4,5,S-tetramethyl-l,3,2-dioxaborolanyl)-1H-pyrazo, 0.09 gm as an oily e, LC/MS (M+H)+: 271. 2006/047369 Step 2. 4-(1—Phenyl—1H-pyrazol—4-yl)-I—[2—(trimethylsilyl)ethoxyjmethyl—IH—pyrrolo[2, 3—b]pyridine Using a procedure analogous to Example 201, Steps B and C, but using l-phenyI(4,4,5,5- tetramethyl~1,3,2-dioxaborolanyl)—1H—pyrazo, the title compound was prepared as an white amorphous powder (0.015 gm, 18%), LC/MS (M+H)+: 261, 1H NMR (DMSO-d.;) 5 12.05 (bs, 1H), , 1H), 8.53(s, 1H), 8.3l(m, 1H), 8.01(m, 2H), 7.63(m, 1H), 7.57—7.52 (m, 3H), 7.36(m, 1H), 7.13(m, 1H).
Example 231: 3-[4-(1H-Pyrrolo[2,3-b]pyridin—4-yl)—1H—pyrazol—l-yl]benzonitrile l/ \ N N Step 1. 4—(1H-Pyrazol—4—yD-I-[2—(trimethylsilyl)eth0x32]methyl—1H-pyrrolo[2,3-b]pyridine N-NH I j \ N N \CH20(CH2)ZSi(CH3)3 4—Bromo—1-[2—(trimethylsilyl)ethoxy]methyl—1H—pyrrolo[2,3-b]pyridine (0.20 g, 0.00061 mol) and ,5,5-tetramethyl~l,3,2-dioxaborolan-2—yl)-lH—pyrazole (0.15 g, 0.00079 mol) were combined in DMF (5.0 mL, 0.064 mol) and then potassium carbonate (0.25 g, 0.0018 mol) in 1 mL water was added. The reaction was degassed with nitrogen, then tetrakis(triphenylphosphine)— palladium(0) (0.08 g, 0.00007 mol) was added and in a sealed tube the reaction was heated to 120 °C oil bath. The reaction was heated for 30 minutes, d to cool and then taken up in ethyl acetate.
The reaction mixture was washed with brine, dried over magnesium sulfate and concentrated to give an oil. The product was purified by FCC on silica gel eluting with a zethyl acetate gradient to give 4-(1H-pyrazol—4-yl)—1—[2~(trimethylsilyl)ethoxy]methyl—1H-pynolo[2,3-b]pyridine (0.13 gm, 70%) as a crystalline white powder, LC /MS : 315, lH NMR (DMSO-ds) 5 13.35 (bs, 1H), 8.59Cbs, 1H), 8.32(d, 1H, J=8.5), 8.26(bs, 1H), 7.76(d, 1H, J=6.0), 7.45(d, 1H, J=8.5), 7.01(d, , 5.73(s, 2H), 3.6l(t, 2H), 0.92(t, 2H), 0.0(s, 9H).
Step 2. 3-[4-(1-[.2-(TrimethylsilyDethoxy]methyl—1H-pyrrolo[2,3-b]pyridz'n-4—yl)-1H-pyrazol—I yl]benzonitrile N N\ CH20(CH2)281(CH3)3 4—(1H—Pyrazol—4—yl)[2-(trimethylsilyl)ethoxy]methyl—1H-pyirolo[2,3-b]pyridine (0.025 g, 0.000080 mol) and (3-cyanophenyl)boronic acid (0.023 g, 0.00016 mol) were combined in DMF (1.50 mL, 0.0194 mol). Then copper(II) diacetate (0.002 g, 0.00001 mol) and pyridine (0.019 mL, 0.00024 mol) were added. The reaction was heated in an open tube to 125 °C for 40 minutes, allowed to cool to rt, taken up in ethyl acetate, and washed with water saturated with sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 3—[4-(1—[2—(trimethylsilyl)ethoxy]methyl-lH-pyrrolo[2,3-b]pyridin-4—yl)-1H—pyrazol-1 -yl]- benzonitrile (0.025 gm, 92%) as an oily residue, LC /MS : 316.
Step 3 Using a procedure analogous to Example 106, Step 4, but using 1—[2-(trimethylsilyl)- ethoxy]methyl-1H—pyrrolo[2,3-b]pyridin—4-yl)-lH—pyrazol—l—yl]benzonitrile, the title compound was ed as an white crystalline powder (0.012 gm, 60%), LC/MS (M+H)+: 286, 1H NMR (DMSO— d5) 5 12.05 (bs, 1H), 9.32(s, 1H), , 1H), , 1H), 8.36(m, 1H), 8.30(d, 1H, J=5.2), 7.83(m, 1H), 7.75(m, 1H), 7.63(m, 1H), 7.51(d, 1H, J=5.2), 7.12(m, 1H).
Example 250: 4-{l-[(1R)—1—Methylbutyl]-1H-pyrazol—4—yl}-1H—pyrrolo[2,3-b]pyridine (250a) and 4-{1—[(IS)-l-Methylbutyl]-lH-pyrazolyl}-lH—pyrrolo[2,3-b]pyridine (250b) 54— >..../* NN_ N_N / ’/ l\\ |\\ / / N N N H andN H Step 1. 4—[1—(1—Methylbutyl)—1H-pyrazol—4—ylj—I—[2-(trimetliylsilyDethmqyj-methyl—1H-pyrrolo[2, 3- b]pyridine 4—(1H—Pyrazol—4—yl)—1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.0002 mol) (see, Example 231, Step 1) was dissolved in DMF (2 mL, 0.02 mol) and cooled at 0 °C.
This solution was treated with sodium hydride (7.0 mg, 0.00029 mol) (60% in oil) and stirred for 15 min. The mixture was then treated with 2—bromopentane (40 mg, 0.0002 mol) and was stirred for 5 h.
The reaction was partitioned between ethyl acetate and water. The c layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude t 4-[1—(1-methylbutyl)-1H- pyrazolyl]-l—[2-(trimethylsilyl)ethoxy]methyl-1H—pyrrolo[2,3-b]py1idine as an oil, LC/MS (M+H)+: 286.
Step 2. 4-[1-(1-Methylbutyl)~1H-pyrazolyl]-1H-pyrrolo[2, 3-bjpyridine Using a procedure analogous to Example 106, Step 4, but using 4—[1-(l-methylbutyl)-1H— pyrazol-4—yl]—1—[2-(trimethylsilyl)ethoxy]methyl-lH—pyrrolo[2,3-b]py1idine, the title compound was prepared as an white amorphous powder (0.025 gm, 60%), LC [MS (M+H)+: 255, 'H NMR (DMSO- d5) 8 12.21 (bs, 1H), , 1H), 8.27(bs, 1H), , 1H), 7.62(m, 1H), 7.49(m, 1H), 7.02(m, 1H), 4.46011, 1H), 1.9—1.8(m, 1H), 1.7—1.6(m, 1H), 1.47(d, 3H), 0(m, 2H), 0.83(t, 3H).
Step 3. Separation ofEnantz'omers The separation of the enantiomers of 4-[1-(1-methylbutyl)-lH-pyrazol—4—yl]—lH—pyrrolo[2,3— b]pyridine from Step 2 was performed by chiral column preparative HPLC separation using an OD—H column eluting with an isopropanolzhexane nt to give the title nds as amorphous white residues, LC IMS (M+H)+: 255, 1H NMR (DMSO-d5) 8 12.21 (bs, 1H), 8.66(s, 1H), 8.27(bs, 1H), 8.25(s, 1H), 7.62(m, 1H), 7.49(rn, 1H), 7.02(m, 1H), 4.46(m, 1H), 1.9-1.8(m, 1H), 1.7-1.6(m, 1H), , 3H), 1.2—1.0(m, 2H), 0.83(t, 3H).
Example 286: 4-Methyl—3-[4-(1H—pyrrolo[2,3-b]pyridin—4-yl)—lH-pyrazol-l—yl]benzonitrile 1?CN N I \ N N Step 1 . 4—Methyl—3—[4-(1 -[2-(trimethylsilyDethoxy]methyl-1H—pyrrolo[2,3-bjpyridinyD—1H- pyrazol-I-yljbenzonitrile WO 70514 l \ N/ N\ CH20(CH2)ZSi(CH3)3 To a mixture of 4-(1H-pyrazoly1)-1—[2~(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]— pyridine (0.050 g, 0.00016 mol) (see, e 231, Step 1) and cesium carbonate (0.10 g, 0.00032 mol) in dry DMF (1.0 mL, 0.013 mol) was added 3-fluoro-4—methy1benzonitrile (0.043 g, 0.00032 mol). The reaction mixture was heated in sealed tube to 120 °C for 5.5 hours. The reaction was allowed to cool and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to give yl[4-(l-[2- (trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3—b]pyridin—4—yl)—lH-pyrazol—l—yl]benzonitrile as a crude product, LC /MS (M+H)+: 430.
Step 2. 4-Methyl—3—[4~(1H—pyrrolo[2, 3-b]pyridin-4—yl)—IH—pyrazol—1—yl]benzonitrile Using a procedure analogous to Example 106, Step 4, but using 4—methyl—3—[4-(l-[2- (trimethylsilyl)ethoxy]methyl-lH—pyrrolo[2,3-b]pyridin~4—yl)-lH—pyrazoLl-yl]benzonitrile, the title compound was prepared as a white amorphous powder (0.037 gm, 88%), LC /MS : 300, 1H NMR (DMSO-d5) 8 12.19 (bs, 1H), 8.98(s, 1H), 8.57(s, 1H), , 1H, J=7.0), 8.08(s, 1H), 7.89(d, 1H, 1:10), 7.66(d, 1H, J=10), 7.63(m, 1H), 7.55(d, 1H), 7.07(m, 1H), 2.4(s, 3H).
Further example compounds of the invention are ed in Tables 7, 8, 9, 10, and 11 below.
The compounds listed in Tables 7, 8, 9, 10 and 11 are racemic unless the enantiomers are indicated separately.
Table 7 2-(lH-pyn‘olo[2,3-b]pyridin yl)—4,5,6,7-tetrahydro-2H- indazole -nitro(1H—pyrrolo[2,3-b]— pyridin—4-yl)~2H—indazole 6-nitro-2—(1H-pyrrolo [2,3—b]— pyridin—4-yl)-2H-indazole 3—[1 —(1H-pyrrolo[2,3—b]pyridin- 4-y1)-1H—imidazolyl]- benzonitrile 4-[4-(3-methoxyphenyl)—1H- imidazol-l-yl]-1H-pyrrolo[2,3- b]pyridine henylthienyl)-1H— pyrrolo[2,3-b]pyn'dine 4-[3-(4-fluorophenyl)~l H-pyrazol-l - BX 120 yl]-1H—pyrrolo[2,3-b]pyridine 4-[3-(3—nitrophenyl)-1H~pyrazol-1 — ’22 2 306 E" 120 yl]-1H-pyrrolo[2,3-b]pyridine 9/CI 4—[3~(4~chlorophenyl)—1H—pyrazol-1 - 123 295 Ex 12° —pyrrolo[2,3~b]pyridine 4—[3—(4-methoxyphenyl)- I H—pyrazol- Ex 120 1-yl]-1H-pyrrolo[2,3~b]pyfidine 4-[1 -(1H-pyrrolo[2,3-b]pyridin—4-yl)- Ex 120 lH—pyrazol—3-yIJbenzonitn'le 3-[1—(1H—pyrrolo[2,3—b]pyridinyl)— BX 120 lH—pyrazol-B -yl]anilinc 4-[3-(3~methoxyphenyl)- I H-pyrazol- Ex 128 l-yI]—l H-pyrrolo[2,3-b]pyridine {3-[1 -(1H—pyrrolo[2,3-b]pyridin-4~ Wi/©\OCHZCN 316 yl)-1H—pyrazolyl]- phenoxy} acetonitrile 2—cyano-N- {3-[1 -(1H-pyrrolo[2,3-b]- 31 pyridin—4-yl)—1H—pyrazolyl]- phenyl}acetamide 3-cyano-N- {3-[1 -( 1 H-pyrrolo[2,3-b]- 132 405 pyridin-4—yl)-l H—pyrazolyl]— "aI)CONH(3-CN-Ph) }benzamide Table 9 (Y)n—Z N N 4-[4—(4—nitrophenyl)— 1 H-pyrazol-l -y1]- BX 153 lH-pyrrolo[2,3-b]pyridine 4.:[1_(]H-pyrrolo[2,3-b]Pyridin'4'yl)' ' Ex 153 1H-pyrazolyl]aniline 152 261 4-(4-pheny1-1H—pyrazol—1-y1)-1H- Ex153 pyrrolo[2,3-b1pyridine \ . . 154 I 262 4—(4-pyr1dmY1'1H'PyraF9l‘1‘YD'IH' BX 153 pyrrolo[2,3-b]Pyndlne 1H-pyrrolo[2,3-b]pyridinyl)- Ex 153 1H-pyrazol~4—y1]benzonitri1e (1H—pyrrolo[2,3—b]pyridin—4-y1)- Ex 153, 1 H-pyrazol-4—yl]phenyl} acetonitrile 4-[4-(3—nitrophenyl)- l H—pyrazol—l -y1] — Ex 153 lH-pyrrolo[2,3-b]pyridine 3-[1-(1H-pyrrolo[2,3-b]pyridinyl)- Ex 153 1H—pyrazolyl]aniline 2006/047369 Q {3—[1-(1H—pynolo[2,3-b1pyridiny1)- ‘ CHch azol—4-yl]pheny1}acetonitrile 4-[1 ~(1H-pyrrolOIZ,3-b]pyridin—4—y1)- 1 H-pyrazoly1]bcnzonitrile NJ"- 3-[1-(lH-pyrrolo[2,3-b]pyridin—4-y1)- 0H 1H-pyrazoly1]phenol methyl 3-[1—(lH-pyrrolo[2,3-b]pyridin- ‘777.Q COZCH3 4-y1)-1H—pyrazolyl]benzoate CHch 1 63E 300 {4-[1—(1H-pyrrolo[2,3.b]pyridin—4-y1)— lH—pyrazolyl]phcnyl} acetom'trile o-N- {3 -[1 -(l H-pyrrolo[2,3-b]'- 164 $11/£:\NHC0CHZCN 343 pyridin-4—yl)—lH-pyrazoI—4-y11- phenyl} acetamide 165 277 4'[1'(1H‘Pyn'010[2,3-b]pyridin-4—y1)- it 1H-pyrazolyl]pheno1 -[1-(lH-pyrrolo[2,3-b]pyn'din—4-yl)- 1H—pyrazo]—4-y1]nicotinonitrile {4-[1-(1H—pyrrolo[2,3-b]pyridinyl)- 1I‘I'Pyl'a'slzol-4—yl]phenoxy} acetonitrile E! 4-(4-cyclohex-1 -en-l -y1-1 H-pyrazol-l - yl)—1H—pyrrolo[2,3 -b]pyridine 4—[4—(4-methoxyphenyl)—1 H—pyrazol—l - yl]— l H-pyrrolq[2,3-b]pyridine Z Z 4-(4-pyrimidinyl-1H-pyrazol-l -yl)- 1H—pyrrolo[2,3-b]pyridine 0Z 3-{hydroxy[l -(1H-pyrrolo[2,3-b]- NH pyridin-4—yl)— l H—pyrazol~4-yl] — methyl} benzonitrile E cyclohex-1 ~en-l-y1methyl)-1H- pyrazol-l —y1]-1H-pyrrolo[2,3-b]pyridine Table 10 (fin—z 4—[1 dimethoxybenzyl)-1H— pyrazol—4-yl]-1H-pyrrolo[2,3- b]pyridine 4-[1 -(l -phenylethy1)-1H-pyrazol yl]-lH-pyrrolo[2,3-b]pyridine 3—{[4-(1H—pynolo[2,3-b]pyridin~4- yl)-1H-pyrazol-l — Ex 201 hyl} benzonitrile 2‘{[4-(1H—pyrrolo[2,3—b]pyridin yl)-lH-pyrazol-1 - Ex 201 yl]methyl} benzonitrile 4- {[4-( lH—pyrrolo[2,3-b]pyridin yl)-1H—pyrazol-1 - BX 201 yl]methyl} benzonitrile l~phenyl—2-[4-( l H—pyrrolo[2,3- b]pyridinyl)-1H—pyrazol-1 - BX 201 yl]ethanone 3,3-dimethyl-l -[4—(1H—pyrrolo[2,3- b]pyridin—4—yl)- 1H-pyrazol-l - yl]butan—2-one 4—{ l -[(5-methy1isoxazol yl)methyl]-1H-pyrazol—4—yl } —1 H- pyrrolo[2,3-b]pyridine 4-[1 —(tetrahydro—2H-pyran ylmethyl)-lH-pyrazoly1]- 1 H- pyrrolo[2,3-b]pyridine 4-(1 hexen-l-y1-1H—pyrazol- 4—y1)—lH—pyrrolo[2,3—b]pyridine 4-[1 -( l -ethylpropyl)- 1 H-pyrazol yl]—l H-pyrrolo[2,3-b]pyridine 267 4-(1-cyclohexyl-lH-pyrazolyl)— lH—pyrrolo[2,3-b]pyfidine 2-[4-(1H—pyrrolo[2,3-b]pyn'din—4-yl)- l zol— 1 -yl]acetamide -(1H—pyrrolo[2,3-b]pyridin yl)-1H-pyrazol-l -y1]methyl} biphenyl- 2—carbonitrile 4-[1-(2-nitrobenzyl)-1H—pyrazol—4- y1]—1H-pyrrolo[2,3-b]pyridine 4-{1~[2,6-dichloro (trifluoromethyl)phenyl]- l H—pyrazol- 4-3/1} -1 H—pyrro]o[2,3-b]pyridinc 220 320 e"\/©\ 4-[1 -(3-nitrobenzyl)-1H—pyrazoI No2 yl]‘lH—pyrrolo[2,3 -b]pyridine 221 I1») U1 "W (II U: 4—[1 —(2-bromobenzyl)-1H-pyrazol "M6 yl]-lH-pyrrolo[2,3-b]py1idine 222 332 ENNHCGW N-phenyl-Z-[4-(1 H~pyrrolo[2,3 - dinyl)-1H-pyrazol~l — yl]propanamide 4- { 1-[3 -(trifluoromethoxy)benzy1]- azol—4—yl} ~l H-pyrrolo[2,3- b]pyridine 4-{ l -[2—fluoro—5—(trifluoromethyl)— benzyl]-lH-pyrazoIy1}-1H- pyrrolo[2,3-b]pyridine 4- {1 —[3~(tn'fluoromethyl)benzyl] -1 H— pyrazol—4~yl} -1 H—pyrrolo[2,3- b]pyridine 4-[1-(pyridinylmethyl)-1H- pyrazolA~yl]—1H-pyrrolo[2,3— dine 4— { l —[( l S)-l —phenylbuty1]-l H- pyrazol—4-yl} -1H-pyn-olo[2,3— b]pyridine 4-{1-[(1R)phenylbutyl]-1H- pyrazol—4—yl} —1H—pyrrolo[2,3— b]pyridine 1—phenyl—2-[4-( l H-pyrrolo[2,3- b]pyridin—4—yl)-1H-pyrazoI—1 - yl]propan-1 -one 4-[1—(2,6-dichlorobenzyl)—1H- 343, 345 pyrazolyl]-1H—pyrrolo[2,3- b]pyridine 4-[1 dimethylphenyl)-1H— l—4—yl]~1H—pyrrolo[2,3- b]pyridine 2—[4—( 1H-pyrrolo[2,3 -b]pyridiny1)- lH-pyrazolyl](trifluoromethyl)- benzonitrile 4—[1 —(4—bromo—3,5,6-trifluoropyridin- 393, 395 _—Z 2—yl)-1H-pyrazolyl]-1H- w TI\/'|'I DJ.1 pyrrolo[2,3-b]pyridine 4-[1 -(cyclopropylmethyl)—1 H- pyrazolyl]-1 H—pyrrolo[2,3— b]pyridine 4-[1-(2,5—dimethylphenyl)-lH— pyrazoly1]-1H-pyrrolo[2,3- b]pyn'dine 4-[1 -(2-methy1phenyl)-lH—pyrazol yl]-1H—pynolo[2,3-b]pyridine 4-[1-(2-methoxyphenyl)-1H-pyrazol— 4—y1]—1H—pyrrolo[2,3-b]pyridine 3—{1-[4-(1H—pyrrolo[2,3-b]pyridin—4- yl)-1H—pyrazol—l - yl]ethyl} benzonitrile ro[4-(1H-pyrrolo[2,3- b]pyn'dinyl)-1H—pyrazol-l - yl]benzonitn'le 4-[1 -(1 -cyclohexylethyl)-1 H—pyrazol- l H-pyrrolo[2,3-b]pyridine 4-fluoro[4-(1H-pyrrolo[2,3- b]pyridin—4~yl)—l zol-l - y1]benzonitrile 2-fluoro[4-(1H-pyrrolo[2,3 ~ b]pyridin—4-y1)-1H—pyrazol-l - yl]benzonitrile 3-fluoro[4—(1H-pyrrolo[2,3- din-4—y1)-1 H-pyrazol-l - yl]benzonitrile 4—(1 - { 1-[3—(triflu0romethyl)— pheny1]ethy1}—1H-pyrazoly1)-1H~ pyrrolo[2,3-b]pyridine 4—[1 -(3,5-dimethylphenyl)-1H- pyrazol—4—yl]—lH—pyrrolo[2,3- dine 4~[4-(1H—pyrrolo[2,3—b]pyridin~4-yl)- lH-pyrazol-l -y]]benzonitrile {4-[4-(1H-pyrrolo[2,3—b]pyridin—4— yI)-1H-pyrazol—1 - yl]pheny1} acetonitn'le 4-[1—(1 -methy1hexyl)- 1 H-pyrazol—4- yIJ—I H—pynolo[2,3~b]pyridine 4~(] -sec-butyl—1H-pyrazo]yl)-1H— pyrrolo[2,3—b]pyridine 4—[ l -(l -phenylpropyl)—1H—pyrazol-4— yl]-lH-pyrrolo[2,3-b]pyridine 4-(1—{ l -[4-(methylsulfonyl)- phenyl]ethyl} -1 H-pyrazol—4-yl)- 1H- pyrrolo[2,3-b]pyridine YCE:CH3 4-{1 -[1 —(3-fluoro-4—methoxy- pheny1)ethy1]-1H-pyrazol-4—yl}-I H- BX 250 pyn‘olo[2,3-b]pyridine 4-(1 - {‘1 -[2-(trifluoromethyl)- 255 357 RD pheny1]ethyl}-lH-pyrazolyl)-1H— BX 250 pyrrolo[2,3—b]pyridine 4—(1 -{ l — [3 ,5—bis(tn’fluoromethyl)— 256 425 £50 phenyl]ethyl} -1H-pyrazolyl)-1H- BX 250 pyrrolo[2,3-b]pyridine 4-{1 -[4-(l H-pyrrolo[2,3~b]pyridin—4— 257 314 50 -pyrazol BX 250 yl]ethyl} itrile 4— {1 -[4—nitro—2— 258 374 6:: (tn'fluoromethyl)phenyl]—1 H—pyrazol- BX 286 4—yl} - 1 olo[2,3-b]pyridine 3—methyl[4—(1H-pyrrolo[2,3— 259 b]pyridinyl)-1H-pyrazol-l - BX 286 1L," yl]benzonitri1e :6 4-[1 -(2—chlorophenyl)-1H-pyrazol—4- Ex 231 3-bromo—4—[4-(l H-pyrrolo[2,3- 261 64, 366 b]pyridin—4-yl)—1 H—pyrazol—l - BX 286 ‘lLL yl]benzonitri1e COzcsz 262 ethyl 4-[4-( 1 H-pyrrolo[2,3-b]pyn'din— BX 286 ‘1’102N 4-y1)-lH-pyrazol-l-y1]benzoate 4-{ 1 -[2-chloronitro(trifluoro- 263 408, 410 ‘1‘; methyl)pheny1]—1H—pyrazol—4-y1}-1H- BX 286 pyrrolo[2,3-b]pyridine 4—( l -{1 -[4-(trifluoromethy1)— 264 phenyl]ethyl} -1H—pyrazolyl)-1H- BX 250 pyrrolo[2,3-b]pyridine 4—[1—(2,3~dihydro~lH—inden~1~yl)—1H— pyrazol—4-yl]—1H—pyrrolo[2,3 - Ex 250 b]pyridine l4-[1-(1,2,3,4-tetrahydronaphthalen-l- yI)—1H-pyrazolyl]-lH-pyrrolo[2,3- dine 4-(1 — { I -[2-chloro(trifluoromethyl)- phenyl]ethyl} -1H—pyrazol-4—yl)~l H- o[2,3-b]pyridine 4—{1-[1-(2,4-dichlorofluoro- phenyl)ethy1]-lH—pyrazol-4—yl}-1H- pyrrolo[2,3-b]pyridine 4-[1-(1 -cyclopentylethyl)-1H- pyrazol»4~yl]—1H-pyrrolo[2,3- b]pyridine 4-[1 -(1 -methy1-3 lpropyl)-1H- pyrazol—4—yl]-1H—pyrrolo[2,3— b]pyridine 4—[1-(1 -cyclobutylethyl)— l H—pyrazol- 4-y1]-1H-pyrrolo[2,3-b]pyridine [2-[4-(1H—pyrrolo[2,3—b]pyridin y1)-1 H-pyrazol-l -yl] (trifluoromethyl)phenyl]acetonitrile (1H-pyrrolo[2,3-b]pyridin-4— yl)-l H-pyrazol-l -yl] (trifluoromethyl)phenyl]acetonitrile 4-{1—[(3E)—penteny1]-1H— pyrazol-4—yl} -1 H-pyrrolo[2,3 — b]pyridine 2—[4—(1H-pyrrolo[2,3—b]pyridiny1)- lH—pyrazol-l -yl]propanenitrile 4-{ 1 —[(3E)—4-pheny1but—3—en-l -yl] - lH-pyrazol—4—yl} -1H-pyrrolo[2,3- b]pyridine 6—[4-(1H-pyrrolo[2,3-b]pyridin—4-yl)— lH-pyrazol-l —yl]hexanenitrile ethyl 3—amino { [4-(1 H-pyrrolo [2,3— b]pyridin—4-yl)-1 H—pyrazol-l -yl] - methyl}propanoate ethyl lH—pynolo[2,3—b]pyridin— 4-yl)-l H-pyrazol-l -yl]propanoate WO 70514 4-[1 -(1 lbutyl)— l H—pyrazol-4— yl]-lH—pyrrolo[2,3-b]pyridine 4'[4'(1H-pyrrolo[2,3-b]pyridin—4-y1)- 1 H'Pyl‘azol—l -yl]butanenitrile [3-chloro[4-(1H-pyrrolo[2,3- 402, 404 b]pyridiny1)-1H-pyrazol-l -yl] (trifluoromethyl)phenyl]acetonitrile -[4—(1H—pyrrolo[2,3-b]pyridinyl)- lH-pyrazol—l -yl](trifluoromethyl)- benzonitrile 4- { I - [2-chloro(trifluoromethyl)- 363, 365 ' pheny1]—1H-pyrazolyl}-1H- pyrrolo[2,3-b]pyridine 4-[4-(1H—pyrrolo[2,3-b]pyridin—4-yl)- 1 H-pyrazolyl](trifluoromethyl)- benzonitn'le 2-[4—(1H-pyrrolo[2,3—b]pyridin-4—y1)_ lH-pyrazol-l-yubenzonitrile 3-chloro—2-[4-(1H-pyrrolo[2,3- 320, 322 b]pyridin—4-yl)-1H-pyrazol-1 — yl]benzonitrile 4-amino—5,6-difluoro-2—[4-(1H- pyrrolo[2,3-b]pyfidinyl)-1H- pyrazol-l-yl]isophthalonitrile 1- { [4-( l H-pyrrolo[2,3-b]pyridin yl)-1H—pyrazolyl]methy]}- ropanccarbonitrile -[4-(1H-pyrrolo[2,3-b]pyridin-4—yl)- lH—pyrazol-l -yl]hexanenitrile methyl[4-(1 H-pyrrolo[2,3 - b]pyridin-4—yl)-1H—pyrazol-1 -yl]- hexanenitrile 4-[1 -(1 -ethylmethylpropyl)—1H- pyrazol-4—y1]-1H—pyrrolo[2,3— b]pyridine o[4-(1H-pyrrolo[2,3- 294 364, 366 .771 b]pyridin—4-yl)-1H—pyrazoI-l - yl]benzonitrile 3-[4-(1H—pyrrolo[2,3-b]pyfidinyl)- 1 H-pyrazol- 1 ~yl](trifluoromethyl)- benzonitrile 2~[4-(1H—pyrrolo[2,3-b]pyridin—4—y1). lH-pyrazoI-l-yl](mfluoromcthy1)- benzonitrile 3-[4-(1H-pyrrolo[2,3-b1pyridin.4.y1)- lH-pyrazol-l -yl](trifluoromethy1)- benzamide 3-[4-(1H—pyrrolo[2,3-b]pyridin—4-yl)- azolyl]cyclohexanone 2'[4'(1H'PYIT010[2,3-b]pyn'dinyl)— lH-pyrazol—l -y1] cyclohexanol 4-(1 — {[1 -(methylsulfony1)piperidin—4- yl]methyl} —l H—pyrazol—4~yl)— 1 H— pyrrolo[2,3-b]pyn'dine 2-[4-(1H-pyrrolo[2,3—b]pyridinyl)- 1 H—pyrazol-l - yl]cyclohexanecarbonitrile 4- { 1 -[2-(trifluoromethyl)phenyl]-1 H- pyrazoly1} -1 H-pyrrolo[2,3- b]pyridine 4-[1-(2,6-dichlorophenyl)-1H- U.) [\J"\0 DJ ()3 r—A pyrazol- 1 H-pyrrolo[2,3 -b]pyridinc (4— {[4-(1H—pyrrolo[2,3-b]pyridin yl)-1H-pyrazol-1 -yl]methyl} — cyclohexyl)methanol 4-[1 -(tetrahydrofi1rany1methyl)- azol—4-yl]—1H-pyrrolo[2,3- b]pyridine 4-[1 -(1 —cyclopentylpropyl)—l H- pyrazol- 4—yl]—1H—pyrrolo[2,3-b}pyridine 4-[1 -(tetrahydrofuranylmethyl)- 1H-pyrazolyl]—l olo[2,3- b]pyridine 2-chloro[4—(1H-pyrrolo[2,3- b]pyridin—4-yl)—lH—pyrazol-l - y1]benzonitn'le 3-[4-(1H—pyrrolo[2,3—b]pyridin—4-yl)— azol-l -y1]—3~(1 ,3-thiazol—5-yl)- .propanenitrile l 1-4~ H-pyITolo[2,3-b] — pyridinyl)-lH—pyrazol-l -yl]- methyl}pyrrolidin—Z-one 3-(1-methyl-lH-imidazol-S-y1)[4- (1H-pyrrolo[2,3-b]pyridiny1)-1H- pyrazolyl]propanenitrile 3-[4-(1H-pyrrolo[2,3—b]pyridin—4—yl)— 1H-pyrazol-1—y1](3- thienyl)propanenitn'1e { 1H—pyrrolo[2,3—b]pyridin—4— yl)-1H-pyrazol y1]cyclopenty1} acetonitrile 4-chloro[4-(1H-pyrrolo[2,3— 314 320, 322 b]pyridin—4—y1)-1H—pyrazol-l - yl]benzonitrile 4-[4-(1H—pyrrolo[2,3-b]pyridin—4-yl)— l H-pyrazol-l —yl]phthalonitrile 3—methyl—4-[4—(1H-pyrrolo[2,3- b]pyridin—4-y1)-l H—pyrazol-l - yl]benzaldehyde 4—[1—(2-methyl—4-nitrophenyl)-1H- pyrazol—4-yl]-I H-pyrrolo[2,3- b]pyridine 3-[4-( l H-pynolo[2,3-b]pyridin—4—,yl)- BX 201 1 H—pyrazol-l -yl]cyclopentanone 4-[1 -(3~furylmethy1)—l H—pyrazol—4— BX 201 yl]-lH-pyrrolo[2 3-b]pynd1ne 4-[1 -(2-furylmethyl)-lH—pyrazol—4- Ex 20‘ yl]-1H—pyrrolo[2,3—b]pyridine 3—{2Qcyano-1~[4—(1H~pynoio[2,3.b]- pyridin—4-y1)-1H—pyrazol-I -yl]ethyl}- benzonitrile {3~methyl-4—[4-(1H—pyrrolo[2,3-b]- pyridin—4-yl)-lH-pyrazol-l —yl]- phenyl}methanol 4—methyl-4—[4—(1H-pyrrolo[2,3- b]pyridiny1)—1H-pyrazol-1 - yl]pentan-2—one 3-(1 -benzofuran~2—yl)—3-[4—(1H— pyrrolo[2,3—b]pyridin—4-yl)-1 H- l~1 opanenitrile trifluoroacetate 3-(3-furyl)[4-(1H-pyrrolo[2,3—b]- pyridinyl)-lH-pyrazol—1 -yl]~ propanenitn'le {3—methyl[4-( 1H—pyIro10[2,3—b]- pyn'dinyl)-lH-pyrazol-1 -y1]- } acetonitrile 4-methyl-3—[4-(7H—pyrrolo[2,3-d]— pyrimidin—4—yl)—1H-pyrazol-l—yl]- benzonitrile trifluoroacetate 4-[1 -(l —cyclopentylpropyl)- lH- pyrazoly11-7H-pyrrolo{2,3—d]— pyrimidine tn'fluoroacetate { 7H—pyrrolo[2,3—d]pyrimidin~ 4-yl)-lH-pyrazol~l -y1]cyclo- pentyl}acetonitri1e trifluoroacetate 3—{(1R)cyano[4-(7H- pyrrolo[2,3—d]pyrimidinyl)— 1H- pyrazol-l -y1]ethy1}benzonitrile trifluoroacetate 3- {(1 S)—2-cyano-1 —[4-(7H- pyrrolo[2,3-d]pyrimidin—4-yl)-lH- pyrazol— 1 -y1]ethyl}benzonitrile tn'fluoroacetate 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4—y1)-1H-pyrazol-1 -yl]—3 -(3 - thienyl)propanenitrile roacetate 4-chloro-3 —[4—(7H-pyrrolo[2,3-d]- 321, 323 pyrimidin-4—yl)-1H-pyrazol-1 -yl]- benzonitrile 3—(3—fi1ry1)[4-(7H-pyrrolo[2,3—d]- 305 pyrimidin—4—yI)—1 H—pyrazol-l -yl]- propanenitrile 3-[4—(7H—pyrrolo[2,3-d]pyrirnidin- 4-yl)—1H—pyrazol-1 -yl]- pentanedinitrile 4-(7H—pynolo[2,3—d]— pyrimidinyl)-1 zol-l -y1]- cyclopenty1}propanenitrile { l -[4—(7H—pyrrolo[2,3—d1pyrimidin- 4-yl)-1H-pyrazol—1-yl]cyclohexyl}- acetonitrile tn'fluoroacetate {3-methyl-4—[4-(7H-pyrrolo[2,3-d]— pyrimidin—4—yl)-l zol-l -yl] — phenyl}mcthanol tn'fluoroacctatc 3-pyridinyl-3—[4—(7H—pyrrolo~ [2,3-d]pyrimidin—4-yl)-lH-pyrazolyl]propanenitrile 3-pyridin-3 -yl[4-(7H—pyrrolo- [2,3-d]pyrimidin—4-yl)—1H-pyrazol- 1-yl]propanenitrile trifluoroacetate 3-[4-(methylthio)phenyl]—3—[4-(7H— pyrrolo[2,3-d]pyrimidiny1)-1H- pyrazol-l ~y1]propanenitrile trifluoroacetate 3—(3-methoxyphenyl)—3—[4—(7H— pynolo[2,3-d]pyrimidin—4-y1)—1H- pyrazol-l ~y1]propanenitrile trifluoroacetate 3-(4-methoxyphenyl)—3-[4—(7H- pyrrolo[2,3-d]pyrimidin—4-yl)— 1H- l-l opanenitrilc {3—methyl—4-[4-(7H—pyn'olo[2,3-d]- pyrimidinyl)-1 zol-l ~yl]- pheny1}acetonitrile trifluoroacetate 3-[4—(methylsulfinyl)phenyl][4— (7H—pyrrolo[2,3-d]pyrimidin—4-yl)— lH-pyrazol-l -yl]propanenitrile methylsulfonyl)pheny1][4- (7H—pyrrolo[2,3—d]pyrimidin»4—yl)- 1 H-pyrazol-l -y1]propanenitrile 3—[3—(cyanomethoxy)phenyl]—3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4—y1)- lH-pyrazol-l -yl]propanenitrile 3-(6-chloropyridin—3—yl)—3—[4-(7H- pyrrolo[2,3-d]pyrimidinyl)-1H— pyrazol-l -y1]propanenitrile - {2-cyano-1 -[4-(7H-pyrrolo- [2,3-d]pyrimidin—4—y1)—1H-pyrazoly1]ethyl}pyridine-2—carbonitrile trifluoroacetate 3—(3,5—dimethy1isoxazolyl)[4— (7H—pyTrolo[2,3-d]pyrimidin—4-yl)— lH—pyrazol—1 -y1]propanenitrile trifluoroacetate 3-[4-(7H—pyrrolo[2,3-d]pyrimidin- 4-y1)—1 H—pyrazol—l -[6— (trifluoromethyl)pyridin-3 -yl]- propanenitfile trifluoroacetate 3-(6-mcthoxypyridiny1)~3-[4- (7H-pyrrolo[2,3 ~d]pyrimidinyl)- 1 H—pyrazol— 1 -yl]propancnitrile trifluoroacetate 3-pyridiny1[4-(7H—pyrrolo- [2,3»d]pyrimidiny1)-1 H—pyrazoly]] propancnitrile 3-(6-bromopyridinyl)[4-(7H— pyrrolo[2,3-d]pyrimidin—4-yl)—1H- l—l —y1]propancnitrile trifluoroacetate 6— {2—cyano- l -[4-(7H—pyrrolo[2,3- d]pyrimidin—4-yl)—1H—pyrazol-l -yl] — pyridine-Z—carbonitrile trifluoroacetate 4-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-y1)-1H—pyrazol—1—yl]- heptanedinitrile 3-(5—bromopyridin—3-yl)—3—[4-(7H- pyrrolo[2,3-d]pyn'midin—4-yl)-1H- pyrazol—l ~yl]propanenitrile 4-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)- l H-pyrazol-l —yl] - heptanedinitrile — no-1 ~[4—(7H—pyrrolo— [2,3-d]pyrimidin—4-yl)-1H—pyrazol- 1 —yl] ethyl} nicotinonitrile trifluoroacetate 3-(2-methoxypyridin—3-y1)[4- (7H-pyrrolo[2,3-d]pyrimidin—4-yl)- 1 H-pyrazol— 1 -yl]propanenitrile trifluoroacetate 3-[4-(cyanomethoxy)phenyl]-3 -[4- (7H-pyrrolo[2,3-d]pyfimidin—4—yl)— 1 H-pyrazoly1]propanenitn'le trifluoroacetate 3-[2-(cyanomethoxy)pheny1]-3 -[4- (7H-pyrrolo[2,3-d]pyrimidin~4-yl)— 1 H—pyrazol-l -yl]propanenitrile roacetate 3-(3 ,5—dibromophcnyI)[4—(7H- pyrrolo[2,3-d]pyrimidin—4—yl)—1 H— pyrazol-l -yl]propanenitrile — {2-cyano-1 -[4-(7H-pyrrolo- [2,3-d]pyrimidin—4-yl)-1 H-pyrazolyl] ethyl} isophthalonitrile roacetate 3—[6-(dimethylamino)pyridin—2—y1]— 3-[4-(7H-pyrrolo[2,3 -d]pyfimidin- 4-yl)-1 H—pyrazol-l —yl]propane- nitrile roacetate 3-(4—bromothienyl)[4—(7H- pyrrolo[2,3-d]pyrimidin—4-yl)-1H- pyrazol—l -yl]propanenitrile trifluoroacetate — {2-cyano-1 -[4-(7H—pyrrolo~ [2,3-d]pyrimidin—4-yl)-1 H-pyrazoly1] ethyl} thiophenecarbonitrile trifluoroacetate 3-(5-bromofluoropheny1)—3-[4- (7H—pyrrolo[2,3-d]pyrimidin—4—yl)- lH-pyrazol-l -yl]propanenitrile trifluoroacetate itrophenyl)[4—(7H— pyrrolo[2,3-d]pyrimidin-4—yl)-1H- pyrazol-l -y1]propanenitrile trifluoroacetate 3-(5-bromomethoxyphenyl)—3- [4-(7H—pyrrolo[2,3-d]pyrimidin yl)-1H—pyrazol—l opanenitrile 3— {2—cyano—1 —[4—(7H-pyrrolo- ]pyrimidin—4-yl)-lH-pyrazolyl] ethyl} methoxybenzonitrile trifluoroacetate 3-(3-bromophcnyl)—3—[4-(7H— pyrrolo[2,3—d]pyrimidin~4-yl)-lH- pyrazol-l -yl]propanenitrile trifluoroacetate 3- {2-cyano-1 -[4-(7I-I-pyrrolo- [2,3-d]pyrimidinyl)—lH—pyrazol- 1 —yl]ethyl } —4—fluorobenzonitrile trifluoroacetate 3-[5-bromo(cyanomethoxy)- ]—3-[4-(7H—pyrrolo[2,3-d] - pyrimidin—4-yl)—1H-pyrazol-1 -y1]- enitrile 3-(4-bromofuryl)-3 -[4-(7H— pyrrolo[2,3-d]pyrimidin—4-yl)-1H- pyrazol-l -yl]propanenitrile 4—(cyanomethoxy)—3—{Z-cyano—l — [4-(7H-pyrrolo[2,3-d]pyrimidin~4- yl)-1H—pyrazol-1 -y1]ethy1} - benzonitrile trifluoroacetate 3—(4—bromopyridin—2-yl)—3 -[4—(7H— pyrrolo[2,3-d]pyrimidinyl)—1H- pyrazol-l —yl]propanenitrile 2- {2-cyano-1 -[4-(7H-pyrrolo- [2,3-d]pyrimidin—4-yl)—1H-pyrazol- l —y1] ethyl} isonicotinonitrile tn'fluoroacetate —{2-cyano-1—[4—(7H—pyrrolo[2,3- midinyl)—1H—pyrazol— 1 —y1]~ ethyl} -3 -fi1ronitn'le trifluoroacetate 3-[2-bromo(cyanomethoxy)- phenyl]—3-[4~(7H—pyrrolo[2,3-d]— pyrimidinyl)—1 H—pyrazol-l —yl]- propanenitrile 4—(cyanomethoxy)-2— {2-cyano-1— [4-(7H—pyrrolo[2,3-d]pyrimidin—4- yl)—1H-pyrazol-1 -yl]ethyl} - benzonitrile trifluoroacetate 3-pyrirnidin—5~yl—3—[4-(7H—pyrrolo- [2,3—d]pyrimidin—4-yl)-lH—pyrazol— l-yl]propanenitrile trifluoroacetate 3—(2—bromopyridin—4—yl)—3 H— pynolo[2,3-d]pyrimidin-4—yl)—1H- pyrazol- 1 —y1]propan§nitrile trifluoroacetate 4- {2-cyano-1 -[4-(7H-pyrrolo- [2,3-d]pyrimidinyl)-lH-pyrazol- 1-yl]ethyl}pyridine-Z-carbonitrile trifluoroacetate 3-(5—methoxypyridiny1)[4- (7H—pyrrolo[2,3-d]pyrimidin-4—yl)- 1H-pyrazol-l -yl]propanenitrile trifluoroacetate 3-(3-chloropheny1)-3 -[4-(7H- pyrIolo[2,3-d]pyrimidin—4-yl)-1H- pyrazol-l opanenitrile trifluoroacetate 3-[4-(7H-pyrrolo[2,3-d]pyrimidin— 1H-pyrazol-1 -yl]-3 -[3 - (trifluoromethyl)phcnyl] - propanenitrile trifluoroacetate 3-(3 ~phenoxyphenyl)—3 -[4-(7H- o[2,3-d]pyrimidinyl)-1H- pyrazoly1]propanenitrile roacetate 3-[4—(7H-pyrrolo[2,3-d]pyrimidin- 4—yl)—1H-pyrazol-l -yl][3- (trifluoromethoxy)phenyl]propane- nitrile trifluoroacetate methyl 3- {2-cyano-l ~[4-(7H- pyrrolo[2,3—d]pyrimidin—4-yl)-1H- l-l -y1]ethyl}benzoate 3-{2-cyano-1 -[4-(7H—pyrrolo- [2,3-d]pyrimidinyl)- 1H-pyrazol- l-yl]ethyl} benzoic acid 3-[3 -( l H-pyrazol—4-yl)phenyl]—3 —[4— (7H-pyrrolo[2,3-d]pyrimidin—4-yl)- 1 H-pyrazol—l -yI]propanenitn'le 3-(3-aminophenyl)-3 —[4—(7H- pyrrolo[2,3-d]pyrimidin—4-yl)— 1H— pyrazol—l -y1]propanenitrile Bis trifluoroacetate N-(3-{2-cyano—1-[4—(7H— o[2,3—d]pyrimidin—4—yl)— 1H— l-l —y1]ethyl }phenyl)- acetamide trifluoroacetate N-(3-{2-cyano[4—(7H- pyrrolo[2,3-d]pyrimidinyl)—1H- pyrazoI-l -yl]ethyl}phenyl)- methanesulfonamide 4-{2-cyano[4-(7H—pynrolo- [2,3 -d]pyrimidinyl)-1H-pyrazol— l -yl] ethyl} ene—Z—cafbonitrile trifluoroacetate S-{2—cyano-1—[4—(7H-pyrrolo— [2,3 -d]pyrimidin—4—yl)-lH—pyrazolyl]ethyl} thiophene-Z-carbonitrile trifluoroacetate 3-[3-(morpholinylcarbonyl)- phenyl]—3-[4-(7H-pyrrolo[2,3-d]- pyrimidin—4-yl)-l H-pyrazol-l -yl] - propanenitrile trifluoroacetate N—(2-aminoethyl){2—cyano—1 -[4- rrolo[2,3-d]pyrimidin—4-yl)- lH-pyrazol-l -yl]ethyl} benzamide Bis trifluoroacetate WO 70514 3—(5-formyl-3 ~thienyl)[4-(7H— pyrrolo[2,3-d]pyrimidinyl)—1H- pyrazol—l -yl]propanenitrile trifluoroacetate 3—{2—cyano-1—[4—(7H-pyrrolo- [2,3—d]pyrimidin-4—yl)~1H—pyrazolyl] ethyl} -N-methy1benzamide trifluoroacetate 2—cyano—N—(3— {2—cyano-1 -[4-(7H« pyrrolo[2,3-d]pyrimidin—4-yl)-1H- I—l —yl]ethyl} phenyl)- acetamide trifluoroacetate N-(3-{2-cyano-l -[4-(7H- pyrrolo[2,3-d]pyrimidiny1)-1H- pyrazol—l -yl]ethyl }phenyl)- nicotinamide Bis trifluoroacetate N—(3-{2-cyano[4-(7H- pyrrolo[2, 3—d]pyrimidinyl)-1 H- pyrazol-l -yl]ethyl}phcnyI)-N'- isopropylurea roacetate isopropyl (3— no—l -[4—(7H— pyrrolo[2,3-d]pyrimidinyl)-1H— pyrazol—l ~y1]ethyl}phenyl)— carbamatc tn'fluoroacetate henylpyridin—3-yl)—3-[4-(7H- pyrr010[2,3-d]pyrimidinyl)—1H- pyrazol-l —yl]propanenitrile- trifluoroacetate 3—(3,3'—bipyridin-5—y1)[4—(7H— pyrrolo[2,3-d]pyrimidin-4—yl)-1H- pyrazol-l -y1]propanenitrile- trifluoroacetate 3-(5-pyrimidin—S~ylpyridin—3~y1)-3 - —pyrrolo[2,3—d]pyrimidin yl)—1H—pyrazolyl]propanenitrile 3-[5-(1-methyl—lH-pyrazolyl)- pyridin—3~y1]~3—[4-(7H—pyrrolo[2,3- d]pyrimidin—4-yl)—lH—pyrazol-l -yl]- propanenitrile trifluoroacetate 3-(5—ethynylpyfidin—3—yl)—3—[4-(7H— pyrrolo[2,3-d]pyrimidin—4-yl)-I H- pyrazol—l opanenitrile trifluoroacetate 3—[5-(phenylthio)pyridin—3—yl]-3—[4— (7H—pyrrolo[2,3-d]pyrimidin—4—yl)- lH—pyrazol-l -y1]propanenitrile trifluoroacetate 3-(2-bromo-1 ,3-thiazolyl)[4- (7H-pyrrolo[2,3—d]pyzimidin-4—yl)— lH-pyrazol-1 -yl]propancnitn'lc ethyl 3-[4-(7H-pyrrolo[2,3-d]- pyrimidin—4—yl)-1H-pyrazolyl]- butanoate 3 -(5-morpholinylpyridin-3 -yl)-3 - [4-(7H-pyrrolo[2,3-d]pyrimidin—4— y1)-1H-pyrazol-1 -y1]propanenitn'le ethyl—1H-pyrazol—4-y1)[4— (7H-pyrrolo[2,3-d]pyrimidin—4—yl)- lH-pyrazol—l —y1]propanenitrile 4-{1—[1-pheny1(lH-1,2,4-triazol- l -yl)ethyl]-1 H-pyrazolyl} -7H- o[2,3—d]pyrimidine 4-{1-[1 -phenyl(4H-1 ,2,4—triazol— 4-yl)ethyl]-l H-pyrazolyl} ~7H— pyrrolo[2,3-d]pyrimidine 3—(3-pyridin—3 —ylphenyl)-3 H— pyrrolo[2,3—d]pyrimidin—4—yl)—1 H- pyrazol-l -yl]propanenitrile 3~[5-(phenylsulfinyl)pyridiny1]- 3—[4-(7H—pyrrolo[2,3—d]pyrimidin— 4—yl)-1H-pyrazol—1 -yl]propane- nitrile trifluoroacetate 3-[5 -(phenylsu1fony1)pyridin—3~yl] — 3-[4-(7I-I—pyrrolo[2,3-d]pyrimidin- 4-yl)-1H-pyrazol-1 -y1]propane~ nitrile roacetate 3-[4—(7H—pyrrolo[2,3—d]pyrimidin- 4-yl)-1 zol-l -yl]pentan-1—ol methyl 7H~pyrrolo[2,3-d]— pyrimidinyl)—1H-pyrazol—l -y1] — pentyl carbonate (1 E)—3~[4~(7H—pyrrolo[2,3—d]- pyrimidinyl)-1H-pyrazol-l -yl]- pentanal oxime (1E)—3~[4—(7H-pyrrolo[2,3-d]- din-4—y1)-1H—pyrazol-1 ~yl]- pentanal O-methyloxime (lZ)—3-[4—(7H—pyrrolo[2,3-d]- pyrimidin—4~yl)— 1 H—pyrazol—l -yI] — pentanal O-methyloxime 4-[1 -(4,4-dibromo-1 —ethylbut—3-en— 1 —yl)-1H~pyrazol—4-yl]-7H— pyrrolo[2,3—d]pyrimidine trifluoroacetate 3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4—yl)-1H—pyrazol-l-yl][5-(l,3- thiazol—Z—ylthio)pyridin-3 -y1]- propanenitrile bis(trifluoroacetate) 3-[5~(ethylthio)pyridin-3 -yl]—3 -[4- (7H—pyrrolo[2,3-d]pyn'midin-4—yl)— lH—pyrazol-l -y1]propanenitrile 4-[1 ~(1 butynyl)-1H- pyrazol—4-yl]-7H-pyrrolo[2,3— d]pyrimidine trifluoroacetate 4-{1—[l—methyl—2-(1H-1,2,4-triazol~ 1 -y1)ethyl]-1H—pyrazolyl} -7H- pyrrolo[2,3-d]pyrimidine 4-[4-(7H-pyrrolo[2,3—d]pyn'midin— 4-y1)-1 H—pyrazol-l —yl]pentanone trifluoroacetate 1 l[4-(7H-pyrrolo- [2,3-d]pyrimidinyl)-1H-pyrazolyl]propan—1 —one 3—[5—(ethylsulfinyl)pyn'din—3-yl] [4-(7H-pyrrolo[2,3 -d]pyrimidin y1)-1 H-pyrazol— 1 -yl]propanenitrile 3-[5-(ethylsulfonyl)pyn'din-3—y1] [4-(7H-pyrrolo[2,3-d]pyrimidin—4— yl)-1H-pyrazol-1—yl]propanenitrile 3-[5-(cyclohexy1thio)pyridinyl]- 7H-pyr:rolo[2,3-d]pyrimidin- 4—yl)-lH-pyrazol—l —y1]- propanenitrile 1 -phenyl[4-(7H-pyrrolo— [2,3-d]pyrimidin—4—yl)—] H—pyrazolyl]propan-1 -ol 1 -phenyl[4-(7H—pyrrolo[2,3—d]- pyrimidinyl)—1H-pyrazol-1 -y1]- propan—l -ol 3 -[3 —(ethylthio)phenyl]-3 ~[4-(7H— pyrrolo[2,3—d]pyrimidin—4-y1)—l H- l-l -yl]propanenitrile 3-[3-(ethylsu1finyl)phenyl][4- (7H-pyrrolo[2,3-d]pyrimidiny1)— lH-pyrazol-l -y1]propanenitn'1e 3-[3-(ethylsulfony1)phenyl][4- (7H-pyrrolo[2,3—d]pyn’midiny1)- 407 lH-pyrazol- l -yl]propanenitrile 3-[3-(ethylsulfonyl)phenyl]-3—[4- (7H-pyrrolo[2,3-d]pyrimidinyl)- l H—pyrazolyl]propanenitrilc cyclohexy1sulfonyl)pyridin—3- yl][4—(7H-pynolo[2,3-d]- pyrimidin-4—y1)-1H—pyrazol-l -yl]- propanenitrile 3-[5-(cyclohexylsulfinyl)pyridin—3 — yl]-3 —[4-(7H—pyrrolo[2,3—d]— pyrimidin—4—yl)-1H-pyrazol—l —yl]- propanenitrile 4-[1 -(1 —methyl—2~phenylethy1)—1H— pyrazol~4-y1] -7H-pyrrolo[2,3-d] - pyrimidine 4- {1 -[1 -methyl-2 -(3 -thienyl)ethyl]- 1H-pyrazolyl } -7H-pyrrolo— [2,3-d]pyrimidine 4-(7H-pyrrolo[2,3-d]- pyrimidin—4-yl)-1H—pyrazol-l -yl]- ethy1}benzonitrile 4-{1-[2-(lH-imidazol-l-yl)-l- methylethyl]-1 H—pyrazol—4-y1} -7H— pyrrolo[2,3-d]pyrimidinc 4-{1-[l-methyI(3-mcthyl-1 ,2,4- oxadiazol-S-yl)ethyl]-1H-pyrazol-4— yl} -7H-pyrrolo[2,3 -d]pyrimidine 3—[3—(methylsulfony1)phenyl]-3—[4— rrolo[2,3-d]pyrimidin~4—yl)— 1H—pyrazol— l —y1]propanenitrile 3—(3~pyridin-4~ylphenyl)—3-[4-(7H- pyrrolo[2,3-d]pyrimidin~4-yl)-1H- pyrazol-l -yl]propanenitrile 4— [1 -(l ~ethylbut-3—en—1 ~yI)-l H— pyrazol—4—yIJ-7H-pyrrolo[2,3-d]- pyrimidine 4-[1-(l,3-dimethylbut—3’eny1)- 1H—pyrazolyl]e7H-pyrrolo[2,3— d]pyrimidine 3-[5~(isopropylthio)pyridinyl] [4-(7H-pyrrolo[2,3-d]pyrimidin-4— yl)-1H-pyrazol-l -yl]propanenitrile 3-[5-(isopropylsulfinyl)pyridin—3 - yl]-3 H-pyrrolo[2,3 -d] - pyrimidinyl)-1 H-pyrazol-l -yl]- propanenitrile isopropylsulfony1)pyridin-3 - yl]—3-[4—(7H-pyrrolo[2,3-d] - pyrimidin—4-yl)-1 H-pyrazol-l ~yl] - propanenitrile 3-[4-(7H~pyrrolo[2,3-d]pyrimidin- 4-yI)-lH—pyrazol-l -yl][5- oromethyl)pyridinyl] - propanenitrile 7H—pyrrolo[2,3~d]pyrimidin- 4-yl)- 1 H-pyrazol-l -yl]-3 -[5- (trifluoromethyl)pyridin-3—yl]- propanenitn'le 2-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)—lH—pyrazolyl]-N-[3- (tn’fluoromethyl)phenyl]- propanamide Nnaphthyl—2-[4-(7H-pyrrolo- [2,3-d]pyrimidinyl)—1H—pyrazoly1]propanamide N—l ~naphthyl—2—[4-(7H—pyrrolo— [2,3-d]pyrimidinyl)-1H-pyrazol— 1 opanamide N-(3-cyanophenyl)—2-[4-(7H- pyrrolo[2,3-d]pyrimidinyl)-1 H- pyrazol—l -yl]pr0panamide N-benzyl-Z—[4-(7H—pyrrolo- [2,3-d]pyrimidin~4-yl)- 1H-pyrazol— 1 -yl]propanamide N-phenyl-Z-[4-(7H-pyrrolo[2,3-d]- pyn'midin—4—yl)-1H-pyrazol-l —y1]- butanamide N-(4-phenoxyphenyD[4-(7H~ pyrrolo[2,3-d]pyrimidin—4-yl)~1 H— pyrazol-l tanamide N-Z-naphthyl-Z-[4-(7H-pyrrolo- [2,3-d]pyrimidin—4-yl)-IH-pyrazol- I'-yl]butanamide N-(3-cyanophenyl)-2—[4-(7H— pyrrolo[2,3-d]pyrimidin—4-yl)— 1 H- pyrazol-l tanamide N—biphenyl—4-yl[4-(7H— pyn'olo[2,3-d]pyrimidinyl)-1H- pyrazol—l —yl]butanamide N-(biphenylylmethyl)~2-[4-(7H— pyrrolo[2,3—d]pyrimidin—4—yl)-1 H- pyrazol~1 -yl]butanamide N-(biphenyl-B-ylmethyl)—2-[4-(7H- pyrrolo[2,3-d]pyrimidin-4~y1)—l H~ l-l -yl]butanamidc N-(4-cyanophenyl)—2—[4—(7H— pyrrolo[2,3-d]pyrimidiny1)—1H- pyrazol— 1 ~yl]butanamide 2006/047369 N-l -naphthyl[4-(7H—pyrrolo- [2,3-d]pyrimidin—4-yl)—l H-pyrazolyl]butanamide -{2-cyano-1 -[4-(7H-pyrrolo- [2,3-d]pyrimidiny1) razol- 1-yl]ethyl } —N-phenylnicotinamide tn'fluoroacetate 4- { 1 -[1 —(5-bromopyridiny1)-4,4- difluorobute n-l -y1]-1H-pyrazol- 4-y1} -7H—pyrrolo[2,3-d]pyrimidine 430, 432 - {4,4-difluoro-1 -[4—(7H- pyrrolo[2,3—d]pyrimidin— 4-y1)—1H- l-l -yl]but-3 -en-l - yl } nicotinonitrile (I CN Step 1: Dimethyl 3-[4—(7-{[2-(trimethylsilyl)eth0xy]methyl}-7H-pyrrolo[2, 3-d]pyrimidin-4—yl)-1H- pyrazolyl]pentanedioate 4—(1H-Pyrazol—4—y1)-7—[2—(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (31.0 g, 0.0983 mol) was suspended in ACN (620 mL, 12 mol), and DBU (9.3 mL, 0.062 mol) was added under nitrogen. The reaction was heated to 65 °C and dimethyl (2E)-pentenedioate (16 mL, 0.12 mol) was added in 5 mL portions over 2 h. After stirring overnight, the reaction was complete. The reaction was allowed to cool to room ature and was concentrated in vacuo to give a dark oil. 2006/047369 The oil was partitioned between ethyl acetate and water. The organic layer was washed with 1.0 N HCl, brine, dried over magnesium sulfate, and then concentrated to give a dark oil. The viscous oil was triturated with ethyl ether 3X 500 mL to give a dark precipitate. The oil was taken up in ethyl e to form a solid. The solids were ted, Washed with ethyl ether and dried to give dimethyl 7— {[2-(trimethylsilyl)ethoxy]methyl} -7H—pyrrolo[2,3-d]pyrimidin—4-y1)-lH-pyrazol-l - yl]pentanedioate as a white powder (29.5 gm, 64%), LC IMS (M+H)+: 474, 1H NMR (DMSO-dfi) 5 9.1 (s,lH), 9.02 (s,1H), 8.65 (s, 1H), 8.11 (d, 1H), , 1H), , 2H), 5.27(m, 1H), 3.65(m, 8H), 3.15(m, 4H), 0.950, 2H), 0.1(s, 9H).
Step 2: 3-[4—(7-[2-(Trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin—4~yl)-1H—pyrazol—I-y[]— pentanedioic acid Dimethyl 3—[4—(7-{[2~(trimethylsilyl)ethoxy]methyl}—7H—pyrrolo[2,3—d]pyrimidinyl)~lH- pyrazol-l—yl]pentanedioate (43.0 g, 0.0908 mol) was dissolved in methanol (271.2 mL, 6.695 mol) and lithium hydroxide monohydrate (15 g, 0.36 mol) dissolved in water (125 mL) was added. The reaction was stirred at rt for 2 h. The methanol was removed in vacuo and a resulting aqueous layer was cooled in an ice bath. The solution was made acidic pH~4 with 1N HCl to give a white precipitate. The solid precipitate was collected, washed with water, dried to give 3-[4~(7-[2- (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyn'midin—4—y1)-lH-pyrazol-l -y1]pentanedioic acid as a white crystalline powder (31.8 gm, 80%), LC /MS (M+H)+: 446, IH NMR (DMSO-d5) 5 8.85_slI-l), 8.75(s, 1H), 8.42(s, 1H), 7.85(d, 1H), 7.17(d, 1H), 5.7l(s, 2H), 5.18(m,1H), , 2H), 3.05(m,4I-I), , 2H), 0.1(s, 9H).
Step 3: 3-[4-(7—[2-(TrimethylsilyDethonymethyl-7H-pyrrolo[2,3—d]pyrimidin-4~yl)-1H—pyrazol—l—yl]— pentanediamide 3—[4-(7—[2—(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-l H-pyrazol-l - yl]pentanedioic acid (31.80 g, 0.07137 mol) was dissolved in DMF (636 mL, 8.21 mol) under nitrogen cooled in an ice bath and CD1 (34.7 g, 0.214 mol) was added. This mixture was allowed to stir for 30 minutes and then allowed to warm to rt. Afier stirring for 2 h ammonia (12.2 g, 0.714 mol) was bubbled through the solution for 30 minutes giving a cloudy suspension. The reaction mixture was concentrated to remove some of the DMF (~200 mL) and then water was added slowly to give a white precipitate. This mixture was cooled in an ice bath and the solid precipitate was collected, washed with water and dried in vacuo to give 3—[4-(7—[2-(trimethylsilyl)ethoxy]methyl~7H- pyrrolo[2,3-d]pyrimidinyl)—1H-pyrazoly1]pentanediamide as a white powder (29.0 gm, 91%), LC /MS (M+H)+: 444, 1H NMR (DMSO—a'a) 5 , 1H), 8.59(s, 1H), 8.40(s, 1H), 7.87(d,1H), 7.75(s,2H), 7.15(d, 1H), 6.95(s, 2H), 5.73(s, 2H), 5.29(m,1H), 3.63(t, 2H), 2.82(m, 2H), 2.73(m, 2H), O.90(t, 2H), 0.1(s, 9H).
Step 4: 3-[4-(7—[2-(Trimethylsibl)ethoxyjmethyl-7H-pyrrolo[2,3-d]pyrimidin—4—yl)-1H~pyrazol—1~yl]- pentanedinitrile 3—[4'(7—[2{Trimethylsilyl)eth0xy]methyl-7H—pyn'olo[2,3-d]pyrimidin—4—yl)~1H—pyrazol-l - yl]pentanediamide (29.0 g, 0.0654 mol) was partially dissolved in DMF (200 mL, 2 mol), DCM (200 mL, 3 mol) and TEA (36 mL, 0.26 mol) and cooled in an ice bath under en atmosphere. The trichloroacetyl chloride (15 mL, 0.14 mol) was added dropwise turning the reaction to a dark solution.
This was stirred at 0 °C for 1/2 h. The reaction was then concentrated to remove the DOM and the resulting DMF solution was diluted with water to precipitate the product. The solid precipitate was collected and washed with water to give a dark solid. The solid was then dissolved in DCM and washed with brine, dried over magnesium sulfate and concentrated to give a very dark oily residue.
The e was taken up in DCM, and hexane was added until the on became slightly cloudy.
This was stirred at rt to precipitate 3—[4—(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3-d]- pyrimidin—4-yl)-1H-pyrazol-l —y1]pentanedinitrile as whiteneedle—like crystals (22.7 gm, 85%), LC /MS (M-l-HT': 408, 1H NMR (DMSO-ds) 8 9.07(s, 1H), 8.87(s, 1H), 8.59(s, 1H), 7.88(d, 1H), 7.19(d, 1H), 5.75(s, 2H), ,1H), 3.62(t, 2H), 3.40(m, 4H), O.91(t, 2H), 0.10(s, 9H).
Step 5: 3-[4-(7H—Pyrrolo[2, 3-djpyrz'midin—4-yD-1H—pyrazol—I—yUpentanedinitrile 3—[4-(7-[2~(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)- l H-pyrazol-l - tanedinitrile (10.0 g, 0.0245 mol) was dissolved in ACN (200 mL, 3.83 mol) and water (20 g, 1.1 mol) at rt. To this lithium uoroborate (23.0 g, 0.245 mol) was added giving a cloudy solution. The on was heated to reflux and monitored by HPLC. Afier heating for 24 h the reaction was allowed to cool to It and then cooled in an ice bath. To this, ammonium hydroxide (23 mL, 0.59 mol) was added slowly. The on was allowed to warm to rt. After stirring for 18 hs the reaction was diluted with water and concentrated in vacuo to remove the ACN, giving a precipitate.
The solids were collected, washed with water and dried to give the title compound as an off—white solid (6. 2 gm, 91%), LC [MS (M+H)+: 278, 'H NMR dé) 5 8.9(s, 1H), 8.72(s,1H), 8.43(s, 1H), 7.59(d, 1H), 6.92(d, 1H), 5.21(m,1H), 3.25(m, 4H).
Example 421: 5—{2-Cyano—l-[4-(7H-pyrrolo[2,3-d]pyrimidin—4—yl)—lH—pyrazol-l-yl]ethyl}- pyridine-Z-carbonitrile trifluoroacetate \ / CN "'0 \ N/ [:1 Step 1: 3-(6—Chloropyridin-3—yl)—3—[4—(7H-pyrrolo[2,3-d]pyrimidin—4—yl)—IH—pyrazol—I-yl]propane— nitrile 3—(6-Chloropyridinyl)[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]— pyrimidin-4—yl)-lH~pyrazolyl]propanenitrile (prepared by methods analogous to those described for Example 61) (0.070 g, 0.00014 mol) in TFA (3.0 mL, 0.039 mol) and DCM (3.0 mL, 0.047 mol) was stirred at room temperature for 1 hour. Solvent was removed in vacuo, and the residue was dissolved in methanol (4.0 mL, 0.099 mol) and nediamine (0.07 mL, 0.001 mol). The reaction mixture was stirred at room temperature overnight. Solvent was d in vacuo, the crude product was purified by ative HPLC eluting with an ACN; water gradient buffered with ammonium hydroxide to pH=10, to give 3—(6-chloropyridinyl)[4-(7H-pyrrolo[2,3-d]pyn'midinyl)—1H— l-l—yl]propanenitrile as a white powder (35mg,69%), LCMS (M+l)+:3so, ‘H NMR (DMSO-dd) 12.21 (b,1H), 9.00 (5,111), 8.78 (s,1H), 8.62 (s,1H), 8.58 (s,1H), 8.00(m,IH), 7.70(m,2H), 7.00(s,1H), 6.22(m,1H), 3.90(m,1H), 3.78(m,1H) Step 2: 5—2—Cyano—I~[4—(7H-pyrrolo[2, rimidin—4—yl)~1H-pyrazol-1—yl]ethylpyridine—Z—carbo- nitrile trifluoroacetate A mixture of hloropyridin—3—yl)—3—[4-(7H—pyrrolo[2,3-d]pyrimidin—4—yl)—1H-pyrazol-l— yl]propanenitrile (0.025 g, 0.000071 mol) and zinc cyanide (0.08 g, 0.0007 mol) in DMF (1.0 mL, 0.013 mol) was degassed with nitrogen. To this mixture, tetrakis(triphenylphosphine)pailadium(0) (0.04 g, 0.00004 mol) was added and the resulting mixture ed again with dinitrogen. The reaction mixture was heated in a sealed tube at 170 °C for 15 minutes in a microwave (Personal Chemistry). After cooling to room temperature, the solids were filtered, rinsed with DMF and the combined solvent was concentrated in vacuo. The residue was tn'turated with hexanes (3x), and hexanes washes were discarded. The crude product was purified by preparative HPLC g with ACN; water gradient containing 0.2% TFA to give the title compound as; a white powder (16 mg, 49.27%), LCMS (M+l)+: 341, 1H NMR (DMSO-ds) 8 12.50(b,1H), 9.05(s,1H), 8,89(s,1H), 8,80(s,1H), 8.58(s,1H), 8.18(m,2H), 7.78(s,1H), 7.05(s,1H), 6.20(m,1H), ,1H), 3.77(m,1H).
Example 428: 4—[4-(7H-Pyrrolo[2,3-d]pyrimidin—4-yl)—1H—pyrazol-l—yl]heptanedinitrile N \ \ "\ N/ Step I .' 3—[4—(7—[2-(Trimethylsilyl)ethoxyjmethyl- 7H—pyrralo[2, 3-d]pyrimidinyl)—IH—pyrazol—I - yl]pentane-I,5-diol Diethyl 3—[4—(7—[2-(trimethylsily1)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1H- pyrazol-l-y1]pentanedioate, prepared substantially as described in Example 407 (0.80 g, 0.0016 mol), was dissolved in THF (40 mL, 0.49 mol) and cooled in an ice bath under a nitrogen atmosphere. To this mixture, 1.0 M lithium tetrahydroaluminate in THF (3.2 mL) was added slowly. The reaction was stirred for 1h, quenched with ice and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give an amber oil.
The product was purified by FCC on silica gel g with an ethyl acetate: methanol gradient to give 3-[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-l H-pyrazol-l -yl]pentane- ol as a clear viscous oil (0.51 gm, 76%), LC /MS (M+H)+: 418, 1H NMR ds) 5, 8.85(s, 1H), 8.4l(s, 1H), 8.37(s, 1H), 7.45(d,1H), 6.83(d, 1H), 5.73(s, 2H), 4.91(m, 1H), 3.75(m,2H), 3.59(m, 2H), 3.45(rn,2H), 2.18(m, 4H), 0.95(m,2H), 0.1(s, 9H).
Step 2: 3-[4—(7—[2-(Trimethylsilyl)ethoxyjmethyl— rolo[2,3-d]pyrz'midin—4—yl)—JH-pyrazol-I- tane-I, 5—diyl dimethanesulfonate A mixture of 3—[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidinyl)—lH- pyrazolyl]pentane-1,5-diol (50 mg, 0.0001 mol) in DCM (2 mL, 0.03 mol) was cooled at 0 °C. To this mixture, TBA (50 uL, 0.0004 mol) was added. The reaction was stirred for 15 s.
Methanesulfonyl chloride (23 uL, 0.00030 mol) was added and the resulting mixture was stirred for 1 hour. Water was added and the t was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and trated to give 3-[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo [2,3-d]pyrimidinyl)-l H-pyrazol-l ~yl] - pentane—l,5-diyl dimethanesulfonate (57 mg, 80 %) as an oil. MS(ES): 574 (M+1).
Step 3: 7—[2—(Trimethylsilyl)ethoxyjmethyl- 7H—pyrrolo[2, 3-d]pyrimidin—4—yl)—1H—pyrazol—I— yljheptanedinitrile To a mixture of 3~[4-(7-[2—(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3-d]pyrimidin—4—yl)— -. lH—pyrazol-l-yl]pentane-l,5-diyl dimethanesulfonate (57 mg, 0.000099 mol) in DMSO (1 mL, 0.01 mol), sodium cyanide (10 mg, 0.0003 mol) was added and the mixture was stirred for 2 hours. The mixture was heated at 60 °C for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over ium sulfate, filtered and concentrated to give 4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3— d]pyrimidin-4—yl)-lH—pyrazolyl]heptanedinitrile (40 mg, 90 %) as an oil. MS(ES): 436 (M+1).
Step 4: 4-[4-(7H-Pyrrolo[2, 3-d]pyrimidin-4—yD—1H—pyrazolyl]heptanedinitrile Using a procedure analogous to Example 61 for the removal of the SEM protecting group, the title nd was prepared as a white amorphous solid, (17 mg, 60%) lH NMR (400 MHz, DMSO): 6, 8.75 (s, 1H), 8.65 (s, 1H), 8.4 (s, 1H), 7.6 (d, 1H), 7.0 (d, 1H), 4.5 (m, 1H), 2.35 (m, 4 H), 2.2 (m, 4H). MS(ES): 306 (M+1).
IS Example 429: 3-(5—Bromopyridin—3-yl)[4-(7H—pyrrolo[2,3-d]pyrimidin-4—yl)—1H—pyrazol—l— panenitrile // Br N\'L/\ Step 1: (ZZ&E)(5-Brom0pyridinyl)acrylonitrile Nc/ -— Br To a mixture of 1.0 M potassium tert-butoxide in THE (2.7 mL) at 0 °C (water-ice bath, under an atmosphere of nitrogen) was added diethyl ethylphosphonate (0.48 mL, 0.0030 mol) in TI-IF (4.0 mL, 0.049 mol), dropwise. The reaction mixture was warmed to room temperature, and then was cooled to 0 °C, ed by dropwise addition of 5-bromonicotinaldehyde (0.5 g, 0.003 mol) in THF (1.0 mL, 0.012 mol). After stirring at room temperature for 20 hours, the reaction mixture quenched with water and extracted with ethyl acetate. The c layer was washed with brine, dried over ous magnesium sulfate, filtered, and concentrated to give a crude product as a dark oil.
The crude product was purified by flash chromatography on silica gel using ethyl acetate-hexanes as eluent to give a mixture of cis and trans isomers (2)—3 -(5-bromopyridinyl)acrylonitn'le as an off- white solid (268 mg, 47.69%). LCMS (M+l)+: 209,211, 1H NMR (400 MHz, CD013): 5, 8.75(s,1H), 8.62(s,1H), 7.90(s,1H), 7.40(d,1H), 6.00(d, 1H).
Step 2: 3-(5-Bromopyridiny1)-3~[4-(7-[2—(trimethylsilyDethoxyjmethyl— 7H-pyrrolo[2, 3-d]pyr— imidin~4-yl)-JH-pyrazol—1~y1]propanenitrile To 4-(1 H-pyrazol—4-y1)—7—[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (0.200 g, 34 mol) in 1.0 mL of dry ACN was added DBU (0.10 mL, 0.00067 mol), f0110Wed by the addition of (2Z&E)~3-(5-bromopyridinyl)acrylonitri1e (0.234 g, 2 mol) in 1.0 mL of ACN. The reaction mixture was stirred at 67 °C for 4 hours. Upon cooling, the e was partitioned between dilute hydrochloric acid and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel using ethyl acetate : s (7:3) to give 3-(5- bromopyridin-3~yl)—3—[4—(7-[2-(trimethy1silyl)-ethoxy]-methyl—7H—pyrrolo[2,3-d]pyrimidin—4—y1)-1H- pyrazol~1~yl]propanenit1ile as an off-white solid (225 mg, 67.66%). LCMS (M+l)+:524,526: 1H NMR (400 MHz, CD013): 5 8.90(s, 1H), 8.80(s, 1H), 8.70(s, 1H), 8.42(s, 1H), 8.40(s, 1H), 8.00(s, 1H), 7.50(d, 1H), 6.82(d, 1H), S.81(m, 1H), 5.75(s, 2H), 3.70(m,1H), 3.60(m, 2H), 3.42(m, 1H), 1.00(m, 2H), 0.08(s, 9H).
Step 3 .' 3-(5-Brom0pyridinyU—3-[4-(7H-pyrrolofl,3-d]pyrimidin-4—yl)-1H-pyrazal—1-yl]pr0pane— ‘ nitrile The 3-(5-bromopyridinyl)-3—[4-(7—[2-(trimethylsily1)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin—4-yl)—lH—pyrazol-l-yl]propanenitrile (0.220 g, 0.000419 mol) in DCM (9.0 mL, 0.14 mol) and TFA (9.0 mL, 0.12 mol) was. stirred at room temperature for 1 hour. The reaction was trated in to give a residue. This crude intermediate was dissolved in methanol (12 mL, 0.30 mol) and ethylenediamine (0.2 mL, 0.003 mol) and Was stirred overnight at room temperature. The reaction was concentrated in vacuo to give the crude product which was purified by preparative HIPLC g with a water : ACN gradient buffered with ammonium hydroxide (pl-1:10) to give (5-bromopyridinyl)[4-(7H-pyrrolo[2,3-d]pyn'midinyl)-1H—pyrazol-l-y1]propanenitrile as an amorphous white powder (118 mg, 71.36%). LCMS :394,396, IH NMR (400 MHz, DMSO- d6): 5,12.05(bs,11-I), 8.98(s, 1H), 7.0(s, 1H), 6.50(m, 2H), 8.50(s, 1H), 8.10(s, 1H), , 1H), , '1 H), 6.21(m, 1H), 3.90(m, 1H), 3.70(m, 1H).
Example 430: 3-[4-(7H-Pyrrolo[2,3—d]pyrimidinyI)—lH—pyrazol-l-yl]pentane—l,5—diol hi\\N/ Using a procedure analogous to Example 61 for the removal of the SEM protecting group but using 3-[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidinyl)-lH-pyrazol-l —yl]- pentane-1,S—diol from Example 428, the title compound was prepared as a white amorphous solid, (25 mg, 70%) 'H NMR (400 MHz, DMSO): 5, 8.65 (s, 1H), 8.6 (s, 1H), 8.25 (s, 1H), 7.6 (d, 1H), 6.0 (d, 1H), 4.6 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 2.1 (m, 2H), , 2H). MS(ES): 288 (M+1).
Example 431: 5-(2-Cyano[4-(7H—pyrrolo[2,3-d]pyrimidiny1)—1H-pyrazol-l-yl]ethyl)- nicotinonitrile bis(trifluoroacetate) //, CN 2TFA Nt\\/ N N A slurry of romopyridinyl)-3—[4-(7H—pyrrolo[2,3-d]pyn'midinyl)—l H-pyrazol-l- yl]propanenitrile (0.050 g, 0.00013 mol) (from Example 429), DMF (2.0 mL, 0.026 mol) and zinc cyanide (0.1 g, 0.001 mol) was degassed by purging with nitrogen. Then tetrakis(triphenyl— phosphine)palladium(0) (0.07 g, 0.00006 mol) was added and the resulting slurry again was ed with nitrogen. The reaction was sealed and heated at 170 °C for 15 minutes in a microwave (Personal Chemistry). The reaction was allowed to cool and the solids were filtered off. The combined DMF fractions were concentrated in vacuo. The residue was triturated with ethyl acetate—hexanes 2:8, then with ethyl ether to removed ducts. The crude productwas purified by preparative HPLC eluting with a water : acetontrile gradient ning 0.2% TFA to give the racemic title compound (43 59.65%). LCMS (M+1)+:341, 1H NMR (400 MHz, DMSO'dG): 5, 12.60(bs, 1H), 9.10(s, 1H), 8.90(s, 1H), 8.80(s, 1H), 8.50(s, 1H), 8.42(s, 1H), 7.78(s, 1H), 7.10(s, 1H), 6.30(m, 1H), 3.90(m, 1H), 3.70(m,1H).
Example 431R and Example 431s The enantiomers R-S—(Z-cyano-l H-pyrrolo[2,3-d]pyn'midin-4—yl)—1H-pyrazol-l -y1]- ethyl)nicotinonitrile and S(2-cyano-1~[4—(7H-pyrrolo[2,3—d]pyrimidinyl)~lH—pyrazol-l-yl]- ethyl)nicotinonitrile were ted by chiral column HPLC.
Example 467: 3-(3—Aminophenyl)—3—[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol-l-yl]- propanenitrile ifluoroacetate) / NH2 2TFA NC \ / N N Step 1 : 3-(3-NitrophenyD[4-(7-[2—(trimethylsilyDethwqyjmethyl- 7H-pyrrolo[2, 3-d]pyrimidin-4—yl)— 1H-pyrazol—J-yl]propanenim'le l 5 To 4-(1 zol—4-yl)-7—[2—(trimethylsi1y1)ethoxy]methyl—7H—pyrrolo[2,3—d]pyrimidine (0.500 g, 0.00158 mol) in 8.0 mL of dry ACN was added DBU (0.24 mL, 0.0016 mol) ed by addition of (2Z)—3-(3-nitrophenyl)acrylonitrile (0.36 g, 0.0021 mol) in 2.0 mL of ACN. The reaction mixture was heated at 67 °C for 18 hours. This was cooled to room temperature, and the mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel using ethyl acetate-hexanes 6:4, to give 3- (3 -nitrophenyl)—3-[4-(7-[2-(trimethylsi1yl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrirnidinyl)-1 H- l-l ~yl]propanenitrile as a dark orange oil, (688 mg, 88.65%). LCMS (M+1)+:490 Step 2. 3-(3-Aminophenyl)—3—(4[2—(trimethylsilyOethoxyj-7H—pyrrolo[2,3-d]pyrimidinyl—IH— pyrazol-J —yl)pr0panenitrile The 3-(3~nitrophenyl)~3-[4-(7-[2-(trimethylsily1)ethoxy]methyl—7H-pyrrolo[2,3-d]py1imidin- 4-yl)-1H—pyrazol-l-y1]propanenitrile (0.630 g, 9 mol) was dissolved in ethanol (65 mL, 1.1 mol), degassed with en, and then palladium (0.55 g, 0.0052 mol) (10% on carbon) was added.
The reaction mixture was again purged with nitrogen, and it was then charged at 50 psi hydrogen in a Parr shaker for 60 minutes. The reaction mixture was filtered and concentrated to give 3-(3-amino- 2006/047369 phenyl)—3 -(4—7—[2-(trimethylsilyl)ethoxy]—7H-pyrrolo[2,3—d]pyrimidiny1-1H-pyrazol-l -yl)propane- nitrile as a colorless oil (550 mg, 95.92%), LCMS =460, Step 3. 3-(3-AminophenyD[4-(7H-pyrrolo[2,3-d]pyrimidinyD-1H.pyrazol—I-yl]propanenitrile bis(trifluor0acetate) Using a procedure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was prepared as a white amorphous solid (18 mg, 38%), LCMS (M+1)+=329: lH NMR (DMSO-ds) 8 12.61 (b,lH), 9.00 (s,1H), 8.80 (s,1H), 8.50 (s,1H),7.78 (m,1H), 7.25( m,1H), 7.18(m,lH), 6.85(m,2H), 6.02 (m.1H), 3.78(m,1H), 3.60 (m,1H).
