NZ563687A - 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide for inhibiting IKK2 (aka IKKbeta) - Google Patents

3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide for inhibiting IKK2 (aka IKKbeta)

Info

Publication number
NZ563687A
NZ563687A NZ563687A NZ56368706A NZ563687A NZ 563687 A NZ563687 A NZ 563687A NZ 563687 A NZ563687 A NZ 563687A NZ 56368706 A NZ56368706 A NZ 56368706A NZ 563687 A NZ563687 A NZ 563687A
Authority
NZ
New Zealand
Prior art keywords
indole
carboxamide
piperidinyl
ethylsulfonyl
methyl
Prior art date
Application number
NZ563687A
Inventor
Jianghe Deng
Jeffrey K Kerns
Qi Jin
Guoliang Lin
Xichen Lin
Michael Lindenmuth
Christopher E Neipp
Hong Nie
Sonia M Thomas
Katherine L Widdowson
Original Assignee
Smithkline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corp filed Critical Smithkline Beecham Corp
Publication of NZ563687A publication Critical patent/NZ563687A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

Disclosed is 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide of formula (I), as defined in the specification.

Description

New Zealand Paient Spedficaiion for Paient Number 563687 Received at IPONZ on 15 June 2011 INDOLE CARBOXAMIDE COMPOUNDS USEFUL AS IKK2 INHIBITORS FIELD OF THE INVENTION The invention is directed to certain indole carboxamide compounds, which are inhibitors 5 of kinase activity. More specifically, the compounds are IKK2 inhibitors. These compounds are useful in the treatment of disorders associated with inappropriate IKK2 (also known as IKK(3) activity, in particular in the treatment and prevention of disorders mediated by IKK2 mechanisms including inflammatory and tissue repair disorders. Such disorders include rheumatoid arthritis, asthma, and COPD (chronic obstructive pulmonary 10 disease).
BACKGROUND OF THE INVENTION An important large family of enzymes is the protein kinase enzyme family. Currently, there are about 500 different known protein kinases. However, because three to four 15 percent of the human genome is a code for the formation of protein kinases, there may be many thousands of distinct and separate kinases in the human body. Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the y-phosphate of the ATP-Mg2+ complex to said amino acid side chain. These enzymes control the majority of the signaling processes inside cells, thereby 20 governing cell function, growth, differentiation and destruction (apoptosis) through reversible phosphorylation of the hydroxyl groups of serine, threonine and tyrosine residues in proteins. Studies have shown that protein kinases are key regulators of many cell functions, including signal transduction, transcriptional regulation, cell motility, and cell division. Several oncogenes have also been shown to encode protein kinases, 25 suggesting that kinases play a role in oncogenesis. These processes are highly regulated, often by complex intermeshed pathways where each kinase will itself be regulated by one or more kinases. Consequently, aberrant or inappropriate protein kinase activity can contribute to the rise of disease states associated with such aberrant kinase activity. Due to their physiological relevance, variety and ubiquitousness, protein kinases 30 have become one of the most important and widely studied family of enzymes in biochemical and medical research.
The protein kinase family of enzymes is typically classified into two main subfamilies: Protein Tyrosine Kinases and Protein Serine/Threonine Kinases, based on the amino 35 acid residue they phosphorylate. The serine/threonine kinases (PSTK), includes cyclic 1 Received at IPONZ on 15 June 2011 AMP- and cyclic GMP-dependent protein kinases, calcium and phospholipid dependent protein kinase, calcium- and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins. Aberrant 5 protein serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases. Accordingly, serine/threonine kinases and the signal transduction pathways which they are part of are important targets for drug design. The tyrosine kinases phosphorylate tyrosine residues. Tyrosine kinases play an equally 10 important role in cell regulation. These kinases include several receptors for molecules such as growth factors and hormones, including epidermal growth factor receptor, insulin receptor, platelet derived growth factor receptor and others. Studies have indicated that many tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Much work is also 15 under progress to identify modulators of tyrosine kinases as well.
Nuclear factor kB (NF-kB) belongs to a family of closely related dimeric transcription factor complexes composed of various combinations of the Rel/NF-KB family of polypeptides. The family consists of five individual gene products in mammals, RelA 20 (p65), NF-kB1 (p50/ p105), NF-kB2 (p49/ p100), c-Rel, and RelB, all of which can form hetero- or homodimers. These proteins share a highly homologous 300 amino acid "Rel homology domain" which contains the DNA binding and dimerization domains. At the extreme C-terminus of the Rel homology domain is a nuclear translocation sequence important in the transport of NF-kB from the cytoplasm to the nucleus. In addition, p65 25 and cRel possess potent transactivation domains at their C-terminal ends.
The activity of NF-kB is regulated by its interaction with a member of the inhibitor IkB family of proteins. This interaction effectively blocks the nuclear localization sequence on the NF-kB proteins, thus preventing migration of the dimer to the nucleus. A wide variety 30 of stimuli activate NF-kB through what are likely to be multiple signal transduction pathways. Included are bacterial products (LPS), some viruses (HIV-1, HTLV-1), inflammatory cytokines (TNFa, IL-1), environmental and oxidative stress and DNA damaging agents. Apparently common to all stimuli however, is the phosphorylation and subsequent degradation of IkB. IkB is phosphorylated on two N-terminal serines by the 35 recently identified IkB kinases (IKK-a and IKK-(3). IKK-(3 is also known as IKK2. Site- Received at IPONZ on 15 June 2011 directed mutagenesis studies indicate that these phosphorylations are critical for the subsequent activation of NF-kB in that once phosphorylated the protein is flagged for degradation via the ubiquitin-proteasome pathway. Free from IkB, the active NF-kB complexes are able to translocate to the nucleus where they bind in a selective manner to 5 preferred gene-specific enhancer sequences. Included in the genes regulated by NF-kB are a number of cytokines and chemokines, cell adhesion molecules, acute phase proteins, immunoregualtory proteins, eicosanoid metabolizing enzymes and anti-apoptotic genes.
It is well-known that NF-kB plays a key role in the regulated expression of a large number of pro-inflammatory mediators including cytokines such as TNF, IL-1 (3, IL-6 and IL-8, cell adhesion molecules, such as ICAM and VCAM, and inducible nitric oxide synthase (iNOS). Such mediators are known to play a role in the recruitment of leukocytes at sites of inflammation and in the case of iNOS, may lead to organ destruction in some 15 inflammatory and autoimmune diseases.
The importance of NF-kB in inflammatory disorders is further strengthened by studies of airway inflammation including asthma, in which NF-kB has been shown to be activated. This activation may underlie the increased cytokine production and leukocyte infiltration 20 characteristic of these disorders. In addition, inhaled steroids are known to reduce airway hyperresponsiveness and suppress the inflammatory response in asthmatic airways. In light of the recent findings with regard to glucocorticoid inhibition of NF-kB, one may speculate that these effects are mediated through an inhibition of NF-kB.
Further evidence for a role of NF-kB in inflammatory disorders comes from studies of rheumatoid synovium. Although NF-kB is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-kB is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium. Furthermore, NF-kB has been shown to be activated in human synovial cells in response to stimulation 30 with TNF-a or IL-1 (3. Such a distribution may be the underlying mechanism for the increased cytokine and eicosanoid production characteristic of this tissue. See Roshak, A. K., et al., J. Biol. Chem., 271, 31496-31501 (1996). Expression of IKK-|3 has been shown in synoviocytes of rheumatoid arthritis patients and gene transfer studies have demonstrated the central role of IKK-(3 in stimulated inflammatory mediator production in 35 these cells. See Aupperele et al. J. Immunology 1999. 163:427-433 and Aupperle et al.
Received at IPONZ on 15 June 2011 J. Immunology 2001;166:2705-11. More recently, the intra-articular administration of a wild type IKK-(3 adenoviral construct was shown to cause paw swelling while intraarticular administration of dominant-negative IKK(3 inhibited adjuvant-induced arthritis in rat. See Tak et al. Arthritis and Rheumatism 2001, 44:1897-1907.
The NF-kb/Rel and IkB proteins are also likely to play a key role in neoplastic transformation and metastasis. Family members are associated with cell transformation in vitro and in vivo as a result of over expression, gene amplification, gene rearrangements or translocations. In addition, rearrangement and/or amplification of the genes encoding 10 these proteins are seen in 20-25% of certain human lymphoid tumors. Further, NF-kB is activated by oncogenic ras, the most common defect in human tumors and blockade of NF-kB activation inhibits ras mediated cell transformation. In addition, a role for NF-kB in the regulation of apoptosis has been reported strengthening the role of this transcription factor in the regulation of tumor cell proliferation. TNF, ionizing radiation and DNA 15 damaging agents have all been shown to activate NF-kB which in turn leads to the upregulated expression of several anti-apoptotic proteins. Conversely, inhibition of NF-kB has been shown to enhance apoptotic-killing by these agents in several tumor cell types. As this likely represents a major mechanism of tumor cell resistance to chemotherapy, inhibitors of NF-kB activation may be useful chemotherapeutic agents as 20 either single agents or adjunct therapy. Recent reports have implicated NF-kB as an inhibitor of skeletal cell differentiation as well as a regulator of cytokine-induced muscle wasting (Guttridge et al. Science; 2000; 289: 2363-2365.) further supporting the potential of NFkB inhibitors as novel cancer therapies.
Several NF-kB inhibitors are described in C. Wahl, et al. J. Clin. Invest. 101(5), 1163-1174 (1998), R. W. Sullivan, etai. J. Med. Chem. 41, 413-419 (1998), J. W. Pierce, etai. J. Biol. Chem. 272, 21096-21103 (1997).
The marine natural product hymenialdisine is known to inhibit NF-kB. Roshak, A., etai., 30 JPET, 283, 955-961 (1997). Breton, J. J and Chabot-Fletcher, M. C., JPET, 282, 459-466 (1997).
Additionally, patent applications have been filed on aminothiophene inhibitors of the IKK2, see Callahan, et al., WO 2002030353; Baxter, et al., WO 2001058890, Faull, etai., WO 35 2003010158; Griffiths, etai., W02003010163; Fancelli, etai., WO 200198290; Granetto, 4 Received at IPONZ on 15 June 2011 et al., WO 2003037886; imidazole inhibitors of IKK2, see Callahan, et al., WO 200230423; anilinophenylpyrimidine inhibitors of IKK2, see Kois, et al., WO 2002046171; (3-carboline inhibitors of IKK2 , see Ritzeler, et al, WO 2001068648, Ritzeler, et al, EP 1134221; Nielsch, etai. DE 19807993; Ritzeler, etai., EP 1209158; indole inhbitors of 5 IKK2, see Ritzeler, etai., WO 2001030774; benzimidazole inhibitors of the IKK2, see Ritzeler, etai., DE 19928424; Ritzeler et al, WO 2001000610; Ritzeler, etai., WO 2004022553; aminopyridine inhibitors of IKK2, see Lowinger, et al, WO 2002024679; Murata, et al, WO 2002024693; Murata, et al., WO 2002044153; aminopyrimidine inhibitors of IKK2, see Bollbuck, et al., WO 2004089913; pyrazole inhibitors of IKK2, see 10 Bergmanis, et al., WO 2003024935;, Metz, et al., WO 2003024936; Geng et al., WO 2003027075; Stealey, etai., WO 2003035625; Xu, etai., WO 200307076; Lennon, etai., WO 2003095430; pyrazinone inhibitors of IKK2, see Boys, et al., WO 2005035527; pyrazolaquinazoline inhibitors of IKK2, see Beaulieu, et al., WO 2002028860; Burke et al, WO 2002060386; Burke, etai. US 20030022898; thiophene tricyclic inhibitors of IKK2, 15 see Belema, et al., WO 2003084959; pyrazolopurine inhibitors of IKK2, see Qiu, et al., WO 2004075846; oxazolo and thiazolo pyridine inhibitors of IKK2, see Pitts, et al., WO 2004106293; quinoline inhibitors of IKK2, Browner, et al., W02002041843, Browner, et al., US 20020161004 and pyridylcyanoguanidine inhibitors of IKK2, see Bjorkling, et al., WO 2002094813, Binderup etai, WO 2002094322 and Madsen, etai., WO 200294265; 20 thienopyridine inhibitors of IKK2, see Cywin, et al., WO 2003103661; Liu, et al., WO 2005035537; benzothiophene inhibitors of IKK2, see Chen et al., WO 2005012283; .The natural products staurosporine, quercetin, K252a and K252b have been shown to be IKK2 inhibitors, see Peet, G. W. and Li, J. J. Biol. Chem., 274, 32655-32661 (1999) and Wisniewski, D., et al., Analytical Biochem. 21 A, 220-228 (1999). Synthetic inhibitors of 25 IKK2 have also been described, see Burke, et al. J. Biol. Chem., 278, 1450-1456 (2003), Murata, etai., Bioorg. Med. Chem. Lett., 13, 913-198 (2003), Murata, et al., Bioorg. Med. Chem. Lett., 14, 4013-4017 (2004), and Murata, etai., Bioorg. Med. Chem. Lett, 14, 4019-4022 (2004) have described IKK2 inhibitors.
Thus, attempts have been made to prepare compounds that inhibit IKK2 activity and a number of such compounds have been disclosed in the art. However, in view of the number of pathological responses that are mediated by IKK2, there remains a continuing need for inhibitors of IKK2 which can be used in the treatment of a variety of conditions.
Received at IPONZ on 15 June 2011 The present inventors have discovered novel indole carboxamide compounds, which are inhibitors of kinase activity, in particular inappropriate IKK2 activity. Such indole carboxamide derivatives are therefore useful in the treatment of disorders associated with inappropriate kinase, in particular inappropriate IKK2 activity in particular in the treatment 5 and prevention of disease states mediated by IKK2 mechanisms including inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage; autoimmune diseases including systemic lupus 10 eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia 15 Telangiestasia.
SUMMARY OF THE INVENTION The invention is directed to novel indole carboxamide derivatives. Specifically, the invention is directed to compounds according to formula (I): where R1, R2, R3, U and V are defined below and to pharmaceutical^ acceptable salts thereof.
Certain aspects of the invention are claimed in this specification. Other aspects of the invention are claimed in New Zealand patent specification 592813, which is divided from this specification.
The compounds of the invention are inhibitors of IKK2 and can be useful in the treatment 30 of disorders associated with inappropriate IKK2 (also known as IKK(3) activity, such as rheumatoid arthritis, asthma, and COPD (chronic obstructive pulmonary disease). Accordingly, the invention is further directed to pharmaceutical compositions comprising a R2 u^V (I) 6 Received at IPONZ on 15 June 2011 compound of the invention. The invention is still further directed to methods of inhibiting IKK2 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
DETAILED DESCRIPTION OF THE INVENTION The invention is directed to compounds according to formula (I): R5 \ N where R1 is the group -XYZ or X is phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, or 2,3-dihydro-1H-indenyl, where said phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, and 2,3-dihydro-1H-indenyl are optionally substituted with one or two substituents each independently selected from the following: 1) halo, 2) nitro, 3) cyano, 4) -NR7R8, ) C-|-Cg-alkyl, 6) CHO, 7) CONH2, and 8) -OR4, where said C-j-Cg-alkyl is optionally substituted with one -NR4R5 group; Y is a bond or C-i-Cq alkylene, where C-j-Cg alkylene is optionally substituted with one or two substituents each independently selected from the following: 7 r5 I Received at IPONZ on 15 June 2011 1) C-|-C3-alkyl optionally substituted by one OR4 group, 2) c3-c7-cycloalkyl, 3) methoxy, 4) hydroxy, and ) heteroaryl; Z is -NR4R5 or heterocycloalkyi, where said heterocycloalkyi is optionally substituted with one or two substituents each independently selected from the following: 1) C-|-Cg-alkyl optionally substituted by one or4 or one heterocycloalkyi group, 2) C3-C7-cycloalkyl, 3) methoxy, 4) -conh2 ) hydroxy, 6) heteroaryl, 7) cf3, 8) phenyl, 9) heterocycloalkyi, and ) n(ch3)2; R2 is selected from 1) H, 2) fluoro, and 25 3) chloro; R3 is selected from 1) H, 2) fluoro, and 30 3) chloro; R4 is selected from 1) Hand 2) CrC6-alkyl, 8 Received at IPONZ on 15 June 2011 where said C-|-C§-alkyl is optionally substituted with one hydroxy or one methoxy group; R5 is selected from 1) H, 2) C5-C6-heterocycloalkyl, 3) -C02Et, 4) C-j-CQ-alkoxy, ) c3-c7-cycloalkyl, 6) C-|-Cg-alkyl, 7) -SO2RIO, and 8) -C(0)R10, where said C3-C7-cycloalkyl and C-|-C0-alkyl are optionally substituted with one to three substituents selected from R6; each R6 is independently selected from 1) -nr7r8, 2) -s02r7, 3) -conh2 4) -cf3, ) -cn, 6) -c02r7, 7) -och2ch2or7, 8) -sr5, 9) c3-c4 alkenyl, ) oh, 11) C-|-Cg-alkoxy, 12) heteroaryl, 13) C3-C7-cycloalkyl, 14) phenyl, ) heterocycloalkyi, and 16) halo, where said heteroaryl, cycloalkyi, phenyl and heterocycloalkyi are optionally substituted with one to two substituents selected from R9; 9 Received at IPONZ on 15 June 2011 R7 is selected from 1) H, 2) C-|-c3-alkyl, and 5 3) phenyl; R8 is selected from 1) H, 2) C-|-c3-alkyl, and 10 3) -C(0)R4; each R9 is independently selected from 1) hydroxy, 2) -OMe, 3) nitro, 4) C-|-C0-alkyl, ) nh2, 6) halo, 7) cf3, 8) C-|-Cg-alkoxy, and 9) cn; R10 is selected from 1) h, 2) C-|-Cg-alkyl, 3) phenyl, 4) c3-c7-cycloalkyl, ) heteroaryl, 6) C-i-Cg-heteroaryl, i 7) heterocycloalkyi, where said C-|-Cg-alkyl is optionally substituted with one or two substituents each independently selected from C3-C7-cycloalkyl and -S-R7; where said heterocycloalkyi is Received at IPONZ on 15 June 2011 optionally substituted with one -C(0)R7 group; and where said phenyl, heteroaryl and C-|-Cg-heteroaryl are optionally substituted with one to two substituents selected from R11; each R11 is independently selected from 5 1) H, 2) C-|-Cg-alkyl, and 3) halo; U is a bond, C-|-Cg alkylene or C2-Cg alkenylene; V is phenyl, 5 or 6 membered heteroaryl, 5-7 membered heterocycloalkyi, C5-C7 cycloalkyi, or c5-c7 cycloalkenyl, each of which is substituted by -N(R7)S(0)mR12, -S(0)mN(R7)R12, -S(0)mR12, or-C(0)R12; m is 1 or 2; and R12 is C-|-Cg-alkyl, C3-C7 cycloalkyi, C-|-Cg-alkyl-C3-C7cycloalkyl, or C-|-Cg-alkyl-phenyl; or a pharmaceutical^ acceptable salt thereof.
One embodiment of the present invention is a compound according to formula (I): where R1 is the group -XYZ; X is phenyl or heteroaryl, where said phenyl and heteroaryl are optionally substituted with one or two substituents each independently selected from the following: 1) halo, 2) nitro, 3) cyano, 4) -NR7R8, ) C-|-Cg-alkyl, 6) CHO, 7) CONH2, and 8) -OR4, where said C-|-Cg-alkyl is optionally substituted with one -NR4R5 group; 11 Received at IPONZ on 15 June 2011 Y is a bond or C-|-Cg alkylene, where C-|-Cg alkylene is optionally substituted with one or two substituents each independently selected from the following: 1) C-|-C3-alkyl optionally substituted by one OR4 group, 2) C3-C7-cycloalkyl, 3) methoxy, 4) hydroxy, and ) heteroaryl; Z is-NR4R5 or heterocycloalkyi, where said heterocycloalkyi is optionally substituted with one or two substituents each independently selected from the following: 1) C-|-Cg-alkyl optionally substituted by one OR4 group, 2) C3-C7-cycloalkyl, 3) methoxy, 4) hydroxy, and ) heteroaryl; R2 is selected from 20 1) H, 2) fluoro, and 3) chloro; R3 is selected from 25 1) H, 2) fluoro, and 3) chloro; R4 is selected from 30 1) Hand 2) C1 -Cg-alkyl, where said C-|-Cg-alkyl is optionally substituted with one hydroxy or one methoxy group; 12 Received at IPONZ on 15 June 2011 R5 is selected from 1) H, 2) C-j-Ce-alkoxy, 3) C3-C7-cycloalkyl, 4) C-|-C6-alkyl, ) -S02R10, and 6) -C(0)R10, where said C3-C7-cycloalkyl and C-j-CQ-alkyl are optionally substituted with one to three substituents selected from R6; each R6 is independently selected from 1) -NR7R8, 2) -S02R7, 3) OH, 4) methoxy, ) heteroaryl, 6) C3-C7-cycloalkyl, 7) phenyl, 8) heterocycloalkyi, and 9) halo, where said heteroaryl, cycloalkyi, phenyl and heterocycloalkyi are optionally substituted with one to two substituents selected from R9; R7 is selected from 25 1) Hand 2) C-|-C3-alkyl; R8 is selected from 1) Hand 30 2) C-|-C3-alkyl; each R9 is independently selected from 1) hydroxy, 2) nitro, 13 Received at IPONZ on 15 June 2011 3) C-|-Cg-alkyl, 4) nh2, ) halo, 6) cf3, 7) C-|-Cg-alkoxy, and 8) CN; R10 is selected from 1) H, 2) CrC6-alkyl, 3) phenyl, 4) C3-C7-cycloalkyl, and ) heteroaryl, where said C-| -Cg-alkyl is optionally substituted with one or two substituents each independently selected from C3-C7-cycloalkyl and -S-R7; where said heterocycloalkyi is optionally substituted with one -C(0)R7 group; and where said phenyl and heteroaryl are optionally substituted with one to two substituents selected from R11; each R11 is independently selected from 1) H, 2) C-j-CQ-alkyl, and 3) halo; U is a bond, C-j-Cg alkylene or C2-C0 alkenylene; V is phenyl, 5 or 6 membered heteroaryl, 5-7 membered heterocycloalkyi, C5-C7 cycloalkyi, or C5-C7 cycloalkenyl, each of which is substituted by -N(R7)S(0)mR12, -S(0)mN(R7)R12, -S(0)mR12, or-C(0)R12; m is 1 or 2; and R12 is C-|-Cg-alkyl, C3-C7 cycloalkyi, C-|-C0-alkyl-C3-C7cycloalkyl, or C-|-C0-alkyl-phenyl; or a pharmaceutical^ acceptable salt thereof. 14 Received at IPONZ on 15 June 2011 Another embodiment of the present invention is a compound according to formula (I): R5 where R1 is the group -XYZ or ^ or X is phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, or 2,3-dihydro-1H-indenyl; 5 Y is a bond or C-i-Cq alkylene; Z is -NR4R5 or heterocycloalkyi, where said heterocycloalkyi is optionally substituted with one or two substituents each independently selected from the following: 1) C-j-CQ-alkyl optionally substituted by one OR4 or one heterocycloalkyi group, 2) C3-C7-cycloalkyl, 3) methoxy, 4) -CONH2 ) hydroxy, 6) heteroaryl; 7) CF3, 8) phenyl, 9) heterocycloalkyi, and ) N(CH3)2; R2 is H; R3 is H; R4 is selected from 1) Hand 2) CrC6-alkyl, where said C-|-Cg-alkyl is optionally substituted with one hydroxy or one methoxy group; R5 is selected from Received at IPONZ on 15 June 2011 1) H, 2) Cs-Cg-heterocycloalkyI, 3) -C02Et, 4) C-|-Cg-alkoxy, ) C3-C7-cycloalkyl, 6) C-| -Cg-alkyl, 7) -SO2RIO, and 8) -C(0)R10, where said C3-C7-cycloalkyl and C-|-Cg-alkyl are optionally substituted with one 10 to three substituents selected from R6; each R6 is independently selected from 1) -NR7R8, 2) -S02R7, 3) -conh2, 4) -cf3, ) -CN, 6) -C02R7, 7) -OCH2CH2OR7, 8) -SR5, 9) C3-C4 alkenyl, ) OH, 11) C-|-Cg-alkoxy, 12) heteroaryl, 13) C3-C7-cycloalkyl, 14) phenyl, ) heterocycloalkyi, and 16) halo, where said heteroaryl, cycloalkyi, phenyl and heterocycloalkyi are optionally 30 substituted with one to two substituents selected from R9; R7 is selected from 1) H, 2) C-|-C3-alkyl, and 16 Received at IPONZ on 15 June 2011 3) phenyl; R8 is selected from 1) H, 5 2) C-|-C3-alkyl, and 3) -C(0)R4; each R9 is independently selected from 1) hydroxy, 2) -OMe 3) nitro, 4) C-|-Cg-alkyl, ) nh2, 6) halo, 7) cf3, 8) C-|-Cg-alkoxy, and 9) CN; R10 is selected from 1) h, 2) C-| -Cg-alkyl, 3) phenyl, 4) C3-C7-cycloalkyl, ) heteroaryl, 6) C-|-Cg-heteroaryl, and 7) heterocycloalkyi, where said C-|-Cg-alkyl is optionally substituted with one or two substituents each independently selected from C3-C7-cycloalkyl and -S-R7; where said heterocycloalkyi is optionally substituted with one -C(0)R7 group; and where said phenyl, heteroaryl and C-|-30 Cg-heteroaryl are optionally substituted with one to two substituents selected from R11; each R11 is independently selected from 1) H, 17 Received at IPONZ on 15 June 2011 2) C-|-C0-alkyl, and 3) halo; U is a bond; V is a 5-7 membered heterocycloalkyi substituted by -S(0)mR12; m is 1 or 2; and R12 is C-|-Cg-alkyl; or a pharmaceutical^ acceptable salt thereof.
Another embodiment of the present invention is a compound according to formula (I): 10 where R1 is the group-XYZ; X is phenyl or heteroaryl; Y is a bond or C-|-C0 alkylene; Z is -NR4R5 or heterocycloalkyi, where said heterocycloalkyi is optionally substituted with one or two substituents 15 each independently selected from the following: 1) C-|-C0-alkyl optionally substituted by one OR4 group, 2) C3-C7-cycloalkyl, 3) methoxy, 4) hydroxy, and ) heteroaryl; is H; is H; is selected from 1) Hand 2) C-|-C6-alkyl, where said C-|-Cg-alkyl is optionally substituted with one hydroxy or one methoxy 30 group; R5 is selected from 1) H, 2) C-|-Cg-alkoxy, R2 R3 R4 18 Received at IPONZ on 15 June 2011 3) C3-C7-cycloalkyl, 4) C-|-C6-alkyl, ) -SO2R10, and 6) -C(0)R10, where said C3-C7-cycloalkyl and C-|-Cg-alkyl are optionally substituted with one to three substituents selected from R6; each R6 is independently selected from 1) NR7R8, 2) S02R7, 3) OH, 4) methoxy, ) heteroaryl, 6) C3-C7-cycloalkyl, 7) phenyl, 8) heterocycloalkyi, and 9) halo, where said heteroaryl, cycloalkyi, phenyl and heterocycloalkyi are optionally substituted with one to two substituents selected from R9; R7 is selected from 1) Hand 2) C^-alkyl; R8 is selected from 1) Hand 2) C-|-C3-alkyl; each R9 is independently selected from 30 1) hydroxy, 2) nitro, 3) C-|-Cg-alkyl, 4) NH2, ) halo, 19 Received at IPONZ on 15 June 2011 6) CF3, 7) C-j-Ce-alkoxy, and 8) CN; R10 is selected from 1) H, 2) CrC6-alkyl, 3) phenyl, 4) C3-C7-cycloalkyl, and 10 5) heteroaryl, where said C-|-Cg-alkyl is optionally substituted with one or two substituents each independently selected from C3-C7-cycloalkyl and -S-R7; where said heterocycloalkyi is optionally substituted with one -C(0)R7 group; and where said phenyl and heteroaryl are optionally substituted with one to two substituents selected from R11; each R11 is independently selected from 1) H, 2) C-|-C0-alkyl, and 3) halo; U is a bond; V is a 5-7 membered heterocycloalkyi substituted by -S(0)mR12; m is 1 or 2; and R12 is C-|-C0-alkyl; or a pharmaceutical^ acceptable salt thereof.
Another embodiment of the present invention is a compound of formula (I) where: where R1 is the group -XYZ; X is 2- or 3- thiophenyl; Y is a bond or C-1-C4 alkylene; Z is-NR4R5 or heterocycloalkyi, 1) C-j-CQ-alkyl optionally substituted by one OR4 or one heterocycloalkyi group, 2) C3-C7-cycloalkyl, 3) methoxy, Received at IPONZ on 15 June 2011 4) -CONH2 ) hydroxy, 6) heteroaryl; 7) CF3, 8) phenyl, 9) heterocycloalkyi, and ) n(ch3)2; R2 is H; 10 R3 is H; R4 is selected from 1) Hand 2) C-,-Cg-alkyl, where said C-|-Cg-alkyl is optionally substituted with one hydroxy or one methoxy group; R5 is selected from 1) C3-c7-cycloalkyl, 2) C-|-C6-alkyl, where said C3-c7-cycloalkyl and C-|-Cg-alkyl are optionally substituted with one to three substituents selected from R6; each R6 is independently selected from 1) -NR7R8, 2) -conh2, 3) -CN, 4) -OCH2CH2OR7, ) C3-C4 alkenyl, 6) OH, 7) C-|-Cg-alkoxy, 8) heteroaryl, 9) C3-c7-cycloalkyl, ) phenyl, 21 Received at IPONZ on 15 June 2011 11) heterocycloalkyi, and 12) halo, where said heteroaryl, cycloalkyi, phenyl and heterocycloalkyi are optionally substituted with one to two substituents selected from R9; R7 is selected from 1) H, 2) C-|-C3-alkyl, and 3) phenyl; R8 is selected from 1) H, 2) C-|-C3-alkyl, and 3) -C(0)R4; each R9 is independently selected from 1) C-|-Cg-alkyl; U is a bond; V is 4-piperidinyl substituted by -S(0)2R12; and R12 is ethyl or isopropyl; or a pharmaceutical^ acceptable salt thereof.
Another embodiment of the present invention is a compound according to formula (I) o ii n w r12 O where the group U-V is and R12 is ethyl or isopropyl.
Another embodiment of the present invention is a compound of formula (II) 22 Received at IPONZ on 15 June 2011 r13 (II) where R13 is -NR14R15 or heterocycloalkyi where said heterocycloalkyi is optionally substituted with one or two substituents selected from the following: 1) C-|-Cg-alkyl optionally substituted by one OR14 group, 2) hydroxy, 3) methoxy, and 4) heteroaryl; R14 is selected from 1) Hand 2) C-,-Cg-alkyl, where said C-|-Cg-alkyl is optionally substituted with one hydroxyl or one methoxy group; R15 is selected from 1) H, 2) methoxy, 3) C3-C7 cycloalkyi, and 20 4) C-|-Cg-alkyl, where said C3-C7cycloalkyl and C-|-Cg-alkyl are optionally substituted with one to three substituents selected from R16; each R16 is independently selected from 25 1) -NR17R18, 2) -S02R17, 23 Received at IPONZ on 15 June 2011 3) OH, 4) methoxy ) heteroaryl, 6) C3-C7cycloalkyl, 7) phenyl, and 8) heterocycloalkyi, where said heteroaryl, cycloalkyi, phenyl and heterocycloalkyi are optionally substituted with one to three substituents selected from R19; R17 is selected from 1) Hand 2) C-|-C3-alkyl; R18 is selected from 15 1) Hand 2) C-,-C3-alkyl; R19 is selected from 1) hydroxy, 2) nitro, 3) C-|-C0-alkyl, 4) nh2, ) halo, 6) CF3, and 7) C-|-Cg-alkoxy; and n is 1 to 3; or a pharmaceutical^ acceptable salt thereof.
Specific examples of compounds of the present invention include the following: 30 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperazinylmethyl)phenyl]-1/-/-indole-7-carboxamide; 24 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({methyl[2-(methylsulfonyl)ethyl]amino} methyl)phenyl]-1/-/-indole-7-carboxamide; 5 5-(3-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(4-{2-[(2-hydroxyethyl)oxy]ethyl}-1-piperazinyl)methyl]phenyl}-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[3-(hydroxymethyl)-1-piperidinyl]methyl} phenyl)-10 1/-/-indole-7-carboxamide; -[3-({bis[2-(methyloxy)ethyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; -{3-[(2,6-dimethyl-4-morpholinyl)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(1,3-thiazol-2-yl)-1 -pyrrolidinyl] methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(2-thienyl)-1-pyrrolidinyl]methyl} phenyl)-1 /-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-2-phenylethyl)(methyl) 20 amino]methyl}phenyl)-1 /-/-indole-7-carboxamide; -(3-{[ethyl(methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; -[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; 5-{3-[(cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-25 carboxamide; -[3-({[(3,4-dihydroxyphenyl)methyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino] methyl}phenyl)-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-(hydroxymethyl)-3-methylbutyl]amino}methyl)phenyl]-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-1-methylethyl) amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(fra/7s-4-hydroxycyclohexyl) amino]methyl}phenyl)-35 1/-/-indole-7-carboxamide; Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[({[1-(1-piperidinyl)cyclohexyl] methyl}amino)methyl]phenyl}-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-hydroxypropyl]amino} methyl)phenyl]-1/-/-indole-7-carboxamide; 5 5-{3-[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(propylamino)methyl]phenyl}-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1-methylethyl)amino] methyl}phenyl)-1/-/-indole-7-10 carboxamide; -(3-{[(1-ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(1 -piperidinylmethyl)phenyl]-1 /-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-piperidinylmethyl)phenyl]-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylamino)methyl]phenyl}-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyl]-1/-/-indole-7-20 carboxamide; -[4-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1/-/-indole-7- carboxamide; -{3-[(cyclopropylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-25 carboxamide; -{3-[(cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; 3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-[4-(1-piperidinylmethyl)phenyl]-1 H-indole-7-carboxamide; 30 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(2-methylpropyl)amino]-2,3-dihydro-1H-inden-5-yl}-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{8-[(2-methylpropyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl}-1H-indole-7-carboxamide; -(5-{[(2-cyanoethyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-35 indole-7-carboxamide; 26 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1,2,3,4-tetrahydro-7-isoquinolinyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; -(3-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2,2,2-trifluoroethyl)amino]methyl}-1,3-thiazol-4-10 yl)-1H-indole-7-carboxamide; -(3-cyano-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-piperidinyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; 15 5-(5-{[(2-cyanoethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -(5-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(phenylsulfonyl)ethyl]amino}methyl)-3-20 thienyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(1-piperidinylmethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-1 H-indole-7-carboxamide; 25 5-(5-{[(2R)-2-(aminocarbonyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -(5-{[(2S)-2-(dimethylamino)-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -(1-{2-[4-(dimethylamino)-1-piperidinyl]ethyl}-1H-pyrazol-4-yl)-3-[1-(ethylsulfonyl)-4-30 piperidinyl]-1 H-indole-7-carboxamide; -[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -[3,4-bis(methyloxy)-5-(4-morpholinylmethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 27 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4,5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4,5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide; 5 5-[3-{[(2,2-dimethylpropyl)amino]methyl}-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(2-hydroxyethyl)(methyl)amino]methyl}-4,5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide; -[3,4-bis(methyloxy)-5-(1-pyrrolidinylmethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-10 1 H-indole-7-carboxamide; -{4-[(dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(1-methylethyl)amino]methyl}-2,3-dihydro-1-benzofuran-6-yl)-1 H-indole-7-carboxamide; 15 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)-2,3-dihydro-1- benzofuran-6-yl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[1-methyl-2-(methyloxy)ethyl]amino}methyl)-2-thienyl]-1H-indole-7-carboxamide; -(5-{[(2-cyanoethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-20 indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2,2,2-trifluoroethyl)amino]methyl}-3-pyridinyl)-1 H-indole-7-carboxamide; -{3-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- indole-7-carboxamide; -(5-{[[2-(diethylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -(5-{[butyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-30 indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(propyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; -(5-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 28 Received at IPONZ on 15 June 2011 -(5-{[[3-(dimethylamino)propyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1 H-indole-7-carboxamide; -(5-{[cyclopentyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(pentyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-methylpropyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(phenylmethyl)amino]methyl}-3-thienyl)-10 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-hydroxyethyl)(methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(2-pyridinyl)ethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 15 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-furanylmethyl)(methyl)amino]methyl}-3- thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(4-pyridinylmethyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; ; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methyl{[1-(1-methylethyl)-3-20 pyrrolidinyl]methyl}amino)methyl]-3-thienyl}-1 H-indole-7-carboxamide; ; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-thienylmethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[1-(2-thienyl)ethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 25 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(3-thienylmethyl)amino]methyl}-3- thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; trifluoroacetate 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(3-pyridinylmethyl)amino]methyl}-3-30 thienyl)-1H-indole-7-carboxamide; trifluoroacetate 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(4-pyrimidinylmethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(methyloxy)ethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 29 Received at IPONZ on 15 June 2011 -{3-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylethyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; 5 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(3-pyridinyl)-1-pyrrolidinyl]methyl}-3-thienyl)-1 H-indole-7-carboxamide; -(5-{[2-(1,1 -dimethy lethyl)-1 -pyrrolidinyl]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-10 piperidinyl]-1 H-indole-7-carboxamide; -{5-[(2-ethyl-1-pyrrolidinyl)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1-pyrrolidinyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 15 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(1-methylethyl)-1-pyrrolidinyl]methyl}-3- thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2S)-2-[(methyloxy)methyl]-1-pyrrolidinyl}methyl)-3-thienyl]-1 H-indole-7-carboxamide; -(5-{[cyclohexyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-20 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1-pyrrolidinyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; -(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(propyl)amino]methyl}-3-thienyl)-1 H- indole-7-carboxamide; 3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-(5-{[methyl(propyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; -(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-30 piperidinyl}-1 H-indole-7-carboxamide; 3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-[5-({methyl[2-(methyloxy)ethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-2-thienyl}-1H-indole-7-carboxamide; Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(propylamino)methyl]-3-thienyl}-1H-indole-7-carboxamide; -{5-[(diethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -(5-{[(2R,5R)-2,5-dimethyl-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-10 piperidinyl]-1 H-indole-7-carboxamide; -{5-[(cyclopropylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -{5-[(cyclobutylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{5-[(dimethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- carboxamide; -(5-{[(cyclopentylmethyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -[5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-20 piperidinyl]-1 H-indole-7-carboxamide; -{5-[(cyclopentylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -(5-{[(cyclopropylmethyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 25 5-[5-({[(1S)-1,2-dimethylpropyl]amino}methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4- piperidinyl]-1 H-indole-7-carboxamide; -(5-{[(2,2-dimethylpropyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(phenylmethyl)amino]methyl}-3-thienyl)-1H-30 indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 31 Received at IPONZ on 15 June 2011 -{5-[(butylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2R)-tetrahydro-2-furanylmethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 5 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2S)-2-[(methyloxy)methyl]-1-pyrrolidinyl}methyl)-3-thienyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2R)-2-[(methyloxy)methyl]-1-pyrrolidinyl}methyl)-3-thienyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-1 H-indole-7-10 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(propylamino)ethyl]phenyl}-1H-indole-7-carboxamide; -{4-[2-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}- 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(4-pyridinylcarbonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; -(4-{[(cyclopentylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-20 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-furanylcarbonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; -{4-[2-(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)-1H- indole-7-carboxamide; -(4-{2-[(cyclobutylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -(4-{2-[(cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-30 indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{2-[(methylsulfonyl)amino]ethyl}phenyl)-1H-indole-7-carboxamide; -(3-{2-[(cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 32 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperazinyl)-3-pyridinyl]-1 H-indole-7-carboxamide trifluoroacetate; -[6-(4-ethyl-1-piperazinyl)-3-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1 -piperidinylmethyl) phenyl]-1 H-indole-7- carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]phenyl}-1H-indole-7-10 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(1-methylethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(propylamino)methyl]phenyl}-1H-indole-7-carboxamide; 5-(4-{[(1-ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- indole-7-carboxamide; -{4-[(cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -{4-[(cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-20 carboxamide; -{4-[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -{4-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{4-[(diethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7- carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-pyrrolidinylmethyl)phenyl]-1 H-indole-7-30 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1R)-2-hydroxy-1-methylethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 33 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(2R)-2-hydroxypropyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[2-hydroxy-1-(hydroxymethyl)ethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 5 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1-methylbutyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1R)-1-methylpropyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]methyl}phenyl)-1H-10 indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1S)-1-methylpropyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; -{4-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(propanoylamino)methyl]phenyl}-1 H-indole-7- carboxamide; -(4-{[(cyclopropylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -(4-{[(cyclobutylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-20 indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-thienylacetyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; -[4-({[(1S)-1,2-dimethylpropyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 25 5-{4-[(butanoylamino)methyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7- carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-methylpropanoyl)amino]methyl}phenyl)-1H-indole-7-carboxamide 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(3-methylbutanoyl)amino]methyl}phenyl)-1H-30 indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methylsulfonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; -[3-({[(1R)-1,2-dimethylpropyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 34 Received at IPONZ on 15 June 2011 -(4-{[(ethylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -(4-{[(butylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1-methylethyl)sulfonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; -(6-amino-2-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1 H-pyrazol-1-yl)phenyl]-1 H-indole-7-carboxamide; 5-[4-(dimethylamino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -(3-aminophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}-1H- indole-7-carboxamide; 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7- carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide; -{5-[(cyclopropylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-20 7-carboxamide; -(5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -(5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 25 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-3-pyridinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(methyloxy)propyl]amino}methyl)-3-30 pyridinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinylmethyl)-3-pyridinyl]-1 H-indole-7-carboxamide; -{5-[(ethylamino)methyl]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; Received at IPONZ on 15 June 2011 -{5-[(dimethylamino)methyl]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-3-pyridinyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-pyridinyl)-1H-indole-7-carboxamide; -(5-{[(2,2-dimethylpropyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-10 indole-7-carboxamide; -[5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(pentylamino)methyl]-2-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2S)-2-methylbutyl]amino}methyl)-2-thienyl]- 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide; -{5-[(butylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-20 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]-1 H-indole-7-carboxamide; -{5-[(cyclopentylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(3-methylbutyl)amino]methyl}-2-thienyl)-1 H- indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-pyridinyl)-1 H-indole-7-carboxamide; -(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-30 indole-7-carboxamide; -[5-({[3-(ethyloxy)propyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]-1 H-indole-7-carboxamide; 36 Received at IPONZ on 15 June 2011 -(5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}-1H-indole-7-carboxamide; 5 5-[5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl]-1 H-indole-7-carboxamide; -(5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-10 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(1 S)-1,2,2-trimethylpropyl]amino}methyl)-2-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(hexylamino)methyl]-2-thienyl}-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylsulfonyl)amino]phenyl}-1 H-indole-7- carboxamide; -[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-pyrrolidinyl)-4-pyridinyl]-1 H-indole-7-20 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinyl)-4-pyridinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-[(2-methylpropyl)amino]-4-pyridinyl}-1H-indole-7-carboxamide; 5-{2-[(2,2-dimethylpropyl)amino]-4-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(propylamino)-4-pyridinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1 H-indole-7-30 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-pyrrolidinylmethyl)-2-thienyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-methylpropyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide; 37 Received at IPONZ on 15 June 2011 -{4-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(1S)-1-(1-pyrrolidinyl)ethyl]-3-thienyl}-1H-indole-7-carboxamide; 5 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(1R)-1-(1-pyrrolidinyl)ethyl]-3-thienyl}-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({(2S)-2-[(methyloxy)methyl]-1-10 pyrrolidinyl}methyl)-2-thienyl]-1 H-indole-7-carboxamide; -(4-{[(2R,5R)-2,5-dimethyl-1-pyrrolidinyl]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-methyl-1-pyrrolidinyl]methyl}-3-thienyl)-1 H-indole-7-carboxamide; 15 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2R)-2-methyl-1-pyrrolidinyl]methyl}-3-thienyl)- 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[1 -(1 -pyrrolidinyl)propyl]-3-thienyl}-1 H-indole-7-carboxamide; -{5-[(dimethylamino)methyl]-3-thienyl}-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-20 1 H-indole-7-carboxamide; -[5-(aminomethyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{2-[(2-methylpropyl)amino]ethyl}-3-thienyl)-1H-indole-7-carboxamide; 5-{5-[2-(dimethylamino)ethyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-pyrrolidinyl)-3-pyridinyl]-1 H-indole-7-carboxamide; -{6-[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-30 carboxamide; -[6-(dimethylamino)-3-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(propylamino)-3-pyridinyl]-1 H-indole-7-carboxamide; 38 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{6-[(1-methylethyl)amino]-3-pyridinyl}-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(4-morpholinyl)-3-pyridinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl}-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-3-thienyl]-1 H-indole-7-10 carboxamide; -{5-[(ethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(1R)-2-hydroxy-1-methylethyl]amino}methyl)-3-thienyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1 -piperidinylmethyl)-3-thienyl]-1 H-indole-7- carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinylmethyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-furanyl}-1 H-indole-7-20 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[1 -(1 -pyrrolidinyl)ethyl]-3-thienyl}-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-2-thienyl]-1 H-indole-7-carboxamide; 5-{5-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7- carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(propylamino)methyl]-2-thienyl}-1H-indole-7-carboxamide; -{5-[(diethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-30 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide; -(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 39 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-furanyl)-1H-indole-7-carboxamide; -(5-{[(cyclopentylmethyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 5 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-3-furanyl]-1 H-indole-7-carboxamide; -{5-[(diethylamino)methyl]-3-furanyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-1,3-thiazol-2-yl]-1 H-indole-10 7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[2-methyl-1-(1-pyrrolidinyl)propyl]-3-thienyl}-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-pyrrolidinylmethyl)-1,3-thiazol-2-yl]-1H-indole-7-carboxamide; 5-{1-[2-(dimethylamino)ethyl]-1 H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H- indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-4-yl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl}-1H-20 indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1 H-indole-7-carboxamide; -{1-[2-(butylamino)ethyl]-1H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{1-[2-(cyclobutylamino)ethyl]-1 H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H- indole-7-carboxamide; -[1-(2-{[2-(diethylamino)ethyl]amino}ethyl)-1H-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(1-methylethyl)amino]ethyl}-1 H-pyrazol-4-yl)-30 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-methylpropyl)amino]ethyl}-1H-pyrazol-4-yl)-1 H-indole-7-carboxamide; -(1-{2-[(cyclopentylmethyl)amino]ethyl}-1H-pyrazol-4-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 40 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(methyloxy)-3-(1-pyrrolidinylmethyl)phenyl]-1H-indole-7-carboxamide; -[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 5 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(methyloxy)-3-(4-morpholinylmethyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4-(methyloxy)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-[(methylamino)methyl]-4-(methyloxy)phenyl]-1H-10 indole-7-carboxamide; -[3-{[(2,2-dimethylpropyl)amino]methyl}-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}-1 H-pyrazol-4-yl)-1H-indole-7-carboxamide; 15 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-fluoro-3-[(methylamino)methyl]phenyl}-1 H- indole-7-carboxamide; -{3,5-bis[(methylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-20 7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-fluoro-3-({[2-hydroxy-1-(hydroxymethyl)ethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-fluoro-3-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 25 5-{3-[(cyclopropylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H- indole-7-carboxamide; -{3-[(cyclobutylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-pyrrolidinylmethyl)phenyl]-1 H-indole-7-30 carboxamide; -{3,5-bis[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -{3,5-bis[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperidinyl)phenyl]-1 H-indole-7-carboxamide; 41 Received at IPONZ on 15 June 2011 -{3-[1-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -{3-[1-(dimethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide; -{3-[(ethylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(propylamino)methyl]phenyl}-1H-10 indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(1-methylethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-methylpropyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 15 5-{3-[(cyclobutylamino)methyl]-5-fluorophenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H- indole-7-carboxamide; -{3-[(dimethylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1-pyrrolidinylmethyl)phenyl]-1H-indole-20 7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(4-morpholinylmethyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1-piperidinylmethyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[1-(methylamino)ethyl]phenyl}-1H-indole-7- carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(1-methylethyl)amino]ethyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl)amino]ethyl}phenyl)-1H-30 indole-7-carboxamide; -{3-[1-(cyclobutylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[1 -(1 -pyrrolidinyl)ethyl]phenyl}-1 H-indole-7-carboxamide; 42 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(3-thiomorpholinyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-piperazinyl)-2-thienyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-piperazinyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(4-morpholinyl)-3-pyridazinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-pyrrolidinyl)-3-pyridazinyl]-1 H-indole-7-10 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-methyl-2- furanyl)methyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2R)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-tetrahydro-2-20 furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; -(3-{[(2,2-dimethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-methylbutyl]amino}methyl)phenyl]-1 H- indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1 R)-1,2,2-trimethylpropyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-30 furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2R)-tetrahydro-2- furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; -[3-({[(1 S)-1,2-dimethylpropyl]amino}methyl)-5-fluorophenyl]-3-[1 -(ethylsulfonyl)-4- piperidinyl]-1 H-indole-7-carboxamide; 43 Received at IPONZ on 15 June 2011 -[3-({[(1 R)-1,2-dimethylpropyl]amino}methyl)-5-fluorophenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(1-methylpropyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 5 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1S)-1,2,2- trimethylpropyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-2-methylbutyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-methylbutyl)amino]methyl}phenyl)-10 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1R)-1,2,2-trimethylpropyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 5-(3-{[(2,2-dimethylpropyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 15 5-(3-{[(cyclopropylmethyl)amino]methyl}-5-fluorophenyl)-3-[1 -(ethylsulfonyl)-4- piperidinyl]-1 H-indole-7-carboxamide; -(3-{[(cyclopentylmethyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(tetrahydro-2H-pyran-4-20 ylmethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-thienylmethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[2-(methyloxy)ethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 