AU2006266028B2 - Chemical compounds - Google Patents

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AU2006266028B2
AU2006266028B2 AU2006266028A AU2006266028A AU2006266028B2 AU 2006266028 B2 AU2006266028 B2 AU 2006266028B2 AU 2006266028 A AU2006266028 A AU 2006266028A AU 2006266028 A AU2006266028 A AU 2006266028A AU 2006266028 B2 AU2006266028 B2 AU 2006266028B2
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indole
carboxamide
ethylsulfonyl
piperidinyl
methyl
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Jianghe Deng
Qi Jin
Jeffrey K. Kerns
Guoliang Lin
Xichen Lin
Michael Lindenmuth
Christopher E. Neipp
Hong Nie
Sonia M. Thomas
Katherine L. Widdowson
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Abstract

The invention is directed to novel indole carboxamide derivatives. Specifically, the invention is directed to compounds according to formula I: Formula (I) where R1 , R2, R3, U and V are defined below and to pharmaceutically acceptable salts thereof. The compounds of the invention are inhibitors of IKK2 and can be useful in the treatment of disorders associated with inappropriate IKK2 (also known as IKKβ) activity, such as rheumatoid arthritis, asthma, and COPD (chronic obstructive pulmonary disease). Accordingly, the invention is further directed to pharmaceutical compositions comprising a 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.

Description

WO 2007/005534 PCT/US2006/025402 CHEMICAL COMPOUNDS 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 IKKP) 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-Mg 2 ' 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 WO 2007/005534 PCT/US2006/025402 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, ReIA 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 KB 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-P). IKK-3 is also known as IKK2. Site 2 WO 2007/005534 PCT/US2006/025402 directed mutagenesis studies indicate that these phosphorylations are critical for the subsequent activation of NF-xB 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. 10 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-1P, 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. 25 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-1p. 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-p has been shown in synoviocytes of rheumatoid arthritis patients and gene transfer studies have demonstrated the central role of IKK-p in stimulated inflammatory mediator production in 35 these cells. See Aupperele et al. J. Immunology 1999. 163:427-433 and Aupperle et al. 3 WO 2007/005534 PCT/US2006/025402 J. Immunology 2001;166:2705-11. More recently, the intra-articular administration of a wild type IKK-p adenoviral construct was shown to cause paw swelling while intra articular administration of dominant-negative IKKp inhibited adjuvant-induced arthritis in rat. See Tak et al. Arthritis and Rheumatism 2001, 44:1897-1907. 5 The NF-KB/Rel and 1KB 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. 25 Several NF-KB inhibitors are described in C. Wahl, et al. J. Clin. Invest. 101(5), 1163 1174 (1998), R. W. Sullivan, et al. J. Med. Chem. 41, 413-419 (1998), J. W. Pierce, et al. J. Biol. Chem. 272, 21096-21103 (1997). The marine natural product hymenialdisine is known to inhibit NF-KB. Roshak, A., et al., 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, et al., WO 35 2003010158; Griffiths, et al., W02003010163; Fancelli, et al., WO 200198290; Granetto, 4 WO 2007/005534 PCT/US2006/025402 et a., WO 2003037886; imidazole inhibitors of IKK2, see Callahan, et al., WO 200230423; anilinophenylpyrimidine inhibitors of IKK2, see Kois, et aL, WO 2002046171; P-carboline inhibitors of 1KK2 , see Ritzeler, et al, WO 2001068648, Ritzeler, et al, EP 1134221; Nielsch, et al. DE 19807993; Ritzeler, et al., EP 1209158; indole inhbitors of 5 IKK2, see Ritzeler, et aL, WO 2001030774; benzimidazole inhibitors of the IKK2, see Ritzeler, et al., DE 19928424; Ritzeler et al, WO 2001000610; Ritzeler, et aL, 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 a., WO 2003024935;, Metz, et al., WO 2003024936; Geng et al., WO 2003027075; Stealey, et al., WO 2003035625; Xu, et a., WO 200307076; Lennon, et al., 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, et al. 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 et al, WO 2002094322 and Madsen, et aL, 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. 274, 220-228 (1999). Synthetic inhibitors of 25 IKK2 have also been described, see Burke, eta. J. BioL Chem., 278, 1450-1456 (2003), Murata, et al., Bioorg. Med. Chem. Lett., 13, 913-198 (2003), Murata, et al., Bioorg. Med. Chem. Lett., 14, 4013-4017 (2004), and Murata, et al., Bioorg. Med. Chem. Lett., 14, 4019-4022 (2004) have described IKK2 inhibitors. 30 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. 5 WO 2007/005534 PCT/US2006/025402 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 (1): 20 R2 U-V R1 R3 N H 0
NH
2 where R1, R2, R3, U and V are defined below and to pharmaceutically acceptable salts thereof. 25 The compounds of the invention are inhibitors of IKK2 and can be useful in the treatment of disorders associated with inappropriate IKK2 (also known as IKKP) activity, such as rheumatoid arthritis, asthma, and COPD (chronic obstructive pulmonary disease). Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting 30 IKK2 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention. 6 C:WRPonb\DCC'JXT418362_ 1 DOC-2902/2012 In another aspect, the present invention is directed to 3-[1-(ethylsulfonyl)-4 piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro- 1 H-isoindol-5-yl]-1 H-indole-7-carboxamide of formula (1) O' N N N H 5 NH2() or a pharmaceutically acceptable salt thereof. In a further aspect, the present invention is directed to a pharmaceutical composition comprising 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H 10 isoindol-5-y]-1H-indole-7-carboxamide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically-acceptable excipients. In another aspect, the present invention is directed to 3-[1-(ethylsulfonyl)-4 piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl]-1 H-indole-7 15 carboxamide, or a pharmaceutically acceptable salt thereof, for use in therapy. In a further aspect, the present invention is directed to 3-[1-(ethylsulfonyl)-4 piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl]-1 H-indole-7 carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of 20 asthma or chronic obstructive pulmonary disease (COPD). In another aspect, the present invention is directed to the use of 3-[1-(ethylsulfonyl)-4 piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl]-1 H-indole-7 carboxamide, or a pharmaceutically acceptable salt thereof, for the manufacture of a 25 medicament for the treatment of asthma or chronic obstructive pulmonary disease (COPD). In a further aspect, the present invention is directed to a method of treating asthma or chronic obstructive pulmonary disease (COPD), comprising administering a safe and 30 effective amount of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro 1H-isoindol-5-yl]-1H-indole-7-carboxamide, or a pharmaceutically acceptable salt thereof to a patient in need thereof. 6A WO 2007/005534 PCT/US2006/025402 DETAILED DESCRIPTION OF THE INVENTION The invention is directed to compounds according to formula (1): R2 U-V R1 R3 N H o NH 2 5 R5\ R5 N N I I where R1 is the group -XYZ or or X is phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, or 2,3-dihydro-1 H-indenyl, where said phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, and 2,3-dihydro 1 H-indenyl are optionally substituted with one or two substituents each independently 10 selected from the following: 1) halo, 2) nitro, 3) cyano, 4) -NR7R8, 15 5) C1-C 6 -alkyl, 6) CHO, 7) CONH 2 , and 8) -OR4, where said C 1
-C
6 -alkyl is optionally substituted with one -NR4R5 group; 20 Y is a bond or C1 -C6 alkylene, where C1 -C6 alkylene is optionally substituted with one or two substituents each independently selected from the following: 1) C1 -C 3 -alkyl optionally substituted by one OR4 group, 25 2) C 3
-C
7 -cycloalkyl, 3) methoxy, 7 WO 2007/005534 PCT/US2006/025402 4) hydroxy, and 5) heteroaryl; Z is -NR4R5 or heterocycloalkyl, 5 where said heterocycloalkyl is optionally substituted with one or two substituents each independently selected from the following: 1) C 1
-C
6 -alkyl optionally substituted by one OR4 or one heterocycloalkyl group, 2) C 3
-C
7 -cycloalkyl, 10 3) methoxy, 4) -CONH 2 5) hydroxy, 6) heteroaryl, 7) CF 3 , 15 8) phenyl, 9) heterocycloalkyl, and 10)
N(CH
3
)
2 ; 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) H and 2) C1 -C 6 -alkyl, where said C1 -C 6 -alkyl is optionally substituted with one hydroxy or one methoxy group; 8 WO 2007/005534 PCT/US2006/025402 R5 is selected from 1) H, 2) C 5
-C
6 -heterocycloalkyl, 3) -CO 2 Et, 5 4) C1 -C 6 -alkoxy, 5) C 3 -0 7 -cycloalkyl, 6) C1 -C 6 -alkyl, 7) -S0 2 R10, and 8) -C(O)R10, 10 where said C 3
-C
7 -cycloalkyl and C 1
-C
6 -alkyl are optionally substituted with one to three substituents selected from R6; each R6 is independently selected from 1) -NR7R8, 15 2) -S0 2 R7, 3) -CONH 2 , 4)
-CF
3 , 5) -CN, 6) -C0 2 R7, 20 7) -OCH 2
CH
2 0R7, 8) -SR5, 9) C3-C4 alkenyl, 10) OH, 11) C 1
-C
6 -alkoxy, 25 12) heteroaryl, 13) C 3
-C
7 -cycloalkyl, 14) phenyl, 15) heterocycloalkyl, and 16) halo, 30 where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally substituted with one to two substituents selected from R9; R7 is selected from 1) H, 9 WO 2007/005534 PCT/US2006/025402 2) C 1
-C
3 -alkyl, and 3) phenyl; R8 is selected from 5 1) H, 2) C1 -C 3 -alkyl, and 3) -C(O)R4; each R9 is independently selected from 10 1) hydroxy, 2) -OMe, 3) nitro, 4) C1 -C 6 -alkyl, 5)
NH
2 , 15 6) halo, 7)
CF
3 , 8) C1-C 6 -alkoxy, and 9) CN; 20 R10 is selected from 1) H, 2) C1-C 6 -alkyl, 3) phenyl, 4) C 3
-C
7 -cycloalkyl, 25 5) heteroaryl, 6) C1 -C 6 -heteroaryl, and 7) heterocycloalkyl, where said C1 -C 6 -alkyl is optionally substituted with one or two substituents each independently selected from C 3
-C
7 -cycloalkyl and -S-R7; where said heterocycloalkyl is 30 optionally substituted with one -C(O)R7 group; and where said phenyl, heteroaryl and C1 C 6 -heteroaryl are optionally substituted with one to two substituents selected from Ri 1; each R11 is independently selected from 10 WO 2007/005534 PCT/US2006/025402 1) H, 2) C 1
-C
6 -alkyl, and 3) halo; 5 U is a bond, C1 -C6 alkylene or C2-C6 alkenylene; V is phenyl, 5 or 6 membered heteroaryl, 5-7 membered heterocycloalkyl, C5-C7 cycloalkyl, or C5-07 cycloalkenyl, each of which is substituted by -N(R7)S(O)mR12, S(O)mN(R7)R12, -S(O)mRl2, or -C(O)R12; 10 m is 1 or 2; and R12 is C1-C 6 -alkyl, C3-C7 cycloalkyl, C1-C 6 -alkyl-C 3
-C
7 cycloalkyl, or C1-C 6 -alkyl phenyl; or a pharmaceutically acceptable salt thereof. 15 One embodiment of the present invention is a compound according to formula (1): where R1 is the group -XYZ; X is phenyl or heteroaryl, where said phenyl and heteroaryl are optionally substituted with one or two 20 substituents each independently selected from the following: 1) halo, 2) nitro, 3) cyano, 4) -NR7R8, 25 5) C1-C6-alkyl, 6) CHO, 7) CONH 2 , and 8) -OR4, where said C 1
-C
6 -alkyl is optionally substituted with one -NR4R5 group; 30 Y is a bond or C1 -C6 alkylene, where C1 -C6 alkylene is optionally substituted with one or two substituents each independently selected from the following: 11 WO 2007/005534 PCT/US2006/025402 1) C1 -C 3 -alkyl optionally substituted by one OR4 group, 2) C 3
-C
7 -cycloalkyl, 3) methoxy, 4) hydroxy, and 5 5) heteroaryl; Z is -NR4R5 or heterocycloalkyl, where said heterocycloalkyl is optionally substituted with one or two substituents each independently selected from the following: 10 1) C 1
-C
6 -alkyl optionally substituted by one OR4 group, 2) C 3
-C
7 -cycloalkyl, 3) methoxy, 4) hydroxy, and 5) heteroaryl; 15 R2 is selected from 1) H, 2) fluoro, and 3) chloro; 20 R3 is selected from 1) H, 2) fluoro, and 3) chloro; 25 R4 is selected from 1) H and 2) C1 -C 6 -alkyl, where said C1 -C 6 -alkyl is optionally substituted with one hydroxy or one methoxy 30 group; R5 is selected from 1) H, 2) C1 -C 6 -alkoxy, 12 WO 2007/005534 PCT/US2006/025402 3) C 3
-C
7 -cycloalkyl, 4) C1 -C 6 -alkyl, 5) -SO 2 R1O, and 6) -C(O)R1O, 5 where said C 3
-C
7 -cycloalkyl and C1 -C 6 -alkyl are optionally substituted with one to three substituents selected from R6; each R6 is independently selected from 1) -NR7R8, 10 2) -S0 2 R7, 3) OH, 4) methoxy, 5) heteroaryl, 6) C 3
-C
7 -cycloalkyl, 15 7) phenyl, 8) heterocycloalkyl, and 9) halo, where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally substituted with one to two substituents selected from R9; 20 R7 is selected from 1) H and 2) C 1
-C
3 -alkyl; 25 R8 is selected from 1) H and 2) C1 -C 3 -alkyl; each R9 is independently selected from 30 1) hydroxy, 2) nitro, 3) C1 -C 6 -alkyl, 4)
NH
2 , 5) halo, 13 WO 2007/005534 PCT/US2006/025402 6)
CF
3 , 7) C1 -C 6 -alkoxy, and 8) CN; 5 R10 is selected from 1) H, 2) C1 -C 6 -alkyl, 3) phenyl, 4) C 3
-C
7 -cycloalkyl, and 10 5) heteroaryl, where said C1 -C 6 -alkyl is optionally substituted with one or two substituents each independently selected from C 3
-C
7 -cycloalkyl and -S-R7; where said heterocycloalkyl is optionally substituted with one -C(O)R7 group; and where said phenyl and heteroaryl are optionally substituted with one to two substituents selected from R1 1; 15 each R1 1 is independently selected from 1) H, 2) C1-C 6 -alkyl, and 3) halo; 20 U is a bond, C1-C6 alkylene or C2-C6 alkenylene; V is phenyl, 5 or 6 membered heteroaryl, 5-7 membered heterocycloalkyl, C5-C7 cycloalkyl, or C5-C7 cycloalkenyl, each of which is substituted by -N(R7)S(O)mR1 2, 25 S(O)mN(R7)R12, -S(O)mR12, or -C(O)R12; m is 1 or 2; and R12 is C 1
-C
6 -alkyl, C3-07 cycloalkyl, C 1
-C
6 -alkyl-C 3
-
7 cycloalkyl, or C1-C 6 -alkyl 30 phenyl; or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention is a compound according to formula (1): 14 WO 2007/005534 PCT/US2006/025402 R5\ R5 N N I I where R1 is the group -XYZ or or X is phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthalenyl, or 2,3-dihydro-1 H-indenyl; Y is a bond or C1-C6 alkylene; Z is -NR4R5 or heterocycloalkyl, 5 where said heterocycloalkyl is optionally substituted with one or two substituents each independently selected from the following: 1) C1 -C 6 -alkyl optionally substituted by one OR4 or one heterocycloalkyl group, 2) C 3
-C
7 -cycloalkyl, 10 3) methoxy, 4) -CONH 2 5) hydroxy, 6) heteroaryl; 7)
CF
3 , 15 8) phenyl, 9) heterocycloalkyl, and 10)
N(CH
3
)
2 ; R2 is H; 20 R3 is H; R4 is selected from 1) H and 25 2) C 1
-C
6 -alkyl, where said C1 -C 6 -alkyl is optionally substituted with one hydroxy or one methoxy group; R5 is selected from 30 1) H, 2) C 5
-C
6 -heterocycloalkyl, 15 WO 2007/005534 PCT/US2006/025402 3) -CO 2 Et, 4) C1 -C 6 -alkoxy, 5) C 3
-C
7 -cycloalkyl, 6) C1 -C 6 -alkyl, 5 7) -SO 2 R1O, and 8) -C(O)R1O, where said C 3
-C
7 -cycloalkyl and C1 -C 6 -alkyl are optionally substituted with one to three substituents selected from R6; 10 each R6 is independently selected from 1) -NR7R8, 2) -S0 2 R7, 3) -CONH 2 , 4) -CF 3 , 15 5) -CN, 6) -CO 2 R7, 7) -OCH 2
CH
2 OR7, 8) -SR5, 9) C3-C4 alkenyl, 20 10) OH, 11) C 1
-C
6 -alkoxy, 12) heteroaryl, 13) C 3
-C
7 -cycloalkyl, 14) phenyl, 25 15) heterocycloalkyl, and 16) halo, where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally substituted with one to two substituents selected from R9; 30 R7 is selected from 1) H, 2) C 1
-C
3 -alkyl, and 3) phenyl; 16 WO 2007/005534 PCT/US2006/025402 R8 is selected from 1) H, 2) C1 -C 3 -alkyl, and 3) -C(O)R4; 5 each R9 is independently selected from 1) hydroxy, 2) -OMe 3) nitro, 10 4) C 1
-C
6 -alkyl, 5)
NH
2 , 6) halo, 7)
CF
3 , 8) C1-C 6 -alkoxy, and 15 9) CN; R10 is selected from 1) H, 2) C 1
-C
6 -alkyl, 20 3) phenyl, 4) C 3
-C
7 -cycloalkyl, 5) heteroaryl, 6) C 1
-C
6 -heteroaryl, and 7) heterocycloalkyl, 25 where said C1 -C 6 -alkyl is optionally substituted with one or two substituents each independently selected from C 3
-C
7 -cycloalkyl and -S-R7; where said heterocycloalkyl is optionally substituted with one -C(O)R7 group; and where said phenyl, heteroaryl and C1
C
6 -heteroaryl are optionally substituted with one to two substituents selected from R1 1; 30 each R11 is independently selected from 1) H, 2) C 1
-C
6 -alkyl, and 3) halo; 17 WO 2007/005534 PCT/US2006/025402 U is a bond; V is a 5-7 membered heterocycloalkyl substituted by -S(O)mR1 2; m is 1 or 2; and 5 R1 2 is C1 -C 6 -alkyl; or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention is a compound according to formula (1): where R1 is the group -XYZ; X is phenyl or heteroaryl; 10 Y is a bond or C1 -C6 alkylene; Z is -NR4R5 or heterocycloalkyl, where said heterocycloalkyl is optionally substituted with one or two substituents each independently selected from the following: 1) C1-C 6 -alkyl optionally substituted by one OR4 group, 15 2) C 3
-C
7 -cycloakyl, 3) methoxy, 4) hydroxy, and 5) heteroaryl; 20 R2 is H; R3 is H; R4 is selected from 25 1) H and 2) C1-C 6 -alkyl, where said C1 -C 6 -alkyl is optionally substituted with one hydroxy or one methoxy group; 30 R5 is selected from 1) H, 2) C1 -C 6 -alkoxy, 3) C 3
-C
7 -cycloalkyl, 4) C1 -C 6 -alkyl, 18 WO 2007/005534 PCT/US2006/025402 5) -SO 2 R10, and 6) -C(O)R1O, where said C 3
-C
7 -cycloalkyl and C1 -C 6 -alkyl are optionally substituted with one to three substituents selected from R6; 5 each R6 is independently selected from 1) NR7R8, 2) S0 2 R7, 3) OH, 10 4) methoxy, 5) heteroaryl, 6) C 3
-C
7 -cycloalkyl, 7) phenyl, 8) heterocycloalkyl, and 15 9) halo, where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally substituted with one to two substituents selected from R9; R7 is selected from 20 1) Hand 2) C1 -C 3 -alkyl; R8 is selected from 1) H and 25 2) C 1
-C
3 -alkyl; each R9 is independently selected from 1) hydroxy, 2) nitro, 30 3) C 1
-C
6 -alkyl, 4)
NH
2 , 5) halo, 6)
CF
3 , 7) C1 -C 6 -alkoxy, and 19 WO 2007/005534 PCT/US2006/025402 8) CN; R1 0 is selected from 1) H, 5 2) C1 -C 6 -alkyl, 3) phenyl, 4) C 3
-C
7 -cycloalkyl, and 5) heteroaryl, where said C1 -C 6 -alkyl is optionally substituted with one or two substituents each 10 independently selected from C 3
-C
7 -cycloalkyl and -S-R7; where said heterocycloalkyl is optionally substituted with one -C(O)R7 group; and where said phenyl and heteroaryl are optionally substituted with one to two substituents selected from R1 1; each R11 is independently selected from 15 1) H, 2) C 1
-C
6 -alkyl, and 3) halo; U is a bond; 20 V is a 5-7 membered heterocycloalkyl substituted by -S(O)mR1 2; m is 1 or 2; and R1 2 is C1 -C 6 -alkyl; or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention is a compound of formula (1) where: 25 where R1 is the group -XYZ; X is 2- or 3- thiophenyl; Y is a bond or C1 -C4 alkylene; Z is -NR4R5 or heterocycloalkyl, 1) C1 -C 6 -alkyl optionally substituted by one OR4 or one heterocycloalkyl 30 group, 2) C 3
-C
7 -cycloalkyl, 3) methoxy, 4) -CONH 2 , 5) hydroxy, 20 WO 2007/005534 PCT/US2006/025402 6) heteroaryl; 7)
CF
3 , 8) phenyl, 9) heterocycloalkyl, and 5 10) N(CH 3
)
2 ; R2 is H; R3 is H; 10 R4 is selected from 1) H and 2) C 1
-C
6 -alkyl, where said C1-C 6 -alkyl is optionally substituted with one hydroxy or one methoxy group; 15 R5 is selected from 1) C 3
-C
7 -cycloalkyl, 2) C 1
-C
6 -alkyl, where said C 3
-C
7 -cycloalkyl and C1 -C 6 -alkyl are optionally substituted with one 20 to three substituents selected from R6; each R6 is independently selected from 1) -NR7R8, 2) -CONH 2 , 25 3) -CN, 4) -OCH 2
CH
2 OR7, 5) C3-C4 alkenyl, 6) OH, 7) C1 -C 6 -alkoxy, 30 8) heteroaryl, 9) C 3
-C
7 -cycloalkyl, 10) phenyl, 11) heterocycloalkyl, and 12) halo, 21 WO 2007/005534 PCT/US2006/025402 where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally substituted with one to two substituents selected from R9; R7 is selected from 5 1) H, 2) C 1
-C
3 -alkyl, and 3) phenyl; R8 is selected from 10 1) H, 2) C 1
-C
3 -alkyl, and 3) -C(O)R4; each R9 is independently selected from 15 1) C1-C 6 -alkyl; U is a bond; V is 4-piperidinyl substituted by -S(O) 2 R1 2; and R1 2 is ethyl or isopropyl; or a pharmaceutically acceptable salt thereof. 20 Another embodiment of the present invention is a compound according to formula (1) 0 11 N\\ R12 where the group U-V is R12and R12 is ethyl or isopropyl. Another embodiment of the present invention is a compound of formula (11) O S R13 )n N N H H2N O 25 where R13 is -NR14R15 or heterocycloalkyl 22 WO 2007/005534 PCT/US2006/025402 where said heterocycloalkyl is optionally substituted with one or two substituents selected from the following: 1) C1 -C 6 -alkyl optionally substituted by one OR1 4 group, 2) hydroxy, 5 3) methoxy, and 4) heteroaryl; R1 4 is selected from 1) H and 10 2) C 1
-C
6 -alkyl, where said C1 -C 6 -alkyl is optionally substituted with one hydroxyl or one methoxy group; R1 5 is selected from 15 1) H, 2) methoxy, 3) C3-C7 cycloalkyl, and 4) C1-C 6 -alkyl, where said C 3
-C
7 cycloalkyl and C1 -C 6 -alkyl are optionally substituted with one to 20 three substituents selected from R1 6; each R1 6 is independently selected from 1) -NR17R18, 2) -S0 2 R17, 25 3) OH, 4) methoxy 5) heteroaryl, 6) C 3
-C
7 cycloalkyl, 7) phenyl, and 30 8) heterocycloalkyl, where said heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally substituted with one to three substituents selected from R1 9; 23 WO 2007/005534 PCT/US2006/025402 R17 is selected from 1) H and 2) C1 -C 3 -alkyl; 5 R1 8 is selected from 1) H and 2) C1 -C 3 -alkyl; R1 9 is selected from 10 1) hydroxy, 2) nitro, 3) C1 -C 6 -alkyl, 4) NH 2 , 5) halo, 15 6) CF 3 , and 7) C1 -C 6 -alkoxy; and n is 1 to 3; or a pharmaceutically acceptable salt thereof. 20 Specific examples of compounds of the present invention include the following: 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(1 -piperidinylmethyl)phenyl]-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(1 -piperazinylmethyl)phenyl]-1 H-indole-7 carboxamide; 25 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinymethyl)phenyl]-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-({methyl[2-(methylsulfonyl)ethy]amino} methyl)phenyl]-1 H-indole-7-carboxamide; 5-(3-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}phenyl)-3-[1 -(ethylsulfonyl)-4 30 piperidinyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-[(4-{2-[(2-hydroxyethyl)oxy]ethyl}-1 piperazinyl)methyl]phenyl}-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[3-(hydroxymethyl)-1 -piperidinyl]methyl} phenyl) 1 H-indole-7-carboxamide; 24 WO 2007/005534 PCT/US2006/025402 5-[3-(f{bis[2-(methyloxy)ethyl]amino~methyl)phenyl]-3-[1 -(ethysulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 5-{3-[(2,6-dimethyl-4-morpholiny)methyl]phenyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 5 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-[2-(1 ,3-thiazol-2-yl)-1 -pyrrolidinyl] methyllphenyl) 1 H-indole-7-carboxamide; 34[1 -(ethylsulfonyl)-4-piperidiny]-5-(3-{[2-(2-thienyl)-1 -pyrrolidinyl]methy} phenyl)-1 H indole-7-carboxamide; 3-[1 -(ethylsu If onyl)-4-pi pe ridinyl]-5-(3-{[(2-hyd roxy-2-p henyl ethyl) (methyl) 10 amino]methyllphenyl)-1 H-indole-7-oarboxamide; 5-(3-{[ethyl(methyl)amino]methyllphenyl)-3-[1 -(ethylsuifonyl)-4-piperidinyl]-1 H-indoie-7 carboxamide; 5-[3-(aminomethyl)phenyl]-3-[1 -(ethylsulfonyi)-4-piperidiny]-1 H-indole-7-carboxamide; 5-{3-[(cyclopentylamino)methy]phenyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 15 carboxamide; 5-[3-({[(3,4-dihydroxypheny)methyl]aminolmethyl)phenyl]-3-[1 -(ethylsulfonyi)-4 piperidinyl]-1 H-indole-7-oarboxamide; 3-[1 -(ethyisulfonyi)-4-piperidinylj-5-(3-{[(2-thienyimethyl)amino] methyl~phenyl)-1 H-indole 7-carboxamide; 20 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-(hydroxymethyl)-3 methylbutyl]aminolmethyl)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethyisu Ifonyl)-4-p iperid inyl] -5- (3-{[(2-hyd roxy- 1 -methyl ethyl) amino]methyllphenyl) 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyi]-5-(3-{[(trans-4-hydroxycyclohexyl) amino] methyllphenyl) 25 1 H-indoie-7-carboxamide; 3-[1 -(ethyisulfonyl)-4-piperidinyl]-5-{3-[([1 -(1 -piperidinyl)cyolohexyl] methyllamino)methyl]phenyl}-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-hydroxypropyl]amino} methyl)phenyl]-l1H indole-7-carboxamide; 30 5-{3-[(ethylamino)methy]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyi)-4-piperidiny]-5-{3-[(propyiamino)methylphenyl-1 H-indole-7 carboxamide; 3-41 -(ethylsulf onyl) -4-p iperidi nyl]-5-(3-{[(1 -methyl ethyl) am ino] methyllpheny)-1 H-indole-7 35 carboxamide; 25 WO 2007/005534 PCT/US2006/025402 5-(3-{[(l -ethyl propyl)amni no] methyllp henyl) -3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidiny]-5-[3-(1 -piperidinylmethyl)phenyl]-1 H-indole-7 carboxamide; 5 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(1 -piperidinyimethyl)phenyl]-l H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylamino)methyl]phenyl-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyll-1 H-indole-7 10 carboxamide; 5-[4-(aminomethyl)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl-1 H-indole-7 carboxamide; 5-{3-[(cyolopropylamino) methyl]phenyl}-3-[l -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 15 carboxamide; 5-{3-[(cyclobutylamino)methyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl-1 H-indole-7 carboxamide; 3-(1 -{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-[4-(1 -pipe ridinyl methyl) phenyl] 1 H-indole-7-carboxamide; 20 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-[(2-methylpropyl)amino]-2,3-dihydro-l H-inden-5-y} 1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{8-[(2-methylpropyl)amino]-5,6,7,8-tetrahydro-2 naphthalenyl}-l H-indole-7-carboxamide; 5-(5-{[(2-cyanoethyl)amino]methyl}-2-fluorophenyl)-3-[l -(ethylsulfonyl)-4-piperidinyl]- 1 H 25 indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(2-f luoro-5-{[(2,2,2-trif luoroethyl)amino]methyllphenyl) 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(l ,2,3,4-tetrahydro-7-isoquinolinyl)-l H-indole-7 carboxamide; 30 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2,2,2-trif luoroethyl)amino]methyllphenyl)-l H indole-7-carboxamide; 5-(3-{[(2-amino-2-oxoethyl)(methyl)aminolmethyllphenyl)-3-I1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2,2,2-trifluoroethyl)amino]methyl-1 ,3-thiazol-4 35 yI)-l H-indole-7-carboxamide; 26 WO 2007/005534 PCT/US2006/025402 5-(3-cyano-5-{[(2,2 ,2-trifluoroethyl)amino]methylphenyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]l1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfony)-4-piperidiny]-5-(5-{[Methyl (1 -methyl-4-piperidinyl)amino] methyl}-3 thienyl)-1 H-indole-7-carboxamide; 5 5-(5-{[(2-oyanoethyl)(methyl)amino]methyl}-3-thieny)-3-[1 -(ethyisu lfonyl)-4-pipe rid inyl] 1 H-indole-7-carboxamide; 5-(5-{[(2-amino-2-oxoethy) (methyl)amino] methyl}-3-thieny)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(phenylsulfonyl)ethyl]aminolmethyl)-3 10 thieny]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1 -pyrrolidinyl)methyl]-3-thienyl}-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-[2-(1 -piperidinylmethyl)-1 -pyrrolidinyl]methyl}-3 thienyl)-1 H-indole-7-carboxamide; 15 5-(5-{[(2 R)-2-(aminocarbonyi)- 1 -pyrroiidinyl]methy}-3-thienyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]l- H-indole-7-carboxamide; 5-(5-{[(2S)-2-(dimethylamino)-1 -pyrrolidinyl]methyl}-3-thienyl)-3-[1 -(ethyisulfonyl)-4 piperidinylj-1 H-indole-7-carboxamide; 5-(1 -{2-[4-(dimethylamino)-1 -pi perid inyl] ethyl)- 1 H-pyrazol-4-y)-3-[1 -(ethylsulfonyl)-4 20 piperidinylj-1 H-indole-7-oarboxamide; 5-[3-[(dimethylamino)methyl]-4,5-bis(methyoxy)phenyl]-3-[1 -(ethylsulfonyi)-4 piperidinyl]-1 H-indole-7-carboxamide; 5-[3,4-bis(methyloxy)-5-(4-morpholinylmethyl)phenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-oarboxamide; 25 3-[1 -(ethylsu lfonyl)-4-pipe rid inyl] -5-[3-f[( 1 -methyl ethyl) ami no] methyl}-4,5 bis(methyloxy)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfony)-4-piperidinyl]-5-[3-{[(1 -methylethyl)amino]methyl}-4,5 bis(methyloxy)phenyl]-1 H-indole-7-carboxamide; 5-[3-{[(2,2-dimethylpropyl)amino]methyl}-4,5-bis(methyloxy)phenyl]-3-[1 30 (ethyisuifonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyi)-4-piperidinyl]-5-[3-{[(2-hydroxyethyl)(methyl)amino]methyl}-4,5 bis(methyloxy)phenyl]-1 H-indoie-7-carboxamide; 5-[3,4-bis(methyloxy)-5-(1 -pyrroiidinylmethyl)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-carboxamide; 27 WO 2007/005534 PCT/US2006/025402 5-{4-[(dimethylamino)methyil-2,3-dihydro-1 -benzofu ran-6-y}-3-[1 -(ethylsulfonyl)-4 piperidinyl]l- 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-oarboxamide; 5 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)-2,3-dihydro-1 benzofuran-6-yJ-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-({[1 -methyl-2-(methyloxy)ethyllaminolmethyl)-2 thienyl]l H-indole-7-carboxamide; 5-(5-{[(2-cyanoethyl)amino]methyl-3-pyridinyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 10 indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2,2,2-trif luoroethyl)amino]methyl-3-pyridinyl) 1 H-indole-7-carboxamide; 5-{3-[(dimethylamino)methyllphenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyll-1 H-indole-7 carboxamide; 15 5-(5-{[ethyl(methyl)amino] methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 5-(5-{[[2-(diethylamino)ethyl](methyl)amino]methyl-3-thienyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-oarboxamide; 5-(5-{[butyl(methyl)amino] methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 20 indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(propyl)amino]methyl-3-thienyl)- 1 H indole-7-carboxamide; 5-(5-{[[2-(dimethylamino) ethyl] (methyl)amino] methyl}-3-th ienyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]l- H-indole-7-oarboxamide; 25 5- (5-{[[3-(dimethylamino) propyl] (methyl) amino] methyl-3-th ienyl)-3-[1 -(ethylsulfonyl) 4-piperidinyl]-1 H-indole-7-oarboxamide; 5-(5-{[oyclopentyl(methyl)amino]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyll 1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(pentyl)aminomethyl-3-thienyl)-1 H 30 indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-methylpropyl)amino]methy}-3 thienyl)-1 H-indole-7-carboxamide; 34[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(phenylmethyl)amino]methyl}-3-thienyl) 1 H-indole-7-oarboxamide; 28 WO 2007/005534 PCT/US2006/025402 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-hydroxyethyl) (methyl)amino]methyl}-3 thienyl)-1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyi[2-(2-pyridinyl)ethyl]aminolmethyl)-3 thienyl]-1 H-indole-7-oarboxamide; 5 3-[l -(ethylsuif onyl)-4-piperidinyl]-5-(5-{[(2-f uranylmethyl) (methyl)amino]methyl}-3 thienyl)-l H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(4-pyridinylmethy)amino] methyl}-3 thienyl)-l H-indole-7-carboxamide; ; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methyl{[1 -(1 -methylethyl)-3 10 pyrrolidinyl]methyllamino)methyl]-3-thienyl-1 H-indole-7-carboxamide;; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-thienylmethyl)amino] methyl}-3 thienyl)-1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[1 -(2-thienyi)ethyl]aminolmethyl)-3 thienyl]-l H-indole-7-oarboxamide; 15 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(3-thienylmethyl)amino]methyl}-3 thienyl)-1 H-indole-7-oarboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyll-5-(5-{[methyl(tetrahydro-2H-pyran-4 ylmethyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; trifluoroacetate 3-[l -(ethylsulfonyl)-4-piperidinylj-5-(5-{[methyl(3-pyridinylmethyl)amino]methyl}-3 20 thienyl)-1 H-indole-7-carboxamide; trifluoroacetate 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(4-pyrimidinylmethyl)amino]methyl-3 thienyl)-1 H-indole-7-oarboxamide; 3-[l -(ethylsulf onyl) -4-piperid inyl] -5-[5-({methyl [2-(methyloxy)ethyl] amino) methyl)-3 thienyl]-l H-indole-7-carboxamide; 25 5-{3-[(dimethylamino)methyl]phenyl-3-1 -(ethylsulfonyl)-4-piperidinyl]-l H-indole-7 carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl (1 -methylethyl)amino] methyl}-3-thienyl) 1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-pi pe rid inyl]-5-{5-[(2-propyl- 1 -pyrrolidinyl)methyll-3-thienyll-1 H 30 indole-7-carboxamide; 3-[l -(ethylsulfonyl) -4-pi pe rid inyl]-5-(5-[2-(3-pyridi nyl)- 1 -pyrrolidinyl] methyi}-3-thienyl) 1 H-indole-7-carboxamide; 5-(5-{[2-(1 ,1 -dimethylethyl)-l -pyrrolidinyl]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-l H-indoie-7-oarboxamide; 29 WO 2007/005534 PCT/US2006/025402 5-{5-[(2-ethyl-1 -pyrrolidinyl)methyl]-3-thienyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]l- H indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1 -pyrrolidinyl]methyl}-3 thienyl)-1 H-indole-7-carboxamide; 5 3-[l .