Example 468: N—(3-(2-Cyano-l-[4-(7H—pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol—l-yl] ethyl)— phenyl)acetamide trifluoroacetate N—N o / HN—< MIC \ N N Step 1 —(3-2—Cyano—1-[4-(7-[2-(trimethylsilyl)ethoxyjmethyl- rolo[2, 3-d]pyrimidin—4-yl)-1H— pyrazol—I—yl]ethylphenyl)acetamide To 3-(3-aminophenyl)—3-[4—(7-[2-(trimethylsi1yl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin- 4-yl)—1H-pyrazol-1—yl]propanenitn'le (0.070 g, 0.00015 mol) (from Example 467) in dry DCM (1.0 2O mL, 0.016 mol) was added TEA (0.042 mL, 0.00030 mol). The reaction was cooled in an ice bath and acetyl chloride (0.016 mL, 0.00023 mol) was added. The reaction mixture stirred for 30 minutes and was diluted with water and ted with ethyl acetate (2x). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give —cyano-l—[4—(7-[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3— d]pyrimidinyl)-lH-pyrazol—l—yl]ethylphenyl)acetamide as a colorless oil, (65 mg, 85.08%), +1)+= 502.
Step 2 N-(3—2—Cyano—1—[4-(7H—pyrrolo[2,3—djpyrz'midin—4—yl)—1H—pyrazol—1—yUethylphenyDacetamide roacetate Using a procedure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was prepared as a white amorphous solid (40 mg, 68.9%), LCMS(M+1)+=372, ‘H NMR (DMSO-d5) 5 12.61 (b,lH), 9.05 (s,1H), 8.79 (s,1H), 8.44 (s,1H), 7.85 (s,1H), 7.55 (s,1H), 7.48 (d,1H), 7.24 , 7.10 (m,2H)), 6.05 (m,1H), 3.70 , 3.48 (m,1H), 1.98 (5,3H).
Example 470: 4—(2—Cyano—1-[4—(7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol—l-yl]ethyl)- thiophene—Z-carbonitrile trifluoroacetate NU \ ./ N N Step 1 a-2~(diethoxymethyl)thiophene A mixture of 4—bromothiophene-Z-carbaldehyde (1.2 g, 0.0063 mol) in ethanol (10 mL, 0.2 mol) was treated with ammonium chloride (0.42 g, 0.0078 mol) and ethyl orthoformate (1.2 g, 0.0078 mol). The mixture was stirred at 60 °C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-bromo—2-(diethoxymethyl)thio- phene as an oil (1.3 g, 81% ). 1H NMR (400 MHz, CDCl3): 5 7.22 (s, 1H), 6.99 (s, 1H), 5.68 (s, 1H), 3.63 (q, 4H) 1.24 (t, 6H).
Step 2 5—(Diethoagzmethyl)thiophenecarbaldehyde A solution of 4-bromo(diethoxymethyl)thiophene (500 mg, 0.002 mol) in ether (5 mL, 0.05 mol) was cooled at -78 °C. To this solution, 2.5 M n-butyllithium in hexane (0.83 mL) was added dropwise. The on was stirred at —78 °C for 1 hour. To the reaction was added DMF (0.4 g, 0.006 mol) at —78 °C and the mixture was stirred for 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with ted sodium de, dried over magnesium sulfate, d and concentrated. The crude residue was purified by flash column chromatography to yield the 5-(diethoxymethyl)thiophenecarbaldehyde as an oil (170 mg, 42.0%). By 1B NMR two different regioisomers of aldehydes were formed and were not separated; (note: NMR shifts are for the major isomer only) 1H NMR (400 MHZ, CDClg): 8_ 9.85 (s, 1H), 8.05, 7.7 (s, 1H), 7.45, 7.15 (s, 1H), 5.7 (s, 1H), 3.65 (m, 2H), 1.25 (m, 2H).
Step 3 (2E)[5—(Dieth0xymethyl)~3—thienyljacrylonitrile To a solution of l cyanomethylphosphonate (100 mg, 0.0008 mol) in THF (2 mL, 0.02 mol) cooled at 0 °C and 1.0 M potassium tert-butoxide in THF (0.8 mL) was added dropwise. The 178 ' bath was d and the on was warmed to room temperature for 30 minutes. The reaction was cooled to 0 °C and a solution of 5-(diethoxymethyl)thiophenecarbaldehyde (170 mg, 0.00079 mol) in THF (2 mL, 0.02 mol) was added drop wise. The reaction was stirred overnight at room temperature. The reaction was partitioned between water and ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium e, d and concentrated.
The crude residue was purified by flash column chromatography on silica gel eluting (ethyl acetatezhexane, 1:5) to give (2E)[5-(diethoxymethyl)thienyl]acrylonitrile as an oil (160 mg, 84.9%). lH NMR (300 MHz, CDC13): 5 7.4—7.0 (m, 3H), 5.65 (m 1H), 4.2 (m, 1H), 3.65 (m, 4H), 1.25 (m, 6H).
Step 4 3—[5—(DiethoxymethyD-3—thienyl]-3—[4-(7—[2-(trimethylsibzlkthoxyjmethyl- rol0[2,3- d]pyrimidinyl)-IH—pyrazol-I-yl]pr0panenitrile To a solution of 4-(1H—pyrazolyl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]- pyrimidine (200 mg, 0.0007 mol) in ACN (2 mL, 0.04 mol) and (2E)—3-[5-(diethoxymethyl)—3- thienyl]acrylonitrile (160 mg, 0.00067 mol) (mixture of regioisomers) DBU (80 uL, 0.0005 mol) was added. The reaction was stirred overnight than water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium de, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting (50% EtOAc/Hexane) to give 3—[5-(diethoxymethyl)—3—thienyl]- 3-[4-(7-[2-(trimethylsilyl)ethonymethyl-7H-pyrrolo [2,3—d]pyrimidinyl)-l H—pyrazol-l —yl]propane- nitrile (160 mg, 43%). 'H NMR (400 MHz, CDC13): 5 8.92 (s, 1H), 8.41 (s, 1H), 8.29 (b, 1H), 7.45(d, 1H), 7.4l(d, 1H), 7.15 (s, 1H), 7.05 (d, 1H), 6.82 (m, 1H), 5.74 (d, 2H), 3.74 (m, 2H), 3.71 (m, 8H), 3.59 (m, 1H), 1.32 (m, 4H), 0.95 (m, 2H), -0.08 (s, 9H); MS(ES):553 (M+1).
Step 5 3-(5-Formylthienyl)[4-(7—[2—(trimethylsilyl)ethopgzjmethyl— 7H-pyrrolo[2,3-d]pyrimidin- 4-y1)-IH-pyrazolyljpr0panenitrile A solution of 3-[5-(diethoxymethyl)—3~thieny1][4-(7-[2—(trimethylsilyl)ethoxy]methyl-7H— pyrrolo[2,3-d]pyrimidin—4-y1)-lH-pyrazol-l-yl]propanenitrile (70 mg, 0.0001 mol) in TI-[F (1 mL, 0.01 mol) was treated with 1 M HCl in water (400 uL). The reaction was stirred at room temperature.
Water was added and the t was ted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over ium sulfate, filtered and concentrated to give 3—(5~fonnyl—3—thienyl)[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin—4— yl)—lH—pyrazol—1—y1]propanenitn'le as a semisolid e (60 mg, 98%). IH NMR (400 MHz, CDClg): 5_ 9.96 (s, 1H), 8.89 (s, 1H), 8.44 (m, 2H), 7.46 (1H), 5.73 (s, 2H), 4.15 (m, 1H), 3.73—3.43 (m, 3H), 1.35 (m, 1H), 1.01 (m, 2H), 0.03 (s, 9H); MS(ES): 479 (M+1). 2006/047369 Step 6: 5-[(E)~(fiydroxyimino)methyl]—3-thienyl-3~[4~(7—[2—(trimethylsilyDethaxyjmethyl- 7H- pyrrolo[2, 3~d]pyrimidin-4—yD-1H-pyrazoL1-yUpropanenitrile A solution of 3—(5-formylthienyl)[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo- [2,3-d]pyrimidin-4—yl)-lH-pyrazol—l—yl]propanenitrile (65 mg, 0.00014 mol) in methanol (2 mL, 0.05 mol) was treated with ylamine hydrochloride (11 mg, 0.00016 mol) and ium bicarbonate (23 mg, 0.00023 mol). The reaction was stirred at room temperature for 4 hours. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3[(E)- (hydroxyimino)methyl]—3—thienyl—3-[4-(7—[2{trimethylsily1)ethoxy]methyl~7H-pyrrolo[2,3—d]~ IO pyrimidin-4—yl)-lH—pyrazol-I-yl]propanenitn'le as a semisolid oil (60 mg, 89.5%). (The crude product contained both isomers of oxime and also both regioisomers of thiophene). MS (ES): 494 (M+l).
Step 7: 4-(2-Cyano-1—[4-(7-[2~(z‘rimethylsilyflethoxyjmethyl- 7H-pyrrolo[2, 3-d]pyrimidin—4—yl)~1H— pyrazol—I—yl]ethyl)thz'ophene—Z—carbon 1'trile To a mixture of 3[(E)-(hydroxyimino)methyl]thieny1-3—[4-(7-[2—(trimethylsilyl)ethoxy]- methyl-7H-pyrrolo[2,3-d]pyrimidin—4—yl)-lH-pyrazol-l;yl]propaneni‘tn'le (70 mg, 0.0001 mol) in pyridine (1 mL, 0.01 mol), methanesulfonyl chloride (100 pL, 0.001 mol) was added. The mixture was stirred at 60 °C for 2 hours. Water was added and the t was extracted with ethyl acetate.
The combined extracts were washed with 0.1 N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give 4-(2-cyano[4-(7~[2-(trimethylsi1yl)ethoxy]methyl-7H—pyrrolo[2,3-d]— pyn'midinyl)-lH-pyrazol-l-yl]ethyl)thiophene—2—carbonitrile as a crude product (30 mg, 44%). MS (ES): 476 (M+1).
Step 8: yano~1-[4—(7H—pyrrolo[2,3-d]pyrimidin—4—yl)—IH—pyrazol—1-yl]ethyl)thi0phene-2— carbonitrz'le trifluoroacetate A mixture of 4-(2-cyano-l—[4-(7—[2-(trimethylsilyl)ethoxy]methyl~7H—pyrrolo[2,3—d]— pyrimidin—4-yl)—lH—pyrazol—l-yl]ethyl)thiophene—Z-carbonitrile (50 mg, 0.000] mol) in DCM (2 mL, 0.03 mol) and TFA (1 mL, 0.01 mol) was stirred for 1 hour: The starting material was consumed and the desired methyl hydroxy compound was formed. The mixture was concentrated in vacuo to remove TFA. The crude ediate was dissolved in methanol (3 mL, 0.07 mol) and was treated with ethylenediamine (1 mL, 0.01 mol). The e was stirred overnight and trated in vacuo. The products were d by preparative I-IPLC eluting with ACN: water with 0.2% TFA to give two regioisomers, the title compound as an amorphous white solid (30 mg, 60 %).
'H NMR (500 MHz, DMSO): (3 8.95 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.70 (d, 1H), 7.05 (d, 1H), 6.25 (m, 1H), 3.80—3.60 (m, 2H); MS (ES): 346 (M+1).
Example 471 : S-(2-Cyano[4-(7H—pyrrolo[2,3-d]pyrimidin—4—yl)~1H-pyrazol—l-yl]ethyl)- thiophene-Z-carbonitrile trifluoroacetate Dl—N CN "It i \ N fl ed as the second regioisomer from Example 470, the title nd was isolated as an amorphous white solid (4 mg, 8%). 1H NMR (500 MHz, DMSO): 8_ 9.0 (s, 1H0, 8.75 (s, 1H), 8.50 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.45 (s, 1H), 7.0 (d, 1H), 6.45 (m, 1H), 3.8 (dd, 2 H); MS (ES): 346 (MM).
Example 472 : 3-[3-(N10rpholin—4-ylcarbonyl)phenyI][4-(7H-pyrrolo[2,3-d]pyrimidinyl)- lH-pyrazol-l-yl]propanenitrile trifluoroacetate rf-N N o 0 L] NU \ / N TFA Step I: 3-(2—cyano[4—(7-[2-(trimethylsily0eth0xy]methyl—7H—pyrrolo[2,3-d]pyrimidin—4—yl)—1H- pyrazol-I—yUethyDbenzoic acid To a solution of methyl 3cyano-l-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- d]pyrimidinyl)-lH-pyrazol-l—yl]ethylbenzoate (50 mg, 0.0001 mol) (prepared as in Example 61) in methanol (2 mL, 0.05 mol), lithium hydroxide (1 mg, 0.0001 mol) in water (1 mL, 0.06 mol) was added slowly. Water was added and also some 1N HCI was added until the solution was slightly acidic. The aqueous layer was extracted with ethyl acetate. The ed extracts were dried over ium sulfate, filtered and concentrated to give 3-(2-cyano[4-(7-[2-(trimethylsilyl)ethoxy]- methyl-7H—pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol-l-y1]ethyl)benzoic acid as a crude residue (35 mg, 72.0%). MS (ES): 489 (M+l).
WO 70514 Step 2: 3-[3-(Morpholine—I—ylcarb0nyl)phenyl]~3~[4~(7-{[2-(trimethylsilyDethoxy]methyl}- 7H- pyrrolo[2,3—d]pyrimidine~4—yl)-IH-pyrazole—I~yl]propanenim'[e To a solution of 3-(2-cyano-1~[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3-d]- pyrimidin—4-yl)-1H-pyrazol—l -yl]ethyl)benzoic acid (40 mg, 0.00008 mol) in DMF (1 mL, 0.01 mol), N,N,N’,N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uroniurn orophosphate (36 mg, 0.000095 mol) and DIPEA (30 uL, 0.0002 mol) were added. The reaction was stirred for 10 minutes and then morpholine (10 mg, 0.00012 mol) was added and the resulting mixture was stirred for 3 hours. Water was added and the product was extracted with ethyl acetate. The combined organic extracts were washed with 1N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give 3-[3- l 0 (morpholine-l —ylcarbonyl)phenyl]~3 -[4—(7- {[2—(trimethylsilyl)ethoxy]methyl } -7H-pyrrolo[2,3- midiney1)-1H-pyrazole-l-y1]propanenitrile as a crude (40 mg, 88%) product. MS (BS): 558 (M+1).
Step 3.' 3-[3-(Morpholiny1carbonyl)phenyU[4-(7H—pyrroIo[2, 3-d]pyrimidiny1)-1H-pyrazol—I — yljpropanenitrile trifluoroacetate Using a procedure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was isolated as an amorphous white solid (18 mg, 50 %). 1H NMR (400 MHz, DMSO): 8_ 9.05 (s, 1H), 8.75 (s, 1H), 8.44 (s, 1H), 7.85 (b, 1H), 7.665 (s, 1H), 7.55- 7.35 (m, 3H), 7.15 (s, 1H), 6.15 (m, 1H), 3.85 (m, 1H), 3.65-3.4 (m, 6H), 3.25 (m, 2H), 3.05 (m, 1H); MS(ES): 428 (M+1).
Example 482: 3-(5-Phenylpyridin-3—yl)[4-(7H—pyrrolo[2,3-d]pyrimidinyl)-lH-pyrazol-l- yl] propanenitrile trifluoroacetate N N TFA Step 1 .’ henylpyridin-3~yl)—3—[4-(7—[2-(trimethylsilyl)ethoxyjmethyl- 7H~pyrrolo[2,3-d]— pyrimidin—4~yl)—1H—pyrazol~I—yl]propanenitrile To a solution of 3-(5-bromopyridin—3—yl)-3—[4-(7—[2-(trimethylsi1yl)ethoxy]methyl—7H- o[2,3—d]pyrimidin-4—yl)-lH—pyrazol-l -y1]propanenitrile (from Example 429) (60 mg, 0.0001 mol) in 1,4-dioxane (2 mL, 0.02 mol), boronic acid (15 mg, 0.00012 mol) and sodium bicarbonate (30 mg, 0.0003 mol) in water (0.5 mL, 0.03 mol) were added. The resulting mixture was degassed using en. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled h the reaction again. The reaction was heated at 80 °C in oil bath for lhour. Water was added and the product was extracted with ethyl acetate. The combined ts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3—(5—pheny1pyridin—3-y1)[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidinyl)-1H-pyrazol-l -y1]propanenitrile (50 mg, 80%) as a crude product. MS (ES): 522 (M+1).
Step 2: 3-(5~Phenylpyridz‘nyl)-3—[4—(7H—pyrrolo[2,3—d]pyrimz'din—4—yI)—1H—pyrazol—I—yl]propane— nitrile trifluoroacetate Using a ure analogous to that of Example 61 for the removal of the SEM protecting group, the title compound was isolated as an amorphous white solid (20 mg, 40 %). IH NMR (400 MHz, DMSO): 5, 9.15 (s, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.22 (5,1H), 7.85 (b, 1H), 7.67 (m, 2H), 7.45(m 2 H), 7.43 (m, 1H), 7.15 (s, 1H), 6.25 (m 1H), 3.95 (dd, 1H), 3.80 (dd, 1H), 3.0 (m, 1H); MS (ES): 392.1 (I\/I+1) Example 486: 3-(S-Ethynylpyridinyl)[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol—l- yl] propaneuitrile trifluoroacetate \ / / \\ N \ \ "\N/ m TFA Step I .' 3-[4—(7—[2-(TrimethylsilyDethoxyjmethyl- 7H-pyrrolo[2, rimidin-4—yD-1H—pyrazol—I -yl_]- 3[(trimethylsilyDethynyljpyridin—3—ylpr0panenitrile .
To a solution of 3-(5—bromopyridinyl)[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidin-4—y1)~lH—pyrazol—l-yl]propanenitrile (from Example 429) (0.080 g, 0.00015 mol) in TEA (0.300 mL, 0.00215 mol) was degassed with nitrogen, and then (I) iodide (0.005 g, 0.00003 mol), (trimethylsilyl)acetylene, and bis(triphenylphosphine)palladium(II)chloride were added. The reaction mixture was sealed in a tube and d at room temperature overnight. The resulting black solution was partitioned between water (10 mL) and ethyl ether. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin-4—yl)- 1 H—pyrazol-l ~y1] WO 70514 —[(tn'methylsilyl)ethynyl]pyridinylpropanenitrile as a yellow oil (60 6), LCMS (M+1>*:542).
Step 2: 3-(5-Ethyny1pyridinyl)—3—[4-(7H-pyrrolo[2, 3—d]pyrim[dinyD-JH-pyrazol-I —yl]pr0pane- nitrile roacetate 7~[2-(Trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin-4—yl)-1 H-pyrazol-l - y1]-3—5-[(trimethylsilyl)ethynyl]pyridinylpropanenitrile (0.050 g, 0.000092 mol) was dissolved in DCM (5.0 mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol). The reaction mixture was stirred at room temperature, for 90 minutes and was concentrated in vacuo. The dry residue dissolved in ol cooled in an ice bath and a solution of potassium hydroxide (0.482 g, 0.00859 mol) in methanol (10 mL, 0.2 mol) was added. The reaction solution was stirred for 30 min was concentrated and the crude product was purified by preparative HPLC eluting with a water: ACN gradient with 0.2% TFA, to give the title compound as a white amorphous solid (15 mg, 35.85%). LCMS (M+l)+:340, 'H NMR (400 MHz, DMSd-da): 8, 12.1(bs, 1H), 9.02(s, 1H), 8.80(s, 1H), 8.70(m, 2H), 8.48(s, 1H), 8.00(s, 1H), 7.80(d, 1H), 7.15(d, 1H), 6.20(m, 1H), 4.82(s, 1H), , 1H), 3.70(m, 1H). e 488: 3-[5-(Phenylthio)pyridin-3—yI]—3-[4-(7H—pyrrolo[2,3—d]pyrimidin—4-yl)—1H— pyrazol-l-yl]propanenitrile trifluoroacetate Q’s CN N\ \ l/NN Step 1 .' 3-[5—(Phenylthiojpyridin—3—yl]—3-[4—(7—[2—(trimethylsilyl)ethoxy]methyl— 7H—pyrrolo[2,3—d]— pyrimidin-4—yl)-1H-pyrazol—1 -yl]propanenitrile To the 3-(5-bromopyridin-3~y1)[4-(7—[2-(tn'methylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]- pyrimidinyl)-1H—pyrazol—1 -yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in dry oxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution was degassed with nitrogen, followed by addition of (9,9—dimethy1—9H—xanthene—4,5- diyl)bis(diphenylphosphine) (0.007 g, 0.0000] mol), bis(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062 mol), and ethiol (0.025 mL, 0.00025 mol). Again the solution was purged with nitrogen. The on mixture in a sealed tube was heated to reflux for 3h. The-reaction mixture was diluted with ethyl acetate, washed with water (2X), brine (1X), dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The crude product was triturated with hexane-ethyl acetate 9:1 to yield 3-[5-(phenylthio)pyridin-3—yl]—3-[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3- d]pyrimidin-4—yl)-lH—pyrazol—l—yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z = 554.2.
Step 2: 3-[5—(Phenylthio)pyridin—3-yl]—3-[4—(7H-pyrrolo[2,3-d]pyrimidin—4-yl)—1H—pyrazol-J-yl]- enizrile trifluoroacetate The 3-[5-(phenylthio)pyridiny1]—3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3— d]pyrimidinyl)—lH—pyrazol-l-yl]propanenitrile (0.110 g, 0.000199 mol) was dissolved in DCM (5.0 for 1 mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol), and the mixture was stirred at room temperature hour. The solvent was removed in vacuo, and the resulting residue was dissolved in methanol (5.0 mL, 0.12 mol), and ethylenediamine (0.1 mL, 0.002 mol) was added. This reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the crude product was purified by LCMS ( pH=2) to yield the title compound as an amorphous solid (62 mg, 58.07%).
IH NMR (400 MHz, DMSO): 3, 12.80 (s), 9.10 (s) 8.87(d), 8.60 (s), 8.50 (s), 8.43 (s), 7.82 (s), 7.78 (m), 7.39 (m), 7.25 (m), 7.18 (d), 6.20 (m), 3.84 (m), 3.70 (m). LC/MS (M+H)+: m/z = 424.15 Example 491: orpholin—4—ylpyridin—3—yl)—3-[4—(7H-pyrrolo[2,3—d]pyrimidin-4—yl)-1H— pyrazol—l~yl]propanenitrile Step I : 4-(5-Brom0pyrz'din—3—yl)morpholine To a solution of [3,5-dibromopyridine (1000 mg, 0.004 mol) in oxane (8 mL, 0.1 mol), morpholine (400 mg, 0.004 mol) and sodium tert—butoxide (400 mg, 0.004 mol) were added. The reaction was bubbled with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.0002 mol) was heated at 80 °C was added and nitrogen was bubbled through for couple of minutes. The mixture overnight. The reaction was d to cool to it and was then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and trated to give a crude residue. The crude product was purified by FCC on silica gel eluting with 1:1, EtOAC:Hexane gave to give romopyn‘din—3-yl)morpholine as a viscous oil (400 mg, 40 %). 'H NMR (400 MHz, CD013): 8. 8.2 (s, 1H), 8.1 (5, 11-1), 7.2 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).
Step 2: 5-Morpholin—4—ylnicotinaldehyde A solution of romopyridinyl)morpholine (100 mg, 0.0004 mol) in ether (2 mL, 0.02 mol) cooled at -78 °C was treated with 2.5 M n-butyllithium in hexane (0.2 mL) and was stirred for 1h. To this mixture was added DMF (0.5 mL, 0.006 mol) dropwise. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 5-morpholin-4— ylnicotinaldehyde (70 mg, 90%) as a crude t. 1H NMR (400 MHz, CDC13): 5 10.1 (s, 1H), 8.0 (s, 2H), 7.6 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).
Step 3: (2E)-3~(5—Morpholin—4-ylpyridinyl)acrylonitrile To a solution of diethyl cyanomethylphosphonate (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) cooled at 0 °C was added 1.0 M potassium tert-butoxide in THF (0.50 mL) dropwise. The cold bath was removed and the reaction was warmed to room temperature over 30 minutes. The reaction was cooled to 0 °C and a solution of holinylnicotinaldehyde (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was d at room temperature for 4 h, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium e, filtered and concentrated to give (2E)(5- morpholiny1pyridin—3—yl)acrylonitri1e (75 mg, 100%) as a mixture of isomers; LC/MS: 216 (M+1).
Step 4: 3—(5—Morpholin-4—ylpyridin-3cyU-3~[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d]- pyrimidin—4—yl)-1H-pyrazol—1 -yl]pr0panenitrile To a solution of 4—(1H—pyrazol—4—yl)~7-[2-(trimethylsi1y1)ethoxy]methyl—7H-pyrrolo[2,3-d]- pyrimidine (120 mg, 0.00038 mol) in ACN (10 mL, 0.2 mol) and (2E)-3—(5-morpholinylpyridin yl)acrylonitrile (70 mg, 0.0003 mol) ( mixture of isomers), DBU (50 uL, 0.0003 mol) was added and the resulting mixture was stirred ght. The mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with saturated sodium de, dried over magnesium sulfate, filtered and concentrated to give orpholinylpyridin—3-yl)-3—[4—(7-[2~ (trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidin—4-yl)-1H-pyrazol-l-yl]propanenitrile (200 mg, 100%) as a crude product; L/MS = 531 (M+1).
Step 5: 3—(S-Morph01in~4-ylpyridin-3—yl)-3—[4—(7H—pyrrolo[2, 3-d]pyrimz'din—4-yl)-IH-pyrazol-I-yl]- propanen itrile Using a procedure ous to Example 61 for the removal of the SEM protecting the title compound was isolated as an ous white solid (18 mg, 50 %). IH NMR (400 MHz, DMSO): 5 8.8 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 8.0 (s, 1H), 7.6 (d, 1H), 7.4 (m, 1H), 6.9 (d, 1H), 6 (m, 1H), 3.8 (dd, 1H), 3.7(m, 4H), 3.6 (dd, 1H), 3.1 (m, 4 H); LC/MS: 401(M+1).
Example 496: Pheuylsulfinyl)pyridin—3—yl][4-(7H~pyrrolo[2,3-d]pyrimidinyl)-1H- pyrazol—l-yl]propanenitrile, e 497: 3-[5-(Phenylsulfonyl)pyridin—3-yl][4—(7H-pyrrolo{2,3-d]pyrimidinyl)-1H- pyrazol-l-yl]propanenitrile N/ W, N—N \ N \ \ "C \ N .> "r: H N N To the solution of 3~[5-(phenylthio)pyn'din—3-yl]-3~[4-(7H-pyrrolo[2,3—d]pyrimidinyl)~1H— pyrazol~l—yl]propanenitrile trifluoroacetate (0.050 g, 0.000093 mol) from e 488, Step 2, in THF (1.0 mL, 0.012 mol) was added MCPBA (0.022 g, 0.00013 mo!) (0.031g of 77% in water), in a water ice bath. The reaction mixture was stirred for 1h at room temperature. The crude products were purified by LCMS (pH=lO). Two peaks were collected : # 1 ~— to yield 3-[5—(phenylsulfinyl)pyridin—3-yl]-3—[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-lH- pyrazol-l-yl]propanenitrile (8 mg, 19.57%). 1H NMR (400 MHz, DMSO): 5_ 12.1 (s), 8.89 (d), 8.80 (d), 8.70 (s), 8.62 (s), 8.40 (s), 8.19 (s), 7.70 (m), 7.58 (s), 7.42 (m), 6.90 (s), 6.20 (m), 3.82 (m), 3.65 (m). LC/MS (M+H)+: m/z = 440.0 # 2 — to yield 3-[5-(phenylsulfonyl)pyridin—3—yl}-3~[4-(7H—pyrrolo[2,3—d]pyrimidinyl)-1H- pyrazol-l-y1]propanenitrile (21 mg, 50%). ‘H NMR (400 MHz, DMSO): 8_ 12.1 (s), 9.10 (s), 8.86 (m), 8.6l(s), 8.40 (m), 7.98 (m), 7.62 (m), 7.58 (m), 6.90 (s), 6.20 (m), 3-82 (In), 3.65 (m). LC/MS (M+H)+; m/z = 456.0 Example 498: 3-[4-(7H—Pyrrolo[2,3-d]pyrimidinyl)-lH-pyrazol—l-yllpentan-l-ol C/‘OH N\ \ N NH Step I: 3-[4-(7—[2-(TrimethylsilyDethoxy]methyl~7H—pyrrolo[2,3-d]pyrimidin-4—yl)—IH— pyrazol—I—yl]pentanal To a solution of 4—(1H-pyrazolyl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidine (100 mg, 0.0003 mol) in ACN (2 mL, 0.04 mol) and DBU (50 uL, 0.0003 mol), the (2B)- pent-Z—enal (4.0El mg, 0.00048 mol) in lml ACN was added drop wise. The reaction was stirred for 1 h, and then water was added and the resulting mixture extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium e, filtered and trated to give the crude as the ed product form. LC/MS (M+H)+: m/z = 400.
Step 2: 3-[4-(7«[2—(Trimethylsilyl)ethoxyjmethyl- 7H-pyrrolo[2,3-d]pyrimidin-4—yl)-IH-pyrazol—J — yUpentan—I—01 A mixture of [3-[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidin-4—yl)—lH— pyrazol—l-yl]pentanal (50 mg, 0.0001 mol) in methanol (2 mL, 0.05 mol) was treated with sodium tetrahydroborate (8 mg, 0.0002 mol). The mixture was stirred at room temperature for l h, and then water was added and the product was extracted with ethyl acetate. The combined c layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the desired product as an oil. LC/MS (M+H)+: m/z = 402.
Step 3: Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compound was isolated as an amorphous white solid (6 mg, 20 %). 1H NMR (400 MHz, DMSO): ,5 8.65 (d, 1H), 8.60 (d, 1H), 7.55 (s, 1H), 6.95 (s, 1H), 4.50 (b, 1H), 4.4 (m, 11-1), 3.4 (m, 1H), 3.2 (m, 1H), 2.1 (m, 1H), 1.8-2.0 (m, 3H), 0.7(t, 3H); LC/MS (M+H)+: m/z = 272. e 499: Methyl 3-[4-(7H-pyrrolo[2,3-d]pyrimidin—4—yl)—1H—pyrazol-l-yllpentyl carbonate be?" Iii \ \ N NH Step 1: Methyl 7—[2-(trimethylsilyDethoxyjmethyl— 7H—pyrrolo[2, 3-djpyrimidinyD—1H- l—I—yl]pentyl carbonate To a solution of [3—[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidinyl)- lH-pyrazol—l-yl]pentan-l-ol (50 mg, 0.000] mol) from Example 498 Step 2 in pyridine (1 mL, 0.01 mol), methyl chloroformate (30 uL, 0.0003 mol) was added. The reaction was stirred for 3h, water was added and the product was extracted with ethyl acetate. The combined organic layers were washed 1N HCl, brine, dried over magnesium sulfate, d and concentrated to give methyl 3-[4- (trimethylsi1y1)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidiny1)-1 H—pyrazolyl]pentyl carbonate as a semisolid e (30 mg, 50%). LC/MS (M+H)+: m/z = 460.
Step 2: Using a procedure ous‘to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (8 mg, 20 %). 1H NMR (400 MHz, DMSO): 5 12.0 (b, 1H), 8.65 (d, 1H), 8.35 (s, 1H), 7.65 (b, 1H), 7.600 , (s, 1H), 7.0 (s, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (s, 3H), 2.1 (m, 1H), 2.2 (m, 1H), 1.95 (m, 2H), 0.75 (t, 3H); LC/MS (M+H)+:m/z= 330.
Example 500(21): (1E)[4-(7H-Pyrrolol2,3-d]pyrimidinyl)-1H—pyrazol-1—yl]pentanal oxime Step 1: (1E)[4-(7-[2-(TrimethylsilyDethostyjmethyl-7H-pyrrolo[2, 3-djpyrimidinyD-IH-pyrazol— 1 -yl]pentanal oxime To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin—4—yl)— 1H—pyrazolyl]pentanal (60 mg, 0.0002 mol) from Example 498, Step 2 in methanol (2 mL, 0.05 mol) was added hydroxylamine hydrochloride (16 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 2 mol). The reaction was stirred at room temperature for 2h, water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (1E)[4-(7-[2—(trimethyl- silyl)ethoxy}methyl-7H-pyrrolo[2,3—d]pyrimidin—4-yl)-lH-pyrazol—l —yl]pentanal oxime as a semisolid residue (50 mg, 80%). LC/MS : m/z = 415.
Step 2: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid. 1H NMR (400 MHz, DMSO): 5 12.0 (b, 1H), 8.6 (m, 2H), 8.2 (m, 1H), 7.5 (d, 1H), 7.1 and 6.5 (t, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 2.6-2.8 (m, 2H), 1.8 (m, 2H), 0.65 (t, 3H); LC/MS (M+H)+: m/z = 285.
Example 501(a): (lE)[4-(7H-Pyrrolo[2,3-d]pyrimidin—4-yl)-lH—pyrazol—l-yl]pentanal 0- methyloxime, Example 502(11): (1Z)[4-(7H-Pyrrolo[2,3-d]pyrimidin—4-yl)—lH—pyrazol—l-yl]pentanal 0- oxime Step 1: (1E)—3-[4—(7—[2-(TrimethylsilyDethoxyjmethyl—7H—pyrrolo[2,3-d]pyrimidinyl)—JH-pyrazol- 1-yl]pentanal yloxime and (1Z)[4—(7-[2-(Trimethylsilyl)ethquy]methyl—7H-pyrr010[2,3—d]pyrimidiny1)-1H—pyrazol—1- yljpentanal O-methyloxime To a solution of 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidinyl)- 1H-pyrazolyl]pentanal (70 mg, 0.0002 mol) in methanol (2 mL, 0.05 mol) was added methoxylamine hydrochloride (19 mg, 0.00022 mol) and potassium bicarbonate (22 mg, 0.00022 mol). The reaction was stirred at room ature for 2h, water was added and the product was extracted with ethyl acetate.‘ The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, was filtered and was concentrated to give 3—[4-(7-[2-(trimethylsilyl)- ethoxy]methy1—7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol—l-yl]pentanal ‘O-methyloxime as a mixture of isomers (70 mg, 90%) crude product. LC/MS (M+H)+: m/z = 429.
Step 2: Using a procedure analogous to Example 61 for the l of the SEM protecting the title compound was isolated as an amorphous white solid (4 mg, 25 %). Isomer 1, 1H NMR (400 MHz, DMSO): 6. 8.7 (s, 2H), 8.3 (s, 1H), 7.6 (s, 1H), 7.3 (t, 1H), 7.0 (s, 1H), 4.6(m, 1H), 3.3 (s, 3H), 2.8 (m, 2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/S (M+H)+: m/z = 299.Isomer 2 (3 mg, 22%), lH NMR (400 MHz, DMSO): ,8 8.7 (s, 2H), 8.3 (s, 1H), 7.6 (s, 1H), 7.0 (s, 1H), 6.7 (t, 1H), 4.5(m, 1H), 3.3 (s, 3H), 2.8-3.0 (m, 2H), 1.9 (m, 2H), 0.8 (t, 3H); LC/MS (M+H)+: m/z = 299.
Example 503: 4- [1-(4,4-Dibromo-l—ethylbut—3—en-l—yl)—1H—pyrazol—4-yl]-7H—pyrrolo [2,3-d]— dine trifluoroacetate Step I .’ 4—[1—(4, 4—Dibromo—1—ethylbut—3—en—I—yl)—1H—pyrazol-4—yl]—7—[2-(trimethylsilyl)ethoxyjmethyl— 7H-pyrrolo[2, 3-d]pyrimidine To a solution of 3-[4-(7-[2—(trimethylsi1y1)ethoxy]methyl-7H—pyrrolo[2,3-d]pyn'midin—4—yl)— lH-pyrazol—l—yl]pentanal (300 mg, 0.0008 mol) in DCM (4 mL, 0.06 mol) cooled at 0 °C, triphenylphosphine (800 mg, 0.003 mol) and carbon tetrabromide (500 mg, 0.002 mol) were added.
The reaction was stirred at 0 °C for 10 min, water was added and extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium de, dried over magnesium sulfate, d and concentrated. The crude product was purified by prep LC-MS (ACN, water, NH4OH) to give 4-[1-(4,4—dibromo-l -ethylbut—3-en—l—yl)-1I-I-pyrazoly1][2-(trimethylsilyl)- ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidine as an amorphous solid (50 mg, 10%). 1H NMR (400 MHz, CDC13): 5 8.9 (s, 2H), 8.4 (s, 1H), 8.3 _ (s, 1H), 7.4 (m, 1H), 7.3 (s, 1H), 6.9 (m, 1H), 6.4 (m, 1H), 5.7 (s, 2H), 4.2 (m, 1H), 3.6 (m, 2H), 2.8 (m, 2H), 2.1 (m, 1H), 2.0 (m, 1H), 1.0 (m, 5H), LC/MS : m/z = 556 Step 2: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an ous white solid (8 mg, 40 %). 1H NMR (400 MHz, DMSO): 8, 8.8 (s, 2H), 8.4 (s, 1H), 7.7 (b, 1H), 7.2 (b, 1H), 6.5 (t, 1H), 4.4 (m, 1H), 2.6 (m, 2H), 1.8 (m, 21-1), 0.8 (t, 3H); LC/MS CM+H)+: m/z =: 426.
Example 506: 4-[1-(l—Ethylbut—3-yn—1-yl)-1H-pyrazolyl]~7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate Step I .' 4—[1—(1-Ethylbut—3-yn-I-yl)-1H-pyrazoI—4—yl]- 7—[2-(trimethylsilyDethoxy]methyl-7H- pyrrolo[2,3—d]pyrimidine A solution of 4—[1-(4,4-dibromoethy1but—3—enyl)-lH-pyrazolyl]—7-[2-(trimethylsilyl)— ethoxy]methyl~7H—pyrrolo[2,3-d]pyrimidine (20 mg, 0.00004 mol) (from Example 503 Step 1) in THF (1 mL, 0.01 mol) at -78 °C was treated with 2.5 M n-butyllithium in hexane (0.032 mL). The mixture was stirred at -78 °C for lb and then at room temperature for 1h. The reaction was quenched with water (1 mL, 0.06 mol) and 1N HCl. The reaction was partitioned between water and ethyl acetate. The organic extract was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-[1—(1-ethylbut—3—yn—1—y1)—1H—pyrazoly1]-7—[2—(tri— methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidine as a semisolid (12 mg, 80%). LC/MS (M+H)+: m/z = 396.
Step 2: Using a ure ous to Example 61 for the l of the SEM protecting the title compound was isolated as an amorphous white solid (4 mg, 30 %). 1H NMR (400 MHz, DMSO): ,5 12.2 (b, 1H), 8.8 (s, 2H), 8.4 (s, 1H), 7.6 (s, 1H), 7.1 (s, 1H), 4.4 (m, 1H), 2.8 (m, 3H), 1.9 (m, 2H), 0.8 (t, 3H); M+H)+: m/z = 266. e 516: (R)[3-(Ethylsulfonyl)phenyl]-3—[4-(7H—pyrrolo[2,3-d]pyrimidinyl)-1H- pyrazol-l-yl]propanenitrile, 2O (S)—3-[3-(Ethylsulfonyl)phenyl][4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol-l-yl]— propanenitrile Step 1: I-Bromo—3-(ethylthi0)benzene Iodoethane (0.46 mL, 0.0058 mol) was added to a sion of 3-bromothiophenol (0.50 mL, 0.0048 mol), ACN (7.11 mL, 0.136 mol) and potassium carbonate (2.0 g, 0.014 mol). The reaction was stirred for 2 h at rt, was diluted with ethyl acetate and filtered to remove the solids. The reaction was concentrated in vacuo to give 1~bromo(ethylthio)benzene as a colorless oil 1.0 gm, 100% Step 2: I-Bromo—3—(ethylsulfonylflaenzene The MCPBA (2.37 g, 10.6 mmol) Was added to a solution of 1-bromo(ethylthio)benzene (1.00 g, 4.80 mmol) in DCM (10 ml, 156 mmol) cooled to 0 °C. The reaction was stirred for 1 h and then was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with magnesium sulfate, d, and concentrated in vacuo. The resulting crude residue was purified by flash column chromatography with a hexane: ethyl acetate gradient to give l—bromo- ylsulfonyl)benzene as a colorless oil 1.1 gm 92%, lH NMR (300 MHz, CDC13): m, 1H), 7.85(d,1H), 7.78(d, 1H) 7.45(t,1H), 3.14(q, 2H), l.25(t, 3H).
Step 3: (ZE & Z)—3-[3-(Ethylsulfonybphenyljacrylonitrile 1-Bromo(ethylsulfonyl)benzene (1.3 g, 0.0052 mol) was dissolved in the DMF (15.0 mL, 0.194 mol) and 2~propenenitrile (0.68 mL, 0.010 mol), TEA (1.4 mL, 0.010 mol) and triphenylphosphine (0.23 g, 0.00089 mol) were added. The resulting solution was ed with nitrogen, and palladium acetate (0.07 g, 0.0003 mol) was added. Again the reaction was degassed with nitrogen and then heated to 110 0C in a sealed tube for 8 hrs. The on was complete by HPLC, and was then allowed to cool to rt and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The product was purified by FCC on silica gel eluting with a hexane; ethyl acetate gradient to give (2E&Z)—3—[3— (ethylsulfonyl)phenyl]acrylonitrile as an amber oil (1.1 gm, 92%) LC/MS (Mi-HY: m/z = 222.