25 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[3- (methyloxy)propyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-furanylmethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(3-methylbutyl)amino]methyl}phenyl)-30 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(5-methyl-2-furanyl)methyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-pyrrolidinyl)phenyl]-1H-indole-7-carboxamide; 44 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(propylamino)methyl]phenyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-{[(2- methylpropyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -[5-({[(1 S)-1,2-dimethylpropyl]amino}methyl)-2-fluorophenyl]-3-[1 -(ethylsulfonyl)-4-10 piperidinyl]-1 H-indole-7-carboxamide; -[5-({[(1 R)-1,2-dimethylpropyl]amino}methyl)-2-fluorophenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -(5-{[(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 15 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-(1-pyrrolidinylmethyl)phenyl]-1H-indole- 7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[2-20 (methyloxy)ethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[3-(methyloxy)propyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-methyl-2-pyrrolidinyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{2-[(2-methylpropyl)amino]ethyl}phenyl)-1H- indole-7-carboxamide; -{3-[2-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[2-(propylamino)ethyl]phenyl}-1 H-indole-7-30 carboxamide; -{3-[2-(dimethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -{3-[2-(dipropylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 45 Received at IPONZ on 15 June 2011 -[3-({[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinylmethyl)-1,3-thiazol-4-yl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-thiazol-4-yl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -pyrrolidinylmethyl)-1,3-thiazol-4-yl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -piperidinylmethyl)-1,3-thiazol-4-yl]-1 H-indole-10 7-carboxamide; -{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -(2-{[ethyl(methyl)amino]methyl}-1,3-thiazol-4-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 15 5-(3-cyano-5-{[(2-methylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4- piperidinyl]-1 H-indole-7-carboxamide; -{3-cyano-5-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylsulfonyl)amino]phenyl}-1 H-indole-7-20 carboxamide; -[4-(acetylamino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 5-[3-(acetylamino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1 H-indole-7-carboxamide; 5-{3-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7- carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methylsulfonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; -{3-[(butanoylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-30 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4- fluorophenyl)carbonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropanoyl)amino]methyl}phenyl)-1H- indole-7-carboxamide; 46 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-furanylcarbonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; -(3-{[(cyclopentylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide 5 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1H-indole-7-carboxamide; -(3-{[(2-ethylbutanoyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -(3-{[(1-benzothien-2-ylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-10 piperidinyl]-1 H-indole-7-carboxamide; -[3-({[(1-acetyl-4-piperidinyl)carbonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 15 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(3-methyl-2-butenoyl)amino]methyl}phenyl)- 1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(heptanoylamino)methyl]phenyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(octanoylamino)methyl]phenyl}-1 H-indole-7-20 carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpentanoyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(3-methylbutanoyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylacetyl)amino]methyl}phenyl)-1H- indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(hexanoylamino)methyl]phenyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutanoyl)amino]methyl}phenyl)-1H-30 indole-7-carboxamide; -(3-{[(cyclobutylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -(3-{[(cyclopropylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 47 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(propanoylamino)methyl]phenyl}-1 H-indole-7-carboxamide; -(3-{[(cyclopentylacetyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[3- (methylthio)propanoyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1-methylethyl)sulfonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; -(3-{[(cyclopropylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-10 indole-7-carboxamide; -[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -[3-({[(4-bromophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 15 5-[3-({[(4-chlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4- piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(3- fluorophenyl)sulfonyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 5-[3-({[(2-chlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-20 piperidinyl]-1 H-indole-7-carboxamide; -[3-({[(2,5-dichloro-3-thienyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -[3-({[(2-chloro-6-methylphenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 25 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-fluoro-2- methylphenyl)sulfonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 5-[3-({[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(propylsulfonyl)amino]methyl}phenyl)-1H-30 indole-7-carboxamide; -(3-{[(butylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(phenylsulfonyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 48 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4- fluorophenyl)sulfonyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 5-[3-({[(4-bromo-2-ethylphenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 5 5-(3-{[(1-benzothien-3-ylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -{3-[({[4-(1,1-dimethylethyl)phenyl]sulfonyl}amino)methyl]phenyl}-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1 H-indole-7-carboxamide; -[3-({[(3,4-difluorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-10 piperidinyl]-1 H-indole-7-carboxamide; -(3-{[(ethylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -(3-{[(2,1,3-benzoxadiazol-4-ylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 15 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(tetrahydro-3- furanylcarbonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 5-{4-[(cyclopentylsulfonyl)amino]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-methyl-2-oxo-1-piperazinyl)phenyl]-1H-20 indole-7-carboxamide; -[6-(4-acetyl-1-piperazinyl)-3-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)amino]methyl}phenyl)-1 H-indole-7- carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]methyl}-30 3-thienyl)-1 H-indole-7-carboxamide; -(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide; -(5-{[(3S)-3-hydroxy-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide; 49 Received at IPONZ on 15 June 2011 -(5-{[cyclopentyl(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide; -(5-{[(2-hydroxyethyl)(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]- 4-piperidinyl}-1H-indole-7-carboxamide; 5-(5-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-3-thienyl)-3-{1 -[(1 -methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-propen-1-yl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; -(5-{[[(3,5-dimethyl-1H-pyrazol-4-yl)methyl](methyl)amino]methyl}-3-thienyl)-3-[1-10 (ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -(5-{[(cyanomethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 15 5-(5-{[[2-(ethyloxy)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4- piperidinyl]-1 H-indole-7-carboxamide; -(5-{[cyclobutyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({2-[(methyloxy)methyl]-1-pyrrolidinyl}methyl)-3-20 thienyl]-1 H-indole-7-carboxamide; -(5-{[(1,1-dimethylethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[3-(trifluoromethyl)-1-piperidinyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 25 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1- methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 5-(5-{[(cyclopropylmethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; -(5-{[[2-(acetylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-30 piperidinyl]-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1R,2R)-2- hydroxycyclopentyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 5-(5-{[(1,1-dimethylpropyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 50 Received at IPONZ on 15 June 2011 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(2S)-2-hydroxypropyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[(2R)-tetrahydro-2-furanylmethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[{2-[(2- hydroxyethyl)oxy]ethyl}(methyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-{methyl[2-(methyloxy)ethyl]amino}ethyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{1-[methyl(propyl)amino]ethyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1/-/-indole-7-carboxamide; and 5-(5-{[(1,1-dioxidotetrahydro-3-thienyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide; or a pharmaceutically acceptable salt thereof.
The inventon as claimed in the present specification is directed to the compound 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-7-carboxamide of formula (I) or a pharmaceutically acceptable salt thereof, and to pharmaceutical compositions comprising the compound and one or more pharmaceutically acceptable excipients, and, optionally, one or more additional pharmaceutically active compounds.
/ N (I) 51 Received at IPONZ on 15 June 2011 Terms and Definitions "AlkyI" refers to a saturated hydrocarbon chain having the specified number of member atoms. For example, C-|-Cg alkyl refers to an alkyl group having from 1 to 6 member atoms. Alkyl groups may be optionally substituted with one or more substituents as 5 defined herein. Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
"Alkylene" when used alone or in forming other groups (such as the C-|-Cg alkylene-heteroaryl, C-|-Cg alkylene-heterocycloalkyl, C-|-Cg alkylene-C^C/cycloalkyl, and C-|-Cg alkylene-C5-C7cycloalkenyl groups) refers to a saturated divalent hydrocarbon chain having the specified number of member atoms. For example, C-|-Cg alkylene refers to an alkylene group having from 1 to 6 member atoms. Alkylene groups may be optionally 15 substituted with one or more substituents as defined herein. Alkylene groups may be straight or branched. Representative branched alkylene groups have one, two, or three branches. Alkylene includes methylene, ethylene, propylene (n-propylene and isopropylene), butylene (n-butylene, isobutylene, and t-butylene), pentylene (n-pentylene, isopentylene, and neopentylene), and hexylene.
"Alkenyl" refers to an unsaturated hydrocarbon chain having the specified number of member atoms and having one or more carbon-carbon double bond within the chain. For example, C2-Cg alkenyl refers to an alkenyl group having from 2 to 6 member atoms. In certain embodiments alkenyl groups have one carbon-carbon double bond within the 25 chain. In other emodiments, alkenyl groups have more than one carbon-carbon double bond within the chain. Alkenyl groups may be optionally substituted with one or more substituents as defined herein. Alkenyl groups may be straight or branched. Representative branched alkenyl groups have one, two, or three branches. Alkenyl includes ethylenyl, propenyl, butenyl, pentenyl, and hexenyl.
"Alkenylene" refers to an unsaturated divalent hydrocarbon chain having the specified number of member atoms and having one or more carbon-carbon double bond within the chain. For example, C2-Cg alkenylene refers to an alkenylene group having from 2 to 6 member atoms. In certain embodiments alkenylene groups have one carbon-carbon 52 Received at IPONZ on 15 June 2011 double bond within the chain. In other emodiments, alkenylene groups have more than one carbon-carbon double bond within the chain. Alkenylene groups may be optionally substituted with one or more substituents as defined herein. Alkenylene groups may be straight or branched. Representative branched alkenylene groups have one, two, or 5 three branches. Alkenyl includes ethylenylene, propenylene, butenylene, pentenylene, and hexenylene.
"Alkynylene" refers to an unsaturated divalent hydrocarbon chain having the specified number of member atoms and having one or more carbon-carbon triple bond within the 10 chain. For example, C2-C0 alkynylene refers to an alkynylene group having from 2 to 6 member atoms. In certain embodiments alkynylene groups have one carbon-carbon triple bond within the chain. In other emodiments, alkynylene groups have more than one carbon-carbon triple bond within the chain. For the sake of clarity, unsaturated divalent hydrocarbon chains having one or more carbon-carbon triple bond within the chain and 15 one or more carbon-carbon double bond within the chain are alkynylene groups. Alkynylene groups may be optionally substituted with one or more substituents as defined herein. Alkynylene groups may be straight or branched. Representative branched alkynylene groups have one, two, or three branches. Alkynyl includes ethylynylene, propynylene, butynylene, pentynylene, and hexynylene.
"Aryl" refers to an aromatic hydrocarbon ring. Aryl groups are monocyclic ring systems or bicyclic ring systems. Monocyclic aryl ring refers to phenyl. Bicyclic aryl rings refer to napthyl and rings wherein phenyl is fused to a cycloalkyi or cycloalkenyl ring having 5, 6, or 7 member atoms. Aryl groups may be optionally substituted with one or more 25 substituents as defined herein.
"Cycloalkyi" refers to a saturated hydrocarbon ring having the specified number of member atoms. Cycloalkyi groups are monocyclic ring systems. For example, C3-Cq cycloalkyi refers to a cycloalkyi group having from 3 to 6 member atoms. Cycloalkyi 30 groups may be optionally substituted with one or more substituents as defined herein. Cycloalkyi includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
"Cycloalkenyl" refers to an unsaturated hydrocarbon ring having the specified number of member atoms and having a carbon-carbon double bond within the ring. For example, 35 C3-C5 cycloalkenyl refers to a cycloalkenyl group having from 3 to 6 member atoms. In 53 Received at IPONZ on 15 June 2011 certain embodiments cycloalkenyl groups have one carbon-carbon double bond within the ring. In other emodiments, cycloalkenyl groups have more than one carbon-carbon double bond within the ring. However, cycloalkenyl rings are not aromatic. Cycloalkenyl groups are monocyclic ring systems. Cycloalkenyl groups may be optionally substituted 5 with one or more substituents as defined herein. Cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
"Enantiomerically enriched" refers to products whose enantiomeric excess is greater than zero. For example, enantiomerically enriched refers to products whose enantiomeric 10 excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.
"Enantiomeric excess" or "ee" is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one 15 enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
"Enantiomerically pure" refers to products whose enantiomeric excess is 99% ee or 20 greater.
"Half-life" ( or "half-lives") refers to the time required for half of a quantity of a substance to be converted to another chemically distinct specie in vitro or in vivo.
"Halo" refers to the halogen radical fluoro, chloro, bromo, or iodo.
"Haloalkyl" refers to an alkyl group wherein at least one hydrogen atom attached to a member atom within the alkyl group is replaced with halo. Haloalkyl includes trifluoromethyl.
"Heteroaryl" refers to an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined herein. Heteroaryl groups are monocyclic ring systems or are 35 fused, spiro, or bridged bicyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 54 Received at IPONZ on 15 June 2011 member atoms. Bicyclic heteroaryl rings have from 7 to 11 member atoms. Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocycloalkyi ring are attached forming a fused, spiro, or bridged bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyi, cycloalkenyl, 5 heterocycloalkyi, or heteroaryl ring are attached forming a fused, spiro, or bridged bicyclic ring system. Heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, benopyranyl, 10 benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, furopyridinyl, and napthyridinyl.
"Heteroatom" refers to a nitrogen, sulphur, or oxygen atom.
"Heterocycloalkyi" refers to a saturated or unsaturated ring containing from 1 to 4 heteroatoms as member atoms in the ring. However, heterocycloalkyi rings are not aromatic. Heterocycloalkyi groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyi groups may be optionally substituted with one or more substituents as defined herein. Heterocycloalkyi groups are monocyclic ring 20 systems having from 4 to 7 member atoms. In certain embodiments, heterocycloalkyi is saturated. In other embodiments, heterocycloalkyi is unsaturated but not aromatic. Heterocycloalkyi includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1,3-25 dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, and azetidinyl.
"Member atoms" refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is 30 covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
"Optionally substituted" indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyi, cycloalkenyl, heterocycloalkyi, or heteroaryl, may be unsubstituted or 35 substituted with one or more substituents as defined herein. "Substituted" in reference 55 Received at IPONZ on 15 June 2011 to a group indicates that a hydrogen atom attached to a member atom within a group is replaced. It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination). In certain embodiments, a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group. 0 "Pharmaceutically acceptable" refers to those compounds, materials, compositions, and 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, or other problem or complication, commensurate with a reasonable benefit/risk As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological 20 Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: ratio. g (grams); L (liters); |jL (microliters); M (molar); mg (milligrams); mL (milliliters); psi (pounds per square inch); mM (millimolar); Hz (Hertz); mol (moles); rt (room temperature); h (hours); TLC (thin layer chromatography); RP (reverse phase); i. v. (intravenous); MHz (megahertz); mmol (millimoles); min (minutes); mp (melting point); Tr (retention time); 56 Received at IPONZ on 15 June 2011 MeOH (methanol); /'-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); AcOEt (ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (/V,/V-dimethylformamide); DMPU (A/,A/'-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroform ate); HOAc (acetic acid); HOSu (A/-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); 10 mCPBA (meta-chloroperbenzoic acid; EDC (1-[3-dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride); BOC (te/f-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (/-butyldimethyIsilyl); DMAP (4-dimethylaminopyridine); BSA (bovine serum albumin); ATP (adenosine triphosphate); HRP (horseradish peroxidase); DMEM (Dulbecco's modified Eagle medium); HPLC (high pressure liquid chromatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF (tetra-n-butylammonium fluoride); HBTU (0-Benzotriazole-1-yl-N,N,N',N'-tetramethyluroniumhexafluoro phosphate); HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid); 25 DPPA (diphenylphosphoryl azide); fHN03 (fuming HN03); EDTA (ethylenediaminetetraacetic acid); TMEDA (N,N,N',N'-tetramethyl-1,2-ethanediamine); NBS (N-bromosuccinimide); HATU (0-(7azabenzobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); DIPEA (diisopropylethylamine); Imes (1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride); dppf (1,1'-bis(diphenylphosphino)ferrocene); MDAP (Mass Directed AutoPrep); 57 Received at IPONZ on 15 June 2011 CH3CN (acetonitrile); EtOAc (ethyl acetate); and NIS (N-iodsuccinimide).
All references to ether are to diethyl ether and brine refers to a saturated aqueous solution of NaCI.
The compounds according to formulae l-ll may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, 10 diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in formulae l-ll, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus, compounds according to formulae l-ll 15 containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
Individual stereoisomers of a compound according to formulae l-ll which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. 20 For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzamatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan 25 will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
The compounds according to formulae l-ll may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in formulae l-ll, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis 35 (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also 58 Received at IPONZ on 15 June 2011 included in formulae l-ll whether such tautomers exist in equilibrium or predominately in one form.
The skilled artisan will appreciate that pharmaceutically-acceptable salts of the 5 compounds according to formulae l-ll may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to formulae l-ll may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to pharmaceutically-10 acceptable salts of the compounds according to formulae l-ll.
As used herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ 15 during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
In certain embodiments, compounds according to formulae l-ll may contain an acidic 20 functional group. Suitable pharmaceutically-acceptable salts include salts of such acidic functional groups. Representative salts include pharmaceutically-acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically-acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically-25 acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
In certain embodiments, compounds according to formulae l-ll may contain a basic functional group and are therefore capable of forming pharmaceutically-acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically-acceptable inorganic acids and pharmaceutically-acceptable organic acids. Representative pharmaceutically-acceptable acid addition salts include hydrochloride, 35 hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, 59 Received at IPONZ on 15 June 2011 trifluoroacetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, 5 hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate (tosylate), and napthalene-2-sulfonate.
As used herein, the term "compounds of the invention" means both the compounds according to formulae l-ll and the pharmaceutically-acceptable salts thereof.
The compounds of the invention may exist in solid or liquid form. In the solid state, the 15 compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, 20 ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. 30 Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for 35 identification. The skilled artisan will appreciate that different polymorphs may be 60 Received at IPONZ on 15 June 2011 produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
Compound Preparation The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are 10 set out below and then specific compounds of the invention are prepared in the Examples section.
Compounds of formulae I and II can be prepared, for example, according to Schemes 1, 2, and 3 depicted below: Scheme 1 Conditions: a) (B0C)20, THF; b) s-BuLi, CIC02Me, TMEDA, Et20; c) N-20 bromosuccinimide, Methylene chloride; d) TFA; e) Mn02, THF; f) LiOH, MeOH, water; g) R1B(OR)2, Imes-HCI, Pd(OAc)2, Dioxane/water; h) HATU, NH3, DMF; i) RCHO (or) RC(0)R', NaOMe, MeOH; j) Pd(OH)2, H2, HOAc, EtOH; k) R4CI, TEA, Methylene chloride (or) (R4)20, DMAP, Methylene chloride 61 Received at IPONZ on 15 June 2011 Scheme 1 represents a general scheme for the preparation of compounds according to formulae I and II wherein R2 and R3 are H, F, or CI, U is a bond or C-|-C6 alkylene or C2- Ce alkenylene and V is C5-C7 cycloalkyi or C5-C7 cycloalkenyl or heterocycloalkyi or heterocycloalkenyl. Scheme 1 also represents a general scheme for the preparation of 5 compounds according to formulae I and II wherein U is C-i-Cq alkylene or C2-Cq alkenylene and V is aryl, or heteroaryl. In Scheme 1, R1 is defined above unless defined otherwise. The indoline 1 depicted as starting material is commercially available. Reaction conditions are as described above in the scheme; however, the skilled artisan will appreciate that certain modifications in the reaction conditions and/or reagents used 10 are possible.
Treatment of indoline 1 with di-tertbutyl dicarbonate in a suitable solvent such as THF or methylene chloride produces the desired BOC protected product. Further transformation to the desired bromide 2 can be accomplished via lithiation using sec-butyllithium in the 15 presence of TMEDA and quenching with methyl chloroformate followed by bromination with N-bromosuccinimide. Treatment of bromide 2 with trifluoroacetic acid followed by oxidation of the resulting indoline to the indole with manganese dioxide and subsequent hydrolysis of the methyl ester to the acid yields the desired carboxylic acid 3. Installation of the substituent R1 can be accomplished via a transition metal mediated coupling using 20 an appropriate catalyst and coupling partner. As an example of such a transformation, for the case in Scheme 1 condition "g", a Suzuki cross-coupling reaction can be completed using a boronic ester or acid in the presence of Pd(OAc)2, Imes-HCI, and Cs2C03 in 1,4-dioxane and water. Preparation of the primary carboxamide 4 can be completed via reaction of the carboxylic acid with ammonia in the presence of HATU. Conversion of 4 25 to 5 incorporating the group U-V is performed via reaction with the appropriate aldehyde or ketone precursor to U-V. This transformation can be completed under either basic or acidic conditions. For the case where the group U-V is fully saturated, a subsequent reduction of the intermediate product will produce the desired product 5. As an example of such a reduction, for the case in Scheme 1 condition "j", a hydrogenation reaction in 30 the presence of Pd(OH)2 completes the transformation to 5. In the case where U-V and/or R1 contains a suitable protecting group, removal of the protecting group under the appropriate conditions and further transformation to other products may be accomplished. Subsequent transformation of the amine function of the group U-V to either the sulfonamide or amide of R4 can be performed with the appropriate sulfonyl or acid 35 chloride or acid anhydride of R4. It will be appreciated by the skilled artisan that upon Received at IPONZ on 15 June 2011 conversion to either the sulfonamide or amide of R4 the resulting product may require further elaboration to R4. This can include but is not limited to suitable protecting and functional group manipulations and reactions with amines/alcohols R5.
Scheme 2 Conditions: a) R1B(OR)2, Imes-HCI, Pd(OAc)2, dioxane/water; b) HATU, NH3, DMF; c) N-10 iodosuccinimide, Methylene chloride; d) VUB(OR)2, Pd(PPh3)4, Cs2C03, 1,4-dioxane, water; e) R2CI, TEA, Methylene chloride (or) (R2)20, DMAP, Methylene chloride Scheme 2 represents a general scheme for the preparation of compounds according to formulae I and II wherein U is a bond and V is aryl or heteroaryl. In Scheme 2, R1 is 15 defined above unless defined otherwise. The indolecarboxylic acid 3 depicted as starting material is obtained as described in Scheme 1. Reaction conditions are as described above in the scheme; however, the skilled artisan will appreciate that certain modifications in the reaction conditions and/or reagents used are possible.
The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for 25 protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions 30 convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound. 63 Received at IPONZ on 15 June 2011 Methods of Use The compounds of the invention are inhibitors of IKK2. These compounds can be useful in the treatment of disorders wherein the underlying pathology is (at least in part) 5 attributable to inappropriate IKK2 (also known as IKK(3) activity such as rheumatoid arthritis, inflammatory bowel disease, asthma, and COPD (chronic obstructive pulmonary disease). "Inappropriate IKK2 activity" refers to any IKK2 activity that deviates from the normal IKK2 activity expected in a particular patient. Inappropriate IKK2 activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing 10 and or control of IKK2 activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation. Accordingly, in another aspect the invention is directed to methods of treating such disorders.
Such disorders include inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, 20 psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia.
The methods of treatment of the invention comprise administering a safe and effective amount of a compound according to formulae l-ll or a pharmaceutically-acceptable salt thereof to a patient in need thereof. Individual embodiments of the invention include methods of treating any one of the above-mentioned disorders by administering a safe 30 and effective amount of a compound according to formulae l-ll or a pharmaceutically-acceptable salt thereof to a patient in need thereof.
As used herein, "treat" in reference to a disorder means: (1) to ameliorate or prevent the disorder or one or more of the biological manifestations of the disorder, (2) to interfere 35 with (a) one or more points in the biological cascade that leads to or is responsible for the 64 Received at IPONZ on 15 June 2011 disorder or (b) one or more of the biological manifestations of the disorder, (3) to alleviate one or more of the symptoms or effects associated with the disorder, or (4) to slow the progression of the disorder or one or more of the biological manifestations of the disorder.
As indicated above, "treatment" of a disorder includes prevention of the disorder. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a disorder or biological manifestation thereof, or to delay the onset of such disorder or biological manifestation thereof.
As used herein, "safe and effective amount" in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective 15 amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the disorder being treated; the severity of the disorder being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired 20 therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
As used herein, "patient" refers to a human or other animal.
The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, 30 transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes 65 Received at IPONZ on 15 June 2011 application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
The compounds of the invention may be administered once or according to a dosing 5 regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of 10 that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the disorder being treated, the severity of the disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of 15 concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from 0.001 mg to 50mg per kg of total body weight.
Additionally, the compounds of the invention may be administered as prodrugs. As used 25 herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify 30 the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, 35 thioesters, carbonates, and carbamates, are well known to those skilled in the art. 66 Received at IPONZ on 15 June 2011 The invention also provides a compound of the invention for use in medical therapy, and particularly in the treatment of disorders mediated by IKK2 activity. Thus, in a further aspect, the invention is directed to the use of a compound according to formulae l-ll or a 5 pharmaceutically-acceptable salt thereof in the preparation of a medicament for the treatment of a disorder characterized by inappropriate IKK2 activity.
Particular disorders characterised by inappropriate IKK2 activity include inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, 10 asthma and COPD (chronic obstructive pulmonary disease);osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage; autoimmune diseases including systemic lupus eythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes, 15 glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia as a result of inhibition of the protein kinase IKK2.
Compositions The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.
The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit 30 dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically may contain, for example, from 0.5mg to 1 g, or from 1mg to 700mg, or from 5mg to 100mg of a compound of the invention. 67 Received at IPONZ on 15 June 2011 The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds 5 of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the 10 pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each 15 excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the 20 patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal 25 administration such as suppositories; (5) inhalation such as aerosols, solutions, and dry powders; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically-acceptable excipients will vary depending upon the particular 30 dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain 35 pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the Received at IPONZ on 15 June 2011 carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, 10 chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in 20 selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium 35 phosphate. The oral solid dosage form may further comprise a binder. Suitable binders Received at IPONZ on 15 June 2011 include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch 5 glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
Where appropriate, dosage unit formulations for oral administration can be 10 microencapsulated. The composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
The compounds of the invention may also be coupled with soluble polymers as targetable 15 drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon 20 caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
In another aspect, the invention is directed to a liquid oral dosage form. Oral liquids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given 25 quantity contains a predetermined amount of a compound of the invention. Syrups can be prepared by dissolving the compound of the invention in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound of the invention in a nontoxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and 30 polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added. 70 Received at IPONZ on 15 June 2011 In another aspect, the invention is directed to a dosage form adapted for administration to a patient by inhalation. For example, the compound of the invention may be inhaled into the lungs as a dry powder, an aerosol, a suspension, or a solution.
Dry powder compositions for delivery to the lung by inhalation typically comprise a compound of the invention as a finely divided powder together with one or more pharmaceutically-acceptable excipients as finely divided powders. Pharmaceutically-acceptable excipients particularly suited for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides.
The dry powder may be administered to the patient via a reservoir dry powder inhaler (RDPI) having a reservoir suitable for storing multiple (un-metered doses) of medicament in dry powder form. RDPIs typically include a means for metering each medicament dose from the reservoir to a delivery position. For example, the metering means may comprise 15 a metering cup, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation.
Alternatively, the dry powder may be presented in capsules (e.g. gelatin or plastic), 20 cartridges, or blister packs for use in a multi-dose dry powder inhaler (MDPI). MDPIs are inhalers wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple defined doses (or parts thereof) of medicament. When the dry powder is presented as a blister pack, it comprises multiple blisters for containment of the medicament in dry powder form. The blisters are typically arranged in regular fashion 25 for ease of release of the medicament therefrom. For example, the blisters may be arranged in a generally circular fashion on a disc-form blister pack, or the blisters may be elongate in form, for example comprising a strip or a tape. Each capsule, cartridge, or blister may, for example, contain between 20(xg-10mg of the compound of the invention.
Aerosols may be formed by suspending or dissolving a compound of the invention in a liquified propellant. Suitable propellants include halocarbons, hydrocarbons, and other liquified gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), 35 pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, Received at IPONZ on 15 June 2011 perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols comprising a compound of the invention will typically be administered to a patient via a metered dose inhaler (MDI). Such devices are known to those skilled in the art.
The aerosol may contain additional pharmaceutically-acceptable excipients typically used with MDIs such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
Suspensions and solutions comprising a compound of the invention may also be administered to a patient via a nebulizer. The solvent or suspension agent utilized for nebulization may be any pharmaceutically-acceptable liquid such as water, aqueous saline, alcohols or glycols, e.g., ethanol, isopropylalcohol, glycerol, propylene glycol, polyethylene glycol, etc. or mixtures thereof. Saline solutions utilize salts which display little or no pharmacological activity after administration. Both organic salts, such as alkali metal or ammonium halogen salts, e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be used for this purpose.
Other pharmaceutically-acceptable excipients may be added to the suspension or solution. The compound of the invention may be stabilized by the addition of an inorganic acid, e.g., hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid; an organic acid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., a complexing agent such as EDTA or citric acid and salts thereof; or an antioxidant such as antioxidant such as vitamin E or ascorbic acid. These may be used alone or together to stabilize the compound of the invention. Preservatives may be added such as benzalkonium chloride or benzoic acid and salts thereof. Surfactant may be added particularly to improve the physical stability of suspensions. These include lecithin, disodium dioctylsulphosuccinate, oleic acid and sorbitan esters.
Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the patient for a prolonged period of time. For example, the active ingredient may be 72 Received at IPONZ on 15 June 2011 delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical compositions adapted for topical administration may be formulated as 5 ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For treatments of the eye or other external tissues, for example mouth and skin, the compositions may be applied as a topical ointment or cream. When formulated in an 10 ointment, the compound of the invention may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the compound of the invention may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical compositions adapted for nasal administration wherein the carrier is a 15 solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the compound of the invention.
Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include 25 suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and 30 tablets. 73 Received at IPONZ on 15 June 2011 EXAMPLES The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. 5 While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of 10 NaCI. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted. 1H NMR spectra were recorded on a Brucker DPX400, a Brucker DPX250, a Brucker 15 AC400, or a Varian Inova 400. Chemical shifts are expressed in parts per million (ppm, 5 units). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).
Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA, JOEL SX-20 102, or a SCIEX-APIiii spectrometer; LC-MS were recorded on Waters ZQ or PE Sciex Single Quadrupole LC/MS API-150 spectrometers.
Preparative HPLC refers to methods where the material was purified by high performance liquid chromatography on a HPLC ABZ+ 5|jm column (10 cm x 21.2 mm i.d.) with 0.1% 25 formic acid in water and 0.05% formic acid in acetonitrile utilising gradient elution at a flow rate of 8 ml/min and UV detection at 254nM.
Unless otherwise stated, silica flash column chromatography and Combiflash refers to the purification of material using Redisep™ pre-packed silica flash columns on an ISCO 30 sq16x machine with the stated solvent systems.
Reverse phase HPLC method A refers to methods where the materials were purified by high performance liquid chromatography on an HPLC S-5 |jm column (75*30 mm i.d.) utilizing gradient elution with the stated solvent systems and UV detection at 254 nm. 74 Received at IPONZ on 15 June 2011 Reverse phase HPLC method B refers to methods where the materials was purified by high performace liquid chromatography on a HPLC Luna C18 (2) 100A column (50x21.2 mm i.d.) utilizing gradient elution with the stated solvent system and UV detection at 254 nm.
LC-MS Experimental Conditions for PE Sciex Single Quadrupole LC/MS API-150: Liquid Chromatograph: System: Shimadzu LC system with SCL-10A Controller and dual UV detector Autosampler: Leap CTC with a Valco six port injector Column: Aquasil/Aquasil (C18 40x1 mm) Inj. Volume (|jL): 2.0 Solvent A: H20, 0.02% TFA Solvent B: MeCN, 0.018% TFA 15 Gradient: linear Channel A: UV214nm Channel B: ELS Step Time (min) Dura.(min) Flow (|jL/min) Sol.A Sol.B 0 0.00 0.00 300.00 95.00 .00 1 0.00 0.01 300.00 95.00 .00 2 0.01 3.20 300.00 10.00 90.00 3 3.21 1.00 300.00 10.00 90.00 4 4.21 0.10 300.00 95.00 .00 4.31 0.40 300.00 95.00 .00 Mass Spectrometer: PE Sciex Single Quadrupole LC/MS API-150 Polarity: Positive Acquisition mode: Profile 75 Received at IPONZ on 15 June 2011 Intermediates Intermediate 1: 1,1-dimethylethyl 2,3-dihvdro-1H-indole-1-carboxylate /^O o Indoline (10 g, 84 mmol) was dissolved in tetrahydrofuran (100 mL) and di-tert-butylcarbonate (22 g, 0.1 mol) was added. The mixture was left stirring for 16 hours at room temperature under an inert nitrogen atmosphere. The tetrahydrofuran was removed in vacuo and the crude product purified by vacuum distillation to give the title compound (15.1 g) as a clear pale pink oil that crystallised upon standing (temperature: 160-162°C, 10 pressure 1-0.1 mm Hg). 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.50 (s, 9 H) 3.04 (t, J=8.7 Hz, 2 H) 3.89 (t, J=8.8 Hz, 2 H) 6.91 (td, J=7.3, 0.8 Hz, 1 H) 7.13 (t, J=7.5 Hz, 1 H) 7.18 (d, J=7.3 Hz, 1 H) 7.5-7.8 (bs, 1 H) r.t. 3.44 min.
Intermediate 2: 1-(1.1-dimethylethyl) 7-methyl 2.3-dihydro-1H-indole-1.7-dicarboxylate 1,1-dimethylethyl 2,3-dihydro-1H-indole-1-carboxylate (5 g, 22.8 mmol) and A/./V./V./V-tetramethyl-1,2-ethanediamine (4.6 mL, 30.5 mmol) was dissolved in dry diethyl ether 20 (300 mL) and cooled to -78°C in an acetone/dry ice bath. Sec-butyl lithium (1.4 M solution in cyclohexanes, 17.6 mL, 24.6 mmol) was added dropwise over 10 minutes and the reaction left stirring for 90 minutes at this temperature. Methyl chloroformate (8.8 mL, 10.8 g, 0.1 mol) was added to the mixture and the reaction was allowed to warm up to room temperature over 1 hour. Water was added carefully to the mixture and the organic 25 layer separated and washed 3 times with more water. The organic layer was dried over 76 Received at IPONZ on 15 June 2011 magnesium sulfate, filtered and concentrated in vacuo to give the title compound (4.91 g) as a gummy yellow solid. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.44 (s, 9 H) 3.06 (t, J= 8.2 Hz, 2 H) 3.69 (s, 3 H) 4.02 (t, J= 8.3 Hz, 2 H) 7.06 (t, J=7.5 Hz, 1 H) 7.35 (d, J=7.5 Hz, 1 H) 7.39 (dd, J=7.4, 1.1 5 Hz, 1 H) MS m/z 278 (M+1)+ r.t. 3.18 min.
Intermediate 3: 1-(1.1-dimethylethyl) 7-methyl 5-bromo-2.3-dihydro-1H-indole-1.7-dicarboxylate 1-(1,1-dimethylethyl) 7-methyl 2,3-dihydro-1 H-indole-1,7-dicarboxylate (3.1 g, 11.2 mmol) 10 and N-bromosuccinimide (2.0 g, 11.2 mmol) were dissolved in dry dichloromethane (100 mL) and stirred under a nitrogen atmosphere at room temperature for 16 hours. The reaction was partitioned with sodium hydroxide solution (2 M), separated and washed with more sodium hydroxide solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a gummy red solid (3.55 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.41 (s, 9 H) 3.09 (t, J=8.3 Hz, 2 H) 3.70 (s, 3 H) 4.02 (t, J=8.3 Hz, 2 H) 7.46 (s, 1 H) 7.60 (s, 1 H) MS m/z 356/358 (1:1 ratio) (M+1)+ r.t. 3.52 min.
Intermediate 4: methyl 5-bromo-2.3-dihydro-1 H-indole-7-carboxylate 1-(1,1-dimethylethyl) 7-methyl 5-bromo-2,3-dihydro-1 H-indole-1,7-dicarboxylate (9 g, 25 mmol) was dissolved in trifluoroacetic acid (6 mL) and stirred at room temperature for 16 hours. Dichloromethane and sodium hydroxide solution (2 M) were added and the g). o o 77 Received at IPONZ on 15 June 2011 organic layer washed twice with sodium hydroxide solution until the aqueous layer pH > 7. The organic layer was then concentrated in vacuo to give the title compound as a brown solid (6.5 g). 1H NMR (400 MHz, DMSO-D6) 5 ppm 2.99 (t, J= 8.5 Hz, 2 H) 3.61 (t, J=8.4 Hz, 2 H) 3.78 5 (s, 3 H) 6.72 (s, 1 H) 7.28 (d, J= 1 Hz, 1 H) 7.46 (d, J=2 Hz, 1 H) MS m/z 256/258 (1:1 ratio) (M+1)+ r.t. 3.32 min.
Intermediates: methyl 5-bromo-1 H-indole-7-carboxylate Methyl 5-bromo-2,3-dihydro-1 H-indole-7-carboxylate (6.5 g, 25 mmol) was dissolved in 10 tetrahydrofuran (100 mL). Activated manganese dioxide (5 nm particle size, 22 g, 0.25 mol) was added and the mixture stirred at room temperature for 16 hours. A further 22 g of activated manganese dioxide was added and the reaction stirred for 96 hours. The reaction was then filtered through celite and concentrated in vacuo to give the title compound (5.1 g) as a beige solid. 1H NMR (400 MHz, DMSO-D6) 5 ppm 3.94 (s, 3 H) 6.58 (d, J=3 Hz, 1 H) 7.48 (d, J= 3 Hz, 1 H) 7.8 (d, J=2 Hz, 1 H) 8.07 (d, J=1.8 Hz, 1 H) 11.39 (bs, 1 H) MS m/z 252/254 (1:1 ratio) (M-1) r.t. 3.41 min.
Intermediate 6: 5-bromo-1H-indole-7-carboxylic acid -bromo-1H-indole-7-carboxylate (5 g, 19.7 mmol) was dissolved in methanol (200 mL) and a solution of lithium hydroxide (0.99 g, 41 mmol) in water (10 mL) was added. The mixture was heated at reflux for 50 hours. The methanol was removed in vacuo and the residue diluted with aqueous hydrochloric acid (2 M). The resulting precipitate was 25 filtered off and dried in a heated vacuum pistol to give the title compound as a beige solid (4.7 g). 78 Received at IPONZ on 15 June 2011 1H NMR (400 MHz, DMSO-D6) 5 ppm 6.54 (dd, J=2.0, 3.2 Hz, 1 H) 7.42 (t, J=2.8 Hz, 1 H) 7.77 (d, J=2 Hz, 1 H) 8.03 (d, J=1.8 Hz, 1 H) 11.27 (s, 1 H) 13.1-13.7 (bs, 1 H) MS m/z 238/240 (1:1 ratio) (M-1) r.t. 3.41 min.
Intermediate 7: 5-bromo-1W-indole-7-carboxamide To a solution of 5-bromo-1/-/-indole-7-carboxylic acid (10.0 g, 42 mmol) in CH2CI2 (100 mL) at room temperature, EDC (9.66 g, 50.4 mmol), HOBt (6.81 g, 50.4 mmol) and NH3 (2.0 M in MeOH, 84 mL, 168 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer was extracted with ethyl acetate (100 mLx2) and the combined organic phase was dried over MgS04 and concentrated to give the crude product (10 g, 98%). This crude product was used directly in the next step without further purification.
LC/MS: m/z 240.0 (M+H), 1.95 min.
Intermediate 8: 1,1-dimethylethyl 4-r7-(aminocarbonyl)-5-bromo-1AY-indol-3-vn-3.6-dihydro-1(2AV)-pvridinecarboxylate cr nh2 To a solution of 5-bromo-1H-indole-7-carboxamide (10 g, 41.84 mmol) in methanol (5mL), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (684 mg, 3.42 mmol) and sodium methoxide (0.5 M in THF, 13.7 mL, 6.84 mmol) were added. The reaction mixture was stirred at reflux temperature for 16 hours. All solvent was evaporated under reduced 79 Received at IPONZ on 15 June 2011 pressure. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The combined organic phase was dried over MgS04 and concentrated under reduced pressure, and purified by flash column chromatography (ethyl acetate/hexanes, 1/1) to give the desired product (7.4 g, 43 %).
LC/MS: m/z 420.0 (M+H), 2.35 min.
Intermediate 9: 1,1-dimethylethyl 4-r7-(aminocarbonvl)-5-bromo-1fV-indol-3-vH-1-piperidine carboxylate To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indol-3-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate (7.41g, 17.64 mmol) in ethanol (600 mL), platinum oxide (200 mg, 5%) was added. The reaction mixture was hydrogenated under an atmosphere of H2 for 16 hours. The resulting mixture was filtered through celite and the filtrate was concentrated. The resulting residue was purified by flash column 15 chromatography (Ethyl acetate/hexanes, 1:4 to 2:1 v/v) to give the desired product (3.6g, 48%).
LC-MS: m/z 422.0 (M+H), 2.25 min.
Intermediate 10: 5-bromo-3-(4-piperidinyl)-1AV-indole-7-carboxamide H M Br CT NH Br CT NH. 80 Received at IPONZ on 15 June 2011 To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1/-/-indol-3-yl]-1-piperidinecarboxylate (1.56 g, 3.7 mmol) in methanol (10 mL), HCI in dioxane (4M, 35.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the resulting residue was partitioned between ethyl acetate (50 mL) and 5% of aqueous NaOH (50 mL). The aqueous layer was washed with ethyl acetate (2x50 mL) and the combined organic phases were dried with MgSC>4 and concentrated under reduced pressure to give the desired product (685 mg, 58%), which was used in the next step without further purification.
LC-MS: m/z 322.0 (M+H), 1.45 min.
Intermediate 11: 5-bromo-3-H-(ethanesulfonvl)-4-piperidinyll-1 AV-indole-7-carboxamide Ethanesulfonyl chloride (4.5 mL, 47.4 mmol) was added dropwise to a solution of 5-bromo-3-(4-piperidinyl)-1 H-indole-7-carboxamide hydrochloride (8.49 g, 23.7 mmol) and triethylamine (13.2 mL, 94.7 mmol) in DMF (80 mL) at 0 °C (bath temperature). The reaction mixture was stirred at 0 °C for 45 min. and was then poured into a 2:1 mixture of EtOAc/H20 (300 mL). The resulting precipitate was filtered off, washed with EtOAc (2 x 50 mL), and set aside. The Et0Ac/H20 bilayer was separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaCI (1 x 100 mL), dried (MgSC>4), filtered, and concentrated under reduced pressure. The crude product was combined with the precipitate isolated above and washed with MeOH (1x10 mL) to give 8.19 g of the title compound (83%).
N Br CT NH.
Alternatively, the title compound may be prepared as follows: To 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (900 mg, 2.8 mmol) in CH2CI2 (100mL) at 0 °C, ethanesulfonyl chloride (0.8 mg, 8.4 mmol) and triethylamine (1.6 mL, Received at IPONZ on 15 June 2011 11.2 mmol) were added. The reaction mixture was stirred at 0 °C for 30 min., after which time the mixture was partitioned between CH2CI2 and water. The aqueous phase was extracted with CH2CI2 (50 mL x 2) and the combined organic phase dried over MgSC>4 and concentrated under reduced pressure. The resulting residue was purified by solid 5 phase extraction on a 500 mg aminopropyl column (International Sorbent Technologies) eluting with chloroform (30 mL x 2) and ethyl acetate (50 mL) to give 800 mg of the title compound (69%).
LC/MS: m/z 414.0 (M+H), 2.2 min.
Intermediate 12: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-(hvdroxvmethyl)phenvn-1AY-indole-7-carboxamide To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (20.0 mg, 0.048 mmol), K3PO4 ( 21.0 mg, 0.096 mmol) and [3-(hydroxymethyl) phenyl] boronic 15 acid (30.0 mg, 0.193 mmol) in dioxane/H20 ( 2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (5.0 mg, 0.0048 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160°C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgS04, concentrated, and 20 purified by reverse phase HPLC method A (water/ CH3CN, 0.1 % TFA 10-90%) to give the title compound (9.7 mg, 46%). 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.25 (t, J= 7.2 Hz, 3H), 1.65 (m, 2H), 2.02 (m, 2H), 2.99 (m, 7H), 3.71 ( m, 2H), 7.16 (s, 1H), 7.42 (m, 3H), 7.77 (m, 2H), 8.02 (m, 2H), 8.22 (m, 1H), 10.91 (s, 1 H).
LC/MS: m/z 442.4 (M+H), r.t: 1.73 min.
Intermediate 13: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(3-formvlphenyl)-1AY-indole-7-carboxamide O NH 82 Received at IPONZ on 15 June 2011 O NH.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(hydroxymethyl)phenyl]-1/-/-indole-7-carboxamide (52.0 mg, 0.120 mmol) in THF (10 mL), Mn02 (360.0 mg, 3.5 mmol) was added at ambient temperature. The resulting suspension was stirred overnight, filtered 5 through celite, and the solid rinsed with THF (3X10 mL). The filtrate was concentrated to give the title compound (51.0 mg, 98%) which was used in the next step without purification.
LC/MS: m/z 440.4 (M+H), r.t: 1.97 min.
Intermediate 14: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r4-(hvdroxvmethyl)phenvn-1AV-indole-7-carboxamide To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (20.0 mg, 0.048 mmol), K3PO4 ( 21.0 mg, 0.096 mmol) and [4-(hydroxymethyl) phenyl] boronic 15 acid (30.0 mg, 0.193 mmol) in dioxane/H20 ( 2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (5.0 mg, 0.0048 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160°C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgS04, filtered, concentrated, 20 and purified by reverse phase HPLC method A (water/ CH3CN, 0.1 % TFA 10-90%) to give the title compound (6.4 mg, 30%).
LC/MS: m/z 442.4 (M+H), r.t: 1.78 min. cr NH. 83 Received at IPONZ on 15 June 2011 Intermediate 15: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(4-formvlphenyl)-1AV-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(hydroxymethyl)phenyl]-1/-/-indole-7-carboxamide (25 mg, 0.058 mmol) in THF (5 mL), Mn02 (160.0 mg, 1.73 mmol) was added at ambient temperature. The resulting suspension was stirred overnight, filtered through celite, and the solid rinsed with THF (3X10 mL). The filtrate was concentrated to give the title compound (15 mg, 58%) which was used in the next step without 10 purification.
LC/MS: m/z 440.4 (M+H), r.t: 2.02 min.
Intermediate 16: 3-ri-(ethylsulfonvl)-4-piperidinvll-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1AV-indole-7-carboxamide To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (1.0 g, 2.42 mmol), Bis(pinacolato)diborane (2.45 g, 9.66 mmol) and potassium carbonate (2.10 g, 21.8 mmol) in DME (15.0 mL) was added Pd2CI2(dppf) after degassing for 5 min. 20 The mixture was then heated in the microwave at 130° C for 11000 sec. Reaction mixture was then diluted with EtOAc (300 mL) and H20 (100 mL) and solid was filtered. The organic layer was then washed with H20 (3 x 80 mL) and brine. Organic laye was O NH N O NH 84 Received at IPONZ on 15 June 2011 dried over MgS04 and concentrated. DCM (40 mL) was then added to remove any byproduct to afford 2.4 g of the title compound.
LC/MS: m/z 462.3 (M+H), r.t: 2.03 min.