- (ethylsuifonyl)-4-piperidinyl]-5-(5-{[2-( 1 -methylethyl)- 1 -pyrrolidinyl] methyl}-3 thienyl)-1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyi)-4-piperidinyl]-5-[5-({(2S)-2-[(methyloxy)methyl]-l pyrrolidinyllmethyl)-3-thienyl]l- H-indole-7-oarboxamide; 5-(5-{[cyclohexyi(methyl)amino]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl] 10 1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1 -pyrrolidinyl]methyl}-3 thienyl)-1 H-indole-7-carboxamide; 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 15 3-[l -(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)aminomethyl-3 thienyl)-1 H-indole-7-carboxamide; 5-(5-{[ethyl(methyl)aminolmethyll-3-thienyl)-3-{1 -[(1 -methylethyl)sulfonyl]-4 20 piperidinyl}-1 H-indole-7-carboxamide; 3-{l -[(1 -methylethyl)sulfonyl]-4-piperidinyl}-5-[5-({methyl[2 (methyloxy)ethyl]aminolmethyl)-3-thienyl]-1 H-indole-7-oarboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-2-thienyl-1 H-indole-7 carboxamide; 25 3-[l -(ethylsulIfonyl)-4-pipe rid inyl]-5-{5-[(2-methyl- 1 -pyrrolidinyl) methyl]-3-thienyl}-1 H indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropy)amino] methyl}-3-thienyl)-1 H indole-7-carboxamide; 3-fl -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(propylamino)methyl]-3-thienyl-1 H-indole-7 30 carboxamide; 5-{5-[(diethylamino)methyll-3-thienyll-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 5-(5-{[(2R,5R)-2,5-dimethyl-1 -pyrrolidinyl]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 30 WO 2007/005534 PCT/US2006/025402 5-{5-[(cyclopropylamino)methyl]-3-thienyl-3-[1 -(ethylsulfonyl)-4-piperidiny]-1 H-indole 7-carboxamide; 5-{5-[(oyclobutylamino) methyll-3-thienyll-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole 7-carboxamide; 5 5-{5-[(dimethylamino)methyl-3-thienyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 5-(5-{[(cyclopentylmethyl)aminolmethyll-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-carboxamide; 5-[5-({[(l R)-1 ,2-dimethylpropyl]aminolmethyl)-3-thienyl]-3-[1 -(ethylsulfonyl)-4 10 piperidinyl]-1 H-indole-7-oarboxamide; 5-{5-[(cyclopentylamino)methyl]-3-thienyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole 7-carboxamide; 5-(5-{[(cyolopropylmethyl)amino]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidiny] 1 H-indole-7-carboxamide; 15 5-[5-({[(l S)-1 ,2-dimethylpropyl]amino}methyl)-3-thienyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5-(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)-1 H 20 indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2S)-tetrahydro-2 fu ranylmethyl~aminolmethyl)-3-thienyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(tetrahydro-2H-pyran-4 ylmethyl)amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide; 25 5-{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]aminolmethyl)-3-thienyl-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2S)-2-[(methyloxy) methyl]- 1 30 pyrrolidinyilmethyl)-3-thienyl]-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2R)-2-[(methyloxy)methyl]-1 pyrrolidinyilmethyl)-3-thienyl]-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulIfonyl)-4-pi peridi nyl]-5-{4-[2-(methylami no) ethyl] ph enyl- 1 H-indole-7 carboxamide; 31 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(propylamino)ethyl]phenyl}-1 H-indole-7 carboxamide; 5-{4-[2-(ethylamino)ethyl]phenyl}-3-[l -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 5 5-{4-[({[l -(1,1 -dimethylethyl)-3-methyl-1 H-pyrazol-5-yllcarbonyl}amino)methyl]phenyl} 3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(4-pyridinylcarbonyl)amino]methyl}phenyl)-1 H indole-7-carboxamide; 5-(4-{[(cyclopentylcarbonyl)amino]methyl}phenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl] 10 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-furanylcarbonyl)amino]methyl}phenyl)-1 H indole-7-carboxamide; 5-{4-[2-(acetylamino)ethyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 15 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)-1 H indole-7-carboxamide; 5-(4-{2-[(cyclobutylcarbonyl)amino]ethyl}phenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 5-(4-{2-[(cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 20 indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{2-[(methylsulfonyl)aminolethyl}phenyl)-1 H indole-7-carboxamide; 5-(3-{2-[(cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 25 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[6-(1 -piperazinyl)-3-pyridinyl]-l H-indole-7 carboxamide trifluoroacetate; 5-[6-(4-ethyl-1 -piperazinyl)-3-pyridinyl]-3-[l -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(1 -piperidinylmethyl) phenyl]-l H-indole-7 30 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(1 -piperidinylmethyl)phenyl]-l H-indole-7 carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]phenyl}-1 H-indole-7 carboxamide; 32 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(1 -methyl ethyl) am ino] methyl )ph enyl)- 1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyll-5-{4-[(propylamino)methyllphenyl}-1 H-indole-7 carboxamide; 5 5-(4-{[(l -ethylpropyl)amino]methyllphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl-1 H indole-7-oarboxamide; 5-{4-[(cyclopentylamino)methyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 5-{4-[(cyolobutylamino) methyljphenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]- 1 H-indole-7 10 carboxamide; 5-{4-[(ethylamino)methyllphenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 5-{4-[(dimethylamino)methyllphenyll-3-[1 -(ethylsulfonyl)-4-piperidinyll-1 H-indole-7 carboxamide; 15 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)pheny]-1 H-indole-7 20 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-({[( 1 S)-2-hydroxy- 1 methylethyl]aminolmethyl)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulf onyl)-4-piperidinyl]-5-[4-({[(1 R)-2-hydroxy-1 methylethyl]amino~methyl)phenyl]-1 H-indole-7-carboxamide; 25 3-[1 -(ethylsulfonyl)-4-piperidinyll-5-[4-({[(2R)-2-hydroxypropyl]aminolmethyl)phenyl] 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-({[2-hydroxy-1 (hyd roxymethyl)ethyl] am inolm ethyl) phenyl]- 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1 -methylbutyl)amino]methyl~phenyl)-1 H 30 indole-7-carboxamide; 3-[1 -(ethylsulf onyl)-4-piperidinyl]-5-[3-({[(1 R)-1 -methyl propyl] am ino) methyl) phenyl] 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]methyllphenyl)-1 H indole-7-carboxamide; 33 WO 2007/005534 PCT/US2006/025402 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1 S)-1 -methylpropyl]aminolmethyl)phenyll 1 H-indole-7-carboxamide; 5-{4-[(acetylamino)methyl]phenyl}-3-[1 -(ethylsu lfonyl)-4-pipe rid inyl]- 1 H-indole-7 carboxamide; 5 3-[1 -(ethylsulfonyl)-4-piperidinyll-5-{4-I(propanoylamino)methyllphenyll-1 H-indole-7 carboxamide; 5-(4-{[(oyolopropylcarbonyl)amino]methyllphenyl)-3-[1 -(ethylsulIfonyl) -4-pipe rid inyl] 1 H-indole-7-carboxamide; 5-(4-{[(cyclobutylcarbonyl)amino]methyllphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 10 indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-thienylaoetyl)amino]methyllphenyl)-l H indole-7-carboxamide; 5-[4-({[(l1 S)-1 ,2-dimethylpropyi]aminolmethyl)phenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-oarboxamide; 15 5-{4-[(butanoylamino)methyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-methylpropanoyl)amino]methyllphenyl)-1 H indole-7-carboxamide 3-[l -(ethylsulfonyl)-4-piperidinyll-5-(4-{[(3-methylbutanoyl)amino]methyllphenyl)-1 H 20 indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methylsulfonyl)amino]methylphenyl)- H indole-7-carboxamide; 5-[3-({[(l R)- 1,2-di methyip ropy[] am inolmethyl) phenyll-3-[1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide; 25 5-(4-{[(ethylsulfonyl)amino]methyllphenyl)-3-[1 -(ethylsuifonyl)-4-piperidinyl]-1 H-indole 7-carboxamide; 5-(4-{[(butylsulfonyl)amino]methyllphenyl)-3-[1 -(ethylsulf onyl)-4-piperidinyl]-1 H-indoie 7-carboxamide; 3-[l -(ethylsufonyl)-4-piperidinyl]-5-[4-({[(1 -methylethyi)sulfonyl]amino~methyl)phenyl] 30 1 H-indole-7-carboxamide; 5-(6-amino-2-pyridinyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[3-(1 H-pyrazol-1 -yl)phenyl]-1 H-indole-7 carboxamide; 5-[4-(dimethylamino)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidiny]-1 H-indole-7 35 carboxamide; 34 WO 2007/005534 PCT/US2006/025402 5-(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}-1 H indole-7-carboxamide; 5-{5-[(ethylamino)methyl]-2-thienyl}-3-1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 5 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidiny]-5-(5-{[(1 -methylethyl)amino]methyl}-2-thienyl)-1 H indole-7-carboxamide; 5-{5-[(cyclopropylamino)methyl]-2-thienyl}-3-1 -(ethylsulfonyl)-4-piperidiny]-1 H-indole 7-carboxamide; 10 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-carboxamide; 5-(5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)-3-1 -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-carboxamide; 5-(5-{[(cyclopropylmethy)amino]methyl}-3-pyridinyl)-3-1 -(ethylsulfonyl)-4-piperidinyl] 15 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethy]amino}methyl)-3-pyridinyl] 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(methyloxy)propyl]amino}methyl)-3 pyridinyl]-1 H-indole-7-carboxamide; 20 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinylmethyl)-3-pyridiny]-1 H-indole-7 carboxamide; 5-{5-[(ethylamino)methyl]-3-pyridinyl}-3-1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 5-{5-[(dimethylamino)methyl]-3-pyridinyl}-3-[1 -(ethylsulfonyl)-4-piperidiny]-1 H-indole 25 7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1 -pyrrolidinyl)methyl]-3-pyridinyl}-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-pyridinyl)-1 H indole-7-carboxamide; 30 5-(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 indole-7-carboxamide; 5-[5-({[(1 R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]-3-[1 -(ethylsulfonyl)-4 35 piperidinyl]-1 H-indole-7-carboxamide; 35 WO 2007/005534 PCT/US2006/025402 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(pentylamino)methyl]-2-thienyl}-1 H-indole-7 carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2S)-2-methybutyl]amino}methyl)-2-thienyl] 1 H-indole-7-carboxamide; 5 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1 -methylbutyl)amino]methyl}-2-thienyl)-1 H indole-7-carboxamide; 5-{5-[(butylamino)methyl]-2-thienyl}-3-[l -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl] 10 1 H-indole-7-carboxamide; 5-{5-[(cyclopentylamino)methyl]-2-thienyll-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole 7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(3-methylbutyl)amino]methyl}-2-thienyl)-1 H indole-7-carboxamide; 15 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1 -methylethyl)amino]methyl}-3-pyridinyl)-l H indole-7-carboxamide; 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[l -(ethylsulfonyl)-4-piperidinyl]-l H indole-7-carboxamide; 5-[5-({[3-(ethyloxy)propyl]amino}methyl)-2-thienyl]-3-[l -(ethylsulfonyl)-4-piperidinyl] 20 1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(methyloxy)propyl]amino}methyl)-2-thieny] 1 H-indole-7-carboxamide; 5-(5-{[(cyclohexylmethyl)amino] methyl}-2-thienyl)-3-[l -(ethylsulfonyl)-4-piperdinyl] 1 H-indole-7-carboxamide; 25 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-{5-[({3-[(l -methylethyl)oxy]propyl}amino)methyl]-2 thienyl}-1 H-indole-7-carboxamide; 5-[5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]-3-[l -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(propyloxy)propyl]amino}methyl)-2-thienyl] 30 1 H-indole-7-carboxamide; 5-(5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(l S)-1,2,2-trimethylpropyl]amino}methyl)-2 thienyl]-l H-indole-7-carboxamide; 36 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(hexylamino)methyl]-2-thienyl-1 H-indoie-7 carboxamide; 3-[1 -(ethylsuifonyl)-4-piperidinyi]-5-{4-[(methylsulfony)amino]phenyl-1 H-indole-7 carboxamide; 5 5-[2-(dimethylamino)-4-pyridinyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indoie-7 carboxamide; 3-[1 -(ethylsu lfonyl)-4-pi pe rid inyl]-5-[2-(1 -pyrrolidinyi)-4-pyridinyl]-l H-indoie-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morphoinyl)-4-pyridinyl]-1 H-indole-7 10 carboxamide; 3-[1 -(ethylsuifonyl)-4-piperidinyl]-5-{2-[(2-methylpropyl)amino]-4-pyridinyl-1 H-indole 7-carboxamide; 5-{2-[(2,2-dimethyipropyl)amino]-4-pyridinyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 15 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 carboxamide; 3-[1 -(ethylsuifonyl)-4-piperidinyl]-5-[4-(1 -pyrrolidinylmethyi)-2-thieny]-1 H-indole-7 20 carboxamide; 3-[1 -(ethylsulfonyi)-4-piperidinyl]-5-(4-{[(2-methylpropyl)amino] methyi}-2-thienyl)- 1 H indole-7-carboxamide; 5-{4-[(dimethyiamino)methyl]-2-thienyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indoie-7 carboxamide; 25 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(1 S)-1 -(1 -pyrroi id inyl) ethyl] -3-th ienyl1- 1 H indole-7-carboxamide; 3-[1 -(ethyisulfonyl)-4-piperidinyl]-5-{5-[(1 R)-1 -(1 -pyrrol id inyl) ethyl] -3-th ieny}- 1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidiny]-5-[4-({ [3-(methyloxy)propyl]aminolmethyl)-2-thienyl] 30 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-({(2S)-2-[(methyloxy)methyl]-1 pyrrolidinyl~methyl)-2-thieny]-1 H-indoie-7-carboxamide; 5-(4-{[(2R,5R)-2,5-dimethyl-1 -pyrrolidinyi]methyl}-2-thienyl)-3-[1 -(ethylsulfonyl)-4 piperidiny]-1 H-indole-7-carboxamide; 37 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-methyl-1 -pyrrolidinyl]methyl}-3-thienyl) 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2R)-2-methyl-1 -pyrrolidinyl]methyl}-3-thienyl) 1 H-indole-7-carboxamide; 5 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{5-[1 -(1 -pyrrolidinyl)propyl]-3-thienyl}-1 H-indole-7 carboxamide; 5-{5-[(dimethylamino)methyl]-3-thienyl}-3-{1 -[(1 -methylethyl)sulfonyl]-4-piperidinyll 1 H-indole-7-carboxamide; 5-[5-(aminomethyl)-3-thienyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 10 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{2-[(2-methylpropy)amino]ethyl}-3-thienyl)-1 H indole-7-carboxamide; 5-{5-[2-(dimethylamino)ethyl]-3-thienyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 15 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[6-(1 -pyrrolidinyl)-3-pyridinyl]-1 H-indole-7 carboxamide; 5-{6-[ethyl(methyl)amino]-3-pyridinyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 5-[6-(dimethylamino)-3-pyridinyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 20 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[6-(propylamino)-3-pyridinyl]-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{6-[(1 -methylethyl)amino]-3-pyridinyl}-1 H-indole-7 carboxamide; 25 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 30 indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-(1 -pyrrolidinylmethyl)-3-thienyl]-1 H-indole-7 carboxamide; 5-{5-[(ethylamino)methyl]-3-thienyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 38 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsuif onyl)-4-piperidinyl]-5-[5-({[( 1 R)-2-hyd roxy-1 -methylethyl]aminolmethyl) 3-thienyl]l H-indole-7-carboxamide; 341l -(ethylsulfonyl)-4-piperidinyl]-5-[5-(1 -piperidinylmethyl)-3-thienyl]-l H-indole-7 carboxamide; 5 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinylmethyl)-3-thienyl]-1 H-indole-7 carboxamide; 3-[l -(ethylsulf onyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3furanyl-1 H-indole-7 carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-{5-[1 -(1 -pyrrolidinyl)ethyll-3-thienyl}-1 H-indole-7 10 carboxamide; 3-[l -(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; 15 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(propylamino)methyl]-2-thienyl-l H-indole-7 carboxamide; 5-{5-[(diethylamino)methyl]-2-thienyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 341l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)aminolmethyl-2-thieny)-l H 20 indole-7-carboxamide; 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino] methyl}-3-furanyl)-1 H indole-7-carboxamide; 25 5-(5-{[(cyclopentylmethyl)amino]methyl}-3-furanyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[5-(l -pyrrolidinylmethyl)-3-furanyl]-1 H-indole-7 carboxamide; 5-{5-[(diethylamino)methyl]-3-fu ranyi}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 30 carboxamide; 3-[l -(ethylsulf onyl)-4-piperidinyl]-5-[5-(1 -pyrrolidinylmethyl)-1 ,3-thiazol-2-yI]-1 H-indole 7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-{5-[2-methyl-1 -(1 -pyrrolidinyl)propyl]-3-thienyl}-l H indole-7-carboxamide; 39 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(1 -pyrrolidinylmethyl)-1 ,3-thiazol-2-y]-1 H-indole 7-carboxamide; 5-{1 -[2-(di methylam ino) ethyl]- 1 H-pyrazol-4-y}-3-[1 -(ethylsulfonyl)-4-piperidinyl-1 H indole-7-carboxamide; 5 3-[1 -(ethylsulf onyl)-4-piperidinyl]-5-{1 -[2-(l -pyrrolidinyl)ethyl]-1 H-pyrazol-4-y}-1 H indole-7-carboxamide; 3-[1 -(ethyisulfonyl)-4-piperidinyl]-5-{1 -[2-(4-morpholinyl) ethyl] -1 H-pyrazol-4-y}-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(1 -{2-[(2-hydroxyethyl)amino]ethyl}-1 H-pyrazol-4 10 yI)-1 H-indole-7-oarboxamide; 5-{1 -[2-(butylami no) ethyl]- 1 H-pyrazol-4-y}-3-[1 -(ethylsulfonyl)-4-piperidinyl-1 H indole-7-carboxamide; 5-{1 -[2-(cyclobutyiami no) ethyl]- 1 H-pyrazol-4-yl}-3-[1 -(ethylsulfonyl)-4-piperidinylj-1 H indole-7-carboxamide; 15 5-[1 -(2-{[2-(diethylamino)ethyl]aminolethyl)-1 H-pyrazol-4-y]-3-[1 -(ethylsulfonyl)-4 piperidiny]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(1 -{2-[( 1 -methylethyl)ami no] ethyl)- 1 H-pyrazol-4-yI) 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinylj-5-(1 -{2-[(2-methyl propyl)am ino] ethyl)- 1 H-pyrazol-4 20 yI)-1 H-indole-7-carboxamide; 5-(1 -{2-[(cyolopentylmethyl)amino]ethyl}-1 H-pyrazol-4-y)-3-[1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(methyloxy)-3-(1 -pyrrolidinylmethyl)phenyl]l- H indole-7-carboxamide; 25 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-carboxamide; 3-[1 -(ethylsulIfonyl)-4-pipe rid inyl]-5-[4-(methyloxy) -3- (4-morp hol inyl methyl) ph enyl] -1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl}-4-piperidinyl]-5-[3-{[(1 -methyl ethyl) am ino] methyl}-4 30 (methyloxy)phenyl]-1 H-indole-7-carboxamide; 3-[l -(ethyisulfonyl)-4-piperidinyll-5-[3-[(methylamino)methyil-4-(methyloxy)phenyl-1 H indole-7-carboxamide; 5-[3-{[(2,2-dimethylpropyl)ami nolmethyl}-4-(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indoie-7-carboxamide; 40 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(1 -{2-[(2-hyd roxyethyl) (methyl) amino] ethyl)- 1 H pyrazol-4-yi)-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{4-fluoro-3-[(methylamino)methyl]pheny1}-1 H indole-7-carboxamide; 5 5-{3,5-bis[(methylamino)methyl]phenyl-3-[1 -(ethylsulfonyl)-4-piperidiny]-1 H-indole-7 carboxamide; 5-{3-[(ethylamino)methy]-4-f luorophenyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole 7-carboxamide; 3-[1 -(ethylsulf onyl)-4-piperidinyl]-5-[4-f Iuoro-3-({[2-hydroxy-1 10 (hydroxymethy)ethyl]aminolmethyl)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-fluoro-3-([(1 S)-2-hydroxy-1 methyl ethyl] am inolmethyl) ph enyl] -1 H-indole-7-carboxamide; 5-{3-[(cyclopropyiamino)methyl]-4-fluorophenyl-3-[1 -(ethylsuifonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 15 5-{3-[(cyclobutylamino)methyl]-4-fluorophenyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(1 -pyrrolidinylmethyl)phenyl]-1 H-indole-7 carboxamide; 5-{3,5-bis[(ethylamino)methyl]phenyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 20 carboxamide; 5-{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; 5-{3-[l -(ethylamino)ethylphenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 25 carboxamide; 5-13-[l -(di methylam ino) ethyl] phenyl}-3-[1 -(ethylsulfonylj-4-piperidinyl-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinylj-5-{3-fluoro-5-[(methylamino)methyl]phenyl-1 H indole-7-carboxamide; 30 5-{3-[(ethylamino)methyl]-5-f luorophenyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole 7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(propylamino)methyl]phenyl}-l H indole-7-carboxamide; 3-[1 -(ethylsuifonyl)-4-piperidinyl]-5-(3-f Iuoro-5-{[(1 -methylethyl)amino]methyllphenyl) 35 1 H-indole-7-carboxamide; 41 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2 methylpropyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 5-{3-[(cyclobutylamino)methyl]-5-fluorophenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 5 5-{3-[(dimethylamino)methyl]-5-fluorophenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1 -pyrrolidinylmethyl)phenyl]-1 H-indole 7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(4-morpholinylmethyl)phenyl]-1 H 10 indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1 -piperidinylmethyl)phenyll-1 H-indole 7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-[1 -(methylamino)ethyl]phenyl}-1 H-indole-7 carboxamide; 15 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{1 -[(1 -methylethyl)amino]ethy}phenyl)-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{1 -[(2-methylpropyl)amino]ethyl}phenyl)-1 H indole-7-carboxamide; 5-{3-[l -(cyclobutylamino)ethyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 20 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-[1 -(1 -pyrrolidinyl)ethyl]phenyl}-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(3-thiomorpholinyl)phenyl]-1 H-indole-7 carboxamide; 25 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-[l -(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[6-(4-morpholinyl)-3-pyridazinyl]-1 H-indole-7 30 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[6-(1 -pyrrolidinyl)-3-pyridazinyl]-l H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{2-[(methylamino)methyl]phenyl}-1 H-indole-7 carboxamide; 42 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-l H indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-methyl-2 furanyl)methyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 5 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2R)-tetrahydro-2 furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-tetrahydro-2 furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 5-(3-{[(2,2-dimethylpropyl)amino]methyl}phenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 10 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; 15 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1 R)-1,2,2 trimethylpropyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2 furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2R)-tetrahydro-2 20 furanylmethyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 5-[3-({[(1 S)-1,2-dimethylpropyl]amino}methyl)-5-fluorophenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5-[3-({[(1 R)-1,2-dimethylpropyl]amino}methyl)-5-fluorophenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 25 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(1 methylpropyl)amino]methyl}phenyl)-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1 S)-1,2,2 trimethylpropyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-2 30 methylbutyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-methylbutyl)amino]methyl}phenyl) 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1 R)-1,2,2 trimethylpropyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 43 WO 2007/005534 PCT/US2006/025402 5-(3-{[(2,2-dimethylpropyl)aminolmethyl}-5-fluorophenyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-l H-indole-7-carboxamide; 5-(3-{[(oyolopropylmethyl)amino]methyl}-5-f luorophenyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5 5-(3-{[(oyolopentylmethyl)amino]methyl}-5-fluorophenyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-l H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-f luoro-5-{[(tetrahydro-2H-pyran-4 ylmethyl)aminojmethyllphenyl)-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyll-5-(3-fluoro-5-{[(2 10 thienylmethyl)amino]methyllphenyl)-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[2 (methyioxy)ethyl]aminolmethyl)phenyl]-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[3 (methyloxy)propyl]aminolmethyl)pheny]-1 H-indole-7-oarboxamide; 15 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2 furanylmethyl)amino]methyllphenyl)-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(3-methylbutyl)amino]methyllphenyl) 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(5-methyl-2 20 furanyl)methyl]aminolmethyl)phenyl]-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]methyllphenyl)-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-pyrrolidinyl)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{2-fiuoro-5-[(methylamino)methylphenyl-1 H 25 indole-7-carboxamide; 3-[1 -(ethylsuifonyl)-4-piperidinyl]-5-{2-f luoro-5-[(propylamino)methyl]phenyl-1 H indole-7-carboxamide; 3-[1 -(ethylsulIfonyl)-4-pi pe rid inyl]-5- (2-fluoro-5-{[(2 methylpropyl)amino]methyllphenyl)-1 H-indole-7-carboxamide; 30 5-(5-{[(2,2-dimethyipropyl)amino]methyl}-2-f luorophenyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5-[5-({[(l S) -1,2-d imethylp ropyilam inolm ethyl) -2-fluoropheny]-3-[l -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-oarboxamide; 5-[5-({[(l R)-1 ,2-dimethylpropyl]aminolmethyl)-2-f luorophenyl]-3-I1 -(ethylsulfonyl)-4 35 piperidinyl]-l H-indole-7-carboxamide; 44 WO 2007/005534 PCT/US2006/025402 5-(5-{[(cyclopropylmethy)amino]methy}-2-fIuropheny)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsu Ifonyl)-4-pipe rid inyl] -5-[2-fluoro-5-(1 -pyrrolidinylmethyl)phenyl]-1 H-indole 7-carboxamide; 5 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-f luoro-5-({[2 (methyloxy)ethyl]aminolmethyl)phenyl]-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-f luoro-5-({[3 10 (methyloxy)propyllaminolmethyl)phenyl]-1 H-indole-7-oarboxamide; 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)aminolethyllphenyl)-1 H indole-7-carboxamide; 15 5-{3-[2-(ethylamino)ethyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-[2-(propylamino)ethylphenyl-1 H-indole-7 carboxamide; 5-{3-[2-(dimethylamino)ethyl]phenyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 20 carboxamide; 5-{3-[2-(dipropylamino)ethyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 carboxamide; 5-[3-({[2-(3,5-dimethyl-1 H-pyrazol-1 -yI)ethyl]aminolmethyl)phenyl]-3-[1 -(ethylsulfonyl) 4-piperidinyl]-1 H-indole-7-carboxamide; 25 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinylmethyl)-1 ,3-thiazol-4-y]-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl-1 ,3-thiazol-4 yI)-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -pyrrolidinylmethyl)-1 ,3-thiazol-4-y]-1 H-indole 30 7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -piperidinylmethyl)-1 ,3-thiazol-4-yl]-1 H-indole 7-carboxamide; 5-{2-[(d im ethylam ino) methyl] -1,3-th iazol-4-y}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 45 WO 2007/005534 PCT/US2006/025402 5-(2-{[ethyl(methyl)amino]methyl}-1 ,3-thiazol-4-yI)-3-[1 -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-carboxamide; 5-(3-cyano-5-{[(2-methylpropyl)amino]methyllphenyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-oarboxamide; 5 5-{3-oyano-5-[(dimethylamino)methyl]phenyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 3-[l -(ethylsulf onyl)-4-piperidinyl]-5-{3-[(methylsulfonyl)aminophenyl-1 H-indole-7 carboxamide; 5-[4-(aoetylamino)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-oarboxamide; 10 5-[3-(acetylamino)phenyl]-3-[1 -(ethylsulfonyi)-4-p ipe rid inyl]-1 H-indole-7-oarboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1 H-indole-7 carboxamide; 5-{3-[(acetylamino) methyl]phenyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]-l H-indole-7 carboxamide; 15 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methylsulfonyl)amino]methyllphenyl)-1 H indole-7-carboxamide; 5-{3-[(butanoylamino)methyl]phenyl-3-[1 -(ethylsulfonyl)-4-piperidinyl]l- H-indole-7 carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4 20 fluorophenyl)oarbonyl]aminolmethyl)phenyl]-1 H-indole-7-carboxamide; 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropanoyl)amino]methyllphenyl)-1 H indole-7-carboxamide; 3-[l -(ethylsuif onyl)-4-piperidinyl]-5-(3-{[(2-furanyloarbonyl)amino] methyllphenyl)-1 H indole-7-carboxamide; 25 5-(3-{[(cyclopentylcarbonyl)amino]methyllphenyl)-3-[l -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-oarboxamide 3-[l -(ethylsulfonyl)-4-p iperidinyl] -5-{3-[(pentanoyl amino) methyl] ph enyl-1 H-indole-7 carboxamide; 5-(3-{[(2-ethylbutanoyl)amino]methyllphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]l- H 30 indole-7-carboxamide; 5-(3-{[(l -benzothien-2-ylcarbonyl)amino]methyl~phenyl)-3-[1 -(ethylsulfonyi)-4 piperidinyl]-1 H-indole-7-carboxamide; 5-[3-({[(1 -acetyi-4-p iperid inyl)carbonyl] amino) methyl) ph enyl] -3-[l -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 46 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsulfonyl)-4-piperidinyl-5-[3-({[(1-methyl-1 H-pyrrol-2 yl)carbonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(3-methyl-2-butenoyl)amino]methyl}phenyl) 1 H-indole-7-carboxamide; 5 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-[(heptanoylamino)methyl]phenyl}-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-[(octanoylamino)methyl]phenyll-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpentanoyl)amino]methyl}phenyl)-1 H 10 indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(3-methylbutanoyl)amino]methyl}phenyl)-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylacetyl)amino]methyl}phenyl)-1 H indole-7-carboxamide; 15 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-[(hexanoylamino)methy]phenyl}-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutanoyl)amino]methyl}phenyl)-1 H indole-7-carboxamide; 5-(3-{[(cyclobutylcarbonyl)amino]methyl}phenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 20 indole-7-carboxamide; 5-(3-{[(cyclopropylcarbonyl)amino]methyllphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl] 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{3-[(propanoylamino)methyl]phenyl}-1 H-indole-7 carboxamide; 