Step 4: 3-[3—(Ethylsulfonprhenylj—3~[4-(7—[2-(trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3- djpyrimidin~4—yl)—1H—pyrazol—I—yUpropanenitrile The (2E&Z)—3-[3~(ethylsulfonyl)phenyl]acrylonitrile (1.0 g, 0.0045 mol) was combined with pyrazolyl)-7—[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (1.3 g, 0.0041 mol) and DBU (0.61 mL, 0.0041 mol) in ACN (10.0 mL, 0.191 mol) under nitrogen at rt. The reaction was stirred at rt for 24 h. This was partitioned between ethyl acetate and water, and 0.]N HCl was added to adjust the pH to 7. The ed organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give a crude oil. The t was purified by FCC on silica gel eluting with a hexane: ethyl acetate nt to give 3—[3~(ethylsulfonyl)phenyl][4-(7-[2- (trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidin~4-yl)-lH—pyrazol-l-yl]propanenitrile as an oil (1.5 gm, 68%). LC/MS : m/z = 537. The oil was a racimate, which was separated by chiral column chromatography (Chiracel OD-H, eluting with ethanol: methanol: hexane 30:30:40, Rt 13.2 and 17.1 minutes) to give the two omers, each as a glass (0.51 gm) LC/MS (M+H)+: m/z = 537, 1H NMR (300 MHz, CDC13): 8 8.89(s, 1H), 8.45(s, 1H), 8.35(s,1H), 8.09(s, 1h), 8.05(d, 1H), 7.75(d, 1H), 7.71(t, 1H), 7.45(d, 1H), 6.83(d, 1H), 5.85(t, 1H), , 2H), 3.78-3.42(m, 4H), 3.18(m, 2H), 1.35(t, 3H), 0.97(t, 2H), 0.05(s, 9H).
Step 5: Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compounds were prepared to give isomer #1 as an amorphous white solid (300 mg, 80 %). 1H NMR (400 MHz, DMSO): 5 9.1 (s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.0 (s, 1H), 7.6-7.9 (m, 4H), 7.1 (s, 1H), 6.3 (m, 1H), 3.9 (m, 1H), 3.7 (m, 1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) (M+H)+: m/z = 407.
Using a ure analogous to Example 61 for the removal of the SEM protecting group the title nds were prepared to give isomer #2 as an amorphous white solid (300 mg, 80 %). lH NMP (400 MHz, DMSO): 8, 9.1 (s, 1H), 8.8 (s, 1H), 8.5 (s, 1H), 8.0 (s, 1H), 7.6-7.9 (m, 4H), 7.1 (s, 1H), 6.3 (m, 1H), 3.9 (m, 1H), 3.7 (m, 1H) 3.2 (q, 2H), 1.0 (t, 3H); MS(ES) : m/z = 407.
Example 526: 4-[1-(1-Ethylbutenyl)-lH—pyrazol—4-yl]-7H-pyrrolo[2,3-d]pyrimidine N \ \ N NH Step 1: 4-[1-(1-Ethy1but—3-en-1~yl)-1H—pyrazol—4-yl]—7—[2-(trimethylsz‘lyl)ethonymethyl-7H-pyrrolo- [2, 3-djpyrimidine To an ice cooled solution of methyl triphenylphosphonium bromide (100 mg, 0.0004 mol) in THF (2 mL, 002 mol) was added 0.5 M potassium bis(trimethylsilyl)amide in toluene (0.8 mL). The mixture was stirred for 1h at 0 °C ice bath, and was then cooled to -78 °C and d with 3-[4—(7-[2- (trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol-l-yl]pentanal (80 mg, 0.0002 mol) (from Example 498). The reaction was stirred at -78 °C and gradually was warmed to room temperature ght. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4—[1-(1-ethylbuten-1—yl)-1H-pyrazolyl][2-(trimethylsilyl)ethoxy]methyl- rolo[2,3-d]pyrimidine 150 mg as a crude product. LC/NIS = 398 (M+1).
Step 2: 4—[1-(1—Ethylbut—3—enyD-1H—pyrazol—4—yU—7H—pyrrolo[2, 3—d]pyrimidine Using a procedure analogous to Example 61 for the removal of the SEM protecting group the title compound was isolated as an amorphous white solid (25 mg, 1%). 1H NMR (400 MHz, DMSO): 8, 8.6 (s, 2H), 8.2 (s, 1H), 7.4 (s, 1H), 6.9 (s, 1H), 5.8 (m, 1H), 5.0 (dd, 2H), 4.2 (m, 1H), 2.4—2.6 (m, 2H), 1.7—1.9 (m, 2H), 0.6 (t, 3H); LC/MS: 268 CM+1).
Example 500: (3R)- and (3S)-4,4,4-Trifluoro~3—[3-(7H—pyrrolo[2,3-d]pyrimidinyl)—1H—pyrrol— 1-yl]butanenitrile F F F F FA34 F . . . , /CN N N / // N\b.) N\ N 'k/SN H H Step I. 4-Chloro— 7-(diethoxymethy0- 7H-pyrrolo[2,3—d]pyrimidine A mixture of 4-chloropyrrolo[2,3—d]pyrirnidine (2.00 g, 0.0130 mol) and ethyl ormate (25 mL, 0.15 mol) was heated to reflux for 2 hours. The solvent was evaporated, and the residue was purified by flash column chromatography (eluting with ethyl acetate/hexanes) to yield the desired product (1.13 g, 34%).
‘H NMR (400 MHz, CDC13'): 8 8.63 (s, 1H), 7.58 (d, 1H), 6.71 (s, 1H), 6.65 (d, 1H), 3.77-3.67 (m, 2H), 3.58—3.49 (m, 2H), 1.23 (t, 3H), 1.23 (t, 3H).
Step 2. 7-(DiethoxymethyD(IH-pyrrol—3-yl)— 7H—pyrrolo[2, 3-djpyrimidine To a degassed solution of 4-chloro(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.13 g, 0.00442 mol) and 1-(triisopropylsi1yl)-3—boronic acid (1.00 g, 0.00374 mol) and sodium ate (0.396 g, 0.00374 mol) in 1,2—dimethoxyethane (15 mL) and water (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.00019 mol). This mixture was d at ambient temperature for 2 hours, and then was heated to reflux for 4 hours. The mixture was then cooled, trated, and purified by flash column chromatography (eluting with ethyl acetate/hexanes) to afford a residue as an oil. ACN was added to the residue, and the product which precipitated was filtered off and washed with a small quantity ofACN (165 mg, 13%). 1H NMR (400 MHz, Ds—dmso): 8_ 11.44 (br s, 1H), 8.66 (s, 1H), 7.80—7.78 (m, 1H), 7.58 (d, 1H), 7.03 (d, 1H), 6.94 (dd, 1H), 6.90 (dd, 1H), 6.75 (s, 1H), 3.74-3.65 (m, 2H), .50 (m, 2H), 1.15 (t, 6H); MS(ES): M+H = 287.
Step 3.
To a solution of 7-(diethoxymethyl)(1H-pyrrolyl)-7H-pyrrolo[2,3-d]pyrimidine (0.125 0.480 mmol) in ACN g, 0.436 mmol) and 4,4,4-trifluorobut—Z-enenitn'le (0.0476 rnL, (1 mL) was added DBU 3 mL, 0.436 mmol). TFA (0.5 mL) was added and the mixture was stirred for 1 hour. The TFA and solvent was d in vacuo. The residue was purified by preparative- HPLC/MS (C-18 eluting with a gradient of Hzo/ACN containing 0.15% NH40H) to afford the product (102 mg, 76%). Where desired, the enantiomers were separated in substantially pure form by chiral I-IPLC (AD-H, 20% EtOH/Hexane). 1H NMR (300 MHz, DG-dmso): 8 12.05 (br s, 1H), 8.65 (s, 1H), 8.04 (s, 1H), 7.56 (dd, 1H), 7.21 (t, 1H), 7.02 (dd, 1H), 6.93 (dd, 1H), 5.89—5.74 (m, 1H), 3.95 (dd, 1H), 3.66 (dd, 1H); MS(ES): M+H = 306.
The analog in Table 12 was prepared in racemic form according to the same procedure, using a different conjugate acceptor and with the exception that in the ate addition in Step 3, the reaction was carried out at 40 0C for 3 days.
Table 12 Method of preparation and chiral separation 3-[3-(7H—pyrrolo[2,3-d]pyrimidinyl)- . . enantiomers lH-pyrrol—l —yl]butanen1tnle not separated The following compounds in Table 13 were prepared as indicated in the column labeled "Method of Prep." and the details of n ary synthetic procedures are ed following Table 13.
N-(3-{2~cyano-l -[4-(7H- pyrrolo[2,3-d]pyrirnidinyl)- lH-pyrazol-l -yl]ethyl}phenyl)- 3-(trifluoromethyl)benzamide N-(3-{[4-(7H-pyn‘olo[2,3- d]pyrimidinyl)—l H-pyrazol— 1 -yI]methy1}phenyl) (trifluoromethyl)benzamide 3-[3-(methylsulfonyl)phenyl]-3 - Ex516 393 [4-(7H—pyrrolo[2,3 -d]pyrimidin- cnch $02CH3 4-yl)-1H-pyrazol-l -yl]- propanenitrile 3—[3-(methylsulfonyl)phenyl]-3 - BX 516 393 [4-(7H—py1rolo[2,3-d]pyrimidin— CHZCN soch3 4-yl)-1H—pyrazol-1 -yl]- propanenitrile N-(3-{[4-(7H-pyrrolo[2,3-d]- BX 469 43 1 pyrimidinyl)-lH—pyrazol-l - yl]methyl}phenyl)benzene- sulfonamide H 3- { [4-(7H—pyrrolo[2,3-d]- Ex 472 a" N CFa 463 pyrimidin—4—yl)~lH-pyrazol-l-’ 605 H yl]methy1}-N-[3-(trifluoro- methyl)phenyl]benzamide 3-{2-cyano—1-[4-(7H- Ex 649 606 422 pyrrolo[2,3-d]pyrimidinyl)- CH CN2 ee#l lH-pyrazol-l'-y1]ethyl}—N,N- dimethylbcnzenesulfonamide 3- {2—cyano-l H— BX 649 606 422 pyrrolo[2,3-d]pyrimidinyl)— CH CN2 ee#2 lH—pyrazol—l-yl]ethyl}—N,N— ylbenzenesulfonamide N—benzyl—3 — no—l —[4-(7H— BX 649 484 pyrrolo[2,3—d]pyrimidinyl)- 607 CHZCN lH-pyrazol—l -yl]ethyl} benzene- sulfonamide trifluoroacetate N—benzyl-3 - {2-cyano-l -[4-(7H- BX 472 H\/© 448 pyrrolo[2,3-d]pyrimidinyl)- 608 CHZCN Vgin/N lH—pyrazol-l -yl]ethyl}- ° benzamide 3-{2—cyano[4-(7H- 04;; 434 pyrrolo[2,3-d]pyrimidin—4-yl)— CHZCN © 1H-pyrazol-l -yl]ethyl} -N- benzamide trifluoroacetate 3-{2-cyano[4-(7H— "H. 2:1: 0J‘ 502 pyrrolo[2,3-d]pyrimidin—4—yl)— CH2CN o=< lH—pyrazol-l hyl} -N-[3 - (trifluoromethyl)phenyl]— benzamide roacetate N—(3—cyanophenyl) {[4—(7H- C2 420 pyrrolo[2,3-d]pyrimidin-4—yl)— lH—pyrazol—l —yl] - methyl }benzamide N-benzyl—S-{[4-(7H—pyrrolo— [2,3-d]pyrimidin—4-yl)- 1H- pyrazol—l -y1]methyl }benzamide N—l -naphthy1—3 - { [4-(7H- pyrrolo[2,3—d]pyrimidin—4~yl)— lH-pyrazol-l -y1]methyl} — benzamide Nnaphthy1—3- {[4-(7H- pyrrolo[2,3—d]pyrimidin—4—yl)— lH—pyrazol-l -yl]methyl} - benzamide N—(3~{[4—(7H-pyrrolo[2,3—d]- pyrimidin—4—yl)-1H-pyrazoI-l - hyl}'phenyl)—2— naphthamide tn'fluoroacetate N-(3~ {[4-(7H~pyrrolo[2,3~d]~ pyrimidin-4—yl)-1H-pyrazol-1 - yl]methyl}phenyl)—1 - naphthamide trifluoroacetate 2-pheny1—N-(3— {[4-(7H- pyrrolo[2,3-d]pyrimidinyl)- IH—pyrazol— 1 —y1]methyl} — )acetamide trifluoroacetate 3-chloro-N-(3-{[4-(7H-pyrrolo- [2,3—d]pyrimidin-4—yl)-1H- pyrazol-l -yl]methyl}pheny1)- benzamide trifluoroacetate N—(3—{2-cyano-l -[4-(7H- pyrrolo[2,3-d]pyrimidin—4-yl)~ 1 H-pyrazol-l -y1]ethyl } pheny1)- 2-naphthamide trifluoroacetate N-(3—{2-cyano-l -[4—(7H- pyrrolo[2,3—d]pyrimidin—4—yl)— lH-pyrazol-l -yl]ethyl}phenyl)- thamide roacetate N—(3- {2-cyano-l -[4-(7H- o[2,3-d]pyrimidinyl)- lH-pyrazol-l thyl}pheny1)- 2—phenylacetamide trifluoroacetate 3-cyano-N-(3-{2-cyano[4- (7H-pyrrolo[2,3—d]pyrimidin—4- -pyrazol-l ~yl]- ethyl}phenyl)benzamide tn'fluoroacetate N—(3- {Z-cyano-l —[4-(7H— pyrrolo[2,3-d]pyrimidin—4-y1)- lH—pyrazol-l —yl]ethyl} - phenyl)benzamide trifluoroacetate N-(3-{2-cyano-1—{4-(7H— pyrrolo[2,3 -d]pyrimidinyl)— azol-l —yl]ethyl }phenyl)- 4—(tr1'fluoromethyl)benzamide trifluoroacetate N-(3-{2-cyano[4—(7H- pyrrolo[2,3-d]pyrimidin-4~yl)- 1 H—pyrazol-l ~y1]ethyl}phenyl)- N'-phenylurea trifluoroacetate 3- {2—cyano-1 I-I-pyrrolo- [2,3-d]pyrimidinyl)-1H- pyrazol—l -y1] ethyl} -N-[4- (tfifluoromethyl)phenyl]- benzamide trifluoroacetate 3— {2-cyano-1—[4—(7H—pyrrolo— [2,3 -d]pyrimidin-4—yl) - lH- pyrazolyl]ethyl} -N-(4- methylphenyl)benzamide trifluoroacetate N—(4—cyanophenyl)-3~ {2~cyano- 1-[4—(7H-pyrrolo[2,3—d] - pyrimidin—4—yl)-1H—pyrazol-l — yl]ethyl } benzamide tn'fluoroacetate 3- {2-cyano-1 -[4—(7H—pyrrolo- [2,3-d]pyrimidin—4-yl) -1H— pyrazol—l hyl } -N-2— naphthylbenzamide trifluoro- 3- {2-cyano-l -[4-(7H-pyrrolo- [2,3-d]pyrimidinyl) -1H— pyrazol-l —yl]ethyl}—N-l - naphthylbenzamide tri- fluoroacetate 3- {2-cyano[4-(‘7H—pyrrolo- [2,3-d]pyrimidin~4-yl) -l H- pyrazol-l -yl]ethyl} -N,N— dimethylbenzamide tri- fluoroacetate 3-{2—cyano[4-(7H-pyrrolo- [2,3—d]pyrimidin—4—y1) —1H- CHZCN pyrazol-l -yl]ethyl} -N-pyridin- 3—ylbenzamide trifluoroacetate 3-{2-cyano[4-(7H-pyrrolo— Z-O 448 [2,3-d]pyrimidinyl) —1H— CHZCN 04"" pyrazol-l -y1] ethyl} -N—methyl- .C; N—phenylbenzamide roacetate 3-{2-cyano-1—[4—(7H—pyrrolo- 04; 440 [2,3—d]pyrimidin-4—yl) —1H— CHZCN O pyrazol-l ~yl]ethyl} -N- cyclohexylbenzamide tri- fluoroacetate 3-{2-cyano[4-(7H-pyrrolo- 526 [2,3—d]pyrimidin—4—yl) -1H- CHZCN 9<3 pyrazol-l -yl]ethyl} -N-(4- phenoxyphenyl)benzamide trifluoroacetate N—(3—cyanophenyl)—3-{2-cyano— "ai: l-[4-(7H—pyrrolo[2,3 -d]- CHZCN pyrimidin—4-yl)—lH—pyrazol—l — yl]ethyl }benzamide trifluoroacetate 0:3"21 N—biphenylyl—3- {2-cyano-l - Ex 472 10 [4—(7H-pyrrolo[2,3-d CHZCN ]pyrimidinyl)—1H—pyrazol-l - yl]ethy1}benzamide trifluoroacetate N-(4-chlorophenyl)-3 - {2-cyano- BX 472 ‘ N 468 1-[4-(7H—pyrrolo[2, 3-d]- CHzCN YO pyrimidinyl)-1 H-pyrazol-l - 0 yl]ethyl }benzamide roacetate 3—{2—cyano[4-(7H-py1rolo- Bx 472 99 CH3 462 [2,3-d]pyrimidin—4-yl) ~1H- N CH;CN Ya pyrazol-l -yl]ethyl} -N-(3,4- 0 ylphenyl)benzamide roacetate 3-{2-cyano[4-(7H-pyrrolo- N OCH3 464 [2,3—d]pyrimidinyl) —1H— CHzCN pyrazol-l -y1]ethyl}-N—(3- o methoxyphcnyl)benzamide trifluoroacetate 3-{2-cyano—1-[4-(7H-pyrrolo- [2,3-d]pyrimidinyl) —l H— CHZCN pyrazol-l hyl}-N—(4— methoxyphenyl)benzamide trifluoroacetate 3-{2-cyano-l -[4—(7H—pyrrolo- [2,3-d]pyrimidinyl) ~1H- l-l -yl]ethyl}-N-isoxazol- 3—ylbenzamide trifluoroacetate 3~{2-cyano—1~[4-(7H—pyrrolo- [2,3-d]pyrimidin—4~yl)—1 H- l—l —y1]ethyl} ~N—methy1— N-phenylbenzenesulfonamide 3- {2-cyano-1 —[4-(7H—pyrrolo- [2, 3 —d]pyrimidin-4—yl)—1H- pyrazol—l -yl]ethyl} —N— propylbenzenesulfonamide 3- {Z—cyano—I -[4-(7H—pyrrolo- [2,3-d]pyrimidin—4-yl)—l H- pyrazol-l -yl]ethyl} -N— phenylbenzenesulfonamide 3-{2-cyano[4-(7H-pyn'olo- [2,3-d]pyrimidin—4—yl) -1H- pyrazol—l —yl]ethyl} -N naphthylbenzene- sulfonamide 3- {2-cyano-l -[4—(7H—pyrrolo- [2,3—d]pyrimidin-4~yl) -1H— l~1 hyl} —N— cyclopropylbenzene— sulfonamide 3-[3—(piperidin—1 fonyl)— phenyl][4—(7H~pyrrolo[2,3~ d]pyrimidin—4—yl)-1H-pyrazol- l —yl]propanenitrile 3-[3-(morpholin—4-ylsulfonyl)- phenyl][4—(7H~pyrrolo[2,3- d]pyrimidin—4-yl)-1H-pyrazoL 1 —yl]propanenitrile 3-{2—cyano~l -[4-(7H-py1rolo- [2,3-d]pyrimidin-4~yl)-1H- pyrazol-l -yl]ethyl} -N-(4— methylphenyl)benzene- sulfonamide trifluoroacetate 3 - {2-cyano-1 H-pyrrolo- [2,3-d]pyrimidin—4-yl)-1H- pyrazol-l -yl]ethyl } -N-(3 ,4— dimethylphenyl)benzene— sulfonamjde trifluoroacetate 3-{2-cyano—1-[4—(7H—pyrrolo— [2,3-d]pyrimidin~4-yl) -1H- pyrazol-l hyl} -N—(3- methoxyphenyl)benzene~ sulfonamide trifluoroacetate 3- {2-cyano-l -[4-(7H-pyrrolo- [2,3-d]pyrimidin—4—yl) ~1H— pyrazol-l -yl]ethyl} -N-(4- methoxyphenyl)benzene— sulfonamide trifluoroacetate 3- {2-cyano- 1 H-pyn'olo— ]pyrimidin—4-yl) -1H— pyrazol-l —yl] ethyl} -N-(3,5— dimethoxyphenyl)benzamide trifluoroacetate 3—{2-cyano[4-(7H-pyrrolo- [2,3-d]pyrimidinyl) -1H— pyrazol-l -yl]ethyl} -N-[4- (dimethylamino)phenyl]- benzamide tn'fluoroacetate 3—[3—(benzy1su1fonyl)phenyl] [4-(7H-pyrrolo[2,3-d]pyrimidin- 4-y1)-1 zol—l -yl] — propanenitrile benzylthio)phenyl] [4- (7H—pyrrolo[2,3-d]pyrimidin yl)-1H-pyrazol-1 -yl] - propanenitrile 4-{[(3-{2-cyano[4-(7H- pyrrolo[2,3—d]pyrimidin—4—yl)— lH-pyrazol-l hyl}phenyl)- sulfonyl]methyl}benzonitrile 3-{2-cyano—1-[4-(7H-pyrrolo- [2,3—d]pyrimidinyl)-1H- pyrazol-l —y1]ethyl} —N—methyl— benzenesulfonamide 3-{2-cyano[4—(7H-pyrrolo- [2,3-d]pyrimidin-4—yl) -1H- pyrazol- l hyl} -N-l - naphthylbenzenesulfonamide N—biphenyl-4—yl {2-cyano-1 - [4-(7H—pyrrolo[2,3-d]pyrimidin- 4-yl)-1H~pyrazol-l -yl]ethyl} - benzenesulfonamide 3-{2—cyano—1—[4-(7H—pyrrolo- [2,3-d]pyrimidinyl) ~1H— pyrazol-l —yl]ethyl}-N—[4— (trifluoromethoxy)phenyl]~ benzamide trifluoroacetatc 3—{2-cyano[4-(7H-pyn'olo- [2,3-d]pyrimidin—4-yl)—1H— pyrazoI-l -yl]ethyl} -N-(2- methoxyphenyl)benzamide tn'fluoroacetate 3-[3-(benzyloxy)phenyl][4- (7H—pyrrolo[2,3-d]pyrimidin y1)- lH—pyrazol-l -yl] - propanenitrile 3—{2—cyano-l H-pyrrolo— [2,3—d]pyrimidin—4-yl)-1 H- pyrazol-l -yl]ethyl} -N- cyclohexylbenzenesulfonamide trifluoroacetate 3 -[3 -(3 ,4-dihydroisoquinolin- 2(1 H)—ylsulfony1)phenyl]-3—[4— rrolo[2,3-d]pyrimidin yl)-1H—p yrazol-l -y1]propane- nitn'le trifluoroacetate 3-{2-cyano[4-(7H-pyrrolo— [2,3-d]pyrimidin—4—y1)-1 H— pyrazol-l -y1]ethyl} -N—(2- methoxyethyl)benzene- sulfonamide tn'fluoroacetate 3-{2-cyano[4-(7H—pyrrolo- [2,3-d]pyrimidin—4—y1)—1H— pyrazol-l —yl]ethyl} -N,N- diethylbenzenesulfonamide 3-{3-[(4-ethylpiperazin—1-yl)- sulfonyl]phenyl} (7H— pyrrolo[2,3-d]-pyrimidinyl)— lH-pyrazol—l -yl]propanenitrile N—l ,3~benzodioxol—5—yl—3 — {2— cyano-l -[4-(7H-pyrrolo[2,3-d] - pyrimidin—4—yl)— l zol-l - yl]ethyl }benzenesulfonamide 3— {3-[(3—methoxybenzy1)- sulfonyl]phenyl } -3—[4-(7H- pyrrolo[2,3-d]pyrimidin—4-yl)- lH-pyrazol—l —yl]-propanenitrile 3- {3-[(4—methoxybenzyl)— sulfonyl]phenyl } —3—[4—(7H— pyrrolo[2,3-d]pyrimidin—4-yl)- lH—pyrazol-l -yl]-propanenitrile 3— {3 -[(2,6-dimethylmorpholin— 4-yl)sulfonyl]phcnyl }[4— rrolo[2,3-d1pyrimidin y1)-1 H—pyra zol-l -yl] - propanenitrile 3 —{3-[(4-oxopiperidin—1 —y1)- sulfonyl]pheny1} [4— (7H- pyrrolo[2,3-d] —pyrimidin—4-y1)- 1 H-pyrazol-l -yl]propanenitrile trifluoroacetate 3-[3 -(isopropylsulfonyl)p henyl][4-(7H—pyrrolo[2,3-d]— pyrimidin—4—yl)-lH-pyrazol-l - yl]propanenitrile trifluoroacetate 3- {3 -[(cyclohexylmethyl)— yl]phenyl} (7H- pyrrolo[2,3-d]pyrimidin—4-yl)- IH-pyrazol—l -y1]-propanenitrile trifluoroacetate 3-[3 -(octahydroisoquinolin- 2(1 H)—ylsulfony1)phenyl][4— (7H—pyrrolo[2,3—d]pyrimidin—4- yl)-lH—pyr azol-l -y1]propane- nitrile roacetate 3-{2—cyano[4-(7H-pyrrolo- [2,3-d]pyrimidin-4—yl) -l H— pyrazolyl]ethyl } -N-(2- phenylethyl)benzene sulfonamide trifluoroacetate 3-[3 -(_pyrrolidin—l -ylsu1fonyl)— phenyl]~3—[4-(7H-pyrrolo[2,3-d]- pyrimidin—4—yl)-1H—pyrazol-1 - yl]propanenitrile N-benzyl-B— {2-cyano—1 -[4—(7H- o[2,3-d]pyrimi din—4—yl)- lH—pyrazol-l hyl} -N- methylbenzenesulfonamide 3 -{ [(3- {2-cyano-1 -[4-(7H- pyrrolo[2,3—d]pyrimidin— 4—y1)- lH-pyrazol-l ~yl]ethyl} - pheny1)sulfonyl]methyl} - benzonitrile 3 - {3 - [(2—naphthylmethyl)- sulfonyl]phenyl } [4-(7H- pyrrolo[2,3-d]pyrimidiny1)- azol-l —y1]propanenitn'le 204_ 3-{3-[( l -phenylethyl)sulfonyl]- phenyl} -3—[4-(7H—pyrrolo[2,3-d]- pyrimidin—4—yl)-lH—pyrazol—l - yl]propanenitrile 3- {2-cyano-l —[4-(7H-pyrrolo- [2,3-d]pyrimidin—4—yl)- lH— pyrazol-l ~y1]ethyl} —N—(2- morpholin~4~ylethyl)— benzenesulfonamide N-(2-aminoethy1) {[(3 - {2— l -[4-(7H—pyrrolo [2,3-d]- pyrimidinyl)-1 H-pyrazol-l - yl]ethyl }phc nyl)sulfonyl] - amino} acetamide 3 -{2-cyano—1—[4-(7H-pyrrolo- [2,3-d]pyrimidin-4—yl) -1H~ pyrazol-l hyl} ~N-[(1 S)-l - phenylethyl]benzenesulfonamide 3 - {2—cyano— l —[4—(7H—pyrrolo— [2,3-d]pyn'midin-4—yl) ~1H- pyrazol-l —y1]ethyl} -N-phenyl— benzamide trifluoroacetatc 3 -{2—cyano[4-(7H-pyrrolo- [2,3-d]pyrimidin-4—yl) —1H— pyrazol-l -yl]ethyl } -N-phenyl - ‘benzamide trifluoroacetate 3- {2-cyano-l —[4-(7H-pyrrolo- [2,3-d]pyrimidinyl) -1H- pyrazol-l hyl}-N- (tetrahydrofuran—Z-yl- )benzenesulfonamide 3 - {3 lopropy1methyl) sulfony1]phenyl} —3-[4—(7 H— pyrrolo[2,3-d]py:rimidinyl)- lH-pyrazol-l -yl]propanenitrile tri fluoroacetate 3- {3-[(4-methylpiperazin—1 -yl)- yIJphenyl} —3 — [4—(7H— pyrrolo[2,3-d]pyrimidin—4-yl)- 1 H—pyrazol—l -yl]propanenitrile l-[(3- {2-cyano—l -[4-(7H—pyrrolo— [2,3-d]pyrimidin—4 -yl)—1H- pyrazol-l -yl]ethy1} - phenyl)sulfonyl]~N,N—diethyl— . i - eridine—S-carboxamidc 3-{3-{(1-oxidothiomorpholin—4— y1)sulfonyl]pheny1}-3—[4-(7H- CHzCN pyrrolo[2,3-d]pyrimidin—4-yl)- lH-pyraz 01-1 -y1]propanenitrile 3-[3-(piperazin— 1 —ylsulfonyl)— Ex 472 phenyl][4-(7H-pyrrolo[2,3—d] - CHZCN pyrimidinyl)- l H-pyrazol-l - yl]propanenitrile 480 3-[4-(7H—pyrrolo[2,3—d]— BX 472 pyrimidinyl)-1 H-pyrazol -1 - CH2CN yl]-3—[3-(thiomorpholin—4—yl- sulfonyl)phenyl]propanenitrilc 478 3- {3-[(4—hydroxypiperidin—l -yl)- BX 472 sulfonyl]phenyl} -3 —[4-(7H- CH2CN o[2,3-d]pyrimidinyl)- lH-pyrazol- 1-yl]propanenitrile tri fluoroacetate 435 3-[3-(isobutylsulfonyl)phcny1]~3- BX 516 [4—(7H-pyrrolo[2 ,3-d]pyn'midin- CHZCN 4—yl)—1H—pyrazol-1 -yl]propane- nitrile trifluoroacetate 477 7H—py1rolo[2,3-d]- Ex516 pyrimidin—4—yl)— 1 H—pyrazol-l - yl] {3 -[(tetrahydro-2H-pyran- 697 CH2CN 4—ylmethyl)sulfonyl] - phenyl } propanenitrile trifluoroacetate 437 3-{3-[(2-methoxyethyl)sulfonyl]- Ex516 is": phenyl}[4-(7H-p yrrolo[2,3— 698 CHZCN "SW \O d]pyrimidin—4-yl)-lH—pyrazol-l — O O yl]propanenitrile roacetate 459 3-{3-[(3 -fury1methyl)sulfonyl]- Ex516 phenyl} -3—[4—(7H-py nolo[2,3- CHZCN d]pyrimidin—4-yl)-1H-pyrazol—1- yl]propanenitrile trifluoroacetate 512 3- {3 -dioxidothiomorpholin- Ex 649 4—y1)sulfonyl]phenyl}-3—[4-(7H- CH2CN pyrrolo[2,3-d]pyrimidinyl)— lH-p yrazol-l ~y1]propanenitrile 3- -acetylpiperazin— 1 -y1)- yl]phenyl} [4—(7H— pyrrolo[2,3—d]pyrimidin—4-yl)- CH2CN lH-pyrazol-l -yl]propanenitrile 3 — {3-[(pyridin-4—ylmethyl)— sulfony11phenyl}-3—[4-(7H— pyrrolo[2,3-d]pyrimidin~4-yl)— lH-pyrazol-l —y1]pr0panenitrile 314 1 —phenylbut-3~yn—1 511%}H- pyrazol-4—yl]—7H— pyrrolo[2,3-d]- 703 CHgC ECH H pyrimidine trifluoroacetate 463 4-(1-{1-[3—(morpholin—4—yl- sulfonyl)phenyl]but—3—yn—1 -yl } — 704 CH2C £I-I 1H—pyrazol—4—y1)—7H-pyrrolo[2,3- d]pyrimidine 339 3-{ 1 H—pyrmlo[2,3—d]— pyrimidin—4—yl)-1H—pyrazol—l — 705 CH2C ECH CN yl]butyny1}benzonitrile trifluoroacetate 342 3-{ l —[4—(7H-pyrrolo[2,3-d]— din-4—yl)- lH-pyrazol-l - 706 CH2C £14 CH=O yl]but—3—yny1}benzaldehyde trifluoroacetate 373 methyl 3-(3—cyanophenyl)[4— . (7H-pyrrolo[2,3-d]pyn'midin y1)-1 H-pyrazol—l —y1]propanoate trifluoroacetatc N,N-dimethyl{ 1 H- pyrrolo[2,3-d]pyrimidin- 4-yl)- lH—pyrazol-l tyn-1 -y1}- CH2C26H esulfonamide trifluoroacetate 3- {2-cyano-1 -[4-(7H-pyrro lo[2,3-d]pyrimidiny1) ~1H- pyrazol-l -y1]ethyl} -N-[4- CH2CN (dimethylamino)phen y1]- benzenesulfonamide 3- {3-mcthoxy—l -[4-(7H-pyrrolo- [2,3—d]pyrimidiny l)-l H— pyrazol-l -y1]propyl} -N,N- dimethylbenzenesulfonamide trifluoroace’cate N-phenyl-3 - { 1 —[4—(7H-pyrrolo- [2,3-d]pyrimidinyl )-1H- pyrazol—l -yl]but—3 -yn-1 —yl} - benzamide trifluoroacctate 4-[ l -(3-methoxy-1 —phenyl— CH2CH2- propy1)—1H—pyrazolyl]~7H- OCH3 pyrrolo[2,3-d]pyrimidine trifluoroacctatc N-[4-(dimethy1amino)pheny1] { l H-pyrrolo[2 ,3—d]— 713 CH2C SCH pyrimidinyl)-1H~pyrazol yl]but-3 -yn-1 —yl}benzamide trifluoroacetate 3 - roxy-1 -[4-(7H—pyrrolo- ]pyrimidinyl)- 1H— 714 pyrazol- 1 —yl]propyl } -N,N— dimethylbenzenesulfonamidc trifluoroacetate ' 341 3— {1 -[4—(7H—pyrrolo[2,3~d]- CH;- pyrimidinyl)-1H-pyrazol-l - 71 5 CN CH=CH2 yl]but—3-en—1 —yl}benzonitrile trifluoroacetate 4- { 1 -[ l ~(3-bromophenyl)but-3 — en-l -yl]-1H—pyrazol- 4—yl} —7H-— pyrrolo[2,3—d]pyrimidine roacetate 3-{4,4-difluoro[4-(7H— . pyrrolo[2,3-d]pyrimidin- 4-y1)- 717 CF2 lH-pyrazol-l -y1]buten-1 -y1} - ‘benzonitrile 4—(1—{4,4-difluoro-l-[3— (morpholin—4-ylsulfonyl)- 718 CHZCH=CF2 phenyl]but—3-en-1 ~yl} -1H- pyrazoIy1)~7H-pyrrolo[2,3-d]- pyrimidine trifluoroacetate 4-(1 — {1 —[3 -(ethylsulfonyl)— phenyl]-4,4—difluorobuten—l - 7 1 9 CH2CH=CF2 yl} - l H—pyrazol—4-yl)-7H— pyrrolo[-2,3—d]pyrimidine trifluoroacetate 4—(1 - {1 -[3-(benzyloxy)phenyl]~ 4,4—difluorobut—3-e n—l -y1}-1H- 720 CHZCH=CF2 l—4-y])-7H—pyrrolo[2,3—d]- pyrimidine trifluoroacetate 320 4-[1 —(2-methoxy—1 -phenylethy1)- CH20CH3 H 1H—pyrazolyl]-7H-pyrrolo~ [2,3-d]pyrimidine 4-(1-{4,4-difluoro[3-(methyl- sulfonyl)phenyl]but—3 -en-1 -yl} - azol-4—yl)-7H-pyrrolo- [2,3-d]pyrimidine trifluoroacetate 3-{[4—(7H—pyrrolo[2,3-d]- pyrimidin—4-yl)-lH-pyrazol-l - y1]methyl} benzonitrile 343 3- {1 -[4-(7H-pyrmlo[2,3-d]- pyrimidin-4—yl)-l H—pyrazol—l — 724 CH2CH2CH3 CN yl}benzonitrile 4-(1-{1—[3-(ethylsulfonyl)- phenyl]—4,4-difluorobutyl} -l H- pyrazol—4-yl)-7H—pyrrolo[2,3-d]- pyrimidine roacetate 4—[1-(4,4—difluoro—1—{3-[(2— methoxyethyl)sulfonyl]phenyl} - en— 1 -y1)—1H-pyrazolyl]— CHch=CF2 7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate Example 649: 3—[3-(Morpholin—4-ylsulfonyl)pheuyl][4-(7H-pyrrolo[2,3-d]pyrimidinyl)—l H- pyrazol-l—yl]propanenitrile q /0 N \ \ Step I: 4-[(3-Bromophenstulfonyljmorpholine Morpholine (0.19 mL, 0.0022 mol) in 1.0 ml of THF was added dropwise to a solution of 3- bromobenzenesulfonyl chloride (0.3 mL, 0.002 mol) and TEA (0.30 mL, 0.0022 mol) in dry 4.0 mL ofTHF cooled in an ice bath. The reaction mixture was stirred overnight at room temperature and was then partitioned n 0.05N HCl and ethyl acetate. The organic layer was washed with water (2X), and brine (IX), and was then dried over anhydrous magnesium sulfate, filtered and then was concentrated in vacuo to give 4-[(3-bromophenyl)sulfonyl]morpholine as a white crystalline product (470 mg, 78%). LCMS (M+H)+: m/z = 306, 308.
Step 2: (2E&Z)—3—[3-(Morph01in—4—ylsulfonyl)phenyl]acrylonitrile The 4-[(3-brornophenyl)sulfonyl]morpholine (0.250 g, 0.000816 mol) was ved in dry DMF (2.5 mL, 0.032 mol) and the mixture was degassed using a stream of nitrogen. To this e was added TEA (0.23 mL, 0.0016 mol), 2-propenenitrile (0.11 mL, 0.0016 mol), palladium acetate (0.011 g, 0.000049 mol), and triphenylphosphine (0.0364 g, 0.000139 mol) and again the mixture was ed with nitrogen. The reaction mixture in a sealed tube was heated at 110 °C for 16 hours. The reaction mixture, after cooling to room temperature, was partitioned between 0.05N HCl and ethyl acetate. The organic layer was washed with water (2X), and brine (1X), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo, to give (2E&Z)—3-[3-(morpholinyl- sulfonyl)phenyl]acrylonitrile as an oil (0.240gm, 85%) which was a mixture of cis and trans isomers.
LCMS (M+H)+: m/z = 279.
Step 3: 3-[3-(Morph01inylsulf0nyl)phenyl][4-(7-[2-(trimethylsilyl)ethoxyjmethyl- 7H—pyrrolo- [2, 3-d]pyrimidin—4—yl)-IH-pyrazol—I—y1]propanenitrile To a mixture of 4-(1H-pyrazol—4—yl)-7—[2—(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]- pyrimidine (0.100 g, 17 mol) and (2E&Z)—3-[3-(morpholinylsu1fonyl)phenyl]acrylonitrile (0.097 g, 0.00035 mol) in dry ACN (2.0 mL, 0.038 mol) was added DBU (0.095 mL, 0.00063 mol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl e. The combined organic phase was washed with water (2X), and brine (1X), dried over magnesium sulfate, filtered and then trated in vacuo to give the crude product. The crude product was purified by silica gel flash column chromatography using ethyl acetate-hexanes (6:4) as an eluent to give 3—[3-(morpholin~4~ylsulfonyl)phenyl]—3-[4-(7— imethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1H—pyrazol-l opanenitm'le as a viscous oil (62 mg, 32.94%). LCMS (IvI+H)+: m/z = 594 Step 4: Using a procedure analogous to Example 61 for the removal of the SEM protecting the title compound was isolated as an amorphous white solid (30 mg, 63.84%. LCMS (M+H)+: m/z = 464. 1H NMR (400 MHz, DMSO—d6): 6 8.88 (s), 8.62 (s), 8.1(s), ), 7.70(m), 7.58(m), 6.95(m), 6.20(m), 3.84(m), ),3.45(m), 2.78(m).
Example 679: cis[4—(7H-Pyrrolo[2,3-d]pyrimidin—4-yl)—1H—pyrazol—1-yl]cyclohexyl— acetonitrile IL / N 0 Step 1: 4-(Hydroxymethylkyclohexanol .
Ethyl 4-oxocyclohexanecarboxylate (2.0 g, 0.012 mol) was dissolved in ether (20.0 mL) and was then cooled at 0 °C Into the mixture was added 1 M lithium tetrahydroaluminate in ether (20 mL) and the resulting mixture was stirred at 0 °C for 2 hours. The reaction was quenched with water (2 mL) and 1 N NaOH (2 mL) and ether was added (100 mL). The precipitated solids were filtered off and the residue was used in the next reaction. lH NMR(CDC13):5 4.02 and 3.75 (m, 1H), 3.45-3.61 (m, 2H), 2.02 (m, 2H), 1.84 (m, 1H), 1.52—1.80 (m, 2H), 1.44 (m, 1H), 1,32 (m, 2H), 1.03 (m, 1H).
Step 2.‘ 4-[(Trityloxy)methyljcyclohexanol. 4-(Hdroxymethyl)cyclohexanol (2.0 g, 0.015 mol) was dissolved in pyridine (15.0 mL) and the mixture was cooled to 0 °C. To the reaction was added triphenylmethyl chloride (4.7 g, 0.017 mol) and the resulting mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours. The on was then concentrated using a rotary evaporator, and the concentrate was extracted with ethyl e.
The organic extracts were washed with water, ted NaCl, dried (MgSO4) and then trated in vacuo. The on was chromatographed on silica gel using 30% EtOAc/hexanes to give the cis isomer (0.74 g) 1H NMR(CDC13):8 7.52 (m, 6H), 7.27 (m, 9H), 3.98 (m, 1H), 2.93 (m, 2H), 1.21-1.68 (m, 9H); and the trans isomer (2.72 g) 1H NMR(CDC13):5 7.44 (m, 6H), 7.20-7.31 (m, 9H), 3.54 (m, 1H), 2.88 (m, 2H), 1. 98 (m, 2H), 1.88 (m, 2H), 1.60 (m, 1H), 0.99-1.37 (m, 4H).
Step 3: trans—4—[(Trigiloxy)methyl]cyclohwgll methanesulfonate. trans—4-[(Trityloxy)methyl]cyclohexanol (2.72 g, 0.00730 mol) was dissolved in chloroform (30.0 mL) and the mixture was cooled at 0 °C To this mixture was added TEA (1.4 mL, 0.010 mol) and methanesulfonyl chloride (0.68 mL, 0.0088 mol) and the resulting mixture was stirred at 0 °C for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, ted NaCl, dried ) and the concentrated in vacuo. 1H NMR (CDC13):8 7.43 (m, 6H), 7.20-7.31 (m, 9H), 4.57 (m, 1H), 3.00 (m, 3H), 2.90 (m, 2H), 2.16 (m, 2H1, 1.93 (m, 2H), 1.09—1.60 (m, SH).