Intermediate 17: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-formvl-2-thienyl)-1AY-indole-7-carboxamide To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (200 10 mg, 0.49 mmol) in dioxane (4.5 mL) and H20 (1.5 mL) was added [5-(hydroxymethyl)-2-thienyl]boronic acid (232 mg, 1.47 mmol), potassium carbonate (406 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium (0) (57 mg, 0.049 mmol). Reaction was run in the microwave at 150° C for 20 min. Aqueous work-up with Et0Ac/H20 gave 447 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-thienyl]-1/-/-indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-thienyl]-1/-/-indole-7-carboxamide (200 mg, 0.46 mmol) in THF (5.0 mL) was added Mn02 (1.21 g, 13.9 mmol). The mixture was stirred at room temperature for 3 h. Filtration of reaction mixture thru celite afforded 100 mg of the title compound (48.8%) LC/MS: m/z 446.2 (M+H), r.t: 2.27 min.
Intermediate 18: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(4-formvl-2-thienyl)-1AY-indole-7-carboxamide 85 Received at IPONZ on 15 June 2011 s o n O cr nh2 To a solution of 3-thiophenecarbaldehyde (3.0 g, 26.8 mmol) in DCM (54 mL) was added aluminum trichloride (8.37 g, 63 mmol) at 0° C. The reaction was then heated to reflux and bromine (1.6 mL, 30.28 mmol) was added dropwise. After addition, the reaction 5 mixture was stirred at reflux for 4 h. After cooling to room temperature, cold H20 (100 mL) was added and extracted with DCM (2 x 100 mL). The combined organic layer was washed with NaHC03 and dried. It was purified by flash chromatography to give 3.62 g of 5-bromo-3-thiophenecarbaldehyde (71%).
To a solution of 5-bromo-3-thiophenecarbaldehyde (250 mg, 1.29 mmol) in dioxane (4.5 mL) and H20 (1.5 mL) was added 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (200 mg, 0.43 mmol), potassium carbonate (250 mg, 2.58 mmol) and tetrakis(triphenylphosphine)palladium (0) (56 mg, 0.049 mmol). The reaction was run in the microwave at 150° C for 20 min. It was then treated with EtOAc and H20 to obtain the crude product. This was then treated with MeOH (10 mL) and the solid was filtered and collected to give 310 mg of the desired title compound.
LC/MS: m/z 446.4 (M+H), r.t: 1.94 min.
Intermediate 19: 3-ri-(ethvlsulfonvl)-4-piperidinvll-5-(5-formvl-3-thienyl)-1AV-indole-7-carboxamide 86 Received at IPONZ on 15 June 2011 O S O N O NH.
To a solution of 4-bromo-2-thiophenecarbaldehyde (1.0 g, 4.48 mmol) in DME (16 mL) was added Bis(pinacolato)diborane (1.48 g, 5.82 mmol), KOAc (1.14 g, 5.11 mmol) and Pd2CI2(dppf) (106 mg, .448 mmol). The reaction was run in the microwave at 150° C for 5 20 min. The solvent was concentrated and an aqueous work-up was performed using EtOAc and H20. The compound was purified by flash chromatography using hexanes and EtOAc to give 1.8 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde.
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (909 mg, 2.2 mmol) in dioxane (7.5 mL) and H20 (2.5 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (1.57 g, 6.6 mmol), potassium carbonate (1.82 g, 13.2 mmol), and tetrakis(triphenylphospine)palladium (0) (30 mg, ,22mmol). The reaction was heated in the microwave at 150° C for 20 min. The mixture was then concentrated to dryness. EtOAc (50 mL) was added to the residue and washed with brine. The precipitate which formed between the water and organic layer was filtered and collected as a brown solid to give 874 mg of the title compound (89%).
LC/MS: m/z 446.4 (M+H), r.t: 1.93 min.
Intermediate 20: 5-Bromoisoindoline In a dried 50mL two necked round-bottom flask equipped with an addition funnel and CaCI2 drying tube was placed 2.0g (13.6mmol) of phthalimide. The flask was then cooled 25 to 0°C in a salt and ice bath. An ice cold mixture of concentrated sulfuric acid and fuming nitric acid (1:1 v/v) 8mL was gradually added with constant stirring. The mixture was then stirred for 30min. at 0°C and allowed to slowly warm to room temperature with stirring Br NH 87 Received at IPONZ on 15 June 2011 over a period of 1h. The reaction mixture was then poured into ice. The resulting solid product was filtered and dried to give 1.6g (61.3%) of 5-nitro-1/-/-isoindole-1,3(2H)-dione as a yellow colour solid.
To a solution of 5-nitro-1 /-/-isoindole-1,3(2/-/)-dione (1.0g, 5.2mmol) in dry THF (15mL) was added 10% Pd/C (0.2g). The mixture was hydrogenated at 30-40 psi for 17h. The catalyst was filtered, and the filtrate was evaporated under vacuo to give 0.5g (59.3%) of 5-amino-1H-isoindole-1,3(2H)-dione as a yellow colour solid.
To a stirred solution of 5-amino-1 H-isoindole-1,3(2H)-dione (1.0g, 6.2mmol) dissolved in sulfuric acid solution (2mL of Con. H2S04 in 7.5mL of H20) at 0°C, was added ice cold sodium nitrite solution ( 0.8g in 2mL of H20) dropwise. After 45min of stirring at 0°C, CuBr (3.4g, 23.7mmol) and HBr[48%] (13.6mL, 4vol. w.r.t. CuBr) were added at the same temperature. The resulting mixture was stirred at 80°C for 8h then poured into crushed 15 ice. Filtered the solid, washed with ice cold water and dried thoroughly to give 0.6g (43.0%) of 5-bromo-1/-/-isoindole-1,3(2H)-dione as a brown colour solid.
In a dried 500mL three necked round bottom flask equipped with a reflux condenser and addition funnel was taken BH3-THF (160mL) solution with dry THF (50mL). The mixture 20 was cooled to 0°C. To this cold solution 5-bromo-1/-/-isoindole-1,3(2/-/)-dione (8.0g, 35.4mmol) in dry THF (100mL) was added gradually and allowed to warm to room temperature. After 10min at room temperature the mixture was refluxed for 16h. The reaction mixture was then cooled to 0°C and quenched with methanol. (Caution: vigorous foaming will occur). 20-30mL of 2N HCL was added and refluxed the mixture for 1h. 25 Cooled the mixture and basified with NaOH solution and extracted with ethyl acetate. Combined organic extracts were washed with water, saturated NaCI solution, dried over Na2S04 and concentrated under vacuo. To the crude product in MeOH (150mL), Et3N (12mL) and di-te/f-butyl dicarbonate (13.8g, 63.23mmol) were added and stirred at room temperature for 16h. The reaction mixture was then concentrated under vacuo. The 30 crude product was diluted with CH2CI2 (200mL), washed with water, saturated NaCI solution, and dried over Na2S04. Crude product was purified by column chromatography using 20%ethyl acetate in hexanes as eluant to afford a colourless solid. To this dioxane-HCI was added at room temperature and stirred for 10 min, the solid obtained was then filtered and dried to give 3.0g (42.8%) of 5-bromoisoindoline hydrochloride salt as an ash 35 colour solid. 88 Received at IPONZ on 15 June 2011 Intermediate 21: 5-bromo-3-(4-piperidinylHAV-indole-7-carboxamide hydrochloride h A 4M solution of HCI in dioxane (194 mL) was added to a solution of 1,1-dimethylethyl 4-5 [7-(aminocarbonyl)-5-bromo-1/-/-indol-3-yl]-1-piperidinecarboxylate (10 g, 23.7 mmol) in methanol (50 mL). The reaction mixture was stirred at room temperature for 4 hours, and the solvent was evaporated under reduced pressure to give the title compound (9.5 g), which was used in the next step without further purification.
LC-MS: m/z 322.4 (M+H), 1.40 min.
Intermediate 22: 5-bromo-3-f1-r(1-methvlethvl)sulfonvn-4-piperidinyl)-1AV-indole-7-carboxamide h cr nh2 Triethylamine (2.6 mL, 18.7 mmol) was added to a solution of 5-bromo-3-(4-piperidinyl)-15 1/-/-indole-7-carboxamide hydrochloride in DMF (15 mL) at 0 °C. The mixture was stirred at room temperature for 10 min, and 2-propanesulfonyl chloride (1.04 mL, 9.32 mmol) was added. Stirring continued for another 30 min, and the reaction mixture was diluted with 1:1 Et0Ac/H20 (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 89 Received at IPONZ on 15 June 2011 saturated NaCI (1 x 100 mL), dried (MgS04), and concentrated under reduced pressure. The crude product was washed with MeOH (2x10 mL) to give the title compound (1.5 g, 75%).
LC/MS: m/z 427.8 (M+H), 1.98 min.
Intermediate 23: 5-(5-formvl-3-thienvl)-3-f1-r(1-methvlethvl)sulfonvn-4-piperidinyl)-1W-indole-7-carboxamide OHC cr nh2 The boronate ester used to make the title compound was prepared in 6 separate equal 10 batches according to the following procedure: To a solution of 4-bromo-2-thiophenecarbaldehyde (1.0 g, 4.48 mmol) in DME (20 mL) was added bis(pinacolato)diborane (1.48 g, 5.82 mmol), KOAc (1.14 g, 5.11 mmol) and Pd2CI2(dppf) (106 mg, 0.448 mmol). The reactions were run in a Smith microwave at 150 °C for 20 min. The 6 reactions were pooled and concentrated under reduced pressure. The 15 residue was taken up in EtOAc (200 mL) and H20 (50 mL). The layers were separated, the organic layer was washed with saturated NaCI (1 x 50 mL), dried (Na2S04), and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with hexanes/EtOAc to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (5 g, 78%).
A solution of 5-bromo-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1/-/-indole-7-carboxamide (428 mg, 1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (960 mg, 4 mmol), Cs2C03 (800 mg, 2.46 mmol), and Pd(PPh3)4 (100 mg, 0.0865 mmol) were heated in a Smith microwave at 160 °C for 20 min. The 25 reaction mixture was filtered and concentrated under reduced pressure. The crude product was washed with MeOH (1x5 mL) to give the title compound (395 mg, 86%). 90 Received at IPONZ on 15 June 2011 LC/MS: m/z 460.4 (M+H), 1.98 min.
Examples Example 1: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-(1-piperidinvlmethyl)phenvn-1AY-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (15.0 mg, 0.034 mmol) in DCM (2 mL) was added piperidine (4.0 ul, 0.04 10 mmol). The reaction solution was stirred at ambient temperature for 1 hr prior to addition of NaBH(OAc)3 (23.0 mg, 0.109 mmol). The resulting mixture was stirred overnight at ambient temperature after which time the solvent was removed under reduced pressure. The resulting residue was dissolved in 1.2 mL DMSO and all undissolved solid was filtered off. This DMSO solution of crude product was purified by reverse phase HPLC 15 (H20/CH3CN, 0.1 % TFA 10-90%) to give the title compound (8.8 mg, 50.5%).
LC/MS: m/z 509.4 (M+H), r.t: 1.87 min.
Example 2: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-(1-piperazinvlmethyl)phenvn-1AY-20 indole-7-carboxamide O NH cr NH '2 91 Received at IPONZ on 15 June 2011 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (15.0 mg, 0.034 mmol), piperazine (3.5 mg, 0.04 mmol) and NaBH(OAc)3 (23.0 mg, 0.102 mmol) were reacted to give the title compound (3.4 mg, 19.7%).
LC/MS: m/z 510.2 (M+H), r.t: 1.43 min.
Example 3: 3-ri-(ethvlsulfonvl)-4-piperidinvll-5-r3-(4-morpholinvlmethvl)phenyll-1 H-indole-7-carboxamide Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (15.0 mg, 0.034 mmol), morpholine (3.5 ul, 0.04 mmol) and NaBH(OAc)3 (23.0 mg, 0.102 mmol) were reacted to give the title compound (7.5 mg, 43%).
LC/MS: m/z 511.2 (M+H), r.t: 1.58 min.
Alternatively, example 3 may be prepared as follows: To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (20 mg, 0.046 mmol) in dichloromethane (1.5 mL) and methanol (1.5 mL) 20 was added morpholine (0.070 mL, 0.276 mmol) and 1 drop of acetic acid. This mixture was stirred for 2 h at room temperature and then sodium borohydride (11 mg, 0.276 mmol) was added. After 30 min the mixture was poured onto an SCX cartridge (5.0 g), and EtOAc (10.0 mL) and MeOH (10.0 mL) were used to flush the cartridge. A 2 M solution of NH3/MeOH (10.0 mL) was used to elute the product and was then 25 concentrated. The residue was dissolved in dimethyl sulfoxide (1.0 mL) and purified by Gilson Preparatory HPLC to give the title compound (17.6 mg, 75%). o cr nh2 92 Received at IPONZ on 15 June 2011 Example 4: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r3-(fmethyir2-(methvlsulfonvl)ethvnamino)methvl)phenvn-1^-indole-7-carboxamide cr NH Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-5 formylphenyl)-1/-/-indole-7-carboxamide (42.0 mg, 0.096 mmol), /V-methyl-2-(methylsulfonyl)ethanamine (12.0 mg, 0.087 mmol) and NaBH(OAc)3 (58.0 mg, 0.261 mmol) were reacted to give the title compound (15.1 mg, 28.0%).
LC/MS: m/z 561.2 (M+H), r.t: 1.58 min.
Example 5: 543-(IT2-(dimethvlamino)ethvn(methvl)amino1methvl}phenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1fV-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (45.0 mg, 0.101 mmol) in DCM (2 mL) was added A/,A/,/\Mrimethyl-1,2-15 ethanediamine (116 ul, 0.90 mmol). The reaction solution was stirred at ambient temperature for 1 hr prior to addition of NaBH(OAc)3 (69 mg, 0.326 mmol). The resulting mixture was stirred overnight at ambient temperature, and additional NaBH(OAc)3 (128 mg, 0.606 mmol) was added. The reaction was stirred for another 2 h, after which time the solvent was removed under reduced pressure. The crude product was purified by 20 reverse phase HPLC (water/CH3CN, 0.1 % TFA 10-90%) to give the title compound (16.0 mg, 29.6%).
LC/MS: m/z 526.8 (M+H), r.t: 1.28 min.
CT NH 93 Received at IPONZ on 15 June 2011 Example 6: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f3-r(4-f2-r(2-hvdroxvethvl)oxv1ethyl)-1-piperazinyl)methvnphenyl)-1Ay-indole-7-carboxamide OH n2i\i u Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-{[2-(1-piperazinyl)ethyl]oxy}ethanol (150 mg, 0.87 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (16.7 mg, 25%).
LC/MS: m/z 598.4 (M+H), r.t: 1.48 min.
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-15 formylphenyl)-1/-/-indole-7-carboxamide (50.0 mg, 0.112 mmol), 3-piperidinylmethanol (98.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound(10.2 mg, 17%).
LC/MS: m/z 539.4 (M+H), r.t: 1.52 min.
Example 7: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(3-U3-(hvdroxvmethvl)-1-piperidinvnmethvl}phenyl)-1fV-indole-7-carboxamide O 94 Received at IPONZ on 15 June 2011 Example 8: 5-|"3-(fbisr2-(methvloxv)ethvnamino)methyl)phenvn-3-ri-(ethylsulfonyl)-4-piperidinvn-1^-indole-7-carboxamide Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-5 formylphenyl)-1/-/-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(methyloxy)-A/-[2-(methyloxy)ethyl]ethanamine (114.3 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (10.5 mg, 16%).
LC/MS: m/z 557.6 (M+H), r.t: 1.62 min.
Example 9: 5-f3-r(2,6-dimethvl-4-morpholinvl)methvnphenvl}-3-ri-(ethvlsulfonyl)-4-pipe ridinvn-1fV-indole-7-carboxamide Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-15 formylphenyl)-1/-/-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2,6-dimethylmorpholine (98.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the title compound (19.6 mg, 32%).
LC/MS: m/z 539.2 (M+H), r.t: 1.75 min.
Example 10: 3-ri-(ethvlsulfonvlM-piperidinvn-5-(3-(T2-(1.3-thiazol-2-yl)-1-pyrrolidinvnmethvl)phenvl)-1AY-indole-7-carboxamide H0N O 95 Received at IPONZ on 15 June 2011 O H0N Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(2-pyrrolidinyl)-1,3-thiazole (132.4 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to 5 give the title compound (20.0 mg, 30.4 %).
LC/MS: m/z 578.6 (M+H), r.t: 1.57 min.
Example 11: 3-ri-(ethvlsulfonvl)-4-piperidinvll-5-(3-{r2-(2-thienyl)-1-10 pvrrolidinvnmethvl)phenyl)-1fV-indole-7-carboxamide Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(2-thienyl)pyrrolidine (132.4 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the 15 title compound (20.0 mg, 30.4 %).
LC/MS: m/z 577.4 (M+H), r.t: 1.78 min.
Example 12: 3-ri-(ethvlsulfonvl)-4-piperidinvll-5-(3-fr(2-hvdroxv-2-phenvlethyl)-(methvl)amino1methvl)phenyl)-1fV-indole-7-carboxamide 96 Received at IPONZ on 15 June 2011 HC H0N Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(methylamino)-1-phenylethanol (129.9 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were 5 reacted to give the title compound (22.1 mg, 36.6 %).
LC/MS: m/z 575.4 (M+H), r.t: 1.66 min.
Example 13: 5-(3-{rethvl(methvl)amino1methvl>phenvl)-3-ri-(ethvlsulfonyl)-4-10 pipe ridinvn-1fV-indole-7-carboxamide Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50.0 mg, 0.112 mmol), /V-methylethanamine (50.7 mg, 0.86 mmol) and NaBH(OAc)3 (58.0 mg, 0.303 mmol) were reacted to give the 15 title compound (11.5 mg, 21 %).
LC/MS: m/z 483.4 (M+H), r.t: 1.57 min.
Example 14: 5-r3-(aminomethvl)phenvn-3-H-(ethvlsulfonvl)-4-piperidinvn-1AY-indole-20 7-carboxamide O 97 Received at IPONZ on 15 June 2011 0=s o // l-LN O To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30.0 mg, 0.072 mmol), Cs2C03 (95 mg, 0.290 mmol) and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (82 mg, 0.350 mmol) in dioxane/H20 (2 mL/0.7 5 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (7.5 mg, 0.0072 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160 °C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgS04, filtered, concentrated, and purified by reverse phase HPLC method A 10 (water/CH3CN, 0.1 % TFA 10-90%) to give the title compound (2.7 mg, 8.5%).
LC/MS: m/z 441.4 (M+H), r.t: 1.54 min.
Example 15: 5-(3-r(cvclopentvlamino)methvllphenvl)-3-ri-(ethvlsulfonyl)-4-pipe ridinvn-1Ay-indole-7-carboxamide Following the general procedure of example 5, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (45 mg, 0.101 mmol), cyclopentylamine (90 uL, 0.090 mmol) and NaBH(OAc)3 (197 mg, 0.93 mmol) were reacted to give the title compound (33.0 mg, 64%).
LC/MS: m/z 509.4 (M+H), r.t: 1.64 min.
H0N 98 Received at IPONZ on 15 June 2011 Example 16: 5-r3-((T(3,4-dihvdroxyphenvl)methvnamino}methvl)phenvn-3-ri-(ethvlsulfonyl)-4-piperidinvn-1rt-indole-7-carboxamide HO HO H,N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-5 carboxamide (50 mg, 0.114 mmol) in dichloroethane (2 mL) was added 4-(aminomethyl)-1,2-benzenediol (12.1 mg, 0.087mmol). The reaction solution was stirred at ambient temperature for 10 min prior to addition of NaBH(OAc)3 (58 mg, 0.261 mmol). The resulting mixture was shaken overnight at ambient temperature after which time the solvent was removed under reduced pressure. The crude product was purified by 10 reverse phase HPLC (water/CH 3CN, 0.1 % TFA 10-90%) to give the title compound (7.4 mg, 12 %).
LC/MS: m/z 563.2 (M+H), r.t: 1.67 min.
Example 17: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(3-{r(3-15 thienylmethvl)amino1methvl)phenyl)-1 H-indole-7-carboxamide o Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol), 1-(3-thienyl)methanamine (9.83 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the 20 title compound (4.7 mg, 7.8 %).
LC/MS: m/z 537.2 (M+H), r.t: 1.62 min.
/ N 99 Received at IPONZ on 15 June 2011 Example 18: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-((T(1/?)-1-(hvdroxvmethyl)-2-methvlpropyllamino)methvl)phenvn-1^-indole-7-carboxamide Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-5 formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol), (2f?)-2-amino-3-methyl-1-butanol (10.2 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (14.9 mg, 25 %).
LC/MS: m/z 527.6 (M+H), r.t: 1.48 min.
Example 19: 3-ri-(ethylsulfonvlM-piperidinvH-5-(3-(r(2-hvdroxv-1-methvlethvl) aminolmethvl)phenyl)-1fV-indole-7-carboxamide: O Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol), 2-amino-1-propanol (6.5 15 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (3.4 mg, 6.0 %).
LC/MS: m/z 499.6 (M+H), r.t: 1.46 min.
Example 20: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(3-(T(frans-4-20 hvdroxvcvclohexvl)amino1methvl)phenyl)-1Ay-indole-7-carboxamide 100 Received at IPONZ on 15 June 2011 HO H,N ^O Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol), frans-4-aminocyclohexanol (10 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title 5 compound (6.0 mg, 9.8 %).
LC/MS: m/z 539.2 (M+H), r.t: 1.54 min.
Example 21: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-f3-r((T1-(1-piperidinvl)cvclohexvnmethvl)amino)methvnphenvl)-1Ay-indole-7-carboxamide Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol), 1-[1-(1-piperidinyl)cyclohexyl]methanamine (17 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (18.7 mg, 27 %).
LC/MS: m/z 620.6 (M+H), r.t: 1.6 min.
Example 22: 3-M-(ethvlsulfonvlM-piperidinvn-5-r3-(m2S)-2-hvdroxypropvnamino)methvl)phenvn-1^-indole-7-carboxamide H0N ^O 101 Received at IPONZ on 15 June 2011 O H0 H0N Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol), (2S)-1-amino-2-propanol (6.5 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title 5 compound (13.1 mg, 23 %).
LC/MS: m/z 499.6 (M+H), r.t: 1.46 min.
Example 23: 5-f3-r(ethvlamino)methvnphenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1fV-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (20 mg, 0.045 mmol) in dichloromethane (0.5 mL) and methanol (0.5 mL) was added ethylamine (130 uL, 0.27 mmol). This mixture was stirred for 1 h at room temperature, and then sodium borohydride (10 mg, 0.27 mmol) was added. The reaction was stirred at ambient temperature overnight, and the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1 % TFA 10-90%) to give the title compound (13.2 mg, 63 %).
LC/MS: m/z 469.4 (M+H), r.t: 1.54 min.
Example 24: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f3-r(propvlamino)methvnphenyl)-1W-indole-7-carboxamide H0N 102 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (20 mg, 0.046 mmol) in dichloromethane (0.7 mL) and methanol (0.7 mL) was added propylamine (22 uL, 0.27 mmol) and 1 drop of acetic acid. This mixture was 5 stirred for 1 h at room temperature and then sodium borohydride (10 mg, 0.27 mmol) was added. The reaction was stirred overnight at ambient temperature, and the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1 % TFA 10-90%) to give the title compound (22.1 mg, 99 %). LC/MS: m/z 483.2 (M+H), r.t: 1.58 min. 0 Example 25: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(3-{r(1-methvlethvl)amino1methvl)phenyl)-1AY-indole-7-carboxamide: Following the general procedure of example 24, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-15 formylphenyl)-1/-/-indole-7-carboxamide (20 mg, 0.045 mmol), isopropylamine (23 uL, 0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give the title compound (11.5 mg, 53 %).
LC/MS: m/z 483.2 (M+H), r.t: 1.52 min.
Example 26: 5-(3-(T(1-ethvlpropvl)amino1methvl)phenvl)-3-ri-(ethvlsulfonyl)-4-pipe ridinvl1-1^-indole-7-carboxamide 103 Received at IPONZ on 15 June 2011 h9n Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (20 mg, 0.045 mmol), 3-pentanamine (32 uL, 0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give the title compound (18.5 5 mg, 80 %).
LC/MS: m/z 511.4 (M+H), r.t: 1.66 min.
Example 27: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r4-(1-piperidinvlmethvl)phenvll-1 H-indole-7-carboxamide: Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.09 mmol), piperidine (0.009 mL, 0.09 mmol) and NaBH(OAc)3 (58 mg, 0.27 mmol) were reacted to give the title compound (8 mg, 17.5 %).
LC/MS: m/z 509.4(M+H), r.t: 1.71 min.
Example 28: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f3-r(methvlamino)methvnphenyl)-1W-indole-7-carboxamide o nh. 104 Received at IPONZ on 15 June 2011 O O Hr H0N Following the general procedure of example 24, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (20 mg, 0.045 mmol), methylamine (130 uL, 0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give title compound (17.0 mg, 83 5 %).
LC/MS: m/z 455.2 (M+H), r.t: 1.48 min.
Example 29: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r4-(4-morpholinvlmethyl)phenvn- 1W-indole-7-carboxamide Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol), morpholine (18 uL, 0.206 mmol) and NaBH(OAc)3 (290 mg, 1.37 mmol) were reacted to give the title compound (2.1 mg, 13 %).
LC/MS: m/z 511.4 (M+H), r.t: 1.63 min.
O H,N 105 Received at IPONZ on 15 June 2011 Example 30: 5-r4-(aminomethvl)phenvn-3-ri-(ethvlsulfonyl)-4-piperidinvn-1fV-indole-7-carboxamide To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30.0 5 mg, 0.072 mmol), Cs2C03 (95 mg, 0.290 mmol) and [4-(aminomethyl) phenyl boronic acid (55 mg, 0.290 mmol) in dioxane/H20 (1.5 mL/0.5 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (7.5 mg, 0.0072 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160°C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The 10 organic layer was washed with brine (10 mL), dried over MgS04, filtered, concentrated, and purified by reverse phase HPLC (water/ CH3CN, 0.1 % TFA 10-90%) to give the title compound (9.8 mg, 31%).
LC/MS: m/z 424.4 (M-NH2), r.t: 1.48 min.
Example 31: 5-f3-r(cvclopropvlamino)methvnphenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1fV-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.113 mmol) in DCM (2 mL) was added cyclopropanamine (19.3 20 mg, 0.339 mmol). The reaction solution was stirred at ambient temperature for 30 min prior to addition of HOAc (1 drop) and NaBH(OAc)3 (75 mg, 0.545 mmol). The resulting mixture was stirred overnight at ambient temperature after which time the solvent was O H,N O 106 Received at IPONZ on 15 June 2011 removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1 % TFA 10-90%) to give the title compound (18.2 mg, 34 %). LC/MS: m/z 481.2 (M+H), r.t: 1.52 min.
Example 32: 5-(3-r(cvclobutvlamino)methvnphenvl}-3-H-(ethvlsulfonvl)-4-piperidinvn-1^-indole-7-carboxamide Following the general procedure of example 31, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.113 mmol), cyclobutanamine (24.1 mg, 10 0.339 mmol) and NaBH(OAc)3 (75 mg, 0.545 mmol) were reacted to give the title compound (19.3 mg, 35 %).
LC/MS: m/z 495.6 (M+H), r.t: 1.55 min.
Example 33: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f3-r(2-methvlpropyl)amino1-2,3-15 dihvdro-1fV-inden-5-yl)-1fV-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) 20 and H20 (1.0 mL) was added 6-bromo-2,3-dihydro-1/-/-inden-1-one (274 mg, 1.30 mmol), and potassium carbonate (360 mg, 2.60 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before the addition of tetrakis (triphenylphosphosphine) palladium (0) (50 mg, 0.043 mmol). The reaction was then heated in the microwave for H2N 107 Received at IPONZ on 15 June 2011 min at 160° C. The reaction was then filtered and the solid was dissolved in EtOAc and H20. The organic layer was separated and concentrated. The crude residue was purified by Gilson Preparatory HPLC to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-oxo-2,3-dihydro-1 /-/-inden-5-yl)-1 /-/-indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-oxo-2,3-dihydro-1/-/-inden-5-yl)-1/-/-indole-7-carboxamide (45 mg, 0.097 mmol) in EtOH (2 mL) and acetic acid (200 (xL) was added 2-methyl-1-propanamine (170 jxL, 1.93 mmol) and sodium cyanoborohydride (20 mg, 0.291 mmol). The resulting mixture was reacted in a CEM microwave tube at 150° C 10 for 40 min. It was then purified by Gilson Preparatory HPLC to give 4.5 mg of the title compound (8.9 %).
LC/MS = m/z 523.4 [M+H] Ret. Time: 1.72 Example 34: 3-ri-(ethvlsulfonvl)-4-piperidinvll-5-{8-r(2-methvlpropyl)amino1-5,6,7,8-15 tetrahvdro-2-naphthalenyl)-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) 20 and H20 (1.0 mL) was added 7-bromo-3,4-dihydro-1(2H)-naphthalenone (292 mg, 1.30 mmol), and potassium carbonate (360 mg, 2.60 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before the addition of tetrakis (triphenylphosphosphine) palladium (0) (50 mg, 0.043 mmol). The reaction was then heated in the microwave for 30 min at 160° C. The reaction was then filtered and the solid was dissolved in EtOAc 25 and H20. The organic layer was separated and concentrated. The crude residue was purified by Gilson Preparatory HPLC to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(8-oxo-5,6,7,8-tetrahydro-2-naphthalenyl)-1/-/-indole-7-carboxamide. 108 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(8-oxo-5,6,7,8-tetrahydro-2-naphthalenyl)-1/-/-indole-7-carboxamide (40 mg, 0.08 mmol) in EtOH (2 mL) and acetic acid (0.2 mL) was added 2-methyl-1-propanamine (140 jaL, 1.6 mmol) and sodium cyanoborohydride (15 mg, 0.24 mmol). The resulting mixture was reacted in a CEM 5 microwave tube at 150° C for 40 min. It was then purified by Gilson Preparatory HPLC to give 3.2 mg of the title compound (7.5 %).
LC/MS = m/z 537.4 [M+H] Ret. Time: 1.71 Example 35: 5-(5-{r(2-cyanoethvl)amino1methvl)-2-fluorophenyl)-3-ri-10 (ethvlsulfonvl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) 15 and H20 (1.0 mL) was added 3-bromo-4-fluorobenzaldehyde (264 mg, 1.30 mmol), and K2C03 (360 mg, 2.60 mmol) in microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis (triphenylphosphosphine) palladium (0) (48 mg, 0.043 mmol). The reaction was heated in a microwave for 30 min at 160° C. The organic layer was separated and concentrated. The residue was dissolved in MeOH until solid 20 precipitated to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1/-/-indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.087 mmol) in dichloromethane (2 mL) and methanol (I mL) was 25 added 3-aminopropanenitrile (53 jaL, 0.524 mmol), and 1 drop of acetic acid. The reaction mixture was stirred at room temperature for 48 h. Sodium borohydride (20 mg, 0.524 mmol) was then added and reacted for 30 min at room temperature. Purified by Gilson Preparatory HPLC to give 14.4 mg of the title compound (32.4 %). 109 Received at IPONZ on 15 June 2011 LC/MS = m/z 512.2 [M+H] Ret. Time: 1.45 Example 36: 3-ri-(ethvlsulfonvl)-4-piperidinyll-5-(2-fluoro-5-fr(2,2,2-trifluoroethvl)amino1methvl>phenyl)-1 H-indole-7-carboxamide trifluoroacetate F r F .—N F / H o F F O f~K F OH To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1/-/-indole-7-carboxamide (20 mg, 0.04 mmol) in dichloromethane (4 mL) and methanol (2 mL) was added 2 drops of acetic acid and 2,2,2-trifluoroethanamine (23 (xL, 0.26 mmol). The resulting mixture was stirred overnight. All solvent was evaporated and dissolved in dimethyl sulfoxide (1 mL). Purified by Gilson Preparatory HPLC to give 5.2 mg of the title compound (24.0 %).
LC/MS = m/z 541.4 [M+H] Ret. Time. 1.67 Example 37: 3-ri-(ethvlsulfonvl)-4-piperidinvll-5-(1,2,3,4-tetrahydro-7-isoquinolinylH H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (60 mg, 0.13 mmol) in dioxane (2 mL) and 110 Received at IPONZ on 15 June 2011 water (1 mL) was added 7-bromo-1,2,3,4-tetrahydroisoquinoline (97 mg, 0.39 mmol) and potassium carbonate (108 mg, 0.78 mmol). This mixture was degassed for 5 min before the addition of tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol). The resulting mixture was reacted in a CEM microwave tube at 160° C for 30 min. The 5 organic layers were separated and concentrated. The resulting residue was dissolved in dimethyl sulfoxide (1 mL) and purified by Gilson Preparatory HPLC to give 3.5 mg of the title compound (5.7 %).
LC/MS = m/z 467.2 [M+H] Ret. Time. 1.48 Example 38: 3-ri-(ethvlsulfonylM-piperidinvn-5-(3-(T(2,2,2- trifluoroethvl)aminolmethvl>phenyl)-1 H-indole-7-carboxamide trifluoroacetate H^N ) To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (200 15 mg, 0.483 mmol) in dioxane (3.0 mL) and H20 (1.0 mL) was added (3-formylphenyl)boronic acid (317 mg, 1.93 mmol), and Cs2C03 (315 mg, 0.97 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis (triphenylphosphosphine) palladium (0) (48 mg, 0.043 mmol). The reaction was heated in a microwave for 30 min at 160° C. The organic layer was separated and concentrated. 20 The residue was dissolved in MeOH until solid precipitated to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.09 mmol) and 2,2,2-trifluoroethylamine (78 (xL, 0.55 mmol) in 25 dichloromethane (2 mL) and methanol (1 mL) was added 2 drops of acetic acid. The mixture was then stirred overnight. Sodium borohydride (20.8 mg, 0.55 mmol) was then added and the mixture was stirred for 30 min. The resulting mixture was concentrated and dissolved in dimethyl sulfoxide followed by purification by Gilson Preparatory HPLC to give 29.4 mg of the title compound (62.5%). n h,c o 111 Received at IPONZ on 15 June 2011 LC/MS = m/z 523.2 [M+H] Ret. Time. 1.66 Example 39: 5-(3-U(2-amino-2-oxoethvl)(methvl)amino1methvl)phenyl)-3-ri-(ethvlsulfonvl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate To a solution 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (44 mg, 0.1 mmol) and /V2-methylglycinamide (76 mg, 0.6 mmol) in 10 dichloromethane (3 mL) and methanol (1.5 mL) was added 3 drops of acetic acid. The mixture was stirred overnight. Sodium triacetoxyborohydride (134 mg, 0.6 mmol) was then added and stirred overnight. The resulting reaction was quenched with sodium biocarbonate (2 mL) and brine (2 mL). Organic layer was then collected and concentrated. The resulting residue was then purified by Gilson Preparatory HPLC to 15 give 13 mg of the title compound (25.4 %).
LC/MS = m/z 512.6 [M+H] Ret. Time. 1.20 Example 40: 3-ri-(ethvlsulfonvl)-4-piperidinyll-5-(2-fr(2.2.2-trifluoroethvl)amino1methyl)-1,3-thiazol-4-vl)-1H-indole-7-carboxamide 20 trifluoroacetate o F oh O 112 Received at IPONZ on 15 June 2011 To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) was added acetic acid (3 drops) and 2,2,2-trifluoroethanamine (120 |jL, 1.5 mmol). The reaction was stirred overnight. Sodium triacetoxyborohydride (335 mg, 1.5 mmol) was then added and reaction was stirred for 6 h. It was then quenched with sodium 5 bicarbonate to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2 mL) and 10 water (0.7 mL) was added N-[(4-bromo-1,3-thiazol-2-yl)methyl]-2,2,2-trifluoroethanamine (30 mg, 0.11 mmol) and potassium carbonate (83 mg, 0.6 mmol). The resulting mixture was degassed for 5 min before the addition of tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.01 mmol). The mixture was reacted in a CEM microwave tube at 160° C for 20 min. Organic layers were separated and concentrated. The resulting residue was 15 purified by Gilson Preparatory HPLC to give 25 mg of the title compound (47.2%).
LC/MS = m/z 530.2 [M+H] Ret. Time. 1.94 Example 41: 5-(3-cvano-5-{r(2,2,2-trifluoroethvl)amino1methvl)phenyl)-3-ri-(ethvlsulfonvl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2.0 mL, 0.7 25 mL) was added 3-bromo-5-formylbenzonitrile (68 mg, 0.3 mmol) and K2C03 (83 mg, 0.6 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis (triphenylphosphosphine) palladium (0) (11 mg, 0.01 mmol). The reaction was heated in a microwave for 20 min at 160° C. It was then purified by Gilson Preparatory 113 Received at IPONZ on 15 June 2011 HPLC to give 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide.
To a solution of 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-5 carboxamide (52 mg, 0.11 mmol) in dichloromethane (3 mL) and methanol (1 mL) was added 20 drops of acetic acid and 2,2,2-trifluoroethanamine (53 jaL, 0.66 mmol). The mixture was stirred for 48 h followed by addition of sodium triacetoxyborohydride (140 mg, 0.66 mmol). The mixture was then stirred for 48 h. The resulting reaction was quenched with sodium biocarbonate and brine was added. The organic layer was 10 separated and purified by Gilson Preparatory HPLC to give 3.6 mg of the title compound (6.0 %).
LC/MS = m/z 548.2 [M+H] Ret. Time. 1.88 Example 42: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(rmethvl(1-methyl-4-15 piperidinvl)amino1methvl)-3-thienyl)-1fV-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in dimethyl sulfoxide (2 mL) was added /V, 1 -dimethyl-4-piperidinamine (128.22 mg, 1.0 mmol), 2 drops of acetic acid and reacted overnight.
Sodium triacetoxyborohydride (212 mg, 1 mmol) was then added and reacted overnight at room temperature. It was then purified by Gilson Preparatory HPLC to give 8 mg of the title compound (13.0 %).
LC/MS = m/z 558.4 [M+H] Ret. Time: 1.32 min Example 43: 5-(5-(T(2-cyanoethvl)(methvl)amino1methvl}-3-thienyl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1AV-indole-7-carboxamide trifluoroacetate o \\ F OH o NH2 114 Received at IPONZ on 15 June 2011 n = The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-piperidinyl)amino]methyl}-3-thienyl)-1/-/-indole-7-carboxamide trifluoroacetate, substituting 3-(methylamino)propanenitrile (84.12 mg, 1.0 mmol) for A/,1-dimethyl-4-piperidinamine to afford 24 mg of the title compound (42.5 %).
LC/MS = m/z 514.4 [M+H] Ret. Time: 1.55 min Example 44: 5-(5-(T(2-amino-2-oxoethvl)(methvl)amino1methvl)-3-thienyl)-3-ri-(ethvlsulfonvl)-4-piperidinvn-1AV-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-piperidinyl)amino]methyl}-3-thienyl)-1/-/-indole-7-carboxamide trifluoroacetate, substituting /V2-methylglycinamide (88.11 mg, 1.0 mmol) for /V,1-dimethyl-4-piperidinamine to afford 19 mg of the title compound (33.3 %).
LC/MS = m/z 518.2 [M+H] Ret. Time: 1.43 min Example 45: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-(fmethyir2- (phenvlsulfonvl)ethvnamino)methyl)-3-thienvn-1rt-indole-7-carboxamide trifluoroacetate 115 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-piperidinyl)amino]methyl}-3-thienyl)-1/-/-indole-7-carboxamide trifluoroacetate, substituting N-methyl-2- (phenylsulfonyl)ethanamine (199.27 mg, 1.0 mmol) for A/,1-dimethyl-4-piperidinamine to afford 30 mg of the title compound (47.3 %).
LC/MS = m/z 629.4 [M+H] Ret. Time: 1.57 min Example 46: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-r(2-phenyl-1-pyrrolidinvl)methvn-3-thienvl'HAV-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2-phenylpyrrolidine (147 mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 120° C for 10 min. Sodium triacetoxyborohydride (220 mg, 1.0 mmol) was then added and the reaction was reacted at room temperature overnight. It was then purified by Gilson Preparatory HPLC to give 14.0 mg of the title compound (22 %).
LC/MS = m/z 577.2 [M+H] Ret. Time: 1.65 min.
Example 47: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(T2-(1-piperidinvlmethyl)-1-Pvrrolidinvnmethviy3-thienyl)-1AY-indole-7-carboxamide 116 Received at IPONZ on 15 June 2011 O nh2 The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl}-1 H-indole-7-carboxamide, substituting 1-(2-pyrrolidinylmethyl)piperidine (168.3 mg, 1.0 mmol) for 2-5 phenylpyrrolidine to afford 21 mg of the title compound (32 %).
LC/MS = m/z 598.4 [M+H] Ret. Time: 1.34 Example 48: 5-(5-(r(2ff)-2-(aminocarbonyl)-1 -pyrrolidinvnmethvl)-3-thienvl)-3-H-(ethvlsulfonyl)-4-piperidinvn-1fV-indole-7-carboxamide O The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl}-1 H-indole-7-carboxamide, substituting D-prolinamide (114 mg, 1.0 mmol) for 2-phenylpyrrolidine to afford 14 mg of the title compound (23 %).
LC/MS = m/z 544.2 [M+H] Ret. Time: 1.39 Example 49: 5-(5-(T(3S)-3-(dimethvlaminoH-pvrrolidinvnmethvl)-3-thienyl)-3-ri- (ethvlsulfonvl)-4-piperidinyll-1fV-indole-7-carboxamide h2n nh2 117 Received at IPONZ on 15 June 2011 O Chiral / N —N The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl}-1 H-indole-7-carboxamide, substituting (2R)-/V,/V-dimethyl-2-pyrrolidinamine (114 mg, 1.0 mmol) for 2-5 phenylpyrrolidine to afford 11 mg of the title compound (18 %).
LC/MS = m/z 544.2 [M+H] Ret. Time: 1.36 Example 50: 5-(1-f2-r4-(dimethvlamino)-1-piperidinvnethvl)-1H-pyrazol-4-vl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane (750 |jL) and H20 (250 |jL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-1-(2-chloroethyl)-1H-pyrazole (26 mg, 0.126 mmol). The reaction mixture was flushed under 15 Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.004 mmol). The reaction was heated in a microwave at 120° C for 20 min. It was then diluted with EtOAc (10 mL), filtered thru celite, followed by an aqueous work-up. The compound was purified by Gilson Preparatory HPLC to give 10 mg of 5-[1-(2-chloroethyl)-1H-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (24%). cr NH. '2 118 Received at IPONZ on 15 June 2011 To a solution of 5-[1-(2-chloroethyl)-1/-/-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (33 mg, 0.071 mmol) in tetrahydrofuran (500 uL) was added N,N-dimethyl-4-piperidinamine (100 |jL,0.71 mmol) and Sodium Iodide (5 mg, 0.018 mmol). The resulting mixture was reacted in a microwave tube at 130° C for 2 h. Performed 5 aqueous wash with EtOAc and water, isolated organic layers and removed all solvent. It was then purified by Gilson Preparatory HPLC to give 7.0 mg of the title compound (14.7 %).
LC/MS = m/z 556 [M+H] Ret. Time: 1.23 min.
Example 51: 5-r3-r(dimethvlamino)methvn-4,5-bis(methyloxv)phenvn-3-ri-(ethvlsulfonvl)-4-piperidinyn-1H-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (500 mg, 1.09 mmol) in dioxane (9.0 mL) 15 and H20 (3.0 mL) was added sodium carbonate (690 mg, 6.51 mmol), and 5-bromo-2,3-bis(methyloxy)benzaldehyde (7.95 mg, 3.25 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (63 mg, 0.054 mmol). The reaction was then heated in a microwave at 120° C for 30 min. All solvent was then concentrated and an aqueous wash was performed with EtOAc and 20 H20. The desired compound then percipiated and was filtered to give 322 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4,5-bis(methyloxy)phenyl]-1/-/-indole-7-carboxamide (59%).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4,5-bis(methyloxy)phenyl]-1/-/-indole-7-carboxamide (30 mg, 0.06 mmol) in methanol (2 mL), zinc chloride (5 mg, 25 0.03 mmol), sodium cyanoborohydride (5 mg, 0.06 mmol) and dimethylamine (100 |jL, 0.30 mmol). The mixture was stirred at room temperature for 2 h then reacted in the microwave at 100° C for 30 min. The resulting mixture was purified by Gilson Preparatory HPLC to give 11 mg of the title compound (34.7 %).
O^ NH2 119 Received at IPONZ on 15 June 2011 LC/MS = m/z 529 [M+H] Ret. Time: 1.67 min.
Example 52: 5-r3,4-bis(methvloxv)-5-(4-morpholinvlmethyl)phenvn-3-ri-(ethvlsulfonvl)-4-piperidinvn-1H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, substituting morpholine (20 |jL, 0.30 mmol) for dimethylamine to afford 8.0 mg of the title compound (23.4 %).
LC/MS = m/z 571 [M+H] Ret. Time: 1.59 min.
Example 53: 3-ri-(ethylsulfonvlM-piperidinvH-5-r3-(r(1-methvlethvl)amino1methvl)-4.5-bis(methvloxy)phenvn-1H-indole-7-carboxamide v in n2 The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, substituting 2-propanamine (20 |jL, 0.30 mmol) for dimethylamine to afford 15 mg of the title compound (46.1 %).
LC/MS = m/z 543 [M+H] Ret. Time: 1.59 min.
Example 54: 3-ri-(ethylsulfonvlM-piperidinvH-5-r3-(r(1-methvlethvl)amino1methvl)-4.5-bis(methvloxv)phenyll-1H-indole-7-carboxamide o 120 Received at IPONZ on 15 June 2011 / o NH, The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide , substituting 40 wt. % methylamine (50 |jL, 0.30 mmol) for dimethylamine to afford 6 mg of the title compound (19.4 %).
LC/MS = m/z 515 [M+H] Ret. Time: 1.46 min.
Example 55: 5-r3-(r(2.2-dimethvlpropvl)aminolmethvl)-4.5-bis(methvloxv)phenyll-3-H -(ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide , substituting (2,2-dimethylpropyl)amine (20 |jL, 0.30 mmol) for dimethylamine to afford 10 mg of the title compound (29.2 %).
LC/MS = m/z 571 [M+H] Ret. Time: 1.75 min.
Example 56: 3-ri-(ethylsulfonvl)-4-piperidinyll-5-r3-fr(2- hvdroxvethvl)(methvl)aminolmethvl)-4.5-bis(methvloxv)phenyll-1H-indole-7- carboxamide O NH.
O 121 Received at IPONZ on 15 June 2011 HO \ The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-5 indole-7-carboxamide , substituting 2-(methylamino)ethanol (20 |jL, 0.30 mmol) for dimethylamine to afford 10 mg of the title compound (29.8 %).
LC/MS = m/z 559 [M+H] Ret. Time: 1.54 min.
Example 57: 5-r3,4-bis(methvloxv)-5-(1-pvrrolidinvlmethyl)phenvn-3-ri-10 (ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-15 indole-7-carboxamide , substituting pyrrolidine (50 |jL, 0.30 mmol) for dimethylamine to afford 13 mg of the title compound (39.1 %).
LC/MS = m/z 555 [M+H] Ret. Time: 1.61 min.
Example 58: 5-(4-r(dimethvlamino)methvn-2.3-dihydro-1-benzofuran-6-vl)-3-ri-20 (ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide NH2 0 122 Received at IPONZ on 15 June 2011 o "NH.
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (113 mg, 0.274 mmol) in dioxane (9.0 mL) and H20 (3.0 mL) was added sodium carbonate 5 (174 mg, 1.64 mmol), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-4-carbaldehyde (150 mg, 0.547 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (16 mg, 0.014 mmol). The reaction was heated in a microwave at 120° C for 30 min. All solvent was then concentrated and purified by flash chromatography using DCM and 10 MeOH to give 120 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2,3-dihydro-1-benzofuran-6-yl)-1/-/-indole-7-carboxamide (91%).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2,3-dihydro-1-benzofuran-6-yl)-1/-/-indole-7-carboxamide (20 mg, 0.042 mmol) in methanol (2 mL) was added 15 dimethylamine (3 |jL ,0.050 mmol), zinc chloride (3 mg, 0.021 mmol) and sodium cyanoborohydride (4 mg, 0.062 mmol). This mixture was reacted in the microwave at 100° C for 1 h and then removed all solvent. The residue was washed with EtOAc and water. All solvent was removed and purified by Gilson Preparatory HPLC to give 6.0 mg of the title compound (19.6 %).
LC/MS = m/z 525 [M+H] Ret. Time: 1.56 min.
Example 59: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(4-(T(1-methvlethvl)amino1methyl)-2,3-dihydro-1 -benzofuran-6-yl)-1 H-indole-7-carboxamide Cr NH2 123 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-{4-[(dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide , substituting 2-propanamine (3 mg ,0.050 mmol) for dimethylamine to afford 9.0 mg of the title compound (28.6 %).
LC/MS = m/z 511 [M+H] Ret. Time: 1.58 min.
Example 60: 3-ri-(ethylsulfonvlM-piperidinvH-5-r4-(4-morpholinvlmethvl)-2.3-dihvdro-1-benzofuran-6-vn-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-{4-[(dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, substituting 2,2-dimethyl-1-propanamine (4 mg, 0.050 mmol) for dimethylamine to afford 8.0 mg of the title compound (24.1 %).
LC/MS = m/z 554 [M+H] Ret. Time: 1.71 min.
Example 61: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r5-((T1-methyl-2-(methvloxv)ethvnamino)methyl)-2-thienvn-1rt-indole-7-carboxamide [5-({[1-methyl-2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid (60 mg, 0.262 mmol) was transferred to a CEM microwave tube with methanol. The methonol was evaporated under a stream of N2. To this was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (80 mg, 0.19 mmol), potassium carbonate (160mg, 124 O NH.
O Received at IPONZ on 15 June 2011 1.16 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol), dioxane (1.5 mL), and water (0.5 mL). The vial was capped and reacted in a CEM microwave at 150° C for 30 min. This solution was loaded onto a 2 g SCX SPE cartridge primed with 3 mL of methanol. The cartidge was then sequentially eluted with water (3 mL), methanol (9 5 mL), and 2M NH3 in MeOH (6 mL). The NH3 in MeOH fractions were dried under a stream of N2 at 40° C. The crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP with UV (230 nm) and MS detection. The desired fractions were passed thru two sequential 500 mg Pharmasil CHQAX cartridge primed with 1 mL of methanol and 1 mL of water. The solvents were evaporated under a stream of N2 at 60° 10 C to give 34.7 mg of the title compound (34 %).
LC/MS = m/z 430 [M+H] Ret. Time: 1.32 min.
Example 62: 5-(5-(r(2-cvanoethvl)amino1methvl)-3-pvridinvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1fV-indole-7-carboxamide n2IN u To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.072 mmol) was added 3-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amino)propanenitrile (24.8 mg, 0.086 mmol). To this mixture was added dioxane (0.75 mL), followed by a solution of potassium carbonate (60 mg, 0.434 mmol) in 20 water (0.25 mL) and SK-CC02-A (4.4 mg, 0.007 mmol). The vials were capped and reacted in a CEM microwave at 150° C for 30 min. The reaction was loaded onto a 2 g SCX SPE cartidge primed with 3 mL of methanol. The cartridge was then sequentially eluted with water (3 mL), methanol (9 mL), and 2M NH3 in MeOH (6 mL). The NH3 in MeOH fractions were dried under a stream of N2 at 40° C. The crude product was 25 purified on the Agilent MDAP with UV (230 nm) and MS detection. The desired fractions were passed thru a 5 g CHQAX cartridge primed with 4 mL of methanol and 4 mL of water. The solvents were evaporated under a stream of N2 at 65° C to give 6.2 mg of the title compound (17.4 %).
LC/MS = m/z 495 [M+H] Ret. Time: 1.29 min. 125 Received at IPONZ on 15 June 2011 Example 63: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(5-(T(2,2,2-trifluoroethvl)amino1methvl}-3-pyridinvl)-1fV-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-(5-{[(2-5 cyanoethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7- carboxamide, substituting 2,2,2-trifluoro-A/-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}ethanamine (24.3 mg, 0.077 mmol) for 3-({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amino)propanenitrile to afford 8.3 mg of the title compound (22.0 %).
LC/MS = m/z 524 [M+H] Ret. Time: 1.55 min.
Example 64: 5-f3-r(dimethvlamino)methvllphenvl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1W-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (45 mg, 0.10 mmol) in DMSO (2 mL) was added 2 M dimethylamine in THF (500 |jL ,1.0 mmol). The reaction mixture was stirred at room temperature for 5 h before addition of sodium triacetoxyborohydride (220 mg, 1.04 mmol). The reaction was then 20 stirred overnight. Compound was purified by Gilson Preparatory HPLC to give 9.0 mg of the title compound (19.2 %).
LC/MS = m/z 469 [M+H] Ret. Time: 1.55 min 126 Received at IPONZ on 15 June 2011 Example 65: 5-(5-(Tethvl(methvl)amino1methvl}-3-thienvl)-3-ri-(ethvlsulfonyl)-4- piperidinvn-1fV-indole-7-carboxamide trifluoroacetate o \\ F O NH.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in dimethyl sulfoxide (2 mL) was added N-methylethanamine (59.1 mg, 1.0 mmol), 2 drops of acetic acid and reacted overnight. Sodium triacetoxyborohydride (212 mg, 1 mmol) was then added and reacted overnight at room temperature. It was then purified by Gilson Preparatory HPLC to give 20.0 mg of 10 the title compound (33.2 %).
LC/MS = m/z 489 [M+H] Ret. Time: 1.50 min Example 66: 5-(5-flT2-(diethvlamino)ethvn(methvl)amino1methvl)-3-thienyl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1^/-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide trifluoroacetate , substituting /V,/V-diethyl-/\/'-methyl-1,2-ethanediamine (130 20 mg, 1.0 mmol) for /V-methylethanamine to afford 30.0 mg of the title compound (44.5 %). LC/MS = m/z 560 [M+H] Ret. Time: 1.41 min. o f oh o nh2 127 Received at IPONZ on 15 June 2011 Example 67: 5-(5-(Tbutvl(methvl)amino1methvl}-3-thienvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1fV-indole-7-carboxamide trifluoroacetate o \\ f oh o nh2 The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide trifluoroacetate , substituting butyl(methyl)amine (87 mg, 1.0 mmol) for N-methylethanamine to afford 10 mg of the title compound (15.8 %).
LC/MS = m/z 517 [M+H] Ret. Time: 1.61 min. 0 Example 68: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-(Tmethvl(propyl)amino1methvl)-3-thienylHAV-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide trifluoroacetate, substituting methyl(propyl)amine (73 mg, 1.0 mmol) for N-methylethanamine to afford 20.0 mg of the title compound (32.4 %).
LC/MS = m/z 503 [M+H] Ret. Time: 1.54 min.
Example 69: 5-(5-flT2-(dimethvlamino)ethvn(methvl)amino1methvl)-3-thienyl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1^/-indole-7-carboxamide trifluoroacetate o o nh2 128 Received at IPONZ on 15 June 2011 O \ / n f oh o nh2 The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-5 carboxamide trifluoroacetate , substituting [2-(dimethylamino)ethyl]methylamine (102 mg, 1.0 mmol) for /V-methylethanamine to afford 26.0 mg of the title compound (40.3 %). LC/MS = m/z 532 [M+H] Ret. Time: 1.48 min.
Example 70: 5-(5-flT3-(dimethvlamino)propvll(methvl)aminolmethvl)-3-thienyl)-3-ri-10 (ethvlsulfonyl)-4-piperidinvn-1AY-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-15 carboxamide trifluoroacetate , substituting [3-(dimethylamino)propyl]methylamine (116 mg, 1.0 mmol) for /V-methylethanamine to afford 21.0 mg of the title compound (31.8 %). LC/MS = m/z 546 [M+H] Ret. Time: 1.49 min.
Example 71: 5-(5-(rcvclopentvl(methvl)amino1methvlV3-thienvl)-3-H-(ethvlsulfonvl)-20 4-piperidinvn-1fV-indole-7-carboxamide trifluoroacetate o \\ o nh2 129 Received at IPONZ on 15 June 2011 O \\ o nh2 The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-5 carboxamide trifluoroacetate , substituting cyclopentyl(methyl)amine (99 mg, 1.0 mmol) for /V-methylethanamine to afford 5.0 mg of the title compound (7.78 %).
LC/MS = m/z 529 [M+H] Ret. Time: 1.65 min.
Example 72: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-{rmethvl(pentvl)amino1methvl)-10 3-thienyl)-1AY-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-15 carboxamide trifluoroacetate , substituting methyl(pentyl)amine (101 mg, 1.0 mmol) for N-methylethanamine to afford 19.0 mg of the title compound (29.5 %).
LC/MS = m/z 531 [M+H] Ret. Time: 161 min.
Example 73: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(rmethyl(2-20 methvlpropvl)amino1methvl)-3-thienyl)-1AV-indole-7-carboxamide trifluoroacetate o nh2 130 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-5 carboxamide trifluoroacetate , substituting methyl(2-methylpropyl)amine (87 mg, 1.0 mmol) for /V-methylethanamine to afford 3.0 mg of the title compound (4.8 %).
LC/MS = m/z 517 [M+H] Ret. Time: 1.61 min.
Example 74: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(5-10 (rmethvl(phenvlmethvl)amino1methvl)-3-thienyl)-1AY-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-(5-15 {[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7- carboxamide trifluoroacetate , substituting methyl(phenylmethyl)amine (121 mg, 1.0 mmol) for /V-methylethanamine to afford 15 mg of the title compound (22.6 %).
LC/MS = m/z 551 [M+H] Ret. Time: 1.67 min.
Example 75: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(5-(r(2- hvdroxvethvlMmethvl)amino1methvl)-3-thienvl)-1AV-indole-7-carboxamide trifluoroacetate 131 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-5 carboxamide trifluoroacetate , substituting 2-(methylamino)ethanol (75 mg, 1.0 mmol) for /V-methylethanamine to afford 27.0 mg of the title compound (43.6 %).
LC/MS = m/z 505 [M+H] Ret. Time: 1.46 min.
Example 76: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r5-(fmethyir2-(2-10 pyridinvl)ethvnamino)methyl)-3-thienvn-1 AY-indole-7-carboxamide trifluoroacetate o o=s^/ / /—N s ( > ij W iW I H O^NH2 F O f oh The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-15 carboxamide trifluoroacetate , substituting methyl[2-(2-pyridinyl)ethyl]amine (75 mg, 1.0 mmol) for /V-methylethanamine to afford 5.0 mg of the title compound (7.36 %).
LC/MS = m/z 566 [M+H] Ret. Time: 1.59 min.
Example 77: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(5-fr(2-20 furanvlmethvl)(methvl)amino1methvl}-3-thienyl)-1AV-indole-7-carboxamide trifluoroacetate 132 Received at IPONZ on 15 June 2011 O tj1 F \ v i m n F——^ o INn2 F OH The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-5 carboxamide trifluoroacetate , substituting 1-(2-furanyl)-/V-methylmethanamine (111 mg, 1.0 mmol) for /V-methylethanamine to afford 19.0 mg of the title compound (29.0 %). LC/MS = m/z 541 [M+H] Ret. Time: 1.59 min.
Example 78: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-{Tmethyl(4-10 pvridinvlmethvl)amino1methvl)-3-thienyl)-1fV-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-15 carboxamide trifluoroacetate , substituting methyl(4-pyridinylmethyl)amine (122 mg, 1.0 mmol) for /V-methylethanamine to afford 31.0 mg of the title compound (46.6 %).
LC/MS = m/z 552 [M+H] Ret. Time: 1.37 min.
Example 79: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-r(methvlU1-(1-methvlethyl)-3-20 pvrrolidinvnmethvl)amino)methvn-3-thienyl)-1AV-indole-7-carboxamide trifluoroacetate o N F OH 133 Received at IPONZ on 15 June 2011 O f oh The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-5 carboxamide trifluoroacetate , substituting methyl{[1-(1-methylethyl)-3-pyrrolidinyl]methyl}amine (156 mg, 1.0 mmol) for /V-methylethanamine to afford 21.0 mg of the title compound (30.0 %).
LC/MS = m/z 586 [M+H] Ret. Time: 1.43 min.