25 5-(3-{[(cyclopentylacetyl)amino]methyl}phenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 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}methy)phenyl] 30 1 H-indole-7-carboxamide; 5-(3-{[(cyclopropylsulfonyl)amino]methyl}phenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide; 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 47 WO 2007/005534 PCT/US2006/025402 5-[3-({[(4-bromophenyl)sulfonyl]amino}methyl)phenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5-[3-({[(4-chlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(3 fluorophenyl)sulfonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 5-[3-({[(2-chlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5-[3-({[(2,5-dichloro-3-thienyl)sulfonyl]amino}methyl)phenyl]-3-[1 -(ethylsulfonyl)-4 10 piperidinyl]-1 H-indole-7-carboxamide; 5-[3-({[(2-chloro-6-methylphenyl)sulfonyl]amino}methyl)phenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-fluoro-2 methylphenyl)sulfonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 15 5-[3-({[(1,2-dimethyl-1 H-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)-1 H indole-7-carboxamide; 5-(3-{[(butylsulfonyl)amino]methyl}phenyl)-3-[1 -(ethylsulfonyl)-4-piperidiny]-1 H-indole 20 7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(phenylsulfonyl)amino]methyl}phenyl)-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4 fluorophenyl)sulfonyl]amino}methyl)phenyl]-1 H-indole-7-carboxamide; 25 5-[3-({[(4-bromo-2-ethylphenyl)sulfonyl]aminolmethy)phenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5-(3-{[(1 -benzothien-3-ylsulfonyl)aminolmethyl}phenyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5-{3-[({[4-(1,1 -dimethylethyl)phenylsulfonyl}amino)methy]phenyl}-3-[1 -(ethylsulfonyl) 30 4-piperidinyl]-1 H-indole-7-carboxamide; 5-[3-({[(3,4-difluorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5-(3-{[(ethylsulfonyl)amino]methyl}phenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole 7-carboxamide; 48 WO 2007/005534 PCT/US2006/025402 5-(3-{[(2, 1,3-benzoxadiazol-4-ylsu Ifonyl)amino]methyllphenyl)-3-[1 -(ethylsu Ifonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(tetrahydro-3 furanyloarbonyl)aminolmethyllphenyl)-1 H-indoie-7-carboxamide; 5 5-{4-[(cyolopentylsulfonyl)amino]phenyl}-3-[1 -(ethylsulIfonyl)-4-pipe rid inyl]- 1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-methyl-2-oxo-1 -piperazinyl)phenyl]-1 H indole-7-carboxamide; 5-[6-(4-acetyl-1 -piperazinyl)-3-pyridinyl]-3-[l -(ethylsu Ifonyl)-4-piperidinyll-1 H-indole-7 10 carboxamide; 3-[1 -(ethyisulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)amino]methyllphenyl)-1 H-indole-7 carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)amino]methyllphenyl)-1 H-indole-7 carboxamide; 15 3-[1 -(ethyisulfonyl)-4-piperidinyl-5-(5-{[4-(1 -pyrrolidinyl)-1 -piperidinyl]methyl}-3 thienyl)-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-(trifluoromethyl)-1 -pyrrolidinyllmethyl} 3-thienyl)-1 H-indole-7-carboxamide; 5-(5-{[(2 R)-2-(hydroxymethyl)-1 -pyrrolidinyl]methyl}-3-thieny)-3-1 -[(1 20 methylethyl)sulfonyl]-4-piperidinyl}-1 H-indole-7-carboxamide; 5-(5-{[(3S)-3-hydroxy-1 -pyrrolidinyl] methyl}-3-thienyl)-3-{1 -[(1 -methylethyl)sulfonylj-4 piperidinyl}-1 H-indole-7-carboxamide; 5-(5-{[oyclopentyl(methy)amino]methyl}-3-thienyl)-3-{1 -[(1 -methylethyl)sulfonyl]-4 piperidinyl}-1 H-indole-7-carboxamide; 25 5-(5-{[(2-hydroxyethyl)(methyl)amino]methyl-3-thienyl)-3-{1 -[(1 -methylethyl)sulfonyl] 4-piperidinyl}-1 H-indole-7-carboxamide; 5-(5-{[(2-amino-2-oxoethyl)(methyl)amino]methyl-3-thienyl)-3-{1 -[(1 methylethyl)sulfonyl-4-piperidinyl}-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-propen-1 -yI)amino]methyl}-3-thienyl) 30 1 H-indole-7-carboxamide; 5- (5-{[[(3,5-di methyl -1 H-pyrazol-4-yI)methyl](methyl)aminolmethyll-3-thienyl)-3-[1 (ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-oarboxamide; 5- (5-{[(cyanom ethyl) (methyl)am ino] methyl-3-th ienyl) -3-[1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide; 49 WO 2007/005534 PCT/US2006/025402 3-[1 -(ethylsulfonyl)-4-piperidinyl-5-(5-{[methyl(1 -methylpropyl)amino]methyl}-3 thienyl)-1 H-indole-7-oarboxamide; 5- (5-{[[2-(ethyloxy) ethyl] (methyl)aminolmethyl-3-th ienyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 5 5-(5-{[cyclobutyl(methyl)amino]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl-1 H indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[5-({2-[(methyloxy) methyl]-1 -pyrrolidinyl~methyl)-3 thienyl]-1 H-indole-7-carboxamide; 5-(5-{[(1 ,1 -dimethyl ethyl) (methy)amino] methyl}-3-th ienyl)-3-[1 -(ethylsulfonyl)-4 10 piperidinyl]-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[3-(trifluoromethyl)-1 -piperidinyl]methyl}-3 thienyl)-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[( 1 S)-2-hydroxy-1 methylethyl] (methyl)aminomethyl}-3-thienyl)-1 H-indole-7-carboxamide; 15 5-(5-{[(cyolopropylmethyl)(methyl)amino]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-oarboxamide; 5-(5-{[[2-(aoetylami no) ethyl] (methyl)amino] methyl}-3-th ienyl) -3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulf onyl)-4-piperidinyl-5-(5-{[[( 1 R,2 R)-2 20 hydroxycyclopentyl] (methyl)amino]methyl}-3-thienyl)- 1 H-indole-7-carboxamide; 5-(5-{[(1 ,1 -dimethylpropyl)(methyl)amino]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4 piperidinyl]l- H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(2S)-2-hydroxypropyl] (methyl)amino]methyl} 3-thienyl)-1 H-indole-7-carboxamide; 25 3-[1 -(ethylsu Ifonyl)-4-piperidinyl]-5-[5-({methyl[(2R)-tetrahydro-2 fu ranylmethyl]aminolmethyl)-3-thieny]-1 H-indole-7-oarboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[{2-[(2 hyd roxyethyl)oxy] ethyl) (methyl)amino] methyl}-3-th ienyl)- 1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidi nyl]-5-[5-( 1 -{methyl [2-(methyloxy) ethyl] ami no~ethyl)-3 30 thienyl]-1 H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{1 -[methyI(propyl)amino]ethyl-3-thieny)-1 H indole-7-carboxamide; 3-[1 -(ethylsuif onyl)-4-piperidinyl-5-(5-{[[(1 S)-2-hyd roxy-1 methylethyl](methyl)aminomethyl-3-thienyl)-1 H-indole-7-carboxamide; and 50 WO 2007/005534 PCT/US2006/025402 5-(5-[(1,1 -dioxidotetrahydro-3-thienyl)(methyl)amino]methyl}-3-thienyl)-3-[1 (ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide; or a pharmaceutically acceptable salt thereof. 5 Terms and Definitions "Alkyl" refers to a saturated hydrocarbon chain having the specified number of member atoms. For example, C1-C6 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 defined herein. Alkyl groups may be straight or branched. Representative branched alkyl 10 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 C1-C6 alkylene 15 heteroaryl, C1-C6 alkylene-heterocycloalkyl, C1-C6 alkylene-C 4
-C
7 cycloalkyl, and Ci C6 alkylene-C 5
-C
7 cycloalkenyl groups) refers to a saturated divalent hydrocarbon chain having the specified number of member atoms. For example, C1-C6 alkylene refers to an alkylene group having from 1 to 6 member atoms. Alkylene groups may be optionally substituted with one or more substituents as defined herein. Alkylene groups may be 20 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. 25 "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-C6 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 chain. In other emodiments, alkenyl groups have more than one carbon-carbon double 30 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. 51 WO 2007/005534 PCT/US2006/025402 "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-C6 alkenylene refers to an alkenylene group having from 2 to 6 member atoms. In certain embodiments alkenylene groups have one carbon-carbon 5 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 three branches. Alkenyl includes ethylenylene, propenylene, butenylene, pentenylene, 10 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 chain. For example, C2-C6 alkynylene refers to an alkynylene group having from 2 to 6 15 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 one or more carbon-carbon double bond within the chain are alkynylene groups. 20 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. 25 "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 cycloalkyl or cycloalkenyl ring having 5, 6, or 7 member atoms. Aryl groups may be optionally substituted with one or more substituents as defined herein. 30 "Cycloalkyl" refers to a saturated hydrocarbon ring having the specified number of member atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-C6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms. Cycloalkyl groups may be optionally substituted with one or more substituents as defined herein. 35 Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 52 WO 2007/005534 PCT/US2006/025402 "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, C3-C6 cycloalkenyl refers to a cycloalkenyl group having from 3 to 6 member atoms. In 5 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 with one or more substituents as defined herein. Cycloalkenyl includes cyclopropenyl, 10 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 excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee. 15 "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 enantiomer was enriched such that it constitutes 95% of the product, then the 20 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 greater. 25 "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. 30 "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. 53 WO 2007/005534 PCT/US2006/025402 "Heteroaryl" refers to an aromatic ring containing from 1 to 4 heteroatoms as Member atoms in the ring. Heteroaryl groups containing more than one heteroaton) 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 5 fused, spiro, or bridged bicyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 member atoms. Bicyclic heteroaryl rings have from 7 to 11 member atoms. Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocycloalkyl ring are attached forming a fused, spiro, or bridged bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, 10 heterocycloalkyl, 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, 15 benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, furopyridinyl, and napthyridinyl. "Heteroatom" refers to a nitrogen, sulphur, or oxygen atom. 20 "Heterocycloalkyl" refers to a saturated or unsaturated ring containing from 1 to 4 heteroatoms as member atoms in the ring. However, heterocycloalkyl rings are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Heterocycloalkyl groups are monocyclic ring 25 systems having from 4 to 7 member atoms. In certain embodiments, heterocycloalkyl is saturated. In other embodiments, heterocycloalkyl is unsaturated but not aromatic. Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1,3 30 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 54 WO 2007/005534 PCT/US2006/025402 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, 5 cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted or substituted with one or more substituents as defined herein. "Substituted" in reference 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 10 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 15 herein for each substituted or optionally substituted group. "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, 20 irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 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 25 example, the Journal of the American Chemical Society or the Journal of Biological 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 30 abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); L (liters); mL (milliliters); pL (microliters); psi (pounds per square inch); 35 M (molar); mM (millimolar); 55 WO 2007/005534 PCT/US2006/025402 i. v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles); rt (room temperature); min (minutes); h (hours); 5 mp (melting point); TLC (thin layer chromatography); Tr (retention time); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); 10 DMSO (dimethylsulfoxide); AcOEt (ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF (NN-dimethylformamide); DMPU (NNLdimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); 15 HOSu (N-hydroxysuccinimide); HOBT (1 -hydroxybenzotriazole); mCPBA (meta-chloroperbenzoic acid; EDC (1 -[3-dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbony); DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); 20 Ac (acetyl); atm (atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP (4-dimethylaminopyridine); BSA (bovine serum albumin); ATP (adenosine triphosphate); HRP (horseradish peroxidase); 25 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 (O-Benzotriazole-1 -yl-N,N,N',N'-tetramethyluroniumhexafluoro phosphate); 30 H EPES (4-(2-hydroxyethyl)-1 -piperazine ethane sulfonic acid); DPPA (diphenylphosphoryl azide); fHNO 3 (fuming HNO 3 ); EDTA (ethylenediaminetetraacetic acid); TMEDA (N,N,N',N'-tetramethyl-1,2-ethanediamine); 35 NBS (N-bromosuccinimide); 56 WO 2007/005534 PCT/US2006/025402 HATU (O-(7azabenzobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); DIPEA (diisopropylethylamine); imes (1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride); 5 dppf (1,1'-bis(diphenylphosphino)ferrocene); MDAP (Mass Directed AutoPrep);
CH
3 CN (acetonitrile); EtOAc (ethyl acetate); 10 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 I-Il may contain one or more asymmetric center 15 (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, 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 I-il, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass any 20 stereoisomer and all mixtures thereof. Thus, compounds according to formulae I-Il 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 I-Il which contain one or 25 more asymmetric center may be resolved by methods known to those skilled in the art. 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 30 silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan 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 35 by converting one enantiomer to the other by asymmetric transformation. 57 WO 2007/005534 PCT/US2006/025402 The compounds according to formulae I-1l may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in formulae I-Il, or in any chemical structure illustrated herein, is not 5 specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in formulae I-1l whether such tautomers exist in equilibrium or predominately in one form. 10 The skilled artisan will appreciate that pharmaceutically-acceptable salts of the compounds according to formulae I-Il may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to formulae I-Il 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 15 into a dosage form. Accordingly, the invention is further directed to pharmaceutically acceptable salts of the compounds according to formulae 1-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 20 toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ 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. 25 In certain embodiments, compounds according to formulae 1-11 may contain an acidic 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 30 sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically 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. 35 58 WO 2007/005534 PCT/US2006/025402 In certain embodiments, compounds according to formulae I-Il 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. 5 Representative pharmaceutically-acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, trifluoroacetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, 10 benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, 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), 15 and napthalene-2-sulfonate. As used herein, the term "compounds of the invention" means both the compounds according to formulae I-1l and the pharmaceutically-acceptable salts thereof. 20 The compounds of the invention may exist in solid or liquid form. In the solid state, the 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 25 involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, 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 30 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 35 forms are typically known as "polymorphs." The invention includes all such polymorphs. 59 WO 2007/005534 PCT/US2006/025402 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 5 melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be 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 10 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 15 defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the Examples section. Compounds of formulae I and li can be prepared, for example, according to Schemes 1, 20 2, and 3 depicted below: Scheme 1 R2 R2 R2 R2 Br Br R1 abc d.e.f q.h , R3 N R3 NBOC R3 N R3 N R3H H H 0 0 HO 0 H 2 N 0 1 2 3 4 R2 U-v R2 U-v i~ R1 k R 1 R3 N R3N H R3
H
2 N 0 H 2 N 0 5 6 60 WO 2007/005534 PCT/US2006/025402 Conditions: a) (BOC) 2 0, THF; b) s-BuLi, CICO 2 Me, TMEDA, Et 2 0; c) N bromosuccinimide, Methylene chloride; d) TFA; e) MnO 2 , THF; f) LiOH, MeOH, water; g) R1 B(OR) 2 , Imes-HCl, Pd(OAc) 2 , Dioxane/water; h) HATU, NH 3 , DMF; i) RCHO (or) RC(O)R', NaOMe, MeOH; j) Pd(OH) 2 , H 2 , HOAc, EtOH; k) R4CI, TEA, Methylene chloride 5 (or) (R4) 2 0, DMAP, Methylene chloride 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 Cl, U is a bond or C1-C6 alkylene or C2 C6 alkenylene and V is C5-C7 cycloalkyl or C5-C7 cycloalkenyl or heterocycloalkyl or 10 heterocycloalkenyl. Scheme 1 also represents a general scheme for the preparation of compounds according to formulae I and II wherein U is C1-C6 alkylene or C2-C6 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 15 will appreciate that certain modifications in the reaction conditions and/or reagents used 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 20 to the desired bromide 2 can be accomplished via lithiation using seo-butyllithium in the 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 25 of the substituent R1 can be accomplished via a transition metal mediated coupling using 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 Cs2CO3 in 1,4 dioxane and water. Preparation of the primary carboxamide 4 can be completed via 30 reaction of the carboxylic acid with ammonia in the presence of HATU. Conversion of 4 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 35 of such a reduction, for the case in Scheme 1 condition "j", a hydrogenation reaction in 61 WO 2007/005534 PCT/US2006/025402 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 5 sulfonamide or amide of R4 can be performed with the appropriate sulfonyl or acid chloride or acid anhydride of R4. It will be appreciated by the skilled artisan that upon 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. 10 Scheme 2 Br R1 U-V U-V a,b,c d e N N N N H H H H HO 0 H2N 0 H 2 N 0
H
2 N 0 3 9 10 11 15 Conditions: a) R1B(OR) 2 , Imes-HCI, Pd(OAc) 2 , dioxane/water; b) HATU, NH 3 , DMF; c) N iodosuccinimide, Methylene chloride; d) VUB(OR) 2 , Pd(PPh 3
)
4 , Cs 2
CO
3 , 1,4-dioxane, water; e) R 2 CI, TEA, Methylene chloride (or) (R 2
)
2 0, DMAP, Methylene chloride Scheme 2 represents a general scheme for the preparation of compounds according to 20 formulae I and II wherein U is a bond and V is aryl or heteroaryl. In Scheme 2, R1 is 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. 25 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 30 intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups 62 WO 2007/005534 PCT/US2006/025402 are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protectinq 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 5 convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound. Methods of Use The compounds of the invention are inhibitors of IKK2. These compounds can be useful 10 in the treatment of disorders wherein the underlying pathology is (at least in part) attributable to inappropriate IKK2 (also known as IKKP) activity such as rheumatoid arthritis, inflammatory bowel disease, asthma, and COPD (chronic obstructive pulmonary disease). "Inappropriate IKK2 activity" refers to any lKK2 activity that deviates from the normal IKK2 activity expected in a particular patient. Inappropriate IKK2 activity may take 15 the form of, for instance, an abnormal increase in activity, or an aberration in the timing 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. 20 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; 25 autoimmune diseases including systemic lupus 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 30 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 1-11 or a pharmaceutically-acceptable salt thereof to a patient in need thereof. Individual embodiments of the invention include 35 methods of treating any one of the above-mentioned disorders by administering a safe 63 WO 2007/005534 PCT/US2006/025402 and effective amount of a compound according to formulae I-Il 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 5 disorder or one or more of the biological manifestations of the disorder, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the 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. 10 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 15 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 20 benefit/risk ratio) within the scope of sound medical judgment. A safe and effective 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 25 treated; the duration of the treatment; the nature of concurrent therapy; the desired 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. 30 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, 64 WO 2007/005534 PCT/US2006/025402 transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or 5 infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration. 10 The compounds of the invention may be administered once or according to a dosing 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 15 regimens for a compound of the invention depend on the pharmacokinetic properties of 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 20 patient being treated, the medical history of the patient to be treated, the nature of 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. 25 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. 30 Additionally, the compounds of the invention may be administered as prodrugs. As used 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 35 compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify 65 WO 2007/005534 PCT/US2006/025402 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 5 vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art. 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 10 aspect, the invention is directed to the use of a compound according to formulae I-Il or a 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 15 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, psoriatic arthritis, alkylosing spondylitis, tissue and organ 20 rejection, Alzheimer's disease, stroke, atherosclerosis, restenosis, 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 as a result of inhibition of the protein kinase IKK2. 25 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 30 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 35 pharmaceutical compositions of the invention may be prepared and packaged in unit 66 WO 2007/005534 PCT/US2006/025402 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. 5 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 10 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 15 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 20 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 25 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 30 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 35 dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may 67 WO 2007/005534 PCT/US2006/025402 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 5 pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the 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. 10 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, 15 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. 20 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 25 selecting suitable pharmaceutically-acceptable excipients. Examples include Reminqton'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). 30 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). 68 WO 2007/005534 PCT/US2006/025402 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 5 its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders 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 10 comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch 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. 15 Where appropriate, dosage unit formulations for oral administration can be 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. 20 The compounds of the invention may also be coupled with soluble polymers as targetable 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 25 in achieving controlled release of a drug, for example, polylactic acid, polepsilon 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 30 as solution, syrups and elixirs can be prepared in dosage unit form so that a given 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 non 35 toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and 69 WO 2007/005534 PCT/US2006/025402 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. 5 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 10 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. 15 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 a metering cup, which is movable from a first position where the cup may be filled with 20 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), cartridges, or blister packs for use in a multi-dose dry powder inhaler (MDPI). MDPIs are 25 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 for ease of release of the medicament therefrom. For example, the blisters may be 30 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 20ptg-10mg of the compound of the invention. Aerosols may be formed by suspending or dissolving a compound of the invention in a 35 liquified propellant. Suitable propellants include halocarbons, hydrocarbons, and other 70 WO 2007/005534 PCT/US2006/025402 liquified gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-1 34a), 1,1 -difluoroethane (HFA-1 52a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, 5 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 10 with MDls 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 15 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 20 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 25 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 30 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. 71 WO 2007/005534 PCT/US2006/025402 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 delivered from the patch by iontophoresis as generally described in Pharmaceutical 5 Research, 3(6), 318 (1986). Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. 10 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 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 15 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 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 20 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 25 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 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 30 stored in a freeze-dried lyophilizedd) 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 tablets. 72 WO 2007/005534 PCT/US2006/025402 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. 1 H 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, 8 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-APliii 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+ 5pm 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 TM pre-packed silica flash columns on an ISCO 30 sql 6x 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 pm column (75x30 mm i.d.) utilizing gradient elution with the stated solvent systems and UV detection at 254 nm. 35 73 WO 2007/005534 PCT/US2006/025402 Reverse phase HPLC method B refers to methods where the materials was purified by high performace liquid chromatography on a HPLC Luna C18 (2) 1 OA column (50x21.2 mm i.d.) utilizing gradient elution with the stated solvent system and UV detection at 254 nm. 5 LC-MS Experimental Conditions for PE Sciex Single Quadrupole LC/MS API-150: Liquid Chromatograph: System: Shimadzu LC system with SCL-1 0A Controller and dual UV detector 10 Autosampler: Leap CTC with a Valco six port injector Column: Aquasil/Aquasil (Cl 8 40x1 mm) Inj. Volume (pL): 2.0 Solvent A: H20, 0.02% TFA Solvent B: MeCN, 0.018% TFA 15 Gradient: linear Channel A: UV 214 nm Channel B: ELS Step Time (min) Dura.(min) Flow (pL/min) Sol.A Sol.B 0 0.00 0.00 300.00 95.00 5.00 20 1 0.00 0.01 300.00 95.00 5.00 2 0.01 3.20 300.00 10.00 90.00 3 3.21 1.00 300.0010.00 90.00 4 4.21 0.10 300.00 95.00 5.00 5 4.31 0.40 300.00 95.00 5.00 25 Mass Spectrometer: PE Sciex Single Quadrupole LC/MS API- 50 Polarity: Positive Acquisition mode: Profile 74 WO 2007/005534 PCT/US2006/025402 Intermediates Intermediate 1: 1,1-dimethylethyl 2,3-dihvdro-1H-indole-l-carboxylate CC N 0 5 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: 160-1620C, 10 pressure 1 - 0.1 mm Hg). 1H NMR (400 MHz, DMSO-D6) 8 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. 15 Intermediate 2: 1-(1,1-dimethylethyl) 7-methyl 2,3-dihydro-1H-indole-1,7 dicarboxylate N O 0 00 1,1-dimethylethyl 2,3-dihydro-1H-indole-1-carboxylate (5 g, 22.8 mmol) and N,N,N,N tetramethyl-1,2-ethanediamine (4.6 mL, 30.5 mmol) was dissolved in dry diethyl ether 20 (300 mL) and cooled to -780C 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 75 WO 2007/005534 PCT/US2006/025402 magnesium sulfate, filtered and concentrated in vacuo to give the title compound (4.91 g) as a gummy yellow solid. 1 H NMR (400 MHz, DMSO-D6) 8 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-1 H-indole-1,7 dicarboxylate Br N 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 15 g). 1 H NMR (400 MHz, DMSO-D6) 8 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. 20 Intermediate 4: methyl 5-bromo-2,3-dihydro-1 H-i ndole-7-carboxylate Br ~N H 0 0 1-(1,1-dimethylethyl) 7-methyl 5-bromo-2,3-dihydro-1H-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 76 WO 2007/005534 PCT/US2006/025402 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). 1 H NMR (400 MHz, DMSO-D6) 8 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. Intermediate 5: methyl 5-bromo-1 H-indole-7-carboxylate Br N H 0 0 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 ptm 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. 15 1 H NMR (400 MHz, DMSO-D6) 8 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-1 H-indole-7-carboxylic acid Br N H 20 HO 0 5-bromo-1 H-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). 77 WO 2007/005534 PCT/US2006/025402 1 H NMR (400 MHz, DMSO-D6) 8 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. 5 Intermediate 7: 5-bromo-1 H-indole-7-carboxamide Br N H
H