Step 4.’ 7-[2~(Trimethylsilyl)ethoxyjmethyl-4—(I-cis[(trityloxy)methyl_]cyclohexyl—IH—pyrazol—4—yl)— 7H-pyrrolo[2,3-djpyrimidz'ne . 4-(1H-Pyrazol—4—yl)-7~[2-(trimethylsily1)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 0.0048 mol) was mixed with sodium hydride (0.34 g, 0.0086 mol) and trans—4- [(trityloxy)methyl]cyclohexyl methanesulfonate (3.00 g, 6 mol) and the mixture was cooled to ~78 °C. To this mixture was added DMF (8.3 mL) and the e was allowed to warm to 25 °C and was stirred for 20 minutes. The warmed mixture was stirred at 55 °C for 48 hours. The on was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated in vacuo. The concentrate was chromatographed on silica gel using 40% EtOAc/hexanes to give the product. LC/MS (M+H)+: 670, 1H NMR(CDC13):8 8.89 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 6.84—7.51 (m, 10H), 6.87 (d, 1H), 5.73 (s, 2H), 4.39 (m, 1H), 3.60 (m, 2H), 3.12 (m, 2H), .11 (m, 9H), 0.96 (m, 2H), 0.00 (s, 9H).
Step 5: cis~4—[4—(7-[2-(Trimethylsibzlkthowjmethyl— 7H-pyrrolo[2,3-d]pyrimidin-4—yD-1H—pyrazol—1 - yljcyclohexylmethanol. 7-[2-(Trimethylsily1)ethoxy]methyl(1 -cis[(trityloxy)methyl]cyclohexyl-1 H—pyrazol—4— yl)-7H—pyrrolo[2,3-d]pyrimidine (0.3 g, 0.0004 mol) was dissolved in methanol (7.0 mL) and THF (2.0 mL, 0.025 mol) and 4.0 M HCl in 1,4-dioxane (0.5 mL) was added. The reaction was then stirred at 25 °C for 2 hours TLC analysis showed no ng material present and LCMS analysis showed the presence of the product. The reaction was added to a saturated NaHCO; solution and was extracted with ethyl acetate. The organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the t. LC/MS (Mi-HY: 428 lH NMR (CDC13):5 8.89 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.44 (d, 1H), 6.87 (d, 1H), 5.73 (d, 2H), 4.41 (m, 1H), 3.51—3.71 (m, 4H), 2.31 (m, 2H), 2.08 (m, 3H), 1.70—1.93 (m, 4H), 0.98 (m, 2H), 0.00 (s, 9H).
Step 6: cis—4—[4—(7—[2—(Trimethylsilyljethoxyjmethyl—7H—pyrrolo[2, 3-djpyrimidin-4—y0-JH—pyrazol—I — yUcyclohexylmethyl methanesulfonate. 3O cis[4-(7—[2—(Trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidinyl)-l H—pyrazol- 1-yl]cyclohexylrnethanol was dissolved in chloroform (3.00 mL) and was cooled to 0 °C To the reaction was added TBA (0.10 mL, 0.00072 mol) and methanesulfonyl chloride (0.05 mL, 0.0006 mol) and this mixture was stirred at 0 °C for 2 hours at which time LCMS showed mainly the t present in the mixture. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, ted NaCl, dried (MgSO4) and concentrated in vacuo. LC/MS (M+H)+: 506 Step 7: cis—4—[4—(7—[2-(Trimethylsr'lyljethoxfyjmethyl-7H-pyrrolo[2, 3—djpyrimia'inyD-1H-pyrazol~1- yUcycIoheJleac-etonitrile . cis—4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4—y1)-lH—pyrazol- l—yl]cyc10hexylmethyl methanesulfonate (0.10 g, 0.00020 mol) and sodium cyanide (0.050 g, 0.0010 mol) and DMSO (1.0 mL) were mixed. The mixture was stirred at 60 °C for 24 hours, at which time LCMS analysis showed most of the starting material had been consumed. The reaction was extracted with ethyl acetate and the c extracts were washed with water, saturated NaC], dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 437, 1H NMR(CDC13):6 8.90 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.43 (m, 1H), 3.60 (m, 2H), 2.45(d, 2H, J = 7.6 Hz), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).
Step 8: cis-4~[4~(7H—Pyrrolo[2,3—d]pyrimidin~4~yl)—1H—pyrazol—I —yl]cycloh exylacetom'trile . ci s[4—(7—[2-(Trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidinyl)— l H-pyrazol - l~yl]cyclohexylacetonitrile (0.080 g, 0.00018 mol) and TFA (0.50 mL, 0.0065 mol) were added to DCM (3.00 mL, 0.0468 mol) and the mixture was stirred at 25 °C for 16 hours. The reaction concentrated by rota-evaporation and the concentrate was dissolved in methanol (3.0 mL, 0.074 mol) and um hydroxide (0.5 mL, 0.01 mol) was added This reaction was stirred at 25 °C for 6 hours at which time LCMS analysis showed no starting material present. The reaction was chromatographed on silica gel using 5% MeOH/EtOAc to give the product.
LC/MS (M+H)+:307, 'H 30D):6 8.64 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.42 (m, 1H), 2.61(d, 2H, J = 8.0 Hz), 2.27 (m, 2H), .15 (m, 7H). e 680: cis[4-(7H-Pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol~l-yl]cyclohexylmethyl thiocyanate l/\l—N N'k \ \ N/ g Step I .' cis[4—(7-[2—(TrimethylsilyDethoxyjmethyl—7H-pyrrolo[2, 3-d ]pyrimidin—4—yl)—IH-pyrazol-1~ yljcyclohexylmethyl thiocyanate eis—4—[4-(7—[2-(Trimethylsilyl)ethoxy]methyl—7H—pyrrolo [2,3~d]pyrimidinyl)- l H-pyrazol- 1-yl]cyclohexylmethyl methanesulfonate (0.10 g, 0 mol) was dissolved in DMSO (1.00 with potassium thiocyanate (0.082 g, 0.00084 mol). The reaction was heated at 68 °C for 4 days at which time LCMS analysis showed ~4:1 product/starting material ratio. The on was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the t. LC/MS (Mi-HY: 469, lH NMR(CDC13):5 8.89 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (m, 1H), 3.60 (m, 2H), 3.05 (m, 2H), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).
Step 2: cis[4-(7H—Pyrrolo[2,3-d]pyrimidin-4—yl)—1H~pyrazol—J-yUcyclohng/lmethyl thiocyanate). 1 0 cis—4—[4-(7~[2—(Trimethylsily1)ethoxy]rnethy1—7H-py1rolo[2,3-d]pyrimidinyl)-lH—pyrazol- 1—yl]cyclohexylmethyl thiocyanate was dissolved in methanol (2.0 mL, 0.049 mol) and DCM (2.0 mL, 0.031 mol), and TFA (0.5 mL, 0.006 mol) was added. The resulting mixture was stirred at 25 °C for 16 hours. TLC analysis showed no starting al present and LCMS analysis showed product.
The reaction was concentrated using a rotary evaporator and the concentrate was chromatographed on silica gel using 2% MeOH/EtOAc to give the product. LC/MS :339, lH NMR(CD30D) 5 8.65 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.43 (m, 1H), 3.20 (d, 2H, J = 7.6 Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H).
Example 681: N-S-[(cis[4-(7H—Pyrrolo[2,3—d]pyrimidinyl)-1H-pyrazolyl]cyclohexyl— methyl)thio]~4H—1,2,4—triazol—3-ylpyrimidin—2—amine trifluoroacetate ’N NH l/V‘N "1C \ N N H TFA Step 1: 5-[(cis[4-(7-[2—(Trimethylsilyl)ethoxyjmethyl-7H—pyrrolo[2.3—d]pyrimidin—4—yl)-1H~ pyrazolyl]cyclohexylmethy1)thio]—4H-1,2, 4—triazal—3-amin cis-4—[4-(7~[2-(Trimethylsilyl)cthoxy]rnethyl-7H-pyrrolo[2,3-d]pyrimidin~4-yl)-1H-pyrazol- l-yl]cyclohexylmethyl methanesulfonate (124.56 mg, 0.00024 mol), and 5-amino—4H-1,2,4-triazole- 3—thiol (43.00 mg, 0.0003702 mol) were dissolved in DMF (1.20 mL) and potassium carbonate (0.122 g, 87 mol) was added. The reaction was stirred at 50 °C for 18h, at which time LCMS showed nearly complete on, and product present. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo.
The concentrate was tographed on silica gel using EtOAc as eluent to give the product.
LC/MS (M+H)+: 526,1H NMR(CDCI3):8 8.90 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.45 (d, 1H), 6.87 1H), 5.73 (S, 2H), 4.45 (brs, 2H), 4.41 (m, 1H), 3.60 (m, 2H), 3.22 (d, 2H, J=7.2 Hz), 2.29 (m, 2H), 1.70-2.10 (m, 7H), 0.98 (m, 2H), 0.00 (s, 9H).
Step 2: 5—[(cis-4—[4—(7H—Pyrrolo[2,3-djpyrimia’in—4—yl)—1H~pyrazol—1 -yl]cyclohexylmethyl)thio]-4H— 1,2,4—triazol—3—amine -[(cis[4—(7-[2—(Trimethylsilyl)ethoxy]rnethyl-7H-pyrrolo[2,3-d]pyrimidin-4—yl)-1H- pyrazoly1]cyclohexylmethyl)thio]—4H—1,2,4-triazolamine (9a) was dissolved in TFA (1 mL) and was stirred for 2h. The solution was concentrated using a rotary evaporator to remove TFA. The residue was dissolved in methanol (1 mL) and ammonium hydroxide (1 mL) added.
The solution was d ght. LCMS showed complete de—protection. The solution was concentrated using a rotary evaporator. The product was isolated by prep LCMS using a 30mm x 100mm C18 ; 11%C‘H3CN—H20 (0.1%TFA), 1.5 min, to 33% at 6 min; 60 mL/min; detector set at m/z 396; retention time, 5.5min (2 runs). The eluate was freeze dried. Yield 21 mg (di-TFA salt). LC/MS (M+H)+:396, lH NMR (dd-DMSO) 8 12.9 (br s, 1H, NH); 8.9 (2 singlets, 2H); 8.5 (s, 1H); 7.9 (m, 1H); 7.3 (m, 1H); 4.4 (m, 1H, NCH); 3.1 (d, 2H); 2.2 (m, 2H); 1.9 (m, 3H); 1.7 (m, 2H); 1.6 (m, 2H). MS(ES) 396 (It/1+1). e 682: N-5~[(cis-4—[4—(7H—Pyrrolo[2,3—d]pyrimidinyl)—1H—pyrazolyl]cyclohexyl- methyl)thio]~4H—1,2,4-triazol—3-ylpyrimidin-2—amine trifluoroacetate N’N\ "\7/N S)—NH NJ\ / \ [IV—N "l \ \ kN/ N H TFA Step 1: N[(cz's—4—[ -(7-[2-(Trimethylsilyl)ethaxyjmethyl—7H-pyrrolo[2,3-d]pyrimidin-4~y1)-1H— pyrazol-I-yl]cyclohexylmethyDthioj-4H-1,2,4—triazol—3-ylpyrz'midin-2—amine In a vial [A] 5—[(cis—4—[4-(7—[2—(trimethylsilyl)ethoxy]methyl-7H~pyrrolo[2,3-d]pyrimidin—4- yl)—1H—pyrazolyl]oyclohexylmethyl)thio]—4H-1,2,4-tn'azolamine (0.047 g, 0.000089 mol) was heated with 2-chloropyrimidine (0.011 g, 0.000096 mol) in 1,4—dioxane (1.00 mL, 0.0128 mol) at 150 °C for 40 minutes in a microwave reactor. LCMS analysis showed that no reaction had taken place. To the reaction was added 2-chloropyrimidine (0.020 g, 7 mol) with cesium carbonate (0.033 g, 0.00010 mol) and copper(I) iodide (4.00 mg, 0.0000210 mol) and this mixture was heated at 115 °C for 3 hours, at which time LCMS analysis showed no ng material present and mainly product was present. The reaction was chromatographed on silica gel using 2% tOAc to give the product. LC/MS (M+1)+:604, lNMR(CDC13): 8.89 (s, 1H), 8.82 m, 2H), 8.43 (s, 1H), 8.30 (s, 1H), 7.44 (d, 1H), 7.23 (m, 1H), 7.03 (br s, 2H), 6.88 (d, 1H), 5.73 (s, 2H), 4.40 (m, 1H), 3.60 (m, 2H), 3.35 (d, 2H), 2.34 (m, 2H), 1.80—2.15 (m, 7H), 0.98 (m, 2H), 0.00 (s, 9H).
Step 2: N[(cis[4-(7H—Pyrr0lo[2, 3—d]pyrimidinyl)-IH-pyrazol—J-yl]cyclohexylmethyl)thio]- 4H-1, 2, 4—triazol—3—ylpyrimfdz'n-2~amine .
N-S—[(ci&4-[4—(7—[2—(Trimethylsily1)ethoxy]methyl—7H—pyrroIo[2,3-d]pyrimidinyl)- 1 H— pyrazol-l-y1]cyclohexylmethyl)thio]-4H-1,2,4~triazoly1pyrimidinarnine (0.024 g, 0.000040 mol) was dissolved in DCM (4.00 mL), and TFA (0.50 mL, 0.0065 mol) was added. The on was stirred at 25 °C for 16 hours and was concentrated in vacuo. The residue was dissolved in methanol (3.00 mL) and concentrated ammonium hydroxide (0.50 mL) was added. This reaction was stirred at °C for 2 hours at which time LCMS analysis showed mostly product. The reaction was concentrated using a rotary evaporator and the concentrate was purified by prep LC to give the product as the trifluoroacetate salt. LC/MS (M+H)+:474, lI-I NMR(CD30D) 5 8.87 (s, 1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.79 (s, 1H), 8.45 (s, 1H), 7.85 (d, 1H), 7.34 (m, 2H), 4.43 (m, 1H), 3.20 (d, 2H, J = 7.6 Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H). ' Example 683: 3~cis—4-[4-(7H-Pyrrolo[2,3-d]pyrimidinyl)—lH—pyrazol—l-yl]cyclohexylpropane— nitrile roacetate KN N N\ I HN / Step 1: 2-(1,4—Dioxaspiro[4.5]dec—8—yl)ethanol.
Ethyl 1,4-dioxaspiro[4.5]dec—S—ylacetate (3.40 g, 0.0149 mol) prepared according to the procedure of Itagaki, Noriaki; Kimura, Mari; Sugahara, Tsutomu; Iwabuchi, Yoshiharu. (Organic Letters 2005; 7(19); 183.) was ved in ether (30.00 mL) and the mixture was cooled to 0 °C. To the reaction was added 1.00 M m tetrahydroaluminate in ether (15.0 mL) and the resulting mixture was stirred at 0 °C for 60 minutes and at 25 °C for 2 hours. The reaction was cooled and water (0.40 mL, 0.022 mol) was added, ed by 1.00 M sodium hydroxide (0 .40 mL).
To the reaction was then added ether (100.00 mL) and the solid that precipitated was filtered off. The filtrate was concentrated using a rotary ator to give the product. lH NMR(CDC13): 3.94 (s, 4H), 3.67 (t, 2H), 1.204.80 (m, 11H).
Step 2: 4-(2—Hydroayethyl)cyclohexanone. 2-(1,4-Dioxaspiro[4.5]dec~8-yl)ethanol (2.70 g, 0.0145 mol) was dissolved in acetone (10.00 mL) and THF (10.00 mL) and 6.00 M HCl (6.00 mL) was added. The reaction was stirred at 25 °C for 16 hours, neutralized with NaHC03 solution and was then extracted with ethyl acetate. The organic extracts were washed with water, and with ted NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification.
'H NMR(CDC13): 3.75 (m, 2H), 2.36 (m, 4H), .13 (m, 7H).
Step 3: 4—(2-Hydroayethy1)cyclohexanol. 4-(2-Hydroxyethyl)cyclohexanone (2.00 g, 0.0141 mol) was dissolved in ether (30.00 mL) and was cooled at 0 °C. To the reaction was added 1.0 M lithium tetrahydroaluminate in ether (14.1 mL) and the resulting mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours. To the reaction was added THF (20.00 mL) and this mixture was cooled at 0 °C and then water (0.40 mL, 0.022 mol) was added, followed by 1.00 M sodium hydroxide (0.40 mL). To the reaction was then added ether ( 100.00 mL) and the resulting mixture was stirred for 10 minutes, then was filtered and the e was concentrated using a rotary evaporator to provide the crude product. The crude product was used in the next reaction without r purification. lI-I NMR(CDC13): 3.96 and 3.57 (m, 1H) minor and major CHOH (~1 :5 ratio) 3.70(m, 2H), 0.94-2.02 (m, 11H).
Step 4: 4-[2-(Tritylqu)ethyl]cyclohexan01. 4—(2—Hydroxyethyl)cyclohexanol (crude from the us reaction) (1.88 g, 0.0130 mol) was dissolved in pyridine (20.00 mL) and was cooled at 0 °C. To the reaction was added tn'phenylmethyl chloride (4.0 g, 0.014 mol) and this mixture was stirred at 0 °C for 2 hours and at 25 °C for 16 hours.
The reaction was concentrated using a rotary evaporator and the concentrate was extracted with ethyl e. The organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel (30%EtOAc/hexanes) to give the trans isomer (1.98 g) 1H C13): 7.42—7.45 (m, 6H), 7.20—7.30 (m, 9H), 3.50 (m, 1H), 3.07 (m, 2H), 1.93 (m, 2H), 1.66 (m, 2H), 1.17-1.60 (m, 5H), 0.89 (m, 2H).
Step 5: trans[2—(Trigil0391)ethyl]cyclohexyl methanesulfonate. trans-4—[2—(Trity1oxy)ethy1]cyclohexanol (1.95 g, 0.00504 mol) was dissolved in chloroform (40.00 mL) and the e was cooled to 0 °C. To the reaction was added TEA (0.98 mL, 0.0071 mol) and methanesulfonyl de (0.47 mL, 0.0060 mol) and this e was stirred at 0 °C for 2 hours The reaction was then ted with ethyl acetate and the organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo.
IH NMR(CDC13): 7.41—7.45 (m, 6H), 7.20~7.32 (m, 9H), 4.55 (m, 1H), 3.07 (m, 2H), 2.10 (m, 2H), 1.70 (m, 2H), 1.20-1.60 (m, 5H), 0.95 (m, 2H).
Step 6: 7—[2—(TrimethylsilyDezhoxyjmethyl~4—(1-cz‘s—4—[2—(trityloxy)ethyl]cyclohexyl—1H—pyrazol-4—y0— 7H—pyrrolo[2,3-d]pyrimidine. 4—(1H-Pyrazol—4—yl)—7—[2—(trimethylsilyl)ethonymethy1-7H-pyrrolo[2,3-d]pyrirnidine (1.0 g, 0.0032 mol) was mixed with sodium hydride (0.23 g, 0.0058 mol) and trans—4—[2— (trityloxy)ethyl]cyclohexyl methanesulfonate (2.10 g, 0.00452 mol) and this mixture was cooled to -78 °C. To the on was added DMF (6.00 mL) and this mixture was allowed to warm to 25 °C and was then stirred for 20 minutes. The reaction was stirred at 55 °C for 48 hours at which time LCMS analysis showed mostly product. The reaction was extracted with ethyl acetate and the organic extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo.
The concentrate was chromatographed on silica gel using 40% EtOAc/hexanes to give the product.
LC/MS (M+H)+:684, 'H NMR(CDC13): 8.89 (s, 1H), 8.35 (br s, 1H), 8.30 (s, 1H), 7.50 (m, 6H), 7.44 (d, 1H), .32 (m, 9H), 6.87 (d, 1H), 5.73 (s, 2H), 4.33 (m, 1H), 3.60 (m, 2H), 3.17 (t, 2H), 1.50- 2.25 (m, 11H). 0.98 (m, 2H), 0.00(s, 9H).
Step 7.‘ 2-cis[4—(7-[2-(Trimethylsilyl)eth0xy]methyl— 7H—pyrrolo[2, rimidin-4—yl)—1H-pyrazol— 1-yUcyclohngvlethanol (7b). 7-[2-(Trimethylsilyl)ethoxy]methy1~4-(1 -cis~4-[2—(trityloxy)ethyl]cyclohexyl—1H-pyrazol-4— yl)-7I-I-pyrrolo[2,3-d]pyrimidine (1.45 and g, 0.00212 mol) was dissolved in methanol (30.00 mL) TI-IF (10.00 mL) and 4.0 M HCl in 1,4-dioxane (2.00 mL) was added. The mixture was stirred at °C for 2 hours, at which time, TLC analysis showed no starting material present and LCMS is showed the presence of the product. The reaction was added into a saturated NaHC03 3O solution, and was then extracted with ethyl acetate. The organic extracts were washed with water and saturated NaCl, then dried (Mgsoo and concentrated in vacuo. The concentrate was tographed on silica gel using EtOAc as eluent to give the product. LC/MS (Mi—HT: 442 Step 8: 2—cis—4-[4—(7-[2-(Trimethylsileethonymethyl—7H-pyrrolo[2,3-djpyrimz‘din~4—yD-1H—pyrazol— I—yUcyclo/zexylethyl methanesulfonate (8b). 2-cis[4-(7-[2-(Trimethylsilyl)ethoxy]rnethyl-7H~pyrrolo[2,3-d]pyrimidinyl)-1H~ pyrazol-1—yl]cyclohexylethanol (0.89 g, 0.0020 mol) was dissolved in DCM (12.00 mL, 0.1872 mol) and was cooled at 0 °C To the reaction was added TEA (0.43 mL, 0.0031 mol) and methanesulfonyl chloride (0.19 mL, 0.0024 mol) and this mixture was stirred at 0 °C for 2 hours at which time LCMS analysis showed mainly product present. The reaction was extracted with ethyl acetate and the organic extracts were washed with water and ted NaCl, then dried (MgSOi) and trated in vacuo.
LC/MS (M+H)+:520, lH NMR(CDCI3): 8.90 (s, 1H), 8.38 (br s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.88 (d, 1H), 5.73 (s, 2H), 4.40 (m, 1H), 4.27 (t, 2H), 3.60 (m, 2H), 3.07 (s, 3H), .40 (m, 11H). 0.98 (In, 2H), , 9H) Step 9: 3—cis[4-(7H-Pyrrolo[2,3—djpyrz'midt'ny0-IH-pyrazol-I~yljcyclohaxyh2ropanenitrile trifluoroacetate (9b). 2—cis[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin—4—yl)-1H- pyrazol-l-yl]cyclohexylethyl methanesulfonate (0.075 g, 0.00014 mol) was dissolved in DMSO (1.50 mL) and sodium cyanide (0.035 g, 0.00072 mol) was added. The reaction was stirred at 40 °C for 16 hours at which time LCMS analysis showed no starting material present. The reaction was then extracted with ethyl acetate and the organic extracts were washed with water and saturated NaCl, then dried (Mgsog and concentrated in vacuo. The residue was dissolved in DCM (3.00 mL) and TFA (0.50 mL, 0.0065 mol) was added. This mixture was stirred at 25 °C for 16 hours at which time LCMS analysis showed mostly the hydroxymethyl intermediate. The mixture was concentrated using a rotary evaporator and the trate was dissolved in methanol (3.00 mL) and concentrated ammonium hydroxide (0.50 mL) was added. The reaction was stirred at 25 °C for 3 hours at which time LCMS analysis showed no starting material present. The reaction was then concentrated using a rotary evaporator and the concentrate was purified by prep LC to give the product as the TFA salt (47.8 mg). LC/MS :321, 'H NMR(CD30D): 8.86 (s, 1H), 8.81(s, 1H), 8.44 (s, 1H), 7.84 (d, 1H), 7.31 (d, 1H), 4.48 (m, 1H), 2.51 (m, 2H), 2.28 (m, 2H), 2.00 (m, 2H), 1.80 (m, 5H), 1.67 (m, 2H). e 684: 5-[(2-cis—4—[4—(7H-Pyrrolo[2,3~d]pyrimidin—4—yl)—1H—pyrazol—l—yl]cyclohexyl- cthyl)thio]-4H-l,2,4-triazolamine trifluoroacetate N NH2 % T \2\zl z Z\/ IZ/ TFA 2006/047369 2-cis[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin—4-yl)-1H— pyrazol—l-yl]cyclohexy1ethyl methanesulfonate (0.060 g, 0.00012 mol) was dissolved in DMF (1.31 mL) with 5-amino-4H-1,2,4-triazolethiol (0.020 g, 7 mol) and potassium carbonate (0.024 g, 0.00017 mol). This e was heated at 40 °C for 18 hours at which time LCMS analysis showed no starting material present. The reaction was d with EtOAc, filtered and was then trated using a rotary evaporator. The residue was dissolved in DCM (3.60 mL) and TFA (0.60 mL, 0.0078 mol) was added. This mixture was stirred at 25 °C for 5 hours and was then trated using rotary evaporator. The residue was dissolved in methanol (3.60 mL) and concentrated ammonium hydroxide (0.60 mL) was added and this mixture was stirred at 25 °C for 2 hours. The reaction concentrated using a rotary evaporator and the trate was purified by prep. LC to give the product. LC/MS (M+H)+:410, lH NMR(CD30D): 8.85 (s, 1H), 8.80(s, 1H), 8.44 (s, 1H), 7.83 (d, 1H), 7.30 (d, 1H), 4.46 (m, 1H), 3.17 (m, 2H), 2.27 (m, 2H), 2.00 (m, 2H), 1.62-1.90 (m, 7H).
Example 685: 4-[4—(7H-Pyrr01012,3-d]pyrimidin—4—yl)—1H-pyrazol—l-yl]cyclohexylideneaceto- nitrile trifluoroacetate / CN N/ \ / T \=N /" Step 1: I, 4-Dioxaspiro[4.5]decan-8—ol 1,4-Dioxa-spiro[4.5]dccanone (2.00 g, 0.0128 mol) was dissolved in ether (50 mL) and the e was cooled to 0 °C. To the reaction was added 1 M lithium tetrahydroaluminate in ether (7.0 mL) and this mixture was stirred at 0 °C for 2 hours at which time TLC analysis showed no starting material present. The on was then quenched with water and l N NaOH (0.5 mL of each) and then filtered. The filtered solid was washed with ether and the combined ether filtrate was concentrated using a rotary evaporator to give the product. NMR (CD013): 3.94 (m, 4H), 3.81 (m, 1H), 1.79-1.92 (m, 4H), 1.54—1.70 (m, 4H).
Step 2: 1,4vDioxaspiro[4.5]dec-8~yl methanesulfonate. l,4-Dioxaspiro[4.5]decan—S-ol (0.40 g, 0.0025 mol) 'was dissolved in chloroform (10.0 mL) and the resulting mixture was cooled at 0 °C. To the mixture was added TEA (0.49 mL, 0.0035 mol) and methanesulfonyl chloride (0.23 mL, 0.0030 mol) and this mixture was stirred at 0 °C for 2 heurs.
The reaction was extracted with ethyl acetate and the c extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without fiirther purification.
‘H NMR(CDC13): 4.85 (m, 1H), 3.95 (m, 4H), 3.02 (s, 3H), 1.98-2.05 (m, 4H), .89 (m, 2H), .70 (m, 2H).
Step 3: 4—[1—(1, 4~Dioxaspiro[4.5]dec~8—yl)—1H—pyrazol-4—yl]—7—[2—(trimethylsz'lyl)ethoxyjmethyl—7H- pyrrolo[2,3—d]pyrimidine .
A mixture of 1,4-dioxaspiro[4.5]decyl methanesulfonate (0.50 g, 0.0015 mol) with 4-(1H— pyrazolyl)[2-(trimethylsily1)ethoxy]methyl-7H-pyrrolo[2,3-d]pyn'midine (0.36 g, 0.0011 mol) and sodium hydride (0.082 g, 0.0020 mol) was cooled at —78 °C and DMF (2.0 mL) was added. The reaction was allowed to warm to 25 °C and was then stirred for 20 s and was then heated to 55 °C for 24 hours. The reaction was then extracted with ethyl acetate. The organic extracts were washed with water and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was tographed on silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS (M+H)+:456, IH NMR(CDC13): 8.89 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.44 (d, 1H), 6.87 (d, 1H), .73 (s, 2H), 4.38 (m, 1H), 4.06 (s, 4H), 3.60 (m, 2H), 2.22-2.31 (m, 4H), 2.00 (m, 2H), 1.86 (m, 2H), 0.98 (m, 2H), 0.00(s, 9H) Step 4: 4-[4—(7—[2—(Trimethylsilyl)ethaw]methyl-7H—pyrr0lo[2,3-djpyrimidinyl)~1H-pyrazol~1— yUcyclohexanone To 4—[1-(1 ,4~dioxaspiro[4.5]dec—8—yl)—lH—pyrazol-4—yl]-7~[2~(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2,3—d]pyrimidine (2.13 g, 0.00467 mol), was added acetone (85 mL) followed by 12 M HCl in water (4.0 mL). The reaction was d at RT. After 1 h, LCMS analysis showed 66% reaction. After 4 h, HPLC showed 80% reaction. Afier 20 h, HPLC showed no change (and no loss of SEM). The reaction mixture was quenched into excess sat'd NaHCO3. The acetone was removed by rote-evaporation. The resulting mixture of aqueous bicarbonate and a white solid was then extracted with EtOAc. The combined organic extract was shaken with sat'd NaCl, dried over , then concentrated to dryness to leave 2.0 g of a crude product. TLC (5% iPrOH—40% EtOAc-hexane): product Rf 0.12 (ketal 0.22). The crude t was purified by automatic flash chromatography on silica gel. Used a 40g column; flow 40 mL/min; [A= 2% iPrOH-hexane] [B= 6% iPrOH-50% EtOAc/hexane]; A, 2 min; nt to B in 25 min, then B for 10 min. The eluent was concentrated 3O using a rotary evaporator to give 1.3 g of a white solid. HPLC Method: Zorbax SB C18, 5 pm, 15 cm, °C, flow 1.2 mL/min, 10% CH3CN-H20 (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; or 268 nm; retention time starting material, 7.4 min; product, 6.9 min (UV max 220, 268, 300, 322 nm). 'H NMR (CDC13) 8 8.8 (s, 1H); 8.3 (m, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.8 (d, 1H); 5.7 (s, 2H); 4.7 (m, 1H, NCH); 3.6 (t, 2H); 2.3-2.5 (m, 8H); 0.9 (t, 2H); ~0.1 (s, 9H). MS(ES) 412 (M+l).
Step 5: 4—[4-(7—[Z—(TrimethylsilyDethoxy]methyl- 7H—pyrrolo[2,3—djpyrimidin—4—yl)—IH-pyrazoI—1 yljcyclohexylz'deneacetonitrile To a solution of 1.0 M potassium tert-butoxide in THF (1.90 mL) at 0 "C was added a solution of diethyl cyanomethylphosphonate (321 uL, 0.00198 mol) in THF (4 mL) dropwise. The reaction was held for 10 min, then it was added to a solution of 7-[2-(trimethylsilyl)- ethoxy]methyl-7H-pyrrolo[2,3~d]pyrimidin—4—yl)-lH-pyrazol-l -y1]cyclohexanone (743 mg, 0.00180 mol) in TI-IF (5 mL) stirring at 0 °C under a nitrogen atmosphere. The reaction was stirred 1.5 h at rt.
LCMS analysis showed clean conversion to the desired product. To the reaction mixture was then added water and EtOAc. The phases were separated and the s phase was extracted with EtOAc. ‘10 The combined organic extract was washed with water, then sat'd NaCl, then dried over NaZSO4, and trated to dryness to yield 0.76 g of a white crystalline solid (TLC (EtOAc) Rf 0.33). product was purified by automatic flash tography on silica gel. Used 40g column; flow 40 mL/min; [A= hexane] [B= EtOAc]; A, 2 min; Gradient to B in 20 min. Rotary evaporation yielded 0.70 g of a white crystalline solid (89% yield). 1H NMR (CDC13) 6 8.9 (s, 1H); 8.3 (s, 2H); 7.4 (d, 1H); 7.3 (s, 1H); 6.9 (d, 1H); 5.7 (s, 2H); 5.3 (s, 1H, olefin); 4.5 (m, 1H, NCH); 3.6 (m, 2H); 3.2 (m, 1H); 2.7 (m, 1H); 2.5 (m, 4H); 2.1 (m, 2H); 1.0 (m, 2H); -O.1 (s, 9H). MS(ES) 435 (M+1).
Step 6: 4—[4—(7H—Pyrrolo[2,3-djpyrimidin-4—y0-IH—pyrazol-J-yl]cyclohexylideneacetom'trile A solution of TFA (0.5 mL, 0.006 mol) and 7~[2—(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol-l-yl]cyclohexylideneacetonitrile (22.7 mg, 0.0000522 mol), was stirred for 1.5h. The solution was then concentrated using a rotary ator to remove TFA. LCMS analysis showed conversion to the hydroxymethyl intermediate, M+H 335. Methanol was added; and the methanol mixture was concentrated again using a rotary ator. The resulting residue was dissolved in methanol (1 mL) and ammonium hydroxide (0.25 mL, 0.0064 mol) was added. The resulting solution was stirred for 16 h. LCMS analysis showed complete de-protection.
The on was then concentrated using a rotary evaporator. The product was ed by prep HPLC using a 30 mm x 100 mm C18 column; 18% CH3CN-H20 (0.1%TFA), 1min, to 35% at 6min; 60 ; detector set at 254nm; retention time, 4.4mm. The eluate was freeze dried. yield 7.6 mg of a white solid (TFA salt; racemic; 34.6%). 1H NMR (déDMSO) 8 12.9 (br s, 1H, NH); 8.9 (s, 2H); 8.5 (s, 1H); 7.8 (m, 1H); 7.3 (m, 1H); 5.6 (s, 1H, olefin); 4.6 (m, 1H,.NCH); 2.8 (m, 1H); 2.6 (m, 1H); 2.5 (m, 2H); 2.3 (m, 2H) 2.0 (m, 2H). MS(ES) 305 (M+1).
Example 686: cis[4-(7H-Pyrrolo[2,3-d]pyrimidinyl)-lH-pyrazol—1-yl] cyclohexanecarbo- nitrile trifluoroacetate WO 70514 Step 1: cis—4-[4—(7—[2-(Trimethylsilyl)ethoxyjmethyl-7H—pyrrolo[2, 3—djpyrimidz‘n-4—yl)—1H-pyraizol—1- yljcyclohexanecarbaldehyde oxime A solution of sulfur trioxide-pyridine complex (53.4 mg, 0.000336 mol) in DMSO (0.3 mL, 0.004 mol) was added to a solution of cis-4~[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3- d]pyrimidin—4-yl)—1H-pyrazol-l—y1]cyclohexylmethanol (57.4 mg, 0.000134 mol) and TEA (56.1 uL, 0.000403 mol) in DCM (0.3 mL, 0.004 mol) at -10 °C. The mixture was stirred vigorously at 10-20 0C for one hour. LCMS analysis showed conversion to the aldehyde. The mixture was then poured into ice-water, and extracted with DCM. The extracts were washed with 10 % citric acid, water, saturated 1‘0 aqueous sodium bicarbonate, water, and brine, and then dried over sodium sulfate. Concentration gave 57 mg of a residue.
To the resulting residue was added hydroxylamine-HCI (50mg), 1 mL 20% K2C03, and 3 mL MeOH and this mixture was stirred at rt until LCMS showed conversion to the corresponding oxime, M+H 441 . The product was ed by prep HPLCMS using a 30 mm x 10, 0 mm, C18 column; 30% CH3CN-H20 (0.1%TFA), 1 min, to 60% at 6 min; 60 mL/min; detector set at m/z 441; retention time, 6.0min. freeze-dried. yield 17.4 mg of a white solid.
Step 2: ciS[4-(7H-Pyrrolo[2,3—d]pyrimidin~4»yl)-IH-pyrazol-I-yUcyclohexanecarbonitrile [A] cis[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1H- pyrazol-l—yl]cyclohexanecarbaldehyde oxime (11.0 mg, 0.0000250 mol) was dissolved in pyridine (0.25 mL, 0.0031 mol), and benzenesulfonyl chloride (10.0 uL, 784 mol) was added and the resulting mixture was stirred at rt. Afier stirring 15 h, LCMS analysis showed formation of the product, M+H 423. The product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 45% CHgCN—Hzo (0.1% NH40H), 1min, to 75% at 6 min; 30 mL/min; detector set at m/z 423; retention time, 4.8 min. The eluent was concentrated using a rotary evaporator to give 8 mg of the d product.
The product was dissolved in TFA (0.25 mL). stirred for 2h. The solution was concentrated using a rotary evaporator to remove TFA. ol was added and the mixture was concentrated again. LCMS showed clean sion to the hydroxymethyl intermediate (M+H 323). The residue was ved in methanol (1 mL) and ammonium hydroxide (0.25 mL) was added. The solution was stirred 0.5 h, at which time, LCMS showed complete de~protection to the desired product M+H 293.
The mixture was then trated by row-evaporation, and the t was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 15% CH3CN-H20 (0.1% TFA), 1.5 min, to 30% 2006/047369 6 min; 30 mL/min; detector set at m/z 293; retention time, 5.2 min. The eluate was freeze dried to yield 5.5 mg of the product as a TFA salt. 1H NMR (dd-DMSO) 5 12.82 (br s, 1H, NH); 8.87 (s, 1H); 8.85 (s, 1H); 8.48 (s, 1H); 7.82 (m, 1H); 7.24 (m, 1H); 4.40 (m, 1H, NCH); 3.22 (m, 1H); 2.05 (m, 6H); 1.79 (m, 2H). MS(ES) 293 (M+1).
Example 687: 2—[(cis-4—[4-(7H—Pyrrolo[2,3-d]pyrimidin—4—yl)-lI~I—pyrazol-l-yl]cyclohexyl- methyl)sulfinyl]benzonitrile trifluoroacetate Step I: 4—[1~(cis-4—[(2-Brom0phenyDthiojmethylcyclohexyl)—1H-pyrazol—4-yl]~7-[2—(trimethylsily0— ethoxyfmethyl— 7H-pyrr010[2,3-d]pyrimidine This compound was prepared from -[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3—d]pyrimidin—4—yl)—1H—pyrazolyl]cyclohexylmethyl methanesulfonate as in Example 686[A]. Yield 73%. The product was purified using the following I-[PLC method: Zorbax SB C18, 5 pm, 15cm, 35 C, flow 1.2 mL/min, 10% CH3CN-H20 (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 254 nm; retention time starting mesylate, 7.5 min; product, 9.9 min (UV 215, 258, 300, & 326 nm). TLC: Rf 0.3 using 35% EtOAc/5% iPrOH/hexane. The product was purified by automated silica gel flash chromatography using 30% EtOAc/5% iPrOH/hexane. lH NMR (CDCl3) 8 8.84 (s, 1H); 8.31 (s, 1H); 8.26 (s, 1H); 7.55 (m, 1H); 7.39 (d, 1H); 7.27 (m, 2H); 7.03 (m, 1H); 6.82 (d, 1H); 5.67 (s, 2H); 4.34 (m, 1H, NCH); 3.55 (m, 2H); 2.98 (d, 2H); 2.28 (m, 2H); 2.02 (m, 3H); 1.83 (m, 4H); 0.92 (m, 2H); ~0.06 (s, 9H). MS(ES) 598/600 1:1 (M—l-l).
Step 2: 2-[(cis~4-[4-(7-[2-(Trimethylsilyl)ethoxyjmethyl-7H-pyrrolo[2,3-d]pyrimidinyl)—1H- pyrazol—1-yl]cyclohexylmethyDthiojbenzonitrile 4-[1 -(cis—4—[(2—Bromopheny1)thio]methylcyclohexyl)- l H—pyrazolyl]—7-[2-(trimethylsilyl)- ]methy1-7H—pyrrolo[2,3-d]pyrimidine (62.7 mg, 0.000105 mol), zinc cyanide (123 mg, 0.00105 mol), and tetrakis(triphenylphosphine)palladium(0) (30.2 mg, 0.0000262 mol) were stirred in DMF (3 mL) and the on was flushed with nitrogen. The solution was then heated to 100 °C for 25 min in a ave reactor. LCMS and HPLC analyses showed > 90% reaction. The product was isolated by prep HPLCMS using a 30 mm x 100 mm C18 ; 52%CH3CN-H20 (0.1%TFA), 1.5 min, to 75% at 6 min; 60 mL/min; detector set at 545 nm. The eluent was concentrated using a rotary evaporator to give 37 mg of the 2~cyanophenylsulfide TFA salt. HPLC Method: Zorbax SB C18, 5 pm, 15 cm, 35 C, flow 1.2 , 10% CH3CN—HZO (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 265 nm; retention time starting material, 9.9 min; product, 8.9 min. MS(ES) 545 (M+1).