Example 80: 3-ri-(ethylsulfonvlM-piperidinvH-5-(5-(rmethvl(2- thienylmethvl)amino1methvl)-3-thienyl)-1AY-indole-7-carboxamide trifluoroacetate o The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-15 carboxamide trifluoroacetate , substituting methyl(2-thienylmethyl)amine (127 mg, 1.0 mmol) for /V-methylethanamine to afford 26.0 mg of the title compound (38.8 %).
LC/MS = m/z 557 [M+H] Ret. Time: 1.72 min.
Example 81: 3-H-(ethvlsulfonvl)-4-piperidinvn-5-r5-((methyiri-(2-20 thienvl)ethvnamino)methyl)-3-thienvn-1AV-indole-7-carboxamide trifluoroacetate / 134 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-5 carboxamide trifluoroacetate , substituting methyl[1-(2-thienyl)ethyl]amine (141 mg, 1.0 mmol) for /V-methylethanamine to afford 6.0 mg of the title compound (8.76 %).
LC/MS = m/z 571 [M+H] Ret. Time: 1.78 min.
Example 82: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(Tmethyl(3-10 thienylmethvl)amino1methvl)-3-thienyl)-1AY-indole-7-carboxamide trifluoroacetate o W x The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-15 carboxamide trifluoroacetate , substituting methyl(3-thienylmethyl)amine (127 mg, 1.0 mmol) for/V-methylethanamine to afford 7.0 mg of the title compound (10.4 %).
LC/MS = m/z 557 [M+H] Ret. Time: 1.78 min.
Example 83: 3-ri-(ethylsulfonvlM-piperidinvH-5-(5-(rmethvl(tetrahvdro-2fV-pvran-4-20 vlmethvl)aminolmethvl)-3-thienyl)-1AV-indole-7-carboxamide trifluoroacetate 135 Received at IPONZ on 15 June 2011 F OH The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-5 carboxamide trifluoroacetate , substituting methyl(tetrahydro-2/-/-pyran-4-ylmethyl)amine (129 mg, 1.0 mmol) for /V-methylethanamine to afford 11.0 mg of the title compound (16.4 %).
LC/MS = m/z 559 [M+H] Ret. Time: 1.63 min.
Example 84: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(Tmethyl(3- Pvridinvlmethvl)amino1methvl)-3-thienyl)-1fV-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-(5-15 {[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7- carboxamide trifluoroacetate , substituting methyl(3-pyridinylmethyl)amine (122 mg, 1.0 mmol) for /V-methylethanamine to afford 9.5 mg of the title compound (14.3 %).
LC/MS = m/z 552 [M+H] Ret. Time: 1.56 min.
Example 85: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(Tmethyl(4- pyrimidinvlmethvl)amino1methvl)-3-thienvl)-1AY-indole-7-carboxamide trifluoroacetate o w N 136 Received at IPONZ on 15 June 2011 O W C /N ^—I The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-5 carboxamide trifluoroacetate , substituting methyl(4-pyrimidinylmethyl)amine (123 mg, 1.0 mmol) for /V-methylethanamine to afford 4.0 mg of the title compound (6.0 %).
LC/MS = m/z 555 [M+H] Ret. Time: 1.65 min.
Example 86: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-({methyir2-10 (methvloxv)ethvnamino)methyl)-3-thienvH-1AY-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (884 mg, 1.98 mmol) in dimethyl sulfoxide (5 mL) was added methyl[2-15 (methyloxy)ethyl]amine (1.86 g, 21 mmol) and HOAc (2 mL, 35 mmol). The reaction was stirred overnight at room temperature, and sodium triacetoxyborohydride (212 mg, 1 mmol) was added. Stirring continued for 1 hr, and CHCI3 (50 mL) was added. The mixture was filtered, the CHCI3 was concentrated under reduced pressure, and the crude product/dmso solution was purified by Gilson Prepatory HPLC to give the title compound 20 (590 mg, 47%).
LC/MS = m/z 519 [M+H] Ret. Time: 1.50 min. o w \ o 137 Received at IPONZ on 15 June 2011 Example 87: 5-f3-r(dimethvlamino)methvnphenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (45 mg, 0.1 mmol) in DMSO (2 mL) was added 2 M methylamine in THF (500 |jL, 1.0 mmol) and stirred at room temperature for 5 h. To the mixture, was then added sodium triacetoxyborohydride (220 mg, 1.0 mmol) and stirred overnight. It was then purified by Gilson Preparatory HPLC to give 9.0 mg of the title compound (15.4 %). 10 LC/MS = m/z 469 [M+H] Ret. Time: 1.55 min.
Example 88: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(rmethyl(1-methvlethvl)amino1methvl)-3-thienyl)-1AV-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (46.0 mg, 0.1 mmol) in DMSO (2.0 mL) was added N-methyl-2-propanamine (73.1 mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 160° C for 10 min. Sodium triacetoxyborohydride (220 mg, 1.0 mmol) was 20 then added and the reaction was reacted at room temperature overnight. It was then purified by Gilson Preparatory HPLC to give 24.0 mg of the title compound (44.2 %). LC/MS = m/z 543 [M+H] Ret. Time: 1.70 min. ° nh. 138 Received at IPONZ on 15 June 2011 Example 89: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f5-r(2-propvl-1-pyrrolidinvl)methvn-3-thienyl}-1fV-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2-propylpyrrolidine (113 mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 120° C for 10 min. Sodium triacetoxyborohydride (220 mg, 1.0 mmol) was then added and the reaction was reacted at room temperature overnight. It was then purified by Gilson Preparatory 10 HPLC to give 21.0 mg of the title compound (38.7 %).
LC/MS = m/z 543 [M+H] Ret. Time: 1.70 min.
Example 90: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(T2-(3-pyridinvl)-1- pyrrolidinvnmethvl)-3-thienvl)-1AY-indole-7-carboxamide o The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1 -pyrrolidinyl)methyl]-3-thienyl}-1 /-/-indole-7-carboxamide , substituting 3-(2-pyrrolidinyl)pyridine (148 mg, 1.0 mmol) for 2-20 propylpyrrolidine to afford 13.0 mg of the title compound (22.5 %).
LC/MS = m/z 578 [M+H] Ret. Time: 1.52 min. o 139 Received at IPONZ on 15 June 2011 Example 91: 5-(5-(T2-(1,1-dimethvlethvl)-1-pvrrolidinvnmethvl)-3-thienyl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1f/-indole-7-carboxamide trifluoroacetate o ii 0=s^ / The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1 -pyrrolidinyl)methyl]-3-thienyl}-1 /-/-indole-7-carboxamide , substituting 2-(1,1-dimethylethyl)pyrrolidine (127 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 11.0 mg of the title compound (16.4 %).
LC/MS = m/z 557 [M+H] Ret. Time: 1.65 min.
Example 92: 5-f5-r(2-ethvl-1-pvrrolidinvl)methvn-3-thienvl)-3-ri-(ethvlsulfonyl)-4-pipe ridinyll-l H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1 -pyrrolidinyl)methyl]-3-thienyl}-1 /-/-indole-7-carboxamide , substituting 2-ethylpyrrolidine (99.0 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 15.0 mg of the title compound (28.4 %).
LC/MS = m/z 529 [M+H] Ret. Time: 1.66 min.
Example 93: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(T2-(2-methvlpropyl)-1-Pvrrolidinvnmethvl)-3-thienyl)-1AV-indole-7-carboxamide trifluoroacetate 140 Received at IPONZ on 15 June 2011 O II 0=S f oh o nh2 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1 -pyrrolidinyl)methyl]-3-thienyl}-1 /-/-indole-7-5 carboxamide , substituting 2-(2-methylpropyl)pyrrolidine (127 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 7.0 mg of the title compound (10.4 %).
LC/MS = m/z 557 [M+H] Ret. Time: 1.74 min.
Example 94: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(T2-(1-methvlethyl)-1-10 pvrrolidinvllmethvl)-3-thienyl)-1AV-indole-7-carboxamide O The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1 -pyrrolidinyl)methyl]-3-thienyl}-1 /-/-indole-7-15 carboxamide , substituting 2-(1-methylethyl)pyrrolidine (113 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 16.0 mg of the title compound (29.5 %).
LC/MS = m/z 543 [M+H] Ret. Time: 1.61 min.
Example 95: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-(((2S)-2-r(methyloxv)methvn-1-20 pvrrolidinvl)methyl)-3-thienvn-1AV-indole-7-carboxamide 141 Received at IPONZ on 15 June 2011 O / -o > cr nh2 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1 -pyrrolidinyl)methyl]-3-thienyl}-1 /-/-indole-7-5 carboxamide , substituting (2S)-2-[(methyloxy)methyl]pyrrolidine (115 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 22.0 mg of the title compound (40.4 %).
LC/MS = m/z 544 [M+H] Ret. Time: 1.44 min.
Example 96: 5-(5-(Tcvclohexvl(methvl)amino1methvl)-3-thienvl)-3-ri-(ethvlsulfonyl)-10 4-piperidinvll-l H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1 -pyrrolidinyl)methyl]-3-thienyl}-1 /-/-indole-7-carboxamide , substituting cyclohexyl(methyl)amine (113 mg, 1.0 mmol) for 2-15 propylpyrrolidine to afford 15.0 mg of the title compound (27.6 %).
LC/MS = m/z 543 [M+H] Ret. Time: 1.64 min.
Example 97: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(r2-(2-methvlpropyl)-1-pyrrolidinvnmethvl)-3-thienvl)-1H-indole-7-carboxamide o II o=s O NH2 142 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1 H-indole-7-carboxamide , substituting 2-(2-methylpropyl)pyrrolidine (127 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 12.0 mg of the title compound (21.6 %).
LC/MS = m/z 557 [M+H] Ret. Time: 1.74 min.
Example 98: 5-(5-(rethvl(methvl)aminolmethvlV3-thienvl)-3-ri-(ethvlsulfonylM-piperidinyll-1 H-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2 drops of acetic acid, ethyl(methyl)amine (59 mg, 1.0 mmol), and stirred at room temperature for 5 h. To this was then added sodium triacetoxyborohydride (212 mg, 1.0 mmol) and reacted overnight. 15 It was then purified by Gilson Preparatory HPLC to give 30.0 mg of the title compound (61.4 %).
LC/MS = m/z 489 [M+H] Ret. Time: 1.50 min.
Example 99: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-(Tmethvl(propyl)amino1methvl)-20 3-thienyl)-1H-indole-7-carboxamide 143 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide, substituting methyl(propyl)amine (73 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 32.0 mg of the title compound (63.7 %).
LC/MS = m/z 503 [M+H] Ret. Time: 1.54 min.
Example 100: 3-f1-r(1-methvlethvl)sulfonvn-4-piperidinyl)-5-(5-(Tmethvl(propyl)amino1methvl)-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1/-/-indole-7-carboxamide (46 mg, 0.10 mmol) in DMSO (2.0 mL) was added 2 drops of acetic acid, methyl(propyl)amine (73 mg, 1.0 mmol), and stirred at room temperature for 5 h. To 15 this was then added sodium triacetoxyborohydride (212 mg, 1.0 mmol) and reacted overnight. It was then purified by Gilson Preparatory HPLC to give 25.0 mg of the title compound (39.6 %).
LC/MS = m/z 517 [M+H] Ret. Time: 1.61 min.
Example 101: 5-(5-{Tethvl(methvl)amino1methvl)-3-thienyl)-3-(1-r(1-methylethvl)sulfonvn-4-piperidinyl)-1 H-indole-7-carboxamide 144 Received at IPONZ on 15 June 2011 O W o=s o nh2 The title compound was prepared according to the general procedure of 3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-(5-{[methyl(propyl)amino]methyl}-3-thienyl)-1/-/-indole-7-carboxamide trifluoroacetate, substituting ethyl(methyl)amine (59 mg, 1.0 mmol) for methyl(propyl)amine to afford 8.0 mg of the title compound (15.9 %).
LC/MS = m/z 503 [M+H] Ret. Time: 1.59 min.
Example 102: 3-(1-r(1-methylethvl)sulfonvll-4-piperidinvl)-5-r5-((methyir2-(methvloxv)ethvnamino)methyl)-3-thienvn-1AY-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-(5-{[methyl(propyl)amino]methyl}-3-thienyl)-1/-/-indole-7-carboxamide trifluoroacetate, substituting methyl[2-(methyloxy)ethyl]amine (89 mg, 1.0 mmol) for methyl(propyl)amine to afford 37.0 mg of the title compound (69.4 %). LC/MS = m/z 533 [M+H] Ret. Time: 1.58 min.
Example 103: 3-ri-(ethvlsulfonvlM-piperidinvll-5-(5-r(methvlamino)methyll-2-thienvl)-1AV-indole-7-carboxamide o w o=s r o nh2 145 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1/-/-indole-7-carboxamide (35 mg, 0.078 mmol) in DMSO (1.0 mL) was added acetic acid (3 drops), 2 M methylamine in THF (0.24 mL, 0.471 mmol), and reacted for 3 h. Sodium 5 triacetoxyborohydride (100 mg, 0.471 mmol) was then added and reaction was stirred overnight. All solvent was removed in vacuo and purified by Gilson Preparatory HPLC. The impure desired fraction was concentrated under reduced pressure and loaded onto a 500 mg SCX SPE cartidge primed with 10 mL of methanol. The cartridge was then sequentially eluted with 2M NH3 in MeOH (10 mL x 2). The NH3 in MeOH fractions were 10 concentrated to give 7.3 mg of the title compound (20%).
LC/MS = m/z 459.6 [M+H] Ret. Time: 1.25 min.
Example 104: 3-H-(ethvlsulfonvl)-4-piperidinvn-5-(5-r(2-methyl-1-pyrrolidinvl)methvn-3-thienvl'HAV-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (3.0 mL) was added acetic acid (3 drops), 2-methylpyrrolidine (0.12 mL, 1.12 mmol) and reacted for 4 h. Sodium triacetoxyborohydride (238 mg, 1.12 mmol) was then added and the reaction was stirred 20 overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 17 mg of the title compound (30%). 146 Received at IPONZ on 15 June 2011 LCMS: 515.4 (M+H), Rt 1.60 min Example 105: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(5-(T(2- methvlpropyl)amino1methvl)-3-thienvl)-1AY-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL) was added acetic acid (4 drops), (2-methylpropyl)amine (0.17 mL, 1.68 mmol), and sodium triacetoxyborohydride (356 mg, 10 1.68 mmol) were reacted. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 15 mg of the title compound (27%).
LCMS: 503.4 (M+H), Rt 1.60 min Example 106: 3-ri-(ethvlsulfonvl)-4-piperidinvll-5-f5-r(propylamino)methvll-3-15 thienvl"HAY-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL) was added acetic acid (3 drops), (2-methylpropyl)amine (0.17 mL, 1.68 mmol), and sodium triacetoxyborohydride (356 mg, 147 Received at IPONZ on 15 June 2011 1.68 mmol) were reacted. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 15 mg of the title compound (27%).
LCMS: 489 (M+H), Rt 1.61 min Example 107: 5-(5-r(diethvlamino)methvn-3-thienvl)-3-H-(ethvlsulfonvl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-10 carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL), was added acetic acid (3 drops), diethylamine (0.12 mL, 1.12 mmol) and stirred for 4 h at room temperature. Sodium triacetoxyborohydride (238 mg, 1.12 mmol) was then added and the reaction was stirred overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 7.0 mg of the title compound (13%).
LCMS: 501.4 (M+H), Rt 1.51 min Example 108: 5-(5-<T(2/?.5/?)-2.5-dimethvl-1-pyrrolidinvllmethvl)-3-thienvl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate O NH.
O NH. 148 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (3 drops), (2R,5R)-2,5-dimethylpyrrolidine (151 mg, 1.123 mmol), and reacted for 4 h. Sodium 5 triacetoxyborohydride (238 mg, 1.123 mmol) was then added. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 27 mg of the title compound (46%).
LCMS: 529.4 (M+H), Rt 1.64 min Example 109: 5-f5-r(cvclopropvlamino)methvH-3-thienvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL), was added acetic acid (5 drops), 15 and cyclopropylamine (0.12 mL, 1.68 mmol) and reacted for 6 h. Sodium triacetoxyborohydride (356 mg, 1.68 mmol) was then added and the reaction was stirred overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 8.0 mg of the title compound (10%).
LCMS: 487.2 (M+H), Rt 1.64 min and 1.68 min Example 110: 5-{5-r(cvclobutvlamino)methvn-3-thienvl)-3-H-(ethvlsulfonvl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate 149 Received at IPONZ on 15 June 2011 r o NH. '2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL), was added acetic acid (4 drops), and cyclobutylamine (0.15 mL, 1.68 mmol) and reacted for 4 h. Sodium 5 triacetoxyborohydride (356 mg, 1.68 mmol) was then added and the reaction was stirred overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 5.0 mg of the title compound (10%).
LCMS: 501.4 (M+H), Rt 1.51 min Example 111: 5-(5-r(dimethylamino)methvll-3-thienyl)-3-ri-(ethylsulfonyl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2-thienyl)-1/-/-indole-7-15 carboxamide (300 mg, 0.67 mmol) in DMSO (4 mL), was added a solution of 2 M dimethylamine in THF (3.36 mL, 6.7 mmol). The reaction was stirred at room temperature for 7 h, and sodium triacetoxyborohydride (1.42 g, 6.7 mmol) was added. o NH '2 150 Received at IPONZ on 15 June 2011 Stirring continued overnight at room temperature. The reaction mixture was purified by reverse phase Gilson Prepatory HPLC to give the title compound (205 mg, 64%).
LCMS: 475.2 (M+H), Rt 1.51 min Example 112: 5-(5-{T(cvclopentvlmethvl)amino1methvl)-3-thienvl)-3-H -(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-10 carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), acetic acid (3 drops), (cyclopentylmethyl)amine (112 mg, 1.123 mmol), and was reacted for 4h. Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was stirred overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 8.0 mg of the title compound (14%).
LCMS: 529.4 (M+H), Rt 1.61 min and 1.64 min Example 113: 5-r5-((T(1 /?)-1,2-dimethylpropvnamino)methvl)-3-thienyll-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate O NH. '2 151 Received at IPONZ on 15 June 2011 f oh h cr nh2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (3 drops), (2R)-3-methyl-2-butanamine (98 mg, 1.123 mmol), and reacted for 4 h. Sodium 5 triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was stirred overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give5.0 mg of the title compound (10%).
LCMS: 517.2 (M+H), Rt 1.65 min Example 114: 5-f5-r(cvclopentvlamino)methvn-3-thienvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-15 carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (3 drops), cyclopentanamine (0.11 mL, 1.123 mmol), and reacted for 4 h. Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was O NH '2 152 Received at IPONZ on 15 June 2011 reacted overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 5.0 mg of the title compound (6.0%).
LCMS: 515.6 (M+H), Rt 1.38 min Example 115: 5-(5-{T(cvclopropvlmethvl)amino1methvl)-3-thienvl)-3-H-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), acetic acid (3 drops), 1-10 cyclopropylmethanamine (0.10 mL, 1.123 mmol), and was reacted for 6 h. Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was stirred overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 5.0 mg of the title compound (10%).
LCMS: 501.4 (M+H), Rt 1.53 min Example 116: 5-r5-«T(1 S)-1.2-dimethvlpropyllamino)methvl)-3-thienvll-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate 153 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), acetic acid (3 drops), (2S)-3-methyl-2-butanamine (98 mg, 1.123 mmol), and was reacted for 6 h. Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was stirred 5 overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 8.0 mg of the title compound (15%).
LCMS: 517.2 (M+H), Rt 1.65 min Example 117: 5-(5-{T(2.2-dimethvlpropvl)amino1methvl)-3-thienvl)-3-H -10 (ethvlsulfonyl)-4-piperidinvn-1AV-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (3 drops), 15 (2,2-dimethylpropyl)amine (0.13 mL, 1.123 mmol), and reacted for 6 h. Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was then added and stirred overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 4.0 mg of the title compound (7%).
LCMS: 517.2 (M+H), Rt 1.68 min and 1.71 min Example 118: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-(T(phenvlmethvl)amino1methyl)-3-thienylHAV-indole-7-carboxamide trifluoroacetate 154 Received at IPONZ on 15 June 2011 F \ F OH H To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (5 drops), (phenylmethyl)amine (0.14 mL, 1.123 mmol), and reacted for 6 h. Sodium 5 triacetoxyborohydride (238 mg, 1.123 mmol) was then added and stirred overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 5.0 mg of the title compound (8%).
LCMS: 537.2 (M+H), Rt 1.68 min Example 119: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r5-((T(2S)-tetrahydro-2- furanvlmethvllamino)methvl)-3-thienyll-1fV-indole-7-carboxamide trifluoroacetate To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-indole-7-carboxamide (50 mg, 0.112 mmol) in dichloromethane (3.0 mL) and methanol (1.5 mL), 15 acetic acid (5 drops), 1-[(2S)-tetrahydro-2-furanyl]methanamine (0.12 mL, 1.123 mmol), and reacted for 6 h. Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction / "O 155 Received at IPONZ on 15 June 2011 mixture was purified by reverse phase Gilson Preparatory HPLC to give 23 mg of the title compound (8%).
LCMS: 531.4 (M+H), Rt 1.58 min Example 120: 3-H-(ethvlsulfonvl)-4-piperidinvn-5-(5-(r(tetrahvdro-2H-pvran-4-vlmethvl)amino1methvl)-3-thienyl)-1AV-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), acetic acid (5 drops), and 10 (tetrahydro-2H-pyran-4-ylmethyl)amine (130 mg, 1.123 mmol), and reacted for 6 h. Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was stirred overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 7.0 mg of the title compound (11%).
LCMS: 545.4 (M+H), Rt 1.52 min cr NH Example 121: 5-f5-r(butvlamino)methvn-3-thienvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate o nh 156 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in dichloromethane (3.0 mL) and methanol (1.5 mL), was added 5 drops of acetic acid, butylamine (0.11 mL, 1.123 mmol) and reacted for 6 h. Sodium borohydride (43 mg, 1.123 mmol) was then added and stirred at room 5 temperature overnight. All solvent was removed in vacuo and dissolved in DMSO (1.0 mL). It was then purified by reverse phase Gilson Preparatory HPLC to give 5.0 mg of the title compound (10%).
LCMS: 503.4 (M+H), Rt 1.63 min Example 122: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r5-((T(2/?)-tetrahydro-2- furanvlmethvnamino)methyl)-3-thienvn-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL), was added acetic acid (5 drops), 1-15 [(2f?)-tetrahydro-2-furanyl]methanamine (130 mg, 1.123 mmol), and the reaction mixture was reacted for 6 h. Sodium triacetoxyborohydride (238 mg, 1.123 mmol) was then added and the reaction was stirred overnight. Additional 1-[(2R)-tetrahydro-2-furanyl]methanamine (130 mg, 1.123 mmol) was then added followed by sodium triacetoxyborohydride after 6 h. The reaction mixture was purified by reverse phase 20 Gilson Preparatory HPLC to give 5.0 mg of the title compound (8.0%).
LCMS: 531.4 (M+H), Rt 1.50 min Example 123: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-(f(2S)-2-r(methyloxv)methvn-1-pyrrolidinvl)methvl)-3-thienvll-1fV-indole-7-carboxamide trifluoroacetate 157 Received at IPONZ on 15 June 2011 \ \^ N F OH T H O NH To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-indole-7-carboxamide (50 mg, 0.112 mmol) in dichloromethane (3.0 mL) and methanol (1.5 mL), was added 5 drops of acetic acid, (2S)-2-[(methyloxy)methyl]pyrrolidine (129 mg, 1.123 5 mmol) and recated at room temperature for 6 h. Sodium borohydride (43 mg, 1.123 mmol) was than added and the reaction was stirred at room temperature overnight. The reaction mixture was purified by reverse phase Gilson Preparatory HPLC to give 8.0 mg of the title compound the (13%).
LCMS: 545.2 (M+H), Rt 1.62 min and 1.66 min.
Example 124: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-(((2ff)-2-r(methyloxv)methvn-1-pyrrolidinvl)methvl)-3-thienvn-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.112 mmol) in dichloromethane (3.0 mL) and methanol (1.5 mL), was added acetic acid (5 drops), (2f?)-2-[(methyloxy)methyl]pyrrolidine (129 mg, 1.123 mmol) and stirred at room temperature for 6 h. Sodium borohydride (43 mg, 1.123 mmol) was then added and the reaction was stirred at room temperature overnight. The mixture O NH 158 Received at IPONZ on 15 June 2011 was purified by reverse phase Gilson Preparatory HPLC to give 5.0 mg of the title compound (13%).
LCMS: 545.2 (M+H), Rt 1.62 min and 1.66 min.
Example 125: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(4-r2-(methvlamino)ethvnphenyl)-1 H-indole-7-carboxamide To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (200 mg, 0.48 mmol) in dioxane and H20 was added was added [4-10 (cyanomethyl)phenyl]boronic acid (232 mg, 0.144 mmol), potassium carbonate (400 mg, 2.88 mmol), and tetrakis(triphenylphosphine)palladium (0) (30 mg, 0.048 mmol). The solution was stirred and heated in the microwave at 160° C for 40 min. The reaction was diluted with EtOAc and H20 and filtered to obtain a yellow crystal as desired product. The solution was washed with brine and H20 and then EtOAc was concentrated. To the 15 reside was added MEOH which precipitated the desired product and then washed again with MeOH to give 5-[4-(cyanomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide.
To 5-[4-(cyanomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (78 mg, 0.173 mmol) in DCM was added 1.5 M diisobutylaluminum hydride solution in 20 toluene (240 mL, 0.346 mmol) at 0° C. The reaction was stirred at 0° C for 20 min. The reaction was then quenched with saturated KNa tartrate solution. The bi-layer was filtered, and the solid was the desired product. Additionally, the organic layer was concentrated to give the desired compound, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-1/-/-indole-7-carboxamide, which was taken on without further 25 purification.
O H2N O 159 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in methanol (5 mL) and methylene chloride (5 mL) at room temperature was added 2 M methylamine in tetrahydrofuran (0.4 mL) followed by 1 drop of acetic acid. The reaction was stirred at room temperature for 2 h followed by an 5 addition of sodium triacetoxyborohydride (200 mg, 0.94 mmol). This reaction was stirred overnight. It was then purified by flash chromatography to give 10 mg of the title compound (19.4%).
LC/MS = m/z 469.4 [M+H] Ret. Time: 1.63 min.
Example 126: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f4-r2-(propylamino)ethvnphenvl)-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-1H-indole-7-carboxamide, 15 substituting 2 M propylamine in tetrahydrofuran (0.4 mL) for methylamine to afford 15 mg of the title compound (27.5%).
LC/MS = m/z 497.6 [M+H] Ret. Time: 1.63 min.
Example 127: 5-f4-r2-(ethvlamino)ethvnphenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-20 1 H-indole-7-carboxamide 160 Received at IPONZ on 15 June 2011 "1 o HN \ M H H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in methanol (5 mL) and methylene chloride (5 mL) at room temperature was added 2 M ethylamine in tetrahydrofuran (0.4 mL), followed by 1 5 drop of acetic acid. The reaction was stirred at room temperature for 2 h followed by an addition of sodium triacetoxyborohydride (200 mg, 0.94 mmol). This reaction was stirred overnight. It was then purified by flash chromatography to give 15 mg of the title compound (28.3%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.57 min.
Example 128: 5-f4-r((T1-(1,1-dimethvlethvl)-3-methvl-1H-pyrazol-5-vllcarbonvl)amino)methvllphenvl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate To a solution of [4-(aminomethyl)phenyl]boronic acid (145 mg, 0.966 mmol) in DMF (2 mL) was added 1-(1,1-dimethylethyl)-3-methyl-1/-/-pyrazole-5-carbonyl chloride (290 mg, 1.45 mmol) and triethylamine (403 |jL, 2.90 mmol). The reaction was stirred for 2 h. It was then quenched and partitioned between EtOAc and H20 and the organic layer was O 161 Received at IPONZ on 15 June 2011 concentrated to give {4-[({[1-(1,1-dimethylethyl)-3-methyl-1/-/-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid.
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (50 5 mg, 0.120 mmol)in dioxane (1 mL) and water (0.4 mL) was added potassium carbonate (74 mg, 0.484 mmol) and {4-[({[1-(1,1-dimethylethyl)-3-methyl-1/-/-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid (153 mg, 0.483 mmol). The reaction mixture was stirred and bubbled with argon for 5 min. before the addition of chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium (II) (7 mg, 0.012 10 mmol). The reaction was stirred for 10 min then heated to 150° C. The reaction was evaporated and purified by Gilson Preparatory HPLC to give 5 mg of the title compound (5.8%).
LC/MS = m/z 605.4 [M+H] Ret. Time: 2.14 min.
Example 129: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(4-(T(4- pyridinvlcarbonvl)amino1methvl>phenyl)-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-20 (ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate , substituting (4-{[(4-pyridinylcarbonyl)amino]methyl}phenyl)boronic acid (124 mg, .480 mmol) for {4-[({[1-(1,1-dimethylethyl)-3-methyl-1 H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid to afford 30 mg of the title compound (45.8%).
LC/MS = m/z 537 [M+H] Ret. Time: 2.04 min.
Example 130: 5-(4-(T(cvclopentvlcarbonvl)amino1methvl)phenvl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide 162 Received at IPONZ on 15 June 2011 o N H H2N O The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate , substituting (4-5 {[(cyclopentylcarbonyl)amino]methyl}phenyl)boronic acid (119 mg, 0.480 mmol) for {4-[({[1 -(1,1 -dimethylethyl)-3-methyl-1 H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid to afford 30 mg of the title compound (47%).
LC/MS = m/z 537 [M+H] Ret. Time: 2.04 min.
Example 131: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(4-(T(2- furanylcarbonvl)aminolmethvl)phenyl)-1 H-indole-7-carboxamide O The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-15 (ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate , substituting (4-{[(2-furanylcarbonyl)amino]methyl}phenyl)boronic acid (118 mg, 0.480 mmol) for {4-[({[1-(1,1-dimethylethyl)-3-methyl-1 H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid to afford 16 mg of the title compound (25%).
LC/MS = m/z 535.5 [M+H] Ret. Time: 1.99 min. 163 Received at IPONZ on 15 June 2011 Example 132: 5-(4-f2-r(cvclobutvlcarbonvl)amino1ethvl)phenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-{4-[2-(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide substituting A/-[2-(4-bromophenyl)ethyl]cyclobutanecarboxamide (100 mg, 0.324 mmol) for A/-[2-(4-bromophenyl)ethyl]acetamide. Purified by flash chromatography to afford 28 mg of the title compound (48.3%).
LC/MS = m/z 537.2 [M+H] Ret. Time: 1.99 min.
Example 133: 5-(4-f2-r(cvclohexvlcarbonvl)amino1ethvl}phenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-{4-[2-(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, substituting /V-[2-(4-bromophenyl)ethyl]cyclohexanecarboxamide (100 mg, 0.324 mmol) 164 Received at IPONZ on 15 June 2011 for A/-[2-(4-bromophenyl)ethyl]acetamide. Purified by flash chromatography to afford 32 mg of the title compound (52.5%).
LC/MS = m/z 565.4 [M+H] Ret. Time: 2.14 min.
Example 134: 5-(3-(2-r(cvclohexvlcarbonvl)amino1ethvl}phenvl)-3-H-(ethvlsulfonvl)-4-piperidinvn-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-{4-[2-(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, substituting /V-[2-(3-bromophenyl)ethyl]cyclohexanecarboxamide (100 mg, 0.324 mmol) for /V-[2-(4-bromophenyl)ethyl]acetamide. The concentrated reaction mixture was purified by Gilson Preparatory HPLC followed by re-purification by flash chromatography to give the title compound.
LC/MS = m/z 565.2 [M+H] Ret. Time: 2.16 min.
Example 135: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r6-(1-piperazinvl)-3-pyridinvn-1AY-indole-7-carboxamide trifluoroacetate To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (100 mg, 0.241 mmol) in dioxane (1.0 mL) and H20 (0.8 mL) was added cesium carbonate (314 mg, 0.964 mmol), and [6-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)-3-pyridinyl]boronic acid (297 mg, 0.964 mmol). The reaction mixture was stirred before addition of tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol). The reaction o o o w 165 Received at IPONZ on 15 June 2011 was heated in a microwave at 160° C for 20 min. Mixture was concentrated and taken up in EtOAc (10 mL) and H20 (5.0 mL). Compound was purified by Gilson Preparatory HPLC to give 129 mg of 1,1-dimethylethyl 4-(5-{7-(aminocarbonyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indol-5-yl}-2-pyridinyl)-1-piperazinecarboxylate and 3-[1-(ethylsulfonyl)-4-5 piperidinyl]-5-[6-(1-piperazinyl)-3-pyridinyl]-1/-/-indole-7-carboxamide (44%).
To a solution of 1,1-dimethylethyl 4-(5-{7-(aminocarbonyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indol-5-yl}-2-pyridinyl)-1-piperazinecarboxylate (130 mg, 0.218 mmol) in methanol (0.3 mL) was added 4 M HCI in dioxane (0.3 mL). The reaction was heated at 10 50° C and stirred for 3 h. Reaction mixture was concentrated and neautralized on a SCX cartridge primed with CH2CI2, followed by MeOH and collection with ammonia in MeOH. 20 mg of desired fraction was concentrated and purified using MDAP HPLC to give 9.4 mg of the title compound (7%).
LC/MS = m/z 497.2 [M+H] Ret. Time: 1.45 min To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[6-(1 -piperazinyl)-3-pyridinyl]-1 /-/-indole-7-carboxamide (40 mg, 0.081 mmol) in dichloromethane was added acetaldehyde (7 mg, 0.162 mmol) and sodium triacetoxyborohydride (100 mg, 0.472 mmol). The reaction was stirred overnight at room temperature. Reaction mixture was then concentrated and dissolved in EtOAc and H20. Salts were filtered and organic layer was 25 concentrated and purified by Gilson Preparatory HPLC to give 39 mg of the title compound (92%).
LC/MS = m/z 525.6 [M+H] Ret. Time: 1.44 min Example 136: 5-r6-(4-ethyl-1-piperazinvl)-3-pvridinvn-3-ri-(ethvlsulfonyl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate '2 166 Received at IPONZ on 15 June 2011 Example 137: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r4-(1-piperidinvlmethyl) phenyll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-5 carboxamide (40 mg, 0.09 mmol) in dichloromethane was added piperidine (9 |jL, 0.09 mmol). The reaction was stirred for 1 h before addition of sodium triacetoxyborohydride (58 mg, 0.27 mmol). The reaction mixture was stirred overnight at room temperature. Mixture was then concentrated and purified by Gilson Preparatory HPLC to give 8.0 mg of the title compound (14%).
LC/MS = m/z 509.4 [M+H] Ret. Time: 1.71 min Example 138: 3-ri-(ethvlsulfonvlM-piperidinvll-5-r3-(1-piperidinvlmethvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in dichloromethane (2 mL) and acetic acid (1 drop) was added piperidine (46 |jL, 0.456 mmol). The reaction was stirred for 2 h at room temperature before the addition of sodium triacetoxyborohydride (75 mg, 0.342 mmol). 167 Received at IPONZ on 15 June 2011 The reaction was then stirred an additional 3 h. The mixture was then purified by Gilson Preparatory HPLC to give 36 mg of the title compound (61%).
LC/MS = m/z 509.4 [M+H] Ret. Time: 1.80 min Example 139: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(4-r(methvlamino)methvnphenyl)-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (20 mg, 0.045 mmol) in dichloromethane (12 mL), Methanol (2 mL) and 10 acetic acid was added methylamine in THF (20 |jL, 0.54 mmol). The reaction mixture was stirred at room temperature for 2 h before addition of sodium triacetoxyborohydride (10.3 mg, 0.270 mmol). The mixture was then stirred for another 3 h before the mixure was concentrated and purified by Gilson Preparatory HPLC to give 6 mg of the title compound (10%).
LC/MS = m/z 454.6 [M+H] Ret. Time: 1.23 min Example 140: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(4-(T(1-methvlethvl)aminolmethvl)phenyl)-1H-indole-7-carboxamide h2n o nh '2 168 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.09 mmol) in DMSO (900 |jL) and acetic acid (2 drops) was added 2-propanamine (93 |jL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was purified 5 by Gilson Preparatory HPLC to afford 30 mg of the title compound (69%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.56 min Example 141: 3-ri-(ethvlsulfonvl)-4-piperidinvll-5-f4-r(propylamino)methvllphenvl)-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (20 mg, 0.045 mmol) in DMSO (900 |jL) and acetic acid (2 drops) was added propylamine (45 |jL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was purified 15 by Gilson Preparatory HPLC to afford 21.1 mg of the title compound (74%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.54 min.
Example 142: 5-(4-{T(1-ethvlpropvl)aminolmethvl)phenvl)-3-H-(ethvlsulfonvl)-4-piperidinyll-l H-indole-7-carboxamide o NH O NH 169 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.09 mmol) in DMSO (900 |jL) and acetic acid (2 drops) was added 3-pentanamine (108 |jL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was purified 5 by Gilson Preparatory HPLC to afford 34.5 mg of the title compound (74%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.69 min Example 143: 5-(4-r(cvclopentvlamino)methvllphenvl)-3-ri-(ethvlsulfonylM-piperidinyll-lH-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.09 mmol) in DMSO (900 |jL) and acetic acid (2 drops) was added cyclopentylamine (108 |jL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was purified 15 by Gilson Preparatory HPLC to afford 11.1 mg of the title compound (20%).
LC/MS = m/z 509.4 [M+H] Ret. Time: 1.66 min.
Example 144: 5-f4-r(cvclobutvlamino)methvnphenvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-l H-indole-7-carboxamide 170 Received at IPONZ on 15 June 2011 N H O NH '2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.091 mmol) in DMSO (900 |jL) and acetic acid (2 drops) was added cyclobutylamine (94 |jL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (120 5 mg, 1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 26.3 mg of the title compound (59%).
LC/MS = m/z 495.4 [M+H] Ret. Time: 1.37 min Example 145: 5-(4-r(ethvlamino)methvllphenvl)-3-ri-(ethvlsulfonvlM-piperidinyll-10 1 H-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (20 mg, 0.046 mmol) in DMSO and acetic acid was added ethylamine (32 |jL, 0.547 mmol). After 2 h, sodium triacetoxyborohydride (120 mg, 1.10 mmol) was 15 added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 11.5 mg of the title compound (55%).
LC/MS = m/z 469.4 [M+H] Ret. Time: 1.52 min. h h2n 171 Received at IPONZ on 15 June 2011 Example 146: 5-f4-r(dimethvlamino)methvnphenvl}-3-ri-(ethvlsulfonyl)-4-piperidinyll-l H-indole-7-carboxamide k h h2n 0 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-5 carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added N- dimethylamine (170 |jL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 28.9 mg of the title compound (54%).
LC/MS = m/z 469.4 [M+H] Ret. Time: 1.52 min. 0 Example 147: 5-f4-r(diethvlamino)methvnphenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-15 carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added diethylamine (36 |jL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 37.6 mg of the title compound (67%).
H2N O 172 Received at IPONZ on 15 June 2011 LC/MS = m/z 497.6 [M+H] Ret. Time: 1.52 min.
Example 148: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r4-(4-morpholinvlmethyl)phenvn-1 H-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added morpholine (30 |jL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 40.3 mg of the title compound (70%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.53 min Example 149: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r4-(1-pyrrolidinvlmethvl)phenvn- 1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added H2N O 173 Received at IPONZ on 15 June 2011 cyclopentylamine (28 |jL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 20.1 mg of the title compound (36%).
LC/MS = m/z 495.4 [M+H] Ret. Time: 1.58 min Example 150: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r4-((T(1S)-2-hvdroxy-1-methylethvllamino)methvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-10 carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added (2S)-2-amino-1-propanol (56 |jL, 0.745 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 25.9 mg of the title compound (15%). LC/MS = m/z 499.6 [M+H] Ret. Time: 1.54 min Example 151: 3-ri-(ethvlsulfonvlM-piperidinvll-5-r4-«T(1/?)-2-hydroxv-1-methvlethvnamino)methvl)phenvn-1 H-indole-7-carboxamide trifluoroacetate h2n o r-o h2n o 174 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added (2f?)-2-amino-1-propanol (56 |jL, 0.745 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound 5 was purified by Gilson Preparatory HPLC to afford 29.6 mg of the title compound (53%). LC/MS = m/z 499.6 [M+H] Ret. Time: 1.47 min Example 152: 3-ri-(ethvlsulfonvl)-4-piperidinvll-5-r4-«T(2/?)-2-hvdroxypropvnamino)methvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added (2f?)-1-amino-2-propanol (56 |jL, 0.745 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound 15 was purified by Gilson Preparatory HPLC to afford 14.7 mg of the title compound (26%). LC/MS = m/z 499.6 [M+H] Ret. Time: 1.46 min.
Example 153: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r4-((T2-hvdroxy-1-(hvdroxvmethvl)ethvnamino)methyl)phenvn-1H-indole-7-carboxamide 20 trifluoroacetate 175 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (40 mg, 0.091 mmol) in DMSO was added 2-amino-1,3-propanediol (50 mg, 0.55 mmol) and acetic acid (1 drop). After 2 h, sodium triacetoxyborohydride (232 mg, 5 1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 15.9 mg of the title compound (28%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.45 min.
Example 154: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(3-(T(1-10 methvlbutvl)amino1methvl)phenyl)-1fV-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3.0 mL) was added 1-2-pentanamine (324 |jL, 2.74 mmol) and acetic acid (1 drop). After 2 h, sodium triacetoxyborohydride (290 15 mg, 1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was then filtered and concentrated. It was then purified by Gilson Preparatory HPLC to afford 9.5 mg of the title compound (13%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.66 min 176 Received at IPONZ on 15 June 2011 Example 155: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-r3-((T(1fl)-1-methylpropvllamino)methyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate f f p oh h2n O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (2.0 mL) was added (2/?)-2-butanamine (69 |jL, 0.684 mmol) and acetic acid (1 drop). After 2 h, sodium triacetoxyborohydride (0.435 mg, 2.05 mmol) was added. Reaction mixture was stirred overnight. Compound was then filtered and concentrated. It was then purified by Gilson Preparatory HPLC to afford 10 18.6 mg of the title compound (33%).
LC/MS = m/z 497.6 [M+H] Ret. Time: 1.70 min Example 156: 3-H-(ethvlsulfonyl)-4-piperidinvn-5-(3-(r(2-methylpropvl)amino1methvl)phenyl)-1 H-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL), MeOH (1.5 mL), and acetic acid (4 h2n O 177 Received at IPONZ on 15 June 2011 drops) was added 2-methyl-1-propanamine (137 |jL, 1.37 mmol) and stirred at room tempertuare. After 2 h, sodium borohydride (23 mg, 0.684 mmol) was added and the reaction mixture was purified by SCX cartridge to give 47.8 mg of the title compound (85%).
LC/MS = m/z 497.2 [M+H] Ret. Time: 1.69 min Example 157: 3-ri-(ethylsulfonvlM-piperidinvll-5-r3-«T(1S)-1-methvlpropyllamino)methvl)phenvll-1 H-indole-7-carboxamide acetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide , substituting (2S)-2-butanamine (138 |jL, 1.37 mmol) for 2-methyl-1-propanamine to afford 43.2 mg of the title compound (76%).
LC/MS = m/z 497.4 [M+H] Ret. Time: 1.84 min Example 158: 5-(4-(T(cvclopropvlcarbonvl)amino1methvl)phenyl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide 178 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-{4-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting cyclopropanecarbonyl chloride (14 |jL, 1.37 mmol) for acetyl chloride. Compound was purified by Gilson Preparatory HPLC to afford 19.1 mg of the title 5 compound (28%).
LC/MS = m/z 509.2 [M+H] Ret. Time: 1.86 min Example 159: 5-(4-<T(cvclobutvlcarbonvl)aminolmethvl)phenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-{4-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting cyclobutanecarbonyl chloride (17 |jL, 1.37 mmol) for acetyl chloride. Compound was purified by Gilson Preparatory HPLC to afford 20.2 mg of the title 15 compound (28%).
LC/MS = m/z 523.2 [M+H] Ret. Time: 1.94 min Example 160: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(4-(T(2-thienvlacetvl)amino1methvl}phenyl)-1H-indole-7-carboxamide h2n o 179 Received at IPONZ on 15 June 2011 N H H2N O The title compound was prepared according to the general procedure of 5-{4-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting (3Z)-3-(methylthio)-3,5-hexadienoyl chloride (18 |jL, 1.37 mmol) for acetyl 5 chloride. Compound was purified by Gilson Preparatory HPLC to afford 13.5 mg of the title compound (18%).
LC/MS = m/z 565.2 [M+H] Ret. Time: 1.98 min Example 161: 5-r4-((T(1S)-1,2-dimethvlpropvnamino)methyl)phenvn-3-ri-10 (ethvlsulfonyl)-4-piperidinvn-1AV-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.091 mmol) in DCM (1.5 mL), MeOH (1.5 mL) and acetic acid was added (2S)-3-methyl-2-butanamine (128 |jL, 1.10 mmol) and stirred at room temperature 15 for 2 h. Sodium borohydride (19 mg, 0.546 mmol) was then added and stirred for 48 h. Compound was then purified by Gilson Preparatory HPLC to give 5.8 mg of the title compound (12%).
LC/MS = m/z 511.2 [M+H] Ret. Time: 1.76 min H2N o 180 Received at IPONZ on 15 June 2011 To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (50 mg, 0.121 mmol) in dioxane (1 mL) and H20 (0.4 mL) was added potassium carbonate (74 mg, 0.484 mmol), and (4{[(methylsulfonyl)amino]methyl}phenyl)boronic acid (110 mg, 0.50 mmol). The reaction mixture was stirred and bubbled thru with Argon 5 for 5 min before addition of chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium (II) (7 mg, 0.012 mmol). The reaction was then stirred and heated for 10 min in a microwave at 160° C. The mixture was concentrated and purified by Gilson Preparatory HPLC to afford 34.3 mg of the title compound (55%).
LC/MS = m/z 519.4 [M+H] Ret. Time: 1.77 min Example 162: 5-r3-«T(1/?)-1.2-dimethvlpropvllamino)methvl)phenvll-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL), MeOH (1.5 mL) and acetic acid was added (2R)-3-methyl-2-butanamine (160 |jL, 1.37 mmol) and stirred at room temperature for 2 h. Sodium borohydride (19 mg, 0.546 mmol) was then added and stirred for 48 h. Compound was then purified by Gilson Preparatory HPLC to give 50 mg of the title 20 compound (86%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.65 min Example 163: 5-(6-amino-2-pvridinvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1fV-indole-7-carboxamide trifluoroacetate H2N o 181 Received at IPONZ on 15 June 2011 F H2N F F O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (83 mg, 0.18 mmol) in dioxane (5 mL) was 5 added 6-bromo-2-pyridinamine (93 mg, 0.54 mmol), potassium carbonate (149 mg, 1.08 mmol) in H20 (1.5 mL) and chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium (II) (19 mg, 0.031 mmol). The reaction was heated in the microwave at 150° C for 20 min. The reaction mixture was then concentrated and an aqueous extraction was performed. Organic layer was then 10 concentrated and purified on a Mass Directed Auto Prep HPLC to give 22.3 mg of the title compound (29%).
LC/MS = m/z 428.6 [M+H] Ret. Time: 1.34 min Example 164: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-(1H-pvrazol-1-vl)phenvn-1H-15 indole-7-carboxamide To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (20 mg, 0.048 mmol) was added [3-(1/-/-pyrazol-1-yl)phenyl]boronic acid (36 mg, 0.193 mmol), dioxane (2.8 mL) and a solution of potassium carbonate (20 mg) in water (1.2 mL). To 20 this mixture was added chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (3 mg, 0.005 mmol). The resulting mixture was reacted in a CEM microwave for 10 min at 160 °C then concentrated under a stream of nitrogen (greenhouse) at 80 °C. The crude product was partitioned between water (2 mL) and CH2CL2 (2 mL). The layers were separated with a hydrophobic frit, and the aqueous r n o nh2 182 Received at IPONZ on 15 June 2011 layer was extracted with CH2CL2 (2x2 mL). The organic layers were pooled and concentrated under a stream of nitrogen at 80 °C. Dimethyl sulfoxide (0.8 mL) was added to residue, which was sonicated for 10 sec, filtered through a cotton plug, and then filtered through a 0.2 nm filter. The crude product was purified on an Agilent MDAP using 5 a Zorbax Eclipse XDB 610 21.2 x 50 mm column to afford 2.3 mg of the title compound (10%).
LC/MS = m/z 478.2 [M+H] Ret. Time: 2.05 min.
Example 165: 5-r4-(dimethvlamino)phenvn-3-ri-(ethvlsulfonvl)-4-piperidinvn-1H-10 indole-7-carboxamide To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (40 mg, 0.097 mmol), dioxane (2.8 mL) and a solution of potassium carbonate (40 mg, 0.289 mmol) in water (1.2 mL). To this mixture was added [4-15 (dimethylamino)phenyl]boronic acid (65 mg, 0.386 mmol) and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (1 mg, 0.002 mmol). The vial was capped and the reaction was reacted in a CEM microwave for 10 min at 160 °C. The reaction was concentrated under a stream of nitrogen at 80 °C. The crude product was taken up in dimethyl sulfoxide (1 mL) and purified through a 1 g silica 20 SPE cartridge eluting with dimethyl sulfoxide (4 mL). The dimethyl sulfoxide was concentrated in a Genevac at 65 °C for 3 h, and the residue was reconstituted in dimethyl sulfoxide (1 mL) and filtered through an acrodisc. The solution of crude product was then purified on the Agilent MDAP (UV 214 selection). The purified product was passed through a polymer-bound carbonate SPE cartridge to afford 2.7 mg of the title compound 25 (6.2%).
LC/MS = m/z 455.2 [M+H] Ret. Time: 1.71 min.
Example 166: 5-(3-aminophenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide 183 Received at IPONZ on 15 June 2011 r O nh.
To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (40 mg, 0.0965 mmol), potassium carbonate (80 mg, 0.578 mmol) and (3-aminophenyl)boronic acid sulfate (145 mg, 0.386 mmol). The mixture was taken 5 up in water (1.2 mL) and dioxane (2.8 mL), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (1 mg, 0.002 mmol) was added. The mixture was then reacted in a CEM microwave for 10 min at 150 °C. Ethyl acetate (2 mL) was added and the layers were separated. The aqueous layer was washed with ethyl acetate (1x2 mL). The organic layers were pooled, concentrated under a stream of nitrogen, 10 and taken up in dimethyl sulfoxide (0.89 mL) and trifluoroacetic acid (0.15 mL). This solution of crude product was purified on an Agilent MDAP eluting with a linear gradient of 30% CH3CN/H20 (0.1% TFA) to 70% CH3CN/H20 (0.1% TFA) at 20 mL/min over 9 min. To the HPLC fraction containing product was added a solution of saturated K2C03 (1 mL), a 1 M solution of sodium hydroxide (1 mL), and ethyl acetate (2 mL). The layers were 15 separated and the aqueous layer was extracted with ethyl acetate (2x2 mL). The organic layers were pooled, filtered through a plug of magnesium sulfate, and concentrated under a stream of nitrogen to give 14.9 mg of the title compound (36%). LC/MS = m/z 427.2 [M+H] Ret. Time: 1.39 min.
Example 167: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-f5-r(2-methyl-1-pyrrolidinvl)methvn-2-thienvl)-1H-indole-7-carboxamide o nh. 184 Received at IPONZ on 15 June 2011 The {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}boronic acid used to prepare 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}-1 H-indole-7-carboxamide was prepared in three separate batches using the procedures shown below: Batch 1: NaBH(OAc)3 (271 mg, 1.28 mmol), HOAc (0.07 mL), and 2-Methylpyrrolidine (0.043 mL, 0.42 mmol) were added to a solution of (5-formyl-2-thienyl)boronic acid (100 mg, 0.64 mmol) in CH2CI2 (4 mL) in a 2-dram vial. The vial was capped and the reaction was stirred at room temperature for 15 h. The reaction mixture was loaded directly onto a 2 g SCX cartridge (pre-equilibrated with MeOH), eluting in sequence with MeOH (12 mL) 10 and a 2 M solution of NH3/MeOH (8 mL). The fractions containing the boronic acid crude product were concentrated under a stream of N2 and dried under high vacuum to give 45 mg of crude product. The crude product was taken up in saturated NaHC03 (2 mL) and extracted with EtOAc (3x2 mL) to give 6.6 mg of crude {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}boronic acid.
Batch 2: NaBH(OAc)3 (271 mg, 1.28 mmol), HOAc (0.07 mL), and 2-Methylpyrrolidine (0.043 mL, 0.42 mmol) were added to a solution of (5-formyl-2-thienyl)boronic acid (100 mg, 0.64 mmol) in 1:1 CH2CI2/MeOH (4 mL) in a 2-dram vial. The vial was capped and the reaction was stirred at room temperature for 15 h. The reaction mixture was loaded 20 directly onto a 2 g SCX cartridge (pre-equilibrated with MeOH), eluting in sequence with MeOH (12 mL) and a 2 M solution of NH3/MeOH (8 mL). The fractions containing the boronic acid crude product were concentrated under a stream of N2 and dried under high vacuum to give 45 mg of crude product. The crude product was taken up in saturated NaHC03 (2 mL) and extracted with EtOAc (3x2 mL) to give 5 mg of crude {5-[(2-methyl-25 1-pyrrolidinyl)methyl]-2-thienyl}boronic acid.
Batch 3: 2-Methylpyrrolidine (0.033 mL, 0.32 mmol) was added to a solution of (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol) in MeOH (1 mL) in a 2-dram vial. The vial was capped and the reaction was stirred at room temperature for 2 h. NaCNBH3 (40 mg, 0.64 30 mol) was added, and stirring continued for 19 h. The reaction mixture was loaded directly onto a 2 g SCX cartridge (pre-equilibrated with MeOH), eluting in sequence with MeOH (12 mL) and a 2 M solution of NH3/MeOH (9 mL). The fractions containing the boronic acid crude product were concentrated under a stream of N2 and dried under high vacuum to give 45 mg of crude product. The crude product was taken up in saturated NaHC03 (2 35 mL) and extracted with EtOAc (3x2 mL) to give 7.8 mg of crude {5-[(2-methyl-1- 185 Received at IPONZ on 15 June 2011 pyrrolidinyl)methyl]-2-thienyl}boronic acid. The crude boronic acid from the above three reactions were pooled and carried on for the preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}-1 H-indole-7-carboxamide (final weight after pooling the three batches of {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-5 thienyl}boronic acid was 19 mg).
A solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (36 mg, 0.0862 mmol), {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}boronic acid (19 mg, 0.0862 mmol) and potassium carbonate (71 mg, 0.517 mmol) was combined in a CEM 10 microwave tube. To this mixture was added water (0.25 mL), dioxane (0.75 mL) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol). The vial was capped and reacted in a CEM microwave for 20 min at 150 °C. To this reaction was added tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and reacted in a microwave for 20 min at 150 °C. Additional tetrakis(triphenylphosphine)palladium(0) (10 15 mg, 0.009 mmol) was added, and the reaction was heated in the CEM microwave for an additional 20 min at 150 °C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL H20), eluting in sequence with water (3 mL), MeOH (9 mL), and a 2 M solution of NH3/MeOH (9 mL). The fraction containing crude product solution was concentrated under a stream of nitrogen, and the residue was taken 20 up in DMSO (3 mL). This DMSO solution of crude product was purified as three separate injections (1 mL each) on the Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H20 (0.1% TFA) then a linear gradient of 10% CH3CN/H20 (0.1% TFA) to 95% CH3CN/H20 (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The two fractions containing product were 25 filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns used per fraction) and concentrated under a stream of nitrogen at 40 0 C to give 13 mg of the title compound (29.3%).
LC/MS = m/z 515.6 [M+H] Ret. Time: 1.62 min.
Example 168: 5-(5-r(ethvlamino)methvll-2-thienvl)-3-ri-(ethvlsulfonylM-piperidinvll-l H-indole-7-carboxamide 186 Received at IPONZ on 15 June 2011 2 ^ The {5-[(ethylamino)methyl]-2-thienyl}boronic acid used to prepare 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide was prepared as follows: A 2 M solution of ethylamine in THF (0.16 mL, 0.32 mmol) was 5 added to a solution of (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol) in MeOH (1 mL) in a 2-dram vial. The vial was capped and the reaction was stirred at room temperature for 2 h. NaCNBH3 (40 mg, 0.64 mmol) was added, and stirring continued for 17 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of 10 NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 47 mg of crude {5-[(ethylamino)methyl]-2-thienyl}boronic acid.