2 N 0 To a solution of 5-bromo-1H-indole-7-carboxylic acid (10.0 g, 42 mmol) in CH 2 Cl 2 (100 mL) at room temperature, EDC (9.66 g, 50.4 mmol), HOBt (6.81 g, 50.4 mmol) and NH 3 (2.0 M in MeOH, 84 mL, 168 mmol) were added. The reaction mixture was stirred at room 10 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 MgSO 4 and concentrated to give the crude product (10 g, 98%). This crude product was used directly in the next step without further purification. 15 LC/MS: m/z 240.0 (M+H), 1.95 min. Intermediate 8: 11 -dimethylethyl 4-[7-(aminocarbonvl-5-bromo-1 H-indol-3-yll-3,6 dihydro-1 (2H-pyridinecarboxylate 0 N Br N H 0
NH
2 20 To a solution of 5-bromo-1 H-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 78 WO 2007/005534 PCT/US2006/025402 pressure. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The combined organic phase was dried over MgSO 4 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 %). 5 LC/MS: m/z 420.0 (M+H), 2.35 min. Intermediate 9:11 -dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indol-3-Vil-1 piperidine carboxylate 0 N Br N H 0
NH
2 10 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 H 2 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)-1 H-indole-7-carboxamide H N Br N H 20 0 NH 2 79 WO 2007/005534 PCT/US2006/025402 To a solution of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-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 5 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 MgSO 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. 10 Intermediate 11: 5-bromo-3-[l-(ethanesulfonyl)-4-piperidinyll-1H-indole-7 carboxamide 0 N Br N H 0
NH
2 Ethanesulfonyl chloride (4.5 mL, 47.4 mmol) was added dropwise to a solution of 5 15 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 2C (bath temperature). The reaction mixture was stirred at 0 9C for 45 min. and was then poured into a 2:1 mixture of EtOAc/H 2 0 (300 mL). The resulting precipitate was filtered off, washed with EtOAc (2 x 50 mL), and set aside. The EtOAc/H 2 0 bilayer was separated, and the aqueous layer 20 was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated NaCl (1 x 100 mL), dried (MgSO 4 ), filtered, and concentrated under reduced pressure. The crude product was combined with the precipitate isolated above and washed with MeOH (1 x 10 mL) to give 8.19 g of the title compound (83%). 25 Alternatively, the title compound may be prepared as follows: To 5-bromo-3-(4-piperidinyl)-1 H-indole-7-carboxamide (900 mg, 2.8 mmol) in CH 2
CI
2 (100mL) at 0 OC, ethanesulfonyl chloride (0.8 mg, 8.4 mmol) and triethylamine (1.6 mL, 80 WO 2007/005534 PCT/US2006/025402 11.2 mmol) were added. The reaction mixture was stirred at 0 0C for 30 min., after which time the mixture was partitioned between CH 2
CI
2 and water. The aqueous phase was extracted with CH 2 Cl 2 (50 mL x 2) and the combined organic phase dried over MgSO 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. 10 Intermediate 12: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-[3-(hydroxvmethvl)phenvl-1H indole-7-carboxamide OHO OH / O N N H 0
NH
2 To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (20.0 mg, 0.048 mmol), K 3 P0 4 ( 21.0 mg, 0.096 mmol) and [3-(hydroxymethyl) phenyl] boronic 15 acid (30.0 mg, 0.193 mmol) in dioxane/H 2 0 ( 2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh 3
)
4 (5.0 mg, 0.0048 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 1600C. 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 MgSO 4 , concentrated, and 20 purified by reverse phase HPLC method A (water/ CH 3 CN, 0.1 % TFA 10-90%) to give the title compound (9.7 mg, 46%). 1 H NMR (400 MHz, DMSO-D6) 8 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, 1H). 25 LC/MS: m/z 442.4 (M+H), r.t: 1.73 min. Intermediate 13: 3-[1 -(ethylsulfonyl)-4-piperidinyll-5-(3-formylphenyl)-1H-indole-7 carboxamide 81 WO 2007/005534 PCT/US2006/025402 O 00-. N N H 0
NH
2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(hydroxymethyl)phenyl]-1 H-indole 7-carboxamide (52.0 mg, 0.120 mmol) in THF (10 mL), MnO 2 (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 (3X1 0 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. 10 Intermediate 14: 3-[1-(ethylsulfonvi)-4-piperidinvil-5-[4-(hydroxymethvl)phenvll-1 H indole-7-carboxamide OH N N H O NH2 To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidiny]-1 H-indole-7-carboxamide (20.0 mg, 0.048 mmol), K 3
PO
4 ( 21.0 mg, 0.096 mmol) and [4-(hydroxymethyl) phenyl] boronic 15 acid (30.0 mg, 0.193 mmol) in dioxane/H 2 0 ( 2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh) 4 (5.0 mg, 0.0048 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 1600C. 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 MgSO 4 , filtered, concentrated, 20 and purified by reverse phase HPLC method A (water/ CH 3 CN, 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. 82 WO 2007/005534 PCT/US2006/025402 Intermediate 15: 3-[l-(ethylsulfonyl)-4-piperidinvll-5-(4-formylphenyl)-1H-indole-7 carboxamide OZ S O N N H O NH2 5 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(hydroxymethyl)phenyl]-1 H-indole 7-carboxamide (25 mg, 0.058 mmol) in THF (5 mL), MnO 2 (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-[1-(ethylsulfonyl)-4-piperidinvil-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide 15 io N 0B N H 0
NH
2 To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 Pd 2
CI
2 (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 H 2 0 (100 mL) and solid was filtered. The organic layer was then washed with H 2 0 (3 x 80 mL) and brine. Organic laye was 83 WO 2007/005534 PCT/US2006/025402 dried over MgSO 4 and concentrated. DCM (40 mL) was then added to remove any by product to afford 2.4 g of the title compound. LC/MS: m/z 462.3 (M+H), r.t: 2.03 min. 5 Intermediate 17: 3-[l-(ethylsulfonyl)-4-piperidinvIl-5-(5-formyl-2-thienvI)-1H-indole 7-carboxamide Ozr O N /s N H 0
NH
2 To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 1500 C for 20 min. Aqueous work-up with EtOAc/H 2 0 gave 447 mg of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-thienyl]-1 H-indole-7-carboxamide. 15 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-thienyl]-1H indole-7-carboxamide (200 mg, 0.46 mmol) in THF (5.0 mL) was added MnO 2 (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%) 20 LC/MS: m/z 446.2 (M+H), r.t: 2.27 min. Intermediate 18: 3-[1-(ethylsulfonyl)-4-piperidinvll-5-(4-formyl-2-thienyl)-1H-indole 7-carboxamide 84 WO 2007/005534 PCT/US2006/025402 OzS O N S 0 N H O 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 Q 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 H 2 0 (100 mL) was added and extracted with DCM (2 x 100 mL). The combined organic layer was washed with NaHCO3 and dried. It was purified by flash chromatography to give 3.62 g of 5-bromo-3-thiophenecarbaldehyde (71 %). 10 To a solution of 5-bromo-3-thiophenecarbaldehyde (250 mg, 1.29 mmol) in dioxane (4.5 mL) and H 2 0 (1.5 mL) was added 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)-1 H-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 1500 C for 20 min. It was then 15 treated with EtOAc and H 2 0 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. 20 Intermediate 19: 3-[1-(ethylsulfonyl)-4-piperidinvll-5-(5-formyl-3-thienvl)-1H-indole 7-carboxamide 85 WO 2007/005534 PCT/US2006/025402 N 0 s H N H O NH 2 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 Pd 2 Cl 2 (dppf) (106 mg, .448 mmol). The reaction was run in the microwave at 150L C for 5 20 min. The solvent was concentrated and an aqueous work-up was performed using EtOAc and H 2 0. 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. 10 To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (909 mg, 2.2 mmol) in dioxane (7.5 mL) and H 2 0 (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 1502 C for 20 min. The mixture 15 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. 20 Intermediate 20: 5-Bromoisoindoline NH Br' In a dried 5OmL two necked round-bottom flask equipped with an addition funnel and CaCl 2 drying tube was placed 2.Og (1 3.6mmol) of phthalimide. The flask was then cooled 25 to OC 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 00C and allowed to slowly warm to room temperature with stirring 86 WO 2007/005534 PCT/US2006/025402 over a period of 1 h. 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 H-isoindole-1,3(2H)-dione as a yellow colour solid. 5 To a solution of 5-nitro-1 H-isoindole-1,3(2H)-dione (1.0g, 5.2mmol) in dry THF (1 5mL) 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-1 H-isoindole-1,3(2H)-dione as a yellow colour solid. 10 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. H 2
SO
4 in 7.5mL of H 2 0) at 0 0 C, was added ice cold sodium nitrite solution ( 0.8g in 2mL of H 2 0) dropwise. After 45min of stirring at 0 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 0 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 H-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 BH 3 -THF (160mL) solution with dry THF (50mL). The mixture 20 was cooled to OC. To this cold solution 5-bromo-1 H-isoindole-1,3(2H)-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 OC and quenched with methanol. (Caution: vigorous foaming will occur). 20-30mL of 2N HCL was added and ref luxed the mixture for 1 h. 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 Na 2
SO
4 and concentrated under vacuo. To the crude product in MeOH (150mL), Et 3 N (12mL) and di-tert-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 CH 2 Cl 2 (200mL), washed with water, saturated NaCl solution, and dried over Na 2
SO
4 . 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.Og (42.8%) of 5-bromoisoindoline hydrochloride salt as an ash 35 colour solid. 87 WO 2007/005534 PCT/US2006/025402 Intermediate 21: 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide hydrochloride H N Br + HCI N H o
NH
2 A 4M solution of HCI in dioxane (194 mL) was added to a solution of 1,1 -dimethylethyl 4 5 [7-(aminocarbonyl)-5-bromo-1H-indol-3-y]-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. 10 Intermediate 22: 5-bromo-34 -1(1 -methylethyl)sulfonyll-4-piperidi nyl-1 H-indole-7 carboxamide 0 N Br N H o
NH
2 Triethylamine (2.6 mL, 18.7 mmol) was added to a solution of 5-bromo-3-(4-piperidinyl) 15 1 H-indole-7-carboxamide hydrochloride in DMF (15 mL) at 0 5C. 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 EtOAc/H 2 0 (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 88 WO 2007/005534 PCT/US2006/025402 saturated NaCl (1 x 100 mL), dried (MgSO4), and concentrated under reduced pressure. The crude product was washed with MeOH (2 x 10 mL) to give the title compound (1.5 g, 75%). LC/MS: m/z 427.8 (M+H), 1.98 min. 5 Intermediate 23: 5-(5-formyl-3-thienyl)-3-fl-(1-methylethyl)sulfonvll-4-piperidinyl} 1 H-indole-7-carboxamide Ozz N S OHC N H O 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 Pd 2
CI
2 (dppf) (106 mg, 0.448 mmol). The reactions were run in a Smith microwave at 150 2C for 20 min. The 6 reactions were pooled and concentrated under reduced pressure. The 15 residue was taken up in EtOAc (200 mL) and H 2 0 (50 mL). The layers were separated, the organic layer was washed with saturated NaCl (1 x 50 mL), dried (Na 2
SO
4 ), 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%). 20 A solution of 5-bromo-3-{1 -[(1 -methylethyl)sulfonyl]-4-piperidinyl}-1 H-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), Cs 2
CO
3 (800 mg, 2.46 mmol), and Pd(PPh 3
)
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 (1 x 5 mL) to give the title compound (395 mg, 86%). 89 WO 2007/005534 PCT/US2006/025402 LC/MS: m/z 460.4 (M+H), 1.98 min. Examples 5 Example 1: 3-1 -(ethylsuIf onyl)-4-piperidinvll-5-[3-(1 -piperidinvimethVl)phenVll-1H indole-7-carboxamide N (N N H O NH 2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-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 (H 2 0/CH 3 CN, 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-[1-(ethylsulfonyl)-4-piperidinvll-5-[3-(1-piperazinvimethvl)phenvll-1 H 20 indole-7-carboxamide N HN N N H O NH 2 90 WO 2007/005534 PCT/US2006/025402 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1 H-indole-7-carboxamide (15.0 mg, 0.034 mmol), piperazine (3.5 mg, 0.04 mmol) and NaBH(OAc)s (23.0 mg, 0.102 mmol) were reacted to give the title compound (3.4 mg, 19.7%). 5 LC/MS: m/z 510.2 (M+H), r.t: 1.43 min. Example 3: 3-[1 -(ethylsu Ifonyl)-4-pi peridinyll-5-3-(4-morphol inyl methyl)phenvil-1 H indole-7-carboxamide N 0 N N H 10 NH2 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1 H-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%). 15 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)-1H-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 NH/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%). 91 WO 2007/005534 PCT/US2006/025402 Example 4: 3-1 -(ethylsuIfonyl)-4-pi peridi nvll-5-[3-({methyl [2 (methylsulfonvl)ethyllaminolmethvl)phenvll-1 H-indole-7-carboxamide NN <S 0N H O NH2 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 5 formylphenyl)-1 H-indole-7-carboxamide (42.0 mg, 0.096 mmol), N-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. 10 Example 5: 5-(3-ff[2-(dimethylamino)ethyll(methvl)aminolmethylphenl)-3-1 (ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide N N _N N H O NH-2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7 carboxamide (45.0 mg, 0.101 mmol) in DCM (2 mL) was added N,N,N-trimethyl-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/CH 3 CN, 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. 92 WO 2007/005534 PCT/US2006/025402 Example 6: 3-[1-(ethylsulfonyl)-4-piperidinvll-5-{3-[(4-{2-[(2-hydroxvethvl)oxylethyll 1 -piperazinvl)methyllphenyl}-1 H-indole-7-carboxamide OH O N /:= i N N N H
H
2 N 0 5 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1 H-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. 10 Example 7: 3-1 -(ethylsulfonyl)-4-piperidinyll-5-(3-ff 3-(hydroxymethvl)-1 piperidinyllmethyl}phenyl)-1 H-indole-7-carboxamide 20 N HO,, N N H H2 N O Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 15 formylphenyl)-1H-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(1 0.2 mg, 17%). LC/MS: m/z 539.4 (M+H), r.t: 1.52 min. 93 WO 2007/005534 PCT/US2006/025402 Example 8: 5-[3-({bis[2-(methyloxy)ethVllami no}methyl)phenyll-3-[1 -(ethylsulfonyl) 4-piperidinvll-1 H-indole-7-carboxamide 0 NN O N N H
H
2 N 0 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 5 formylphenyl)-1 H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(methyloxy)-N-[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. 10 Example 9: 5-{3-[(2,6-dimethyl-4-morpholinvl)methyllphenvll-3-[1-(ethvlsulfonvl)-4 piperidinyll-1 H-indole-7-carboxamide 0 0 Ii O // N O=S"/ N N H
H
2 N 0 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 15 formylphenyl)-1H-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. 20 Example 10: 3-1 -(ethylsulf onyl)-4-pi peridi nVll-5-(3-{[2-(1,3-thiazol-2-y)-1 pyrrolidinvllmethyl}phenvl)-1H-indole-7-carboxamide 94 WO 2007/005534 PCT/US2006/025402 0 NO/ N N S NN ~N H
H
2 N 0 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1H-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-[1-(ethylsulfonyl)-4-piperidinvil-5-(3-ff2-(2-thienvi)-1 10 pyrrolidinvllmethyllphenyl)-1 H-indole-7-carboxamide 0 Og/ N N ~N H
H
2 N 0 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1H-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-l-(ethylsulfonyl)-4-piperidinvil-5-(3-{f(2-hydroxy-2-phenvlethyl) (methyl)aminolmethyllphenVl)-1 H-indole-7-carboxamide 95 WO 2007/005534 PCT/US2006/025402 0// CH S---/ 3 N/ CH HO N H H2N O Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), 2-(methylamino)-1 phenylethanol (129.9 mg, 0.86 mmol) and NaBH(OAc)s (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-fiethyl(methvl)aminolmethylphenvl)-3-[1-(ethylsulfonyl)-4 10 piperidinvll-1 H-indole-7-carboxamide // 0: N N H
H
2 N 0 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1H-indole-7-carboxamide (50.0 mg, 0.112 mmol), N-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-[3-(aminomethyl)phenvll-3-1 -(ethylsulfonyl)-4-piperidinyll-1 H-indole 20 7-carboxamide 96 WO 2007/005534 PCT/US2006/025402 0 H2N O==gS N N H
H
2 N 0 To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (30.0 mg, 0.072 mmol), Cs 2
CO
3 (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/H 2 0 (2 mL/0.7 5 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh 3
)
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 MgSO 4 , filtered, concentrated, and purified by reverse phase HPLC method A 10 (water/CH 3 CN, 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-f3-[(cyclopentvlamino)methyllphenvl}-3-[1-(ethylsulfonvl)-4 piperidinyll-1 H-indole-7-carboxamide p 0 HN / N N H 15
H
2 N 0 Following the general procedure of example 5, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1H-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%). 20 LC/MS: m/z 509.4 (M+H), r.t: 1.64 min. 97 WO 2007/005534 PCT/US2006/025402 Example 16: 5-r3-(ff(3,4-dihVdroxVphenvl)methyllaminolmethvl)phenvil-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide HO HO O H NO/ N H
H
2 N 0 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-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 3 CN, 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-[1-(ethylsulfonvi)-4-piperidinvil-5-(3-ff(3 15 thienvlmethvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide O N S N H H2N O Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1H-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. 98 WO 2007/005534 PCT/US2006/025402 Example 18: 3-1 -(ethylsu Ifonyl)-4-pi peridi nyll-5-[3-(f[(1R)-1-(hydroxymethyl)-2 methylpropyllaminolmethvl)phenvil-1 H-indole-7-carboxamide 0 S N H N HO N H
H
2 N 0 Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 5 formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), (2R)-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. 10 Example 19: 3-[l-(ethylsulfonyl)-4-piperidinvil-5-(3-f[(2-hydroxy-1-methylethyl) aminolmethyllphenyl)-1 H-indole-7-carboxamide: IN H N HO N 2 Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1H-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-[1 -(ethylsulfonyl)-4-pi peridi nyll-5-(3-4(trans-4 20 hydroxvcvclohexvl)aminolmethVl}phenvl)-1 H-indole-7-carboxamide 99 WO 2007/005534 PCT/US2006/025402 0 HO,, 0--.// HO O N N N H
H
2 N 0 Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1 H-indole-7-carboxamide (50 mg, 0.114 mmol), trans-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: 3-1 -(ethylsuIfonyl)-4-piperidinl1-5-13-r(fr1 -(1 piperidinvl)cvclohexyllmethyllamino)methyllphenvl}-1 H-indole-7-carboxamide 0 Q H Ns NN N H 10
H
2 N 0 Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1 H-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 %). 15 LC/MS: m/z 620.6 (M+H), r.t: 1.6 min. Example 22: 3-1 -(ethylsuIfonvl)-4-piperidinyll-5-[3-(ff (2 S)-2 hydroxvpropyllaminolmethvl)phenyll-1 H-indole-7-carboxamide 100 WO 2007/005534 PCT/US2006/025402 0 HO,, H O/ N N N H
H
2 N 0 Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1H-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-{3-f(ethylamino)methyllphenvll-3-[1-(ethylsulfonvl)-4-piperidinvll-1 H indole-7-carboxamide 0 0 N N N H 10
H
2 N 0 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-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 15 was stirred at ambient temperature overnight, and the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH 3 CN, 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. 20 Example 24: 3-ri-(ethylsulfonyl)-4-piperidinvll-5-f3-F(propylamino)methyllphenvl} 1 H-indole-7-carboxamide 101 WO 2007/005534 PCT/US2006/025402 0 HN N H
H
2 N 0 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-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/CH 3 CN, 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. 10 Example 25: 3-l-(ethylsulfonvl)-4-piperidinvil-5-(3-ff(l methylethvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide: 0 Y ~O HN N/ IN H
H
2 N 0 Following the general procedure of example 24, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 15 formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.045 mmol), isopropylamine (23 uL, 0.27 mmol) and NaBH 4 (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. 20 Example 26: 5-(3-f(1 -ethyl propyl)aminolmethyl}phenyl)-3-[1 -(ethylsulfonyll)-4 piperidinvll-1 H-indole-7-carboxamide 102 WO 2007/005534 PCT/US2006/025402 H0N HN N H
H
2 N 0 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.045 mmol), 3-pentanamine (32 uL, 0.27 mmol) and NaBH 4 (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: 3-1 -(ethylsulfonyl)-4-piperidinvll-5-[4-(1 -piperidi nvlmethvIphenvll-1 H indole-7-carboxamide: O=S=O N \N / N H 10 0 NH 2 Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1H-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 %). 15 LC/MS: m/z 509.4(M+H), r.t: 1.71 min. Example 28: 3-[1 -(ethylsuIfonyl)-4-piperidinvll-5-{3-[(methylami no)methyllphenvl} 1 H-indole-7-carboxamide 103 WO 2007/005534 PCT/US2006/025402 0 0 HN N N H
H
2 N 0 Following the general procedure of example 24, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1 H-indole-7-carboxamide (20 mg, 0.045 mmol), methylamine (130 uL, 0.27 mmol) and NaBH 4 (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-[1 -(ethylsuIfonyl)-4-piperidi nvll-5-[4-(4-morpholi nvlmethyl)phenyll 1 H-indole-7-carboxamide 0 O N N N H 10 H2N O Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4 formylphenyl)-1H-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 %). 15 LC/MS: m/z 511.4 (M+H), r.t: 1.63 min. 104 WO 2007/005534 PCT/US2006/025402 Example 30: 5-[4-(ami nomethVl)phenvll-341 -(ethylsulfonyll-4-piperidinyll-1 H-indole 7-carboxamide 0 NH2 N N H H2N O To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (30.0 5 mg, 0.072 mmol), Cs 2
CO
3 (95 mg, 0.290 mmol) and [4-(aminomethyl) phenyl boronic acid (55 mg, 0.290 mmol) in dioxane/H 2 0 (1.5 mL/0.5 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh 3
)
4 (7.5 mg, 0.0072 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 1600C. 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 MgSO 4 , filtered, concentrated, and purified by reverse phase HPLC (water/ CH 3 CN, 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. 15 Example 31: 5-f3-l(cyclopropylamino)methyllphenvl}-3-[1-(ethylsulfonvl)-4 piperidinyll-1 H-indole-7-carboxamide 0 HN O N N H
H
2 N 0 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-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 105 WO 2007/005534 PCT/US2006/025402 removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH 3 CN, 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. 5 Example 32: 5-{3-[(cyclobutylamino)methyllphenvl}-3-[1-(ethylsulfonyl)-4 piperidinvll-1 H-indole-7-carboxamide 9O HN N H
H
2 N 0 Following the general procedure of example 31, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3 formylphenyl)-1 H-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: 3-1 -(ethylsulfonyl)-4-piperidi nyll-543-[(2-methyllpropyl)aminol-2,3 15 dihvdro-1 H-inden-5-yl}-1 H-indole-7-carboxamide trifluoroacetate NH N N F o H F.
H
2 N 0 F OH To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1 ,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) 20 and H 2 0 (1.0 mL) was added 6-bromo-2,3-dihydro-1 H-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 106 WO 2007/005534 PCT/US2006/025402 30 min at 1602 C. The reaction was then filtered and the solid was dissolved in EtOAc and H 2 0. 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 H-inden-5-yl)-1 H-indole-7-carboxamide. 5 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-oxo-2,3-dihydro-1 H-inden-5-yl)-1 H indole-7-carboxamide (45 mg, 0.097 mmol) in EtOH (2 mL) and acetic acid (200 pLL) was added 2-methyl-1-propanamine (170 [tL, 1.93 mmol) and sodium cyanoborohydride (20 mg, 0.291 mmol). The resulting mixture was reacted in a CEM microwave tube at 1500 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-l-(ethylsulfonvl)-4-piperidinvil-5-f8-(2-methylpropvl)aminol-5.6,7,8 15 tetrahydro-2-naphthalenyl}-1H-indole-7-carboxamide trifluoroacetate NHO N F O N F H\ H2N O F OH To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-y)-1 H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) 20 and H 2 0 (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 1609 C. The reaction was then filtered and the solid was dissolved in EtOAc 25 and H 2 0. 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 H-indole-7-carboxamide. 107 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(8-oxo-5,6,7,8-tetrahydro-2 naphthalenyl)-1 H-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 jiL, 1.6 mmol) and sodium cyanoborohydride (15 mg, 0.24 mmol). The resulting mixture was reacted in a CEM 5 microwave tube at 1500 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-WF(2-cvanoethvl)aminolmethyl}-2-fluorophenv)-3-[1 10 (ethylsulfonyl)-4-pi peridinyll-1 H-indole-7-carboxamide trifluoroacetate N N N HH N H \ O F F
NH
2 F OH To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (200 mg, 0.434 mmol) in dioxane (3.0 mL) 15 and H 2 0 (1.0 mL) was added 3-bromo-4-fluorobenzaldehyde (264 mg, 1.30 mmol), and
K
2
CO
3 (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 160L, 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)-1H indole-7-carboxamide. To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1 H-indole-7 carboxamide (40 mg, 0.087 mmol) in dichloromethane (2 mL) and methanol (I mL) was 25 added 3-aminopropanenitrile (53 tL, 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 %). 108 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 512.2 [M+H] Ret. Time: 1.45 Example 36: 3-[1-(ethylsulfonvl)-4-piperidinvil-5-(2-fluoro-5-f[(2,2,2 trif luoroethyl)aminolmethyllphenyl)-1 H-indole-7-carboxamide trifluoroacetate 5 sZ=o I F F NNF N F H - / \ N\/ F H 2N 0F 0 F-H F OH To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1 H-indole-7 carboxamide (20 mg, 0.04 mmol) in dichloromethane (4 mL) and methanol (2 mL) was 10 added 2 drops of acetic acid and 2,2,2-trifluoroethanamine (23 gL, 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 15 Example 37: 3-1 -(ethylsulfonyl)-4-piperidi nyll-5-(1,2,3,4-tetrahydro-7 isoquinolinyl)-1 H-indole-7-carboxamide trifluoroacetate H O NN N H F O F 2 F OH 20 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 (60 mg, 0.13 mmol) in dioxane (2 mL) and 109 WO 2007/005534 PCT/US2006/025402 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 1600 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 10 Example 38: 3-fl-(ethylsulfonvi)-4-piperidinvll-5-(3-ff(2,2,2 trifluoroethvl)aminolmethyllphenVl)-1H-indole-7-carboxamide trifluoroacetate
H
2 N 0 / \ H - N F F F F o
F-H
-
F \OH
H
2 c o To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (200 15 mg, 0.483 mmol) in dioxane (3.0 mL) and H 2 0 (1.0 mL) was added (3 formylphenyl)boronic acid (317 mg, 1.93 mmol), and Cs 2
CO
3 (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 1602 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 H-indole-7-carboxamide. To a solution of 3-[1-(ethylsulfonyl)-4-piperidiny]-5-(3-formylphenyl)-1H-indole-7 carboxamide (40 mg, 0.09 mmol) and 2,2,2-trifluoroethylamine (78 gL, 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%). 110 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 523.2 [M+H] Ret. Time. 1.66 Example 39: 5-(3-ff(2-amino-2-oxoethyl)(methvl)aminolmethyllphenyl)-3-[1 (ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate 5 0
H
2 N 0 0 H2C N/N \..-- H N F O 2 0 F OH To a solution 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-indole-7 carboxamide (44 mg, 0.1 mmol) and AF-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 Example40: 3-[1-(ethylsulfonvl)-4-piperidinvll-5-(2-{[(2,2,2 trifluoroethyl)aminolmethyl}-1,3-thiazol-4-vl)-1 H-indole-7-carboxamide 20 trifluoroacetate S F O N N N HF F F o F+ SF OH N INH H 2 0 111 WO 2007/005534 PCT/US2006/025402 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 pL, 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 H-indole-7-carboxamide. 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 (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(O) (11 mg, 0.01 mmol). The mixture was reacted in a CEM microwave tube at 1600 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-cyano-5-ff(2,2,2-trifluoroethvl)aminolmethyllphenvl)-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 20
H
3 C N FN FF F O N F H 0 NH2 F OH 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 (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 K 2
CO
3 (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 1602 C. It was then purified by Gilson Preparatory 112 WO 2007/005534 PCT/US2006/025402 HPLC to give 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7 carboxamide. To a solution of 5-(3-cyano-5-formylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 ptL, 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: 3-1 -(ethylsuifonyl)-4-piperidinyll-5-(5-frmethyl(l -methyl-4 15 piperidinvl)aminolmethyl}-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate 0S N F O N F OH 0 NH2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7 carboxamide (50 mg, 0.11 mmol) in dimethyl sulfoxide (2 mL) was added N,1-dimethyl-4 piperidinamine (128.22 mg, 1.0 mmol), 2 drops of acetic acid and reacted overnight. 20 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 25 Example 43: 5-(5-ff(2-cyanoethyl)(methvl)aminolmethyl}-3-thienyl)-3-[1 (ethylsulfonyl)-4-pi peridinyll-1 H-indole-7-carboxamide trifluoroacetate 113 WO 2007/005534 PCT/US2006/025402 0 N s N N
CH
3 F a - N F H F OH o NH 2 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) 5 1 H-indole-7-carboxamide trifluoroacetate, substituting 3-(methylamino)propanenitrile (84.12 mg, 1.0 mmol) for N,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 10 Example 44: 5-(5-{[(2-amino-2-oxoethyl)(methvl)aminolmethyll-3-thienvl)-3-[1 (ethylsulfonvl)-4-pi peridinyll-1 H-indole-7-carboxamide trifluoroacetate F o F OH N 0\\
NH
2 The title compound was prepared according to the general procedure for 3-[1 15 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1 -methyl-4-piperidinyl)amino]methyl}-3-thienyl) 1 H-indole-7-carboxamide trifluoroacetate, substituting AF-methylglycinamide (88.11 mg, 1.0 mmol) for N,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 20 Example 45: 3-[1 -(ethylsuIfonyl)-4-pi peridinyll-5-[5-({methyll2 (phenylsulfonyl)ethyllaminomethyl)-3-thienyll-1 H-indole-7-carboxamide trifluoroacetate 114 WO 2007/005534 PCT/US2006/025402 0 O=s2 N s F-F/0 N F OH o NH 2 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) 5 1 H-indole-7-carboxamide trifluoroacetate, substituting N-methyl-2 (phenylsulfonyl)ethanamine (199.27 mg, 1.0 mmol) for N,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 10 Example 46: 3-[1 -(ethylsu lfonvl)-4-piperidinvil-5-{5-[(2-phenvl-1 pyrrolidinvl)methyll-3-thienvll-1H-indole-7-carboxamide 0 N S N/ N H O NH2 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-phenylpyrrolidine (147 15 mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 1200 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. 20 Example 47: 3-i 1-(ethylsuilfonyll)-4-pi peridi nyll-5-(5-f[2-(1 -piperidi nyl methyl)-1 pyrrolidinvllmethyll-3-thienvl)-1 H-indole-7-carboxamide 115 WO 2007/005534 PCT/US2006/025402 N NN H O
NH