Step 3: 2—[(ciS[4-(7H-Pyrrolo[2, 3-d]pyrimidin-4—yl)-1H—pyrazol~1-yl]cyclohexylmethstulj'inyU— itrile A solution of 2-[(cis-4~[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4— yl)-1H-pyrazolyl]cyclohexylmethyl)thio]benzonitrile (30.6 mg, 562 mol), in TFA (1 mL) was stirred for 2 h. The solution was concentrated using a rotary evaporator to remove TFA. Methanol was added, and the mixture was concentrated again. The resulting residue was ved in methanol (1 mL) and ammonium ide (1 mL) was added. The resulting solution was stirred overnight, at which time HIPLC showed complete deprotection. The product was isolated by prep I-H’LCMS using a 19 mm x 100 mm C18 column; 30% CH3CN-H20 (0.1% TFA), 1.5 min, to 59% at 6 min; 30 mL/min; detector set at m/z 415 nm; ion time, 4.7 min. The eluate was concentrated using a rotary evaporator to give 36 mg of the sulfide TFA salt, a colorless glassy material. NMR (dg-DMSO) 8 12.82 (br s, 1H, NH); 8.84 (2 singlets, 2H); 8.45 (s, 1H); 7.8 (m, 2H); 7.64 (m, 2H); 7.34 (td, 1H); 7.24 (s, 1H); 4.39 (m, 1H, NCH); 3.23 (d, 2H); 2.19 (m, 2H); 1.89 (m, 3H); 1.72 (m, 4H). MS(ES) 415 (M+1). This material was then dissolved in CHzClz and cooled to 0 °C. To the cooled e was added MCPBA(12.9 mg, 0.0000562 mol), and the resulting mixture was stirred for 1 h. LCMS showed conversion to the t, and no ing sulfide. The reaction mixture was concentrated by rotovap, and the product was isolated by prep I-IPLCMS using a 19 mm x 100 mm C18 column; 18% CH3CN-H20 (0.1% TFA), 1. 0 min, to 35% at 6 min; 30 mL/min; detector set at m/z 431 nm; retention time, 5.6 min. The product was isolated from the eluent by freeze—drying. The yield was 27.6 mg of the TFA salt. The I-[PLC method was: Zorbax SB C18, 5 um, 15 cm, 35 °C, flow 1.2 mL/min, 10% CH3CN~H20 (0.05% TFA), to 100% CH3CN in 9.0 min; stop time 12.3 min; detector 268 nm; retention time starting material, 5.6 min; sulfoxide, 4.8 min; sulfone, 5.2 min; MCPBA, 6.0 min. 1H NMR (CDC13) 5 12.1 (br s, 1H, NH); 9.0 (s, 1H); 8.9 (s, 1H); 8.3 (s, 1H); 8.1 (m, 1H); 7.9 (m, 1H); 7.8 (m, 1H); 7.6 (m, 2H); 7.0 (m, 1H); 4.4 (m, 1H, NCH); 3.1 (dd, 1H); 2.9 (dd, 1H); 2.5 (m, 1H); 2.3 (m, 1H); 2.3-1.7 (m, 7H). MS(ES) 431 (M+1).
Example 688: 2-[(cis—4—[4-(7H—Pyrrolo[2,3—d]pyrimidin-4—yl)-1H—pyrazol—1-yl]cyclohexyl- methyl)sulfonyllbenzonitrile trifluoroacetate 2-[(cis~4-[4-(7H-Pyrrolo[2,3-d]pyrimidin—4-yl)—l H—pyrazol-l -y1]cyclohexylmethyl)su1finyl]- benzonitn'le (17.2 mg, 0.0000400 mol) (21 mg TFA salt), was dissolved in DCM (10 mL) and cooled to 0 0C. To this mixture was added MCPBA (18 mg, 0.0000800 mol). The resulting mixture was stirred for 1h at 0 0C, and then for 16 h at rt. HPLC and LCMS showed 80 area% t, and 3 area% sulfoxide. The MCPBA was removed using a sat'd NaHCO3 wash, and the resulting washed mixture was concentrated by row—evaporation. The product was isolated by prep HPLCMS using a 19 mm x 100 mm C18 column; 23%CH3CN-H20 (0.1%TFA), 1.0 min, to 43% at 6 min; 30 mL/min; detector set at m/z 447 nm; retention time, 5.1 min. The product was isolated from the eluent by -drying. The yield was 5 mg of the TFA salt. 1H NMR (do-DMSO) 5 12.70 (br s, 1H, NH); 8.83 (s, 1H); 8.82 (s, 1H); 8.41 (s, 1H); 8.21 (dd, 1H); 8.16 (dd, 1H); 8.01 (td, 1H); 7.95 (td, 1H); 7.78 (s, 1H); 7.19 (s, 1H); 4.34 (m, 1H, NCH); 3.62 (d, 2H); 2.28 (m, 1H); 2.10 (m, 2H); 1.90 (m, 2H); 1.72 (m, 4H). MS(ES) 447 (M+1).
Example 689: 3—[4-(7H-Pyrrolo[2,3—d]pyrimidin-4—yl)-1H—pyrazol—l—yl]cyclohexylacetonitrile oroacetate NI \ kN/ H TFA Step 1 : 3—[4—(7—[2—(TrimethylsilyDethoxyjmezhyl- rolo[2,3-d]pyrimidinyl)-IH-pyrazol-I-ylj— cyclohexanone To a solution of 4—(1H-pyrazoly1)—7—[2-(tn‘methylsilyl)ethoxy]methy1-7H-pyrrolo[2,3—d]- pyrimidine (309 mg, 0.980 mmol) in ACN (6 mL) was added ohexen-l—one (190 1.1L, 01.96 mmol), followed by DBU (40 uL, 0.3 mmol). The resulting mixture was stirred for one hour at which point LCMS indicated complete addition. The e was reduced in vacuo and the crude product was purified by column chromatography to obtain the product (397 mg, 98%). 1H NMR (400 MHz, CDC13): 5 8.84 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 7.45 (d, 1H), 6.79 (d, 1H), 5.67 (s, 2H), 4.61 (m, 1H), 3.55 (m, 2H), 3.05-2.90 (m, 2H), 2.45-2.30 (m, 4H), 2.05 (m, 1H), 1.90 (m, 1H), 0.92 (m, 2H), —0.06 (s, 9H). MS (EI) m/z = 412.2 (M+H).
Step 2: (2E, Z)-3—[4—(7—[2-(TrimethylsilyDethoxyjmezhyl— 7H-pyrrolo[2,3-d]pyrimidin-4—yl)—1H— pyrazol—I—yl]cyclohexylideneacetonitrile To a solution of t—BuOK in THF (1.0 M, 0.255 mL, 0.255 mol) at 0 °C was added a solution of diethyl cyanomethylphosphonate (43 uL, 0.27 mmol) in THF (0.6 mL) dropwise. The reaction was held for 10 minutes, then a solution of 3-[4—(7-[2-(trimethylsi1yl)ethoxy]methyl-7H-pyrrolo[2,3—d]— pyrimidin-4—y1)—1H—pyrazol-l —yl]cyclohexanone (100.0 mg, 0.2430 mmol) in TI-IF (0.34 mL) was added dropwise. After complete addition, the cooling bath was removed and the reaction was held at ambient ature for 16 hours, at which point LCMS indicated complete on to yield the desired product as a mixture ofE and Z isomers (87.9 mg, 83%). 1H NMR (400 MHz, CD013): 5 8.84 (s, 0.5H), 8.83 (s, 0.5 H), 8.27 (d, 1H), 8.25 (s, 1H), 7.40 (3, 051-1), 7.39 (s, 0.511), 6.81 (d, 0.5H), 6.79 (d, 0.5H), 5.67 (s, 2H), 5.28 (s, 0.5H), 5.24 (s, 0.5H), 4.4 (m, 1H), 3.55 (m, 2H), 3.1—2.8 (m, 2H), 2.5- 2.1 (m, 6H), 0.92 (m, 2H), -0.06 (s, 9H). MS (EI) m/z = 435.2 (M+H).
Step 3: 3-[4-(7-[2—(Trimethylsilyl)ethoxy]methyl— 7H-pyrrolo[2, 3—d]pyrimidin-4—yl)-1H—pyrazolyl]- cyclohexylacetonitrile To (2E, 4—(7-[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)—1H- l-l-y1]cyclohexylideneacetonitrile (42.0 mg, 0.0966 mmol) was added THF (0.5 mL). The resulting on was cooled to -78 °C, and then 1.0 M L-Selectride® in THF (120 uL, 0.12 mmol) was added dropwise. The reaction was held at -78 °C for 1h at which point LCMS indicated complete reduction. The reaction was quenched at -78 °C by addition of saturated aqueous NH4C1 and EtOAc, and was then d to warm to ambient temperature. The phases were separated and the aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with water, then saturated NaCl, and then was dried over MgSO4. The crude product was purified by column chromatography to obtain the product (26.5 mg, 63%). 1H NMR (400 MHz, CDC13): 8 8.84 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.39 (d, 1H), 6.81 (d, 1H), 5.67 (s, 2H), 4.53 (m, 1H), 3.52 (m, 2H), 2.6—1.4 (m, 11H), 0.92 (m, 2H), -0.06 (s, 9H). MS (EI) m/z = 437.2 (M+H).
Step 4: 3-[4—(7H—Pyrrolo[2, 3—djpyrimidin-4—yD—IH—pyrazol—I—yljcycloheagvlacetonitrile trifluoroacetate To 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1 H-pyrazol-l — lohexylacetonitrile (30.1 mg, 0.0689 mmol) was added DCM (1.0 mL) and TFA (1.0 mL). The ing mixture was stirred for 1 hour at ambient ature, at which point LCMS indicated complete cleavage to the N—hydroxymethyl ediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (37 uL, 0.55 mmol), afier which the reaction was stirred for 5 hours, at which point LCMS indicated complete reaction. The solvent was removed and the residue was purified by preparative LCMS to provide the product as a TFA salt (24 mg, 83%). 1H NMR (400 MHz, CD3OD)I 5 8.91 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.31 (s, 1H), 4.69 (s, 1H), 2.58 (d, 2H), 2.54.5 (m, 9H). MS (EI) m/z = 307.10 (M+H). 2006/047369 e 690: 5—({cis[4-(7H-Pyrrolo[2,3-d]pyrimidinyl)-lH—pyrazol—l-yl]cyclohexyl}thio)— 1H—1,2,4-triazolamine bis(trifluoroacetate) QS\( "'I‘\ l/U'rN '\5:3 2TFA N N Step I : trans-4—[4—(7-[2—(Trimethylsily0ethoxyjmethyl— 7H-pyrrolo[2, 3—d]pyrimidinyl)—IH— pyrazol—I-yl]cyclohexanol A solution of 4—[4-(7-[2—(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4—yl)-1 H- pyrazol-l-yl]cyclohexanone (662 mg, 1.61 mmol) in THF (5 mL) was cooled to 0 °C and lithium tetrahydroaluminate (2M in THF, 0.804 mL, 1.61 mmol) was added slowly. The mixture was allowed to warm slowly to t temperature until LCMS indicated complete reduction. The reaction was cooled to 0 °C and quenched with dropwise on of water (0.5 mL). DCM was added, and the mixture was stirred for 1 hour at ambient ature, after which the precipitated solids were removed by filtration. The filtrate was d in vacuo to leave a white solid (0.63g, 99%). HPLC of the solid showed an approximately 4:1 ratio of trans to cis product. Tlc (6:3:1 EtOAc:hexaneszisopropanol) gave an Rf of 0.25 for the cis product , and 0.18 for the trans product.
The product was purified by flash chromatography on silica gel to recover 230 mg of the pure trans alcohol and 25 mg pure of the cis alcohol, and 350 mg ofmixed isomers. 1H NMR (400 MHz, CDC13)I 5 8.83 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.39 (d, 1H), 6.81 (d, 1H), .67 (s, 2H), 4.24 (m, 1H), 3.79 (m, 1H), 3.54 (m, 2H), 2.28 (m, 2H), 2.17 (m, 2H), 1.94 (m, 2H), 1.53 (m, 2H), 0.92 (m, 2H), 0.06 (s, 9H). MS (EI) m/z = 414 (M+H).
Step 2: trans-4—[4-(7—[2—(Trimethylsilyl)ethoxy]methyl— 7H-pyrrolo[2,3—djpyrimz'din-4—yD-1H—pyrazol— J—yljcyclohexyl methanesulfonate To trans[4—(7-[2—(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimidinyl)-1 H- pyrazol—l-y1]cyclohexanol (154 mg, 0.372 mmol) was added DCM (1.0 mL) and TBA (73 uL, 0.52 mmol). The resulting solution was then cooled to O "C and methanesulfonyl chloride (34 uL, 0.45 mmol) was added. The reaction was held for 2 hours, at which point tlc and LCMS indicated complete reaction. The reaction was partitioned between water and DCM, the phases were ted and the aqueous phase was extracted with additional solvent. The combined organic phase was washed with water, then saturated NaCl, then was dried over MgSO4 and reduced in vacuo to give the crude product which was used without further purification (173 mg, 95%). 'H NMR (400 MHz, CDClg): 8 8.83 (s, 1H), 8-24 (s, 2H), 8.24 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.77 (m, 1H), 4.27 (m, 1H), 3.54 (m, 2H), 3.06 (s, 3H), 2.36 (m, 4H), 2.03 (m, 2H), 1.82 (m, 2H), 1.53 (m, 2H), 0.92 (m, 2H), —0.06 (s, 9H). MS (EI) m/z = 492.1 (M+H).
Step 3: 5-({cis[4-(7H-Pyrrolo[2,3-djpyrimidin—4-y0-IH-pyrazol—I-yl]cyclohexyl}thio)—IH-I.2,4- l-S-amine bis(trz_'fluoroacetate) To a solution of trans~4-[4-(7—[2-(trimethylsilyl)ethoxy]methyl-7H~pyrrolo[2,3-d]pyrimidin— 4-yl)-lH-pyrazol—1-yl]cyclohexyl methanesulfonate (42 mg, 0.085 mmol) in DMF (800 uL) was ‘ added 3-amino-lH-l,2,4—triazolethiol (30 mg, 0.26 mmol) and KZCOJ (36 mg, 0.26 mmol). The reaction was sealed and held at 100 0C for 2 hours at which point LCMS indicated conversion to desired product. The reaction was diluted with water and extracted successively with ether, ethyl acetate, and 3:1 chlorofonn:isopropyl alcohol. The combined organic phase was washed with water, then saturated NaCl, dried over MgSO4 and reduced in vacuo, and the crude product was purified by column chromatography to give 5-( {cis[4—(7—{[2-(trimethylsilyl)ethoxy]methyl}—7H-pyrrolo[2,3- midinyl)-lH—pyrazol-l—yl]cyclohexyl}thio)—1H—l,2,4-triazol-3—amine (27.3 mg, 63%). To the product was added DCM (0.5 mL) and TFA (0.5 mL), and the reaction was stirred for 1 hour at ambient temperature at which point LCMS indicated complete cleavage to the N-hydroxymethyl intermediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by NH40H (0.3 mL), the reaction was stirred for 16 hours at which point LCMS ted complete deprotection. The solvent was d and the residue was purified by preparative LCMS to provide the product as a bis-TFA salt (15.1 mg, 29%). 'H NMR (400 MHz, CD3OD)I 8 8.77 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 7.74 (d, 1H), 7.21 (d, 1H), 4.40 (m, 1H), 3.97 (m, 1H), 2.25(m, 2H), 2.04 (m, 6H).
MS (EDQm/z = 382.2 (M+H).
Example 691: N-{S-[({cis[4-(7H—Pyrrolo[2,3-d]pyrimidin-4—yl)-lH—pyrazol-l-yl]cyclohexyl}- methyl)thio]—4H—l,2 azol-3—yl}methanesulfonamide trifluoroacetate ,— HN. ,o / 003; "l? \ N N Step I. N[(cis[4—(7—[2—(Trimethylsilyl)ethoxyjmethyl- 7H-pyrrolo[2, 3-d]pyrimidinyl)-IH— pyrazol-I-yljcyclohexylmethyljthioj-4H-1,2,4-triazol~3-ylmethanesulfonamide —[(cis—4—[4~(7~[2~(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidin—4-yl)-l H- pyrazol-l—yl]cyclohexylmethyl)thio]~4H-1,2,4-triazolamine (30.00 mg, 5.706E-5 mol) was dissolved in DCM (2.00 mL, 0.0312 mol) with TEA (0.024 mL, 0.00017 mol) and was cooled at 0 °C.
To the reaction was added esulfonyl chloride (0.0066 mL, 0.000086 mol) and the resulting mixture was stirred at 0 °C for 60 minutes, at which time LCMS analysis showed mostly product.
The reaction was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+1)+:604 Step 2. N[(cis-4—[4-(7H-Pyrrolo[2, 3-d]pyrimidinyl)-1H—pyrazol-I -yl]cyclohexylmethyl)thio]— 4H—1, 2,4—triazol—3~ylmethanesulfonamide Into a l-neck round—bottom flask [A] N—S-[(cis[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H- o[2,3-d]pyrimidinyl)-l H—pyrazol-l ~yl]cyclohexylmethyl)thio]~4H-1 ,2,4—triazol-3 -ylmethane- ulfonamide (0.025 g, 0-000041 mol) was dissolved in DCM (3.00 mL, 0.0468 mol) and TFA (mL, 0.006 mol) was added. The reaction was d at 25 °C for 16 hours at which time LCMS analysis showed no starting material present. The reaction was concentrated using a rotary evaporator and was dissolved in methanol (2.00 mL, 0.0494 mol) and 16 M ammonia in water (0.2 mL) was added. The reaction was stirred at 25 °C for 3 hours at which time LCMS analysis showed no starting material present. The reaction was concentrated using a rotary evaporator and was purified by prep LC to give the product as the tfifluoroacetate salt. LC/MS (M+l)+:474, 1H NMR(CD3OD): 8.87 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 7.85 (d, 1H), 7.33 (d, 1H), 4.48 (m, 1H), 3.36 (s, 3H), 3.23 (d, 2H), 2.30 (m, 2H), 2.04 (m, 3H), 1.85 (m, 4H). e 692: -[4-(7H-Pyrrolo [2,3-d]pyrimidin-4—yl)-lH-pyrazol-l-yl]-l-(1H-1,2,4-triazol- 1—yl)cyclohexyl] acetonitrile «"17 N ‘ N AN HNWNOW— H 1H-1,2,4-Triazole (91.0 mg, 2 mol), DBU (174 uL, 0.00070 mol), [A] 4-[4-(7-[2- (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidiny1)-1H—pyrazol-l ~yl]cyclohexylidene~ acetonitrile (86.4 mg, 0.000199 mol), and ACN (2.0 mL) were stirred at It. After 4d, LCMS showed about 58 area% product (two peaks, M+H 504, ratio 1:1). The DBU in the on was neutralized with TFA. The product was ed by prep HPLC using a 30 mm x 100 mm C18 column; 32% CH3CN—H20 (0.1%TFA), 1 min, to 47% at 6 min; 60 mL/min; detector set at 254 nm; retention time, .1(A) & 5.4 (13) min. The eluent was concentrated using a rotary evaporator to give 22 mg of (A) & 36 mg of (B).
Deprotection: The products were ved separately in TFA (0.5 mL) and stirred for 1h.
LCMS showed conversion to the hydroxymethyl derivative (M+H 404). The ons were concentrated using a rotary evaporator to remove TFA. Methanol was added, and the resulting mixtures were concentrated again. The resulting residue was dissolved in methanol (1 mL), and ammonium hydroxide (0.25 mL) added. The solution was stirred 0.5h. LCMS showed te de- protection (M+H 374) and the mixture was then concentrated by roto—evaporation. Each isomer was ed by prep HPLCMS using a 19 mm x 100 mm C18 column; 15% CH3CN-HZO (0.1% TFA.), 1.5 min, to 32% at 6 min; 30 mL/min; or set at m/z 374; retention time, 4.5 min (A) & 4.7 min (B) .
The eluates were freeze dried. Yield 13 mg isomer A and 24 mg isomer B (TFA salts, white solids).
NMR analysis (including NOE & COSY) was consistent with expectation for the structures, with A=cis, and B=trans. NMR (erMSO) 5 cis: 12.94 (br s, 1H, NH); 8.95 (s, 1H); 8.87 (s, 1H); 8.81 (s, 1H); 8.42 (s, 1H); 8.14 (s, 1H); 7.85 (m, 1H); 7.22 (m, 1H); 4.48 (m, 1H, NCH); 3.12 (s, 2H); 2.84 (m, 2H); 2.07 (m, 4H); 1.69 (m, 2H). MS(ES) 374 (M+l). trans: 12.85 (br s, 1H, NH); 8.94 (s, 1H); 8.89 (s, 1H); 8.84 (s, 1H); 8.47 (s, 1H); 8.11 (s, 1H); 7.84 (m, 1H); 7.26 (m, 1H); 4.50 (m, 1H, NCH); 3.48 (s, 2H); 2.42—2.10 (m, 8H). MS(ES) 374 (M+l).
Example 705: 3—1—[4—(7H—Pyrrolo[2,3—d]pyrimidin—4—yl)-IH-pyrazol-l—yl]but—3—yn—1—yl-benzo- nitrile trifluoroacetate "t \ \ N/ pg Step 1: 3—{1—[4~(7—{[2—(Trimezhylsilyl)ethoxy]methy1}— 7H-pyrrolo[2,3—d]pyrimidin~4~yl)~1H-pyrazol— 1 ut-3—yn-J —yl}benzonitrile "t \ V— N/ N 1 M utylaluminum e in hexane (0.31 mL) was added dropwise to a solution of methyl 3-(3-cyanophenyl)-3~[4-(7-[2-(t1imethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidin yl)-1H-pyrazol—l~y1]propanoate (100 mg, 0.0002 mol) (prepared by using a procedure ous to Example 712, Step 1) in DCM (3 mL, 0.05 mol) and the mixture was cooled to -78 °C. The reaction ‘ mixture was stirred at —78 °C for 4 h and was afterward quenched with cold methanol (3 mL, 0.07 mol). The reaction was allowed to wann to 0 °C and potassium carbonate (60 mg, 0.0004 mol) and Bestmann-Ohira reagent (1.5 eq, 57 mg) (E. Quesada et al, Tetrahedron, 62 (2006) 6673—6680) were added. The reaction was stirred at room temperature overnight, and then partitioned between ethyl acetate and water. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give the crude product. The crude product was purified using silica gel (EtOAC/I-Iexane 1:3 to 1:1) to give the desired t, 3—{1—[4-(7-{[2-(trimethylsilyl)ethoxy]- methyl}-7H-pyrrolo[2,3-d]pyrimidin-4—yl)-lH-pyrazol-l—yl]but—3—yn—l—yl}benzonitrile (40 mg of mixture). m/z = 469 (M+1).
Step 2: 3-1 -[4-(7H-Pyrrolo[2, 3-djpyrimidin-4~yl)-1H—pyrazol—I-yl]but~3-yn—1-ylbenzonitrile trifluoroacetate Using a procedure analogous to Example 712, Step 4, the title compound was prepared (4.5 mg, 46%) as an amorphous white solid. 1H NMR (500 MHz, DMSO): 5_ 12.5 (b, 1H), 9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 8 (s, 1H), 7.8 (m 2H), 7.7 (s, 1H), 7.6 (m, 1H), 7 (m, 1H), 5.9 (m, 1H), 3.4 (dd, 1H), 3.2 (dd, 1H), 2.9 (s, 1H). m/z = 339 (M+1). e 706: 3-{1-[4-(7H—Pyrrolo[2,3~d]pyrimidin-4—yl)—1H-pyra yl]but—3—yn—1—yl}benz— aldehyde trifluoroacetate Using the procedure of e 705, the title compound was prepared as a secondary product (4.5 mg, 46%) as an amorphous white solid. 1H NMR (400 MHz, CD013): ,5 10 (s, 1H), 9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 8 (s, 1H), 7.9 (m 1H), 7.8 (m, 1H), 7.7 s, 1H), 7.6 (m, 1H), 7.1 (s, 1H), 5.9 (m, 1H), 3.4 (dd, 1H), 3.2 (dd, 1H), 2.9 (s, 1H). m/z= 342.
Example 712: 4-[1-(3-Methoxyphenylpropyl)-1H-pyrazolyl]- 7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate N-N<© " o HOJW’FF.
N," \ F 1‘ ’ N NH Step 1: Methyl 3—pheny1—3-[4—(7-[2-(trimethylsilyl)ethoxyjmethyl-7H—pyrrolo[2,3-d]pyrimidin~4—yl)— IH-pyrazol-I-yl]propanoate A solution of methyl (2E)-3—phenylacrylate (500 mg, 0.003 mol) in ACN (2 mL, 0.04 mol) was slowly added to a solution of 4-(1H-pyrazolyl)[2-(trimethylsilyl)ethoxy]methyl-7H- pyrrolo[2,3~d]pyrimidine (0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 "L, 0.003 mol).
The on was d at room temperature over the weekend. The reaction was partitioned n water and EtOAc. The organic layer was washed with saturated sodium chloride, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel using EtOAc/Hexane (1:2 to 1:1) gave methyl 3-phenyl[4-(7—[2-(trimethylsilyl)ethoxy]methyl-7H— pyrrolo[2,3-d]pyrimidinyl)—lH-pyrazol-l -yl]propanoate (500 mg, 70%) as a semisolid residue. 1H NMR (400 MHz, CD013): ii 8.9 (s, 1H), 8.4 (s, 2H), 7.4 (m, 5H), 6.8 (d, 1H), 6 (m, 1H), 5.7 (s, 2H), 3.7-3.8 (m, 3H), 3.6 (m, 2H), 2.2 (m, 1H), 1.4 (m, 2H), 1.1 (m, 2H), 0.02 (s, 9H), m/z = 478 (M+1).
Step 2: 3-Phenyl—3—[4—(7-[2-(trz'methylsilyDet/zoxyjmethyl- 7H—pyrrolo[2,3—dprrimidin—4-yl)—1H— pyrazol-I-yl]propan-1 ~01 ll \ x I N N Diisobutylaluminum hydride in hexane (1 M, 0.69 mL) was added to a on of methyl 3— phenyl[4—(7—[2—(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d]pyrimidin—4—yl)—l zolyl]- propanoate (150 mg, 0.00031 mol) in DCM (3 mL, 0.05 mol) and the mixture was cooled to -78 °C under a nitrogen atmosPhere. The reaction was stirred for 1 h at -78 °C and was allowed to warm to room temperature for 4 hrs. The reaction was quenched with methanol (100 uL), and saturated ammonium chloride (100 pL), and then taken up in ethyl acetate dried over MgSO4 and filtered. The filtrate was concentrated to give y1~3-[4—(7-[2-(tn'methylsilyl)ethoxy]methyl—7H-pyrrolo[2,3- d]pyrimidin—4-yl)-lH—pyrazol—l-yl]propan-1—ol (130 mg, 92%) as an oil. m/z = 450 (M+l).
Step 3: 4»[1—(3—Methoxy—I—phenylpropyl)-IH-pyrazol—4-ylj- 7—[2-(trimethylsilyvethoxyjmethyl-7H- pyrrolo[2, 3~djpyrimidine [:12\ \ \I’ Si...
N N l__/ Sodium e (9.6 mg, 0 mol) was added to a solution of 3-phenyl-3—[4-(7-[2-(tri- methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin—4-yl)-lH—pyrazol-l —yl]propan-l-ol (120 mg, 0.00027 mol) in DMF (3 mL, 0.04 mol) and the mixture was cooled to 0 °C. The reaction was stirred for 20 min and methyl iodide (22 uL, 0.00035 mol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and'concentrated to give 4— 2006/047369 [1 ~(3~methoxy-l —phenylpropyl)v1 H-pyrazol—4—yl][2-(tn‘methylsily1)ethoxy]methyl-7H-pyrrolo[2,3 - d]pyrimidine (100 mg, 88%) as a semisolid. m/z = 464 (M+1).
Step 4: 4-[1—(3—Methoxy—I—phenylpmpyD-IH-pyrazolyl]- 7H—pyrrola[2,3-d]pyrz'midine trifluoroacetate Trifluoroacetic Acid (2 mL, 0.02 mol) was added to a mixture of 4-[1-(3—methoxy-l— phenylpropyl)-lH-pyrazol—4-yl]-7~[2-(trimethylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (80 mg, 0.0002 mol) in DCM (3 mL, 0.05 mol) at room temperature. The starting material was consumed after stirring for 2hrs and the reaction solution was concentrated to remove the TFA. The crude reaction was diluted with methanol (3 mL, 0.07 mol) and was d with nediamine (0.3 mL, 0.004 mol) at room temperature. The reaction mixture was stirred for 18 he and was concentrated and purified using HPLC on a C-18 column g with an ACN: water gradient containing 0.2% TFA, to give the title compound (43 mg, 60%) as a white amorphous solid. 1H NMR (400 MHz, CDClg): 358.9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 7.8 (s, 1H), 7.4 (m, 1H), 7.3 (m, 5H), 7.2 (b, 1H), 5.7 (m, 1H), 3.3 (m, 1H), 3.2 (s, 3H), 2.7 (m, 1H), 2.4 (m, 1H). m/z = 334 (M+1).
Example 715: 3-1—[4—(7H-Pyrrolo[2,3-d]pyrimidin-4—yl)-lH—pyrazol—1-yl]hut—3-en-l-ylbenzo- nitrile trifluoroacetate i //N N-N .
/ Ho’ufi/F . FF "i \ \ N NH A mixture of [4[1-(3-bromophenyl)but-3—en-l—y1]~1H—pyrazolA—yl—7H~pyrrolo[2,3-d]~ pyrimidine (20 mg, 0.00005 mol) in DMF (2 mL, 0.02 mol) and zinc cyanide (60 mg, 0.0005 mol) was degassed with a nitrogen stream. The mixture was then treated with tetrakis(triphenyl- phosphine)palladium(0) (40 mg, 0.00003 mol), again degassed with en, and was then heated in a microwave reactor to 170 °C for 15 min. The on was allowed to cool, was filtered and purified by HPLC on a C-18 column g with an ACN/water/TFA gradient to give the title compound (10 mg, 40%) as a white amorphous solid.
‘H NMR (400 MHz, DMSO): ,5 8.9 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 7.9 (s, 1H), 7.8 (m, 3H), 7.6 (m, 1H), 7.1 (b, 1H), 5.6-5.8 (m, 2H), 5.1 (d, 1H), 5 (d, 1H), 3.3 (m, 1H), 3 (m, 1H). m/z= 341 (M+1).
Example 716: 4-1—[1-(3-Bromophenyl)but-3—en-l—ylj—1H—pyrazolyl-7H-pyrrolo[2,3-d1- pyrimidine N / 'L Zx/ Step I: 3-(3—Brom0phenyl)—3—[4-(7—[2—(trimethylsilyUethonymethyl- 7H—pyrrolo[2, 3-d]pyrimidin-4— yl)-IH—pyrazol—I—ylj’propanal "Ex\SifLL ’ N Diisobutylaluminum hydride in hexane (1 M, 4 mL) was added to a ~78 °C on of ethyl 3-(3-bromophenyl)-3—[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyxrolo[2,3—d]pyrimidinyl)-lH- pyrazol—l—yl]propanoate (600 mg, 0.001 mol) in DCM (6 mL, 0.09 mol). After stirringfor 4 h, the reaction was quenched with cold methanol (300 pL), and then saturated ammonium chloride (500 uL) was added and the resulting solution was stirred for 1 h. The reaction was partitioned between water and EtOAc. The c layer was washed with brine, dried over Mgsoq, filtered and concentrated.
The product was d by flash chromatography on silica gel g with hexane: EtOAc, (2:1 to 1:2), to give 3-(3~bromophenyl)-3—[4—(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin—4—yl)—1H—pyrazol-l—yl]propanal (400 mg, 70%) as an oil.. II-I NMR (400 MHz, CDC13): 6 9.9 (s, 1H), 8.9 (s, 1H), 8.4 (s, 2H), 7.6 (d, 1H), 7.5 (cl, 1H), 7.4 (d, 1H), 7.3-7.4 (m, 2H), 6.8 (d, 1H), 6.1 (m, 1H), 5.7 (s, 2H), 4 (m, 1H), 3.6 (m, 2H), 3.3 (dd, 1H), 1.0 (m, 2H), 0.01(s, 9H). m/z = 526, 528 (NI-H).- Step 2: 4[1~(3—BromophenyUbut—3-en—J321]-1H-pyrazol—4-yl[2—(trimethylsilyDethoxy]methyl— 7H—pyrrolo[2, 3—d]pyrimidine ‘ 236 le \ x z N N Potassium tert—butoxide in THF (EM, 200 uL) was added to a solution of triphenyl- phosphonium iodide (80 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) at 0 °C. The reaction was stirred at room ature for 1h and then cooled to ~78 °C. The romophenyl)~3-[4-(7—[2-(trimethyl- silyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidiny1)-lH-pyrazol-l-yl]propanal (90 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was allowed to warm to room temperature gradually. The reaction was partitioned between water and EtOAc. The c layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel eluting with EtOAczHexane, (1:1). to give 4[1-(3- bromophenyl)but—3-en~1 —yl]-1H—pyrazolyl[2—(trimethylsilyl)ethoxy]methy1-7H-pyrrolo[2,3— midine (35 mg, 40%) as an oil. m/z = 524, 526 (M+1).
Step 3: 4-1—[1 —(3—Bramophenyl)but—3—en—1—yl]—1H—pyrazol~4—yl—7H—pyrrolo[2, 3-d]pyrimidine Using a procedure analogous to Example 712, Step 4, but using 4[1-(3-bromophenyl)but— 3—enyl]—1H-pyrazol—4—yl-7—[2-(trimethylsilyl)ethoxy]methyl~7H-pynolo[2,3—d]pyrimidine the title compound was prepared (10 mg, 30%) as a white amorphous solid, lH NMR (400 MHz, DMSO): {5 8.9(s,1H), 8.8(s,1H), 8.4(s,1H), 7.8(s,1H), 7.7(s,1H), 7.5 (m,2H), 7.3(m,1H), 7.1(s,lH), 5.7(m,2H), .2(d,1H), 5.0(d,lH), 3.2(m,1H), 3.0(m,1H). m/z = 394, 396 (M+1).
Example 717: 3-(4,4-Difluoro)—1—[4~(7H-pyrrolo[2,3-d]pyrimidin—4—yl)—lH—pyrazol-l-yl]but en-l-ylbenzonitrile N\ux\ N NH 2006/047369 Step 1: 1—(3—Br0mopheny1)-4, 4-difluorobut—3—en—1~yl]—1H-pyrazol—4~yl} —7—{[2—(trimethylsilyD- ethoxy]methyl}—7H—pyrrolo[2,3-d]pyrimidine N \ "\N/ N \Si/x 00/" To a solution of 3-(3~bromopheny1)[4-(7-[2—(trimethylsilyl)ethoxy]methyl-7H—py1rolo[2,3- d]pyrimidin—4~yl)—1H-pyrazol—l—yl]propanal (0.05 g, 9 mol) in MN—dimethylacetamide (2 mL, 0.02 mol) was added triphenylphosphine (0.1 g, 0.0006 mol), dibromodifluoromethane (50 uL, 0.0006 mol) and 0.76 M zinc in THF (0.7 mL). The reaction was stirred at room temperature for 18 113. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC ID on silica gel eluting with EtOAc, Hexane (1:2) to give 4~{1-[1~(3-bromophenyl)~4,4—difluorobut—3-en- l-y1]—1H-pyrazol-4—yl}~7-{[2-(trimethylsilyl)ethoxy]methyl}—7H-pyrrolo[2,3—d]pyrimidine (20 mg, 40%) as a clear oil. m/z = 560, 562 (M+1).
Step 2: 4-1 -[1~(3-Bromophenyl)—4, 4-difluor0butenyl]-1H'—pyrazol-4—yl- 7H—pyrralo[2, 3-d]- 1 5 pyrimidine MK x \ N NH Using a procedure analogous to Example 712, Step 4, but using 4-{1-[1-(3—bromophenyl)—4,4- obut-B-cn-l -yl]-1H-pyrazolyl} {[2-(trimethylsi1y1)ethoxy]methyl} ~7H-pyrrolo [2,3— d]pyrimidine, the compound 4—1—[1-(3—bromophenyl)-4,4-difluor0butenyl]-1H—pyrazolyl-7H- pyrrolo[2,3-d]pyrimidine was prepared (30 mg, 99%) as an oil. m/z = 430, 432 (M+1).
Step 3: 3-4, 4-Difluor0-1 ~[4-(7H-pyrrolo[2, 3-d]pyrimidinyl)—IH-pyrazol-I~yl]but—3-en-—I—yl— benzonitrile N\ \ N NH A mixture of 4[1~(3-brornophenyl)-4,4-difluorobutenyl]-lH-pyrazol—4—yl—7H— pyrrolo[2,3—d]pyrimidine (30 mg, 7 mol) in DMF (2 mL, 0.02 mol) and zinc cyanide (80 0.0007 mol) was degassed with nitrogen. The mixture was then treated with tetrakis(tripheny1- ine)palladium(0) (50 mg, 0.00004 mol) and was degassed with nitrogen, and then was heated in microwave at 170 °C for 15 min. The reaction was then allowed to cool, filtered and purified by HPLC on a C-18 column eluting with an ACN/water/TFA gradient to give the title compound (10 mg, %) as a white amorphous solid. 1H NMR (400 MHz, DMSO): 58.9 (s, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 7.9 (s, 1H), 7.7 ~7.8 (m, 3H), 7.5 (m, 1H), 7.1 (m, 1H), 5.7 (m, 1H), 4.3—4.4 (m, 1H), 3.1 (m, 1H), 2.9 (m, 1H). m/z = 377 (M+1).
The following compounds in Table 14 were prepared as indicated in the column labeled "Prep. Ex. No." and the details of certain exemplary synthetic procedures are provided following Table 14.
Table 14 4—D -( 1 penty1buten-1 - -pyrazol—4-y1]-7H— pyrrolo[2,3-d]pyrimidine- tn'fluoroacetate salt 4—[1 -(l -methy1buten-1 H- pyrazol—4—yl]-7H-pyrrolo[2,3-d]- pyrimidinptrifluoroacetatesalt 4-[1~(1 -cyclopentyl-2— cyclopropylethy1)- 1 H—pyrazol yl]-7H-pyrrolo[2,3~d]- pyrimidinptrifluoroacetate salt 4-[1 clopentylbutyn—l - yl)—1H-pyrazol—4—yl]—7H- pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 4-[1 -(1 -cyclopenty]butyl)-1H— lyl]—7H—pyrrolo[2,3—d]— pyrimidinga trifluoroacetate salt 4-[1-(1-cyclopentyl-4,4- difluorobut—3-en-1 —yl)-1H- pyrazol-4—yl]-7H-pyrrolo[2,3-d]— pyrimidine trifluoroacetate salt 4—1 -[4,4—difluoro- l —(tetrahydro- furan-S-y1)buten~1 -yl}—1H- pyrazoly1-7H-pyrrolo[2,3-d]- pyrimidine trifluoroacetate salt 4-[1-(1 -methylbuten—l —yl)- 1H- pyrazolyl]-7H—pyrrolo[2,3-d]- pyrimidine trifluoroacetate salt 4-[1-(1-cyclopropyl-4,4—difluoro- en-l —y1)—l H—pyrazol—4-yl]— 7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 4-[1-(1-cyclopentyl-4,4—difluoro- buty1)-lH-pyrazol—4-yIJ-7H- pyrrolo[2,3-d]pyrimidine trifluoroacetate salt 3-(1 lcyclopentyl)-3—[4- (7H—pyrrolo[2,3-d]pyrimidin yl)—1H—pyrazol-l -yl]propane- nitrile trifluoroacetate salt (3R)- and (3S)—4,4-dimethyl—3- [4—(7—[2—(trimethylsi1yl)ethoxy]— -7H—pyrrolo[2,3-d]— pyrimidin—4—yl)-l H-pyrazol—l — yl]pentanenitrile trifluoroacetate salt 1-2—cyano[4-(7H—pyrrolo[2,3— d]pyn'midin—4-yl)—1H~pyrazol-l -' yl]ethylcyclopropanecarbonitrile trifluoroacetate salt N-[(1cyano[4-(7H- o[2,3-d]pyrimidinyl)- lH-pyrazol—l ~yl]ethylcyclo— pentyl)methy]]benzamide 3-1 -[(Benzyloxy)methyl]cyclo- pentyl[4-(7H-pyrrolo[2,3-d]— pyrimidinyl)-1 H—pyrazol-I - yl]propanenitrile tn'fluoroacetate salt 3-[1 {methylsulfonyl)pyrrolidin- 3-y1][4-(7H-pyrrolo[2,3-d]~ pyrimidin—4-yl)—1H—pyrazol-1 - panenitrile trifluoroacetate salt N‘-cyano(cyanomethyl)[4- (7H-pyrrolo[2,3-d]pyrimidin-4‘ yl)-1 H-pyrazol-l-y1]pipen'dine-l - carboximidamide 4[2,2,2-trifluoro—1 -(1H— imidazol-Z-y1methyl)ethyl]-1 H- pyrazol-4—yl~7H—pyrrolo[2,3-d]— pyrimidine 4-(1-(1R)—2,2,2-trifluoro-l -[(4- methyl—1 ,3—thiazol—2-y1)— methy1]ethyl—1H-pyrazoly])- 7H-pyrrolo[2,3-d]pyrimidine 4-1 -[1 uoromethyl)but—3—yn- 1-y1]—1H—pyrazol—4—y1-7H- pyrrolo[2,3-d]pyrimidine 4-1 —[ l uoromethyl)but-3—en- 1-yl]-1H—pyrazol~4-yl-7H— pyrrolo[2,3-d]pyrimidine 4-1 -[1 -(trifluoromethy1)butyl] ~ 1H-pyrazol—4-yl—7H-pyrrolo- [2,3-d]pyrimidine 4[4,4—difluoro-l —(trifluoro— methyl)but-3~en-1 -yl]- lH- pyrazolyl~7H—pyrrolo[2,3—d]- 'midine 4—1—[4,4—difluoro-l-(trifluoro- methyl)butyl]-1H-pyrazolyl— 7H-pyrrolo[2,3—d]pyrimidine "' Step 1 of example 731 was modified as follows: The Ph3P and CFzBrz were combined in DMAC at 0 °C and then allowed to warm to room temperature until the ylid formation was complete as determined by LCMS. The solution of the ylid was then re-cooled to 0 °C and the de and zinc were added to the ylid solution and the reaction was slowly warmed to room ature. e 727: 4-[1-(l-Cyclopentylbuten-l-yl)-1H—pyrazolyl]-7H-pyrrolo[2,3-dlpyrimidine trifluoroacetate salt N \ \ N NH 'TFA Step 1: (2E)—3—Cyclopentylacrylic acid To a solution of c acid (1.06 g, 10.2 mol) in pyridine (1.2; mL) was added piperidine (0.15 mL) and cyclopentaneearbaldehyde (1.00 g, 10.2 mmol). The mixture was heated to 40 °C for 2 hours, followed by stirring at room temperature for 16 hours. The mixture was then cooled in an ice bath and 2N HCl was added to acidify. The product was extracted with ether. The ether extract was washed with aq. HCl and brine, dried over sodium sulfate, d, and the solvent was removed in vacuo to afford the product (1.30 g, 77%), which was used without fmther purification. 1H NMR (300 MHz, CD013): 57.06 (dd, 1H), 5.80 (dd, 1H), 2.70-2.54 (m, 1H), 1.93-1.32 (m, 8H); MS(ES):141(M+H). 2006/047369 Step 2. Methyl (2E)cyclopentylac;ylate To a solution of ~cyclopentylacrylic acid (1.3 g, 9.3 mmol) in DCM (65 mL) at 0 °C was added oxalyl chloride (3.1 mL, 37 mmol), dropwise. The resulting solution was stirred at 0 °C for 40 minutes, then at room temperature for 2 hours. The volatiles were evaporated to afford (2E) cyclopentylacryloyl chloride as a ess liquid. A portion of this (2E)—3~cyclopentylacryloyl chloride (0.75 g, 4.7 mol) was ved in methanol (10 mL) and the resulting solution was stirred for 2 hours. The solvent was evaporated to afford the product (700 mg, 96%). 1H NMR (300 MHz, CDC13): 56.94 (dd, 1H), 5.79 (dd, 1H), 3.71 (s, 3H), 2.66—2.50 (m, 1H), 1.92- 1.27 (m, 8H).