To a CEM microwave tube containing {5-[(ethylamino)methyl]-2-thienyl}boronic acid (47 mg, 0.254 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-15 carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), dioxane (1.5 mL), H20 (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol). The reaction was heated in a CEM microwave for 30 min at 150 °C. (This run was aborted prior to 30 min due to excessive pressure build-up). The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), 20 eluting in sequence with H20 (3 mL), MeOH (9 mL) and a 2 M solution of NH3/MeOH (6 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40 °C, and the crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H20 (0.1% TFA) then a linear gradient of 10% CH3CN/H20 (0.1% TFA) to 25 95% CH3CN/H20 (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns used per fraction) and concentrated under a stream of nitrogen at 60° C to give 8.8 mg of the title compound (10%).
LC/MS = m/z 429.8 [M+H] Ret. Time: 1.25 min.
Received at IPONZ on 15 June 2011 Example 169: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(5-(T(1-methvlethvl)amino1methvl)-2-thienyl)-1H-indole-7-carboxamide \ H Vn h2n o Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), isopropylamine (0.027 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 41 mg of crude (5-{[(1-methylethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(1-methylethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 74 mg of the title compound (37%).
LC/MS = m/z 430.2 [M+H] Ret. Time: 1.29 min.
Example 170: 5-f5-r(cvclopropvlamino)methvn-2-thienvl)-3-ri-(ethvlsulfonyl)-4-pipe ridinyll-l H-indole-7-carboxamide Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), cyclopropylamine (0.022 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 63 mg of crude {5-[(cyclopropylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(cyclopropylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and h o-n h2n 188 Received at IPONZ on 15 June 2011 tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give impure title compound. The impure title compound was purified again with the Agilent MDAP and isolated as the free base according to the procedure shown in Example 5 to give 6.8 mg of the title compound (7.2%).
LC/MS = m/z 430.2 [M+H] Ret. Time: 1.62 min.
Example 171: 5-(5-fr(2.2-dimethvlpropyl)aminolmethvl)-2-thienvl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (2,2-dimethylpropyl)amine (0.037 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 73 mg of crude (5-{[(2,2- dimethylpropyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 21 mg of the title compound (21%).
LC/MS = m/z 430.2 [M+H] Ret. Time: 1.45 min.
Example 172: 5-(5-(T(cvclopropvlmethvl)amino1methvl)-2-thienvl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide M2N U Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-25 (ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid h2n dimethylpropyl)amino]methyl}-2-thienyl)boronic acid.
The crude (5-{[(2,2- 189 Received at IPONZ on 15 June 2011 (50 mg, 0.32 mmol), (cyclopropylmethyl)amine (0.027 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 73 mg of crude (5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5- {[(cyclopropylmethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-5 3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 19.1 mg of the title compound (20%).
LC/MS = m/z 430.2 [M+H] Ret. Time: 1.33 min.
Example 173: 5-(5-(T(cvclopropvlmethvl)amino1methvl)-3-pvridinvl)-3-ri-(ethvlsulfonvl)-4-piperidinyn-1H-indole-7-carboxamide The (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- pyridinyl]methyl}amine used to prepare 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-15 pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide was prepared as follows: (Cyclopropylmethyl)amine (0.011 mL, 0.129 mmol) was added to a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol) in MeOH (1 mL) in a 2-dram vial. The vial was capped and the reaction was stirred at room temperature for 17 h. NaCNBH3 (16 mg, 0.258 mmol) was added, and 20 stirring continued for 30 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 21 mg of crude (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine.
To a CEM microwave tube containing (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (21 mg, 0.0725 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.0723 mmol), dioxane (0.75 mL), a solution of potassium carbonate (60 mg, 0.434 mmol) in H20 (0.25 mL), and 30 chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (4.4 190 Received at IPONZ on 15 June 2011 mg, 0.00723 mmol). The reaction was heated in a CEM microwave for 30 min at 150 °C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with H20 (3 mL), MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40 5 °C and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H20 (0.1% TFA) then a linear gradient of 10% CH3CN/H20 (0.1% TFA) to 95% CH3CN/H20 (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 65 °C to give impure title compound, which was repurified on the Agilent MDAP as shown above to give 25 mg of the title compound (70%).
LC/MS = m/z 496.6 [M+H] Ret. Time: 1.35 min.
Example 174: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-r5-((T2- (methvloxv)ethvnamino)methvl)-3-pvridinvn-1H-indole-7-carboxamide Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-20 dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [2-(methyloxy)ethyl]amine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 19 mg of crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-25 bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (4.4 mg, 0.00723 mmol) to give 15 mg of the title compound (46%).
LC/MS = m/z 500.6 [M+H] Ret. Time: 1.52 min. 191 Received at IPONZ on 15 June 2011 Example 175: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-r5-((T3-(methvloxv)propvnamino)methvl)-3-pyridinvn-1 H-indole-7-carboxamide r h2n Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-5 3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [3-(methyloxy)propyl]amine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 22 mg of crude [3-(methyloxy)propyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [3-(methyloxy)propyl]{[5-(4,4,5,5-10 tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (4.4 mg, 0.00723 mmol) to give 31 mg of the title compound (83%).
LC/MS = m/z 514.4 [M+H] Ret. Time: 1.46 min.
Example 176: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-(4-morpholinvlmethyl)-3-pyridinyn-1H-indole-7-carboxamide Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), morpholine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 28 mg of crude 4- crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7- 192 h2n {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine. The Received at IPONZ on 15 June 2011 carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (4.4 mg, 0.00723 mmol) to give 15.8 mg of the title compound (43%).
LC/MS = m/z 512.2 [M+H] Ret. Time: 1.38 min.
Example 177: 5-f5-r(ethvlamino)methvn-3-pyridinvl)-3-ri-(ethvlsulfonvl)-4-pipe ridinyll-1 H-indole-7-carboxamide Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-10 3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of ethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 19 mg of crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-15 3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl- (dinorbornylphosphine)palladium(ll) (4.4 mg, 0.00723 mmol) to give 12.3 mg of the title compound (36%).
LC/MS = m/z 470.4 [M+H] Ret. Time: 1.44 min.
Example 178: 5-{5-r(dimethvlamino)methvn-3-pvridinvl}-3-ri-(ethvlsulfonyl)-4-piperidinyll-l H-indole-7-carboxamide Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2- 193 Received at IPONZ on 15 June 2011 dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of dimethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 23 mg of crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-5 2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (4.4 mg, 0.00723 mmol) to give 5.4 mg of the title compound (16%).
LC/MS = m/z 470.6 [M+H] Ret. Time: 1.35 min.
Example 179: 3-ri-(ethylsulfonvlM-piperidinvll-5-f5-r(2-methyl-1-Pvrrolidinvl)methvn-3-pyridinvl)-1 H-indole-7-carboxamide Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), 2-methylpyrrolidine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-20 yl)pyridine. The crude 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (4.4 mg, 0.00723 mmol) to give 6 mg of the title 25 compound (16%).
LC/MS = m/z 512.6 [M+H] Ret. Time: 1.67 min.
Example 180: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(5-(T(2-methylpropvl)amino1methvl)-3-pvridinyl)-1 H-indole-7-carboxamide 194 Received at IPONZ on 15 June 2011 h2n Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), isobutylamine (0.013 5 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 21 mg of pyridinyl]methyl}amine. The crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium 10 carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (4.4 mg, 0.00723 mmol) to give 12.5 mg of the title compound (35%).
LC/MS = m/z 498.2 [M+H] Ret. Time: 1.38 min.
Example 181: 5-(5-(T(2,2-dimethvlpropvl)amino1methvl)-3-pvridinvl)-3-ri-(ethvlsulfonvl)-4-piperidinyn-1H-indole-7-carboxamide Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-20 dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), (2,2-dimethylpropyl)amine (0.015 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-25 bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.0723 mmol), crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- h2n 195 Received at IPONZ on 15 June 2011 potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (4.4 mg, 0.00723 mmol) to give 12.7 mg of the title compound (34%).
LC/MS = m/z 512.4 [M+H] Ret. Time: 1.51 min.
Example 182: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(5-(T(2-methvlbutvl)amino1methvl)-2-thienyl)-1H-indole-7-carboxamide The {5-[(ethylamino)methyl]-2-thienyl}boronic acid used to prepare 3-[1-(ethylsulfonyl)-4-10 piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide was prepared as follows: A solution of (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol) in MeOH (0.5 mL) and a solution of NaCNBH3 (40 mg, 0.64 mmol) in MeOH (0.5 mL) were added to (2-methylbutyl)amine (28 mg, 0.32 mmol) in a 2-dram vial. The vial was capped and the reaction was stirred at room temperature for 20 h. The reaction mixture was 15 filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 43 mg of crude (5-{[(2-methylbutyl)amino]methyl}-2-thienyl)boronic acid.
To a CEM microwave tube containing the crude (5-{[(2-methylbutyl)amino]methyl}-2-thienyl)boronic acid (43 mg, 0.188 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), dioxane (1.5 mL), H20 (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol). The reaction was heated in a CEM microwave for 30 min at 150 °C. The 25 reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with H20 (3 mL), MeOH (9 mL) and a 2 M solution of NH3/MeOH (6 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40 °C, and the crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 50 mm) eluting at 20 mL per min 196 Received at IPONZ on 15 June 2011 for 1 min with 10% CH3CN/H20 (0.1% TFA) then a linear gradient of 10% CH3CN/H20 (0.1% TFA) to 95% CH3CN/H20 (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical 5 Technologies) to remove TFA and concentrated under a stream of nitrogen at 50 °C to give 16.2 mg of the title compound (17%).
LC/MS = m/z 430.4 [M+H] Ret. Time: 1.75 min.
Example 183: 5-r5-({T(1R)-1.2-dimethvlpropvnamino)methvl)-2-thienvn-3-H-10 (ethvlsulfonvl)-4-piperidinyn-1H-indole-7-carboxamide Chiral Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2- thienyl)boronic acid (50 mg, 0.32 mmol), [(1R)-1,2-dimethylpropyl]amine (28 mg, 0.32 15 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1 R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to 20 give 20.5 mg of the title compound (30%).
LC/MS = m/z 430.4 [M+H] Ret. Time: 1.75 min.
Example 184: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f5-r(pentylamino)methvn-2-thienyl)-1H-indole-7-carboxamide 197 Received at IPONZ on 15 June 2011 Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2- thienyl)boronic acid (50 mg, 0.32 mmol), pentylamine (29 mg, 0.32 mmol), and NaCNBH3 5 (40 mg, 0.64 mmol) were reacted to give 45 mg of crude {5-[(pentylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(pentylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.7 mg of the title compound (20%).
LC/MS = m/z 430.6 [M+H] Ret. Time: 1.75 min.
Example 185: 3-ri-(ethylsulfonvlM-piperidinvll-5-r5-«T(2S)-2-methvlbutvnamino)methvl)-2-thienvH-1H-indole-7-carboxamide Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2- thienyl)boronic acid (50 mg, 0.32 mmol), [(2S)-2-methylbutyl]amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude [5-({[(2S)-2-methylbutyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(2S)-2- methylbutyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 37.6 mg of the title compound (39%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.67 min. 198 Received at IPONZ on 15 June 2011 Example 186: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(5-(T(1-methvlbutvl)amino1methvl)-2-thienyl)-1H-indole-7-carboxamide Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-5 methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2- thienyl)boronic acid (50 mg, 0.32 mmol), (l-methylbutyl)amine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude (5-{[(1-methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(1 - methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-10 (ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 35.2 mg of the title compound (60%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.62 min.
Example 187: 5-(5-r(butvlamino)methvn-2-thienvl)-3-H-(ethvlsulfonvl)-4-piperidinyll-l H-indole-7-carboxamide Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2- thienyl)boronic acid (50 mg, 0.32 mmol), butylamine (24 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 49 mg of crude {5-[(butylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(butylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 199 Received at IPONZ on 15 June 2011 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 27.2 mg of the title compound (24%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.56 min.
Example 188: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-«T2- (methvloxv)ethvnamino)methvl)-2-thienvH-1H-indole-7-carboxamide Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2- thienyl)boronic acid (50 mg, 0.32 mmol), [2-(methyloxy)ethyl]amine (24 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 42 mg of crude [5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[2- (methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 15 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give impure title compound. The impure title compound was repurified using the HPLC and ammonium hydroxide SPE workup shown in preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide to give 15 mg of the title compound (15%).
LC/MS = m/z 430.2 [M+H] Ret. Time: 1.33 min.
Example 189: 5-f5-r(cvclopentvlamino)methvll-2-thienvl)-3-ri-(ethvlsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide 200 Received at IPONZ on 15 June 2011 Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2- thienyl)boronic acid (50 mg, 0.32 mmol), cyclopentylamine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 48 mg of crude {5-5 [(cyclopentylamino)methyl]-2-thienyl}boronic acid. The crude {5- [(cyclopentylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 93.5 mg of the title compound (85%).
LC/MS = m/z 430.4 [M+H] Ret. Time: 1.64 min.
Example 190: 3-ri-(ethylsulfonvlM-piperidinyll-5-(5-(r(3-methylbutvl)amino1methvl)-2-thienvl)-1H-indole-7-carboxamide Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1 H-indole-7-carboxamide, (5-formyl-2- thienyl)boronic acid (50 mg, 0.32 mmol), (3-methylbutyl)amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 46 mg of crude (5-{[(3-methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3- methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 38.3 mg of the title compound (37%).
LC/MS = m/z 430.4 [M+H] Ret. Time: 1.75 min.
Example 191: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(5-{r(1-methvlethvl)amino1methvl)-3-pvridinyl)-1H-indole-7-carboxamide 201 Received at IPONZ on 15 June 2011 ^ 2 The (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- pyridinyl]methyl}amine used to prepare 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-pyridinyl)-1H-indole-7-carboxamide was prepared as 5 follows: isopropylamine (0.011 mL, 0.129 mmol) was added to a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol) in MeOH (1 mL) in a 2-dram vial. NaCNBH3 (16 mg, 0.258 mmol) was then added, the vial was capped and the reaction was stirred at room temperature for 24 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), 10 eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 22 mg of crude (1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine.
To a CEM microwave tube containing (1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-15 dioxaborolan-2-yl)-3-pyridinyl]methyl}amine (22 mg, 0.080 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (50 mg, 0.121 mmol), K2C03 (100 mg, 0.724 mmol), dioxane (1.5 mL), H20 (0. 5 mL), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(ll) (7.3 mg, 0.012 mmol). The reaction was heated in a CEM microwave for 30 min at 150 °C. The 20 reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with H20 (3 mL), MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 50 °C and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 100 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H20 (0.1% TFA) then a linear 25 gradient of 10% CH3CN/H20 (0.1% TFA) to 95% CH3CN/H20 (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 50 °C to give 27.2 mg of the title compound (70%).
LC/MS = m/z 484 [M+H] Ret. Time: 1.25 min. 202 Received at IPONZ on 15 June 2011 Example 192: 5-(5-(T(2-ethvlbutvl)amino1methvl)-2-thienvl)-3-ri-(ethvlsulfonvl)-4-pipe ridinvll-1 H-indole-7-carboxamide The {5-[(ethylamino)methyl]-2-thienyl}boronic acid used to prepare 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide was prepared as follows: A solution of (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol) in MeOH (0.5 mL) and a solution of NaCNBH3 (40 mg, 0.64 mmol) in MeOH (0.5 mL) were added to (2-ethylbutyl)amine (32 mg, 0.32 mmol) in a 2-dram vial. 10 The vial was capped and the reaction was stirred at room temperature for 20 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 48 mg of crude (5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)boronic acid.
To a CEM microwave tube containing the crude (5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)boronic acid (48 mg, 0.199 mmol) was added a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol) in dioxane (1.75 mL), a solution of K2C03 (130 mg, 0.942 mmol) in H20 (0.25 mL), and 20 tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The reaction was heated in a CEM microwave for 30 min at 150 °C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with MeOH (3 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 50 °C, and the crude product was taken up in dimethyl sulfoxide 25 (1.1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 100 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H20 (0.1% TFA) then a linear gradient of 10% CH3CN/H20 (0.1% TFA) to 95% CH3CN/H20 (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; 30 United Chemical Technologies) to remove TFA and concentrated under a stream of 203 Received at IPONZ on 15 June 2011 nitrogen at 50 °C to give impure title compound. The impure title compound was repurified on an Agilent MDAP and free based with the ammonium hydroxide column as shown above to give 8.5 mg of the title compound (10%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.72 min.
Example 193: 5-r5-((T3-(ethvloxv)propvnamino)methyl)-2-thienvn-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-10 (ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(ethyloxy)propyl]amine (34 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(ethyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3- (ethyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-15 [1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 8.1 mg of the title compound (10%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.62 min.
Example 194: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-r5-({r3- (methvloxv)propvnamino)methyl)-2-thienvn-1H-indole-7-carboxamide Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid 204 Received at IPONZ on 15 June 2011 (50 mg, 0.32 mmol), [3-(methyloxy)propyl]amine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3- (methyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-5 [1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide to give 7.6 mg of the title 10 compound (9%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.50 min.
Example 195: 5-(5-fr(cvclohexvlmethvl)amino1methvlV2-thienvl)-3-ri-(ethvlsulfonvl)-4-piperidinvn-1H-indole-7-carboxamide Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (cyclohexylmethyl)amine (37 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude (5-20 {[(cyclohexylmethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5- {[(cyclohexylmethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the 25 procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide. The purified product was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2C03 (1 mL). The organic layer was concentrated to give 4.7 mg of the title compound (6%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.82 min. 205 Received at IPONZ on 15 June 2011 Example 196: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-f5-r(f3-r(1-methvlethvl)oxvlpropyl)amino)methvn-2-thienvl)-1 H-indole-7-carboxamide o cr nh2 Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), {3-[(1-methylethyl)oxy]propyl}amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude {5-[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid. The crude {5-[({3-[(1 -10 methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). After purification on an Agilent MDAP twice as shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-15 carboxamide, the impure title compound was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL) to give 7.6 mg of the title compound (9%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.62 min.
Example 197: 5-r5-((T2-(ethvloxv)ethvnamino)methvl)-2-thienvn-3-ri-(ethvlsulfonyl)-20 4-piperidinyn-1 H-indole-7-carboxamide Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [2-(ethyloxy)ethyl]amine (30 mg, 0.32 mmol), and NaCNBH3 (40 mg, c r" 206 Received at IPONZ on 15 June 2011 0.64 mmol) were reacted to give 30 mg of crude [5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and 5 tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown for preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide to give 6 mg of the title compound (7%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.66 min.
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-15 (ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(propyloxy)propyl]amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3- (propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-20 [1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified twice on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide. The purified product was washed 25 with a 20:4:1 mixture of hexaness/EtOAc/MeOH (2.5 mL), taken up in EtOAc (2 mL) and washed with saturated K2C03 (1 mL). The organic layer was concentrated to give to give 1.4 mg of the title compound (2%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.66 min.
Example 198: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-r5-((T3-(propvloxv)propyllamino)methvl)-2-thienvll-1H-indole-7-carboxamide (propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid.
The crude [5-({[3- 207 Received at IPONZ on 15 June 2011 Example 199: 5-(5-(T(3,3-dimethvlbutvl)amino1methvl)-2-thienvl)-3-ri-(ethvlsulfonvl)-4-piperidinyn-1H-indole-7-carboxamide cr nh2 Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-5 (ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (3,3-dimethylbutyl)amine (32 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude (5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-10 (ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 4.5 mg of the title compound (5%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.79 min.
Example 200: 3-ri-(ethvlsulfonvlM-piperidinvll-5-r5-(miS)-1.2.2-trimethvlpropvnamino>methvl)-2-thienvn-1 H-indole-7-carboxamide Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid 20 (50 mg, 0.32 mmol), [(1 S)-1,2,2-trimethylpropyl]amine (32 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1 S)-1,2,2-trimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1 S)-1,2,2-trimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2CQ3 (130 r 208 Received at IPONZ on 15 June 2011 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 10.3 mg of the title compound (12%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.62 min.
Example 201: 3-H -(ethvlsulfonvl)-4-piperidinvn-5-f5-r(hexylamino)methvn-2-thienyl)-1H-indole-7-carboxamide Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), hexylamine (33 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude {5-[(hexylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(hexylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol).
The crude product was purified once on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide to give 13 mg of the title compound (16%).
LC/MS = m/z 430.6 [M+H] Ret. Time: 1.92 min.
Example 202: 5-r2-(dimethvlamino)-4-pyridinvn-3-ri-(ethvlsulfonvl)-4-piperidinvn-1 H-indole-7-carboxamide trifluoroacetate nh2 / O n r F O NH '2 209 Received at IPONZ on 15 June 2011 To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-4-pyridinyl)-1/-/-indole-7-carboxamide (40 mg, 0.093 mmol) was added dimethylamine (1 mL, 0.015 mmol) and DMF (0.3 mL). The resulting mixture was reacted in a microwave for 1 h at 180° C. All solvent was evaporated and the mixture was then purified by Gilson Preparatory HPLC to give 18.2 mg of the title compound (34.4%).
LC/MS = m/z 456.2 [M+H] Ret. Time: 1.54 min.
Example 203: 5-(6-rethvl(methvl)aminol-3-pyridinvl)-3-ri-(ethvlsulfonvlM-piperidinyll-lH-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (1 mL) for dimethylamine to afford 48.9 mg of the title compound (27.1%).
LC/MS = m/z 482.2 [M+H] Ret. Time: 1.62 min.
Example 204: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r2-(4-morpholinvl)-4-pyridinvn-1H-indole-7-carboxamide trifluoroacetate o NH.
O NH. '2 210 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting morpholine (1 mL) for dimethylamine to afford 12 mg of the title compound (21.1%).
LC/MS = m/z 498.6 [M+H] Ret. Time: 1.47 min.
Example 205: 3-ri-(ethvlsulfonvlM-piperidinvll-5-(2-r(2-methvlpropyl)aminol-4-pyridinylVI H-indole-7-carboxamide trifluoroacetate u i\in2 The title compound was prepared according to the general procedure of 5-[2- (dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (1 mL) for dimethylamine to afford 11.1 mg of the title compound (20%).
LC/MS = m/z 484.2 [M+H] Ret. Time: 1.68 min.
Example 206: 5-f2-r(2,2-dimethylpropvl)aminol-4-pvridinyl)-3-ri-(ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate O NH, 211 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting 2,2-dimethyl-1-propanamine (1 mL) for dimethylamine to afford 9 mg of the title compound (15.8%).
LC/MS = m/z 498.6 [M+H] Ret. Time: 1.75 min.
Example 207: 3-ri-(ethvlsulfonvlM-piperidinvll-5-r2-(propvlamino)-4-pyridinvll-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-[2- (dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting propylamine (1 mL) for dimethylamine to afford 18.2 mg of the title compound (33.5%).
LC/MS = m/z 470.4 [M+H] Ret. Time: 1.57 min.
Example 208: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f4-r(methylamino)methvn-2-thienvl)-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2-thienyl)-1/-/-indole-7-20 carboxamide (45 mg, 0.1 mmol) in methylene chloride (2 mL) and methanol (1 mL) was 212 Received at IPONZ on 15 June 2011 added 2 M methylamine (0.5 mL). The reaction mixture was stirred at room temperature for 5 h followed by an addition of sodium tetrahydridoborate (37.83 mg, 1 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was concentrated and purified using Gilson Preparatory HPLC to give 16.8 mg of the title compound (29.2%).
LC/MS = m/z 461.6 [M+H] Ret. Time: 1.40 min.
Example 209: 3-ri-(ethvlsulfonvlM-piperidinvll-5-r4-(1-pyrrolidinvlmethvl)-2-thienyll-1 H-indole-7-carboxamide trifluoroacetate cr nh2 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (0.083 mL) for 2 M methylamine to afford 14.8 mg of the title compound (24.1%).
LC/MS = m/z 470.4 [M+H] Ret. Time: 1.57 min.
Example 210: 3-H-(ethvlsulfonyl)-4-piperidinvn-5-(4-(r(2- methylpropvl)amino1methvl)-2-thienyl)-1 H-indole-7-carboxamide trifluoroacetate Cr NH2 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1 H-indole-7- 213 Received at IPONZ on 15 June 2011 carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (0.1 mL) for 2 M methylamine to afford 15.4 mg of the title compound (25%).
LC/MS = m/z 503.2 [M+H] Ret. Time: 1.42 min.
Example 211: 5-(4-r(dimethylamino)methvn-2-thienvl)-3-H-(ethvlsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1 H-indole-7-10 carboxamide trifluoroacetate, substituting dimethylamine (0.5 mL) for 2 M methylamine to afford 9 mg of the title compound (15.3%).
LC/MS = m/z 475.2 [M+H] Ret. Time: 1.27 min.
Example 212: 3-ri-(ethvlsulfonvlM-piperidinvll-5-(5-r(1S)-1-(1-Pvrrolidinvl)ethyll-3-15 thienylV1H-indole-7-carboxamide 0 nh, To 5-(5-acetyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (10 mg, 0.02 mmol) was added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and pyrrolidine (0.03 mL, 0.30 mmol). The resulting mixture was reacted in a microwave for 214 Received at IPONZ on 15 June 2011 40 min at 150° C. All the solvent was evaporated and the crude product was partitioned between ethyl acetate (1.5 mL) and 1M sodium hydroxide (0.2 mL). The reaction was purified by SFC to give the title compound as 100% chirally pure.
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.54 min.
Example 213: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f5-r(1R)-1-(1-pyrrolidinvl)ethvn-3-thienvl)-1H-indole-7-carboxamide To 5-(5-acetyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (10 10 mg, 0.02 mmol) was added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and pyrrolidine (0.03 mL, 0.30 mmol). The resulting mixture was reacted in a microwave for 40 min at 150° C. All the solvent was evaporated and the crude product was partitioned between ethyl acetate (1.5 mL) and 1M sodium hydroxide (0.2 mL). The reaction was purified by SFC to give the title compound as 100% chirally pure.
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.54 min.
Example 214: 3-H-(ethvlsulfonyl)-4-piperidinvn-5-r4-((r3- (methvloxv)propvnamino)methyl)-2-thienvn-1H-indole-7-carboxamide trifluoroacetate -N H F 0 // h \ - OH —o To a solution of 5-[(1Z)-1-(ethenylthio)-4-oxo-1-buten-1-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (45 mg, 0.1 mmol) in methylene chloride (2 mL) and 215 Received at IPONZ on 15 June 2011 methanol (1 mL) was added 3 drops of acetic acid and 3-(methyloxy)-1-propanamine (89.14 mg,1 mmol). The resulting mixture was stirred for 6 h followed by an addition of sodium borohydride (37.83 mg, 1 mmol). The reaction was stirred at room temperature overnight. The solvent was evaporated and the mixture was then purified by Gilson Preparatory HPLC to give 23.7 mg of the title compound (37.5%).
LC/MS = m/z 519.4 [M+H] Ret. Time: 1.69 min.
Example 215: 3-ri-(ethvlsulfonvlM-piperidinvll-5-r4-(((2S)-2-r(methvloxv)methyll-1-pvrrolidinvl)methyl)-2-thienvn-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]-1H-indole-7-carboxamide trifluoroacetate , substituting (2S)-2-[(methyloxy)methyl]pyrrolidine (115.18 mg, 1 mmol) for 3-(methyloxy)-l-propanamine to afford 3 mg of the title compound (4.6%).
LC/MS = m/z 545.2 [M+H] Ret. Time: 1.78 min.
Example 216: 5-(4-{T(2R.5R)-2.5-dimethvl-1-pvrrolidinvnmethvl)-2-thienvl)-3-H-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate O NH, f o F^: F OH O NH 216 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]-1H-indole-7-carboxamide trifluoroacetate (64.3 mg, 1 mmol) for 3-(methyloxy)-1-propanamine to afford 6.4 mg of the title compound (10%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.69 min.
Example 217: 3-ri-(ethylsulfonvlM-piperidinvll-5-(5-(r(2S)-2-methyl-1-pvrrolidinvnmethvlV3-thienvl)-1H-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (600 mg, 1.348 mmol) in dimethyl sulfoxide (10 mL) was added of 20 drops of acetic acid and (2S)-1,2-dimethylpyrrolidine (1.37 mL, 13.483 mmol). The resulting mixture was stirred at room temperature for 6 h followed by an addition of sodium triacetoxyborohydride (2.858 g, 13.483 mmol). The reaction was stirred at room temperature overnight then purified by SFC. This compound was separated by RTP CASS Group. The fraction of enantiomer #1 is 99.7% chirally pure to give 119.9 mg of the title compound (17.3%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.56 min.
Example 218: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(T(2R)-2-methyl-1-pyrrolidinvllmethvl)-3-thienvl)-1H-indole-7-carboxamide Cr NH 217 Received at IPONZ on 15 June 2011 cr NH '2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (600 mg, 1.35 mmol) in dimethyl sulfoxide (10 mL) was added of 20 drops of acetic acid and 2-methylpyrrolidine (1.37 mL, 13.5 mmol). The resulting mixture was 5 stirred at room temperature for 6 h followed by an addition of sodium triacetoxyborohydride (2.86 g, 13.5 mmol). The reaction was stirred at room temperature overnight then purified by Gilson Preparatory HPLC. This compound was then separated to give the title compound as 98.6% chirally pure.
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.56 min.
Example 219: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-H-(1-Pvrrolidinvl)propvn-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-15 dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (250 mg, 0.541 mmol) in dioxane (4.5 mL) and H20 (1.5 mL) was added 1-(4-bromo-2-thienyl)-1-propanone (356 mg, 1.62 mmol), potassium carbonate (447 mg, 3.24 mmol), and tetrakis(triphenylphosphine)palladium(0) (64 mg, 0.055 mmol). The reaction was run in the microwave at 150° C for 20 min. An aqueous work-up was performed using EtOAc and H20 followed by addition of MeOH (20 20 mL) to the crude product. The desired product percpitated and was filtered to give 110 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-propanoyl-3-thienyl)-1/-/-indole-7-carboxamide (43%). '2 218 Received at IPONZ on 15 June 2011 To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-propanoyl-3-thienyl)-1/-/-indole-7-carboxamide (60 mg, 0.13 mmol) was added sodium cyanoborohydride (49.2 mg, 0.78 mmol), pyrrolidine (0.2 mL, 1.95 mmol), ethanol (3 mL) and acetic acid (0.4 mL). The resulting 5 mixture was reacted in a microwave for 30 min at 150° C. All solvent was evaporated and the mixture was then purified by Gilson Preparatory HPLC to give 12 mg of the title compound (14.4%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.65 min.
Example 220: 5-f5-r(dimethvlamino)methvn-3-thienvl)-3-f1-r(1-methvlethyl)sulfonvn-4-piperidinyl)-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in dimethyl sulfoxide (2 mL) was added 3 drops of 15 acetic acid and trimethylamine (0.55 mL, 1.1 mmol). The resulting mixture was stirred at room temperature for 6 h followed by an addition of sodium triacetoxyborohydride (233 mg, 1 mmol). This was then stirred at room temperature overnight then purified by Gilson Preparatory HPLC to give 29.4 mg of the title compound (44.3%).
LC/MS = m/z 489.4 [M+H] Ret. Time: 1.32 min.
Example 221: 5-r5-(aminomethvl)-3-thienvn-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate ! N N 219 Received at IPONZ on 15 June 2011 o o=s / N H2N 2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in methylene chloride (2 mL) and methanol (1 mL) was added ammonium acetate (84.7 mg, 1.1 mmol) and sodium cyanoborohydride (4.84 mg, 5 0.077 mmol). The resulting mixture was stirred at room temperature overnight. All solvent was evaporated and the mixture was then purified by Gilson Preparatory HPLC to give 1.8 mg of the title compound (2.9%).
LC/MS = m/z 447.2 [M+H] Ret. Time: 1.53 min.
Example 222: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(5-f2-r(2- methylpropvl)aminolethvl)-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate n To a solution of [2-(4-bromo-2-thienyl)ethyl]amine (100 mg, 0.48 mmol) in DCM (2.0 mL) and MeOH (1.0 mL) was added acetic acid (3 drops) and 2-methylpropanal (105 mg, 1.44 15 mmol). The reaction was stirred overnight at room temperature before addition of Sodium borohydride (53.3 mg, 1.44 mmol). Reaction run for 1 h and then treated with EtOAc and brine. Organic layers were then dried and concentrated to give 80mg of [2-(4-bromo-2-thienyl)ethyl](1-methylethyl)amine (64%). cr "nh2 220 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (139 mg, 0.3 mmol) in dioxane (3 mL) and water (1 mL) was added [2-(4-bromo-2-thienyl)ethyl](1-methylethyl)amine (50 mg, 0.2 mmol), potassium carbonate (82.8 mg, 0.6 mmol) and 5 tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol). The resulting mixture was reacted in a microwave for 20 min at 150° C. All solvent was evaporated and the mixture was then purified by Gilson Preparatory HPLC to give 18 mg of the title compound (9.5%).
LC/MS = m/z 517.2 [M+H] Ret. Time: 1.68 min. 0 Example 223: 5-f5-r2-(dimethvlamino)ethvn-3-thienvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate To a solution of [2-(4-bromo-2-thienyl)ethyl]amine (100 mg, 0.48 mmol) in DCM (2.0 mL) and MeOH (1.0 mL) was added acetic acid (3 drops) and formaldehyde, 37% in H20 (105 mg, 1.44 mmol). The reaction was stirred overnight at room temperature before addition of Sodium borohydride (53.3 mg, 1.44 mmol). Reaction run for 1 h and then treated with EtOAc and brine. Organic layers were then dried and concentrated to give 50mg of 20 2-(4-bromo-2-thienyl)-/\/,/V-dimethylethanamine (44%).
To a solution of of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (139 mg, 0.345 mmol) in dioxane (3 mL) and water (1 mL) was added 2-(4-bromo-2-thienyl)-/\/,/V-dimethylethanamine (50 mg, 25 0.23 mmol), potassium carbonate (82.8 mg, 0.69 mmol) and tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol). The resulting mixture was reacted in a microwave for 20 min at 150° C. All solvent was evaporated and the mixture O=o / 2 221 Received at IPONZ on 15 June 2011 was then purified by Gilson Preparatory HPLC to give 12 mg of the title compound (5.8%).
LC/MS = m/z 489.2 [M+H] Ret. Time: 1.54 min.
Example 224: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r6-(1-pvrrolidinvl)-3-pvridinvH-1H-indole-7-carboxamide trifluoroacetate To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (110 mg, 0.27 mmol) in dioxane (2.0 mL) and H20 (0.7 mL) was added (6-fluoro-3-10 pyridinyl)boronic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.026 mmol). The reaction was run in the microwave for 20 min at 150° C. The reaction was then treated with EtOAc and brine and purified by flash chromatography to give 50 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1/-/-indole-7-carboxamide (43%).
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1/-/-indole-7-carboxamide (25 mg, 0.058 mmol) was added pyrrolidine (3 mL). The resulting mixture was reacted in a microwave for 30 min at 100° C. All extra pyrrolidine was evaporated and it was then purified by Gilson Preparatory HPLC to give 25 mg of the title compound (72.4%). 20 LC/MS = m/z 482.2 [M+H] Ret. Time: 1.67 min.
Example 225: 5-f6-rethvl(methvl)amino1-3-pvridinvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate O NH '2 222 Received at IPONZ on 15 June 2011 O NH '2 To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (110 mg, 0.27 mmol) in dioxane (2.0 mL) and H20 (0.7 mL) was added (6-fluoro-3-pyridinyl)boronic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16 mmol), 5 and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.026 mmol). The reaction was run in the microwave for 20 min at 150° C. The reaction was then treated with EtOAc and brine and purified by flash chromatography to give 50 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1/-/-indole-7-carboxamide (43%).
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1/-/-indole-7-carboxamide (40 mg, 0.093 mmol) was added dimethylamine (1 mL) and DMF (0.3 mL). The resulting mixture was reacted in a microwave for 1 h at 200° C. The resulting mixture was washed with water. Ethyl acetate was added and the organic layer was evaporated and purified by Gilson Preparatory HPLC to afford 34.4 mg of the title compound (63.4%). 15 LC/MS = m/z 470 [M+H] Ret. Time: 1.50 min.
Example 226: 5-r6-(dimethvlamino)-3-pvridinvn-3-ri-(ethvlsulfonyl)-4-piperidinvn- 1 H-indole-7-carboxamide trifluoroacetate o NH, '2 223 Received at IPONZ on 15 June 2011 To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (110 mg, 0.27 mmol) in dioxane (2.0 mL) and H20 (0.7 mL) was added (6-fluoro-3-pyridinyl)boronic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.026 mmol). The reaction was run 5 in the microwave for 20 min at 150° C. The reaction was then treated with EtOAc and brine and purified by flash chromatography to give 50 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1/-/-indole-7-carboxamide (43%).
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1/-/-indole-7-carboxamide (50 10 mg, 0.116 mmol) was added dimethylamine (1 mL) and DMF (0.3 mL). The resulting mixture was reacted in a microwave for 1 h at 200° C the purified by Gilson Preparatory HPLC to afford 8.4 mg of the title compound (12.7%).
LC/MS = m/z 456.2 [M+H] Ret. Time: 1.39 min.
Example 227: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r6-(propvlamino)-3-pyridinvn-1H- indole-7-carboxamide trifluoroacetate To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (110 mg, 0.27 mmol) in dioxane (2.0 mL) and H20 (0.7 mL) was added (6-fluoro-3- pyridinyl)boronic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.026 mmol). The reaction was run in the microwave for 20 min at 150° C. The reaction was then treated with EtOAc and brine and purified by flash chromatography to give 50 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1/-/-indole-7-carboxamide (43%).
To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1/-/-indole-7-carboxamide (50 mg, 0.116 mmol) was added propylamine (1 mL) and DMF (0.3 mL). The resulting O NH '2 224 Received at IPONZ on 15 June 2011 mixture was reacted in a microwave for 5 h at 200° C was purified by Gilson Preparatory HPLC to afford 24.5 mg of the title compound (36.2%).
LC/MS = m/z 470.2 [M+H] Ret. Time: 1.49 min.
Example 228: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(6-r(1-methvlethyl)amino1-3-pyridinyl>-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-{6-[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-10 carboxamide trifluoroacetate, substituting 2-propanamine (64.3 mg, 1 mmol) for dimethylamine to afford 9.8 mg of the title compound (14.5%).
LC/MS = m/z 470.4 [M+H] Ret. Time: 1.52 min.
Example 229: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r6-(4-morpholinvl)-3-pyridinvn-1H-15 indole-7-carboxamide The title compound was prepared according to the general procedure of 5-{6-[ethyl(methyl)amino]-3-pyridinyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting morpholine (1 mL) for dimethylamine to afford 20 40.1 mg of the title compound (69.5%). 225 Received at IPONZ on 15 June 2011 LC/MS = m/z 498.6 [M+H] Ret. Time: 1.44 min.
Example 230: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f5-r(methylamino)methvn-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate / N \ N H > N H F OH O NH. '2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (20 mg, 0.045 mmol) in methanol (1.5 mL) and methylene chloride (1.5 mL) was added methylamine (0.13 mL). The resulting mixture was stirred at room temperature for 2 h followed by the addition of sodium tetrahydridoborate (9.18 mg, 10 0.27 mmol). This was stirred at room temperature for 1 h. All solvent was evaporated and it was then purified by Gilson Preparatory HPLC to give 12.4 mg of the title compound (48%).
LC/MS = m/z 461.4 [M+H] Ret. Time: 1.48 min.
Example 231: 3-ri-(ethvlsulfonvlM-piperidinvll-5-(5-(r(1-methvlethvl)aminolmethyl)-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 /-/-indole-7-carboxamide (30 mg, 0.067 mmol) in methanol (0.5 mL) and methylene chloride (1 mL) 20 was added 2-propanamine (23.8 mg, 0.402 mmol). The resulting mixture was stirred for O NH '2 226 Received at IPONZ on 15 June 2011 2.5 h followed by an addition of sodium tetrahydridoborate (15.2 mg, 0.402 mmol). The reaction was stirred at room temperature for 1 h. All solvent was evaporated and it was then purified by Gilson Preparatory HPLC to give 19.5 mg of the title compound (48.3%). LC/MS = m/z 489.2 [M+H] Ret. Time: 1.54 min.
Example 232: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-(1-pvrrolidinvlmethyl)-3-thienyll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 /-/-indole-7-10 carboxamide (30 mg, 0.067 mmol) in methanol (0.5 mL) and methylene chloride (1 mL) was added pyrrolidine (85 mg, 1.195 mmol). The resulting mixture was stirred for 1.5 h followed by an addition of sodium triacetoxyborohydride (85 mg, 0.402 mmol). The reaction was stirred at room temperature for 2 h. All solvent was evaporated and it was then purified by Gilson Preparatory HPLC to give 22.5 mg of the title compound (54.6%). 15 LC/MS = m/z 501.4 [M+H] Ret. Time: 1.52 min.
Example 233: 5-(5-r(ethvlamino)methvll-3-thienvl)-3-ri-(ethvlsulfonvlM-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate O NH '2 /^N H O NH. '2 227 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (30 mg, 0.067 mmol) in methanol (3 mL), methylene chloride (3 mL) was added ethylamine (0.2 mL, 0.402 mmol). After 2 h sodium tetrahydridoborate (27 mg, 0.402 mmol) was added and the mixture was allowed to rest 1 h. All solvent was 5 evaporated and it was then purified by Gilson Preparatory HPLC to give 15 mg of the title compound (38%).
LC/MS = m/z 475.4 [M+H] Ret. Time: 1.52 min.
Example 234: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r5-(fr(1R)-2-hvdroxy-1-10 methvlethvnamino)methvl)-3-thienvH-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-{5-[(ethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide 15 trifluoroacetate, substituting (2R)-2-amino-1-propanol (0.031 mL, 0.402 mmol) for ethylamine to afford 16.2 mg of the title compound (39.1%).
LC/MS = m/z 505.4 [M+H] Ret. Time: 1.42 min.
Example 235: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r5-(1-piperidinvlmethvl)-3-thienyn- 1 H-indole-7-carboxamide trifluoroacetate (salt) O nh2 cr nh, '2 228 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (30 mg, 0.067 mmol) in dimethyl sulfoxide (2 mL) was added piperidine (70 mg, 0.670 mmol). The resulting mixture was allowed to rest for 2 h then socium triacetoxyborohydride (142 mg, 0.670 mmol) was added. This mixture was stirred at 5 room temperature overnight then purified by Gilson Preparatory HPLC to give 16.2 mg of the title compound (38.5%).
LC/MS = m/z 514.8 [M+H] Ret. Time: 1.37 min.
Example 236: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-(4-morpholinvlmethyl)-3-10 thienyll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-3-thienyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting morpholine (70 mg, 0.670 mmol) for piperidine 15 to afford 6.3 mg of the title compound (14.9%).
LC/MS = m/z 517 [M+H] Ret. Time: 1.54 min.
Example 237: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f5-r(methylamino)methvn-3-furanvl)-1 H-indole-7-carboxamide trifluoroacetate cr NH '2 229 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3.0 mL) and H20 (1.0 mL) was added 4-bromo-2-furancarbaldehyde (58 mg, 0.33 mmol), potassium carbonate (89.8 mg, 0.66 mmol), and tetrakis(triphenylphosphine)palladium(0) (14 mg, 5 0.012 mmol). The reaction was heated in the microwave for 20 min at 150° C to give 58 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1/-/-indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1/-/-indole-7-carboxamide (20.6 mg, 0.05 mmol) in DMSO (0.5 mL) was added methylamine (0.24 mL, 10 0.5 mmol) in 2 M tetrahydrofuran. The resulting mixture was reacted for 6 h followed by an addition of sodium triacetoxyborohydride was added. This was then purified by Gilson Preparatory HPLC to afford 5.5 mg of the title compound (32.8%).
LC/MS = m/z 459.4 [M+H] Ret. Time: 1.42 min.
Example 238: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f5-ri-(1-pyrrolidinvl)ethvn-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (300 mg, 0.65 mmol) in dioxane (9 mL) and 20 H20 (3 mL) was added 1-(4-bromo-2-thienyl)ethanone (400 mg, 1.95 mmol), potassium carbonate (538 mg, 3.90 mmol), and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.060 mmol). The reaction was run in the microwave at 150° C for 20 min. An aqueous work-up was performed using EtOAc and H20 followed by addition of MeOH (3 mL) to the crude product. The desired product percpitated and was filtered to give 230 mg of 3-[1-25 (ethylsulfonyl)-4-piperidinyl]-5-(5-propanoyl-3-thienyl)-1 H-indole-7-carboxamide (77%).
To a solution of 5-(5-acetyl-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 /-/-indole-7-carboxamide (50 mg, 0.11 mmol) in DMF (0.8 mL) and acetic acid (0.2 mL) was added pyrrolidine (30.92 mg, 0.44 mmol) and N,N-dimethylformamide (30 mg, 0.44 mmol). The cr nh2 230 Received at IPONZ on 15 June 2011 reaction mixture was reacted in a microwave for 20 min at 150° C. The results were then purified twice by Gilson Preparatory HPLC to give 3.7 mg of the title compound (5.3%). LC/MS = m/z 515.4 [M+H] Ret. Time: 1.62 min.
Example 239: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-(1-pyrrolidinvlmethvl)-2-thienyll-1 H-indole-7-carboxamide trifluoroacetate To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1/-/-indole-7-carboxamide (40 mg, 0.09 mmol) in dilmethyl sulfoxide (0.5 mL) was added 2M pyrrolidine (0.074 mL, 0.90 10 mmol). The resulting mixture was allowed to rest for 6 h followed by an addition of sodium triacetoxyborohydride (233 mg, 9.90 mmol). This was then allowed to rest for 2 h then purified by Gilson Preparatory HPLC to give 6.5 mg of the title compound (11.7%). LC/MS = m/z 515.4 [M+H] Ret. Time: 1.62 min.
Example 240: 5-(5-r(dimethylamino)methvll-2-thienyl)-3-ri-(ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1/-/-indole-7-carboxamide (35 mg, 0.09 mmol) in dilmethyl sulfoxide (0.5 mL) was added 2M dimethylamine (0.4 mL, 20 0.90 mmol). The resulting mixture was allowed to rest for 6 h followed by an addition of 231 Received at IPONZ on 15 June 2011 sodium triacetoxyborohydride (233 mg, 9.90 mmol). This was then allowed to rest for 2 h then purified by Gilson Preparatory HPLC to give 17.8 mg of the title compound (33.6%). LC/MS = m/z 475.2 [M+H] Ret. Time: 1.53 min.
Example 241: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-{5-r(propylamino)methvH-2-thienvl)-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-{5-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-10 carboxamide trifluoroacetate, substituting propylamine (0.064 mL, 0.90 mmol) for2M dimethylamine to afford 8.9 mg of the title compound (16.4%).
LC/MS = m/z 487.2 [M+H] Ret. Time: 1.80 min.
Example 242: 5-(5-r(diethylamino)methvll-2-thienvl)-3-ri-(ethvlsulfonylM-15 piperidinvll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-{5-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting diethylamine (0.081 mL, 0.90 mmol) for2M 20 dimethylamine to afford 16.6 mg of the title compound (29.9%).
LC/MS = m/z 502.0 [M+H] Ret. Time: 1.71 min. 232 Received at IPONZ on 15 June 2011 Example 243: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(5-(T(2- methylpropvl)amino1methvl)-2-thienyl)-1 H-indole-7-carboxamide trifluoroacetate To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1/-/-indole-7-carboxamide (30 mg, 0.09 mmol) in dilmethyl sulfoxide (0.5 mL) was added 2-methyl-1-propanamine (0.068 mL, 0.90 mmol). The resulting mixture was allowed to rest for 6 h followed by an addition of sodium triacetoxyborohydride (233 mg, 9.90 mmol). This was then allowed to rest for 2 h then purified by Gilson Preparatory HPLC to give 2.7 mg of the title compound (4.9%).
LC/MS = m/z 501.4 [M+H] Ret. Time: 1.79 min.
Example 244: 5-(5-<T(2.2-dimethvlpropyl)aminolmethvl)-3-furanvl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3.0 mL) and H20 (1.0 mL) was added 4-bromo-2-furancarbaldehyde (58 mg, 0.33 mmol), potassium carbonate (89.8 mg, 0.66 mmol), and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol). The reaction was heated in the microwave for 20 min at 150° C to give 58 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1/-/-indole-7-carboxamide. o nh cr NH, '2 233 Received at IPONZ on 15 June 2011 To 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1/-/-indole-7-carboxamide (60 mg, 0.14 mmol) was added 2,2-dimethyl-1-propanamine (60 mg, 0.14 mmol) in dimethyl sulfoxide (0.5 mL) was added 2,2-dimethyl-1-propanamine (122 mg, 1.40 mmol). The 5 resulting mixture was allowed to rest for 6 h followed by an addition of sodium triacetoxyborohydride (233 mg, 9.90 mmol). This was then allowed to rest for 2 h then purified by Gilson Preparatory HPLC to give 23.8 mg of the title compound (27.7%). LC/MS = m/z 501.1 [M+H] Ret. Time: 1.67 min.
Example 245: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(5-(T(2- methylpropvl)amino1methvl)-3-furanyl)-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-15 carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (102.4 mg, 1.4 mmol) for 2,2-dimethyl-1-propanamine to afford 31.7 mg of the title compound (37.7%).
LC/MS = m/z 487.2 [M+H] Ret. Time: 1.44 min.
Example 246: 5-(5-(T(cvclopentvlmethvl)amino1methvl)-3-furanyl)-3-ri-20 (ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate Cr "NH2 234 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting 1-cyclopentylmethanamine (137 mg, 1.4 mmol) 5 for 2,2-dimethyl-1-propanamine to afford 22 mg of the title compound (25.1%).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.59 min.
Example 247: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-(1-pyrrolidinvlmethvl)-3-furanyll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (99.6 mg, 1.4 mmol) for 2,2-15 dimethyl-1-propanamine to afford 6 mg of the title compound (7.2%).
LC/MS = m/z 485.2 [M+H] Ret. Time: 1.50 min.
Example 248: 5-f5-r(diethylamino)methvn-3-furanylV3-ri-(ethvlsulfonvl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate 235 Received at IPONZ on 15 June 2011 F~K F OH '2 The title compound was prepared according to the general procedure of 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting 2M diethylamine (102.4 mg, 1.4 mmol) for 2,2-dimethyl-1-propanamine to afford 10.1 mg of the title compound (12%).
LC/MS = m/z 487.4 [M+H] Ret. Time: 1.50 min.
Example 249: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-(1-pvrrolidinvlmethyl)-1,3-thiazol-2-yll-l H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (500 mg, 1.1 mmol) in dioxane (12 mL) and H20 (4 mL) was added 2-bromo-1,3-thiazole-5-carbaldehyde (634 mg, 3.3 mmol), potassium carbonate (898 mg, 8.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (210 mg, 0.181 mmol). Reaction was run in the microwave at 150° C for 20 min. Aqueous work-up performed to give crude product. The reaction was then repeated in the microwave at 150° C for 30 min to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-1,3-thiazol-2-yl)-1 /-/-indole-7-carboxamide.