2 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-ff(2R)-2-(aminocarbonyl)-1-pyrrolidinvllmethyll-3-thienvl)-3-f1 (ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide O O= H 2 N :::O N/ HN H 10 0 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 D-prolinamide (114 mg, 1.0 mmol) for 2-phenylpyrrolidine to afford 14 mg of the title compound (23 %). 15 LC/MS = m/z 544.2 [M+H] Ret. Time: 1.39 Example 49: 5-(5-ff(3S)-3-(dimethylamino)-1-pyrrolidinvllmethyl}-3-thienvl)-3-[1 (ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide 116 WO 2007/005534 PCT/US2006/025402 O Chiral O=Sd N S N\ \ N H O NH2 The title compound was prepared according to the general procedure for 3-[l (ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1 -pyrrolidinyl)methyl]-3-thienyl}-1 H-indole-7 carboxamide, substituting (2R)-NN-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-[4-(dimethylamino)-1-piperidinvllethvl}-1H-pyrazol-4-yI)-3-rl (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate N N N N F O N F F OH N H 10 0 NH 2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane (750 pL) and H 2 0 (250 pL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-1-(2 chloroethyl)-1 H-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 1200 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-chloroethy)-1H pyrazol-4-yl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (24%). 20 117 WO 2007/005534 PCT/US2006/025402 To a solution of 5-[1-(2-chloroethyl)-1 H-pyrazol-4-yl]-3-[1 -(ethylsulfonyl)-4-piperidinyll-1 H indole-7-carboxamide (33 mg, 0.071 mmol) in tetrahydrofuran (500 uL) was added NN dimethyl-4-piperidinamine (100 pL,0.71 mmol) and Sodium Iodide (5 mg, 0.018 mmol). The resulting mixture was reacted in a microwave tube at 1300 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. 10 Example 51: 5-[3-f(dimethylamino)methyll-4,5-bis(methyloxv)phenvil-3-l1 (ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide og NN H O NH2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1 ,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (500 mg, 1.09 mmol) in dioxane (9.0 mL) 15 and H 2 0 (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 1200 C for 30 min. All solvent was then concentrated and an aqueous wash was performed with EtOAc and 20 H 2 0. 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 H-indole-7 carboxamide (59%). To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4,5-bis(methyloxy)phenyl] 1 H-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 pL, 0.30 mmol). The mixture was stirred at room temperature for 2 h then reacted in the microwave at 1000 C for 30 min. The resulting mixture was purified by Gilson Preparatory HPLC to give 11 mg of the title compound (34.7 %). 118 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 529 [M+H] Ret. Time: 1.67 min. Example 52: 5-[3,4-bis(methyloxy)-5-(4-morpholinvlmethvl)phenvll-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide N N 5 O NH2 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 pL, 0.30 mmol) for dimethylamine to afford 8.0 mg of the title compound (23.4 %). 10 LC/MS = m/z 571 [M+H] Ret. Time: 1.59 min. Example 53: 3-[1 -(ethylsuifonyl)-4-piperidi nvll-5-[3-ff(1 -methylethyl)ami nolmethyll 4,5-bis(methvloxv)phenvll-1 H-indole-7-carboxamide H N O NH2 15 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 pL, 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. 20 Example 54: 3-[1 -(ethylsulfonyl)-4-piperidinyll-5-[3-{1 -methylethvl)aminolmethyl} 4,5-bis(methvloxv)phenvll-1 H-indole-7-carboxamide 119 WO 2007/005534 PCT/US2006/025402 // N O H N H 0 NH2 The title compound was prepared according to the general procedure of 5-13 [(dimethylamino)methyl]-4,5-bis(methyloxy)pheny]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide , substituting 40 wt. % methylamine (50 pL, 0.30 mmol) for 5 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-F3-f(2,2-dimethylpropvl)aminolmethyll-4,5-bis(methyloxv)phenvil-3 [1-(ethylsulfonv)-4-piperidinvll-1 H-indole-7-carboxamide 10 0 2 The title compound was prepared according to the general procedure of 5-[3 [(dimnethylamino)methyl]-4,5-bis(methyloxy)phenyl-3-[1 -(ethyisulfonyl)-4-piperidinyl]- 1H indole-7-carboxamide , substituting (2,2-dimethylpropyl)amine (20 pL, 0.30 mmol) for 15 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-[1 -(ethylsulfonl)-4-piperidinll-5-[3-fi(2 hydroxyethl)(methl)aminalmethl-4.5-bis(methylox)phenl-1 H-i ndole-7 20 carboxamide 120 WO 2007/005534 PCT/US2006/025402 N O N HO H 0
NH
2 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 pL, 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-[3,4-bis(methyloxy)-5-(1-pvrrolidinvimethvl)phenvil-3-[l 10 (ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide N H O NH2 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 pL, 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-[(dimethylamino)methyll-2.3-dihvdro-1-benzofuran-6-vIl-3-[1 20 (ethylsulfonyl)-4-pi peridi nyll-1 H-indole-7-carboxamide 121 WO 2007/005534 PCT/US2006/025402 OsO O N NN O NH2 To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (113 mg, 0.274 mmol) in dioxane (9.0 mL) and H 2 0 (3.0 mL) was added sodium carbonate 5 (174 mg, 1.64 mmol), and 6-(4,4,5,5-tetramethy-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 1200 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 H-indole-7-carboxamide (91%). To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2,3-dihydro-1-benzofuran-6 yl)-1H-indole-7-carboxamide (20 mg, 0.042 mmol) in methanol (2 mL) was added 15 dimethylamine (3 pL ,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 1000 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 %). 20 LC/MS = m/z 525 [M+H] Ret. Time: 1.56 min. Example 59: 3-F1 -(ethylsulf onyl)-4-piperidi nvll-5-(4-f(1 -methylethyll)ami nolmethyll 2,3-dihydro-1-benzofuran-6-y)-1H-indole-7-carboxamide O2 H O NH2 122 WO 2007/005534 PCT/US2006/025402 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 5 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-I1 -(ethylsulfonyl)-4-pi peridi nvll-5-[4-(4-morphol inyl methyl)-2.3 dihydro-1 -benzof uran-6-vll-1 H-indole-7-carboxamide ON NN 10 0 NH2 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] 1 H-indole-7-carboxamide, substituting 2,2-dimethyl-1 -propanamine (4 mg, 0.050 mmol) 15 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: 3-1 -(ethylsuifonyl)-4-piperidi nvIl-5-[5-({ f1-methyl-2 (methyloxy)ethyllaminolmethyl)-2-thienvil-1 -indole-7-carboxamide Hac\ N
H
3 c N H 20
H
2 N 0 [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 N 2 . To this was added 5-bromo-3-[1-(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide (80 mg, 0.19 mmol), potassium carbonate (160mg, 123 WO 2007/005534 PCT/US2006/025402 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 1500 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 NH 3 in MeOH (6 mL). The NH 3 in MeOH fractions were dried under a stream of N 2 at 400 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 N 2 at 600 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-ff(2-cyanoethyl)aminolmethyl}-3-pyridinyl)-3-1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide io N N HI N N H 15
H
2 N 0 To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-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 1500 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 NH 3 in MeOH (6 mL). The NH 3 in MeOH fractions were dried under a stream of N 2 at 400 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 N 2 at 650 C to give 6.2 mg of the title compound (17.4 %). LC/MS = m/z 495 [M+H] Ret. Time: 1.29 min. 30 124 WO 2007/005534 PCT/US2006/025402 Example 63: 3-1 -(ethylsulfonyl)-4-pi peridi nVIl-5-(5-ff(2,2,2 trifl uoroethy~aminolmethyl}-3-pyridinyl)-l H-indole-7-carboxamide N N F F H N F N H
H
2 N 0 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 H-indole-7 carboxamide, substituting 2,2,2-trifluoro-N-{[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 %). 10 LC/MS = m/z 524 [M+H] Ret. Time: 1.55 min. Example 64: 5-{3-[(dimethylamino)methyll phenvl}-3-1 -(ethylsulfonyl)-4-pi peridinyll 1 H-indole-7-carboxamide 0 N N H 0
NH
2 15 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7 carboxamide (45 mg, 0.10 mmol) in DMSO (2 mL) was added 2 M dimethylamine in THF (500 pL ,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 125 WO 2007/005534 PCT/US2006/025402 Example 65: 5-(5-{ethyl(methyl)aminolmethyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate N S F O F OH O NH2 5 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-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-f[[2-(diethylamino)ethyll(methvl)aminolmethyl)-3-thienvi)-3-[1 (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate N N F N F O H F-H 15 F OH 0 NH 2 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 H-indole-7 carboxamide trifluoroacetate , substituting NN-diethyl-N-methy-1,2-ethanediamine (130 20 mg, 1.0 mmol) for N-methylethanamine to afford 30.0 mg of the title compound (44.5 %). LC/MS = m/z 560 [M+H] Ret. Time: 1.41 min. 126 WO 2007/005534 PCT/US2006/025402 Example 67: 5-(5-{[butyl(methylami nol methyll-3-thienvl)-3-[l -(ethylsu Ifonyl)-4 piperidinvll-1 H-indole-7-carboxamide trifluoroacetate N S N F 0 N F H F OH 0
NH
2 5 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 H-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. 10 Example 68: 3-Fl-(ethylsulfonvl)-4-piperidinyll-5-(5-f[methyl(propyl)aminolmethyll 3-thienyi)-1 H-indole-7-carboxamide trifluoroacetate 0 N S F 0 N F H F OH 0
NH
2 15 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 H-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. 20 Example 69: 5-(5-{[[2-(dimethylamino)ethyll(methvl)aminolmethyl}-3-thienvl)-3-[1 (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate 127 WO 2007/005534 PCT/US2006/025402 O N S F O N F / H F OH 0 NH 2 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 H-indole-7 5 carboxamide trifluoroacetate , substituting [2-(dimethylamino)ethyl]methylamine (102 mg, 1.0 mmol) for N-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-fF[3-(dimethylamino)propyll(methvl)aminolmethyl}-3-thienv)-3-[1 10 (ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 0,1 N N S N F 0 F N F OH H 0
NH
2 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 H-indole-7 15 carboxamide trifluoroacetate , substituting [3-(dimethylamino)propyl]methylamine (116 mg, 1.0 mmol) for N-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-fFcyclopentyl(methyl)aminolmethyll-3-thienvl)-3-[1-(ethylsulfonvi) 20 4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate 128 WO 2007/005534 PCT/US2006/025402 N F F OH 0 H2 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 H-indole-7 5 carboxamide trifluoroacetate , substituting cyclopentyl(methyl)amine (99 mg, 1.0 mmol) for N-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-[1 -(ethylsulfonvl)-4-piperidinvll-5-(5-4rmethyl(Pentvl)ami nolmethyll 10 3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate O N N N F-H H F OH 0
NH
2 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 H-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-[1 -(ethylsu Ifonyl)-4-pi peridi nvil-5-(5-ffmethyl(2 20 methylpropvl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate 129 WO 2007/005534 PCT/US2006/025402 0 N S N F o N F H F OH O
NH
2 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 H-indole-7 5 carboxamide trifluoroacetate , substituting methyl(2-methylpropyl)amine (87 mg, 1.0 mmol) for N-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-[1-(ethylsulfonvl)-4-piperidinvll-5-(5 10 {[methyl(phenvlmethvl)aminolmethyll-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate O
O
N S N FH F OH 0 NH 2 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 H-indole-7 carboxamide trifluoroacetate , substituting methyl(phenylmethyl)amine (121 mg, 1.0 mmol) for N-methylethanamine to afford 15 mg of the title compound (22.6 %). LC/MS = m/z 551 [M+H] Ret. Time: 1.67 min. 20 Example 75: 3-[1-(ethylsulfonvl)-4-piperidinvil-5-(5-f[(2 hydroxvethyl)(methvl)aminolmethvl}-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate 130 WO 2007/005534 PCT/US2006/025402 F 00 F O F OH N S N 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 H-indole-7 5 carboxamide trifluoroacetate , substituting 2-(methylamino)ethanol (75 mg, 1.0 mmol) for N-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-fl-(ethylsulfonyl)-4-piperidinvll-5-f5-({methvl[2-(2 10 pyridinvl)ethyllaminolmethyl)-3-thienvll-1 H-indole-7-carboxamide trifluoroacetate 0 0= / N s N N IN H o NH 2 F o F4 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 H-indole-7 15 carboxamide trifluoroacetate , substituting methyl[2-(2-pyridinyl)ethyl]amine (75 mg, 1.0 mmol) for N-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: 3-1 -(ethylsuIfonyl)-4-piperidi nyll-5-(5-ff(2 20 furanvlmethVl)(methvl)aminolmethyll-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate 131 WO 2007/005534 PCT/US2006/025402 0 0=S N S N SF o H F 4
NH
2 H 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 H-indole-7 5 carboxamide trifluoroacetate , substituting 1-(2-furanyl)-N-methylmethanamine (111 mg, 1.0 mmol) for N-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-[1 -(ethylsuIfonvI-4-Piperidinvil-5-(5-f[methyl(4 10 pyridinvlmethvl)aminolmethyl}-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate 0 O=S IN S N F O NH2 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 H-indole-7 15 carboxamide trifluoroacetate , substituting methyl(4-pyridinylmethyl)amine (122 mg, 1.0 mmol) for N-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: 3-1 -(ethylsu Ifonyl)-4-piperidinvll-5-{5-[(methyl{f[1-(1 -methylethyl)-3 20 pyrrolidinyllmethyllamino)methyll-3-thienyl}-1 H-indole-7-carboxamide trifluoroacetate 132 WO 2007/005534 PCT/US2006/025402 0 O= N S N N H FH O NH2 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 H-indole-7 5 carboxamide trifluoroacetate substituting methyl{[1 -(1 -methylethyl)-3 pyrrolidinyl]methyl}amine (156 mg, 1.0 mmol) for N-methylethanamine to afford 21.0 mg of the title compound (30.0 %). LC/MS = m/z 586 [M+H] Ret. Time: 1.43 min. 10 Example 80: 3-1 -(ethylsulfonvl)-4-pi peridinvll-5-(5-fmethvl(2 thienvimethyl)aminolmethyll-3-thienyl)-I H-indole-7-carboxamide trifluoroacetate 0 O= N S N F F OH O0 H 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 H-indole-7 15 carboxamide trifluoroacetate , substituting methyl(2-thienylmethyl)amine (127 mg, 1.0 mmol) for N-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-[1-(ethvlsulfonyl)-4-piperidinyll-5-[5-({methvl[1-(2 20 thienvl)ethyllamino}methyl)-3-thienvll-1 H-indole-7-carboxamide trifluoroacetate 133 WO 2007/005534 PCT/US2006/025402 0 N S N\ s N F o F 0 NH 2 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 H-indole-7 5 carboxamide trifluoroacetate , substituting methyl[1-(2-thienyl)ethyl]amine (141 mg, 1.0 mmol) for N-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: 3-1 -(ethylsulfonyl)-4-piperidinvll-5-(5-{[methyl(3 10 thienvlmethvl)aminolmethyll-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate N S F H F OH O N2 The title compound was prepared according to the general procedure of 5-(5 {[ethyl(methyl)aminolmethyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl}-1 H-indole-7 15 carboxamide trifluoroacetate , substituting methyl(3-thienylmethyl)amine (127 mg, 1.0 mmol) for N-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-[1-(ethylsulfonyl)-4-piperidinvIl-5-(5-ffmethyl(tetrahvdro-2H-pyran-4 20 vlmethvl)aminolmethyl}-3-thienl')-1 H-indole-7-carboxamide trifluoroacetate 134 WO 2007/005534 PCT/US2006/025402 0 N 0s F o N 0 H F O NH 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 H-indole-7 5 carboxamide trifluoroacetate , substituting methyl(tetrahydro-2H-pyran-4-ylmethyl)amine (129 mg, 1.0 mmol) for N-methylethanamine to afford 11.0 mg of the title compound (16.4 LC/MS = m/z 559 [M+H] Ret. Time: 1.63 min. 10 Example 84: 3-F1 -(ethylsuIfonyl)-4-piperidi nyll-5-(5-fFmethvl(3 pyridinvlmethvl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate 0 N NN F O NH F OH The title compound was prepared according to the general procedure of 5-(5 15 {[ethyl(methyl)amino]methy}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidiny]-1 H-indole-7 carboxamide trifluoroacetate , substituting methyl(3-pyridinylmethyl)amine (122 mg, 1.0 mmol) for N-methylethanamine to afford 9.5 mg of the title compound (14.3 %). LC/MS = m/z 552 [M+H] Ret. Time: 1.56 min. 20 Example 85: 3-[1 -(ethylsuifonyl)-4-pi peridi nvil-5-(5-{Fmethvl(4 pyrimidinylmethvl)aminolmethyll-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate 135 WO 2007/005534 PCT/US2006/025402 N NAN F 0 N F NH 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 H-indole-7 5 carboxamide trifluoroacetate , substituting methyl(4-pyrimidinylmethyl)amine (123 mg, 1.0 mmol) for N-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-l-(ethylsulfonyl)-4-piperidinvil-5-[5-(fmethyl[2 10 (methyloxy)ethyllaminolmethyl)-3-thienil-1 H-indole-7-carboxamide trifluoroacetate 0 N 0N\ F N N FH F OH o NH 2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formy-3-thienyl)-1 H-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 CHCI 3 (50 mL) was added. The mixture was filtered, the CHC1 3 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. 136 WO 2007/005534 PCT/US2006/025402 Example 87: 5-{3-[(dimethylamino)methyllphenvl}-3-[l-(ethylsulfonvl)-4-piperidinyll 1 H-indole-7-carboxamide trifluoroacetate F O F OH N N H O
NH
2 5 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7 carboxamide (45 mg, 0.1 mmol) in DMSO (2 mL) was added 2 M methylamine in THF (500 pL, 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: 3-1 -(ethylsulfonyl)-4-pi peridinvll-5-(5-f[methyl(1 methylethvl)aminolmethyll-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate 0 N \ s F F OH O NH 2 15 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-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 1600 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. 137 WO 2007/005534 PCT/US2006/025402 Example 89: 3-[1 -(ethylsuifonyl)-4-piperidi nvIl-5-f5-[(2-propvl-1 -pyrrol idi nyl)methvll 3-thienvl}-1 H-indole-7-carboxamide 0 O=S N S N \/ N H O NH 2 5 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-propylpyrrolidine (113 mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 1200 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: 3-1 -(ethylsulfonyl)-4-pi peridinvll-5-(5-f [2-(3-pyridinvl)-1 pyrrolidinyulmethyll-3-thienvl)-1 H-indole-7-carboxamide O N S N \/ N H 15 2 NH2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propy-1 -pyrrolidinyl)methyl]-3-thienyl}-1 H-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. 138 WO 2007/005534 PCT/US2006/025402 Example 91: 5-(5-{[2-(1,1-dimethylethyl)-1-pyrrolidinyulmethyll-3-thienVl)-3-[l (ethylsulfonvi)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate 0 IN S N F O N F OH O NH 2 5 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-(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. 10 Example 92: 545-[(2-ethyl-1 -pyrrolidi nyl)methyll-3-thienyl}-3-1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide 0 O= N S N \/ N H O NH 2 15 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-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. 20 Example 93: 3-1 -(ethylsulfonyl)-4-piperidi nyll-5-(5-f[2-(2-methyl propyl)-1 pyrrolidinyllmethyll-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate 139 WO 2007/005534 PCT/US2006/025402 N S N F 0 N F O H F-F 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 H-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-i1-(ethylsulfonvl)-4-piperidinvll-5-(5-fF2-(1-methylethyl)-1 10 pyrrolidinyllmethyll-3-thienvli)-1 H-indole-7-carboxamide 2 O=S N S N N H 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 H-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: 3-1 -(ethylsulfonyl)-4-piperidinvil-5-f5-(f(2S)-2-f(methyloxv)methvll-1 20 pyrrolidinvlmethyl)-3-thienvll-1 H-indole-7-carboxamide 140 WO 2007/005534 PCT/US2006/025402 O \ / N H O NH 2 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 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-{[cyclohexyl(methvl)aminolmethyl}-3-thienvl)-3-[1-(ethylsulfonvi) 10 4-piperidinyll-1 H-indole-7-carboxamide 2 N S N H O NH 2 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 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-[1-(ethylsulfonvl)-4-piperidinvIl-5-(5-ff2-(2-methVlpropyl)-1_ pyrrolidinyulmethyll-3-thienyl)-1 H-indole-7-carboxamide 141 WO 2007/005534 PCT/US2006/025402 0 N S N N H O NH 2 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 5 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-{[ethyl(methyl)aminolmethyll-3-thienyl)-3-[1 -(ethylsu Ifonyl)-4 piperidinyll-1 H-indole-7-carboxamide N S N H 10 O NH2 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-[1-(ethylsulfonyl)-4-piperidinvil-5-(5-ffmethyl(propyl)aminolmethyll 20 3-thienyl)-1 H-indole-7-carboxamide 142 WO 2007/005534 PCT/US2006/025402 N S /N\ N H O NH 2 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 H-indole-7 carboxamide, substituting methyl(propyl)amine (73 mg, 1.0 mmol) for 2-propylpyrrolidine 5 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: 341-0 -methylethyl)sulfonyll-4-piperidinvll-5-(5 {[methyl(propvl)aminolmethyl}-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate 0 S NN F OH F O NH2 10 F OH To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H 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. 20 Example 101: 5-(5-f[ethyl(methvl)aminolmethyl}-3-thienyl)-3-{1-[(1 methylethvl)sulfonvll-4-piperidinvl}-1 H-indole-7-carboxamide 143 WO 2007/005534 PCT/US2006/025402 S -N N H O NH2 The title compound was prepared according to the general procedure of 3-{1-[(1 methylethyl)sulfonyl]-4-piperidinyll-5-(5-{[methyl(propyl)amino]methyll-3-thienyl)-1 H indole-7-carboxamide trifluoroacetate, substituting ethyl(methyl)amine (59 mg, 1.0 mmol) 5 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-[(1-methylethvl)sulfonVll-4-piperidinvl}-5-[5-({methvl[2 (methyloxv)ethyllaminolmethyl)-3-thienvll-1 H-indole-7-carboxamide 0 S -N N O H 10 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 H indole-7-carboxamide trifluoroacetate, substituting methyl[2-(methyloxy)ethyl]amine (89 15 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-[1-(ethylsulfonvi)-4-piperidinvll-5-f5-[(methylamino)methyll-2 thienyl}-1 H-indole-7-carboxamide 144 WO 2007/005534 PCT/US2006/025402 NH 4 1O N /S N H O NH 2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1H-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 NH 3 in MeOH (10 mL x 2). The NH 3 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: 341 -(ethylsulfonyl)-4-pi peridinvll-545-f(2-methyl-1 pyrrolidinvl)methyll-3-thienvl}-1 H-indole-7-carboxamide trifluoroacetate Oz
S-
F F -'N F OH H 15 2 NH2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1 H-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%). 145 WO 2007/005534 PCT/US2006/025402 LCMS: 515.4 (M+H), Rt 1.60 min Example 105: 3-1 -(ethylsuifonyl)-4-piperidi nyll-5-(5-ff(2 methylpropvl)aminolmethyl}-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate 50 2 H N N S F O F N F OH H 5 O NH 2 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 (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-[l-(ethylsulfonyl)-4-piperidinvll-5-{5-[(propylamino)methyll-3 15 thienyll-1 H-indole-7-carboxamide trifluoroacetate H 0::: 0 2 S F F \ N IF OH H O NH 2 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), (2-methylpropyl)amine (0.17 mL, 1.68 mmol), and sodium triacetoxyborohydride (356 mg, 146 WO 2007/005534 PCT/US2006/025402 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 5 Example 107: 5-{5-[(diethylamino)methyll-3-thienvl}-3-[l-(ethylsulfonyl)-4 piperidi nyl-1 H-indole-7-carboxamide trifluoroacetate Ozzs 1 'O N N FO F+. N F OH H O NH 2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-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%). 15 LCMS: 501.4 (M+H), Rt 1.51 min Example 108: 5-(5-{(2R,5R)-2,5-dimethyl-1 -pyrrolidinvllmethyll-3-thienvl)-3-[l (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate S \ / F O F--4) N F OH H 20 2 NH2 147 WO 2007/005534 PCT/US2006/025402 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 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 10 Example 109: 5-5-(cyclopropvlamino)methyll-3-th ienvl}-3-1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate S'O L\ H N N S F IF OH N H O NH2 To a solution of 3-[l-(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 20 Example 110: 5-{5-f(cyclobutylamino)methyll-3-thienvl}-3-[1-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 148 WO 2007/005534 PCT/US2006/025402
SS
\ / F F OH N H O NH 2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidiny]-5-(5-formyl-3-thienyl)-1H-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 10 Example 111: 5-f5-r(dimethylamino)methyll-3-thienvil-3-[1-(ethylsulfonl)-4 piperidi nyl-1 H-indole-7-carboxamide trifluoroacetate -N N S F F OH N H O NH 2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2-thienyl)-1H-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. 149 WO 2007/005534 PCT/US2006/025402 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 5 Example 112: 5-(5-ff(cyclopentvlmethvl)aminolmethyl}-3-thienvi)-3-l (ethylsulfonyl)-4-piperidi nyl-1 H-indole-7-carboxamide trifluoroacetate NH N S F O F F OH N H O NH 2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-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%). 15 LCMS: 529.4 (M+H), Rt 1.61 min and 1.64 min Example 113: 5-[5-({[(1R)-1,2-dimethylpropyllaminolmethyl)-3-thienvll-3-[1 (ethylsulfonvl)-4-piperidinyil-1 H-indole-7-carboxamide trifluoroacetate 150 WO 2007/005534 PCT/US2006/025402 NH N S F O F - - N F OH H O NH2 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 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 10 Example 114: 5-{5-[(cyclopentylamino)methyll-3-thienvl}-3-[1-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate O.:) ( -NHN F F F OHH O NH2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-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 151 WO 2007/005534 PCT/US2006/025402 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 5 Example 115: 5-(5-f{(cyclopropvlmethvl)aminolmethyll-3-thienvi)-3-[1 (ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate NH N S F F OH N H O NH2 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 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 15 Example 116: 5-[5-(F(1 S)-1,2-dimethylpropyllaminolmethyl)-3-thienll-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate /'-O ;NH N S F 0 F-+ N F OH H O NH2 152 WO 2007/005534 PCT/US2006/025402 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 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 triacetoxyborohyd ride (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-ff(2,2-dimethylpropvllaminolmethyl}-3-thienvi)-3-[1 10 (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate 00 N HN S F OH O 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), 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 20 Example 118: 3-1 -(ethylsulfonyl)-4-pi peridinyll-5-(5- F(phenylmethyl)ami nol methyll 3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate 153 WO 2007/005534 PCT/US2006/025402 OZ) N HN S F O FH N F OH H O NH 2 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 10 Example 119: 3-fl-(ethylsulfonvl)-4-piperidinvil-5-f5-(ff(2S)-tetrahvdro-2 furanylmethyllaminolmethyl)-3-thienvll-1 H-indole-7-carboxamide trifluoroacetate COO N HN S F O FH N F OH H O NH 2 To a solution of 3-[l-(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), 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 154 WO 2007/005534 PCT/US2006/025402 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 5 Example 120: 3-1 -(ethvlsu lfonyl)-4-pi peridi nvIl-5-(5-f[(tetrahVdro-2H-pVran-4 ylmethyl)aminolmethyll-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate 0 0 NN S F O F F OHN O NH 2 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 15 Example 121: 5-{5-[(butylamino)methyll-3-thienvl}-3-[l-(ethylsulfonvl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate H N/ O N N F O F N : OH H O NH2 155 WO 2007/005534 PCT/US2006/025402 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 10 Example 122: 3-[1-(ethylsulfonvl)-4-piperidinvll-5-[5-({[(2R)-tetrahvdro-2 furanylmethyllaminolmethyl)-3-thienyIl-1 H-indole-7-carboxamide trifluoroacetate 0 / 0O N HN F IF OH N O NH 2 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 [(2R)-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: 3-1 -(ethylsulfonyl)-4-piperidi nvil-5-[5-((2S)-2-f(methyloxy)methyl1-1 pyrrolidinvilmethyl)-3-thienyll-1 H-indole-7-carboxamide trifluoroacetate 156 WO 2007/005534 PCT/US2006/025402 N N F O F N F OH H O NH 2 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, (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. 10 Example 124: 3-[1 -(ethylsulfonyl)-4-pi peridi nvil-5-[5-(f(2R)-2-[(methyIoxy)methyIl-1 pyrrolidinyllmethyl)-3-thienvll-1 H-indole-7-carboxamide trifluoroacetate N/ O 0 ~SN '\ / F F N F OH H O NH 2 15 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), (2R)-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 157 WO 2007/005534 PCT/US2006/025402 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. 5 Example 125: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-f4-[2-(methylamino)ethyllphenvl.
1 H-indole-7-carboxamide 0 I O=,s HN N N H H2N O To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (200 mg, 0.48 mmol) in dioxane and H 2 0 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 160L) C for 40 min. The reaction was diluted with EtOAc and H 2 0 and filtered to obtain a yellow crystal as desired product. The solution was washed with brine and H 2 0 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 H-indole 7-carboxamide. To 5-[4-(cyanomethy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-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 00 C. The reaction was stirred at 00 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 H-indole-7-carboxamide, which was taken on without further 25 purification. 158 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-1 H-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. 10 Example 126: 3-[1-(ethylsulfonvl)-4-piperidinyll-5-f4-[2-(propylamino)ethyllphenvl 1 H-indole-7-carboxamide HN N NN VH H2N O The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-1 H-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-{4-[2-(ethylami no)ethyllphenyl}-3-[1 -(ethylsulfonyl)-4-pi peridi nyll 20 1 H-indole-7-carboxamide 159 WO 2007/005534 PCT/US2006/025402 HN N VN H H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-1H-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. 10 Example 128: 5-{4-[(f1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5 vllcarbonvllamino)methyllphenvl}-3-[1-(ethylsulfonyl)-4-piperidinyll-1H-indole-7 carboxamide trifluoroacetate 0 NH N N-N F N F OH H2N O 15 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-1H-pyrazole-5-carbonyl chloride (290 mg, 1.45 mmol) and triethylamine (403 pL, 2.90 mmol). The reaction was stirred for 2 h. It was then quenched and partitioned between EtOAc and H 2 0 and the organic layer was 160 WO 2007/005534 PCT/US2006/025402 concentrated to give {4-[({[1 -(1 , 1 -dimethylethyl)-3-methyl- 1 H-pyrazol-5 yl]carbonyl}amino)methyl]phenyl}boronic acid. To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 H-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 (11) (7 mg, 0.012 10 mmol). The reaction was stirred for 10 min then heated to 1500 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. 15 Example 129: 3-[1-(ethylsulfonyl)-4-piperidinvIl-5-(4-ff(4 pyridinvicarbonvl)aminolmethyllpheni)-1 H-indole-7-carboxamide 0 0 NH N N ...