Step 3. Methyl 3—cyclopentyl—3-[4—(7—[2-(trimethylsilyDethoxyjmethyl~7H—pyrrolo[2,3—d]pyrimidin—4— yl)-IH-pyrazol— I~yl]propanoate To a solution of 4—(1H-pyrazolyl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- midine (2.9 g, 9.2 mmol) and methyl (2E)-3—cyclopentylacrylate (1.70 g, 11.0 mmol) in ACN (100 mL), was added DBU (2.7 mL, 18 mmol). The resulting mixture was stirred for 96 hours. The ACN was removed in vacuo, and the resulting residue was dissolved in ethyl acetate. This solution was washed with 1.0 N HCl, followed by brine, and then dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-70% ethyl e in hexanes) afforded the product (2.73 g, 63%). 1H NMR (300 MHZ, CDC13): 5, 8.84 (s, 1H), 8.28 (s, 2H), 7.39 (d, 1H), 6.81 (d, 1H), 5.67 (s, 2H), 4.46 (dt, 1H), 3.60 (s, 3H), 3.54 (t, 2H), 3.18 (dd, 1H), 2.89 (dd, 1H), 2.59-2.42 (m, 1H), 1.95—1.80 (m, 1H), 1.75—1.10 (m, 7H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):470(M+H).
Step 4. opentyl—3-[4-(7-[2-(trimethylsibzl)ethoxy]methyl—7H—pyrrolo[2,3-d]pyrimidin—4—yl)~1H- pyrazol—I—yUpropanal To a solution of methyl 3-cyclopenty1—3—[4-(7~[2~(trimethylsilyl)ethoxy]methyl-7H—pyrrolo- ]pyrimidinyl)-lH-pyrazol—l -yl]propanoate (0.501 g, 1.07 mmol) in THF (5.0 mL) at -78 l’C was added 1.00 M utylaluminum hydride in DCM (2.35 mL) dropwise. The reaction was stirred with gradual warming to ~10 °C over the course of 2 hours. At this temperature, a further portion of 1.0 M diisobutylaluminum hydride in DCM (1.50 mL) was added. When the reaction was determined to be complete by LCMS, a saturated solution of K/Na taitrate was added, followed by ether. The ing mixture was stirred for two hours at room temperature. The organic layer was separated and washed with water, and brine, then dried over sodium sulfate and the solvent was removed in vacuo to give a viscous oil, which was used without further purification.
MS(ES):442(M+H).
To a solution of oxalyl chloride (0.108 mL, 1.28 mmol) in DCM (10.0 mL) at -78 °C was added DMSO (151 uL, 2.13 mmol). After stirring for 5 minutes, 3—cyclopenty1—3~[4—(7—[2— (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazol-l -yl]propan01 (47 1 mg, 1.07 mmol) in DCM (3.00 mL) was added. The e was stirred for 30 minutes at -78 °C.
TEA (594 uL, 4.26 mmol) was then added. The resulting mixture was then allowed to warm to room temperature over the course of 30 minutes. Water was added, and the layers were separated. The organic layer was washed successively with 0.1 N HCl, water, saturated sodium bicarbonate solution, and brine, and was then dried over sodium sulfate and the solvent was d in vacuo. Flash column chromatography (eluting with a gradient of 0-60% ethyl acetate in hexanes) afforded the product (384 mg, 82%). lH NMR (300 MHz, CDCls): 8 9.73 (s, 1H), 8.87 (s, 1H), 8.71 (br s, 1H), 8.30 (s, 1H), 7.47 (br s, 1H), 6.88 (br s, 1H), 5.69 (s, 2H), 4.66~4.49 (m, 1H), 3.54 (t, 2H), 3.40 (ddd, 1H), 2.95 (ddd, 1H), 2.55-2.44 (m, 1H), 2.01—1.21 (m, 8H), 0.98 (t, 2H), 0.00 (s, 9H); MS(ES):440(M+H).
Step 5. 1—Cyclopentylbut-3—en—1~yl)—1H—pyrazol—4~yl]—7—[2—(trimethylsilyDethoxyjmethyl—7H— pyrrclo[2,3-d]pyrimidine To a solution of 1.0 M potassium utoxide in THF (0.207 mL) in THF (2.0 mL) at 0 °C was added tn'phenylmethylphosphonium bromide (77.8 mg, 0.218 mmol). The resulting mixture warmed to room temperature and allowed to stir for 30 minutes. A solution of 3-cyclopentyl[4-(7- [2—(tn'methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]pyrimidinyl)—lH~pyrazol~1 —y1]propanal (0.100 g, 0.228 mmol) in THF (2.0 mL) was added. After 30 minutes, the mixture was quenched by the addition of saturated ammonium chloride solution and the product was then ted with ether. The ether extract was dried over sodium sulfate and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient of 0-40% ethyl acetate in hexanes) afforded the product (40 mg, 44%). 1H NMR (400 MHz, : 5 8.84 (s, 1H), 8.26 (s, 1H), 8.19 (br s, 1H), 7.40 (s, 1H), 6.83 (br s, 1H), .67 (s, 2H), 5.60 (ddt, 1H), 5.01 (dq, 1H), 4.97-4.93 (m, 1H), 3.99 (dt, 1H), 3.54 (t, 2H), 2.79—2.60 (m, 2H), 2.60-2.40 (m, 1H), 1.99-1.89 (m, 1H), 1.75-1.41 (m, 5H), 1.37—1.12 (m, 2H), 0.92 (t, 2H), - 0.06 (s, 9H); MS(ES):43'8(M+H).
Step 6. 4-[1-(1-Cyclopentylbuten-I-y1)-IH—pyrazolyl]-7H-pyrrolo[2,3-djpyrimidine trifluoroacetate salt 4-[1 ~(1 —Cyclopenty1but—3-en—1 -yl)-l H-pyrazol-4—yl]-7—[2{trimethylsilyl)ethoxy]methyl-7H— pyirolo[2,3—d]pyrimidine (13 mg, 0.030 mmol) was dissolved in DCM (3 mL) and TFA (0.5 mL) was added. The ing solution was stirred at room temperature for 3 hours. The t was removed in vacuo. The residue was ved in THF (2 mL), and 6 N NaOH (1 mL) was added. The mixture was stirred at room temperature for 1 hour, and then was ioned n water and ethyl acetate.
The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H20 and ACN ning 0.1% TFA) afforded the product (10 mg, 80%). 1H NMR (400 MHz, d5—DMSO): 612.73 (s, 1H), 8.88 (s, 2H), 8.43 (s, 1H), 7.79 (t, 1H), 7.19 (dd, 1H), .60 (ddt, 1H), 5.00-4.93 (m, 1H), 4.91—4.87 (m, 1H), 4.23 (dt, 1H), 2.76-2.59 (m, 2H), 2.47-2.34 (m, 1H), .82 (m, 1H), 1.68-1.22 (m, 6H), 1.21-1.09 (m, 1H); MS(ES):308(M+H).
Example 729: 4-[1-(l—Cyclopentylcyclopropylethyl)—lH—pyrazolyl]-7H—pyrrolo[2,3-d]- pyrimidine trifluoroacetate salt £11 'TFA Step 1. 4-[1 -(1-Cyclopenwl—Z—cyclopropylethyl}!H—pyrazol-4—yl]—7-[2-(trimethylsily0ethoxyjmethyl- 7H—pyrrolo[2,3—djpyrimidine trifluoroacetate salt A solution of 4-[1-(1-cyclopentylbuteny1)-1H-pyrazolyl][2—(trimethylsilyl)- ethoxy]methy1-7H-pyrrolo[2,3-d]pyrimidine (prepared in Example 727, Step 5) (54.0 mg, 0.123 mmol) in DCM (1 mL) was added to a freshly prepared ethereal solution of excess CHzNz held at 0 °C. Palladium acetate (10.0 mg, 0.044 mol) was added. After standing for 2 hours, the excess ‘CI‘IzNz was quenched by the addition of acetic acid. The solution was then d with timber DCM, washed successively with saturated sodium bicarbonate solution, water, and brine, and dried over sodium sulfate, and the solvent was removed in vacuo. Purification via preparative—HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) afforded the product (13 mg, 18%). 1H NMR (300 MHz, CDClg): 5 9.05 (s, 1H), 8.81 (d, 1H), 8.35 (s, 1H), 7.59 (t, 1H), 7.03 (t, 1H), 5.76 (s, 2H), 4.10 (t, 1H), 3.59 (t, 2H), 2.57—2.36 (m, 1H), 2.15—2.00 (m, 1H), 2.00-1.83 (m, 1H), 1.79—1.40 (m, 6H), l.37~l.09 (m, 2H), 0.97 (t, 2H), .26 (m, 3H), 0.07- '0.15 (m, 11H); MS(ES):452(M+H).
Step 2. 4—[1-(1-Cyclopenwl—Z-cyclopropyletlzyD-IH-pyrazol—4—yU—7H-pyrrolo[2, 3—d]pyrimidin,e trifluoroacetate salt 4-[1 -(l —Cyclopentylcyclopropylethyl)—1H-pyrazol—4-yl]-7~[2—(trimethylsilyl)ethoxy]- methyl-7H-pyrrolo[2,3—d]pyrimidine trifluoroacetate salt (13 mg, 0.023 mol) was stirred at room ature in a solution of DCM (2 mL) ning TFA (1.5 mL) for two hours. The solvent was and 6N NaOH (2 mL) was removed in vacuo. The resulting residue was redissolved in THF (3 mL), between water and ethyl acetate. The added. After stirring for one hour, the mixture was partitioned removed in vacuo. Purification via organic layer was dried over sodium sulfate and the solvent was afforded preparative-HPLC/MS (C18 eluting with a nt ofH20 and ACN containing 0.1% TFA) the product (9 mg, 90%). .
IH NMR (400 MHz, O): _8 12.75 (s, 1H), 8.90 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 7.81 (s, 1H), 1.88-1.76 (m, 1H), 1.68—1.37 (m, 7.22 (s, 1H), 4.19 (dt, 1H), 2.43-2.29 (m, 1H), 2.03-1.92 (m, 1H), "0.14- '0.24 (m, 5H), .08 (m, 3H), 0.43-0.26 (m, 2H), 0.24—0.13 (m, 1H), 0.07— '0.03 (m, 1H), 1H); MS(ES):322(M+H).
Example 730: 4-[1-(1-Cyclopentylbut—3—yn-l—yl)-1H—pyrazolyl]-7H-pyrrolo[2,3-d] pyrimidine trifluoroacetate salt "t i \ N H 'TFA Step I . 4—[1 -(I-Cyclopentylbut-3—yn-I-yl)-IH—pyrazol—4-yl]—7-[2—(trimethylsilyDethoxyjmethyl- pyrrolo[2,3-d]pyrimidine ) at 0 °C To a mixture of potassium carbonate (38.4 mg, 0.278 mmol) in ol (2.0 mL) was added a solution of 3-cyclopentyl[4-(7—[2-(tn'methylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]- pyrimidin—4-yl)—1H—pyrazol-l—yl]propanal (prepared as in Example 727, step 4) (61.0 mg, 0.139 mmol) in methanol (1.0 mL), ed by a solution of dimethyl (l-diazooxopropyl)phosphonate (40.0 mg, 0.208 mmol) in ol (1.0 mL). The mixture was slowly warmed to ambient diluted with water and extracted with ethyl temperature and stirred for 16 hours. The mixture was then ammonium chloride, and then dried acetate. The combined extracts Were washed with water, saturated over sodium sulfate and the solvent was removed in vacuo to afford the product, which was used t further purification (52 mg, 86%).
'H NMR (300 MHz, CDC13): 5 8.85 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 7.41 (d, 1H), 6.84 (d, 1H), .67 (s, 2H), 4.14 (ddd, 1H), 3.53 (t, 2H), 2.90 (ddd, 1H), 2.79 (ddd, 1H), 2.66-2.49 (m, 1H), 1.98 (t, 1H), 2.00-1.88 (m, 1H), 1.78—1.44 (m, 5H), 1.39—1.11 (m, 2H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):436(M+H).
Step 2. 4—[1-(1-Cyclopentylbut-3—yn-1~yD-IH-pyrazol—4-ylj-7H—pyrrolo[2,3-d]pyrimidin_e trifluoroacetate salt A solution of 1-cyclopentylbutyn-1~y1)-1H—pyrazoly1][2-(trimethylsilyl)- ethoxyjmethyl-7H-pyrrolo[2,3—d]pyrimidine (52 mg, 0.12 mmol) in DCM (3 mL) and TFA (1 mL) was d for 2 hours. The solvents were removed in vacuo. The resulting e was dissolved in THF (3 mL) and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (€18 eluting with a gradient of H20 and ACN containing 0.1% TFA) afforded product (30 mg, 60%). 1H NMR (300 MHz, dé—DMSO): 6, 12.72 (s, 1H), 8.91 (s, 1H), 8.84 (s, 1H), 8.47 (s, 1H), 7.80 (s, 1H), 7.19 (s, 1H), 4.34 (dt, 1H), 2.97-2.69 (m, 3H), 2.50-2.32 (m, 1H), 1.93-1.77 (m, 1H), 1.70-1.09 (m, 7H); MS(ES):306(M+H).
Example 731: 4-[l-(l—Cyclopentylbutyl)-1H-pyrazol—4-yl]-7H-pyrrolo[2,3—d]pyrimidine trifluoroacetate salt If—N K/NN H 'TFA 4—[1 -(1 -Cyclopenty1but-3—yn-1 —y1)—1H—pyrazolyl]-7H-pyrrolo[2,3-d]pyrimidine ro- acetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in ol (2 mL) and a catalytic amount of 5% Pd—C was added. The e was stirred under 1 atmosphere of en via an affixed balloon. Afier 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).
‘H NMR (400 MHz, d5-DMSO)Z 5 12.73 (s, 1H), 8.86 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 7.79 (t, 1H), 7.20 (d, 1H), 4.11 (dt, 1H), 2.43-2.26 (m, 1H), 2.02-1.70 (m, 3H), 1.68-1.35 (m, 4H), 1.33-0.89 (m, 5H), 0.83 (t, 3H); MS(ES):310(M+H).
Example 732: 4-[l-(l-Cyclopentyl-4,4-difluorobuten-l-yl)-1H—pyrazol—4-yl]-7H-pyrrolo[2,3— d]pyrimidin_e trifluoroacetate salt 2006/047369 1/\ \ N N H 'TFA Step 1. 4—[1—(1-Cyclopentyl—4,4~difluor0but~3-enyl)—1H—pyrazol—4—yl]- 7-[2—(trimethylsilyDethoxyj— methyl—7H—pyrrolo[2,3—d]pyrimidine To a solution of openty1—3-[4—(7—[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d]— pyrimidinyl)-1H-pyrazol-l-yl]propanal (prepared as in Example 727, Step 4) (181 mg, 0.41 mmol) 1.12 mmol) followed by in MN-dimethylacetamide (3.6 mL) was added triphenylphosphine (294 mg, of 2.5 g in 50 dibromodifluoromethane (235 mg, 1.12 mmol). Rieke® Zinc (1.8 mL of a suspension for 4.5 ml THF) was then added in one portion. The resulting mixture was'stirred at room temperature hours. The mixture was filtered through diatomaceous earth. The filtrate was partitioned between dried over sodium sulfate, ether and water. The ether layer was washed with water, and brine, then with a gradient from O- and the solvent was removed in vacuo. Flash column chromatography (eluting % ethyl acetate in hexanes) afforded product (104 mg, 53%). 1H NMR (400 MHz, CDC13): {5 8.91 (3, 11-1), 8.51 (br s, 1H), 8.34 (s, 1H), 7.51 (d, 1H), 6.93 (d, 1H), 5.74 (s, 2H), 4.05 (ddd, 1H), 4.04—3.96 (m, 1H), 3.60 (t, 2H), 2.78—2.62 (m, 2H), 2.58-2.45 (m, 1H), .87 (m, 10H), 0.00 (s, 9H); :474(M+H). 3-d]pyrimidin,e Step 2. 4—[1 ~(J-Cyclopentyl—4, 4—dz'flu0robut-3—en-1 -yl)-1H-pyrazol—4—yl]- 7H—pyrrolo[2, trifluoroacetate salt A solution of 4-[1—(1-cyclopentyl—4,4-difluorobut—3-en—1—yl)—lH—pyrazoly1][2-(tri- methylsilyl)ethoxy]methyl-7H—pyrrolo[2,3-d]pyrimidine (41 mg, 0.086 mmol) in DCM (3 mL) and then concentrated in TFA (1.5 mL) was stirred for two hours at room temperature. The solution was THF (3 mL), and 6N NaOH (2 mL) was added. After vacuo. The resulting residue was redissolved in The organic layer was stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. dried Purification via ative- over sodium sulfate and the solvent was removed in vacuo. afforded the desired HPLC/MS (C18 eluting with a nt of H20 and ACN containing 0.1% TFA) product (39 mg, 98%). 1H NMR (400 MHz, ds-DMSO): 5 12.72 (s, 1H), 8.84 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 7.80 (t, 1H), 1.69-1.06 (m, 7H); 7.18 (d, 1H), 4.32 (ddt 1H), 4.20 (dt, 1H), 2.72-2.37 (m, 3H), .81 (m, 1H), MS(ES):344(M+H).
WO 70514 Where conjugate acceptors, such as were used in Example 737, Step 3 were not commercially available, such compounds were generated according to the procedure provided below for ethyl (2E)- 3~(tetrahydrofuran—3-yl)acry1ate (toward the preparation of Example 733).
Preparation of ethyl (2E)—3—(tetrahydrofiiranyl)acrylate: Step A: Tetrahydrofurancarbaldehyde To a solution of Dess-Martin periodinane (3.37 g, 7.95 mmol) in DCM (20 mL) was added tetrahydrofuran-B—ylmethanol (0.701 mL, 7.23 mmol). The reaction was stirred at t temperature for 2 hours, and the solvent was then removed in vacuo. Flash column tography (using DCM as eluent) afforded the product as a clear oil, which was used without further purification. lH NMR (400 MHz, CDC13)I _5 9.65 (d, 1H), 4.12-4.07 (m, 1H), 3.92-3.85 (m, 2H), 3.80—3.73 (m, 1H), 3.10-3.02 (m, 1H), 2.26-2.10 (m, 2H).
Step B: Ethyl —(tetrahydrofuran—3—yl)acrylate To a 0 °C mixture of sodium e (60% in mineral oil) (382 mg, 9.40 mmol) in DMF (15.0 mL) (TI-IF may also be used) was added triethyl phosphonoacetate (1.72 mL, 8.68 mmol) dropwise.
The resulting mixture was warmed to room temperature and stirred for 30 minutes, then was led to 0 °C, at which time a solution of tetrahydrofuran-B-carbaldehyde (724 mg, 7.23 mmol) in DMF (4.0 mL) was added dropwise. The resulting mixture was stirred at this ature for 1.5 hours, at which time the mixture was diluted with water and the product was extracted with ether. The combined extracts were washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. Flash column tography (eluting with a gradient from 0-40% ethyl acetate in hexanes) afforded the product (640 mg, 52%). lH NMR (400 MHz, CDC13)I 5 6.87 (dd, 1H), 5.86 (dd, 1H), 3.96—3.88 (m, 2H), 3.81 (dd, 1H), 3.53 (dd, 1H), 3.04-2.93 (m, 1H), 2.20—2.10 (m, 1H), 2.03 (s, 3H), 1.79 (dq, 1H).
Example 736: 4-[1-(1-Cyclopentyl—4,4-difluorobutyl)—lH—pyrazolyl]~7H—pyrrolo[2,3-d]- pyrimidine trifluoroacetate salt N\ \ ‘K/NN H -TFA 4-[1 -(1 —Cyclopentyl-4,4—difluorobut-3—en~1~yl)—1H—pyrazol—4—yl]—7H—pyrrolo[2,3 —d]- pyrimidine trifluoroacetate salt (prepared as in Example 731) (20.0 mg, 0.041 mmol) was dissolved in methanol (3 mL), and a catalytic amount of 5% Pd on C was added. The mixture was stirred at room temperature for 2 hours, under an here of hydrogen provided by an affixed balloon. The mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) to afford product (4 mg, 21%). 1H NMR (400 MHz, d5—DMSO): 8 12.74 (s, 1H), 8.88 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 7.80 (t, 1H), 7.20 (dd, 1H), 6.05 (tt, 1H), 4.17 (dt, 1H), 2.47-2.34 (m, 1H), 2.14-1.08 (m, 12H); MS(ES):346(M+I-I).
Example 737: 3-(1-Methylcyclopentyl)[4-(7H—pyrrolo[2,3—d]pyrimidin-4~yl)-1H—pyrazol-l- yllpropanenitrile trifluoroacetate salt fl -TFA Step 1. 1—Methylcyclopentanecarbaldehyde To a solution of entanecarbaldehyde (1.00 mL, 9.36 mmol) in DCM (47 mL) at 0 °C was added solid potassium tert—butoxide (1.44 g, 12.2 mmol) in one portion followed by methyl iodide (1.7 mL, 28 mmol) in one portion. Afier 30 minutes at 0 °C, the reaction mixture was allowed to warm to room temperature and stirred at that ature for 16 hours. The mixture was poured into brine, and the layers were separated. The organic layer was dried over sodium e, ed and concentrated, and used without further purification in Step 2.
Step 2: (ZZ)- and (2E)(1~Methylcyclopenty0acrylonitrile WO 70514 To a solution of 1.0 M potassium tert—butoxide in THF (9.36 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (1.59 mL, 9.8] mmol) in THF (10 mL) dropwise. The cooling bath was d and the reaction was warmed to room temperature followed by re-cooling to 0 "C, at which time a solution of 1-methylcyclopentanecarbaldehyde (1.0 g, generated in Step 1) in THF (2 mL) was added se. The bath was removed and the on was stirred at ambient temperature for 3 hours. To the mixture was added water and ethyl ether. The aqueous layer was further extracted with ethyl ether. The combined extracts were washed with brine, dried over sodium sulfate, filtered and adsorbed onto silica gel in vacuo. Flash column chromatography (eluting with a gradient from 0-10% ethyl acetate in hexanes) afforded product as a mixture with hexanes, which product was used without further purification in Step 3.
Step 3: 3-(1-Methylcyclopentyl)[4-(7H-pyrrolo[2, 3«djpyrimz'din-4—yl)-1H—pyrazol-I-yl]pr0pane- nitrile trifluoroacetate salt To a mixture of 4-(1H-pyrazolyl)~7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3- deyrimidine (0.134 g, 0.426 mmol) in ACN (3 mL) was added a mixture of (2Z)- and (2E)~3-(1- methylcyclopenty1)acrylonitn'1e (0.12 g, 0.9 mmol) followed by DBU (0.13 mL, 0.90 mmol). The reaction was heated to 60 °C for 6 h. The ACN was d in vacuo. Ethyl e was added, ed by 0.1 N HCl. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and the solvent was ated. The crude material was deprotected by stirring with TFA (2 mL) in DCM (8 mL) for 2 hours. The solvent and TFA were removed in vacuo. TI-IF (8 mL) was used to dissolve the residue, and 6.0 M sodium hydroxide in water (8 mL) was added. The reaction was stirred in this basic mixture for 2 hours. Ethyl acetate was used to extract the product. The combined extracts were dried 4) and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) afforded product (44 mg, 24%).
‘H NMR (400 MHz, erMSO): 5 12.71 (s, 1H), 9.00 (s, 1H), 8.85 (s, 1H), 8.51 (s, 1H), 7.81 (s, 1H), 7.18 (s, 1H), 4.72 (dd, 1H), 3.47 (dd, 1H), 3.21 (dd, 1H), 1.74-1.51 (m, 6H), 1.44-1.32 (m, 1H), 1.09- 1.00 (m, 1H), 0.97 (s, 3H); MS(ES):321(M+H).
Example 739: 1-2—Cyano-l-[4~(7H—pyrrolo[2,3-d]pyrimidin—4-yl)—IH-pyrazol-l-yl]ethylcyclo~ propanecarbonitrile trifluoroacetate salt N N H -TFA Step1 : 1—(HydroxymethyDcyclopr-opanecarbonitrile Ethyl 1-cyanocyclopropanecarboxylate (801 mg, 5.76 mmol) in THF (12.0 mL) was treated with lithium ydroborate (251 mg, 11.5 mmol). The solution was heated to reflux for 1.5 hours.
Upon cooling to room temperature, the reaction was quenched with water, and extracted with ethyl e. The combined extracts were dried over MgSO4, filtered and concentrated to afford a clear oil, which was used without further purification in the following step (482 mg, 86%). 1H NMR (400 MHz, CDC13): 5 3.61 (s, 2H), 1.27 (dd, 2H), 0.98 (dd, 2H).
Step2: ylcyclopropanecarbom'trile Dess—Martin inane (1.11 g, 2.62 mmol) was dissolved in DCM (12 mL) and 1- (hydroxymethyl)cyclopropanecarbonitrile (231 mg, 2.38 mmol) was added. The reaction was stirred at ambient temperature for one hour. The mixture was then d by flash column chromatography (eluting with a gradient from 0-80% ethyl acetate in hexanes) to afford the product (106 mg, 46%). 1H NMR (400 MHz, CD013): 5 9.35 (s, 1H), .74 (m, 4H).
Step 3 .' 1-[(E)Cyanovinyljcyclopropanecarbonitrz'le To a solution of 1.0 M potassium tert-butoxide in THF (1.12 mL) at 0 °C was added slowly dropwise a solution of diethyl cyanomethylphosphonate (210 mg, 1.2 mmol) in THF (2 mL). The cold bath was removed and the reaction was warmed to ambient temperature. The solution was then re- cooled to 0 °C and a solution of ylcyclopropanecarbonitrile (101 mg, 1.06 mmol) in THF (1.0 mL) was added dropwise. The cold bath was removed and the reaction was d for 3 hours at ambient temperature. The mixture was then diluted with ether and water, the ether solution was separated, washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. Flash column chromatography (eluting with a gradient from 0-60% ethyl ether in hexanes) afforded the product (24 mg, 19%). lH NMR (400 MHz, CD013): 5 5.94 (d, 1H), 5.82 (d, 1H), 1.80 (dd, 2H), 1.39 (dd, 2H).
Step 4: 1—2-Cyan0—1-[4-(7—[2—(trimethylsilyl)ethoxy]methyl- 7H-pyrrolo[2, 3-d]pyrimidin~4-yl)—1H— pyrazol-I—yl]ethylcyclopropanecarbonitrile To a solution of 4—(1H-pyrazolyl)-7~[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]- pyrimidine (61.4 mg, 0.195 mmol) and 1~[(E)cyanoviny1]cyclopropanecarbonitrile (23 mg, 0.19 mmol) in ACN (2 mL) was added DBU (58 uL, 0.39 mmol) and the resulting mixture was stirred for 16 hours. The ACN was evaporated, and the e was dissolved in ethyl acetate. This solution washed with 1.0 N HCl, water, and brine, and dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-80% ethyl acetate in hexanes) afforded the product (49 mg, 58%).
'H NMR (400 MHz, : _8 8.85 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H), .68 (s, 2H), 3.54 (dd, 1H), 3.51 (dd, 1H), 3.36 (dd, 1H), 1.62 (ddd, 1H), 1.45 (ddd, 1H), 1.34 (ddd, 1H), 1.25 (ddd, 1H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):434(M+H).
Step 5.‘ 1—2-Cyan0—I—[4-(7H—pyrrolo[2, 3-d]pyrimidin-4—yl)—IH—pyrazol-J~yl]ethylcyclopropane- carbonizrile trifluoroacetate salt 1 no— 1 —[4—(7—[2—(trimethylsi1yl)ethoxy]methyl—7H-pyrrolo[2,3—d]pyrimidin-4—yl)— 1H- pyrazol-l-yI]ethylcyclopropanecarbonitrile (48 mg, 0.11 mmol) was stirred in a mixture of DCM (3 mL) and TFA (2 mL) for 3 hours. The solvents were removed in vacua and the e was re- ved in THF (3 mL). 6N NaOH (2 mL) was added and the resulting mixture was stirred at ambient temperature for 3 hours. The crude reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate and the solvent was d in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) afforded product (20 mg, 43%).
IH NMR (400 MHz, d6-DMSO): 512.74 (s, 1H), 8.99 (s, 1H), 8.88 (s, 1H), 8.60 (s, 1H), 7.83 (t, 1H), 7.17 (dd, 1H), 4.55 (dd, 1H), 3.66 (dd, 1H), 3.54 (dd, 1H), 1.55—1.30 (m, 4H); MSCES):304(M+H). e 740: N-[(1Cyano-1—{4-(7H—pyrrolo[2,3-d]pyrimidin—4-yl)-—1H-pyrazol—1-yl]ethyl- cyc10pentyl)methyl]benzamide °>—© . 0;...
N—‘N "t\\/ Step 1: Methyl 1~cyanocyclopentanecarboxylate To a solution of acetic acid, cyano—, methyl ester (2.66 mL, 30.3 mmol) and 1,4— dibromobutane, (3.62 mL, 30.3 mmol) in acetone (50 mL) was added potassium carbonate (8.37 g, 60.6 mmol). The reaction was d at ambient temperature for 16 hours. The reaction was filtered through aceous earth and concentrated._ The resulting residue was partitioned between ether and saturated l solution, and the aqueous layer was extracted with two further portions of ether.
The combined ethereal extracts were washed with brine, and dried over sodium sulfate, then filtered and the solvent was removed in vacuo. Flash column tography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded the product (2.92 g, 63%).
'H NMR (300 MHz, CDClg): 53.82 (s, 3H), 2.30-2.21 (m, 4H), 1.93-1.82 (m, 4H).
Step 2: Methyl 1-[(tert-butoxycarbonyl)amino]methylcyclopentanecarboxylate To a solution of methyl 1-cyanocyclopentanecarboxylate (1.26 g, 8.22 mmol) in methanol (100 mL) was added cobalt dichloride (2.1 g, 16.0 mmol). The purple mixture was cooled in an ice- water bath. Sodium tetrahydroborate (3.11 g, 82.2 mmol) was added nwise with caution (exothermic) to provide a black mixture. Upon complete addition, cooling was discontinued and the reaction was stirred for 40 minutes under nitrogen and the reaction was quenched by the careful '15 addition of 1N HCI (700 ml). The methanol was removed in vacuo, and the solution was then made alkaline (pH ~ 9) by the addition of concentrated NH40H(aq). The mixture was extracted with DCM (6 times), and the combined DCM extracts were dried over sodium sulfate and concentrated to afford the crude product as a light yellow oil. To this crude amine in DCM (50 ml) was added di—tert- butyldicarbonate (1.31 g, 6.01 mmol) and the reaction was stirred at 25 °C for 30 minutes. The reaction was diluted with water and ted with ethyl acetate three times. The combined ts were dried over sodium sulfate, filtered, and the solvent removed in vacuo. The crude residue was d by flash column chromatography to yield the desired product (1.5 g, 71%). 1H NMR (300 MHz, CDC13): 5 5.03 (s, 1H), 3.69 (s, 3H), 3.26 (d, 2H), 2.02-1.33 (m, 17H).
Step 3: tert—Butyl [1{hydrwgzmethybcyclopentyljmethylcarbamate To a solution of methyl l—[(tert—butoxycarbonyl)amino]methylcyclopentanecarboxylate (1.50 g, 5.83 mmol) in THF (25.0 mL) at ~78 0C was added dropwise 1.0 M diisobutylaluminum hydride in DCM (17.5 mL). The on was stirred for 2 hours with slow warming to —10 °C. A ted solution of K/Na tartrate was added, followed by ether. This mixture was stirred for 30 minutes at 3O ambient temperature and the organic layer was separated and washed with water, and brine. The c layer was then dried over sodium sulfate, and the solvent was removed in vacuo to afford the product (1.03 g, 77%). lHNMR (300 MHz, CDCla): 8_ 4.90 (br s, 1H), 3.27 (s, 2H), 3.06 (d, 2H), 1.5- 1.17 (m, 8H), 1.44 (s, 9H).
Step 4: tert-Butyl [(1formylcyclopenbiDmethyl]carbamate To a solution of oxalyl chloride (456 uL, 5.38 mmol) in DCM (30.0 mL) at ~78 °C was added DMSO (637 uL, 8.97 mmol) and the resulting mixture was stirred for 5 minutes. tert~Butyl [l- (hydroxymethyl)cyclopentyl]methylcarbamate (1.03 g, 4.48 mmol) in DCM (10.0 mL) was added and the resulting mixture was stirred for 30 minutes at -78 0C. TEA (2.50 mL, 17.9 mmol) was added and the resulting e was allowed to warm to ambient temperature over 30 minutes. Water was added.
The organic phase was washed tially with 0.1 N HCl, water, saturated sodium onate solution, and brine, and then dried over sodium sulfate and the solvent was removed in vacuo to afford the product (957 mg, 94%). 1H NMR (300 MHz, CDC13): 5 9.39 (s, 1H), 4.94 (br s, 1H), 3.25 (d, 2H), 1.89-1.46 (m, 8H), 1.41 (s, 9H).
Step 5: rem-Bug)! (I-[(E)~2-cyanovinyl]cyclopentylmethyl)carbamate and tert—bulyl (1—[(Z)—2-cyano- vinyl]cyclopentylmethyDcarbamate To a on of 1.0 M potassium tert-butoxide in THF (4.4 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (820 mg, 4.6 mmol) in THF (6.0 mL) dropwise. The cold bath was removed and the reaction was warmed to ambient temperature. The mixture was then re—cooled to 0 °C and a solution of tert-butyl [(1~formy1cyclopentyl)methyl]carbamate (952 mg, 4.19 mmol) in TI-IF (4.0 mL) was added dropwise. The reaction was allowed to warm to ambient temperature and the warmed mixture was stir for 16 hours. The reaction e was then diluted with ether and water.
The organic layer was separated and washed sequentially with water and brine, then dried over sodium sulfate, then filtered, and the solvent was removed in vacuo to afford the product (1.05 g, 99%) as a mixture of (E) and (Z) isomers. 1H NMR (300 MHZ, CD013): 5 6.71 (d, 1H, E), 6.46 (d, 1H, Z), 5.36 (d, 1H, Z), 5.36 (d, 1H, E), 4.70 (br s, 1H, 2), 4.51 (br s, 1H, E), 3.25 (d, 2H, Z), 3.13 (d, 2H, E), 1.88-1.48 (m, 8H (E) and 8H (2)), 1.43 (s, 9H (E) and 9H (2)); MS(ES):151(M+H-Boc).
Step 6: tert-Butyl [(1cyano-I—[4—(7-[2—(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3-d]pyrimiiiin- 4—yl)~1H-pyrazol—1—yl]ethylcyclopentyl)methyl]carbamate To a solution of pyrazol~4—yl)—7—[2—(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3-d]- dine (355 mg, 1.12 mmol) and tert—butyl (1-[(E)—2—cyanovinyl]cyclopentylmethyl)carbamate and tert-butyl (l—[(Z)—2-cyanovinyl]cyclopentylmethyl)carbamate as a e of isomers (329 mg, 1.31 mmol)-in ACN (10 mL) was added DBU (0.168 mL, 1.12 mmol). The resulting mixture was stirred at ambient temperature for 3 hours followed by heating to 60 0C for 2.5 hours. The ACN was removed in vacuo and the resulting residue was d by flash column chromatography (eluting with 0-55% ethyl acetate in hexanes) to afford the product (350 mg, 55%).
‘H NMR (300 MHz, (31301,): ,8 8.85 (s, 1H), 8.37 (br s, 1H), 8.34 (s, 1H), 7.41 (d, 1H), 6.82 (d, 1H), .68 (s, 2H), 5.37 (br s, 1H), 4.52 (dd, 1H), 3.54 (t, 2H), 3.40 (dd, 1H), 3.23 (dd, 1H), 3.08 (d, 1H), 2.90 (dd, 1H), 1.84-1.47 (m, 8H), 1.45 (s, 9H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):566(M+H).
Step 7: N-[(I—2—Cyan0-1—[4-(7H-pyrrolo[2, 3-d]pyrimidin—4-yl)—1H—pyrazol—I-yUethylcyclopentyl)— methyljbenzamide A solution of utyl [(1cyano-1—[4-(7-[2—(trimethylsilyl)ethoxy]methyl—7H-pyrrolo[2,3— d]pyrimidinyl)-lH-pyrazol-l-yl]ethylcyclopenty1)methyl]carbamate (175 mg, 0.309 mmol) in DCM (5 mL) and TFA (5 mL) was stirred for 3 hours and the solvents were then removed in vacuo.
The resulting residue was stirred in a mixture of THF (3 mL) and 6N NaOH (3 mL) for 3 hours. The THF was removed in vacuo, and water (10 mL) was added. The mixture was extracted with l portions of DCM containing 15% isopropanol. The combined extracts were dried over sodium sulfate and the solvents were removed in vacuo to afford the product, which was used without fiirther purification. MS(ES):336(M+H).
To a solution of 3—[1~(aminomethyl)cyclopentyl]-3—[4—(7H—pyrrolo[2,3~d]pyrimidin~4—yl)—l H- pyrazol—l-yl]propanenitrile (31 mg, 0.060 mmol) and benzoyl chloride (7.0 uL, 0.060 mol) in DCM (1.0 mL), was added TBA (17 uL, 0.12 mmol). After 15 minutes, the solvent was removed in vacuo and the mixture was purified via preparative-HPLC/MS (C18 eluting first with a gradient of H20 and ACN containing 0.1% TFA, followed by chromatographic cation, eluting with a gradient of H20 and ACN containing 0.15% NH40H) to afford the product (7 mg, 27%). 1H NMR (400 MHz, O): 512.12 (s, 1H), 8.95 (s, 1H), 8.68 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 7.92-7.87 (m, 2H), 7.60 (d, 1H), 7.59-7.48 (m, 3H), 7.02 (d, 1H), 4.83 (dd, 1H), 3.52—3.45 (m, 2H), 3.42 (dd, 1H), 3.27 (dd, 1H), 2.06—1.95 (m, 1H), 1.68-1.12 (m, 7H); MS(ES):440(M+H).
Example 741: 3[(Benzyloxy)methyl]cyclopentyl—3~[4-(7H—pyrrolo[2,3-d]pyrimidinyl)-1H— pyrazol-l-yl]propanenitrile trifluoroacetate salt H -TFA Step 1: rowmethyDcyclopentanecarbonitrile A e ofmethyl l—cyanocyclopentanecarboxylate (prepared in Example 740, Step 1) (500 mg, 3.0 mmol) in THF (7 mL) was treated with lithium tetrahydroborate (100 mg, 6.0 mmol). The resulting solution was heated to reflux for 3 hours, then stirred at ambient temperature for 16 hours.
The mixture was ed by the addition of water, and was extracted with ethyl acetate. The combined organic extracts were dried over NaZSO4, then filtered and the solvent was removed in vacuo to afford the product (387 mg, 95%). 1H NMR (300 MHz, CDCI3): 53 .62 (s, 2H), 2.39-1.60 (m, 8H).
Step 2: nazloxy)methy1]cyclopentanecarbom'trile To a solution of 1—(hydroxymethyl)cyclopentanecarbonitrile (0.30 g, 2.0 mmol) in DMF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 0.101 g, 2.52 mol). The resulting mixture was stirred for 20 minutes, ed by the addition of benzyl bromide (0.28 mL, 2.4 mmol).
The on was stirred at ambient temperature for 64 hours. Additional sodium hydride (60% sion in mineral oil, 0.060 g, 1.5 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) were added and the reaction was stirred for an additional 30 minutes. Water was then added to the mixture, followed by brine, and the aqueous layer was extracted with ethyl acetate. The extracts were combined and dried over sodium sulfate, and the solvent was then removed in vacuo. To the ing e was added water. The product was isolated by extraction with diethyl ether. The al extracts were dried over sodium e, and the solvent was evaporated. Flash column chromatography (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded product (330 mg, 64%). 1H NMR (300 MHz, CD013): 67.40-727 (m, 5H), 4.62 (s, 2H), 3.44 (s, 2H), 2.18—2.03 (m, 2H), 1.90— 1.62 (m, 6H).
Step 3: 1-[(Benzyloxy)methyl]cyclopentanecarbaldehyde To a mixture containing nzyloxy)methyl]cyclopentanecarbonitn'le (0.16 g, 0.75 mmol) in toluene (5 mL) at 0 °C was added 1.0 M diisobutylaluminum hydride in hexanes (0.8 mL). The reaction was stirred at 0 °C for 1.5 hours, during which time the starting nitrile was consumed. The reaction was cooled to ~78 0C and quenched by the addition of methanol. The mixture was warmed to ambient temperature and 3 N HCl was added. Following stirring for 45 minutes, solid NaCl was added, and the mixture was extracted with three portions of ethyl acetate. The combined extracts were 3O dried (Na2804), and filtered, and the solvent was removed in vacuo. Flash column chromatography of the resulting residue (eluting with a gradient from 0-30% ethyl acetate in hexanes) afforded the product (20 mg, 12%). lH NMR (300 MHz, CDC13): f) 9.60 (s, 1H), 7.38-7.26 (m, 5H), 4.52 (s, 2H), 3.54 (s, 2H), 2.00—1.89 (m, 2H), 1.66-1.46 (m, 6H).