O NH '2 236 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-1,3-thiazol-2-yl)-1/-/-indole-7-carboxamide (25 mg, 0.06 mmol) in dimethyl sulfoxide (1 mL) was added pyrrolidine (0.05 mL, 0.60 mmol). The resulting mixture was stirred at room temperature for 6 h followed by an addition of sodium triacetoxyborohydride (160 mg, 0.60 mmol). The resulting 5 mixture was stirred overnight then purified by Gilson Preparatory HPLC to give 6.3 mg of the title compound (17.1%).
LC/MS = m/z 502.2 [M+H] Ret. Time: 1.35 min.
Example 250: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-r2-methyl-1-(1-10 pyrrolidinvl)propvn-3-thienvl)-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3 mL) and H20 (1 mL) was added potassium carbonate (89.8 mg, 0.66 mmol), 1-(4-bromo-2-15 thienyl)-2-methyl-1-propanone (87 mg, 0.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol). The reaction was run in a microwave for 20 min at 150° C followed by an aqueous work-up with EtOAd and H20. The reaction was then concentrated and treated with 1 N NaOH and extracted with EtOAc. The compound was purified by flash chromatography using DCM and MeOH to 20 give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-methylpropanoyl)-3-thienyl]-1 H-indole-7-carboxamide.
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-methylpropanoyl)-3-thienyl]-1/-/-indole-7-carboxamide (40 mg, 0.02 mmol) in EtOH (1.5 mL) and acetic acid (0.2 mL) was 25 added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and pyrrolidine (0.03 mL, 0.3 mmol). The resulting mixture was reacted in a microwave for 40 min at 150° C. All solvent was then evaporated, and basified in sodium hydroxide and extracted with ethyl '2 237 Received at IPONZ on 15 June 2011 acetate. This was then purified by Gilson Preparatory HPLC to give 13 mg of the title compound.
LC/MS = m/z 543.4 [M+H] Ret. Time: 1.71 min.
Example 251: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r4-(1-pvrrolidinvlmethyl)-1,3-thiazol-2-vl1-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-formyl-1,3-thiazol-4-yl)-1/-/-indole-7-carboxamide (42 mg, 0.094 mmol) in DMSO (2 mL) was added pyrrolidine (0.08 mL, 10 0.940 mmol). The resulting mixture was stirred at room temperature for 6 h followed by an addition of sodium triacetoxyborohydride. This mixture was stirred at room temperature overnight then purified by Gilson Preparatory HPLC to give 15.1 mg of the title compound (26.1%).
LC/MS = m/z 502.4 [M+H] Ret. Time: 1.54 min.
Example 252: 5-{1-r2-(dimethvlamino)ethvn-1H-pyrazol-4-vl)-3-ri-(ethvlsulfonvl)-4-pipe ridinyll-l H-indole-7-carboxamide O NH '2 \ N O NH '2 238 Received at IPONZ on 15 June 2011 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (40 mg, 0.084 mmol), [2-(4-bromo-1H-pyrazol-1-yl)ethyl]dimethylamine (27 mg, 0.126 mmol) and sodium carbonate (53 mg, 0.5 mmol) was suspended in dioxane (750 |jL) and water (250 |jL). This was flushed with argon for 5 10 min before the addition of tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol). The resulting mixture was reacted in a microwave for 20 min at 120° C then diluted with EtOAc (10 mL). The mixture was filtered through Celite and an aqueous wash was performed. It was then purified by Gilson Preparatory HPLC to give 6 mg of the title compound (15%).
LC/MS = m/z 473.4 [M+H] Ret. Time: 1.48 min.
Example 253: 3-ri-(ethvlsulfonvlM-piperidinvll-5-(1-r2-(1-Pvrrolidinvl)ethyll-1H-Pvrazol-4-ylVI H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane (750 |jL) and H20 (250 |jL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-1-(2-chloroethyl)-1/-/-pyrazole (26 mg, 0.126 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.004 20 mmol). The reaction was heated in a microwave at 120° C for 20 min. It was then diluted with EtOAc (10 mL), filtered thru celite, followed by an aqueous work-up. The compound was purified by Gilson Preparatory HPLC to give 10 mg of 5-[1-(2-chloroethyl)-1H-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (24%).
To a solution of 5-[1-(2-chloroethyl)-1/-/-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (33 mg, 0.071 mmol), pyrrolidine (60 |jL, 0.710 mmol) and sodium O NH '2 239 Received at IPONZ on 15 June 2011 iodide (5 mg, 0.018 mmol) was added tetrahydrofuran (500 |jL). This mixture was reacted in a microwave for 2 h at 130° C and given an aqueous wash with EtOAc and water. Organic layer was then isolated and all solvent was removed. It was then purified by Gilson Preparatory HPLC to give 11 mg of the title compound (25%).
LC/MS = m/z 499.6 [M+H] Ret. Time: 1.34 min.
Example 254: 3-ri-(ethvlsulfonvlM-piperidinvll-5-(1-r2-(4-morpholinvl)ethyll-1H-pyrazol-4-yl)-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1- (ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-4-yl}-1 H-indole-7-carboxamide trifluoroacetate, substituting morpholine (70 |jL, 0.71 mmol) for the pyrrolidine to afford 15 mg of the title compound (34%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.46 min.
Example 255: 3-ri-(ethylsulfonvl)-4-piperidinyn-5-(1-f2-r(2-hvdroxvethvl)aminolethyl)-1H-pvrazol-4-vl)-1 H-indole-7-carboxamide trifluoroacetate '2 240 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane (750 |jL) and H20 (250 |jL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-1-(2-5 chloroethyl)-1/-/-pyrazole (26 mg, 0.126 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.004 mmol). The reaction was heated in a microwave at 120° C for 20 min. It was then diluted with EtOAc (10 mL), filtered thru celite, followed by an aqueous work-up. The compound was purified by Gilson Preparatory HPLC to give 10 mg of 5-[1-(2-chloroethyl)-1H-10 pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (24%).
A solution of 5-[1-(2-chloroethyl)-1/-/-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (20 mg, 0.043 mmol), 2-aminoethanol (26 mg, 0.43 mmol) and sodium iodide (5 mg, 0.022 mmol) in tetrahydrofuran (1 mL) was reacted in a microwave 15 for 2 h at 130° C. The tetrahydrofuran was then removed and the mixture was given an aqueous was of EtOAc and water. The organic layer was then separated and all solvent was removed. The mixture was then purified by Gilson Preparatory HPLC to give 8 mg of the title compound (31%).
LC/MS = m/z 489.2 [M+H] Ret. Time: 1.40 min.
Example 256: 5-f1-r2-(butylamino)ethvn-1 H-pyrazol-4-vlV3-ri-(ethvlsulfonyl)-4-piperidinvll-lH-indole-7-carboxamide trifluoroacetate 241 Received at IPONZ on 15 June 2011 F OH H O NH '2 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting 1-butanamine (31 mg, 0.43 mmol) for 5 the 2-aminoethanol to afford 7 mg of the title compound (26%).
LC/MS = m/z 499.4 [M+H] Ret. Time: 1.39 min.
Example 257: 5-f1-r2-(cvclobutvlamino)ethvn-1H-pvrazol-4-vl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1 H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting cyclobutanamine (31 mg, 0.43 mmol) for the 2-aminoethanol to afford 10 mg of the title compound (38%).
LC/MS = m/z 501.4 [M+H] Ret. Time: 1.48 min.
Example 258: 5-ri-(2-(T2-(diethvlamino)ethvnamino)ethvl)-1H-pyrazol-4-vn-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate 242 Received at IPONZ on 15 June 2011 \ f OH T H \ O NH.
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting N,N-diethyl-1,2-ethanediamine (50 mg, 5 0.43 mmol) for the 2-aminoethanol to afford 12 mg of the title compound (42%).
LC/MS = m/z 545.2 [M+H] Ret. Time: 1.25 min.
Example 259: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(1-(2-r(1-methvlethvl)amino1ethyl)-1 H-pyrazol-4-yl)-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1 H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (25 mg, 0.43 mmol) for the 2-aminoethanol to afford 9 mg of the title compound (35%).
LC/MS = m/z 487.2 [M+H] Ret. Time: 1.47 min. 243 Received at IPONZ on 15 June 2011 Example 260: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(1-f2-r(2-methylpropvl)amino1ethvl)-1H-pvrazol-4-yl)-1 H-indole-7-carboxamide trifluoroacetate cr nh2 The title compound was prepared according to the general procedure of 3-[1- (ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1 H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (31 mg, 0.43 mmol) for the 2-aminoethanol to afford 8 mg of the title compound (30%).
LC/MS = m/z 501.2 [M+H] Ret. Time: 1.45 min. 0 Example 261: 5-(1-(2-r(cyclopentvlmethvl)aminolethvl)-1H-pvrazol-4-vl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-15 (ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate, substituting cyclopentanamine (37 mg, 0.43 mmol) for the 2-aminoethanol to afford 11 mg of the title compound (40%).
O NH '2 244 Received at IPONZ on 15 June 2011 LC/MS = m/z 513.4 [M+H] Ret. Time: 1.47 min.
Example 262: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r4-(methvloxy)-3-(1-pyrrolidinvlmethvl)phenvn-1H-indole-7-carboxamide trifluoroacetate To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (610 mg, 2.33 mmol) in dioxane (19 mL) and H20 (6.3 mL), was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (963 mg, 2.33 mmol), and sodium carbonate (1.48 g, 13.9 mmol). After flushing with Agron for 10 min, 10 tetrakis(triphenylphosphine)palladium(0) (134 mg, 0.166 mmol) was added. The reaction was heated in the microwave 120° C for 120 min. Compound was purified by flash chromatography using DCM and MeOH to give 632 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1/-/-indole-7-carboxamide (58%).
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1/-/-indole-7-carboxamide (50 mg, 0.107 mmol), pyrrolidine (45 |jL, 0.214 mmol), zinc chloride (10 mg, 0.054 mmol) and sodium cyanoborohydride (7 mg, 0.107 mmol) in methanol (5 mL) was stirred at room temperature for 2 h. To this mixture was added 0.1 normal solution of sodium hydroxide in water (2 mL). The methanol was then evaporated. The aqueous 20 phase was extracted with EtOAc (5 mL) three times. The organic phase was then washed with brine (5 mL) twice. All solvent was then removed. The mixture was purified by Gilson Preparatory HPLC to give 9 mg of the title compound (13%).
LC/MS = m/z 525.6 [M+H] Ret. Time: 1.67 min.
Example 263: 5-r3-r(dimethylamino)methvn-4-(methvloxy)phenvn-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate 245 Received at IPONZ on 15 June 2011 o=s=o I To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (610 mg, 2.33 mmol) in dioxane (19 mL) and H20 (6.3 mL), was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (963 mg, 2.33 mmol), 5 and sodium carbonate (1.48 g, 13.9 mmol). After flushing with Agron for 10 min, tetrakis(triphenylphosphine)palladium(0) (134 mg, 0.166 mmol) was added. The reaction was heated in the microwave 120° C for 120 min. Compound was purified by flash chromatography using DCM and MeOH to give 632 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1/-/-indole-7-carboxamide (58%).
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1/-/-indole-7-carboxamide (50 mg, 0.214 mmol), dimethylamine (107 |jL, 0.214 mmol), zinc chloride (10 mg, 0.054 mmol) and sodium cyanoborohydride (7 mg, 0.107 mmol) in methanol (5 mL) was stirred at room temperature for 2 h. To this mixture was added 0.1 normal 15 solution of sodium hydroxide in water (2 mL). The methanol was then evaporated. The aqueous phase was extracted with EtOAc (5 mL) three times. The organic phase was then washed with brine (5 mL) twice. All solvent was then removed. The mixture was purified by Gilson Preparatory HPLC to give 4 mg of the title compound (6.1%).
LC/MS = m/z 499.4 [M+H] Ret. Time: 1.56 min.
Example 264: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r4-(methvloxy)-3-(4-morpholinvlmethyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate 246 Received at IPONZ on 15 June 2011 o=s=o I The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (20 |jL, 0.214 mmol) for the 5 dimethylamine to afford 12 mg of the title compound (17%).
LC/MS = m/z 541.6 [M+H] Ret. Time: 1.69 min.
Example 265: 3-ri-(ethvlsulfonvlM-piperidinvll-5-r3-{T(1-methvlethvl)aminolmethyl)-4-(methyloxv)phenyll-1 H-indole-7-carboxamide trifluoroacetate o=s=o I The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (15 |jL, 0.214 mmol) for the dimethylamine to afford 16 mg of the title compound (24%).
LC/MS = m/z 513.2 [M+H] Ret. Time: 1.62 min. 247 Received at IPONZ on 15 June 2011 Example 266: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-r(methylamino)methvn-4-(methyloxy)phenvn-lH-indole-7-carboxamide trifluoroacetate 0=s=0 I The title compound was prepared according to the general procedure of 5-[3-5 [(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- indole-7-carboxamide trifluoroacetate, substituting methylamine (50 |jL, 0.214 mmol) for the dimethylamine to afford 10 mg of the title compound (16%).
LC/MS = m/z 485.2 [M+H] Ret. Time: 1.57 min.
Example 267: 5-r3-(T(2.2-dimethvlpropvl)amino1methvl'M-(methvloxv)phenvn-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate o=s=o I The title compound was prepared according to the general procedure of 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- 248 Received at IPONZ on 15 June 2011 indole-7-carboxamide trifluoroacetate, substituting 2,2-dimethyl-1-propanamine (20 |jL, 0.214 mmol) for the dimethylamine to afford 11 mg of the title compound (16%).
LC/MS = m/z 541.2 [M+H] Ret. Time: 1.77 min.
Example 268: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(1-(2-r(2-hvdroxvethvl)(methvl)amino1ethvl)-1H-pyrazol-4-vl)-1H-indole-7-carboxamide A solution of 5-[1-(2-chloroethyl)-1/-/-pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.065 mmol), 2-(methylamino)ethanol (500 |jL, 6.5 mmol) 10 and sodium iodide (3 mg, 0.016 mmol) in tetrahydrofuran (1 mL) was reacted in a microwave for 2 h at 130° C. An aqueous work-up was performed on the resulting mixture. This was then purified by Gilson Preparatory HPLC to give 9 mg of the title compound (17%).
LC/MS = m/z 503.2 [M+H] Ret. Time: 1.40 min.
Example 269: 3-ri-(ethvlsulfonvlM-piperidinyll-5-f4-fluoro-3-r(methylamino)methvnphenyl)-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-fluoro-3-formylphenyl)-1/-/-indole-7-20 carboxamide (16.0 mg, 0.035 mmol) in dichloromethane (1 mL) and methanol (1 mL) was added 2M methylamine in THF (105 |jL, 0.21 mmol) and 1 drop of acetic acid. This mixture was stirred for 3 h. Sodium tetrahydridoborate (8.4 mg, 0.21 mmol) was added 249 Received at IPONZ on 15 June 2011 and the mixture was stirred for 1 h. The resulting mixture was concentrated and dissolved in dimethyl sulfoxide (1.5 mL). It was then purified by Gilson Preparatory HPLC to give 6.4 mg of the title compound (31.2%).
LC/MS = m/z 473.4 [M+H] Ret. Time: 1.50 min.
Example 270: 5-f3,5-bisr(methylamino)methvllphenvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 5-(3,5-diformylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-10 carboxamide (10 mg, 0.2 mmol) in dichloromethane (1 mL) and methanol (1 mL) was added methylamine (64 |jL, 0.128 mmol) and 1 drop of acetic acid. The resulting mixture was stirred for 3 h at room temperature then sodium tetrahydridoborate (5.1 mg, 0.128 mmol) was added. This was stirred for 1 h then concentrated and purified by Gilson Preparatory HPLC to give 3 mg of the title compound (23.4%).
LC/MS = m/z 498.6 [M+H] Ret. Time: 1.17 min.
Example 271: 5-{3-r(ethvlamino)methvn-4-fluorophenvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-fluoro-3-formylphenyl)-1/-/-indole-7-carboxamide (35 mg, 0.076 mmol) in dichloromethane (1 mL) and methanol (1 mL) was added 2 M ethylamine (230 |jL, 0.46 mmol) and 1 drop of acetic acid. The mixture was stirred for 1 h at room temperature then tetrahydrofuran (1 mL) was added. The mixture was stirred for 30 min followed by the addition of sodium tetrahydridoborate (17.5 mg, o h,n o F 250 Received at IPONZ on 15 June 2011 0.46 mmol). The resulting mixture was stirred for an additional 1 h, concentrated and purified by Gilson Preparatory HPLC to give 20 mg of the title compound (43.8%). LC/MS = m/z 487.4 [M+H] Ret. Time: 1.46 min.
Example 272: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r4-fluoro-3-(fr2-hydroxv-1-(hvdroxvmethvl)ethvnamino)methyl)phenvn-1H-indole-7-carboxamide trifluoroacetate (salt) OH OH The title compound was prepared according to the general procedure of 5-{3-10 [(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7- carboxamide trifluoroacetate, substituting 2-amino-1,3-propanediol (42 mg, 0.46 mmol) for ethylamine to afford 21 mg of the title compound (42.7%).
LC/MS = m/z 533.2 [M+H] Ret. Time: 1.39 min.
Example 273: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r4-fluoro-3-((T(1S)-2-hydroxv-1-methylethvnamino)methyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate (salt) OH The title compound was prepared according to the general procedure of 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-20 carboxamide trifluoroacetate, substituting (2S)-2-amino-1-propanol (37 mg, 0.46mmol) for ethylamine to afford 26 mg of the title compound (54.2%).
LC/MS = m/z 517.2 [M+H] Ret. Time: 1.44 Example 274: 5-f3-r(cvclopropvlamino)methvn-4-fluorophenvlV3-ri-(ethvlsulfonyl)-25 4-piperidinyn-1 H-indole-7-carboxamide trifluoroacetate 251 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting cyclopropylamine (32 mg, 0.46 mmol) for 5 ethylamine to afford 23 mg of the title compound (49.4%).
LC/MS = m/z 499.6 [M+H] Ret. Time: 1.75 min.
Example 275: 5-(3-r(cyclobutvlamino)methvH-4-fluorophenvl)-3-ri-(ethvlsulfonvlM-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting cyclobutanamine (39 mg, 0.46 mmol) for ethylamine to afford 20 mg of the title compound (42%).
LC/MS = m/z 513.2 [M+H] Ret. Time: 1.58 min.
Example 276: 3-ri-(ethvlsulfonvlM-piperidinvll-5-r3-(1-pyrrolidinvlmethvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate f 252 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (33 mg 0.74 mmol) in dichloromethane (0.5 mL) and methanol (0.5 mL) was added pyrrolidine (32 mg, 0.444 mmol) and 1 drop of acetic acid. The mixture was stirred for 2 min then sodium tetrahydridoborate (17.8 mg, 0.444 mmol) was added. This was 5 then stirred overnight then concentrated and by Gilson Preparatory HPLC to give 9.7 mg of the title compound (21.5%) LC/MS = m/z 495.4 [M+H] Ret. Time: 1.67 min.
Example 277: 5-(3.5-bisr(ethvlamino)methvnphenvlV3-ri-(ethvlsulfonyl)-4-10 piperidinyll-lH-indole-7-carboxamide trifluoroacetate To a solution of 5-(3,5-diformylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (27 mg, 0.058 mmol) in dichloromethane (1.5 mL) and methanol (1.5 mL) was added ethylamine (31.4 mg, 0.696 mmol) and 1 drop of acetic acid. The resulting mixture was stirred for 2 h then sodium tetrahydridoborate (13.2 mg, 0.348 mmol) was added. This was stirred for another 50 min then purified by Gilson Preparatory HPLC to give 20 mg of the title compound (53.9%).
LC/MS = m/z 526.6 [M+H] Ret. Time: 1.41 min.
Example 278: 5-f3,5-bisr(dimethvlamino)methvnphenyl)-3-ri -(ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formyl-5-mercaptophenyl)-1/-/-indole-7-carboxamide (34 mg, 0.058 mmol) in dichloromethane (1.5 mL) and methanol 25 (1.5 mL) was added dimethylamine (31.4 mg, 0.696 mmol) and a drop of acetic acid. The resulting mixture was stirred for 2 h at room temperature then sodium tetrahydridoborate 253 Received at IPONZ on 15 June 2011 (13.2 mg, 0.348 mmol) was added. This was stirred for another 30 min then purified by Gilson Preparatory HPLC to give 11 mg of the title compound (29.6%).
LC/MS = m/z 526.6 [M+H] Ret. Time: 1.27 min.
Example 279: 3-H -(ethvlsulfonvl)-4-piperidinvn-5-r3-(2-piperidinvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2 mL) and 10 H20 (0.7 mL) was added 2-(3-chlorophenyl)piperidine (46 mg, 0.2 mmol). Potassium carbonate (55 mg, 0.4 mmol) and, after being degassed for 5 min, tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.5 mmol) was added. The resulting mixture was reacted in a 300W CEM microwave for 30 min at 160° C then the solids were filtered off. The solvent was evaporated and the solution was purified by Gilson 15 Preparatory HPLC to give 13.2 mg of the title compound (21.7%).
LC/MS = m/z 495.4 [M+H] Ret. Time: 1.76 Example 280: 5-f3-ri-(ethvlamino)ethvnphenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide trifluoroacetate A solution of 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol), ethylamine (19.9 mg, 0.441 mmol) and sodium cyanoborohydride (30 mg, 0.441 mmol) in N,N-dimethylformamide (0.8 mL) and acetic acid (0.2 mL) was reacted in a microwave for 20 min at 150° C. The reaction was purified 25 by Gilson Preparatory HPLC to give 20.6 mg of the title compound (39%). 254 Received at IPONZ on 15 June 2011 LC/MS = m/z 483.2 [M+H] Ret. Time: 1.67 Example 281: 5-f3-ri-(dimethvlamino)ethvnphenvl}-3-ri-(ethvlsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate -(3-acetylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 /-/-indole-7-carboxamide (50 mg, 0.11 mmol), dimethylamine (220 |jL, 0.44 mmol) and sodium cyanoborohydride (30 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (400 |jL) and acetic acid (100 |jL). The resulting mixture was reacted in a Smith 150 W microwave for 20 min. at 150° C. 10 The reaction was purified by Gilson Preparatory HPLC to give 14.6 mg of the title compound (22.2%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.63 Example 282: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-f3-fluoro-5-15 r(methylamino)methvnphenyl)-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-formylphenyl)-1/-/-indole-7-carboxamide (32 mg, 0.07 mmol) in dichloromethane (1.5 mL) and methanol (1.5 mL) was added 2 M methylamine in THF (210 |j|, 0.42 mmol) and 1 drop of acetic acid. The 20 resulting mixture was stirred for 3 h at room temperature then sodium tetrahydridoborate (15 mg, 0.42 mmol) was added. This mixture was stirred for 1 hour then concentrated and purified by Gilson Preparatory HPLC to give 30 mg of the title compound (73.1%). LC/MS = m/z 473.6 [M+H] Ret. Time: 1.73 min. 255 Received at IPONZ on 15 June 2011 Example 283: 5-f3-r(ethvlamino)methvn-5-fluorophenvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-5 (ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7- carboxamide trifluoroacetate, substituting 2 M ethanamine in THF (210 ul, 0.42 mmol) for methanamine to afford 6.5 mg of the title compound (15.5%).
LC/MS = m/z 487.4 [M+H] Ret. Time: 1.64 min.
Example 284: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-f3-fluoro-5- r(propylamino)methvllphenvl)-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-15 carboxamide trifluoroacetate, substituting propylamine (21 mg, 0.42 mmol) for methanamine to afford 31 mg of the title compound (72%).
LC/MS = m/z 501.4 [M+H] Ret. Time: 1.54 Example 285: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(3-fluoro-5-(r(1-20 methylethvl)amino1methvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate F F 256 Received at IPONZ on 15 June 2011 F The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (21 mg, 0.42 mmol) for 5 methanamine to afford 28.5 mg of the title compound (66.2%).
LC/MS = m/z 501.4 [M+H] Ret. Time: 1.53 min.
Example 286: 3-H -(ethvlsulfonvlM-piperidinyll-5-(3-fluoro-5-(r(2-methylpropvl)amino1methvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (21 mg, 0.42 mmol) for methanamine to afford 10 mg of the title compound (22.7%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.72 min.
Example 287: 5-f3-r(cvclobutvlamino)methvn-5-fluorophenvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate F 257 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting cyclobutylamine (21.5 mg, 0.42 mmol) for methanamine to afford 33 mg of the title compound (75.2%).
LC/MS = m/z 513.2 [M+H] Ret. Time: 1.50 min.
Example 288: 5-(3-r(dimethvlamino)methvll-5-fluorophenvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting 2M dimethylamine in THF (210 ul, 0.42 mmol) for methanamine to afford 33.7 mg of the title compound (80.2%).
LC/MS = m/z 487.2 [M+H] Ret. Time: 1.43 min.
Example 289: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-r3-fluoro-5-(1-pyrrolidinvlmethvl)phenvll-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (20.4 mg, 0.42 mmol) for methanamine to afford 18 mg of the title compound (41%).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.63 min. o f 258 Received at IPONZ on 15 June 2011 Example 290: 3-H -(ethvlsulfonyl)-4-piperidinvn-5-r3-fluoro-5-(4-morpholinvlmethyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate h2n The title compound was prepared according to the general procedure of 3-[1-5 (ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting morpholine (22 mg, 0.42 mmol) for methanamine to afford 22.9 mg of the title compound (50.9%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.47 min.
Example 291: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-r3-fluoro-5-(1- piperidinvlmethvl)phenyll-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-15 carboxamide trifluoroacetate, substituting piperidine (22 mg, 0.42 mmol) for methanamine to afford 13.4 mg of the title compound (29.9%).
LC/MS = m/z 527.6 [M+H] Ret. Time: 1.62 Example 292: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-{3-ri-(methvlamino)ethvnphenyl)-20 1 H-indole-7-carboxamide trifluoroacetate 259 Received at IPONZ on 15 June 2011 H O H,N F OH To a solution of 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (20 mg, 0.044 mmol) in ethanol was added methylamine hydrochloride salt and 1 drop of concentrated hydrochloride. The mixture was reacted in a CEM microwave 5 at 100° C for 10 min then sodium tetrahydridoborate was added. The resulting mixture was reacted in a CEM microwave at 50° C for 5 min then all solvent was evaporated. It was again dissolved in dimethyl sulfoxide then purified by Gilson Preparatory HPLC to afford 16.5 mg of the title compound (64.4%).
LC/MS = m/z 469.4 [M+H] Ret. Time: 1.45 min. 0 Example 293: 3-ri-(ethylsulfonvl)-4-piperidinyn-5-(3-f1-r(1-methvlethvl)amino1ethvl)phenylHH-indole-7-carboxamide trifluoroacetate To a solution of 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-15 carboxamide (20 mg, 0.044 mmol), in N,N-dimethylformamide (0.8 mL) and acetic acid (0.2 mL) was added 2-propanamine (75 pL, 0.88 mmol) and sodium cyanoborohydride (6 mg, 0.09 mmol). The resulting mixture was reacted in a Smith microwave at 70° C for 1 h. The solid was filtered off and then purified by Gilson Preparatory HPLC to afford 19.4 mg of the title compound (72.2%).
LC/MS = m/z 497.4 [M+H] Ret. Time: 1.44 min.
Example 294: 3-ri-(ethylsulfonvl)-4-piperidinyll-5-(3-f1-r(2-methylpropvl)aminolethvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate 260 Received at IPONZ on 15 June 2011 H,N ^O F OH To a solution of 5-(3-acetylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 /-/-indole-7-carboxamide (30 mg, 0.066 mmol), in ethanol (1.2 mL) and acetic acid (0.3 mL) was added (2-methylpropyl)amine (101 mg, 1.98 mmol) and sodium cyanoborohydride (13.5 5 mg, 0.198 mmol). The resulting mixture was reacted in a Smith microwave at 70° C for 1 h. All solvent was evaporated and dimethyl sulfoxide was used to dissolve the solid. It was then purified by Gilson Preparatory HPLC to afford 22.7 mg of the title compound (55.1%).
LC/MS = m/z 511.2 [M+H] Ret. Time: 1.52 min. 0 Example 295: 5-(3-ri-(cvclobutvlamino)ethvnphenvl)-3-ri-(ethvlsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-15 (ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl)amino]ethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate, substituting cyclobutylamine (101 mg, 1.98 mmol) for (2-methylpropyl)amine to afford 29.1 mg of the title compound (70.8%).
LC/MS = m/z 509.4 [M+H] Ret. Time: 1.52 min.
Example 296: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-{3-ri-(1- pvrrolidinvl)ethvnphenvl)-1H-indole-7-carboxamide trifluoroacetate 261 Received at IPONZ on 15 June 2011 H,N ^O The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl)amino]ethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (101 mg, 1.98 mmol) for (2-5 methylpropyl)amine to afford 29.2 mg of the title compound (71%).
LC/MS = m/z 509.4 [M+H] Ret. Time: 1.49 min.
Example 297: 3-H -(ethvlsulfonvl)-4-piperidinvn-5-r3-(3-thiomorpholinyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (60 mg, 0.13 mmol) in dioxane (1.5 mL) and water (0.5 mL) was added 3-(3-chlorophenyl)thiomorpholine (84 mg, 0.39 mmol) and potassium carbonate (107.6 mg, 0.78 mmol). This mixture was degassed for 5 min then 15 tetrakis(triphenylphosphine)palladium(0) (14.0 mg, 0.013 mmol) was added. The resulting mixture was reacted in a microwave for 30 min at 160° C. The solid was filtered off and all solvents were evaporated. The resulting solution was re-dissolved in dichloromethane and separator was used to remove water. The mixture was concentrated to give organic solvent and then purified by Gilson Preparatory HPLC to 20 give 7.4 mg of the title compound (11 %).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.54 Example 298: 3-H -(ethvlsulfonvl)-4-piperidinvn-5-r5-(2-piperazinyl)-2-thienvn-1 H-indole-7-carboxamide trifluoroacetate 262 Received at IPONZ on 15 June 2011 Hr H,N T 0 F OH O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (60 mg, 0.13 mmol) in dioxane (1.5 mL) and water (0.5 mL) was added 2-(5-bromo-2-thienyl)piperazine (102 mg, 0.39 mmol) and 5 potassium carbonate (108 mg, 0.78 mmol). This mixture was degassed for 5 min then tetrakis(triphenylphosphine)palladium(0) (15.0 mg, 0.013 mmol) was added. The resulting mixture was reacted in a microwave for 30 min at 160° C. The solid was filtered off and all solvents were evaporated. The resulting solution was re-dissolved in dichloromethane and separator was used to remove water. The mixture was 10 concentrated to give organic solvent and then purified by Gilson Preparatory HPLC to give 29.1 mg of the title compound (36.4%).
LC/MS = m/z 502.4 [M+H] Ret. Time: 1.31 Example 299: 3-H -(ethvlsulfonvl)-4-piperidinvn-5-r4-(2-piperazinvl)phenyll-1 H-15 indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-piperazinyl)-2-thienyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting 2-(4-bromophenyl)piperazine (94 mg, 0.39 mmol) for2-(5-20 bromo-2-thienyl)piperazine to afford 20.5 mg of the title compound (25.9%).
LC/MS = m/z 496.4 [M+H] Ret. Time: 1.25 Example 300: 3-H -(ethvlsulfonvl)-4-piperidinvn-5-r3-(2-piperazinvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate o HN H,N ^O F OH 263 Received at IPONZ on 15 June 2011 NH F OH F O o To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (60 mg, 0.13 mmol) in dioxane (1.5 mL) and water (0.5 mL) was added 2-(3-chlorophenyl)piperazine (63.7 mg, 0.325 mmol) and 5 potassium carbonate (90 mg, 0.650 mmol). This mixture was degassed for 5 min then tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.011 mmol) was added. The resulting mixture was reacted in a microwave for 30 min at 160° C. The solid was filtered off and all solvents were evaporated. The resulting solution was re-dissolved in dichloromethane and separator was used to remove water. The mixture was concentrated to give organic 10 solvent and then purified by Gilson Preparatory HPLC to give 21.7 mg of the title compound (27.4%).
LC/MS = m/z 496.4 [M+H] Ret. Time: 1.28 min.
Example 301: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r6-(4-morpholinvl)-3-pyridazinvn- 1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 4-(6-chloro-3-pyridazinyl)morpholine (65 mg, 0.325 mmol) for 20 2-(3-chlorophenyl)piperazine to afford 3.1 mg of the title compound (3.9%).
LC/MS = m/z 499.6 [M+H] Ret. Time: 1.57 min.
Example 302: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r6-(1-pvrrolidinvl)-3-pyridazinvn- 1 H-indole-7-carboxamide trifluoroacetate 264 Received at IPONZ on 15 June 2011 O The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 3-chloro-6-(1-pyrrolidinyl)pyridazine (60 mg, 0.325 mmol) for 5 2-(3-chlorophenyl)piperazine to afford 4.1 mg of the title compound (5.3%).
LC/MS = m/z 483.2 [M+H] Ret. Time: 1.44 min.
Example 303: 3-H-(ethvlsulfonvl)-4-piperidinvn-5-f2-r(methvlamino)methvnphenyl)-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-(2-bromophenyl)-/\/-methylmethanamine (65 mg, 0.325 mmol) for 2-(3-chlorophenyl)piperazine to afford 14.6 mg of the title compound (19.8%). 15 LC/MS = m/z 455.0 [M+H] Ret. Time: 1.57 min.
Example 304: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(3-(T(2-thienylmethvl)amino1methvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate o h,n o nh 265 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (44 mg, 0.1 mmol) in dichloromethane (2 mL) and methanol (2 mL) was added 1-(2-thienyl)methanamine (33.6 mg, 0.6 mmol) and 1 drop of acetic acid. This mixture was stirred for 2 h then sodium tetrahydridoborate (22.8 mg, 0.6 mmol) was 5 added. The resulting mixture was stirred for 1 h. It was then concentrated and again dissolved in dimethyl sulfoxide (3 mL). It was then purified by Gilson Preparatory HPLC to give 41.7 mg of the title compound (74.5%).
LC/MS = m/z 537.2 [M+H] Ret. Time: 1.81 min.
Example 305: 3-H -(ethylsulfonvl)-4-piperidinvn-5-r3-((T(5-methyl-2- furanvl)methvllamino)methvl)phenyll-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1 H-indole-7-15 carboxamide trifluoroacetate, substituting 1-(5-methyl-2-furanyl)methanamine (32 mg, 0.6 mmol) for 1-(2-thienyl)methanamine to afford 29.3 mg of the title compound (54.7%). LC/MS = m/z 535.2 [M+H] Ret. Time: 1.74 min.
Example 306: 3-H -(ethylsulfonvl)-4-piperidinvn-5-r3-((T(2R)-tetrahydro-2-20 furanylmethvnamino)methyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate, substituting 1-[(2R)-tetrahydro-2-furanyl]methanamine (31.5 266 Received at IPONZ on 15 June 2011 mg, 0.6 mmol) for 1-(2-thienyl)methanamine to afford 36.9 mg of the title compound (70.3%).
LC/MS = m/z 525.6 [M+H] Ret. Time: 1.63 min.
Example 307: 3-H -(ethvlsulfonvl)-4-piperidinvn-5-r3-((r(2S)-tetrahydro-2- furanylmethvllamino)methvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1 H-indole-7-10 carboxamide trifluoroacetate, substituting 1-[(2S)-tetrahydro-2-furanyl]methanamine (31.5 mg, 0.6 mmol) for 1-(2-thienyl)methanamine to afford 39.2 mg of the title compound (74.7%).
LC/MS = m/z 525.6 [M+H] Ret. Time: 1.61 min.
Example 308: 5-(3-fr(2.2-dimethvlpropvl)amino1methvl)phenvl)-3-H-(ethvlsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1 H-indole-7-20 carboxamide trifluoroacetate, substituting 2,2-dimethyl-1-propanamine (30.6 mg, 0.6 mmol) for 1-(2-thienyl)methanamine to afford 30.4 mg of the title compound (59.5%). LC/MS = m/z 511.4 [M+H] Ret. Time: 1.69 min.
Example 309: 3-ri-(ethylsulfonvl)-4-piperidinyll-5-(3-fr(2-25 methylbutvl)amino1methvl)phenyl)-1 H-indole-7-carboxamide 267 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (44 mg, 0.1 mmol) in dichloromethane (2 mL) and methanol (1 mL) was added 2-methyl-1-butanamine (52 mg, 0.6 mmol) and 1 drop of acetic acid. This mixture 5 was stirred for 2 h then sodium tetrahydridoborate (22.8 mg, 0.6 mmol) was added. The resulting mixture was stirred for 1 h. It was then concentrated and again dissolved in dimethyl sulfoxide (3 mL). It was then purified by Gilson Preparatory HPLC to give 28.4 mg of the title compound (55.6%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.71 0 Example 310: 3-H -(ethylsulfonyl)-4-piperidinvn-5-r3-((T(2S)-2-methvlbutvnamino)methvl)phenvn-1H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-15 (ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-1 H-indole-7- carboxamide, substituting (2S)-2-methyl-1-butanamine (52 mg, 0.6 mmol) for 2-methyl-1-butanamine to afford 30 mg of the title compound (58.7%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.68 Example 311: 3-H-(ethvlsulfonvlM-piperidinvH-5-r3-(mim-1.2.2-trimethvlpropyllamino>methvl)phenvll-1 H-indole-7-carboxamide 268 Received at IPONZ on 15 June 2011 H,N O The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide, substituting (2R)-3,3-dimethyl-2-butanamine (60 mg, 0.6 mmol) for 2-5 methyl-1-butanamine to afford 24.5 mg of the title compound (46.7%).
LC/MS = m/z 525.6 [M+H] Ret. Time: 1.67 Example 312: 3-H -(ethvlsulfonvl)-4-piperidinvn-5-r3-fluoro-5-((T(2S)-tetrahydro-2-furanylmethvnamino)methyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.087 mmol) in dichloromethane (2 mL) and methane (1 mL) was added 1-[(2S)-tetrahydro-2-furanyl]methanamine (53 mg , 0.525 mmol) and 2 drops of acetic acid. The resulting mixture was stirred for 2 h at room temperature followed by an 15 addition of sodium tetrahydridoborate (20 mg, 0.525 mmol). This mixture was stirred for 30 min then concentrated and purified by Gilson Preparatory HPLC to give 26.6 mg of the title compound (46.6%).
LC/MS = m/z 543.4 [M+H] Ret. Time: 1.60 min.
Example 313: 3-H -(ethvlsulfonvl)-4-piperidinvll-5-r3-fluoro-5-«T(2R)-tetrahvdro-2-furanylmethvllamino)methvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate F 269 Received at IPONZ on 15 June 2011 o O HN o o.
F The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 5 , substituting 1-[(2R)-tetrahydro-2-furanyl]methanamine (53 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 27.1 mg of the title compound (47.4%). LC/MS = m/z 543.4 [M+H] Ret. Time: 1.58 min.
Example 314: 5-r3-((T(1S)-1,2-dimethvlpropvnamino)methyl)-5-fluorophenvn-3-ri-10 (ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 15 , substituting (2S)-3-methyl-2-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 19.3 mg of the title compound (42%).
LC/MS = m/z 529.6 [M+H] Ret. Time: 1.65 Example 315: 5-r3-({T(1R)-1.2-dimethvlpropvnamino)methvl)-5-fluorophenvn-3-H-20 (ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate 270 Received at IPONZ on 15 June 2011 F h,n The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 5 , substituting (2R)-3-methyl-2-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 19.5 mg of the title compound (34.9%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.82 min.
Example 316: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(3-fluoro-5-(T(1-10 methylpropvl)aminolmethvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 15 , substituting 2-butanamine (37 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 27.7 mg of the title compound (50.6%).
LC/MS = m/z 515.4 [M+H] Ret. Time: 1.63 min.
Example 317: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-fluoro-5-«T(1S)-1.2.2-20 trimethvlpropvnamino>methyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate 271 Received at IPONZ on 15 June 2011 h,n The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 5 , substituting (2S)-3,3-dimethyl-2-butanamine (52 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 19.8 mg of the title compound (34.7%).
LC/MS = m/z 543.4 [M+H] Ret. Time: 1.78 min.
Example 318: 3-H -(ethvlsulfonyl)-4-piperidinvn-5-r3-fluoro-5-((T(2S)-2-10 methvlbutvnamino)methyl)phenvn-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 15 , substituting (2S)-2-methyl-1-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 23.3 mg of the title compound (41.7%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.62 min.
Example 319: 3-H -(ethvlsulfonvl)-4-piperidinyll-5-(3-fluoro-5-fr(2-20 methylbutvl)aminolmethvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate F 272 Received at IPONZ on 15 June 2011 F h,n The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 5 , substituting 2-methyl-1-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 30.5 mg of the title compound (54.5%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.73 min.
Example 320: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-r3-fluoro-5-((T(1R)-1,2,2-10 trimethvlpropvnamino>methyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 15 , substituting (2R)-3,3-dimethyl-2-butanamine (52 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 24.9 mg of the title compound (43.6%).
LC/MS = m/z 543.4 [M+H] Ret. Time: 1.73 min.
Example 321: 5-(3-fr(2.2-dimethvlpropvl)amino1methvl)-5-fluorophenvl)-3-H-20 (ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate 273 Received at IPONZ on 15 June 2011 F H,N The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 5 , substituting 2,2-dimethyl-1-propanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 14 mg of the title compound (25%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.79 min.
Example 322: 5-(3-(T(cvclopropvlmethvl)amino1methvl)-5-fluorophenvl)-3-ri-10 (ethvlsulfonvl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 15 , substituting 1-cyclopropylmethanamine (37 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 21.1 mg of the title compound (38.7%).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.69 min.
Example 323: 5-(3-(T(cvclopentvlmethvl)amino1methvl)-5-fluorophenvl)-3-ri-20 (ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate F 274 Received at IPONZ on 15 June 2011 F H,N The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 5 , substituting 1-cyclopentylmethanamine (52 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 21.6 mg of the title compound (37.9%).
LC/MS = m/z 541.4 [M+H] Ret. Time: 1.82 min.
Example 324: 3-H -(ethvlsulfonvl)-4-piperidinvn-5-(3-fluoro-5-(r(tetrahydro-2H-10 pvran-4-vlmethvl)amino1methvl)phenyl)-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 15 , substituting 1-(tetrahydro-2H-pyran-4-yl)methanamine (60 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 40.1 mg of the title compound (68.7%). LC/MS = m/z 557.4 [M+H] Ret. Time: 1.54 min.
Example 325: 3-H -(ethvlsulfonvl)-4-piperidinyll-5-(3-fluoro-5-fr(2-20 thienvlmethvl)amino1methvl)phenvl)-1 H-indole-7-carboxamide trifluoroacetate F H,N O F OH 275 Received at IPONZ on 15 June 2011 F The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 5 , substituting 1-(2-thienyl)methanamine (59 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 24.4 mg of the title compound (41.9%).
LC/MS = m/z 555.4 [M+H] Ret. Time: 1.67 min.
Example 326: 3-H -(ethvlsulfonvl)-4-piperidinvn-5-r3-fluoro-5-({r2-10 (methyloxv)ethvnamino)methyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 15 , substituting 2-(methyloxy)ethanamine (39 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 31 mg of the title compound (56.5%).
LC/MS = m/z 517.2 [M+H] Ret. Time: 1.52 min.
Example 327: 3-H -(ethvlsulfonyl)-4-piperidinvn-5-r3-fluoro-5-((T3-20 (methvloxv)propvnamino)methyl)phenvn-1H-indole-7-carboxamide trifluoroacetate F F OH 276 Received at IPONZ on 15 June 2011 O F The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 5 , substituting 3-(methyloxy)-1-propanamine (46 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 27.3 mg of the title compound (48.7%).
LC/MS = m/z 531.4 [M+H] Ret. Time: 1.54 min.
Example 328: 3-H -(ethvlsulfonyl)-4-piperidinvn-5-(3-fluoro-5-(T(2-10 furanylmethvl)amino1methvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 15 , substituting 1-(2-furanyl)methanamine (50 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 24.8 mg of the title compound (43.7%).
LC/MS = m/z 539.4 [M+H] Ret. Time: 1.63 min.
Example 329: 3-H -(ethvlsulfonyl)-4-piperidinvn-5-(3-fluoro-5-(T(3-20 methylbutvl)amino1methvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate f f oh 277 Received at IPONZ on 15 June 2011 F H7N F OH The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 5 , substituting 3-methyl-1-butanamine (45 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 27.6 mg of the title compound (49.4%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.67 min.
Example 330: 3-H -(ethylsulfonvl)-4-piperidinvn-5-r3-fluoro-5-((T(5-methyl-2-10 furanvl)methvnamino)methvl)phenvH-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate 15 , substituting 1-(5-methyl-2-furanyl)methanamine (58 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 28.3 mg of the title compound (48.8%). LC/MS = m/z 553.6 [M+H] Ret. Time: 1.78 min.
Example 331: 3-H-(ethvlsulfonyl)-4-piperidinvn-5-(3-(T(2-20 methylpropvl)amino1methvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate F H,N O 278 Received at IPONZ on 15 June 2011 F F F H,N To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in dichloromethane (2 mL) and methanol (1 mL) was added 2-methyl-1-propanamine (70 pL, 0.683 mmol) and 2 drops of acetic acid. This 5 mixture was stirred for 2 h at room temperature and then sodium tetrahydridoborate (26 mg, 0.683 mmol) was added. After 30 min the mixture was concentrated and was dissolved in dimethyl sulfoxide (2 mL) and purified by Gilson Preparatory HPLC to give 19.8 mg of the title compound (61%).
LC/MS = m/z 497.4 [M+H] Ret. Time: 1.57 Example 332: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-(2-pyrrolidinvl)phenvn-1H-indole-7-carboxamide trifluoroacetate A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-15 2-yl)-1/-/-indole-7-carboxamide (70 mg, 0.151 mmol), 2-(3-iodophenyl)pyrrolidine (70 mg, 0.456 mmol) in potassium carbonate (126 mg, 0.910 mmol) in dioxane (2 mL) and water (1 mL) was degassed for 5 min and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) was added. The mixture was reacted in a CEM microwave for 20 min at 160° C. The organic layers were then separated and concentrated. This was then 20 dissolved in dimethyl sulfoxide (1 mL) and purified by Gilson Preparatory HPLC to give 48 mg of the title compound (59.5%).
LC/MS = m/z 481.0 [M+H] Ret. Time:1.47 279 Received at IPONZ on 15 June 2011 Example 333: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-f2-fluoro-5-r(methylamino)methvnphenyl)-1 H-indole-7-carboxamide trifluoroacetate o F F H \ H2N F OH To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.087 mmol) in dichloromethane (2 mL) and methanol (1 mL) was added methanamine (262 pL, 0.524 mmol) and 1 drop of acetic acid. After being stirred for 2 h at room temperature, sodium tetrahydridoborate (20 mg, 0.524 mmol) was added and allowed to stand for 30 min. The mixture was then purified by Gilson Preparatory 10 HPLC to give 12.3 mg of the title compound (58.6%).
LC/MS = m/z 473.4 [M+H] Ret. Time:1.55.
Example 334: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-f2-fluoro-5-r(propylamino)methvllphenvl)-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting propylamine (44 pL, 0.524 mmol) for methanamine to afford 15.4 mg of the title compound (61.5%).
LC/MS = m/z 501.4[M+H] Ret. Time: 1.55 280 Received at IPONZ on 15 June 2011 Example 335: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(2-fluoro-5-(T(2-methylpropvl)aminolmethvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate f OH The title compound was prepared according to the general procedure of 3-[1- (ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (53 pL, 0.524 mmol) for methanamine to afford 15 mg of the title compound (62.9%) LC/MS = m/z 515.4 [M+H] Ret. Time: 1.55 Example 336: 5-(5-(T(2,2-dimethvlpropvl)amino1methvl)-2-fluorophenyl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-15 (ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting 2,2-dimethyl-1-propanamine (46 pL, 0.524 mmol) for methanamine to afford 14.3 mg of the title compound (64.3%).
LC/MS = m/z 530.2[M+H] Ret. Time: 1.59 281 Received at IPONZ on 15 June 2011 Example 337: 5-r5-((T(1S)-1,2-dimethvlpropvnamino)methyl)-2-fluorophenvn-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1- (ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting (2S)-3-methyl-2-butanamine (46 pL, 0.524 mmol) for methanamine to afford 17.3 mg of the title compound (64.3%) LC/MS = m/z 529.4 [M+H] Ret. Time: 1.69 Example 338: 5-r5-((T(1R)-1,2-dimethvlpropvnamino)methyl)-2-fluorophenvn-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-15 (ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting (2R)-3-methyl-2-butanamine (46 pL, 0.524 mmol) for methanamine to afford 15 mg of the title compound (64.3%).
LC/MS = m/z 529.4 [M+H] Ret. Time: 1.70 282 Received at IPONZ on 15 June 2011 Example 339: 5-(5-(T(cvclopropvlmethvl)amino1methvl)-2-fluorophenyl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate F < F H F OH H2N^O The title compound was prepared according to the general procedure of 3-[1-5 (ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7- carboxamide trifluoroacetate, substituting 2-methyl-1-butanamine (38 pL, 0.524 mmol) for methanamine to afford 16.2 mg of the title compound (62.7%).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.57 Example 340: 3-ri-(ethvlsulfonvl)-4-piperidinyll-5-r2-fluoro-5-(1- Pvrrolidinvlmethvl)phenyll-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-15 carboxamide trifluoroacetate, substituting pyrrolidine (44 pL, 0.524 mmol) for methanamine to afford 10 mg of the title compound (62.7%).
LC/MS = m/z 513.4 [M+H] Ret. Time: 1.62 Example 341: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-r2-fluoro-5-(4-20 morpholinvlmethyDphenvll-lH-indole-7-carboxamide trifluoroacetate 283 Received at IPONZ on 15 June 2011 F F OH H2N ^O The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1 H-indole-7-carboxamide trifluoroacetate, substituting morpholine (45 pL, 0.524 mmol) for 5 methanamine to afford 15 mg of the title compound (64.3%) LC/MS = m/z 529.4 [M+H] Ret. Time: 1.52 Example 342: 3-ri-(ethvlsulfonvl)-4-piperidinyn-5-r2-fluoro-5-((T2-(methyloxv)ethvnamino)methyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1/-/-indole-7-carboxamide (40 mg, 0.087 mmol) in dichloromethane (2 mL) and methanol (1 mL) was added 2-(methyloxy)ethanamine (54 pL, 0.524 mmol) and 1 drop of acetic acid. After being stirred over the weekend at room temperature, sodium tetrahydridoborate (20 mg, 15 0.524 mmol) was added and allowed to stand for 30 min. The mixture was then purified by Gilson Preparatory HPLC to afford 11.4 mg of the title compound (63%).
LC/MS = m/z 517.2 [M+H] Ret. Time: 1.57 Example 343: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-r2-fluoro-5-({r3-20 (methvloxv)propvnamino)methyl)phenvn-1H-indole-7-carboxamide trifluoroacetate 284 Received at IPONZ on 15 June 2011 O F F F l-LN The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[2-(methyloxy)ethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 3-(methyloxy)-1-propanamine (53 |jL, 5 0.524 mmol) for 2-(methyloxy)ethanamine to afford 15 mg of the title compound (64.5%) LC/MS = m/z 531.4 [M+H] Ret. Time: 1.60 Example 344: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r3-(1-methyl-2-pyrrolidinvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-pyrrolidinyl)phenyl]-1 /-/-indole-7-carboxamide (20 mg, 0.04 mmol), formaldehyde (9.5 mL, 0.125 mmol) and sodium triacetoxyborohydride in dichloromethane (2 mL) was added 2 drops of acetic acid. The resulting mixture was stirred overnight at room temperature. All solvent was evaporated 15 and the result was re-dissolved in dimethyl sulfoxide (1 mL). The mixture was then separated twice by Gilson Preparatory HPLC to afford 8.9 mg of the title compound (60.9%).
LC/MS = m/z 495.4 [M+H] Ret. Time: 1.54 h2n 285 Received at IPONZ on 15 June 2011 Example 345: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(3-f2-r(2-methylpropvl)amino1ethvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (60 mg, 0.13 mmol), [2-(3-bromophenyl)ethyl](2-methylpropyl)amine (100 mg, 0.39 mmol) and potassium carbonate (108 mg, 0.780 mmol) in dioxide (2 mL) and water (0.7 mL). The resulting mixture was degassed for 5 min then tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.013 mmol) was added. This was reacted in a CEM microwave for 20 min at 160° C. The reaction was then purified using Gilson Preparatory HPLC to afford 44 mg of the title compound (62.5%).
LC/MS = m/z 511.2 [M+H] Ret. Time: 1.79 Example 346: 5-f3-r2-(ethylamino)ethvnphenylV3-ri-(ethvlsulfonvlM-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate HN^ HN H„N 286 Received at IPONZ on 15 June 2011 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (40.4 mg, 0.09 mmol), 2-(3-bromophenyl)-N-ethylethanamine (60 mg, 0.263 mmol) and potassium carbonate (72 mg, 0.526 mmol) in dioxane (2 mL) and water (0.7 mL) was degassed for 5 min. To this was added 5 tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.009 mmol). The resulting mixture was reacted in a CEM microwave for 20 min at 160° C. The reaction was then purified using Gilson Preparatory HPLC to afford 38.6 mg of the title compound (59.7%).
LC/MS = m/z 482.8 [M+H] Ret. Time: 1.54 Example 347: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-f3-r2-(propvlamino)ethvnphenyl)-1 H-indole-7-carboxamide trifluoroacetate A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (25 mg, 0.055 mmol), potassium carbonate (46 mg, 0.33 15 mmol) and [2-(3-bromophenyl)ethyl]propylamine (40 mg, 0.165 mmol) in dioxane (2 mL) and water (0.7 mL) was degassed for 5 min then tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmol) was added. The resulting mixture was reacted in a CEM microwafe for 20 min at 160° C. The reaction was then separated using Gilson Preparatory HPLC to afford 17.6 mg of the title compound (61%).
LC/MS = m/z 497.4 [M+H] Ret. Time: 1.97 Example 348: 5-(3-r2-(dimethylamino)ethvllphenvlV3-ri-(ethvlsulfonyl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate HN H2N O 287 Received at IPONZ on 15 June 2011 F F UM H2N^O F A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (60 mg, 0.13 mmol), potassium carbonate (108 mg, 0.78 mmol) and 2-(3-bromophenyl)-N,N-dimethylethanamine (90 mg, 0.39 mmol) in dioxane (2 5 mL) and water (0.7 mL) was degassed for 5 min then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) was added. The resulting mixture was reacted in a CEM microwafe for 20 min at 160° C. The reaction was then separated using Gilson Preparatory HPLC to afford 30 mg of the title compound (59.7%). LC/MS = m/z 483.2 [M+H] Ret. Time: 1.60 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (66 mg, 0.14 mmol), potassium carbonate (120 mg, 0.86 mmol) and (2-phenylethyl)dipropylamine (120 mg, 0.43 mmol) in dioxane (2 mL) and 288 Example 349: 5-(3-r2-(dipropylamino)ethvllphenvl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate Received at IPONZ on 15 June 2011 water (0.7 mL) was degassed for 5 min then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.014 mmol) was added. The resulting mixture was reacted in a CEM microwafe for 20 min at 160° C. The reaction was then separated using Gilson Preparatory HPLC to afford 9 mg of the title compound (65.3%).
LC/MS = m/z 455.0 [M+H] Ret. Time: 1.55 Example 350: 5-r3-((r2-(3.5-dimethvl-1H-pyrazol-1-vl)ethvllamino>methvl)phenvll-3-H -(ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-indole-7- carboxamide (44 mg, 0.1 mmol), 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethanamine (105 mg, 0.6 mmol) in dichloromethane (3 mL) and methanol (1.5 mL) was added 3 drops of acetic acid. The resulting mixture was stirred overnight then sodium triacetoxyborohydride (134 mg, 0.6 mmol) was added. This mixture was stirred overnight. The resulting mixture was 15 quenched with sodium bicarbonate (2 mL) and brine (2 mL) and organic layer was collected and concentrated. The reaction was then separated using Gilson Preparatory HPLC to afford 26 mg of the title compound (67.7%) LC/MS = m/z 563.2 [M+H] Ret. Time: 1.51 Example 351: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r2-(4-morpholinvlmethylH,3-thiazol-4-vl1-1 H-indole-7-carboxamide trifluoroacetate n f h,n o 289 Received at IPONZ on 15 June 2011 V H,N To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) was added morpholine (130ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr, the mixture was quenched with Sat. NaHC03 (4.0 mL) and brine (3.0 mL). The organic layer was separated and concentrated to give 200 mg of 4-[(4-bromo-1,3-thiazol-2-yl)methyl]morpholine (76 %).