N H H2N O The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1 dimethylethyl)-3-methyl-1 H-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. 25 Example 130: 5-(4-{[(cyclopentvlcarbonyl)aminolmethyllphenyl)-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide 161 WO 2007/005534 PCT/US2006/025402 0 eNH N N H H2N O The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1 dimethylethyl)-3-methyl-1 H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1 (ethylsulfonyl)-4-piperidinyl]-1H-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. 10 Example 131: 3-[1-(ethylsulfonyl)-4-piperidinvll-5-(4-ff(2 furanvlcarbonvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide 0 0 O1 COINH N N H H2N O The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1 dimethylethyl)-3-methyl-1 H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1 15 (ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate , substituting (4 {[(2-furanylcarbonyl)aminolmethyl}phenyl)boronic acid (118 mg, 0.480 mmol) for {4-[({[1 (1,1-dimethylethyl)-3-methyl-1H-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. 162 WO 2007/005534 PCT/US2006/025402 Example 132: 5-(4-f2-[(cyclobutvcarbonl)aminolethyllphenv)-3-[1-(ethylsulfonyl) 4-piperidi nyl-1 H-indole-7-carboxamide 0 H N H H2N O 5 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 N-[2-(4-bromophenyl)ethyl]cyclobutanecarboxamide (100 mg, 0.324 mmol) for N-[2-(4-bromophenyl)ethyl]acetamide. Purified by flash chromatography to afford 28 mg of the title compound (48.3%). 10 LC/MS = m/z 537.2 [M+H] Ret. Time: 1.99 min. Example 133: 5-(4-{2-[(cyclohexylcarbonvllami nolethyllphenvl)-3-[1 -(ethylsulfonyl) 4-piperidinvll-1 H-indole-7-carboxamide 0 HNN N H H2N O 15 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 N-[2-(4-bromophenyl)ethyl]cyclohexanecarboxamide (100 mg, 0.324 mmol) 163 WO 2007/005534 PCT/US2006/025402 for N-[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. 5 Example 134: 5-(3-{2-f(cyclohexylcarbonvl)ami nolethyllphenl)-3-1 -(ethylsulfonyl) 4-piperidi nyl-1 H-indole-7-carboxamide 00 N H 2N O The title compound was prepared according to the general procedure of 5-{4-[2 (acetylamino)ethyl]phenyll-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide, 10 substituting N-[2-(3-bromophenyl)ethyl]cyclohexanecarboxamide (100 mg, 0.324 mmol) for N-[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. 15 Example 135: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-[6-(1-piperazinvi)-3-pyridinvll-1H indole-7-carboxamide trifluoroacetate HN N\\ N~ 0N HN F O F 'N F OHH H2N O To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (100 20 mg, 0.241 mmol) in dioxane (1.0 mL) and H 2 0 (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 164 WO 2007/005534 PCT/US2006/025402 was heated in a microwave at 1602 C for 20 min. Mixture was concentrated and taken up in EtOAc (10 mL) and H 2 0 (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]-1H-indol-5-yl}-2-pyridinyl)-1-piperazinecarboxylate and 3-[1-(ethylsulfonyl)-4 5 piperidinyl]-5-[6-(1 -piperazinyl)-3-pyridinyl]-1 H-indole-7-carboxamide (44%). To a solution of 1,1-dimethylethyl 4-(5-{7-(aminocarbonyl)-3-[1-(ethylsulfonyl)-4 piperidinyl]-1H-indol-5-yl}-2-pyridiny)-1-piperazinecarboxylate (130 mg, 0.218 mmol) in methanol (0.3 mL) was added 4 M HCl in dioxane (0.3 mL). The reaction was heated at LO 50L C and stirred for 3 h. Reaction mixture was concentrated and neautralized on a SCX cartridge primed with CH 2
CI
2 , 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 15 Example 136: 5-'6-(4-ethyl-1-piperazinvl)-3-pyridinvll-3-1-(ethylsulfonvl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate K0 NN N N F O F F OH H O NH2 20 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperazinyl)-3-pyridinyl]-1H 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 H 2 0. 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 165 WO 2007/005534 PCT/US2006/025402 Example 137: 3-1 -(ethylsulfonyl)-4-piperidinyll-5-[4-(1 -piperidinylmethyl) phenyll 1 H-indole-7-carboxamide trifluoroacetate ND N 0 F 0 F N F OHH O NH 2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7 5 carboxamide (40 mg, 0.09 mmol) in dichioromethane was added piperidine (9 pL, 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%). 10 LC/MS = m/z 509.4 [M+H] Ret. Time: 1.71 min Example 138: 3-ri-(ethylsulfonvl)-4-piperidinvil-5-[3-(1-piperidinvimethyl)phenvll 1 H-indole-7-carboxamide trifluoroacetate N/O N F F N \H H F OH H2N O 15 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7 carboxamide (50 mg, 0.114 mmol) in dichloromethane (2 mL) and acetic acid (1 drop) was added piperidine (46 pL, 0.456 mmol). The reaction was stirred for 2 h at room temperature before the addition of sodium triacetoxyborohydride (75 mg, 0.342 mmol). 166 WO 2007/005534 PCT/US2006/025402 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 5 Example 139: 3-f1 -(ethylsulfonyl)-4-piperilinyll-5-{4-f(methylamino)methVllphenyll 1 H-indole-7-carboxamide trifluoroacetate NH N F H H F OH H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylpheny)-1H-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 pL, 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%). 15 LC/MS = m/z 454.6 [M+H] Ret. Time: 1.23 min Example 140: 3-fl-(ethylsulfonvl)-4-piperidinvil-5-(4-f{(1 methylethvl)aminolmethyllphenyl)-1 H-indole-7-carboxamide 167* "INH N N H O NH 2 167 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyphenyl)-1H-indole-7 carboxamide (40 mg, 0.09 mmol) in DMSO (900 pL) and acetic acid (2 drops) was added 2-propanamine (93 pL, 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-Fl-(ethylsulfonvl)-4-piperidinvIl-5-f4-[(propylamino)methyllphenvil 1 H-indole-7-carboxamide trifluoroacetate '" NH N
F
0 F N F OH H 10 0 NH2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7 carboxamide (20 mg, 0.045 mmol) in DMSO (900 pL) and acetic acid (2 drops) was added propylamine (45 pL, 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-{f(1 -ethylpropyl)ami nol methyllphenyl)-3-[1 -(ethVisuIfonVI)-4 piperidinyll-1 H-indole-7-carboxamide NH N N H 20 0 NH2 168 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7 carboxamide (40 mg, 0.09 mmol) in DMSO (900 pL) and acetic acid (2 drops) was added 3-pentanamine (108 pL, 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-[(cyclopentvlamino)methyllphenvl}-3-1 -(ethylsulfonvi)-4 piperidinvll-1 H-indole-7-carboxamide trifluoroacetate NH N F F OH N H 10 H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl)-5-(4-formylphenyl)-1H-indole-7 carboxamide (40 mg, 0.09 mmol) in DMSO (900 pL) and acetic acid (2 drops) was added cyclopentylamine (108 pL, 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-{4-R(cyclobutylamino)methyllphenv}-3-[1 -(ethylsulfonyl)-4 piperidinvll-1 H-indole-7-carboxamide 169 WO 2007/005534 PCT/US2006/025402 NH N N H O NH 2 To a solution of 3-[1 -(ethylsulfony)-4-piperidinyl]-5-(4-formylphenyl)-1 H-indole-7 carboxamide (40 mg, 0.091 mmol) in DMSO (900 pL) and acetic acid (2 drops) was added cyclobutylamine (94 pL, 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-(ethylamino)methyllphenvl-3-[1-(ethylsulfonvl)-4-piperidinvil 10 1 H-indole-7-carboxamide NH N N H H 2N O To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-indole-7 carboxamide (20 mg, 0.046 mmol) in DMSO and acetic acid was added ethylamine (32 pL, 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. 170 WO 2007/005534 PCT/US2006/025402 Example 146: 5-{4-[(dimethylamino)methyllphenvl}-3-[l-(ethylsulfonvl)-4 piperidinvll-1 H-indole-7-carboxamide N N N H H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7 5 carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added N dimethylamine (170 pL, 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. 10 Example 147: 5-{4-[(diethylamino)methyllphenvl}-3-[1-(ethylsulfonyl)-4-piperidinvll 1 H-indole-7-carboxamide N N N H H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7 15 carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added diethylamine (36 pL, 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%). 171 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 497.6 [M+H] Ret. Time: 1.52 min. Example 148: 3-l-(ethvlsulfonyl)-4-piperidinvil-5-[4-(4-morpholinvimethvl)phenvll 1 H-indole-7-carboxamide 50 O0 O0 4 N N N H 5 H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7 carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added morpholine (30 pL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by 10 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: 3-1 -(ethylsulfonyl)-4-piperidinvll-5-[4-(1 -pyrrol idinyl methyl)phenvil 1 H-indole-7-carboxamide trif I uoroacetate N N F F - - N F OH H 15 H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7 carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added 172 WO 2007/005534 PCT/US2006/025402 cyclopentylamine (28 pL, 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 5 Example 150: 3-1 -(ethylsuifonyl)-4-piperidi nvIl-5-[4-({(1 S)-2-hydroxy-1 methylethyllaminolmethvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate HO O NH N F O F N F OH H H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7 10 carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added (2S)-2-amino-1-propanol (56 pL, 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 15 Example 151: 3-[1-(ethylsulfonvi)-4-piperidinvll-5-[4-(ff(1R)-2-hydroxy-1 methylethyllaminolmethvl)phenvil-1 H-indole-7-carboxamide trifluoroacetate HO NH N IF O F F OH N H H2N O 173 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyphenyl)-1H-indole-7 carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added (2R)-2-amino-1-propanol (56 pL, 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-[1-(ethylsulfonvi)-4-piperidinvil-5-[4-({[(2R)-2 hydroxvpropyllaminolmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate HO ,' r O.Z::O NH N IF O F F OH 10 H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7 carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added (2R)-1-amino-2-propanol (56 pL, 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-[1 -(ethylsu lfonyl)-4-piperidinvll-5-[4-(ff2-hydroxy-1 (hydroxymethvl)ethyllaminolmethvl)phenvll-1 H-indole-7-carboxamide 20 trifluoroacetate 174 WO 2007/005534 PCT/US2006/025402 OH N N OH F O F F OH H H2N O 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-[1 -(ethylsuifonyl)-4-piperidi nyll-5-(3-ff (1 10 methylbutyl)aminolmethyl}phenyi)-1 H-indole-7-carboxamide trifluoroacetate F O F NH04 0 F N ~N H H2N O To a solution -of -3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7 carboxamide (50 mg, 0.114 mmol) in DMSO (3.0 mL) was added 1-2-pentanamine (324 pL, 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 175 WO 2007/005534 PCT/US2006/025402 Example 155: 3-1 -(ethylsu lfonyl)-4-pi peridinvll-5-[3-(fW(1R)-1 methylpropyllamino}methvl)phenvll-1H-indole-7-carboxamide trifluoroacetate
O-
NHN F O F F OH 2 0 H2N 5 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7 carboxamide (50 mg, 0.114 mmol) in DMSO (2.0 mL) was added (2R)-2-butanamine (69 pL, 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-[l-(ethylsulfonvl)-4-piperidinvll-5-(3-ff(2 methylpropvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide NH N N H 15 H2N O To a solution of 3-[l-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7 carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL), MeOH (1.5 mL), and acetic acid (4 176 WO 2007/005534 PCT/US2006/025402 drops) was added 2-methyl-1-propanamine (137 pL, 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%). 5 LC/MS = m/z 497.2 [M+H] Ret. Time: 1.69 min Example 157: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-[3-(f[(1S)-1 methylpropyllaminolmethyl)phenvil-1 H-indole-7-carboxamide acetate 0
Z
NHN OH N H Nha 0 10 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 pL, 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 15 Example 158: 5-(4-f(cyclopropvlcarbonvl)aminolmethyl}phenvi)-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide V-1NH N N H H2N O 177 WO 2007/005534 PCT/US2006/025402 The title compound was prepared according to the general procedure of 5-{4 [(acetylamino)methyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide substituting cyclopropanecarbonyl chloride (14 pL, 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-{[(cyclobutvlcarbonvl)aminolmethylphenvi)-3-[1-(ethylsulfonyl) 4-piperidinvll-1 H-indole-7-carboxamide 0
O,
CTINH N N H 10 H2N O The title compound was prepared according to the general procedure of 5-{4 [(acetylamino)methyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide substituting cyclobutanecarbonyl chloride (17 pL, 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: 3-1 -(ethylsuifonyl)-4-pi peridinvll-5-(4-f[(2 thienvlacetvl)aminolmethyllphenyl)-1 H-indole-7-carboxamide 178 WO 2007/005534 PCT/US2006/025402 0 0-- r NH N 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 H-indole-7-carboxamide substituting (3Z)-3-(methylthio)-3,5-hexadienoy chloride (18 pL, 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-[4-(f (1S)-1.2-dimethylpropyllamino}methvl)phenil-3-[1 10 (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate ZO ,NH N F N F OH H H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-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 pL, 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 179 WO 2007/005534 PCT/US2006/025402 To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (50 mg, 0.121 mmol) in dioxane (1 mL) and H 2 0 (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 (11) (7 mg, 0.012 mmol). The reaction was then stirred and heated for 10 min in a microwave at 1600 C. The mixture was concentrated and purified by Gilson Preparatory HPLC to afford 34.3 mg of the title compound (55%). 10 LC/MS = m/z 519.4 [M+H] Ret. Time: 1.77 min Example 162: 5-[3-({(1 R)-1,2-dimethylpropyllaminolmethvl)phenvll-3-[1 (ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate F O HN N F F OH N H H2N O 15 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-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 pL, 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-pyridinyl)-3-[1-(ethylsulfonvl)-4-piperidinyll-1H-indole-7 carboxamide trifluoroacetate 180 WO 2007/005534 PCT/US2006/025402
--
1 N O NN F O F N F OH H 0 H 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 (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 H 2 0 (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 1500 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-f1-(ethylsulfonvl)-4-piperidinvl1-5-3-(1H-pyrazol-1-vl)phenvll-1H 15 indole-7-carboxamide o0-s N N N N H 0
NH
2 To 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (20 mg, 0.048 mmol) was added [3-(1 H-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(l) (3 mg, 0.005 mmol). The resulting mixture was reacted in a CEM microwave for 10 min at 160 0C then concentrated under a stream of nitrogen (greenhouse) at 80 0C. The crude product was partitioned between water (2 mL) and CH 2
CL
2 (2 mL). The layers were separated with a hydrophobic frit, and the aqueous 181 WO 2007/005534 PCT/US2006/025402 layer was extracted with CH 2
CL
2 (2 x 2 mL). The organic layers were pooled and concentrated under a stream of nitrogen at 80 0C. 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 prm 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-[4-(dimethylamino)phenvil-3-[1-(ethylsulfonvl)-4-piperidinvl-1H 10 indole-7-carboxamide ozzs N N H 0
NH
2 To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfony)-4-piperidinyl]-1H 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(Il) (1 mg, 0.002 mmol). The vial was capped and the reaction was reacted in a CEM microwave for 10 min at 160 0C. The reaction was concentrated under a stream of nitrogen at 80 0C. 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 0C 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-aminophenyl)-3-[1 -(ethylsulfonvl')-4-piperidinyll-1 H-indole-7 carboxamide 182 WO 2007/005534 PCT/US2006/025402 ozno
NH
2 N N H 0
NH
2 To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H 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 (1 x 2 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% CH 3
CN/H
2 0 (0.1% TFA) to 70% CH 3
CN/H
2 0 (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 (2 x 2 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. 20 Example 167: 3-ri-(ethylsulfonyl)-4-piperidinvil-5-f5-[(2-methyl-1 pVrrolidinVl)methVll-2-thienVl}-1H-indole-7-carboxamide NDN O:: N H 0
NH
2 183 WO 2007/005534 PCT/US2006/025402 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: 5 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 CH 2 Cl 2 (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 NH/MeOH (8 mL). The fractions containing the boronic acid crude product were concentrated under a stream of N 2 and dried under high vacuum to give 45 mg of crude product. The crude product was taken up in saturated NaHCO 3 (2 mL) and extracted with EtOAc (3 x 2 mL) to give 6.6 mg of crude {5-[(2-methyl-1 pyrrolidinyl)methyl]-2-thienyl}boronic acid. 15 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 CH 2 Cl 2 /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 NH/MeOH (8 mL). The fractions containing the boronic acid crude product were concentrated under a stream of N 2 and dried under high vacuum to give 45 mg of crude product. The crude product was taken up in saturated NaHCO 3 (2 mL) and extracted with EtOAc (3 x 2 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. NaCNBH 3 (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 NH/MeOH (9 mL). The fractions containing the boronic acid crude product were concentrated under a stream of N 2 and dried under high vacuum to give 45 mg of crude product. The crude product was taken up in saturated NaHCO 3 (2 35 mL) and extracted with EtOAc (3 x 2 mL) to give 7.8 mg of crude {5-[(2-methyl-1 184 WO 2007/005534 PCT/US2006/025402 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 H-indole-7-carboxamide (36 mg, 0.0862 mmol), {5-[(2-methyl-1 -pyrrolidinyl)methyl]-2-thienyllboronic 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 0C. To this reaction was added tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and reacted in a microwave for 20 min at 150 0C. Additional tetrakis(triphenylphosphine)paladium(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 H 2 0), eluting in sequence with water (3 mL), MeOH (9 mL), and a 2 M solution of NH/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-C1 8 column: 21.2 x 50 mm) eluting at 20 mL per min for 1 min with 10% CH 3
CN/H
2 0 (0.1% TFA) then a linear gradient of -10% CH 3
CN/H
2 0 (0.1% TFA) to 95% CH 3
CN/H
2 0 (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. 30 Example 168: 5-{5-[(ethylamino)methyll-2-thienvl}-3-1-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide 185 WO 2007/005534 PCT/US2006/025402 t0-o N /_\ s N H
H
2 N 0 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. NaCNBH 3 (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 NH/MeOH (9 mL). The NH/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-thienyllboronic acid (47 mg, 0.254 mmol) was added 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 15 carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), dioxane (1.5 mL), H 2 0 (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 H 2 0 (3 mL), MeOH (9 mL) and a 2 M solution of NH/MeOH (6 mL). The NH/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-C1 8 column: 21.2 x 50 mm) eluting at 20 mL per min for 1 min with 10% CH 3
CN/H
2 0 (0.1% TFA) then a linear gradient of 10% CH 3
CN/H
2 0 (0.1% TFA) to 25 95% CH 3
CN/H
2 0 (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 600 C to give 8.8 mg of the title compound (10%). 30 LC/MS = m/z 429.8 [M+H] Ret. Time: 1.25 min. 186 WO 2007/005534 PCT/US2006/025402 Example 169: 3-[l-(ethylsulfonvl)-4-piperidinvl-5-(5-f[(1 methylethvl)aminolmethyl}-2-thieni)-1 H-indole-7-carboxamide 0oo N SH N N H
H
2 N 0 5 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 NaCNBH 3 (40 mg, 0.64 mmol) were reacted to give 41 mg of crude (5-{[(1-methylethyl)amino]methy}-2 thienyl)boronic acid. The crude (5-{[(1 -methylethyl)amino]methyl}-2-thienyl)boronic acid 10 was then reacted with 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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. 15 Example 170: 5-f5-(cyclopropylami no)methyll-2-thienvl}-3-[1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide oj N S N H
H
2 N 0 Following the general procedure of 5-{5-[(ethylamino)methyll-2-thienyl}-3-[1 20 (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 NaCNBH 3 (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 H-indole-7-carboxamide (80 25 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and 187 WO 2007/005534 PCT/US2006/025402 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%). 5 LC/MS = m/z 430.2 [M+H] Ret. Time: 1.62 min. Example 171: 5-(5-ff(2,2-dimethylpropvl)aminolmethyl}-2-thienvl)-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide N N s N H
H
2 N 0 10 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 NaCNBH 3 (40 mg, 0.64 mmol) were reacted to give 73 mg of crude (5-{[(2,2 dimethylpropyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(2,2 15 dimethylpropyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1 (ethylsulfonyl)-4-piperidinyl]-1H-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. 20 Example 172: 5-(5-ff(cyclopropvlmethvl)aminolmethyll-2-thienvl)-3-l (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide N H S I N H
H
2 N 0 Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1 25 (ethylsulfonyl)-4-piperidinyl-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid 188 WO 2007/005534 PCT/US2006/025402 (50 mg, 0.32 mmol), (cyclopropylmethyl)amine (0.027 mL, 0.32 mmol), and NaCNBH 3 (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]-1H-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. 10 Example 173: 5-(5-ff(cyclopropvlmethvl)aminolmethyll-3-pyridinvl)-3-f1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide 0o-r N N HI N H HN 0 The (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y)-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. NaCNBH 3 (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 NH/MeOH (9 mL). The NH/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. 25 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 H-indole-7-carboxamide (30 mg, 0.0723 mmol), dioxane (0.75 mL), a solution of potassium carbonate (60 mg, 0.434 mmol) in H 2 0 (0.25 mL), and 30 chloro-2-(dimethylaminomethyl)-ferrocen-1 -yl-(dinorbornylphosphine)palladium(l11) (4.4 189 WO 2007/005534 PCT/US2006/025402 mg, 0.00723 mmol). The reaction was heated in a CEM microwave for 30 min at 150 0C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with H 2 0 (3 mL), MeOH (6 mL) and a 2 M solution of NH/MeOH (9 mL). The NH/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% CH 3
CN/H
2 0 (0.1% TFA) then a linear gradient of 10% CH 3
CN/H
2 0 (0.1% TFA). to 95% CH 3
CN/H
2 0 (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; 10 United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 65 0C 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. 15 Example 174: 3-l-(ethylsulfonvi)-4-piperidinvll-5-[5-({f2 (methyloxv)ethyllaminolmethyl)-3-pyridinyll-1 H-indole-7-carboxamide o z N N H I N H
H
2 N 0 Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridiny) 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-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 NaCNBH 3 (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-y)-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 H-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. 30 190 WO 2007/005534 PCT/US2006/025402 Example 175: 3-[1-(ethylsulfonyl)-4-piperdinyll-5-[5-(ff3 (methyloxv)propyllaminolmethyl)-3-pyridinil-1 H-indole-7-carboxamide N N HI N H
H
2 N 0 Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl) 5 3-[1-(ethylsulfonyl)-4-piperidinyl-1H-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 NaCNBH 3 (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)propy]{[5-(4,4,5,5 10 tetramethyl-1,3,2-dioxaboroan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5 bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-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%). 15 LC/MS = m/z 514.4 [M+H] Ret. Time: 1.46 min. Example 176: 3-[1-(ethylsulfonvl)-4-piperidinvll-5-[5-(4-morpholinvlmethyl)-3 pyridinvll-1 H-indole-7-carboxamide orso iO0 N N 0 N N N H
H
2 N 0 20 Following the general procedure of 5-(5-{[(cyclopropylmethyl)aminomethyl}-3-pyridinyl) 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-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 NaCNBH 3 (16 mg, 0.258 mmol) were reacted to give 28 mg of crude 4 {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine. The 25 crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y)-3-pyridinyl]methyl}morpholine was then reacted with 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyll-1 H-indole-7 191 WO 2007/005534 PCT/US2006/025402 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. 5 Example 177: 5-f5-[(ethylamino)methyll-3-pyridinvl}-3-1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide 0-f /N N H _NN H HaN 0 Following the general procedure of 5-(5-{[(cyclopropylmethyl)aminomethyl}-3-pyridinyl) [0 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yI)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of ethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH 3 (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-y)-3 pyridinyl]methyl)amine. The crude ethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y) 15 3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl] 1 H-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%). 20 LC/MS = m/z 470.4 [M+H] Ret. Time: 1.44 min. Example 178: 5-f5-[(dimethylamino)methyll-3-pyridinvl-3-[1-(ethylsulfonyl)-4 piperidinvll-1 H-indole-7-carboxamide N N N H
H
2 N 0 25 Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl) 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2 192 WO 2007/005534 PCT/US2006/025402 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 NaCNBH 3 (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-y) 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]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl (dinorbornylphosphine)palladium(lI) (4.4 mg, 0.00723 mmol) to give 5.4 mg of the title compound (16%). 10 LC/MS = m/z 470.6 [M+H] Ret. Time: 1.35 min. Example 179: 3-[1 -(ethylsulfonyl)-4-piperidinyll-545-[(2-methyl-1 pyrrolidinyl)methyll-3-pyridi nyl-1 H-indole-7-carboxamide ;o szzo N N N N H
H
2 N 0 15 Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl) 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-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 NaCNBH 3 (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-y)pyridine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4 piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl (dinorbornylphosphine)palladium(II) (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-[1-(ethylsulfonyl)-4-piperidinyll-5-(5-ff(2 methylpropyl)aminolmethyll-3-pyridinyi)-1 H-indole-7-carboxamide 193 WO 2007/005534 PCT/US2006/025402 N NN I-I NN N N H
H
2 N 0 Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl) 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-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 NaCNBH 3 (16 mg, 0.258 mmol) were reacted to give 21 mg of crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 pyridinyl]methyllamine. The crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-y)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1 (ethylsulfonyl)-4-piperidinyl]-1H-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(I) (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. 15 Example 181: 5-(5-f[(2,2-dimethylpropvl)aminolmethyl-3-pyridinyl)-3-1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide zo N N N N NN H
H
2 N 0 Following the general procedure of 5-(5-{[(cyclopropylmethyl)aminomethyl}-3-pyridiny) 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2 20 dioxaborolan-2-yi)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), (2,2 dimethylpropyl)amine (0.015 mL, 0.129 mmol), and NaCNBH 3 (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-y)-3-pyridinyl]methyl}amine. The crude (2,2-dimethylpropyl){[5-(4,4,5,5 tetramethyl-1, 3,2-dioxaborolan-2-y)-3-pyridinyl] methyl}ami ne was then reacted with 5 25 bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), 194 WO 2007/005534 PCT/US2006/025402 potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen 1-yl-(dinorbornylphosphine)palladium(Il) (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. 5 Example 182: 3-[1-(ethylsulfonvi)-4-piperidinvil-5-(5-ff(2 methylbutvl)aminolmethyll-2-thienvl)-1 H-indole-7-carboxamide o r N N H /s N H
H
2 N 0 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 NaCNBH 3 (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 NH 3 /MeOH (9 mL). The NH/MeOH fraction was concentrated under a stream of nitrogen to give 43 mg of crude (5-{[(2 methylbutyl)amino]methyl}-2-thienyl)boronic acid. 20 To a CEM microwave tube containing the crude (5-{[(2-methylbutyl)amino]methyll-2 thienyl)boronic acid (43 mg, 0.188 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), dioxane (1.5 mL), H 2 0 (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 0C. The 25 reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with with 3 mL MeOH), eluting in sequence with H 2 0 (3 mL), MeOH (9 mL) and a 2 M solution of NH/MeOH (6 mL). The NH 3 /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-C1 8 column: 21.2 x 50 mm) eluting at 20 mL per min 195 WO 2007/005534 PCT/US2006/025402 for 1 min with 10% CH 3
CN/H
2 0 (0.1% TFA) then a linear gradient of 10% CH 3
CN/H
2 0 (0.1% TFA) to 95% CH 3
CN/H
2 0 (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-[5-(f(1R)-1,2-dimethylpropyllamino}methyl)-2-thienyll-3-[1 10 (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide Chiral /j N N H N H
H
2 N 0 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), [(1 R)-1,2-dimethylpropyl]amine (28 mg, 0.32 15 mmol), and NaCNBH 3 (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]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K 2
CO
3 (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-[1-(ethylsulfonyl)-4-piperidinvil-5-f5-[(pentvlamino)methyll-2 thienyll-1 H-indole-7-carboxamide 196 WO 2007/005534 PCT/US2006/025402 0 N N H /5 N H
H
2 N 0 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 NaCNBH 3 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 H-indole-7-carboxamide (65 mg, 0.157 mmol), K 2
CO
3 (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%). 10 LC/MS = m/z 430.6 [M+H] Ret. Time: 1.75 min. Example 185: 3-[1-(ethylsulfonvl)-4-piperidinvil-5-[5-({[(2S)-2 methylbutyllaminolmethyl)-2-thienvil-1 H-indole-7-carboxamide 0- i N O NN H N H
H
2 N 0 15 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 NaCNBH 3 (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 20 methylbutyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1 (ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K 2
CO
3 (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. 25 197 WO 2007/005534 PCT/US2006/025402 Example 186: 3-[1-(ethylsulfonyl)-4-piperidinvIl-5-(5-f[(1 methylbutvl)aminolmethyll-2-thienvl)-1 H-indole-7-carboxamide o e N N H N H
H
2 N 0 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), (1-methylbutyl)amine (29 mg, 0.32 mmol), and NaCNBH 3 (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]methyll-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1 10 (ethylsulfonyl)-4-piperidinyl]-1H-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. 15 Example 187: 5-{5-[(butylami nomethyll-2-thienyl}-3-[1 -(ethylsulfonyl)-4 piperidinvll-1 H-indole-7-carboxamide 0-O N N H N H
H
2 N 0 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 20 thienyl)boronic acid (50 mg, 0.32 mmol), butylamine (24 mg, 0.32 mmol), and NaCNBH 3 (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]-1H-indole-7-carboxamide (65 mg, 198 WO 2007/005534 PCT/US2006/025402 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. 5 Example 188: 3-[1-(ethylsulfonvl)-4-piperidinvil-5-[5-(fI2 (methyloxv)ethyllaminolmethyl)-2-thienvil-1 H-indole-7-carboxamide -0 oj- N N H N H
H
2 N 0 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 10 thienyl)boronic acid (50 mg, 0.32 mmol), [2-(methyloxy)ethyl]amine (24 mg, 0.32 mmol), and NaCNBH 3 (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]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 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)-1 H-indole-7-carboxamide to give 15 mg of the title compound (15%). 20 LC/MS = m/z 430.2 [M+H] Ret. Time: 1.33 min. Example 189: 5-{5-[(cyclopentylamino)methyll-2-thienvl}-3-[1-(ethylsulfonvl)-4 piperidinyll-1 H-indole-7-carboxamide N NN H
H
2 N 0 199 WO 2007/005534 PCT/US2006/025402 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 NaCNBH 3 (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]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (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%). 10 LC/MS = m/z 430.4 [M+H] Ret. Time: 1.64 min. Example 190: 3-[1-(ethylsulfonyl)-4-piperidinvll-5-(5-ff(3 methylbutyl)aminolmethyll-2-thienyl)-1 H-indole-7-carboxamide /s8
/-
HN N HH HN 0 15 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 NaCNBH 3 (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 20 methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1 (ethylsulfonyl)-4-piperidinyl]-1H-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. 25 Example 191: 3-[1 -(ethylsulfonyl)-4-piperidinyll-5-(5-f(1 methylethyl)aminolmethyl}-3-pvridinVi)-1 H-indole-7-carboxamide 200 WO 2007/005534 PCT/US2006/025402 N N H N N N H 0
NH
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)-1 H-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. NaCNBH 3 (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 NH/MeOH (9 mL). The NH/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]methyllamine (22 mg, 0.080 mmol) was added 5-bromo-3 [1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (50 mg, 0.121 mmol), K2C03 (100 mg, 0.724 mmol), dioxane (1.5 mL), H 2 0 (0. 5 mL), and chloro-2 (dimethylaminomethyl)-ferrocen-1 -yl-(dinorbornylphosphine)palladium(I1I) (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 H 2 0 (3 mL), MeOH (6 mL) and a 2 M solution of NH/MeOH (9 mL). The NH/MeOH fraction was dried under a stream of nitrogen at 50 0C 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% CH 3
CN/H
2 0 (0.1% TFA) then a linear 25 gradient of 10% CH 3
CN/H
2 0 (0.1% TFA) to 95% CH 3
CN/H
2 0 (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 0C to give 27.2 mg of the title compound (70%). 30 LC/MS = m/z 484 [M+H] Ret. Time: 1.25 min. 201 WO 2007/005534 PCT/US2006/025402 Example 192: 5-(5-{[(2-ethyl butyl)aminolmethyll-2-thenyl)-3-1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide /Ns N H N H 0
NH
2 5 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 NaCNBH 3 (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 NH/MeOH (9 mL). The NH/MeOH fraction was concentrated under a stream of nitrogen to give 48 mg of crude (5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)boronic acid. 15 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]-1H-indole-7-carboxamide (65 mg, 0.157 mmol) in dioxane (1.75 mL), a solution of K2C03 (130 mg, 0.942 mmol) in H 2 0 (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 0C. 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 NH/MeOH (9 mL). The NH/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% CH 3
CN/H
2 0 (0.1% TFA) then a linear gradient of 10% CH 3
CN/H
2 0 (0.1% TFA) to 95% CH 3
CN/H
2 0 (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 202 WO 2007/005534 PCT/US2006/025402 nitrogen at 50 OC 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. 5 Example 193: 5-[5-(f[3-(ethyloxv)propyllaminolmethyl)-2-thienvil-3-l (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide N N H N H 0
NH
2 Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1 10 (ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(ethyloxy)propyl]amine (34 mg, 0.32 mmol), and NaCNBH 3 (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]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K 2
CO
3 (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. 20 Example 194: 3-[1-(ethVlsulfonvl)-4-piperidinll-5-[5-({[3 (methyloxv)propyllaminolmethyl)-2-thienvll-1 H-indole-7-carboxamide 0N N H H 0
NH
2 Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1 (ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid 203 WO 2007/005534 PCT/US2006/025402 (50 mg, 0.32 mmol), [3-(methyloxy)propyl]amine (29 mg, 0.32 mmol), and NaCNBH 3 (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]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K 2 C0 3 (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 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-f{(cyclohexvlmethvl)aminolmethyll-2-thienyl)-3-rl (ethylsulfonvl)-4-piperidi nyl-1 H-indole-7-carboxamide N H /_S N H 15 0 NH 2 Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1 (ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (cyclohexylmethyl)amine (37 mg, 0.32 mmol), and NaCNBH 3 (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]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K 2
CO
3 (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%). 30 LC/MS = m/z 430 [M+H] Ret. Time: 1.82 min. 204 WO 2007/005534 PCT/US2006/025402 Example 196: 3-1 -(ethylsulfonyl)-4-piperdinyll-5-f5-[(13-(1 methylethvl)oxylpropyllamino)methyll-2-thienvl}-1 H-indole-7-carboxamide N H N H 0
NH
2 5 Following the general procedure of 5-(5-{[(2-ethylbutyl)aminolmethyl}-2-thienyt)-3-[1 (ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), {3-[(1-methylethyl)oxy]propyljamine (38 mg, 0.32 mmol), and NaCNBH 3 (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]-1H-indole-7-carboxamide (65 mg, 0.157 mmol),
K
2 C0 3 (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-[5-({f2-(ethyloxv)ethyllaminolmethyl)-2-thienvl-3-1-(ethylsulfonyl) 20 4-piperidinyll-1 H-indole-7-carboxamide 0 Oz O NHN Following the general procedure of 5-(5-{{(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1 (ethylsulfonyl)-4-piperidinyl]-1H-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, 205 WO 2007/005534 PCT/US2006/025402 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]-1H-indole-7 carboxamide (65 mg, 0.157 mmol), K 2
CO
3 (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. 10 Example 198: 3-[1-(ethylsulfonvl)-4-piperidinvil-5-r5-(ff3 (propyloxv)propvIlaminolmethyl)-2-thienvll-1 H-indole-7-carboxamide / / H N H 0 NH, 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 NaCNBH 3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3 (propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3 (propyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3 20 [1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K 2
CO
3 (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. 206 WO 2007/005534 PCT/US2006/025402 Example 199: 5-(5-{[(3,3-dimethylbutyl)aminolmethyll-2-thienvl)-3-[1 (ethylsulfonvl)-4-piperidi nyl-1 H-indole-7-carboxamide N N H N H 0
NH
2 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 NaCNBH 3 (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]methyll-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1 10 (ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (65 mg, 0.157 mmol), K 2 C0 3 (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. 15 Example 200: 3-ri-(ethVlsulfonvl)-4-piperidinvll-5-[5-(ff(1S)-1,2,2 trimethylpropyllaminolmethyl)-2-thienvll-1 H-indole-7-carboxamide N N H /s8 -~N H O
NH
2 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), [(1S)-1,2,2-trimethylpropyllamine (32 mg, 0.32 mmol), and NaCNBH 3 (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 H-indole-7-carboxamide (65 mg, 0.157 mmol), K 2
CO
3 (130 207 WO 2007/005534 PCT/US2006/025402 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. 5 Example 201: 3-1 -(ethylsulfonyl)-4-pi peridinvll-5-{5-[(hexylami no)methyll-2 thienyll-1 H-indole-7-carboxamide oz:zz~ N N H N H 0
NH
2 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 10 (50 mg, 0.32 mmol), hexylamine (33 mg, 0.32 mmol), and NaCNBH 3 (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 H-indole-7-carboxamide (65 mg, 0.157 mmol), K2C03 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). 15 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 13 mg of the title compound (16%). LC/MS = m/z 430.6 [M+H] Ret. Time: 1.92 min. 20 Example 202: 5-r2-(dimethylamino)-4-pyridinvil-3-l-(ethylsulfonyl)-4-piperidinyl 1 H-indole-7-carboxamide trifluoroacetate N N /O N I F F 0 F OH H O NH2 208 WO 2007/005534 PCT/US2006/025402 To 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-4-pyridinyl)-1 H-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 1800 C. All solvent was evaporated and the mixture was then purified by Gilson Preparatory HPLC to give 18.2 5 mg of the title compound (34.4%). LC/MS = m/z 456.2 [M+H] Ret. Time: 1.54 min. Example 203: 5-f6-[ethyl(methvl)aminol-3-pyridinvl}-3-[1-(ethvlsulfonyi)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate NO F F F OH 10 0 NH2 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 pyrrolidine (1 mL) for dimethylamine to afford 48.9 mg of the title compound (27.1%). 15 LC/MS = m/z 482.2 [M+H] Ret. Time: 1.62 min. Example 204: 3-r1-(ethylsulfonyl)-4-piperidinvIl-5-[2-(4-morpholinyl)-4-pyridinyll-1H indole-7-carboxamide trifluoroacetate O N N / & 0 N F OH H O NH2 209 WO 2007/005534 PCT/US2006/025402 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%). 5 LC/MS = m/z 498.6 [M+H] Ret. Time: 1.47 min. Example 205: 3-[l-(ethylsulfonvl)-4-piperidinvil-5-f2-[(2-methylpropvl)aminol-4 pyridinyll-1 H-indole-7-carboxamide trifluoroacetate O N H N/<O N F F F OH O NH2 10 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. 15 Example 206: 5-f2-[(2,2-di methylpropyl)ami nol-4-pyridinyll-3-[1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate NH O N1 F 0N F OH S NH21 210 WO 2007/005534 PCT/US2006/025402 The title compound was prepared according to the general procedure of 5-[2 (dimethylamino)-4-pyridinyl]-3-[1 -(ethylsulfonyl)-4-piperidiny]-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%). 5 LC/MS = m/z 498.6 {M+H] Ret. Time: 1.75 min. Example 207: 3-1 -(ethylsulfonvl)-4-piperidinvll-5-L2-(propylamino)-4-pyridinvll-1H indole-7-carboxamide trifluoroacetate NH N / 40 N I F F O F OH O NH2 10 The title compound was prepared according to the general procedure of 5-[2 (dimethylamino)-4-pyridinyl]-3-[1 -(ethylsulfonyl)-4-piperidiny]-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. 15 Example 208: 3-1 -(ethylsulfonvl)-4-piperidinvll-5-f4-[(methylamino)methyll-2 thienyll-1 H-indole-7-carboxamide trifluoroacetate 0/ FOK NN H F F FN F O O NH 2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2-thienyl)-1 H-indole-7 20 carboxamide (45 mg, 0.1 mmol) in methylene chloride (2 mL) and methanol (1 mL) was 211 WO 2007/005534 PCT/US2006/025402 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 5 compound (29.2%). LC/MS = m/z 461.6 [M+H] Ret. Time: 1.40 min. Example 209: 3-l-(ethylsulfonyl)-4-piperidinvil-5-[4-(1-pyrrolidinvimethvl)-2 thienyll-1 H-indole-7-carboxamide trif luoroacetate NN F O F OH 10 0 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%). 15 LC/MS = m/z 470.4 [M+H] Ret. Time: 1.57 min. Example 210: 3-[l-(ethylsulfony)-4-piperidinvll-5-(4-f(2 methylpropvl)aminolmethyl}-2-thienvi)-1 H-indole-7-carboxamide trifluoroacetate O N/ S N .