Step 4: (2E)- and (2Z)1-[(Benzyloxy)methyl]cyclopentylacrylonitrile To a stirred solution of diethyl cyanomethylphosphonate (18 uL, 0.11 mmol) in THF (1 mL) was added 1.0 M potassium tert-butoxide in THF (0.10 mL). The resulting mixture was stirred 30 minutes, afier which a on of 1—[(benzyloxy)methyl]cyclopentanecarbaldehyde (0.020 g, 0.092 mmol) in THF (1 mL) was added. The resulting mixture was d for 16 hours. Water was then added to the reaction and the resulting e was extracted with three ns of ethyl ether. The combined extracts were washed with brine, then dried over sodium sulfate, decanted fiorn the sodium e, and the solvent was removed in vacuo to afford the product, which was used without further purification in the subsequent conjugate addition step. 1H NMR (400 MHz, : 5, 7.37—7.27 (m, 5H), 6.80 (d, 1H (E)), 6.59 (d, 1H (Z)), 5.34 (d, 1H (E)), 5.33 (d, 1H (Z)), 4.53 (s, 2H (Z)), 4.50 (s, 2H (E)), 3.45 (s, 2H (Z)), 3.31 (s, 2H (E)), 1.80-1.55 (m, 8H); MS(ES)=242(M+H).
Step 5: 3-1 -[(Benzylo;gz)methyl]cyclopen31—3-[4-(7H-pyrrolofi2, 3~d]pyrz'midt'n—4-yD-IH~pyrazol yljpropanenitrile roacetate salt To a mixture of (2E)- and (2Z)—3-1~[(benzyloxy)methy1]cyclopentylacrylonitrile (generated in Step 4) and 4—(1H-pyrazol~4-yl)[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d]pyrimidine (0.037 g, 0.12 mmol) in ACN (1.5 mL) was added DBU (18 uL, 0.12 mmol). The resulting mixture was stirred at t temperature for 3 hours, and then was heated to 60 0C for 28 hours. The reaction mixture was diluted with diethyl ether and 0.1 N HCl. The layers were separated and the aqueous layer was ted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate, ed, and the solvent was removed in vacuo. The resulting residue Was dissolved in DCM (3 mL) and TFA (0.75 mL), and this solution was stirred for 3 hours. The solvents were removed in vacuo, and the resulting residue was dissolved in THF (5 mL) and 6.0 M sodium hydroxide in water (3 mL) and stirred for 2 hours. The reaction mixture was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted, and the solvent was removed in vacuo. The crude mixture was purified by preparative- HPLC/MS (C18 eluting with a gradient of H20 and ACN containing 0.1% TFA) and lyophilized to afford the d product (10 mg, 20% over the two steps). 1H NMR (400 MHz, dG—DMSO): 512.71 (br s, 1H), 8.99 (s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 7.80 (s, 3O 1H), 7.38-7.23 (m, 5H), 7.19-7.16 (m, 1H), 4.92 (dd, 1H), 4.50 (d, 1H), 4.44 (d, 1H), 3.49 (dd, 1H), 3.35 (d, 1H), 3.23 (dd, 1H), 3.05 (d, 1H), 1.92-1.82 (m, 1H), 1.66-1.27 (m, 7H); MS(ES):427(M+H).
Example 742: 3-[l-(Methylsulfonyl)pyrrolidin—3—yll—3-[4-(7H-pyrrolo[2,3—d]pyrimidin—4—yl)-1H— pyrazol-l-yl]propanenitrile trifluoroacetate salt u 'TFA Step I: Benzyl 3-(hydroxymethpryrrolidine—I-carboxylate To a solution of 1-[(benzyloxy)carbonyl]pyrrolidine—3-carboxy1ic acid (1.0 g, 4.0 mmol) in THZF (37 mL) at 0 °C was added dropwise a solution of 1.0 M borane in THF (16.4 mL). The reaction was allowed to warm to room temperature and stir for 16 hours. The mixture was cooled to 0 °C and 10% HCl (50 mL) was added. After the addition, the mixture was extracted with DCM, and the extract was washed sequentially with saturated NaI-ICO; solution and brine, then dried over sodium sulfate, filtered and the solvent was removed in vacuo. The product was used without further purification in the subsequent oxidation step.
]H NMR (300 MHz, CD013): 5 .26 (m, 5H), 5.11 (s, 2H), 3.61-3.31 (m, 5H), 3.18 (dt, 1H), 2.75 (br s, 0.45H), 2.59 (br s, 0.45H), .31 (m, 1H), 2.19 (br s, 0.1H), 2.05-1.89 (m, 1H), 1.77- 1.58 (m, 1H); MS(ES):236(M+H).
Step 2: Benzyl ylpyrrolidine-1~carboxylate DMSO (597 nL, 8.42 mmol) was added to a solution of oxalyl chloride (427 uL, 5.05 mmol) in DCM (25 mL) at -78 °C. After 5 minutes, benzyl 3—(hydroxymethyl)pyrrolidinecarboxylate (generated in Step 1) was added. The reaction was continued for 30 minutes at -78 °C. TEA (2.3 mL, 17 mmol) was then added. The resulting mixture was then d to warm to room temperature over the course of 30 minutes. Water was then added. The layers were separated and the organic phase was washed sequentially with 0.1 N HCl, water, saturated NaHC03, and brine. The organic phase was then dried over sodium e and the solvent was removed in vacuo to afford the product (0.82 88% over two steps). 1H NMR (300 MHz, CDCl3): 6 9.68 (d, 1H), 7.38—7.28 (m, 5H), 5.13 (s, 2H), 3.79 (dd, 1H), 3.65-3.35 (m, 3H), 3.11~2.99 (m, 1H), .04 (m, 2H).
Step 3: Benzyl 3—[(E)—2—cyan0vinyljpyrrolidine-I-carboxylate and benzyl 3—[(Z)-2—cyanovinyl]— pyrrolidine—I-carb0xylate To a solution of 1.0 M potassium tert-butoxide in THF (4.40 mL) at 0 °C was added a solution of diethyl cyanomethylphosphonate (820 mg, 4.6 mmol) in THE (6.0 mL) dropwise. The cold bath was removed and the reaction was warmed to room ature and stirred for 15 minutes. The mixture was cooled to 0 °C and a solution of benzyl 3-formylpyrrolidine—1—carboxylate (0.82 g, 2.3 mmol) in THF (4.00 mL) was added dropwise. Cooling was discontinued and the reaction stirred for 16 hours at ambient temperature. The mixture was diluted with ether and water, the layers were ted and the organic layer was washed with water, followed by brine, and then dried over sodium sulfate, filtered and the solvent was removed in vacuo. The resulting residue was purified by flash column chromatography (eluting with a gradient from 0—35% ethyl acetate in hexanes) to afford the product as a mixture ofE and Z isomers (246 mg, 42%). 1H NMR (300 MHz, CDClg): 8 7.41—7.27 (m, 5H), 6.70—6.58 (m, 0.3H (E)), 6.38 (dt, 0.7H (Z)), 5.50- .30 (m, 1H), 5.14 (s, 2H), 3.79-3.11 (m, 5H), 2.27-2.06 (m, 1H), 1.90—1.70 (m, 1H); MS(ES):279(M+Na).
Step 4.’ Benzyl 3—2—cyano~1—[4—(7—[2-(trimethylsilyDethoaqyjmethyl— 7H—pyrrolo[2, rimidin-4—yl)- IH—pyrazol—J—yl]ethylpyrrolidine—l-carboxylate To a mixture of benzyl cyanovinyl]pyrrolidinecarboxylate and benzyl 3-[(Z) cyanovinyIprrrolidine-l~carboxylate (241 mg, 0.940 mmol) and DBU (234 uL, 1.57 mmol) in ACN (13 mL) was added pyrazolyl)[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3— d]pyrimidine (250 mg, 0.78 mmol). The mixture was d at ambient temperature for 3 hours. The solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate, and the c layer was washed sequentially with 1N HCl, water, saturated NaI-IC03, and brine. The washed solution was dried over sodium sulfate and the solvent was removed in vacuo. Purification via flash column chromatography (eluting with a gradient of 0-100% [5% MeOH/DCM] in hexanes) afforded the produce as a mixture of diastereomers (400 mg, 89%).
'H NMR (400 MHz, CDC]; a mixture of diastereomers):5 8.85 (s, 1H), .28 (m, 2H), 7.42-7.25 (m, 6H), 6.80-6.76 (m, 1H), 5.69-5.66 (m, 2H), 5.15-5.04 (m, 2H), 4.464.32 (m, 1H), 3.84-3.84 (m, 6H), 3.54 (t, 2H), 2.26-2.13 (m, 1H), 1.84-1.54 (m, 2H), 0.95-0.89 (m, 2H), -0.06 (s, 9H); MS(ES):572(M+H).
Step 5. 3-Pyrrolidin-3—yl—3-[4-(7-[2-(trimethylsilyl)ethoxyflnethyl- 7H—pyrrolo[2,3-d]pyrimidin-4—y1)- azol—I-yl]pr0panenitrile Benzyl 3-2—cyano—1 -[4-(7-[2-(trimethylsilyl)ethoxy]methyl—7H—pyrrolo[2,3—d1pyrimidin-4— yl)—1H-pyrazol—1-y1]ethylpyrrolidine—1-carboxylate (161 mg, 0.282 mmol) was dissolved in methanol (5 mL), and a catalytic amount of 5% Pd-C was added, The suspension was stirred at t temperature for 1 hour under an atmosphere of en provided by a balloon. A catalytic amount of % Pd-C was then added, and the reaction stirred for 2 hours under an here of en provided by a balloon. The mixture was then filtered, and purified via preparative—I-IPLC/MS (C18 eluting with a nt of H20 and ACN containing 0.15% NH40H) to afford the product as a mixture of diastereomers (57 mg, 46%). ' IH NMR (400 MHz, CDClg, a mixture of diastereomers): 5 8.84 (s, 1H), 8.34-8.32 (m, 2H), 7.40 (d, 1H), 6.81—6.78 (m, 1H), 5.67 (s, 2H), 4.38 (dt, 1H), 3.54 (t, 2H), 3.30—1.38 (m, 9H), 0.92 (t, 2H), -0.06 (s, 9H); MS(ES):438(M+H).
Step 6.‘ 3-[1-(MethylsulfonpryrrolidinyU[4-(7H-pyrrolo[2, 3-d]pyrimidin-4—yl)~1H-pyrazol—1- yljpropanenitrile trifluoroacetate salt To a solution of 3-pyirolidinyl-3—[4-(7-{[2-(trimethylsilyl)ethoxy]methyl} ~7H—pyrrolo[2,3- d]pyrimidinyl)1H—pyrazol—1—yl]propanenitrile (25 mg, 0.057 mmol) and TBA (10 ML, 0.074 mmol) in DCM (1.0 mL) at 0 "C was added methanesulfonyl de (6 uL, 0.074 mmol). The reaction was allowed to reach ambient temperature and stir for 16 hours. Half of the solvent was removed in vacuo and TFA (1 mL) was added. to the vial. Afier stirring for 1 hour at room temperature, the solvents were removed in vacuo and the resulting residue reconstituted in THF (0.5 mL). To this was added 6 N NaOH (1 mL) and this solution was stirred for 2 hours. The reaction mixture was extracted with five portions of ethyl acetate. The combined ts were dried (NaZSO4), decanted and concentrated.
Preparative-HPLC/MS (C18 eluting with a gradient ofH20 and ACN containing 0.1% TFA) was used to afford the product (16 mg, 57%). lH NMR (400 MHz, ds—DMSO, a mixture of reomers): 5 12.69 (s, 1H), 8.98 (s, 0.5H), 8.95 (s, 0.5H), 8.84 (s, 1H), 8.53—8.51 (m, 1H), 7.80-7.77 (m, 1H), 7.16-7.13 (m, 1H), 4.86-4.75 (m, 1H), .48 (m, 1H), 3.42-3 .08 (m, 4H), 2.99-2.91 (m, 1H), 2.90 (s, 1.5H), 2.85 (s, 1.5H), 2.16-2.07 (m, 1H), 1.82—1.70 (m, 1H), 1.64-1.48 (m, 1H); MS(BS):386(M+H).
Example 743: N'-Cyano(cyanomethyl)—4-[4-(7H-pyrrolo[2,3—d]pyrimidin-4~yl)—lH—pyrazol-l— yl]piperidine—l-carboximidamide N N u \\ \ N / NH N\\’_ / 2 Step I: tert-Butyl 4-(cyanomethylene)pzperidine—1-carboxy1ate To a solution of 1.0 M potassium utoxide in THF (10.1 mL) at 0 °C was added a solution of diethyl ethylphosphonate (1.66 mL, 0.0102 mol) in THF (20 mL) dropwise. The reaction was held for 10 min, then added to a solution of tert—butyl 4-0x0piperidinecarboxylate WO 70514 (2.00 g, 0.0100 mol) in THF (30 mL) stirring at 0 °C under an atmosphere of nitrogen. After completeaddition, the cold bath was removed and the on was allowed to stir 1.0 h at 20 °C.
LCMS analysis showed the desired product and no remaining starting material. HPLC showed the t UVmax at 200 & 230 nm. Water and EtOAc were added to the reaction e. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined c phase was washed with water, then saturated NaCl, then dried over , and concentrated to dryness to provide 2.5 g of the product as a yellow oil. TLC (25% EtOAc/hexane) Rf 0.22. The product was purified by automatic flash chromatography on silica gel. Used a 40g column; flow 40 mL/min; [A= hexane] [B= EtOAc]. A, 4 min; Gradient to 20% B in 30 min. Collected 44 mL fractions. The t eluted in 21-27 min. The fractions were contrated to yield 0.67 g of a white solid. 1H NMR (CDC13) 5 5.19 (s, 1H); 3.51 (m, 4H); 2.56 (t, 2H); 2.33 (t, 2H); 1.50 (s, 9H). MS(ES) 245 (M+Na, weak; base peak M+H—56 = 167).
Step 2: tert-Butyl 4-(cyanomethyl)—4—[4-(7—[2-(trimethylsilyl)ethoxy]methyl—7H~pyrrolo[2,3—d]- pyrimidin-4—yl)~1H—pyrazolyl]piperidinecarbo.xy1ate 4-(1H-Pyrazolyl)—7-[2-(trimethylsilyl)ethoxy]methy1—7H—pyrrolo[2,3—d]pyrimidine (0.840 g, 2.66 mmol) was slurried in a mixture of ACN (20 mL) and DBU (398 uL, 2.66 mmol), and tert~ butyl 4-(cyanomethylene)piperidine—1—carboxylate (0.651 g, 2.93 mmol) was added, The pyrazole did not dissolve at 20° C, but a solution was formed when the mixture was heated to 40 °C for 1h. LCMS and HPLC analyses showed about 20% conversion to product. The e was stirred at 40-45 0C overnight. HPLC showed 60 area% product. The ACN was d by retory evaporator at 20 °C. To the resulting residue was added saturated NaHCO; and EtOAc. The organic layer was shaken with more aqueous saturated NaHCO3, then dried (Nazson and rotovaped to give 1.6g of a brown oil residue. TLC (60% EtOAc/hexane): product Rf = 0.25. The product was purified by automatic flash chromatography on silica gel, using a 40g column, at a flow of 40 mL/min; [A= hexane] [B= EtOAc].
A, 3min; Gradient to 100% B in 50 min. Collected 44 mL ons. The product eluted in 24—29 min; the pyrazole in 39-46 min; and the olefin in 13-15 min. Solvent was removed in vacuo for the appropriate fractions to give 0.27 g olefin; 0.30 g pyrazole; and a yield of 0.67 g of the product, all of which were isolated as white solids. 1H NMR (CDCI3) 6 8.84 (s, 1H); 8.42 (s, 1H); 8.33 (s, 1H); 7.40 3O (d, 1H); 6.79 (d, 1H); 5.67 (s, 2H); 3.94 (m, 2H); 3.54 (m, 2H); 3.07 (m, 2H); 2.90 (s, 2H); 2.72 (m, 2H); 2.08 (m, 2H); 1.45 (s, 9H); 0.91 (m, 2H); -0.06 (s, 9H). MS(ES) 538 (M+H).
Step 3: 4-[4-(7H-Pyrrolo[2, 3—d]pyrimidin—4-yl)—IH—pyrazol—1-yl]piperidin-4—ylacetom'trr'le tert—Butyl 4-(cyanomethyl)~4-[4-(7-[2-(trimcthylsilyl)ethoxy]methyl-7H-pyrrolo[2,3—d]- pyrimidin—4-yl)—1H—pyrazol—l -yl]piperidine—l -carboxylate (0.670 g, 1.24 mmol) was dissolved in TFA (5.0 mL, 65 mmol) and was stirred for 1.3 h. LCMS showed conversion to the hydroxymethyl intermediate, M+H 338. The solution was concentrated to remove the TFA. Methanol was added to the resulting residue, and the resulting mixture was concentrated. The ing residue was dissolved in methanol (10 mL) and 15.0 M ammonium hydroxide in water (1.66 mL) was added. The resulting solution was stirred for 2 h. LCMS and HPLC analyses showed complete deprotection. The mixture was concentrated. Toluene was added to the ing residue and the resulting mixture was concentrated to provide a white lid. Most of this intermediate product was used for the next step. The rest was purified by prep HPLC using a 30 mm x 100 mm C18 column; 8% ACN-HzO (0.1% NILOH), 1.0min, to 27% at 6min; 60 mL/min; detector set at m/z 308; retention time, 5.4 min.
Tubes containing pure product were combined and freeze dried to give 13.6 mg of the product. 1H NMR SO) 5 12.07 (s, 1H); 8.68 (s, 1H); 8.62 (s, 1H); 8.36 (s, 1H); 7.54 (d, 1H); 7.00 (d, 1H); 3.16 (s, 2H); 2.87 (m, 2H); 2.55 (m, 4H); 1.94 (m, 2H). MS(ES) 308 (M+H).
Step 4: Methyl N-cyan0(cyanomethyD[4-(7H-pyrrolo[2,3—d]pyrimidinyl)—1H-pyrazol—I -yl]- piperidine—I -carbimid0thioate 7H~Pyrrolo[2,3-d]pyrimidin—4-yl)-1H—pyrazol-l—yl]piperidin—4~ylacetonitrile (361 mg, 1.17 mmol) and N-cyano-S,S’-dimethyldithioimido carbonate (344 mg, 2.35 mmol) were dissolved in isopropyl alcohol (2.5 mL) and DMSO (2.5 mL) at 20 °C. After 16 h reaction time, LCMS analysis showed the presence of some product, M+H 406; of the reagent, M+H 147; and of the piperidine, M+H 308. HPLC analysis showed about 2% reaction. The HPLC method was: Zorbax SB C18, Sum, cm, 35 DC, flow 1.2 mL/min, 5% ACN—HzO (0.05% TFA), 1.5 min, to 100% ACN in 15.0 min; detector set at 324, 225, and 265 nm. The retention time of the starting material was 4.9 min (UV max 224, 262, 292, & 325 nm); of the product, 6.5 min (UV max 226, 262, 290, & 324nm); and of the reagent, 7.7min (UV max . To the product was added TEA (327 uL, 2.35 mmol), and the resulting mixture was stirred at RT. After ng for 3 h, HPLC and LCMS es showed 60% reaction. The product and the unreacted piperidine were isolated by prep HPLC using a 30 mm x 100 mm C18 column; 5%ACN-H20 FA), 1.0min, to 35% at 6min; 60 mL/min; detector set at 326 nm. The retention time for the product was 5.9 min; and for the ng piperidine was 3.5—4.3 min.
The product was freeze dried to yield 301 mg of a white solid TFA salt. 1H NMR (d6-DMSO) 6 12.85 (s, 1H); 9.01 (s, 1H); 8.90 (s, 1H); 8.59 (s, 1H); 7.85 (m, 1H); 7.30 (m, 1H); 4.23 (m, 2H); 3.35 (m, 2H); 3.30 (s, 2H); 2.78 (m, 2H); 2.68 (s, 3H); 2.16 (m, 2H). MS(ES) 406 (M+H).
Step 5: NLCyano—4-(cyanomethy1)—4-[4-(7H~pyrrolo[2, 3-d]pyrimidinyl)—1H—pyrazol—1-yl]piperi— dine-1—carb0ximidamide Methyl N—cyanoA—(cyanomethyl)—4-[4—(7H-pyrrolo[2,3~d]pyrimidin—4—y1)—lH—pyrazol-l—yl]- piperidine-l-carbimidothioate (41.3 mg, 0.102 mmol) (53 mg TFA salt) was dissolved in 2.0 M ammonia in isopropyl alcohol (4.00 mL). The resulting mixture was heated to 100 °C for 1 h in a ave reactor. Analysis by HPLC and LCMS showed 60% reaction to give the expected M+H 375 (50 ._ To this mixture was added 2 mL of 7 N NH3/MeOH. The resulting mixture was heated at 120 °C for one hour. HPLC and LCMS analyses showed no remaining starting material.
The reaction mixture was concentrated on a rotory evaporator. The product was isolated by prep HPLCMS using a 30 mm x 100 mm C18 column, eluting with a solvent gradient; 10% ACN—Hzo (0.1%TFA), 1.5min, to 30% at 6min; 60mL/min; detector set at m/z 375; retention time, 4.7 min. The eluate was freeze-dried to yield 11.7 mg of the t TFA salt as a white solid. 1H NMR (d6- DMSO) 6 12.69 (s, 1H, NH); 8.92 (s, 1H); 8.81 (s, 1H); 8.51 (s, 1H); 7.75 (m, 1H); 7.22 (m, 1H); 7.18 (s, 2H, NH2); 3.84 (m, 2H); 3.23 (s, 2H); 2.99 (m, 2H); 2.60 (m, 2H); 1.97 (m, 2H). MS(ES) 375 (M+H).
Example 744: 4[2,2,2—Trifluoro—l-(lH—imidazol-Z-ylmethyl)ethyl]—1H—pyrazol—4-yl-7H-pyr— ,3—d]pyrimidine F ""3 N‘\ \ N NH Step1 .' (3R)-4, 4, 4-Trifluoro[4-(7-[2-flrz’methylsilyDethoxyj’methyl— 7H-pyrrolo[2, 3—d]pyrimidin~4- yl)-IH-pyrazol-I~yl]butanal F N'N N\ \ N N To a ~70 °C solution of (3R)-4,4,4-trifluoro[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyr- rolo[2,3-d]pyrimidin-4—yl)-lH—pyrazol-l-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93, Step1) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL).
The resulting mixture was stirred for 3h and allowed to warm during this time al from —70 to ~25 °C, afier which the reaction was cooled back at -70 °C. Methanol (1.5 mL, 0.037 mol) was added, followed by 2.0 M HCl in water (15 mL). Insoluble material was then filtered from the reaction mixture. The organic e was washed tially with: 2.0 M HCl in water, water and saturated aqueous NaCl. The washed organic phase was dried over sodium sulfate and was concentrated using a rotory evaporator to give 0.58 g of the crude product as a pale yellow foam/solid. The crude product was chromatographed with 0—80% ethyl acetate/hexanes to give the purified product (0.9 g) as a pale orange oil (47% yield). 1H NMR (400 MHz, CDC13): 8 9.85 (1H, s); 8.95 (1H, s); 8.5 (1H, s); 8.4 (1H, s); 7.5 (1H, d); 6.85 (1H, d); 5.75 (2H, s); 5.5 (1H, m); 4.0 (1H, dd); 3.6 (2H, t); 3.3 (1H, dd); 1.99 (2H, t); 0.0 (9H, 3). MS (M+H): 440.
Step2: 4—1-[2,2,2-Trifluoro-I—(1H;imidazol—2—ylmethyDethylj-IH—pyrazol—4—yl— 7-[2—(trimethylsily0- ethoxyjmethyl- 7H-pyrrolo[2, 3—d]pyrimidine ("NH F 'N‘ N N \ \ N N A solution of 4,4,4-trifluoro-3—[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyn'olo[2,3-d]— din—4—yl)—1H—pyrazolyl]butanal (0.138 g, 0.000314 mol), 7.0 M ammonia in methanol (1 mL), ethanedial (0.5 mL, 0.004 mol) and acetic acid (20 uL, 0.0004 mol) in ol (2 mL, 0.05 mol) was microwaved on 100 watts, at 80 °C for 60 minutes. Following the microwave reaction, ethyl acetate/water was added. The organic phase was separated and washed with ted NaHCO; and saturated NaCl. The washed c phase was dried and concentrated (rotory evaporator) to give 196 mg of the crude product as an orange glass. The crude product was purified by chromatography with 0—100% ethyl acetate/hexanes to give 57 mg ofpurified product as an off—white solid (38% yield).
‘H NMR (400 MHz, CD013): 8 8.91 (1H, s); 8.4 (1H, s); 8.2 (1H, s); 7.5 (1H, d); 7.0 (2H, s); 6.83 (1H, d); 5.75 (2H, s); 5.62 (1H, m); 4.15 (1H, dd); 3.8 (1H, dd); 3.6 (2H, t); 1.99 (2H, t); 0.0 (9H, 5).
MS (M+H): 478.
Step3: 4—1 —[2, 2,2—Trifluoro—1—(JH—imidazol—Z—ylmethyl)ethylj—IH—pyrazol—4—yl— 7H—pyrrolo[2, 3-d]— pyrimidine A solution of 4—1—[2,2,2-trifluoro(1H-imidazolylmethyl)ethyl]-1H-pyrazol—4—yl-7—[2- (trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.055 g, 0.12 mmol) in chloro— ethane (1 mL, 10 mmol) and TFA (0.5 mL, 6 mmol) was stirred overnight. The reactiOn was trated to provide an orange oil. The oil was stirred in methanol (1 mL, 20 mmol) and 8.0 M ammonium hydroxide in water (1 mL) for 4h. This mixture was then concentrated to e a crude product as an orange glass/solid. The crude t was purified by Prep HPLC (leO) to give 28 mg of purified product as a colorless glass, which was triturated with 2—methoxy—2-methylpropane (1 mL, 8 mmol), and then filtered and washed to provide 15 mg of the product as a white solid (38% yield) which then was dried rt-50 °C for 3h. lH NMR (400 MHz, DMSO): 5 12.13 (1H, 5); 11.89 (1H, s); 8.65 (1H, s); 8.37 (1H, s); 7.6 (1H, d); 6.95 (1H, d); 6.92 (1H, d); 5.91 (1H, m); 3.78 (1H, dd); 3.47 (H, dd). MS (M+H): 348.
Example 745: 4-(1-(1R)-2,2,2-Trifluoro—l~[(4-methyl-l,3-thiazolyl)methyl]ethyl-IH-pyrazol- 4-yl)-7H-pyrrolo[2,3-d1pyrimidine F N43 N'\i/\ Step 1: (3R)—4, 4, 4-Trifluoro[4-(7H-pyrrolo[2, 3~d]pyrimidinyl)-IH-pyrazol—I -yl]butane— z'de .- 2} F N ' N N '\ \ 'L , N NH A suspension ofphosphorus pentasulfide (0.46 g, 1.0 mmol) in l (0.5 mL, 8 mmol) was stirred for lh. (3R)-4,4,4-Trifluoro[4-(7H-pyrro]o[2,3—d]pyrirnidin~4-yl)—1H-pyrazol-Llebutane- nitrile (0.15 g, 0.50 mmol) (see, Example 93) was added and the resulting e was heated at 80 °C in a sealed vial for 0.5h, during which reaction the mixture became a yellow solution. The reaction was heated ovemight. The reaction was then cooled to rt. Water (1 g, 60 mmol) and ethyl acetate were added to the mixture. The organic phase was separated and washed with saturated NaHC03 and saturated aqueous NaCl. The washed organic phase was then dried and concentrated to give 387 mg of a crude product as a white glass/oil. The crude product was chromatographcd With 0- % MeOI-I/DCM, 0-1%NH40H to give 0.13 g of the purified product as a white solid (76% yield).
‘H NMR (400 MHz, CDClg): 8 8.7 (1H, s); 8.5 (1H, s); 8.3 (1H, s); 7.4 (1H, d); 7.0 6.75 (1H, d); 5.82 (1H, In); 3.75 (1H, dd); 3.2 (1H, dd). MS (M+H): 341.
A suspension of (3R)-4,4,4-trifluoro—3-[4-(7H-pyrrolo[2,3—d]pyrimidinyl)-lH—pyrazol-l— yl]butanethioamide (0.038 g, 0.00011 mol), chloroacetone (15 uL, 0.00019 mol) in ethanol (1 mL, 0.02 mol) and 1,2-dichloroethane (1 mL, 0.01 mol) was heated to reflux overnight. Following this, the reaction mixture was d to remove insoluble material. The filtrate was dissolved in MeOH (1 -mL) and DMF (1 mL) and purified by prep HPLC at leO to provide 6 mg of the purified product as a ess glass/oil, which was then triturated with MTBE/hexanes and was dried at 40 °C overnight to give 5.2 mg of the purified product as an off-white solid (13% yield). l0 1H NMR (400 MHz, CD013): 8 10.11 (1H, s); 8.88 (1H, s); 8.42 (1H, s); 8.38 (1H, s); 7.45 (1H, d); 6.79 (1H, s); 6.65 (1H, d); 5.41 (1H, m); 4.15 (1H, dd); 3.75 (H, dd); 2.18 (3H, 5). MS (M+H): 379.
Example A: In vitro JAK Kinase Assay Compounds herein were tested for inhibitory activity of JAK targets ing to the following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAKl (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a. 781-1124) with an N~terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAK], JAKZ or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). 10505 of compounds were measured for each kinase in the reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. The ATP tration in the reactions was 90 uM for Jakl, 30 M for Jak2 and 3 M for Jak3. Reactions were carried out at room temperature for 1 hr and then stopped with 20 "L 45 mM EDTA, 300 nM SA—APC, 6 nM Eu-Py20 in assay buffer n Elmer, Boston, MA). g to the um labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, MA). Compounds having an [cm of 10 M or less for any of the above-mentioned JAK targets were considered active.
Example B: ar Assays One or more compounds herein were tested for inhibitory ty ofJAK targets according to at least one of the ing cellular assays.
Cancer cell lines dependent on cytokines and hence AT signal transduction, for growth, were plated at 6000 cells per well (96 well plate format) in RPMI 1640, 10% FBS, and l nG/mL of appropriate cytokine. Compounds were added to the cells in DMSO/media (final concentration 0.2% DMSO) and incubated for 72 hours at 37 °C, 5% 002. The effect of compound on cell viability was assessed using the CellTiter-Glo scent Cell Viability Assay (Promega) followed by nt n Elmer, Boston, MA) quantitation. Potential off—target effects of compounds were measured in parallel using a non-JAK driven cell line with the same assay readout.
Compounds having an 1050 of 10 1.1M or less with selectivity for JAK driven proliferation were ered active. All experiments were performed in duplicate.
The above cell lines can also be used to examine the effects of compounds on phosphorylation of JAK kinases or potential downstream substrates such as STAT proteins, Akt, ShpZ, or Erk. These ments can be performed following an overnight cytokine starvation, followed by a brief preincubation with compound (2 hours or less) and cytokine stimulation of approximately 1 hour or less. Proteins are then extracted from cells and analyzed by ques familiar to those schooled in the art including Western blotting or ELISAs using antibodies that differentiate between orylated and total protein. These experiments can utilize normal or cancer cells to investigate the activity of nds on tumor cell survival biology or on mediators of inflammatory disease. For example, with regards to the latter, cytokines such as IL-6, IL—12, IL—23, or IFN can be used to stimulate JAK activation resulting in phosphorylation of STAT protein(s) and potentially in transcriptional s (assessed by array or qPCR technology) or production and/or secretion of proteins, such as IL—17. The ability of compounds to t these cytokine mediated effects can be measured using techniques common to those schooled in the art.
Compounds herein can also be tested in cellular models designed to evaluate their potency and activity against mutant JAKs, for example, the JAK2V617F mutation found in myeloid erative disorders. These experiments often utilize cytokine dependent cells of hematological lineage (eg. BaF/3) into which the wild-type or mutant JAK kinases are ectopically expressed (James, C., et al. Nature 434:1144-1148; Staerk, J., et a1. JBC 280:41893—41899). Endpoints include the effects of compounds on cell survival, proliferation, and phosphorylated JAK, STAT, Akt, or Erk proteins.
Certain compounds herein have been or can be evaluated for their activity inhibiting T-cell proliferation. Such as assay can be considered a second cytokine (i. e. JAK) driven proliferation assay and also a stic assay of immune suppression or inhibition of immune activation. The following is a brief outline of how such experiments can be performed. Peripheral blood mononuclear cells (PBMCs) are ed from human whole blood samples using Ficoll Hypaque separation method and T—cells (fraction 2000) can be obtained from PBMCs by elutriation. Freshly isolated human T- cells can be maintained in culture medium (RPMI 1640 mented witth% fetal bovine serum, 100 U/ml penicillin, 100 gig/m] streptomycin) at a density of 2 x 106 cells/ml at 37 °C for up to 2 days.
For IL—2 stimulated cell proliferation analysis, T—cells are first treated with Phytohemagglutinin (PHA) at a final concentration of 10 ug/mL for 72h. After washing once with PBS, 6000 Well are plated in 96-well plates and treated with compounds at different concentrations in the culture medium in the presence of 100 U/mL human IL-2 (ProSpec-Tany Gene; Rehovot, Israel). The plates are incubated at 37 °C for 72h and the proliferation index is ed using CellTiter—Glo Luminescent reagents following the manufactory ted protocol (Promega; Madison, WI).
Example C: In vivo anti~tumor efficacy Compounds herein can be ted in human tumor xenografi models in immune compromised mice. For example, a tumorigenic variant of the INA-6 plasmacytoma cell line can be used to inoculate SCID mice subcutaneously (Burger, R., et a1. Hematol J. 2:42—53, 2001). Tumor bearing animals can then be randomized into drug or vehicle ent groups and ent doses of compounds can be administered by any number of the usual routes including oral, i.p., or continuous infusion using implantable pumps. Tumor growth is followed over time using calipers. Further, tumor samples can be harvested at any time alter the initiation of treatment for analysis as described above (Example B) to evaluate compound effects on JAK activity and downstream signaling pathways. In addition, selectivity of the compound(s) can be assessed using xenograft tumor models that are driven by other know kinases (e. g. Bcr—Abl) such as the K562 tumor model.
Example D: Murine Skin Contact Delayed Hypersensitivity Response Test Compounds herein can also be tested for their efficacies (of ting JAK targets) in the T— cell driven murine delayed hypersensitivity test model. The murine skin contact delayed-type hypersensitivity (DTH) response is considered to be a valid model of clinical contact dermatitis, and other T—lymphocyte mediated immune ers of the skin, such as psoriasis ol Today. 1998 Jan;l9(1):37—44). Murine DTH shares multiple characteristics with psoriasis, including the immune infiltrate, the accompanying increase in inflammatory cytokines, and keratinocyte hyperproliferation.
Furthermore, many classes of agents that are ious in treating sis in the clinic are also effective inhibitors of the DTH response in mice s Actions. 1993 Jan;38(1-2):1 16—21).
On Day 0 and l, Balb/c mice are sensitized with a topical application, to their shaved abdomen with the antigen 2,4,dinitro—fluorobenzene (DNFB). On day 5, cars are measured for thickness using an engineer’s eter. This measurement is recorded and used as a baseline. Both of the animals’ ears are then challenged by a topical application of DNFB in a total of 20 ,uL (10 [IL on the internal pinna and 10 ML on the external pinna) at a concentration of 0.2%. Twenty—four to seventy-two hours alter the challenge, ears are measured again. Treatment with the test compounds was given hout the sensitization and nge phases (day -1 to day 7) or prior to and 3O throughout the challenge phase (usually afiemoon of day 4 to day 7). Treatment of the test compounds (in ent concentration) was administered either systemically or topically (topical application of the treatment to the cars). Efficacies of the test compounds are ted by a reduction in ear swelling comparing to the situation without the treatment. Compounds causing a reduction of % or more were considered efficacious. In some experiments, the mice are challenged but not sensitized (negative control).
The inhibitive effect (inhibiting activation of the JAK-STAT pathways) of the test compounds can be confirmed by histochemical analysis. Activation of the JAK~STAT pathway(s) results in the formation and translocation of functional transcription factors. Further, the influx of immune cells and the increased proliferation of keratinocytes should also provide unique expression profile changes in the ear that can be investigated and quantified. Formalin fixed and paraffin embedded ear sections (harvested after the challenge phase in the DTH model) are subjected to immunohistochemical analysis using an dy that specifically interacts with phosphorylated STAT3 (clone 58E12, Cell Signaling Technologies). The mouse ears are treated with test compounds, vehicle, or dexamethasone (a clinically efficacious treatment for psoriasis), or without any treatment, in the DTH model for isons. Test nds and the dexamethasonc can produce similar transcriptional changes both qualitatively and quantitatively, and both the test compounds and thasone can reduce the number of infiltrating cells. Both systemically and tOpical administration of the test compounds can produce inhibitive effects, i.e., reduction in the number of infiltrating cells and inhibition of the transcriptional changes.
Example E: In vivo anti-inflammatory activity Compounds herein can be or have been evaluated in rodent or non—rodent models designed to replicate a single or complex ation response. For instance, rodent models of arthritis can be used to evaluate the therapeutic potential of compounds dosed preventatively or therapeutically.
These models include but are not limited to mouse or rat collagen—induced arthritis, rat adjuvant— induced arthritis, and collagen antibody—induced arthritis. Autoimmune diseases including, but not limited to, multiple sis, type I-diabetes mellitus, uveoretinitis, itis, myasthenia gravis, immunoglobulin pathies, myocarditis, airway sensitization (asthma), lupus, or colitis may also be used to evaluate the therapeutic potential of compounds herein. These models are well established in the research community and are familiar to those ed in the art (Current Protocols in Immunology, Vol 3., Coligan, J.E. et al, Wiley Press; Methods in Molecular y: Vol. 225, Inflammation Protocols, Winyard, P.G. and Willoughby, D.A., Humana Press, 2003.). s modifications of the invention, in addition to those bed herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present ation is incorporated herein by reference in its entirety.

Claims (10)

What is claimed is:
1. 1. A ceutical composition comprising a compound, which is opentyl[4-A pharmaceutical ition comprising a compound, Which is 3—cyclopentyl—3—[4— (7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]propanenitrile, or a ceutically(7H—pyrrolo[2,3—d]pyrimidin—4—yl)—1H—pyrazol—1—yl]propanenitrile, or a pharmaceutically acceptable salt f, and a pharmaceutically acceptable carrier; wherein said composition is ptable salt thereof, and a pharmaceutically acceptable carrier; Wherein said composition is to be orally administered and provides sustained release of said compound or said salt. be orally administered and es sustained release of said compound or said salt.
2. 2. The pharmaceutical composition of claim 1, wherein the compound is (3R)The pharmaceutical composition of claim 1, Wherein the compound is (3R)—3— cyclopentyl[4-(7H-pyrrolo[2,3-d]pyrimidinyl)-1H-pyrazolyl]propanenitrile, or acyclopentyl—3—[4—(7H—pyrrolo[2,3—d]pyrimidin—4—yl)— 1H—pyrazol— 1 —yl]propanenitrile, or a pharmaceutically acceptable salt thereof. pharmaceutically acceptable salt thereof.
3. 3. The pharmaceutical composition of claim 2, wherein said composition is a unit dosageThe pharmaceutical composition of claim 2, Wherein said composition is a unit dosage form. form.
4. 4. The pharmaceutical composition of claim 3, wherein said unit dosage form is a tablet. The pharmaceutical composition of claim 3, Wherein said unit dosage form is a .
5. 5. The pharmaceutical composition of claim 3, wherein said unit dosage form is a capsule. The pharmaceutical composition of claim 3, Wherein said unit dosage form is a capsule.
6. 6. The pharmaceutical composition of claim 3, n said unit dosage form furtherThe pharmaceutical composition of claim 3, Wherein said unit dosage form further comprises an c coating. comprises an enteric coating.
7. 7. The pharmaceutical composition of claim 3, wherein the unit dosage form sesThe pharmaceutical composition of claim 3, Wherein the unit dosage form comprises from about 5 to about 1000 mg of said compound or said salt. from about 5 to about 1000 mg of said compound or said salt.
8. 8. The ceutical composition of claim 2, further comprising one or more excipientsThe pharmaceutical composition of claim 2, further sing one or more excipients selected from lactose, dextrose, e, sorbitol, mannitol, starches, gum acacia, calciumselected from lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, tes, tragacanth, gelatin, calcium silicate, microcrystalline cellulose,phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. polyVinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
9. 9. The pharmaceutical composition of claim 2, further comprising microcrystallineThe pharmaceutical composition of claim 2, further comprising microcrystalline ose. cellulose. 271 271
10. 10. The pharmaceutical composition of claim 2, r comprising lactose. The pharmaceutical composition of claim 2, further comprising lactose. 272 272
NZ762863A 2005-12-13 2006-12-12 Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors NZ762863B2 (en)

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NZ778831A NZ778831A (en) 2005-12-13 2006-12-12 Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
US74990505P 2005-12-13 2005-12-13
US60/749,905 2005-12-13
US81023106P 2006-06-02 2006-06-02
US60/810,231 2006-06-02
US85062506P 2006-10-10 2006-10-10
US60/850,625 2006-10-10
US85687206P 2006-11-03 2006-11-03
US60/856,872 2006-11-03
US85940406P 2006-11-16 2006-11-16
US60/859,404 2006-11-16
NZ74800006 2006-12-12

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NZ762863A true NZ762863A (en) 2021-08-27
NZ762863B2 NZ762863B2 (en) 2021-11-30

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