A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (46 mg, 0.1 mmol), 4-[(4-bromo-1,3-thiazol-2-yl)methyl]morpholine (79 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) in dioxane (2 mL) and water (0.7 mL) was degassed for 5 min then triacetoxyborohydride (11 mg, 0.1 mmol) was added. This mixture was reacted in a CEM microwave for 20 min at 160° C. The organic layer was collected and concentrated. The residue was re-dissolved with dimethyl sulfoxide (1 mL) and was then purified using Gilson Preparatory HPLC to afford 26.6 mg of the title compound (63.2%) LC/MS = m/z 518.2 [M+H] Ret. Time: 1.49 Example 352: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(2-{r(2- methvlpropyl)amino1methvl)-1,3-thiazol-4-vl)-1H-indole-7-carboxamide trifluoroacetate H.N 290 Received at IPONZ on 15 June 2011 To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) was added iso-propyl amine (152ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr, the mixture was quenched with Sat. NaHC03 (4.0 mL) and brine (3.0 mL). The organic 5 layer was separated and concentrated to give 145 mg of the title compound (58 %).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carbaldehyde (46 mg, 0.1 mmol), 2-methyl-1-propanamine (70 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) in dioxane (2 mL) and 10 water (0.7 mL) was added triacetoxyborohydride (11 mg, 0.01 mmol). This solution was degassed for 5 min then reacted in a CEM microwave for 20 min at 160°C. The organic layer was separated and concentrated. It was then purified using Gilson Preparatory HPLC to afford 24 mg of the title compound (61.8%) LC/MS = m/z 504.2 [M+H] Ret. Time: 1.43 Example 353: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r2-(1-pvrrolidinvlmethyl)-1,3-thiazol-4-vn-1H-indole-7-carboxamide To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) was added pyrrolidine (124ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr, the mixture was quenched with Sat. NaHC03 (4.0 mL) and brine (3.0 mL). The organic layer was separated and concentrated to give 200 mg of the title compound (82 %).
The title compound was prepared according to the general procedure of 3-[1- (ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-thiazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate , substituting pyrrolidine (74 mg, 0.3 mmol) for 2-methyl-1-propanamine to afford 6.3 mg of the title compound (50%) 291 Received at IPONZ on 15 June 2011 LC/MS = m/z 500.4 [M+H] Ret. Time: 1.22 Example 354: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r2-(1-piperidinvlmethyl)-1,3-thiazol-4-vn-1H-indole-7-carboxamide N S X (\ N H,N O To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) was added piperidine (150ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr, the mixture was quenched with Sat. NaHC03 (4.0 mL) and brine (3.0 mL). The organic layer 10 was separated and concentrated to give 166 mg of the title compound (64 %).
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-thiazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate 15 , substituting piperidine (78 mg, 0.3 mmol) for2-methyl-1-propanamine to afford 15.5 mg of the title compound (51.6%).
LC/MS = m/z 517.4 [M+H] Ret. Time: 1.29 Example 355: 5-f2-r(dimethvlamino)methvn-1,3-thiazol-4-vl)-3-ri-(ethvlsulfonylM-20 piperidinvll-1 H-indole-7-carboxamide trifluoroacetate To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) was added dimethyl amine (2.0M, 3.0 mL) and 3 drops of AcOH. The mixture was 292 Received at IPONZ on 15 June 2011 stirred for 48 hr and then Na(OAc)3BH (1,33g, 6.0 mmol) was added. After 12 hr, the mixture was quenched with Sat. NaHC03 (4.0 mL) and brine (3.0 mL) and separator was used to get the DCM organic layer. The organic layer was concentrated to give 90 mg of desired product (40%).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (46 mg, 0.1 mmol), dimethylamine (69 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) in dioxane (2 mL) and water (0.7 mL) was added triacetoxyborohydride (12 mg, 0.01 mmol). This mixture was 10 degassed for 5 min. The mixture was then reacted in a microwave for 20 min at 160° C. The organic layers were separated and concentrated. It was then purified using Gilson Preparatory HPLC to afford 23 mg of the title compound (59%) LC/MS = m/z 474.4 [M+H] Ret. Time: 1.20 Example 356: 5-(2-(Tethyl(methvl)amino1methyl'H,3-thiazol-4-vl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 20 mL) was added /V-methylethanamine (470ul, 6.0 mmol) and 3 drops of AcOH. The mixture was stirred for 48 hr and then Na(OAc)3BH (1,33g, 6.0 mmol) was added. After 12 hr, the mixture was quenched with Sat. NaHC03 (4.0 mL) and brine (3.0 mL) and separator was used to get the DCM organic layer. The organic layer was concentrated to give 160 mg of the title compound (68 %).
The title compound was prepared according to the general procedure of 5-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting ethyl(methyl)amine (73 mg, 0.3 mmol) for dimethylamine to afford 25 mg of the title compound (60.4%). 293 Received at IPONZ on 15 June 2011 LC/MS = m/z 490.4 [M+H] Ret. Time: 1.25 Example 357: 5-(3-cvano-5-(T(2-methvlpropyl)amino1methvl)phenvl)-3-ri-(ethvlsulfonvl)-4-piperidinvn-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-formylbenzonitrile (1.0 g, 7.6 mmol) in TFA (4.0 mL) at 0° C under argon atmosphere was added concentrated H2S04 (6.0 mL) dropwise followed by addition of NBS in small portion. The mixture was warmed to room temperature slowly and then stirred for 12 h under argon atmosphere. Upon reaction completion, the mixture 10 was poured into ice-H20 (80 mL), PdCI2 (117 mg, 0.658 mmol) and the solid was collected and dried over vacuum overnight to give 1.50 g of 3-bromo-5-formylbenzamide (86%).
LC/MS = m/z 228.2 [M+H] Ret. Time: 1.37 To a solution of 3-bromo-5-formylbenzamide (1.5 g, 6.58 mmol) in H20 (50.0 mL) and MeCN (50.0 mL) was added PdCI2 (117 mg, 0.658 mmol). The mixture was stirred for 72 h at room temperature and another portion of H20 (100 mL) and MeCN (100 mL) was added followed with addition of PdCI2 (100mg, 0.56mol). The mixture was stirred for another 12 hr and concentrated. The residue was dissolved in EtOAc (200 mL), washed 20 with brine (3 X 50.0 mL), dried over Na2S04 and concentrated, and then was purified by chromatography (10% EtOAc in hexanes) to give 550 mg of 3-bromo-5-formylbenzonitrile (40%).
Toa solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-25 dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2.0 mL) and H20 (0.7 mL) was added 3-bromo-5-formylbenzonitrile (68 mg, 0.3 mmol), and potassium carbonate (83 mg, 0.6 mmol). The mixture was degassed for 5 min befire addition of tetrakis (triphenylphosphine) palladium (0) (12 mg, 0.01 mmol). The mixture was reacted 294 Received at IPONZ on 15 June 2011 in the microwave at 160° C for 20 min. The compound was purified by Gilson Preparatory HPLC to give 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide.
To a solution of 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (47 mg, 0.1 mmol) in dichloromethane (3 mL) and methanol (1 mL) was added a few drops of acetic acid and methyl(2-methylpropyl)amine (64 pL, 0.6 mmol). This mixture was stirred overnight followed by an addition of 20 drops of acetic acid and sodium triacetoxyborohydride (0.6 mmol). The reaction was mixed for 4 h followed by an 10 addition of methyl (2-methylpropyl) amine (64 pL, 0.6 mmol) and sodium triacetoxyborohydride (0.6 mmol). The mixture was stirred overnight then quenched with sodium biocarbonate and brine. The organic layer was separated by SOX cartridge and concentrated. It was then separated using Gilson Preparatory HPLC to afford 10.3 mg of the title compound (63.6%).
LC/MS = m/z 522.4 [M+H] Ret. Time: 1.65 Example 358: 5-f3-cvano-5-r(dimethvlamino)methvnphenvl)-3-ri-(ethvlsulfonylM-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate O The title compound was prepared according to the general procedure of 5-(3-cyano-5-{[(2-methylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting trimethylamine (300 |jL, 0.3 mmol) for methyl(2-methylpropyl)amine to afford 10.5 mg of the title compound (61%).
LC/MS = m/z 494.4 [M+H] Ret. Time: 1.48 Example 359: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-(4-morpholinvlmethyl)phenvn-1 H-indole-7-carboxamide trifluoroacetate N 295 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (80 mg, 0.181 mmol) in DCM was added morpholine (50 pL, 0.545 mmol). The reaction was stirred at room temperature for 30 min before the addition of sodium 5 triacetoxyborohydride (120 mg, 0.545 mmol). The reaction was run at room temperature overnight and then concentrated. Compound was purified by Gilson Preparatory HPLC to afford 28.6 mg of the title compound (25%).
LC/MS = m/z 511.4 [M+H] Ret. Time: 1.48 min Example 360: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-r3-((T(4- fluorophenvl)carbonvnamino)methvl)phenvn-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-{3-15 [(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 4-fluoro-/V-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}benzamide (125 mg, 0.352 mmol) for /V-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}acetamide. Compound was purified by Gilson Preparatory HPLC to give 18.3 mg of the title compound (27%).
LC/MS = m/z 563.1 [M+H] Ret. Time: 2.07 min 296 Received at IPONZ on 15 June 2011 Example 361: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(3-(T(2- furanvlcarbonvl)amino1methvl)phenyl)-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-{3-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting /V-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-2-furancarboxamide (115 mg, 0.352 mmol) for A/-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}acetamide. Compound was purified by Gilson Preparatory HPLC to give 8.1 mg of the title compound (12%).
LC/MS = m/z 535 [M+H] Ret. Time: 1.89 min Example 362: 5-(3-<T(cyclopentvlcarbonvl)aminolmethvl)phenyl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 5-{3-[(acetylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting /V-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}cyclopentanecarboxamide (116 mg, 0.352 mmol) for N-{[3-(4,4,5,5- N F OH N 297 Received at IPONZ on 15 June 2011 tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}acetamide. Compound was purified by Gilson Preparatory HPLC to give 9.2 mg of the title compound (14%).
LC/MS = m/z 535 [M+H] Ret. Time: 1.89 min Example 363: 5-(3-{T(1-benzothien-2-vlcarbonvl)amino1methvl)phenyl)-3-ri-(ethvlsulfonvl)-4-piperidinyn-1H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1/-/-indole-7-10 carboxamide substituting /V-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl}-1-benzothiophene-2-carboxamide (57 mg, 0.144 mmol) for/V-{[3-(4,4,5,5-tetramethyM ,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 601.2 [M+H] Ret. Time: 2.18 min Example 364: 5-r3-((r(1-acetvl-4-piperidinvl)carbonvnamino)methyl)phenvn-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide O NH '2 298 Received at IPONZ on 15 June 2011 o A rw N H O NH '2 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1/-/-indole-7-carboxamide substituting 1-acetyl-/V-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-5 yl)phenyl]methyl}-4-piperidinecarboxamide (56 mg, 0.144 mmol) for A/-{[3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 594.4 [M+H] Ret. Time: 1.87 min Example 365: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-((T(1-methvl-1fV-pyrrol-2-vl)carbonvnamino}methyl)phenvn-1H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1/-/-indole-7-15 carboxamide substituting 1-methyl-/V-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1/-/-pyrrole-2-carboxamide (49 mg, 0.144 mmol) for N-{[3-(4,4,5,5- \ O NH '2 299 Received at IPONZ on 15 June 2011 tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 548.4 [M+H] Ret. Time: 2.02 min Example 366: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(3-(r(2- thienvlacetvl)amino1methvl}phenyl)-1AV-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1/-/-indole-7-10 carboxamide substituting /V-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl}-2-(2-thienyl)acetamide (51 mg, 0.144 mmol) for N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Mass Directed Auto Prep HPLC to give 10.3 mg of the title compound (18.2%).
LC/MS = m/z 565.2 [M+H] Ret. Time: 1.95 min Example 367: 5-(3-{T(cvclobutvlcarbonvl)amino1methvl)phenvl)-3-H-(ethylsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide H2N o 300 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1/-/-indole-7-carboxamide substituting A/-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}cyclobutanecarboxamide (45 mg, 0.144 mmol) for A/-{[3-(4,4,5,5-5 tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Mass Directed Auto Prep HPLC to give 4.3 mg of the title compound (8%).
LC/MS = m/z 523.4 [M+H] Ret. Time: 1.90 min Example 368: 5-(3-{T(cvclopropylcarbonvl)amino1methvl)phenvl)-3-ri-10 (ethvlsulfonvl)-4-piperidinvn-1AV-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1/-/-indole-7-carboxamide substituting /V-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl}cyclopropanecarboxamide (43 mg, 0.144 mmol) for /V-{[3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Mass Directed Auto Prep HPLC to give 5.5 mg of the title compound (11%).
LC/MS = m/z 509.2 [M+H] Ret. Time: 1.85 min Examples 369: 5-(3-(r(cvclopropylsulfonvl)aminolmethvl)phenvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide H H2n^O 301 Received at IPONZ on 15 June 2011 H O NH '2 To a solution of 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (35 mg, 0.079 mmol) in DMF (1.0 mL) and DCM (1.0 mL) was added cyclopropanesulfonyl chloride (11 mg, 0.079 mmol) and DIEA (14 pL, 0.079 mmol). 5 Reaction was sirred at room temperature overnight. Compound was purified by Gilson Preparatory HPLC to give 7.2 mg the title compound (17%).
.LC/MS = m/z 545.4 [M+H] Ret. Time: 1.94 min Example 370: 5-r3-((T(2,5-dichlorophenvl)sulfonvnamino)methyl)phenvn-3-ri-10 (ethvlsulfonyl)-4-piperidinvn-1AV-indole-7-carboxamide To a solution of 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (40 mg, 0.096 mmol) in DMF (1.0 mL) and DCM (1.0 mL) was added 2,5-dichlorobenzenesulfonyl chloride (86 mg, 0.352 mmol) and DIEA (62 pL, 0.352 mmol). 15 Reaction was sirred at room temperature for 6 h. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 6.6 mg the title compound (11%).
.LC/MS = m/z 649.2 [M+H] Ret. Time: 2.25 min o NH 302 Received at IPONZ on 15 June 2011 Example 371: 5-r3-((T(4-bromophenvl)sulfonvnamino)methyl)phenvn-3-ri-(ethvlsulfonvl)-4-piperidinyn-1H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-[3-({[(2,5-5 dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 4-bromobenzenesulfonyl chloride (90 mg, 0. 352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 19.4 mg the title compound (31%).
LC/MS = m/z 659.4 [M+H] Ret. Time: 2.20 min 0 Example 372: 5-r3-((T(4-chlorophenvl)sulfonvnamino)methyl)phenvn-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-[3-({[(2,5-15 dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting (2E,4E)-5-chloro-2,4,6-heptatriene-2-sulfonyl chloride (80 mg, 0. 352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then 303 Received at IPONZ on 15 June 2011 concentrated and purified by Gilson Preparatory HPLC to give 7.5 mg the title compound (13%).
LC/MS = m/z 615.2 [M] Ret. Time: 2.19 min Example 373: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-«T(3- fluorophenvl)sulfonvnamino)methvl)phenvn-1H-indole-7-carboxamide F The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-10 7-carboxamide substituting 3-fluorobenzenesulfonyl chloride (69 mg, 0. 352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 7.3 mg the title compound (13%).
LC/MS = m/z 599.2 [M+H] Ret. Time: 2.15 min Example 374: 5-r3-(fr(2-chlorophenvl)sulfonvHamino)methyl)phenvn-3-ri-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide O NH '2 304 Received at IPONZ on 15 June 2011 H O NH 2 The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 2-chlorobenzenesulfonyl chloride (74 mg, 0. 352 mmol) for 5 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 17.3 mg the title compound (29%).
LC/MS = m/z 615.2 [M] Ret. Time: 2.15 min Example 375: 5-r3-((T(2,5-dichloro-3-thienvl)sulfonvnamino)methyl)phenvn-3-ri-10 (ethvlsulfonyl)-4-piperidinvn-1AV-indole-7-carboxamide CI The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 2,5-dichloro-3-thiophenesulfonyl chloride (86 mg, 0. 352 15 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 16.7 mg the title compound (27%).
O NH '2 305 Received at IPONZ on 15 June 2011 LC/MS = m/z 655.2 [M] Ret. Time: 2.24 min Example 376: 5-r3-((T(2-chloro-6-methvlphenvl)sulfonvnamino)methyl)phenvn-3-ri-(ethvlsulfonvl)-4-piperidinvn-1H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 2-chloro-6-methylbenzenesulfonyl chloride (86 mg, 0. 352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated 10 and purified by Gilson Preparatory HPLC to give 17.9 mg the title compound (30%). LC/MS = m/z 629.4 [M] Ret. Time: 2.19 min Example 377: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r3-({r(5-fluoro-2-methvlphenvl)sulfonvllamino)methvl)phenvn-1H-indole-7-carboxamide 306 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 5-fluoro-2-methylbenzenesulfonyl chloride (86 mg, 0. 352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated 5 and purified by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 613.2 [M+H] Ret. Time: 2.18 min Example 378: 5-r3-((r(1.2-dimethvl-1fV-imidazol-4-vl)sulfonvllamino)methvl)phenyll-3-ri-(ethvlsulfonyl)-4-piperidinvn-1AY-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 1,2-dimethyl-1/-/-imidazole-4-sulfonyl chloride (69 mg, 0. 352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated 15 and purified by Gilson Preparatory HPLC to give 1.9 mg the title compound (3.3%).
LC/MS = m/z 599.2 [M+H] Ret. Time: 1.76 min Example 379: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(3-(r(phenvlsulfonvl)amino1methvl>phenyl)-1AV-indole-7-carboxamide 307 Received at IPONZ on 15 June 2011 O NH '2 The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting benzenesulfonyl chloride (62 mg, 0. 352 mmol) for 2,5-5 dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 13.4 mg the title compound (24%).
LC/MS = m/z 581.6 [M+H] Ret. Time: 2.10 min Example 380: 3-ri-(ethylsulfonvlM-piperidinvll-5-r3-«T(4-10 fluorophenvl)sulfonvllamino)methvl)phenyll-1AV-indole-7-carboxamide F The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 4-fluorobenzenesulfonyl chloride (69 mg, 0. 352 mmol) for 308 Received at IPONZ on 15 June 2011 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 11.5 mg the title compound (20%).
LC/MS = m/z 599.2 [M+H] Ret. Time: 2.10 min Example 381: 5-r3-((r(4-bromo-2-ethvlphenvl)sulfonvnamino}methvl)phenvn-3-H-(ethvlsulfonvl)-4-piperidinyn-1H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-10 7-carboxamide substituting 4-bromo-2-ethylbenzenesulfonyl chloride (100 mg, 0. 352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 2.7 mg the title compound (4%).
LC/MS = m/z 687.6 [M] Ret. Time: 2.38 min Example 382: 5-(3-{T(1-benzothien-3-vlsulfonvl)amino1methvl)phenvl)-3-H-(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide Br O NH '2 309 Received at IPONZ on 15 June 2011 H O NH '2 The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 1-benzothiophene-3-sulfonyl chloride (82 mg, 0. 352 mmol) 5 for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 3.9 mg the title compound (6%).
LC/MS = m/z 637.4 [M+H] Ret. Time: 2.19 min Example 383: 5-f3-r((T4-(1,1-dimethvlethvl)phenvnsulfonvl)amino)methvnphenyl)-3-10 ri-(ethvlsulfonyl)-4-piperidinvn-1AV-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 4-(1,1-dimethylethyl)benzenesulfonyl chloride (82 mg, 0. 352 O NH '2 310 Received at IPONZ on 15 June 2011 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 15.6 mg the title compound (26%). LC/MS = m/z 637.4 [M+H] Ret. Time: 2.35 min Example 384: 5-r3-((r(3,4-difluorophenvl)sulfonvnamino)methyl)phenvn-3-ri -(ethvlsulfonyl)-4-piperidinvn-1H-indole-7-carboxamide F The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-10 7-carboxamide substituting 3,4-difluorobenzenesulfonyl chloride (75 mg, 0. 352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 617.2 [M+H] Ret. Time: 2.16 min Example 385: 5-(3-(T(2,1,3-benzoxadiazol-4-vlsulfonvl)amino1methvl)phenyl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1fV-indole-7-carboxamide 311 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide substituting 2,1,3-benzoxadiazole-4-sulfonyl chloride (77 mg, 0. 352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give the title compound.
LC/MS = m/z 623.4 [M+H] Ret. Time: 2.10 min Example 386: 3-ri-(ethvlsulfonvlM-piperidinvll-5-(3-(r(tetrahydro-3-furanylcarbonvl)aminolmethvl)phenyl)-1 H-indole-7-carboxamide To a solution of tetrahydro-3-furancarboxylic acid (17 mg, 0.144 mmol) in DCM (2.0 mL) was added pyridine (3 drops) and oxalyl chloride (18 mg, 0.144 mmol). Reaction mixture was stirred overnight at room temperature. To the mixture was then added 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (40 mg, 0.096 mmol) in DMF (1.0 mL) and DIEA (33 |jL, 0.192 mmol). Reaction mixture was stirred at room temperature overnight. Reaction mixture was concentrated under nitrogen and purifed by Gilson Preparatory HPLC to give 5.3 mg the title compound (10%).
LC/MS = m/z 539.2 [M+H] Ret. Time: 1.80 min Example 387: 5-f4-r(cyclopentvlsulfonvl)amino1phenyl)-3-ri-(ethylsulfonyl)-4-piperidinyll-lH-indole-7-carboxamide trifluoroacetate 312 Received at IPONZ on 15 June 2011 F OH O NH '2 To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (20 mg, 0.048 mmol) was added chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium (II) (10 mg, 0.016 mmol), potassium carbonate (13.4 mg, 0.097 mmol), and 5 N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopentanesulfonamide (34 mg, 0.097 mmol) in dioxane (3 mL) and H20 (1 mL). The reactin mixture was heated in a microwave at 160° C for 10 min. The reaction mixture was concentrated under nitrogen and purified by Gilson Preparatory HPLC to give 8.6 mg the title compound (32%).
LC/MS = m/z 559.2[M+H] Ret. Time: 2.00 min 0 Example 388: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r4-(4-methyl-2-oxo-1-piperazinyl)phenvn-1H-indole-7-carboxamide To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (20 mg, 0.048 15 mmol) was added 4-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-piperazinone (31 mg, 0.097 mmol) in dioxane (3.0 mL) and H20 (1.0 mL), potassium carbonate (13 mg, 0.097 mmol) and H 313 Received at IPONZ on 15 June 2011 chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium (II) (10 mg, 0.016 mmol). The reaction mixture was reacted in a microwave at 160° C for 10 min. The reaction mixture was heated in a microwave at 160° C for 10 min. The reaction mixture was concentrated under Nitrogen and purified by Gilson Preparatory HPLC. The 5 desired fraction in CH3CN and H20 was treated with saturated potassium carbonate to neautralize salts and then concentrated to give 1.9 mg the title compound (8%).
LC/MS = m/z 524.6 [M+H] Ret. Time: 1.49 min Example 389: 5-r6-(4-acetvl-1-piperazinvl)-3-pvridinvn-3-H-(ethvlsulfonvl)-4-10 piperidinyll-lH-indole-7-carboxamide trifluoroacetate O To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[6-(1 -piperazinyl)-3-pyridinyl]-1 /-/-indole-7-carboxamide (40 mg, 0.080 mmol) in dicloromethane at 0° C, was added acetyl chloride (7 pL, 0.096 mmol) and DIEA (11.6 pL, 0.12 mmol). Reaction mixture was 15 reacted for 0.5 h from 0° C to room temperature and then quenched with H20.
Compound was purified by MDAP HPLC to give 7 mg of the title compound (40%). LC/MS = m/z 539.4 [M+H] Ret. Time: 1.27 min Example 390: 3-ri-(ethylsulfonvl)-4-piperidinyll-5-(4-20 fr(methyloxv)amino1methvl>phenyl)-1 H-indole-7-carboxamide 2 314 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL) and MeOH (1.5 mL) was added O-5 methylhydroxylamine (114 mg, 1.71 mmol). The reaction was stirred overnight. The solvent was then concentrated and purified by Gilson Preparatory HPLC to give 38 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)imino]methyl}phenyl)-1/-/-indole-7-carboxamide (76%).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)imino]methyl}phenyl)-1/-/-indole-7-carboxamide (21.5 mg, 0.046 mmol) in DCM (3.0 mL) and MeOH (3.0 mL) was added drops of HCI in 1,4-dioxane to maintain pH = 4 at 0° C. Sodium cyanoborohydride (29 mg, 0.46 mmol) was then added and stirred overnight at room temperature. Additional HCI in 1,4-dioxane was added to maintain pH = 4 in addition to sodium cyanoborohydride (45 mg, 0.72 mmol). Reaction mixture then stirred over 48 h. Additional HCI in 1,4-dioxane was added to maintain pH = 4 at 0° C and stirred till room temperature was achieved. Mixture was quenched with H20. DCM was then added for aqueous work-up and mixture was concentrated. The reside was then take up in DCM and purified on the SCX SPE cartridge to afford 15.2 mg of the title compound (70%).
LC/MS = m/z 471.6 [M+H] Ret. Time: 1.67 min Example 391: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(3-{r(methyloxv)amino1methvl>phenyl)-1 H-indole-7-carboxamide 315 Received at IPONZ on 15 June 2011 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1/-/-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3.0 mL) was added O-methylhydroxylamine (57 mg, 0.684 mmol). The reaction was stirred overnight.
Additional O-methylhydroxylamine (0.342 mmol) was added to ther eaction mixture and stirred for 48 h. The solvent was then concentrated and purified by Gilson Preparatory HPLC to give 29.8 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)imino]methyl}phenyl)-1/-/-indole-7-carboxamide (56%).
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)imino]methyl}phenyl)-1/-/-indole-7-carboxamide (58 mg, 0.123 mmol) in DCM (3.0 mL) and MeOH (3.0 mL) was added HCI in 1,4-dioxane to maintain pH = 4 at 0° C. Sodium cyanoborohydride (176 mg, 3.69 mmol) was then added and stirred overnight for 48 h. The compound was purified by Gilson Preparatory HPLC to give 20.0 mg of the title compound (89%).
LC/MS = m/z 471.6 [M+H] Ret. Time: 1.75 min Example 392: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-{r4-(1-pvrrolidinyl)-1-piperidinvnmethvl}-3-thienyl)-1AV-indole-7-carboxamide trifluoroacetate 316 Received at IPONZ on 15 June 2011 F OH H To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.112 mmol) in DMSO (2.0 mL) was added 4-(1-pyrrolidinyl)piperidine (173 mg, 1.12 mmol) and acetic acid (5 drops). After 6 h, sodium 5 triacetoxyborohydride (238 mg, 1.12 mmol) was added and the reaction was stirred overnight, The reaction mixture was purified by Gilson Preparatory HPLC to give 17.0 mg of the title compound (26%).
LC/MS = m/z 584.4 [M+H] Ret. Time: 1.38 min Example 393: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-{T(2S)-2-(trifluoromethyl)-1-Pvrrolidinvnmethvl)-3-thienvl)-1AV-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (50 mg, 0.112 mmol) in DCM (3.0 mL) and MeOH (1.5 mL) was added (2S)-15 2-(trifluoromethyl)pyrrolidine (156 mg, 1.12 mmol) and acetic acid (5 drops). After 6 h of stirring at room temperature, sodium borohydride (43 mg, 1.12 mmol) was added and the 317 Received at IPONZ on 15 June 2011 reaction was stirred overnight at room temperature. The reaction mixture was purified by Gilson Preparatory HPLC to give 5.0 mg of the title compound (8%).
LC/MS = m/z 569.4 [M+H] Ret. Time: 2.37 min Example 394: 5-(5-{T(2R)-2-(hvdroxvmethvl)-1-pvrrolidinvnmethvl)-3-thienyl)-3-f1-r(1-methylethvl)sulfonvn-4-piperidinyl)-1 H-indole-7-carboxamide To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1/-/-10 indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added (2R)-2-pyrrolidinylmethanol (101.15 mg, 1 mmol) and 2 drops of acetic acid. The resulting mixture was stirred at room temperature for 4 h followed by an addition of sodium triacetoxyborohydride (212 mg, 0.54 mmol). The mixture was reacted overnight. It was then purified by Gilson Preparatory HPLC to give 20.5 mg of the title compound (69.7%). 15 LC/MS = m/z 546 [M+H] Ret. Time: 1.47 min.
Example 395: 5-(5-<T(3S)-3-hvdroxv-1-pyrrolidinvllmethvl)-3-thienvl)-3-(1-r(1-methvlethvl)sulfonvn-4-piperidinvlV1 H-indole-7-carboxamide H,N H,N 318 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H-indole-7-carboxamide, substituting (3S)-3-pyrrolidinol (90.13 mg, 1.20 mmol) for (2R)-2-pyrrolidinylmethanol to afford 12.8 mg of the title compound (53.1%). 5 LC/MS = m/z 532 [M+H] Ret. Time: 1.45 min.
Example 396: 5-(5-<Tcyclopentvl(methvl)aminolmethvl)-3-thienyl)-3-f1-r(1-methvlethvl)sulfonvll-4-piperidinyl)-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide, substituting N-methylcyclopentanamine (90.13 mg, 1.20 mmol) for (2R)-2-pyrrolidinylmethanol to afford 10 mg of the title compound (54.3%) 15 LC/MS = m/z 544.2 [M+H] Ret. Time: 1.65 min.
Example 397: 5-(5-(T(2-hvdroxvethvl)(methvl)amino1methvl)-3-thienyl)-3-f1-r(1-methylethvl)sulfonvn-4-piperidinyl)-1 H-indole-7-carboxamide N H2N N H2N 319 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H-indole-7-carboxamide, substituting 2-(methylamino)ethanol (90.13 mg, 1.20 mmol) for (2R)-2-pyrrolidinylmethanol to afford 8 mg of the title compound (51.9%), 5 LC/MS = m/z 520 [M+H] Ret. Time: 1.44 min.
Example 398: 5-(5-fr(2-amino-2-oxoethvlMmethvl)aminolmethvl)-3-thienyl)-3-(1-r(1-methylethvl)sulfonvll-4-piperidinvl)-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide, substituting N2-methylglycinamide (90.13 mg, 1.200 mmol) for (2R)-2-pyrrolidinylmethanol to afford 15 mg of the title compound 15 (53.2%).
LC/MS = m/z 520 [M+H] Ret. Time: 1.44 min.
Example 399: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-(Tmethyl(2-propen-1-vl)amino1methvl)-3-thienyl)-1 H-indole-7-carboxamide nh2 Allylamine (0.034 mL, 0.449 mmol) and HOAc (0.026 mL, 0.449 mmol) were added to a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (20 mg, 0.0449 mmol) in DMSO (0.5 mL) in a 1-dram vial. NaBH(OAc)3 (95 320 Received at IPONZ on 15 June 2011 mg, 0.449 mmol) was then added, the vial was capped and the reaction was stirred at room temperature for 15 h. NaCNBH3 (28 mg, 0.449 mmol) and MeOH were added, and the reaction was stirred for an additional 4 h. An aqueous solution of 37 wt% formaldehyde (0.069 mL, 0.898 mmol) was added, and the reaction was stirred for an 5 additional 1 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with MeOH (3 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen at 50 °C, and the residue was dissolved in DMSO (1 mL) and purified on a Gilson HPLC (Xbridge Prep C18 column: 19 x 100 mm) eluting at 20 mL per min with a 10 linear gradient running from 10% CH3CN/H20 (0.1% NH4OH) to 70% CH3CN/H20 (0.1% NH4OH) over 15 min. The fractions containing the title compound were concentrated under a stream of nitrogen at 50 °C to give 5.2 mg of the title compound (23%).
LC/MS = m/z 501.4 [M+H] Ret. Time: 1.48 min.
Example 400: 5-(5-(Tr(3,5-dimethyl-1 H-pvrazol-4-vl)methvn(methvl)amino1methyl)-3-thienyl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide n To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (45 mg, 100 pmol) in dimethyl sulfoxide (1.0 mL) was added 1 -(3,5-20 dimethyl-1 H-pyrazol-4-yl)-N-methylmethanamine ( 320 pmol) and 2 to 3 drops of glacial acetic acid. The resulting mixture is agitated overnight. After 18 h, sodium triacetoxyborohydride (200 mg, 1000 pmol) is added. This mixture is agitated for 1.5 h followed by purification by Gilson Preparatory HPLC to give 6.24 mg of the title compound (11.0%).
LC/MS = m/z 569.3 [M+H] Ret. Time: 1.42 min.
Example 401: 5-(5-(T(cvanomethvl)(methvl)amino1methvl)-3-thienyl)-3-ri-(ethylsulfonvlM-piperidinyll-1 H-indole-7-carboxamide N ct nh 321 Received at IPONZ on 15 June 2011 O o=s / N H O NH. '2 The title compound was prepared according to the general procedure of 5-(5-{[[(3,5-dimethyl-1H-pyrazol-4-yl)methyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-5 piperidinyl]-1 H-indole-7-carboxamide , substituting (methylamino)acetonitrile (320 pmol) for 1-(3,5-dimethyl-1 H-pyrazol-4-yl)-N-methylmethanamine to afford 6.36 mg of the title compound (12.7%).
LC/MS = m/z 430 [M+H] Ret. Time: 1.70 min.
Example 402: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-(Tmethyl(1-methvlpropvl)amino1methvl)-3-thienyl)-1H-indole-7-carboxamide To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (45 mg, 0.1 mmol) in dimethyl sulfoxide (1 mL) was added 2-butanamine (1 15 mmol), 1 to 2 drops of acetic acid and sodium triacetoxyborohydride (211 mg, 1 mmol). The resulting mixture was capped and stirred for 18 h followed by an addition of sodium cyanoborohydride (62 mg, 1 mmol) in methanol (0.5 mL). This was stirred for 3 h followed by an addition of formaldehyde, 37% in water, (1.5 mL). This was purified through SCX (2 g) cartridge eluting with methanol followed by NH3 in methanol. Further 20 purification was performed by Gilson Preparatory HPLC. XBridge C18 Column (P/N '2 322 Received at IPONZ on 15 June 2011 186002978) using a gradient of 10% acetonitrile to 70% acetronile in water with 0.1% NH4OH to give 14.4 mg of the title compound (27.9%).
LC/MS = m/z 517.3 [M+H] Ret. Time: 1.58 min.
Example 403: 5-(5-{Tr2-(ethvloxv)ethvlKmethvl)amino1methvl)-3-thienvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-thienyl)-1 H-10 indole-7-carboxamide , substituting 2-(ethyloxy)ethanamine (1 mmol) for added 2-butanamine to afford 6.1 mg of the title compound (11.5%).
LC/MS = m/z 533.2 [M+H] Ret. Time: 1.57 min.
Example 404: 5-(5-<Tcvclobutvl(methvl)aminolmethvl)-3-thienvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-thienyl)-1 H-20 indole-7-carboxamide H O NH. 323 Received at IPONZ on 15 June 2011 , substituting cyclobutylamine (1 mmol) for added 2-butanamine to afford 3.7 mg of the title compound (5.9%).
LC/MS = m/z 515.3 [M+H] Ret. Time: 1.64 min.
Example 405: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r5-((2-r(methyloxv)methvn-1-pyrrolidinvl)methvl)-3-thienvn-1H-indole-7-carboxamide trifluoroacetate / The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-thienyl)-1 H-10 indole-7-carboxamide , substituting 2-[(methyloxy)methyl]pyrrolidine (1 mmol) for added 2-butanamine to afford mg of the title compound (7.6%).
LC/MS = m/z 545.3 [M+H] Ret. Time: 1.65 min.
Example 406: 5-(5-<T(1.1-dimethylethvl)(methvl)aminolmethvl)-3-thienyl)-3-ri-(ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate u imm2 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-thienyl)-1 H-20 indole-7-carboxamide o h,n 324 Received at IPONZ on 15 June 2011 , substituting 2-methyl-2-propanamine (1 mmol) for added 2-butanamine to afford 10.9 mg of the title compound (17.3%).
LC/MS = m/z 517.3 [M+H] Ret. Time: 1.61 min.
Example 407: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-{T3-(trifluoromethyl)-1-piperidinvnmethvl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate F The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-thienyl)-1 H- indole-7-carboxamide , substituting 3-(trifluoromethyl)piperidine (1 mmol) for added 2-butanamine to afford 5.4 mg of the title compound (7.8%).
LC/MS = m/z 583.3 [M+H] Ret. Time: 1.73 min.
Example 408: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-(5-(Tr(1S)-2-hvdroxy-1-methvlethvn(methvl)amino1methvlV3-thienvl)-1H-indole-7-carboxamide trifluoroacetate To a vial containing (2f?)-2-amino-1-propanol (90.13 mg, 1.2 mmol) was added a solution 20 of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (30 mg, 0.067 mmol) in DMSO (300 |jL) and acetic acid (50 |jL). The resulting mixture was shaken for 5 min followed by an addition of sodium triacetoxyborohydride (250 mg, 1.20 325 Received at IPONZ on 15 June 2011 mmol) in DMSO (800 pL). The mixture was shaken overnight. Sodium cyanoborohydride (79 mg, 1.20 mmol) in methanol (300 pL) was then added and stirred for 48 h. This was followed by an addition of formaldehyde (100 pL). The reaction was then stirred for 1 h followed by a 2g SCX crude cartridge separation. The solids were then filtered off, 5 solution was concentrated and purification was repeated on a 5 g SCX cartridge eluting with ammonia in MeOH. The ammonia in MeOH fraction collection was concentrated and separated using Gilson Preparatory HPLC to afford 18.6 mg of the title compound (43.9%).
LC/MS = m/z 519.3 [M+H] Ret. Time: 1.49 min. 0 Example 409: 5-(5-(T(cvclopropvlmethvl)(methvl)amino1methvl)-3-thienyl)-3-ri-(ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate |-I2l\l U The title compound was prepared according to the general procedure of 3-[1-15 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1 -methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting (cyclopropylmethyl)amine (1.20 mmol) for (2/?)-2-amino-1-propanol to afford 6.2 mg of the title compound (14.7%).
LC/MS = m/z 515.3 [M+H] Ret. Time: 1.61 min.
Example 410: 5-(5-(Tr2-(acetvlamino)ethvn(methvl)amino1methvl)-3-thienyl)-3-ri-(ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 326 Received at IPONZ on 15 June 2011 O N H H,N The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting N-(2-5 aminoethyl)acetamide (1.20 mmol) for (2R)-2-amino-1 -propanol to afford 13.6 mg of the title compound (30.8%) LC/MS = m/z 546.2 [M+H] Ret. Time: 1.47 min.
Example 411: 3-ri-(ethvlsulfonvlM-piperidinyll-5-(5-<Tr(1R.2R)-2-10 hvdroxvcvclopentvn(methvl)amino1methviy3-thienvl)-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-15 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1 -methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting (1R,2R)-2-aminocyclopentanol (1.20 mmol) for (2R)-2-amino-1-propanol to afford 9.6 mg of the title compound (21.8%) LC/MS = m/z 545.3 [M+H] Ret. Time: 1.54 min.
Example 412: 5-(5-{T(1.1-dimethvlpropvl)(methvl)amino1methvlV3-thienvl)-3-H-(ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate Chiral H,N 327 Received at IPONZ on 15 June 2011 N H,N The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-5 3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting (1,1- dimethylpropyl)amine (1.20 mmol) for (2f?)-2-amino-1-propanol to afford 13.1 mg of the title compound (30.3%) LC/MS = m/z 531.3 [M+H] Ret. Time: 1.65 min.
Example 413: 3-ri-(ethylsulfonvlM-piperidinvH-5-(5-frr(2S)-2- hvdroxvpropvn(methvl)amino1methvl)-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-15 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1 -methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting (2S)-1-amino-2-propanol (1.20 mmol) for (2f?)-2-amino-1-propanol to afford 15.3 mg of the title compound (36.1%) LC/MS = m/z 519.3 [M+H] Ret. Time: 1.49 min.
Example 414: 3-H-(ethvlsulfonvl)-4-piperidinvn-5-r5-((methvir(2RHetrahvdro-2-furanvlmethvnamino)methyl)-3-thienvn-1H-indole-7-carboxamide trifluoroacetate Chiral 328 Received at IPONZ on 15 June 2011 H,N O The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-5 3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting [(2R)-tetrahydro-2-furanylmethyl]amine (1.20 mmol) for (2R)-2-amino-1-propanol to afford 15.5 mg of the title compound (35.1%) LC/MS = m/z 545.3 [M+H] Ret. Time: 1.58 min.
Example 415: 3-ri-(ethvlsulfonyl)-4-piperidinvn-5-(5-{r{2-r(2- hvdroxvethvl)oxv1ethvl)(methvl)amino1methvl>-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate The title compound was prepared according to the general procedure of 3-[1-15 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1 -methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting 2-[(2-aminoethyl)oxy]ethanol (1.20 mmol) for (2R)-2-amino-1-propanol to afford 17.2 mg of the title compound (38.7%).
LC/MS = m/z 549.5 [M+H] Ret. Time: 1.48 min.
Example 416: 3-ri-(ethylsulfonvl)-4-piperidinvn-5-r5-(1-fmethyir2-(methvloxv)ethvnamino)ethvl)-3-thienvn-1 H-indole-7-carboxamide trifluoroacetate HO H,N ^O 329 Received at IPONZ on 15 June 2011 o— o < F H F OH H2N^O To a solution of 5-(5-acetyl-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 /-/-indole-7-carboxamide (46 mg, 0.1 mmol) in EtOH (2.0 mL) and AcOH (0.2 mL) was added methyl[2-(methyloxy)ethyl]amine (200 pL, 2.0 mmol) and sodium cyanoborohydride (50 5 mg, 0.8 mmol). The mixture was reacted in the microwave at 120° C for 2 h. Additional methyl[2-(methyloxy)ethyl]amine (100 pL, 1.0 mmol) and sodium cyanoborohydride (25 mg, 0.4 mmol) was added and reacted for another 3 h in the microwave at 120° C for 2 h. This was then followed by another addition of methyl[2-(methyloxy)ethyl]amine (100 pL, 2.0 mmol) and sodium cyanoborohydride (25 mg, 0.4 mmol) and reacted for another 3 h 10 in the microwave at 120° C for 2h. All solvent was concentrated and purified by Gilson Preparatory HPLC to afford 20 mg of the title compound (38%).
LC/MS = m/z 533.2 [M+H] Ret. Time: 1.46 min.
Example 417: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-{1-rmethvl(propyl)amino1ethvl)-15 3-thienylHAV-indole-7-carboxamide trifluoroacetate To a solution of 5-(5-acetyl-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 /-/-indole-7-carboxamide (46 mg, 0.1 mmol) in EtOH (2.0 mL) and AcOH (0.2 mL) was added N-methyl-1-propanamine (200 pL, 2.0 mmol) and sodium cyanoborohydride (50 mg, 0.8 20 mmol). The mixture was reacted in the microwave at 120° C for 120 min. Additional N-methyl-1-propanamine (100 pL, 1.0 mmol) and sodium cyanoborohydride (25 mg, 0.4 mmol) was added and reacted for another 3 h in the microwave at 120° C for 120 min. All o 330 Received at IPONZ on 15 June 2011 solvent was concentrated, dissolved in DMSO and solids were filtered. It was then purified by Gilson Preparatory HPLC to afford 18 mg of the title compound (35%).
LC/MS = m/z 517.2 [M+H] Ret. Time: 1.52 min.
Example 418: 5-(2,3-dihvdro-1H-isoindol-5-vl)-3-H-(ethvlsulfonvlM-piperidinvn-1H-indole-7-carboxamide cr nh2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-10 dioxaborolan-2-yl)-1/-/-indole-7-carboxamide (150 mg, 0.325 mmol) in dioxane (0.75 mL) and water (0.25 mL), was added 5-bromo-2,3-dihydro-1/-/-isoindole hydrochloride (130 mg, 0.651 mmol), and cesium carbonate (636 mg, 1.952 mmol). The reaction mixture was kept under argon for 10 min before addition of tetrakis(tripehnylphosphine)palladium(0) (19 mg, 0.016 mmol). The resultant mixture was 15 heated in a microwave for 20 min at 150° C. Mixture was then purified by HPLC to give 11 mg of the title compound.
LC/MS = m/z 453 [M+H] Ret. Time: 1.33 min.
Example 419: 5-(2-ethvl-2.3-dihvdro-1H-isoindol-5-vl)-3-H-(ethvlsulfonvl)-4-20 pipe ridinvll-1 H-indole-7-carboxamide o. 331 Received at IPONZ on 15 June 2011 To a solution of 5-(2,3-dihydro-1/-/-isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (20 mg, 0.044 mmol) in MeOH (1 mL), was added acetaldehyde (6 mg, 0.133 mmol), sodium cyanoborohydride (6 mg, 0.088 mmol) and zinc chloride (6 mg, 0.044 mmol). The resultant mixture was heated in a microwave for 30 min at 100° C. 5 Mixture was then concentrated, filtered and purified by Gilson Preparatory HPLC to give 8.2 mg of the title compound.
LC/MS = m/z 481 [M+H] Ret. Time: 1.40 min.
Example 420: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-r2-(1-methvlethvl)-2.3-dihydro-1H-10 isoindol-5-vn-1AV-indole-7-carboxamide To a solution of 5-(2,3-dihydro-1/-/-isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-indole-7-carboxamide (30 mg, 0.066 mmol) in MeOH (0.5 mL), was added 2-propanone 15 (12 mg, 0.198 mmol), sodium cyanoborohydride (8 mg, 0.133 mmol) and zinc chloride (9 mg, 0.066 mmol). The resultant mixture was heated in a microwave for 30 min at 100° C. Mixture was then concentrated, filtered and purified by Gilson Preparatory HPLC to give 0.8 mg of the title compound.
LC/MS = m/z 495.5 [M+H] Ret. Time: 1.56 min.
Example 421: 5-r2-(1,2-dimethvlpropvl)-2.3-dihydro-1 H-isoindol-5-vn-3-H-(ethylsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide N 332 Received at IPONZ on 15 June 2011 The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-5 7-carboxamide, substituting 3-methyl-2-butanone (17 mg, 0.198 mmol) for 2-propanone to afford 14.6 mg of the title compound.
LC/MS = m/z 523 [M+H] Ret. Time: 1.55 min.
Example 422: 3-ri-(ethvlsulfonvlM-piperidinvll-5-r2-(1-methvlpropyl)-2.3-dihvdro-10 1H-isoindol-5-vn-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-15 7-carboxamide, substituting 2-butanone (14 mg, 0.198 mmol) for 2-propanone to afford 14.6 mg of the title compound.
LC/MS = m/z 509 [M+H] Ret. Time: 1.48 min.
Example 423: 5-r2-(1-ethvlpropvl)-2.3-dihvdro-1H-isoindol-5-vn-3-ri-(ethvlsulfonyl)-20 4-piperidinyn-1H-indole-7-carboxamide 333 Received at IPONZ on 15 June 2011 o. r' N The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-5 7-carboxamide, substituting 3-pentanone (17 mg, 0.198 mmol) for 2-propanone to afford 13.8 mg of the title compound.
LC/MS = m/z 523 [M+H] Ret. Time: 1.58 min.
Example 424: 5-(2-cvclopentvl-2.3-dihvdro-1H-isoindol-5-vl)-3-ri-(ethvlsulfonylM-10 pipe ridinvll-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-15 7-carboxamide, substituting cyclopentanone (17 mg, 0.198 mmol) for 2-propanone to afford 4.8 mg of the title compound.
LC/MS = m/z 521 [M+H] Ret. Time: 1.54 min.
Example 425: 5-r2-(cvclopropylmethvl)-2.3-dihvdro-1H-isoindol-5-vll-3-ri-20 (ethylsulfonvlM-piperidinyll-1 H-indole-7-carboxamide N H o^^m2 334 Received at IPONZ on 15 June 2011 cr /""" h The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-5 7-carboxamide, substituting cyclopropanecarbaldehyde (14 mg, 0.198 mmol) for 2-propanone to afford 10.8 mg of the title compound.
LC/MS = m/z 507 [M+H] Ret. Time: 1.47 min.
Example 426: 5-r2-(2.2-dimethvlpropyl)-2.3-dihvdro-1 H-isoindol-5-vH-3-ri-10 (ethylsulfonyl)-4-piperidinvn-1 H-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-15 7-carboxamide, substituting 2,2-dimethylpropanal (17 mg, 0.198 mmol) for 2-propanone to afford 12.7 mg of the title compound.
LC/MS = m/z 523 [M+H] Ret. Time: 1.60 min.
Example 427: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(2-methvl-2,3-dihydro-1H-isoindol-20 5-yl)-1H-indole-7-carboxamide n 335 Received at IPONZ on 15 June 2011 n —N H The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-5 7-carboxamide, substituting formaldehyde (6 mg, 0.198 mmol) for 2-propanone to afford 1.2 mg of the title compound.
LC/MS = m/z 467 [M+H] Ret. Time: 1.37 min.
Example 428: 3-H-(ethvlsulfonyl)-4-piperidinvn-5-(2-10 (T(phenvlsulfonvl)amino1carbonvl)-2,3-dihydro-1H-isoindol-5-vl)-1 H-indole-7-carboxamide To a solution of 5-(2,3-dihydro-1/-/-isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1/-/-15 indole-7-carboxamide (30 mg, 0.066 mmol) in DMSO (1.0 mL), was added benzenesulfonyl isocyanate (15 mg, 0.079 mmol). The resultant mixture was stirred overnight at room temperature. Mixture purified by Gilson Preparatory HPLC to give 15.5 mg of the title compound.
LC/MS = m/z 637 [M+H] Ret. Time: 1.94 min.
/ ^ O M cr nh2 336 Received at IPONZ on 15 June 2011 Example 429: 5-(5-(T(2/?)-2-(aminocarbonvl)-1-pvrrolidinvnmethvl)-3-thienyl)-3-f1- r(1-methvlethvl)sulfonvll-4-piperidinvl)-1 H-indole-7-carboxamide h2n h2n To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1/-/-indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added D-prolinamide (114 mg, 1 mmol) and 2 drops of acetic acid. The resulting mixture was stirred at room temperature for 4 h followed by an addition of sodium triacetoxyborohydride (212 mg, 1.0 10 mmol). The mixture was reacted overnight. It was then purified by Gilson Preparatory HPLC to give 20.4 mg of the title compound.
LC/MS = m/z 557 [M+H] Ret. Time: 1.56 min.
Example 430: 3-ri-(ethylsulfonyl)-4-piperidinvn-5-(5-(Tr2-15 (ethylthio)ethvll(methvnaminolmethvl)-3-thienyl)-1 H-indole-7-carboxamide To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1/-/-indole-7-carboxamide (40 mg, 0.09 mmol) in DMSO (2 mL) was added [2-(ethylthio)ethyl]amine (105 mg, 1 mmol), acetic acid (50 pL), and sodium triacetoxyborohydride (212 mg, 1.0 mmol). The resulting mixture was stirred overnight. To the mixture was added sodium cyanoborohydride (80 mg, 1.2 mmol) and stirred 25 overnight followed by addition of formaldehyde (100 (iL, 1.2 mmol). The mixture was N 337 Received at IPONZ on 15 June 2011 then stirred for an additional 3 h. It was then purified by Gilson Preparatory HPLC to give 7.0 mg of the title compound.
LC/MS = m/z 550 [M+H] Ret. Time: 1.68 min.
Example 431: 3-H-(ethvlsulfonvl)-4-piperidinvn-5-(5-flT2-r(2- hvdroxvethvl)thiolethvl)(methvl)amino1methvl)-3-thienyl)-1Ay-indole-7-carboxamide The title compound was prepared according to the general procedure of 3-[1- (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[2-(ethylthio)ethyl](methyl)amino]methyl}-3-thienyl)-1/-/-indole-7-carboxamide substituting 2-[(2-aminoethyl)thio]ethanol (121 mg, 1.0 mmol) for [2-(ethylthio)ethyl]amine to afford 16.0 mg of the title compound.
LC/MS = m/z 566 [M+H] Ret. Time: 1.52 min.
Example 432: 3-H-(ethvlsulfonvl)-4-piperidinvn-5-(5-flT2-hvdroxv-1-(hvdroxvmethvl)ethvn(methvl)aminolmethvl)-3-thienyl)-1 H-indole-7-carboxamide ,OH The title compound was prepared according to the general procedure of 3-[1- (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[2-(ethylthio)ethyl](methyl)amino]methyl}-3-thienyl)-1/-/-indole-7-carboxamide substituting 2-amino-1,3-propanediol (91 mg, 1.0 mmol) for [2-(ethylthio)ethyl]amine to afford 15.0 mg of the title compound. 338 Received at IPONZ on 15 June 2011 LC/MS = m/z 535 [M+H] Ret. Time: 1.44 min.
Example 433: ethyl r(4-f7-(aminocarbonvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indol-5-vl)-2-thienvl)methvnmethyl carbamate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl}-1/-/-indole-7-carboxamide (50 mg, 0.11 mmol) in DMF (1.0 mL) at 0° C was added triethylamine (0.06 mL, 0.44 mmol), and ethyl chloridocarbonate (0.021 mL, 0.22 mmol). The resultant mixture was reacted for 30 min followed by purification on Gilson Preparatory HLPC to afford 31.4 mg of the title compound (53.5%).
LC/MS = m/z 533.2 [M+H] Ret. Time: 2.06 min.
Example 434: ethyl A/-r(4-f7-(aminocarbonvl)-3-ri-(ethvlsulfonyl)-4-piperidinvn-1 H-indol-5-vl)-2-thienvl)methvn-A/-methvlglycinate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (45 mg, 100 |jmol) in dimethyl sulfoxide (1.0 mL) was added ethyl N-methylglycinate (320 |jmol) and 2 to 3 drops of glacial acetic acid. The resulting mixture is agitated overnight. After 18 h, sodium triacetoxyborohydride (200 mg, 1000 |jmol) is added. This mixture is agitated for 1.5 h followed by purification by Gilson Preparatory HPLC to give 16.5 mg of the title compound (30.0%).
LC/MS = m/z 547.1 [M+H] Ret. Time: 1.55 min. o NH 339 Received at IPONZ on 15 June 2011 Example 435: 3-ri-(ethvlsulfonvl)-4-piperidinvn-5-(5-(Tr(1S)-2-hydroxv-1-methvlethvn(methvl)amino1methvl)-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate (salt) o f oh To a vial containing (2S)-2-amino-1-propanol (91 mg, 1.2 mmol) was added a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1/-/-indole-7-carboxamide (30 mg, 0.067 mmol) in DMSO (300 |jL) and acetic acid (50 |jL). The resulting mixture was shaken for 5 min followed by an addition of sodium triacetoxyborohydride (250 mg, 1.20 mmol) in DMSO (800 |jL). The mixture was shaken overnight. Sodium cyanoborohydride (79 mg, 1.20 mmol) in methanol (300 |jL) was then added and stirred for 48 h. This was followed by an addition of formaldehyde (100 |jL). The reaction was then stirred for 1 h followed by a 2g SCX cartridge separation. The solids were then filtered off, solution was concentrated and purification was repeated on a 5 g SCX cartridge eluting with ammonia in MeOH. The ammonia in MeOH fraction collection was concentrated and separated using Gilson Preparatory HPLC to afford 18.7 mg of the title compound.
LC/MS = m/z 519.3 [M+H] Ret. Time: 1.49 min.
Example 436: 5-(5-(T(1,1-dioxidotetrahvdro-3-thienvl)(methvl)amino1methyl)-3-thienyl)-3-ri-(ethvlsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate F OH The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}- / N 340 Received at IPONZ on 15 June 2011 3-thienyl)-1/-/-indole-7-carboxamide trifluoroacetate, substituting (1,1-dioxidotetrahydro-3-thienyl)amine (1.20 mmol) for (2S)-2-amino-1-propanol to afford 9.3 mg of the title compound.
LC/MS = m/z 579 [M+H] Ret. Time: 1.54 min.
Biological Data IKK2 Assay Recombinant human IKKp (residues 1-737) was expressed in baculovirus as a C-terminal GST-tagged fusion protein, and its activity was assessed using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Briefly, IKK2 (0.5 nM - 5nM final) diluted in assay buffer (50 mM HEPES, 10 mM MgCI2, 1 mM CHAPS pH 7.4 with 1 mM DTT and 0.01% w/v BSA) was added to wells containing various concentrations of compound or DMSO vehicle (1.7% final). The reaction was initiated by the addition of GST-IB substrate (25 nM final)/ATP (1 |jM final), in a total volume of 6 |jl. The reaction 15 was incubated for 15 minutes at room temperature, then terminated by the addition of 3 |jl of detection reagent in buffer containing 50mM EDTA (100 mM HEPES pH 7.4, 150 mM NaCI, 50mM EDTA and 0.01% w/v BSA) containing antiphosphoserine-IB-32/36 monoclonal antibody 12C2 (Cell Signalling Technology, Beverly Massachusetts, USA) labelled with W-1024 europium chelate (Wallac OY, Turku, Finland), and an APC-labelled 20 anti-GST antibody (Prozyme, San Leandro, California, USA) was added and the reaction was further incubated for 60 minutes at room temperature. The degree of phosphorylation of GST-IB was measured using a BMG Rubystar plate reader (BMG Labtech, Aylesbury, UK) as a ratio of specific 665 nm energy transfer signal to reference europium 620 nm signal.
Results The compounds of Examples 1-31, 33, 35-51, 53-58, 60-97, 100-116, 118-121, 123-137, 139-163, 165-172, 174-197, 199-220, 222-242, 244-276, 279-330, 332-358, 360-385, 387-402, 404-419, 421-426, and 428-436 were tested for activity against IKK2 and these 30 Examples were found to be inhibitors of IKK2. These compounds had a plC50 of 5.0 or greater. Examples 277 and 278 were also tested for activity against IKK2 and these two compounds were found to have a plC50 of less than 5.0.
Monocyte Assay Effect of IKK-p inhibition on human monocyte stimulated cytokine production was assessed as follows: Monocytes were isolated from heparinized whole blood by Ficoll gradient, followed by purification of CD14+ cells using MACS magnetic cell separation 341 Received at IPONZ on 15 June 2011 beads. Isolated monocytes were then adhered to 96-well culture plates at 1 x 106 cells/mL in RPMI 1640 10% FBS (JRH Biosciences, Lenexa KS) for2h. Test compounds are added to the wells 30 minutes prior to stimulation with a final vehicle concentration of 0.1% DMSO. Monocytes were activated by the addition of 200 ng/mL endotoxin (LPS; E. 5 coli serotype 026:B6)(Sigma, St. Louis, MO.) and incubated for 24 hrs at 37 C. Cell-free supernates were analyzed by ELISA or Alphascreen for TNF-a. ELISAs were performed using Pharmingen matched pair Abs, and Alphascreen was performed using Alphascreen acceptor and donor beads from Perkin Elmer and anti-human TNF and biotinylated anti-human TNF Abs from R&D Systems. Viability of the cells was determined by 10% trypan 10 blue exclusion.
Results Certain Examples of this invention were tested in the monocyte assay. Examples 1-3, 5-13, 16-23, 25-31, 33, 37, 42-44, 61, 65-69, 71-73, 75-78, 83, 86-89, 92, 96, 100-117, 119-15 121, 123-127, 129-131, 139, 141, 144, 151, 154-157, 160-164, 166-167, 169-172, 182, 191, 208-214, 216-220, 222, 223, 227, 230-248, 250, 251, 269, 271, 273-276, 279-83, 285-90, 292-296, 298, 304-327, 329, 332-337, 342, 343, 346, 348, 353, 356-358, 361, 366-368, 370-373, 376, 380, 382, 391, 394-397, 399-404, 406, 408, 409, 412, 417-419, 432, 434, and 435 were found to have an IC50 of <2 (xM in this assay.
Examples 4, 15, 24, 34-36, 50, 70, 118, 128, 132-134, 136, 137, 140, 143, 146-148, 153, 158, 159, 165, 168, 192-194, 196, 197, 200-207, 224, 249, 253-262, 270, 272, 299-303, 330, 338-341, 360, 362, 363, 365, 374, 375, 377-379, 381, 383, 385, 388-390, 392, and 393 did not inhibit by >65 % at 1 (xM (top dose tested).
Examples 39, 40, 45-49, 58-60, 62, 63, 74, 79-81, 84, 85, 90, 91, 94, 95, 97, 173-181, 184-190, 195, 198, 328, 345, 347, 349-353, 345, 355, 429-431, 433, and 436 showed < 60% inhibition at 300 nM.
Variable results were obtain in the monocyte assay for Examples 38, 64, 82, 215, 297, 344, 364, and 369. 342 Received at IPONZ on 15 June 2011