H FN F OHH O NH2 20 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl-2-thienyl}-1 -indole-7 212 WO 2007/005534 PCT/US2006/025402 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. 5 Example 211: 5-{4-[(dimethylamino)methyll-2-thienvl}-3-[1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate O// - N F N F OH H 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 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+HJ Ret. Time: 1.27 min. Example 212: 3-[1-(ethylsulfonvl)-4-piperidinvil-5-f5-[(1S)-1-(1-pvrrolidinyl)ethvll-3 15 thienyl}-1 H-indole-7-carboxamide 094 N S NN H O NH 2 To 5-(5-acetyl-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 213 WO 2007/005534 PCT/US2006/025402 40 min at 1500 C. All the solvent was evaporated and the crude product was partitioned between ethyl acetate (1.5 mL) and 1 M 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. 5 Example 213: 3-[1-(ethylsulfonyi)-4-piperidinvil-5-f5-[(1R)-1-(1-pyrrolidinvlethyll-3 thienvl}-1 H-indole-7-carboxamide ON /0 S N H O NH2 To 5-(5-acetyl-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 1500 C. All the solvent was evaporated and the crude product was partitioned between ethyl acetate (1.5 mL) and 1 M sodium hydroxide (0.2 mL). The reaction was purified by SFC to give the title compound as 100% chirally pure. 15 LC/MS = m/z 515.4 [M+H] Ret. Time: 1.54 min. Example 214: 3-l-(ethylsulfonyl)-4-piperidinvi'l-5-[4-({f3 (methyloxy)propyllaminolmethyl)-2-thienil-1 H-indole-7-carboxamide trifluoroacetate 2144 NN /-- F O SOHH 20 0 NH2 To asolution of 5-[(1 Z)-1 -(ethenylthio)-4-oxo-1 -buten-1 -yl]-3-[1 -(ethylsulfonyl)-4 piperidinyl]-1 H-indole-7-carboxamide (45 mg, 0. 1 mmol) in methylene chloride (2 ml) and 214 WO 2007/005534 PCT/US2006/025402 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 5 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-l-(ethylsulfonyl)-4-piperidinvil-5-I4-({{2S)-2-f(methyloxv)methyll-1 pyrrolidinvl}methyl)-2-thienvll-1 H-indole-7-carboxamide trifluoroacetate 0,/ N /0 0o S )NN H F O NH2 F2 10 F OH 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]-1 H indole-7-carboxamide trifluoroacetate , substituting (2S)-2-[(methyloxy)methyl]pyrrolidine (115.18 mg, 1 mmol) for 3 15 (methyloxy)-1 -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-{[(2R,5R)-2,5-dimethyl-1-pyrrolidinvllmethyll-2-thienvl)-3-[1 (ethylsulfonvi)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate Chiral /8 N b S F O N F OH 20 2 NH2 215 WO 2007/005534 PCT/US2006/025402 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]-1 H indole-7-carboxamide trifluoroacetate (64.3 mg, 1 mmol) for 3-(methyloxy)-l-propanamine to afford 6.4 mg of the title 5 compound (10%). LC/MS = m/z 529.4 [M+H] Ret. Time: 1.69 min. Example 217: 3-[1 -(ethylsulfonyl)-4-piperidinvl-5-(5-{f(2S)-2-methyl-1 pvrrolidinyllmethyl}-3-thienvl)-1 H-indole-7-carboxamide ONN N H 10 0 NH2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-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 15 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. 20 Example 218: 3-[l -(ethylsulfonyl)-4-piperidinvll-5-(5-f{(2R)-2-methyl-1 pyrrolidinvllmethyll-3-thienyl)-1 H-indole-7-carboxamide 216 WO 2007/005534 PCT/US2006/025402 S DNN H O NH2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-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. 10 Example 219: 3-[1-(ethylsulfonvl)-4-piperidinvil-5-f5-[1-(1-pvrrolidinvl)propyll-3 thienvl}-1 H-indole-7-carboxamide trifle uoroacetate N
/
S F /O N F H H F OH O NH 2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 15 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (250 mg, 0.541 mmol) in dioxane (4.5 mL) and H 2 0 (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 1502 C for 20 min. An aqueous work-up was performed using EtOAc and H 2 0 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 H-indole-7 carboxamide (43%). 217 WO 2007/005534 PCT/US2006/025402 To 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-propanoy-3-thienyl)-1 H-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 1500 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. 10 Example 220: 5-{5-[(dimethylamino)methyll-3-thienvl}-3-{1-[(1-methylethvl)sulfonvll 4-piperidinvl}-1 H-indole-7-carboxamide trifluoroacetate S F H F OH O NH2 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 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. 20 Example 221: 5-[5-(aminomethyl)-3-thienll-3-1 -(ethylsulfonyl)-4-piperidi nyll-1 H indole-7-carboxamide trifluoroacetate 218 WO 2007/005534 PCT/US2006/025402 20 F OH O=Sa N S H2N2 F OIN F OH O NH2 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 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. 10 Example 222: 3-1-(ethylsulfonvl)-4-piperidinvil-5-(5-f2-(2 methylpropyl)aminolethyl-3-thenyl)-1 H-indole-7-carboxamide trif luoroacetate O II N S F F OH O NH-2 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%). 219 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-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 1500 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. 10 Example 223: 5-{5-[2-(dimethylamino)ethyll-3-thienyll-3-[1 -(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate F OH F OH I1 O NH2 15 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 H 2 0 (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)-NN-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 H-indole-7-carboxamide (139 mg, 0.345 mmol) in dioxane (3 mL) and water (1 mL) was added 2-(4-bromo-2-thienyl)-NN-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 1500 C. All solvent was evaporated and the mixture 220 WO 2007/005534 PCT/US2006/025402 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. 5 Example 224: 3-[1-(ethylsulfonyl)-4-piperidinyll-5-[6-(1-pyrrolidinyi)-3-pyridinyll-1H indole-7-carboxamide trifluoroacetate NN NF N F N F OH H O N2 To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (110 mg, 0.27 mmol) in dioxane (2.0 mL) and H 2 0 (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 1500 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 H-indole-7-carboxamide (43%). 15 To 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-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 1000 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-{6-ethyl(methvl)aminol-3-pyridinvl}-3-1-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trif luoroacetate 221 WO 2007/005534 PCT/US2006/025402 0 ",N N N F N F OH H O NH 2 To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidiny]-1 H-indole-7-carboxamide (110 mg, 0.27 mmol) in dioxane (2.0 mL) and H 2 0 (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 1500 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 H-indole-7-carboxamide (43%). 10 To 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-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 2000 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-[6-(dimethylamino)-3-pyridinvil-3-[1-(ethylsulfonyi)-4-piperidinyll 1 H-indole-7-carboxamide trifluoroacetate / 40 ...- N N F F O F OH O NH 2 222 WO 2007/005534 PCT/US2006/025402 To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (110 mg, 0.27 mmol) in dioxane (2.0 mL) and H 2 0 (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 1500 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 H-indole-7-carboxamide (43%). To 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-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 2000 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. 15 Example 227: 3-[1-(ethylsulfonyl)-4-piperidinyll-5-[6-(propylamino)-3-pyridinvll-1 H indole-7-carboxamide trifluoroacetate H N0 N 7N F O F OH H O NH 2 To a solution of 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (110 mg, 0.27 mmol) in dioxane (2.0 mL) and H 2 0 (0.7 mL) was added (6-fluoro-3 20 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 1500 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 H-indole-7-carboxamide (43%). 25 To 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H-indole-7-carboxamide (50 mg, 0.116 mmol) was added propylamine (1 mL) and DMF (0.3 mL). The resulting 223 WO 2007/005534 PCT/US2006/025402 mixture was reacted in a microwave for 5 h at 2000 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. 5 Example 228: 3-fl-(ethylsulfonyl)-4-piperidinvIl-5-{6-(l-methylethvl)aminol-3 pyridinyl}-1 H-indole-7-carboxamide trifluoroacetate 0 / NHN N FN F OH H O NH2 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-Fl-(ethylsulfonyl)-4-piperidinvil-5-[6-(4-morpholinvi)-3-pyridinvil-1H 15 indole-7-carboxamide 0O O N! O " N N N H O NH 2 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%). 224 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 498.6 [M+H] Ret. Time: 1.44 min. Example 230: 3-1 -(ethylsulfonyl)-4-pi peridinyll-5-{5-(methylami no)methyll-3 thienyl}-1 H-indole-7-carboxamide trifluoroacetate N F F O F OH 5 O NH2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-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. 15 Example 231: 3-[l-(ethylsulfonyl)-4-piperidinvll-5-(5-ff(1-methylethvllaminolmethyl} 3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate N SN F N F OH H O NH 2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-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 225 WO 2007/005534 PCT/US2006/025402 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. 5 Example 232: 3-[1 -(ethylsuifonyl)-4-piperidi nyll-5-5-(1 -pyrrolidinyl methyl)-3 thienyll-1 H-indole-7-carboxamide trifluoroacetate N/ S.:O IS F F ECH F OH O NH2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-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-f5-[(ethylamino)methyll-3-thienvll-3-[1 -(ethylsulfonyl)-4-pi peridinyll 1 H-indole-7-carboxamide trif I uoroacetate N S / -N H F F OH H O NH 2 226 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-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-[1 -(ethylsulfonyl)-4-piperidinyll-5-[5-({(1R)-2-hydroxy-1 10 methylethyllamino}methyl)-3-thienyll-1 H-indole-7-carboxamide trif luoroacetate .(saltQ f0/m ON / S HOJN H F N F OH O NH 2 The title compound was prepared according to the general procedure of 5-{5 [(ethylamino)methyl]-3-thienyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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-[1-(ethylsulfonyl)-4-piperidinvll-5-[5-(1-piperidinvlmethyl)-3-thienyll 20 1 H-i ndole-7-carboxamide trifluoroacetate N! O S F O F N \ H O NH12 227 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-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: 3-1 -(ethylsulf onyl)-4-piperidi nvIl-5-[5-(4-morpholi nvlmethyl)-3 10 thienyll-1 H-indole-7-carboxamide trifluoroacetate 0 2O S N Oj F F N -H. H F OH O NH-2 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-[1 -(ethylsulfonyl)-4-piperidinvl-5-{5-[(methylamino)methyll-3 furanyll-1 H-indole-7-carboxamide trifluoroacetate 01
/
F OHO 20 2 228 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3.0 mL) and
H
2 0 (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 1500 C to give 58 mg of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1 H-indole-7-carboxamide. To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1 H-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. 15 Example 238: 3-1 -(ethylsulfonyl)-4-pi peridinvll-545-[1-(1 -pyrrolidinvIlethyIl-3 thienvl}-1 H-indole-7-carboxamide trif luoroacetate S F F OH 0 NH2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (300 mg, 0.65 mmol) in dioxane (9 mL) and 20 H 2 0 (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 1502 C for 20 min. An aqueous work-up was performed using EtOAc and H 2 0 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 H-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 229 WO 2007/005534 PCT/US2006/025402 reaction mixture was reacted in a microwave for 20 min at 1500 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. 5 Example 239: 3-[1-(ethylsulfonyi)-4-piperidinvl-5-[5-(1-pyrrolidinvimethyl)-2 thienyll-1 H-indole-7-carboxamide trifiuoroacetate O-ZI N F OH H O NH2 To 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thieny)-1 H-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. 15 Example 240: 5-{5-[(dimethylamino)methyll-2-thienvl}-3-[1-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 0 O N N F N F OH O NH 2 To 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thieny)-1 H-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 230 WO 2007/005534 PCT/US2006/025402 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. 5 Example 241: 3-[1 -(ethylsuifonyl)-4-piperidi nyll-5-f5-(propylami no)methyll-2 thienvl}-1 H-indole-7-carboxamide trifluoroacetate NN HH / 0 F //N F O HH 0 NH2 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) for 2M 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-[(diethylami no)methyll-2-thienvl}-3-1 -(ethylsulfonyll)-4 15 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate -\N N F O F YOH 0 NH 2 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) for 2M 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. 231 WO 2007/005534 PCT/US2006/025402 Example 243: 3-[1-(ethylsulfonvl)-4-piperidinvil-5-(5-ff(2 methylpropvl)aminolmethyll-2-thienvl)-1 H-indole-7-carboxamide trifluoroacetate N N H F O F- N F OH O NH 2 5 To 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1 H-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 10 (4.9%). LC/MS = m/z 501.4 [M+H] Ret. Time: 1.79 min. Example 244: 5-(5-{[(2,2-dimethylpropvl)aminolmethyll-3-furanyl)-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate /0* NN H F OHN 15 O NH2 To a solution of 3-[l-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3.0 mL) and
H
2 0 (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, 20 0.012 mmol). The reaction was heated in the microwave for 20 min at 1500 C to give 58 mg of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1 H-indole-7-carboxamide. 232 WO 2007/005534 PCT/US2006/025402 To 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1 H-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. 10 Example 245: 3-f1-(ethylsulfonvl)-4-piperidinyIl-5-(5-ff(2 methylpropvl)aminolmethyll-3-furanyl)-1 H-indole-7-carboxamide trifluoroacetate o /0 /04 4 H F O N F-H H F OH O NH2 The title compound was prepared according to the general procedure of 5-(5-{[(2,2 dimethylpropyl)amino]methyl}-3-furany)-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-f{(cyclopentylmethyl)aminolmethyll-3-furanyl)-3-[1 20 (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate 233 WO 2007/005534 PCT/US2006/025 40 2 0 , /f /SO N O N H F O F OH O N2 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-l-(ethvlsulfonvl)-4-piperdinvil-5-r5-(1-pyrrolidinvimethyl)-3 furanyll-1 H-indole-7-carboxamide trifluoroacetate N O F F OH 10 O NHa2 The title compound was prepared according to the general procedure of 5-(5-{[(2,2 dimethylpropyl)aminomethyl}-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-{5-[(diethylamino)methyll-3-furanyll-3-[1-(ethylsulfonyllj-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 234 WO 2007/005534 PCT/US2006/025402 0 IF N FH IF OH O NH 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 5 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: 3-1 -(ethylsulfonyl)-4-piperidinvll-5-[5-(1 -pyrrol idi nvlmethyl)-1,3 thiazol-2-vIl-1 H-indole-7-carboxamide trif luoroacetate O'/ CN N N F 10 O NH2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl}-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-y)-1 H-indole-7-carboxamide (500 mg, 1.1 mmol) in dioxane (12 mL) and
H
2 0 (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) 15 (210 mg, 0.181 mmol). Reaction was run in the microwave at 1500 C for 20 min. Aqueous work-up performed to give crude product. The reaction was then repeated in the microwave at 1500 C for 30 min to give 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl 1,3-thiazol-2-yl)-1 H-indole-7-carboxamide. 235 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-1,3-thiazol-2-yl)-1 H-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: 3-1 -(ethylsulfonyll)-4-piperidinyll-5-{5-[2-methyl-1-(1 10 pyrrolidinvl)propyll-3-thienvl}-1 H-indole-7-carboxamide trifluoroacetate S IF O N FH H IF OH O NH2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3 mL) and
H
2 0 (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 1502 C followed by an aqueous work-up with EtOAd and H 2 0. 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 H 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 1500 C. All solvent was then evaporated, and basified in sodium hydroxide and extracted with ethyl 236 WO 2007/005534 PCT/US2006/025402 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. 5 Example 251: 341 -(ethylsulfonyl)-4-piperidi nvll-5-[4-(1 -pyrrol idinyl methyl)-1,3 thiazol-2-vll-1 H-indole-7-carboxamide trifluoroacetate C )NS N/S O NN IF N F OH H O NH2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-formyl-1,3-thiazol-4-yl)-1 H-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. 15 Example 252: 5-fl-[2-(dimethylamino)ethvll-1H-pyrazol-4-vl}-3-[l-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide NN N" NN NN H O NH2 237 WO 2007/005534 PCT/US2006/025402 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan 2-yl)-1 H-indole-7-carboxamide (40 mg, 0.084 mmol), [2-(4-bromo-1 H-pyrazol-1 yl)ethyl]dimethylamine (27 mg, 0.126 mmol) and sodium carbonate (53 mg, 0.5 mmol) was suspended in dioxane (750 pL) and water (250 pL). 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 1200 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%). 10 LC/MS = m/z 473.4 [M+H] Ret. Time: 1.48 min. Example 253: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-1 -[2-(1-pyrrolidinvl)ethvl1-1H pyrazol-4-yl}-1 H-indole-7-carboxamide trifluoroacetate O 'O N NN ONN F F N F OH H 0
NH
2 15 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane (750 pL) and H 2 0 (250 pL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-1-(2 chloroethyl)-1 H-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 1200 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)-1 H pyrazol-4-yl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (24%). 25 To a solution of 5-[1-(2-chloroethyl)-1 H-pyrazol-4-yl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide (33 mg, 0.071 mmol), pyrrolidine (60 p L, 0.710 mmol) and sodium 238 WO 2007/005534 PCT/US2006/025402 iodide (5 mg, 0.018 mmol) was added tetrahydrofuran (500 pL). 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%). 5 LC/MS = m/z 499.6 [M+H] Ret. Time: 1.34 min. Example 254: 3-[1 -(ethylsuifonyl)-4-piperidinyll-541 -2-(4-morphol i nvl)ethyll-1 H pyrazol-4-yl}-1H-indole-7-carboxamide trif I uoroacetate N N F O F N F OH H 0
NH
2 10 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{1 -[2-(1 -pyrrolidinyl)ethyl]-1 H-pyrazol-4-yl}-1 H-indole-7 carboxamide trifluoroacetate, substituting morpholine (70 pL, 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. 15 Example 255: 3-[1-(ethylsulfonyl)-4-piperidinvll-5-(1-{2-f(2 hydroxyethyl)aminolethyll-1 H-pyrazol-4-yl)-1H-indole-7-carboxamide trifluoroacetate 239 WO 2007/005534 PCT/US2006/025402 HO NNN H N N F o F N F OH H 0
NH
2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-indole-7-carboxamide (40 mg, 0.090 mmol) in dioxane (750 pL) and H 2 0 (250 pL) was added sodium carbonate (53 mg, 0.50 mmol), and 4-bromo-1 -(2 5 chloroethyl)-1 H-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 1200 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)-1 H 10 pyrazol-4-yl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (24%). A solution of 5-[1-(2-chloroethyl)-1 H-pyrazol-4-yl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 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 1300 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. 20 Example 256: 541-[2-(butylamino)ethyll-1 H-pVrazo-4-y}-3-[1 -(ethVlsulfonVI)-4 piperidinvll-1 H-indole-7-carboxamide trifluoroacetate 240 WO 2007/005534 PCT/US2006/025402 N N H -- ,NN
F
0 F N F OH 0 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}-1 H-pyrazol-4-yl)-1 H 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-fl-[2-(cyclobutylamino)ethvll-1H-pyrazol-4-vIl-3-rl-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate N N H N F N F OH H 10 0 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}-1 H-pyrazol-4-yl)-1 H indole-7-carboxamide trifluoroacetate, substituting cyclobutanamine (31 mg, 0.43 mmol) for the 2-aminoethanol to afford 10 mg of the title compound (38%). 15 LC/MS = m/z 501.4 [M+H] Ret. Time: 1.48 min. Example 258: 5-[l-(2-fF2-(diethylamino)ethyllaminolethyl)-lH-pyrazol-4-vil-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 241 WO 2007/005534 PCT/US2006/025402 N N N H -\N' N F 0 F OH H 0
NH
2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfony)-4-piperidinyl]-5-(1 -{2-[(2-hydroxyethyl)amino]ethyl}-1 H-pyrazol-4-yl)-1 H 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-l-(ethylsulfonvi)-4-piperidinvil-5-(1-{2-((1-methylethyllaminolethyll 1 H-pyrazol-4-y)-1 H-indole-7-carboxamide trifluoroacetate NN H N/ F F IN IF OH H 10 O 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-y)-1 H 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%). 15 LC/MS = m/z 487.2 [M+H] Ret. Time: 1.47 min. 242 WO 2007/005534 PCT/US2006/025402 Example 260: 3-[1-(ethylsulfonyl)-4-piperidinvIl-5-(1-f2-[(2 methylpropVl)aminolethVl}-1 H-pyrazol-4-yl)-1 H-indole-7-carboxamide trifluoroacetate NN N/ F O FH N F OH H O NH2 5 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)-1 H 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. 10 Example 261: 5-(1-f2-[(cyclopentylmethvl)aminolethvl}-1H-pyrazol-4-vl)-3-[1 (ethylsulfonyl)-4-piperidi nyll-1 H-indole-7-carboxamide trifluoroacetate N F N F OH H 0
NH
2 The title compound was prepared according to the general procedure of 3-[1 15 (ethylsulfonyl)-4-piperidinyl]-5-(1 -{2-[(2-hydroxyethyl)amino]ethyl}-1 H-pyrazol-4-yl)-1 H indole-7-carboxamide trifluoroacetate, substituting cyclopentanamine (37 mg, 0.43 mmol) for the 2-aminoethanol to afford 11 mg of the title compound (40%). 243 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 513.4 [M+H] Ret. Time: 1.47 min. Example 262: 3-r1-(ethylsulfonvl)-4-piperidinyll-5-[4-(methyloxy)-3-(1 pyrrolidinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate N NN F O O NH2 F 5 F OH 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 H-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 1200 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 H-indole-7-carboxamide (58%). 15 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1 H-indole 7-carboxamide (50 mg, 0.107 mmol), pyrrolidine (45 pL, 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. 25 Example 263: 5-[3-[(dimethylamino)methVll-4-(methyloxV)phenvll-3-[1 (ethylsulfonyl)-4-pi peridinyll-1 H-indole-7-carboxamide trifluoroacetate 244 WO 2007/005534 PCT/US2006/025402 O=S=O N N N H F- | 0 NH2 F OH 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 H-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 1200 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 H-indole-7-carboxamide (58%). 10 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4-(methyloxy)phenyl]-1 H-indole 7-carboxamide (50 mg, 0.214 mmol), dimethylamine (107 pL, 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. 20 Example 264: 3-1 -(ethylsulfonyl)-4-piperidi nvIl-5-[4-(methyloxy)-3-(4 morpholinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate 245 WO 2007/005534 PCT/US2006/025402 O=S=O N OzSz H O O NH2 F O F-H F OH The title compound was prepared according to the general procedure of 5-[3 [(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide trifluoroacetate, substituting morpholine (20 pL, 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-l-(ethylsulfonvi)-4-piperidinvil-5-[3-{[(1-methylethvl)aminolmethyll 4-(methyloxy)phenvil-1 H-indole-7-carboxamide trifluoroacetate O=S=O N NH F O N F- H 10~ ~ F OH 0N 10 2 The title compound was prepared according to the general procedure of 5-[3 [(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide trifluoroacetate, substituting 2-propanamine (15 pL, 0.214 mmol) for the dimethylamine to afford 16 mg of the title compound (24%). 15 LC/MS = m/z 513.2 [M+H] Ret. Time: 1.62 min. 246 WO 2007/005534 PCT/US2006/025402 Example 266: 3-[1-(ethylsulfonyl)-4-piperidinvll-5-f3-[(methylamino)methyll-4 (methyloxv)phenvll-1 H-indole-7-carboxamide trifluoroacetate O=S=O N N N F O H F OH O N2 The title compound was prepared according to the general procedure of 5-[3 5 [(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide trifluoroacetate, substituting methylamine (50 pL, 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. 10 Example 267: 5-[3-f{(2,2-dimethylpropvl)aminolmethyll-4-(methyloxv)phenvll-3-[1 (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate O=S=O N 7NH /N H F O NH2 F F OH The title compound was prepared according to the general procedure of 5-[3 [(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 247 WO 2007/005534 PCT/US2006/025402 indole-7-carboxamide trifluoroacetate, substituting 2,2-dimethy-1 -propanamine (20 pL, 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. 5 Example 268: 3-1 -(ethylsuIf onyll)-4-pi peridi nyll-5-(1 42-f(2 hydroxvethyl)(methvl)aminolethyl}-1 H-pyrazol-4-yl)-1 H-indole-7-carboxamide 0: N N N HO N H 0
NH
2 A solution of 5-[1-(2-chloroethyl)-1 H-pyrazol-4-yl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H indole-7-carboxamide (30 mg, 0.065 mmol), 2-(methylamino)ethanol (500 pL, 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 1300 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. 15 Example 269: 3-[l-(ethylsulfonvl)-4-piperidinvll-5-{4-fluoro-3 F(methylamino)methyllphenvl}-1 H-indole-7-carboxamide trif luoroacetate HN O F N N H F O
IF-|
H2 N O F OH To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-fluoro-3-formylphenyl)-1 H-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 pL, 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 248 WO 2007/005534 PCT/US2006/025402 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. 5 Example 270: 5-{3,5-bis[(methylamino)methyllphenvil-3-[1-(ethylsulfonvI)-4 pi peridi nyll-1 H-i ndole-7-carboxamide trif I uoroacetate H /0 N H| N F O
H
2 N O FOH To a solution of 5-(3,5-diformylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7 10 carboxamide (10 mg, 0.2 mmol) in dichloromethane (1 mL) and methanol (1 mL) was added methylamine (64 pL, 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%). 15 LC/MS = m/z 498.6 [M+H] Ret. Time: 1.17 min. Example 271: 5-f3-[(ethylamino)methyll-4-fluorophenvl}-3-rl-(ethylsulfonvl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 0 HN O F N N F H F OH
H
2 N 0 20 To a solution o3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4-fluoro-3-formylphenyl)-1 H-indole-7 carboxamide (35 mg, 0.076 mmol) in dichloromethane (1 mL) and methanol (1 mL) was added 2 M ethylamine (230 pL, 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, 249 WO 2007/005534 PCT/US2006/025402 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. 5 Example 272: 3-i1-(ethylsulfonvl)-4-piperidinvll-5-r4-fluoro-3-({[2-hydroxv-1 (hydroxymethvl)ethyllaminolmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate (salt) H H N F N F O H HN O F 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. 15 Example 273: 3-[1-(ethvlsulfonvl)-4-piperdinvil-5-4-fluoro-3-(f(1S)-2-hydroxy-1 methylethyllaminolmethvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate (salt) H HN F N F H F F OH
H
2 N 0 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-{3-[(cyclopropylamino)methyll-4-fluorophenil-3-11-(ethylsulfonyl) 25 4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 250 WO 2007/005534 PCT/US2006/025402 HN o7 N F N F H F OH
H
2 N 0 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-[(cyclobutylamino)methyll-4-fluorophenvil-3-[1-(ethylsulfonvl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate HN O0O NN F F F O 10
H
2 N 0 F 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 carboxamide trifluoroacetate, substituting cyclobutanamine (39 mg, 0.46 mmol) for ethylamine to afford 20 mg of the title compound (42%). 15 LC/MS = m/z 513.2 [M+H] Ret. Time: 1.58 min. Example 276: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-[3-(1-pyrrolidinvimethvl)phenvil 1 H-indole-7-carboxamide trifluoroacetate N o 0 N F F O H F-H F OH
H
2 N 0 251 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-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-bis[(ethylami no)methyllphenyll-3-[1 -(ethylsulfonyl)-4 10 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 0 H/ N "NN NH F
H
2 N 0 F OH To a solution of 5-(3,5-diformylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 15 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. 20 Example 278: 5-{3,5-bis[(dimethylamino)methyllphenvl-3-[l-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate O N O / N H F
...--
NF OH
H
2 N 0 F OH To a solution of 3-[l-(ethylsulfonyl)-4-piperidinyl]-5-(3-formyl-5-mercaptopheny)-1 H 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 252 WO 2007/005534 PCT/US2006/025402 (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. 5 Example 279: 3-I1 -(ethylsulfonyl)-4-pi peridinVll-5-3-(2-pperidinyi)phenyll-1 H indole-7-carboxamide trifluoroacetate 0 HN 0-' N FO H
F
H
2 N 0 F OH To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-y)-1 H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2 mL) and 10 H 2 0 (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 1600 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 Example280: 543-1 -(ethylamino)ethyllphenvl}-3-1 -(ethvlsulfonvl)-4-piperidinvil 1 H-indole-7-carboxamide trifluoroacetate HN O- /0 N N F O H FH 20
H
2 N 0 F OH A solution of 5-(3-acetylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 1500 C. The reaction was purified 25 by Gilson Preparatory HPLC to give 20.6 mg of the title compound (39%). 253 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 483.2 [M+H] Ret. Time: 1.67 Example 281: 5-{3-[1-(dimethylamino)ethyllphenyl}-3-[1-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate N N F O 5
H
2 N O F OH 5-(3-acetylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (50 mg, 0.11 mmol), dimethylamine (220 pL, 0.44 mmol) and sodium cyanoborohydride (30 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (400 pL) and acetic acid (100 pL). The resulting mixture was reacted in a Smith 150 W microwave for 20 min. at 1500 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-[1-(ethylsulfonvl)-4-piperidinyll-5-f3-fluoro-5 15 [rmethylamino)methyllphenyll-1 H-indole-7-carboxamide trifluoroacetate 0 N F N F O H F
H
2 N 0 F OH To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-formylphenyl)-1 H-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 pl, 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. 254 WO 2007/005534 PCT/US2006/025402 Example 283: 5-{3-[(ethylamino)methyll-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 0 HN O N F N F
H
2 N O F OH 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. 10 Example 284: 3-1 -(ethylsulfonyl)-4-pi peridinyll-5-{3-fI uoro-5 f(propylamino)methyllphenvl}-1 H-indole-7-carboxamide trifluoroacetate 0 HN N F N F O H F H 2 N 0 F OH 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-[l-(ethylsulfonyl)-4-piperidinyll-5-(3-fluoro-5-{{{1 20 methylethyl)aminolmethyl}phenvl)-1 H-indole-7-carboxamide trifluoroacetate 255 WO 2007/005534 PCT/US2006/025402 0 HN O N F F~~~ N 0 N F H F OH
H
2 N 0 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-[1-(ethylsulfonyl)-4-piperidinvil-5-(3-fluoro-5-ff(2 methylpropvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide trifluoroacetate 0 HN O /S N F H F OH 10
H
2 N 0 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methylphenyl}-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%). 15 LC/MS = m/z 515.4 [M+H] Ret. Time: 1.72 min. Example 287: 5-{3-[(cyclobutylamino)methyll-5-fluorophenvl}-3-[l-(ethylsulfonyl)-4 piperidinvll-1 H-indole-7-carboxamide trifluoroacetate HN N F N F O H F / HN 0j F OH 256 WO 2007/005534 PCT/US2006/025402 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%). 5 LC/MS = m/z 513.2 [M+H] Ret. Time: 1.50 min. Example 288: 5-{3-[(dimethylamino)methyll-5-fluorophenvl}-3-[l-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate .-- 0 N F N F O H H 2 N 0 F OH 10 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. 15 Example 289: 3-[1-(ethvlsulfonvl)-4-piperidinvll-5-[3-fluoro-5-(1 pyrrolidinvlmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate (N O, N F -K, O F OH