Claims (4)

WHAT WE CLAIM IS:
1. 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-7-carboxamide of formula (I) or a pharmaceutically acceptable salt thereof.
2. 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-7-carboxamide of formula (I), according to claim 1.
3. A pharmaceutical composition comprising a) 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1/-/-isoindol-5-yl]-1/-/-indole-7-carboxamide, or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically-acceptable excipients.
4. A pharmaceutical composition according to claim 3, which further comprises one or more additional pharmaceutically active compounds. / N (I) 343
NZ563687A 2005-06-30 2006-06-28 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide for inhibiting IKK2 (aka IKKbeta) NZ563687A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US69525605P 2005-06-30 2005-06-30
PCT/US2006/025402 WO2007005534A2 (en) 2005-06-30 2006-06-28 Chemical compounds

Publications (1)

Publication Number Publication Date
NZ563687A true NZ563687A (en) 2011-07-29

Family

ID=37605008

Family Applications (1)

Application Number Title Priority Date Filing Date
NZ563687A NZ563687A (en) 2005-06-30 2006-06-28 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide for inhibiting IKK2 (aka IKKbeta)

Country Status (19)

Country Link
EP (1) EP1896014A4 (en)
JP (1) JP5059756B2 (en)
KR (1) KR20080021077A (en)
CN (1) CN101247804B (en)
AR (1) AR055343A1 (en)
AU (1) AU2006266028B2 (en)
BR (1) BRPI0611674A2 (en)
CA (1) CA2613068A1 (en)
EA (1) EA014083B1 (en)
IL (1) IL187786A0 (en)
MA (1) MA29566B1 (en)
MX (1) MX2007016541A (en)
NO (1) NO20080457L (en)
NZ (1) NZ563687A (en)
PE (1) PE20070173A1 (en)
TW (1) TWI380973B (en)
UA (1) UA99699C2 (en)
WO (1) WO2007005534A2 (en)
ZA (1) ZA200709948B (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0315950D0 (en) 2003-06-11 2003-08-13 Xention Discovery Ltd Compounds
PE20060748A1 (en) * 2004-09-21 2006-10-01 Smithkline Beecham Corp INDOLCARBOXAMIDE DERIVATIVES AS KINASE INHIBITORS IKK2
GB0525164D0 (en) * 2005-12-09 2006-01-18 Xention Discovery Ltd Compounds
JP2009519968A (en) * 2005-12-16 2009-05-21 スミスクライン・ビーチャム・コーポレイション Chemical substance
PE20081889A1 (en) 2007-03-23 2009-03-05 Smithkline Beecham Corp INDOL CARBOXAMIDES AS INHIBITORS OF IKK2
WO2010080474A1 (en) * 2008-12-19 2010-07-15 Bristol-Myers Squibb Company Carbazole and carboline kinase inhibitors
US8354539B2 (en) 2009-03-10 2013-01-15 Glaxo Group Limited Indole derivatives as IKK2 inhibitors
EP3013337B1 (en) * 2013-06-26 2018-10-31 Abbvie Inc. Primary carboxamides as btk inhibitors
EP3209656B1 (en) * 2014-10-24 2020-04-01 Bristol-Myers Squibb Company Indole carboxamides compounds useful as kinase inhibitors

Family Cites Families (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1272842A (en) * 1997-08-06 2000-11-08 伊莱利利公司 2-acylaminopropanamines as tachykinin receptor antagonists
DE19807993A1 (en) 1998-02-26 1999-09-02 Bayer Ag Treating tumor necrosis factor mediated inflammatory disease, e.g. arteriosclerosis, using new or known beta-carboline derivatives
DE19928424A1 (en) 1999-06-23 2000-12-28 Aventis Pharma Gmbh New aminoacid residue substituted benzimidazole derivative I(kappa)B-kinase inhibitors, useful for treating NF(kappa)B-related disorders e.g. rheumatoid arthritis, asthma, Alzheimer's disease and cancer
EP1194425B1 (en) 1999-06-23 2005-08-10 Aventis Pharma Deutschland GmbH Substituted benzimidazole
DE19951360A1 (en) 1999-10-26 2001-05-03 Aventis Pharma Gmbh Substituted indoles
GB0003154D0 (en) 2000-02-12 2000-04-05 Astrazeneca Uk Ltd Novel compounds
EP1268477B1 (en) 2000-03-15 2010-04-21 Sanofi-Aventis Deutschland GmbH Substituted beta-carbolines with ikb-kinase inhibiting activity
EP1209158A1 (en) 2000-11-18 2002-05-29 Aventis Pharma Deutschland GmbH Substituted beta-carbolines
EP1134221A1 (en) 2000-03-15 2001-09-19 Aventis Pharma Deutschland GmbH Substituted beta-carbolines as lkB kinase inhibitors
JP2001278886A (en) * 2000-03-28 2001-10-10 Dai Ichi Seiyaku Co Ltd Benzoxazine derivative and medicament containing the same
US6414013B1 (en) 2000-06-19 2002-07-02 Pharmacia & Upjohn S.P.A. Thiophene compounds, process for preparing the same, and pharmaceutical compositions containing the same background of the invention
JP4272338B2 (en) 2000-09-22 2009-06-03 バイエル アクチェンゲゼルシャフト Pyridine derivatives
ATE319713T1 (en) 2000-10-03 2006-03-15 Bristol Myers Squibb Co AMINO-SUBSTITUTED TETRACYCLIC COMPOUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS AND DRUGS CONTAINING SAME.
US6869956B2 (en) 2000-10-03 2005-03-22 Bristol-Myers Squibb Company Methods of treating inflammatory and immune diseases using inhibitors of IκB kinase (IKK)
JP2004523476A (en) 2000-10-12 2004-08-05 スミスクライン・ビーチャム・コーポレイション NF-κB inhibitor
EP1328272A1 (en) 2000-10-12 2003-07-23 SmithKline Beecham Corporation Nf-kappa-b inhibitors
ES2305125T3 (en) 2000-10-26 2008-11-01 Amgen Inc. ANTI-INFLAMMATORY AGENTS.
JP2002193938A (en) 2000-12-01 2002-07-10 Bayer Ag 4-arylpyridine derivative
US7122544B2 (en) 2000-12-06 2006-10-17 Signal Pharmaceuticals, Llc Anilinopyrimidine derivatives as IKK inhibitors and compositions and methods related thereto
PL364111A1 (en) 2001-02-01 2004-12-13 Bristol-Myers Squibb Company Methods of treating inflammatory and immune diseases using inhibitors of ikappab kinase (ikk)
MXPA03010669A (en) 2001-05-24 2004-07-01 Leo Pharma As Novel pyridyl cyanoguanidine compounds.
WO2002094265A1 (en) 2001-05-24 2002-11-28 Leo Pharma A/S A method of modulating nf-$g(k)b activity
US20030045515A1 (en) 2001-05-24 2003-03-06 Lise Binderup Combination medicament for treatment of neoplastic diseases
US6638679B2 (en) 2001-07-12 2003-10-28 Kodak Polychrome Graphics, Llc Photosensitive compositions having mixtures of alkoxy and non-alkoxy diazonium salt containing compounds
SE0102617D0 (en) 2001-07-25 2001-07-25 Astrazeneca Ab Novel compounds
SE0102616D0 (en) 2001-07-25 2001-07-25 Astrazeneca Ab Novel compounds
JP2005507922A (en) 2001-09-19 2005-03-24 ファルマシア・コーポレイション Substituted indazole compounds for the treatment of inflammation
BR0212611A (en) 2001-09-19 2004-08-17 Pharmacia Corp Substituted pyrazolyl compounds for the treatment of inflammation
BR0212661A (en) 2001-09-19 2004-08-24 Pharmacia Corp Substituted pyrazolyl benzenesulfamide compounds for the treatment of inflammation
MXPA04002682A (en) 2001-09-19 2004-06-18 Pharmacia Corp Substituted pyrazolo compounds for the treatment of inflammation.
CA2464924A1 (en) 2001-10-30 2003-05-08 Pharmacia Corporation Heteroaromatic carboxamide derivatives for the treatment of inflammation
AU2003222106A1 (en) 2002-04-03 2003-10-20 Bristol-Myers Squibb Company Thiopene-based tricyclic compounds and pharmaceutical compositions comprising same
MXPA04010952A (en) 2002-05-09 2005-01-25 Pharmacia Corp Substituted pyrazolyl compounds for the treatment of inflammation.
NZ537394A (en) 2002-06-06 2006-12-22 Boehringer Ingelheim Pharma Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
GB0217757D0 (en) * 2002-07-31 2002-09-11 Glaxo Group Ltd Novel compounds
JP4332112B2 (en) * 2002-08-09 2009-09-16 メルク エンド カムパニー インコーポレーテッド Tyrosine kinase inhibitor
DE10237722A1 (en) 2002-08-17 2004-08-19 Aventis Pharma Deutschland Gmbh Indole or benzimidazole derivatives for the modulation of IKappaB kinase
WO2004075846A2 (en) 2003-02-25 2004-09-10 Bristol-Myers Squibb Company Pyrazolopurine-based tricyclic compounds and pharmaceutical compositions comprising same
GB0308466D0 (en) 2003-04-11 2003-05-21 Novartis Ag Organic compounds
US7176214B2 (en) 2003-05-21 2007-02-13 Bristol-Myers Squibb Company Imidazo-fused oxazolo[4,5-β]pyridine and imidazo-fused thiazolo[4,5-β]pyridine based tricyclic compounds and pharmaceutical compositions comprising same
JP2007533602A (en) * 2003-07-31 2007-11-22 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Substituted benzothiophene compounds and their use
US7265148B2 (en) * 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7291733B2 (en) 2003-10-10 2007-11-06 Boehringer Ingelheim Pharmaceuticals, Inc. Substituted tricyclic heterocycles and their uses
CA2541667A1 (en) 2003-10-14 2005-04-21 Pharmacia Corporation Substituted pyrazinone compounds for the treatment of inflammation
GB0400895D0 (en) * 2004-01-15 2004-02-18 Smithkline Beecham Corp Chemical compounds
AR050253A1 (en) * 2004-06-24 2006-10-11 Smithkline Beecham Corp COMPOSITE DERIVED FROM INDAZOL CARBOXAMIDE, COMPOSITION THAT INCLUDES IT AND ITS USE FOR THE PREPARATION OF A MEDICINAL PRODUCT
CN101060842A (en) * 2004-09-21 2007-10-24 葛兰素集团有限公司 Chemical compounds
PE20060748A1 (en) * 2004-09-21 2006-10-01 Smithkline Beecham Corp INDOLCARBOXAMIDE DERIVATIVES AS KINASE INHIBITORS IKK2

Also Published As

Publication number Publication date
UA99699C2 (en) 2012-09-25
AU2006266028B2 (en) 2012-03-15
CN101247804B (en) 2012-09-26
MA29566B1 (en) 2008-06-02
IL187786A0 (en) 2008-08-07
CN101247804A (en) 2008-08-20
EP1896014A4 (en) 2010-07-21
KR20080021077A (en) 2008-03-06
WO2007005534A3 (en) 2007-04-26
EP1896014A2 (en) 2008-03-12
NO20080457L (en) 2008-01-29
PE20070173A1 (en) 2007-03-14
ZA200709948B (en) 2009-03-25
TW200738588A (en) 2007-10-16
JP2009500338A (en) 2009-01-08
EA014083B1 (en) 2010-08-30
TWI380973B (en) 2013-01-01
JP5059756B2 (en) 2012-10-31
MX2007016541A (en) 2008-03-07
AR055343A1 (en) 2007-08-22
AU2006266028A1 (en) 2007-01-11
EA200800183A1 (en) 2008-08-29
WO2007005534A2 (en) 2007-01-11
CA2613068A1 (en) 2007-01-11
BRPI0611674A2 (en) 2009-04-28
WO2007005534A8 (en) 2008-01-17

Similar Documents

Publication Publication Date Title
US8354406B2 (en) Chemical compounds
US7858796B2 (en) Chemical compounds
EP1758578B1 (en) Novel indazole carboxamides and their use
ES2317184T3 (en) DERIVATIVES OF INDOL AND ITS USE AS INHIBITORS OF KINASES IN PARTICULAR OF IKK2.
AU2006266028B2 (en) Chemical compounds
US20080262040A1 (en) Chemical Compounds
US20080293802A1 (en) Chemical Compounds
US20080269291A1 (en) Chemical Compounds

Legal Events

Date Code Title Description
PSEA Patent sealed
RENW Renewal (renewal fees accepted)
RENW Renewal (renewal fees accepted)

Free format text: PATENT RENEWED FOR 3 YEARS UNTIL 28 JUN 2016 BY THOMSON REUTERS

Effective date: 20130514

LAPS Patent lapsed