H
2 N 0 The title compound was prepared according to the general procedure of 3-[1 20 (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. 257 WO 2007/005534 PCT/US2006/025402 Example 290: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-[3-fluoro-5-(4 morpholinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate N O" N F F O
H
2 N 0 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. 10 Example 291: 3-l-(ethylsulfonvl)-4-piperidinvil-5-[3-fluoro-5-(1 piperidinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate 0 N O, N F F Y H H 2 N 0 F OH 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-[1 -(ethylsuIfonyl)-4-pi peridinvll-5-{3-[1 -(methylami nolethyllphenvil 20 1 H-indole-7-carboxamide trifluoroacetate 258 WO 2007/005534 PCT/US2006/025402 0 HN 0O/ N N F O H F-H
H
2 N 0 F OH To a solution of 5-(3-acetylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 1000 C for 10 min then sodium tetrahydridoborate was added. The resulting mixture was reacted in a CEM microwave at 500 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. 10 Example293: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-(3-{1-[(1 methylethvl)aminolethyllphenvl)-1 H-indole-7-carboxamide trifluoroacetate 0 HN N N F o H F
H
2 N 0 F OH To a solution of 5-(3-acetylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 700 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%). 20 LC/MS = m/z 497.4 [M+H] Ret. Time: 1.44 min. Example 294: 3-fl-(ethylsulfonyl)-4-piperidinvil-5-(3-.{1-[(2 methylpropvl)aminolethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate 259 WO 2007/005534 PCT/US2006/025402 HN 0 /S N N F O H F O
H
2 N 0 F OH To a solution of 5-(3-acetylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 700 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. 10 Example 295: 5-f3-[1-(cyclobutvlamino)ethyllphenvll-3-rl-(ethylsulfonvi)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate HN N H F OH
H
2 N 0 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. 20 Example 296: 3-l-(ethylsulfonyl)-4-piperidinvil-5-f3-[1-(1 pyrrolidinyl)ethyllphenyl}-1 H-indole-7-carboxamide trifluoroacetate 260 WO 2007/005534 PCT/US2006/025402 N O/ N N F H F OH
H
2 N 0 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-[1 -(ethylsulfonyl)-4-piperidi nvIl-5-[3-(3-thiomorpholi nvl)phenvll-1 H indole-7-carboxamide trifluoroacetate NH o N F F O H
F
10
H
2 N O F OH To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-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 1600 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-[1 -(ethylsulfonyl)-4-pi peridi nvll-5-[5-(2-pi perazi nyl)-2-thienvil-1 H indole-7-carboxamide trifluoroacetate 261 WO 2007/005534 PCT/US2006/025402 NH O HN s N N H F
H
2 N 0 F OH To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-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 1600 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: 3-1 -(ethylsulfonyl)-4-piperidi nvIl-5-r4-(2-piperazi nylphenyll-1 H 15 indole-7-carboxamide trifluoroacetate rNH N HN FN FO H2N O F OH 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) for 2-(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-f1-(ethylsulfonvl)-4-piperidinvil-5-[3-(2-piperazinvl)phenvll-1H indole-7-carboxamide trifluoroacetate 262 WO 2007/005534 PCT/US2006/025402 HN NH 0 N N F H F NH O F OH 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 (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 1600 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-[1-(ethylsulfonvl)-4-piperidinvll-5-[6-(4-morpholinvi)-3-pyridazinvll 15 1 H-indole-7-carboxamide trifi uoroacetate ,0 N N NN N F FO F OH
H
2 N 0 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1 H-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-f1-(ethylsulfonvl)-4-piperidinvil-5-[6-(1-pyrrolidinvl)-3-pyridazinvll 1 H-i ndole-7-carboxamide trif I uoroacetate 263 WO 2007/005534 PCT/US2006/025402 0-s N N ,NN N F F'OH
H
2 N o F OH The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1 H-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-[1-(ethylsulfonyl)-4-piperidinvil-5-{2-[(methylamino)methyllphenvll 1 H-indole-7-carboxamide trifluoroacetate NH O N F F O H F OH 10
H
2 N 0 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfony)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1 H-indole-7-carboxamide trifluoroacetate, substituting 1-(2-bromophenyl)-N-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-[1-(ethylsulfonvl)-4-piperidinvil-5-(3-ff(2 thienylmethvl)aminolmethyllphenyl)-1 H-indole-7-carboxamide trifluoroacetate 7 S - 1) 0 HN N F N F O F OH NH o 264 WO 2007/005534 PCT/US2006/025402 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-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. 10 Example 305: 3-ri-(ethylsulfonyl)-4-piperidinvil-5-[3-(fF(5-methyl-2 furanvl)methyllamino}methvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate 00 HN N N F O N H F OH NH 0 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-[1-(ethylsulfonyl)-4-piperidinvll-5-[3-({[(2R)-tetrahvdro-2 20 furanvlmethyllamino}methvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate QO HN O N F O
H
2 N O F OH 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 (31.5 265 WO 2007/005534 PCT/US2006/025402 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. 5 Example 307: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-[3-(f(2S)-tetrahvdro-2 furanylmethyllaminolmethvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate 0O HN N NN H F
H
2 N 0 F OH 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. 15 Example 308: 5-(3-ff(2,2-dimethylpropvl)aminolmethyllphenvi)-3-[1-(ethylsulfonyl) 4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 0 HN 0/ N F
H
2 N O F OH 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-[1-(ethylsulfonyl)-4-piperidinvil-5-(3-fT(2 25 methylbutyl)aminolmethyllphenyl)-1 H-indole-7-carboxamide 266 WO 2007/005534 PCT/US2006/025402 HN N N H NH 0 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-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 10 Example 310: 3-[1-(ethylsulfonvl)-4-piperidinvll-5-[3-({[(2S)-2 methylbutyllaminolmethvl)phenvll-1 H-indole-7-carboxamide HN O.::: N N H NH 0 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 20 Example 311: 3-[1 -(ethylsulfonyl)-4-piperidinyll-5-[ 3-({f(1 R)-1,2,2 trimethylpropyllamino}methyl)phenyll-1 H-indole-7-carboxamide 267 WO 2007/005534 PCT/US2006/025402 4Y 0 HN N SN H HaN 0 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-[1-(ethylsulfonyl)-4-piperidinvil-5-[3-fluoro-5-({[(2S)-tetrahvdro-2 furanvlmethyllaminolmethl)phenvll-1 H-indole-7-carboxamide trifluoroacetate I HN O /S N F F O F OH 10
H
2 N 0 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-formylphenyl)-1 H-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. 20 Example 313: 3-[l-(ethVlsulfonyl)-4-piperidinvll-5-[3-fluoro-5-(f{(2R)-tetrahydro-2 furanylmethyllamino}methvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate 268 WO 2007/005534 PCT/US2006/025402 0 HN -S N F FF
H
2 N 0 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]-1 H-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-[3-(ff(1 S)-1,2-dimethylpropyllaminolmethyl)-5-fluorophenvll-3-[1 10 (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide HN N F AN H
H
2 N 0 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]-1 H-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-[3-({1 R)-1,2-dimethylpropyllaminolmethyl)-5-fluorophenyll-3-[1 20 (ethylsulfonyl)-4-piperidinvll-1H-indole-7-carboxamide trifluoroacetate 269 WO 2007/005534 PCT/US2006/025 40 2 0 HN N F \ F O N F H F OH
H
2 N 0 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]-1 H-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-[1-(ethylsulfonyl)-4-piperidinvil-5-(3-fluoro-5-fr(1 10 methylpropvl)aminolmethyllphenyl)-1 H-indole-7-carboxamide trifluoroacetate O HN N F N F-H H,
H
2 N O 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 furanyimethyl]amino}methyl)phenyl]-1 H-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-[1-(ethylsulfonyl)-4-piperidinyll-5-[3-fluoro-5-({[(1S)-1,2.2 O trimethylpropyllaminomethvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate 270 WO 2007/005534 PCT/US2006/025402 HN O F/ F NN F 0 FHO
H
2 N O F OH The title compound was prepared according to the general procedure of 3-[1 (ethylsu lfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2 furanylmethyl]amino}methyl)phenyl]-1 H-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. Example318: 3-[1-(ethylsulfonvl)-4-piperidinvil-5-[3-fluoro-5-({f(2S)-2 10 methylbutyllaminolmethvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate HN O N F F O H
H
2 N 0 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 fu ranylmethyl]amino}methyl) ph enyl]-1 H-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-[1-(ethylsulfonyi)-4-piperidinyll-5-(3-fluoro-5-ff(2 0 methylbutvl)aminolmethyllphenyl)-1 H-indole-7-carboxamide trifluoroacetate 271 WO 2007/005534 PCT/US2006/025402 HNo 0 N F F o H F O
H
2 N 0 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfony)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2 furanylmethyllamino}methyl)phenyl]-1 H-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. Example320: 3-r1-(ethylsulfonvi)-4-piperidinvil-5-f3-fluoro-5-({f(1R)-1,2,2 10 trimethylpropyllaminolmethvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate HN O N F 'N 0N N F F OH HZN 0 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2 furanylmethyl]aminolmethyl)phenyl]-1 H-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-{[(2,2-dimethylpropvl)aminolmethyll-5-fluorophenvl)-3-(1 20 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 272 WO 2007/005534 PCT/US2006/025402 0 HN N F F 0 N F F OH HaN 0 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]-1 H-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-{[(cyclopropvlmethvl)aminolmethyll-5-fluorophenvi)-3-[1 10 (ethylsulfonvl)-4-piperidi nyl-1 H-indole-7-carboxamide trifluoroacetate HN N F F 0 N F 4 0O F OH
H
2 N 0 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]-1 H-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-ff(cyclopentvlmethvl)aminolmethyl}-5-fluorophenvi)-3-[1 20 (ethylsulfonyl)-4-piperidi nyl-1 H-indole-7-carboxamide trifluoroacetate 273 WO 2007/005534 PCT/US2006/025402 P0 HN N F F N F H
H
2 N 0 F OH The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahyd ro-2 furanylmethyl]amino}methyl)pheny]-1 H-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+Hj Ret. Time: 1.82 min. Example 324: 3-1 -(ethylsuIfonyl)-4-pi peridinyll-5-(3-fluoro-5-f{(tetrahvdro-2H 10 pyran-4-yImethvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide trifluoroacetate 0O HN O N F N F H F
H
2 N 0 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]-1 H-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: 3-1 -(ethylsulf onyl)-4-piperidinvl-5-(3-fl uoro-5-{[(2 20 thienylmethvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide trifluoroacetate 274 WO 2007/005534 PCT/US2006/025402 P 0 HN 0- // N F N F O H F
H
2 N O 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 furanyimethyl]amino}methyl)phenyl]-1 H-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-[1-(ethylsulfonvi)-4-piperidinvll-5-[3-fluoro-5-(f[2 10 (methyloxv)ethyllaminolmethvl)phenyll-1 H-indole-7-carboxamide trifluoroacetate HN O N F N H F OH
H
2 N 0 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)pheny]-1 H-indole-7-carboxamide trifluoroacetate 15 , substituting 2-(methyloxy)ethanamine (39 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2 furanylmethanamine 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-I1 -(ethylsu Ifonyl)-4-piperidi nyll-5-I3-fI uoro-5-(If 3 20 (methyloxv)propyllaminolmethvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate 275 WO 2007/005534 PCT/US2006/025402 HN O N F N F+ O
H
2 N O 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]-1 H-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-f1-(ethylsulfonyl)-4-pi peridinvil-5-(3-fluoro-5-{f(2 10 furanvlmethvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide trifluoroacetate HN O N F F 0 FF N F H F OH
H
2 N 0 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}methy)phenyl]-1 H-indole-7-carboxamide trifluoroacetate 15 , substituting 1-(2-furanyl)methanamine (50 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2 furanyllmethanamine 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-[1-(ethylsulfonyl)-4-piperidinvl1-5-(3-fluoro-5-ff(3 20 methylbutvl)aminolmethyllphenyl)-1 H-indole-7-carboxamide trifluoroacetate 276 WO 2007/005534 PCT/US2006/025402 HN N F N F
H
2 N o F OH The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahyd ro-2 furanylmethyl]amino}methyl)phenyl]-1 H-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-[1-(ethvlsulfonyl)-4-piperidinvIl-5-[3-fluoro-5-(ff(5-methyl-2 10 furanvl)methyllaminolmethvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate 00 HN N F F O N H H F OH
H
2 N 0 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}-1 H-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-[1-(ethylsulfonyl)-4-piperidinvll-5-(3-{[(2 20 methylpropvl)aminolmethyl}phenyl)-1 H-indole-7-carboxamide trifluoroacetate 277 WO 2007/005534 PCT/US2006/025402 HN O N F O FN F OH
H
2 N 0 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-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 10 Example 332: 3-l-(ethylsulfonvl)-4-piperidinvil-5-f3-(2-pyrrolidinvl)phenvil-1H indole-7-carboxamide trifluoroacetate 0 NH . N ~N F O / N F H F OH H 2 N 0 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan 15 2-yl)-1 H-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 1600 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:1.47 278 WO 2007/005534 PCT/US2006/025402 Example 333: 3-1 -(ethylsulfonyl)-4-piperidinvil-5-{2-fluoro-5 r(methylamino)methyllphenyll-1 H-indole-7-carboxamide trifluoroacetate N F /N F O H F-F H2 N O F OH 5 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1H-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-fl-(ethylsulfonvl)-4-piperidinvll-5-{2-fluoro-5 f(propylamino)methyllphenvl}-1 H-indole-7-carboxamide trifluoroacetate HNO N F 0F / N I / H F F OH HN O 15 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methylphenyl}-1H-indole-7 carboxamide trifluoroacetate, substituting propylamine (44 pL, 0.524 mmol) for methanamine to afford 15.4 mg of the title compound (61.5%). 20 LC/MS = m/z 501.4[M+H] Ret. Time: 1.55 279 WO 2007/005534 PCT/US2006/025402 Example 335: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-(2-fluoro-5-ff(2 methylpropyl)aminolmethyl}phenvl)-1 H-indole-7-carboxamide trifluoroacetate O HN 2 N F /N F O YH FH \ H2N O F OH 5 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 10 Example 336: 5-(5-{(2,2-dimethylpropyl)aminolmethyll-2-fluorophenvl)-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate N F 0F / N H F OH H2 The title compound was prepared according to the general procedure of 3-[1 15 (ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyi}-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: 1.59 280 WO 2007/005534 PCT/US2006/025402 Example 337: 5-f5-({[(1S)-1,2-dimethylpropyllaminolmethyl)-2-fluorophenvil-3-[l (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate HN O, N F O F / N F H 5 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 10 Example 338: 5-f5-({I(1R)-1,2-dimethylpropyllaminolmethvl)-2-fluorophenvil-3-l (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate HN O,/ N F O F / N F H F OH H2N O 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: 1.70 281 WO 2007/005534 PCT/US2006/025402 Example 339: 5-(5-ff(cyclopropvlmethvl)aminolmethyll-2-fluorophenvl)-3-[l (ethylsulfonyl)-4-pi peridi nyl-1 H-indole-7-carboxamide trifluoroacetate O HN O,/ N 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 10 Example 340: 3-[1-(ethylsulfonvl)-4-piperidinvll-5-[2-fluoro-5-(1 pyrrolidinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate N F O F / IN F H IF OH H 2N 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 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-[1-(ethylsulfonyl)-4-piperidinyll-5-[2-fluoro-5-(4 20 morpholinylmethyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate 282 WO 2007/005534 PCT/US2006/025402 00 NO N F H F OH H 2N 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-Fl-(ethylsulfonvl)-4-piperidinvil-5-[2-fluoro-5-(f2 (methyloxv)ethyllaminolmethvl)phenvll-1 H-indole-7-carboxamide trif luoroacetate HNO F O F/ 0 I F H 10 F OH H2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-formylphenyl)-1H-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-Fl-(ethylsulfonyl)-4-piperidinvll-5-[2-fluoro-5-([3 20 (methyloxv)propyllaminolmethvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate 283 WO 2007/005534 PCT/US2006/025402 0 NO H N F O F / N F OH H2N O The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[2-(methyloxy)ethyl]amino)methy)phenyl]-1 H indole-7-carboxamide trifluoroacetate, substituting 3-(methyloxy)-1 -propanamine (53 pL, 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: 3-1 -(ethylsulf onyl)-4-piperidinyll-543-(1 -methyl-2 pyrrolidinyl)phenyll-1 H-indole-7-carboxamide trifluoroacetate NYN F H F I N F H 10 F2N O To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-pyrrolidinyl)phenyl]-1 H-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: 1.54 284 WO 2007/005534 PCT/US2006/025402 Example 345: 3-i1-(ethylsulfonyl)-4-piperidinvll-5-(3-{2-[(2 methylpropyl)aminolethyllphenyl)-1 H-indole-7-carboxamide trifluoroacetate HN N F O N F OH H2N 5 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1 H-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) 10 was added. This was reacted in a CEM microwave for 20 min at 1600 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 15 Example 346: 5-{3-[2-(ethylamino)ethyllphenvl}-3-l-(ethylsulfonyl)-4-piperidinvll 1 H-indole-7-carboxamide trifluoroacetate HN N F N F OH H2N O 285 WO 2007/005534 PCT/US2006/025402 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan 2-yl)-1 H-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 1600 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 10 Example 347: 3-[1-(ethylsulfonyl)-4-piperidinvil-5-{3-[2-(propylaminolethyllphenvl 1 H-indole-7-carboxamide trifluoroacetate HN 00 S N F o F N H IF OH
H
2 N 0 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan 2-yl)-l H-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 1600 C. The reaction was then separated using Gilson Preparatory HPLC to afford 17.6 mg of the title compound (61%). 20 LC/MS = m/z 497.4 [M+H] Ret. Time: 1.97 Example 348: 5-{3-[2-(dimethylamino)ethyllphenvl}-3-[1-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 286 WO 2007/005534 PCT/US2006/025402 N O,0 N F 0 N F H F OHHN 0 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan 2-yl)-1H-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 1600 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 10 Example 349: 5-f3-[2-(dipropylamino)ethyllphenvil-3-[1-(ethylsulfonvi)-4 piperidinvll-1 H-indole-7-carboxamide trif luoroacetate N0' 0 N F N F OH H2N O [5 A solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan 2-yl)-1 H-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 287 WO 2007/005534 PCT/US2006/025402 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 1600 C. The reaction was then separated using Gilson Preparatory HPLC to afford 9 mg of the title compound (65.3%). 5 LC/MS = m/z 455.0 [M+H] Ret. Time: 1.55 Example 350: 5-[3-(fF2-(3,5-dimethyl-1H-pyrazol-1-vl)ethyllaminolmethvl)phenvil-3 [1 -(ethylsuIfonyl)-4-pi peridinyll-1 H-indole-7-carboxamide trifluoroacetate N HN N FO 0 N FH F OH
H
2 N 0 10 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 20 Example 351: 3-[1-(ethylsulfonvi)-4-piperidinvll-5-[2-(4-morpholinvlmethyl)-1,3 thiazol-4-vll-1 H-indole-7-carboxamide trifluoroacetate 288 WO 2007/005534 PCT/US2006/025402 0" N' S N S N FO N F H F OH H 2 N 0 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 5 mixture was quenched with Sat. NaHCO3 (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 10 2-yl)-1 H-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 1600 C. The organic layer was collected and concentrated. The residue was re 15 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-[1-(ethylsulfonvl)-4-piperidinvll-5-(2-{f(2 20 methylpropyl)aminolmethyl}-1,3-thiazol-4-vl)-1 H-indole-7-carboxamide trifluoroacetate /00 HO ,O N\XS N NP F F N +2< H F OH H 2N 289 WO 2007/005534 PCT/US2006/025402 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 (1 52ul, 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. NaHCO3 (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)-1 H-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 1600C. 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 15 Example 353: 3-f1-(ethylsulfonvl)-4-piperidinvll-5-[2-(1-pvrrolidinvlmethyl)-1,3 thiazol-4-vll-1 H-indole-7-carboxamide O0 S O N N S N -'' N H
H
2 N 0 To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 20 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. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic layer was separated and concentrated to give 200 mg of the title compound (82 %). 25 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-y)-1 H indole-7-carboxamide trifluoroacetate , substituting pyrrolidine (74 mg, 0.3 mmol) for 2-methyl-i -propanamine to afford 6.3 mg of the title compound (50%) 290 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 500.4 [M+H] Ret. Time: 1.22 Example 354: 3-[1 -(ethvlsulfonyl)-4-piperidinyll-5-[2-(1 -piperidinylmethyl)-1,3 thiazol-4-vll-1 H-indole-7-carboxamide 0"0 O~ ,,0 N S C) N N S N N H 5
H
2 N 0 To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) was added piperidine (1 50ul, 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. NaHCO3 (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-thiazo-4-yl)-1 H indole-7-carboxamide trifluoroacetate 15 , substituting piperidine (78 mg, 0.3 mmol) for 2-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-{2-[(dimethylamino)methyll-1,3-thiazol-4-vl}-3-[1-(ethylsulfonyl)-4 20 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate O> ,,0 N S -N s N F o N F H F OH H 2 N 0 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.OM, 3.0 mL) and 3 drops of AcOH. The mixture was 291 WO 2007/005534 PCT/US2006/025402 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. NaHCO3 (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%). 5 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-y)-1 H-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 15 Example 356: 5-(2-f{ethyl(methvl)aminolmethyll-1,3-thiazol-4-yI)-3-[1 (ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 0"0 O S N SN N F 0 N F H F OH H 2 N 0 To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 20 mL) was added N-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. NaHCO3 (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 %). 25 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%). 292 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 490.4 [M+H] Ret. Time: 1.25 Example 357: 5-(3-cyano-5-ff(2-methylpropvl)aminolmethyllphenyl)-3-[1 (ethylsulfonyl)-4-piperidi nyl-1 H-indole-7-carboxamide trifluoroacetate H N N F/ o F F OH N 5H2N 0 H To a solution of 3-formylbenzonitrile (1.0 g, 7.6 mmol) in TFA (4.0 mL) at 00 C under argon atmosphere was added concentrated H 2
SO
4 (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-H 2 0 (80 mL), PdCI 2 (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 15 To a solution of 3-bromo-5-formylbenzamide (1.5 g, 6.58 mmol) in H 2 0 (50.0 mL) and MeCN (50.0 mL) was added PdC 2 (117 mg, 0.658 mmol). The mixture was stirred for 72 h at room temperature and another portion of H 2 0 (100 mL) and MeCN (100 mL) was added followed with addition of PdCl 2 (100mg, 0.56moi). 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 Na2SO4 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-y)-1H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2.0 mL) and
H
2 0 (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 293 WO 2007/005534 PCT/US2006/025402 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]-1H-indole-7 carboxamide. 5 To a solution of 5-(3-cyano-5-formylphenyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl-1 H-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%). 15 LC/MS = m/z 522.4 [M+H] Ret. Time: 1.65 Example 358: 5-{3-cyano-5-[(dimethylamino)methyllphenvl}-3-[1-(ethVlsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate N / 1 --N N O F F OH F N
H
2 N H 0 20 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 pL, 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 25 Example 359: 3-1 -(ethylsulfonyl)-4-piperidinyll-5-[3-(4-morpholinylmethyl)phenyll 1 H-indole-7-carboxamide trifluoroacetate 294 WO 2007/005534 PCT/US2006/025402 00 N O N F F+ F OH N H H2N 0 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-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 10 Example 360: 3-fl-(ethylsulfonyl)-4-piperidinvil-5-[3-(ff(4 fluorophenvl)carbonvllamino}methvl)phenvll-1 H-indole-7-carboxamide trifluoroacetate
O-.
SO N F\ 0 N F O H F0 NH2 F OH The title compound was prepared according to the general procedure of 5-{3 15 [(acetylamino)methyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide substituting 4-fluoro-N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)phenyl]methyl}benzamide (125 mg, 0.352 mmol) for N-{[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%). 20 LC/MS = m/z 563.1 [M+H] Ret. Time: 2.07 min 295 WO 2007/005534 PCT/US2006/025402 Example 361: 3-1 -(ethylsulfonyl)-4-piperidi nVIl-5-(3-ff(2 furanvlcarbonvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide trifluoroacetate
O-'
0 ' N H N O N IF O H F-+ \ O NH 2 F OH 5 The title compound was prepared according to the general procedure of 5-{3 [(acetylamino)methyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-2 furancarboxamide (115 mg, 0.352 mmol) for N-{[3-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)phenyl]methyl}acetamide. Compound was purified by Gilson 10 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-f[(cyclopentvlcarbonvl)aminolmethyllphenl)-3-f1 (ethylsulfonyl)-4-pi peridinyll-1 H-indole-7-carboxamide trifluoroacetate N H O F N F H 15 F OH 0 NH2 The title, compound was prepared according to the general procedure of 5-{3 [(acetylamino)methyl]phenyl}-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)phenyl]methyl}cyclopentanecarboxamide (116 mg, 0.352 mmol) for N-{[3-(4,4,5,5 296 WO 2007/005534 PCT/US2006/025402 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 5 Example 363: 5-(3-{[(1-benzothien-2-yicarbonyl)aminolmethyllphenyl)-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide S 0 NHN NN H 0 NH2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-indole-7 10 carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)phenyl]methyl}-1-benzothiophene-2-carboxamide (57 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 Gilson Preparatory HPLC to give the title compound. LC/MS = m/z 601.2 [M+H] Ret. Time: 2.18 min 15 Example 364: 5-[3-({[1 -acetyl-4-piperidinvilcarbonyllaminolmethvl)phenvil-3-l (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide 297 WO 2007/005534 PCT/US2006/025402 0 N H 0 NH2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-indole-7 carboxamide substituting 1 -acetyl-N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 5 yl)phenyl]methyl}-4-piperidinecarboxamide (56 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 Gilson Preparatory HPLC to give the title compound. LC/MS = m/z 594.4 [M+H] Ret. Time: 1.87 min 10 Example 365: 3-[1 -(ethylsulfonyl)-4-piperidinvil-5-[3-(ff(1 -methyl-1 H-pyrrol-2 vl)carbonvllamino}methvl)phenyll-1 H-indole-7-carboxamide 0 O0 NHN N H 0 NH 2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-indole-7 15 carboxamide substituting 1-methyl-N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)phenyl]methyl}-1 H-pyrrole-2-carboxamide (49 mg, 0.144 mmol) for N-{[3-(4,4,5,5 298 WO 2007/005534 PCT/US2006/025402 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 5 Example 366: 3-Fl-(ethylsulfonvl)-4-piperidinvll-5-(3-f((2 thienvlacetvl)aminolmethyllphenyl)-1 H-indole-7-carboxamide S/ 0 HN /0" N N H H2N O The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-indole-7 10 carboxamide substituting N-{[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 15 Example 367: 5-(3-ff(cyclobutvlcarbonv)aminolmethyllphenvl)-3-[l-(ethylsulfonyl) 4-piperidinyll-1 H-indole-7-carboxamide HNN N H H2N O 299 WO 2007/005534 PCT/US2006/025402 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-indole-7 carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)phenyl]methyl}cyclobutanecarboxamide (45 mg, 0.144 mmol) for N-{[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-fF(cyclopropylcarbonvl)aminolmethyl}phenvl)-3-[1 10 (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide HNN N H H2N O The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1 H-indole-7 carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 15 yl)phenyl]methyl}cyclopropanecarboxamide (43 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 5.5 mg of the title compound (11%). LC/MS = m/z 509.2 [M+H] Ret. Time: 1.85 min 20 Examples 369: 5-(3-{[(cyclopropyisulfonv)aminolmethVl}phenVl)-3-[1 (ethylsulfonyl)-4-piperidi nyl-1 H-indole-7-carboxamide 300 WO 2007/005534 PCT/US2006/025402 0 II NN N H 0 NH2 To a solution of 5-[3-(aminomethyl)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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-[3-({[(2.5-dichlorophenvl)sulfonvllaminolmethvl)phenvll-3-[1 10 (ethylsulfonvi)-4-piperidi nyl-1 H-indole-7-carboxamide I'acI CI S=O O NH N -~N H 0
NH
2 To a solution of 5-[3-(aminomethyl)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 301 WO 2007/005534 PCT/US2006/025402 Example 371: 5-[3-({[(4-bromophenvl)sulfonvilaminolmethyl)phenyll-3-[1 (ethylsulfonyl)-4-piperidinylI-1 H-indole-7-carboxamide Br NH N N ~N H 0
NH
2 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 H-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 10 Example 372: 5-3-({(4-chlorophenvl)sulfonvllamino}methvl)phenvil-3-[1 (ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide C0 10 0,k NHN N H 0 NH2 The title compound was prepared according to the general procedure of 5-[3-({[(2,5 15 dichlorophenyl)sulfonyl]aminolmethyi)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 302 WO 2007/005534 PCT/US2006/025402 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 5 Example 373: 3-[1-(ethylsulfonyl)-4-piperidinvll-5-[3-({f(3 fluorophenvl)sulfonvllamino}methvl)phenvll-1H-indole-7-carboxamide F O I I I OL N N H 0 NH2 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 H-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 15 Example 374: 5-[3-(f{(2-chlorophenvl)sulfonvllamino}methvl)phenyll-3-f1 (ethylsulfonyl)-4-pi peridi nyll-1 H-indole-7-carboxamide 303 WO 2007/005534 PCT/US2006/025402 Cl 0O 1 0O S-'O NH N H 0 NH2 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 H-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-[3-({[(2,5-dichloro-3-thienvl)sulfonyllaminolmethvl)phenvll-3-[l 10 (ethylsulfonyl)-4-piperidinVIl-1 H-indole-7-carboxamide Cl S OO Cl N0HN/O N H 0 NH2 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 H-indole 7-carboxamide substituting 2,5-dichloro-3-thiophenesulfony 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%). 304 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 655.2 [M] Ret. Time: 2.24 min Example 376: 5-[3-({[(2-chloro-6-methylphenvl)sulfonyllamino}methvl)phenvil-3-l1 (ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide 0 0 CI NHN N H 5 2 NH2 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 H-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-[1-(ethylsulfonyl)-4-piperidinvil-5-f3-(f(5-fluoro-2 methylphenvl)sulfonvllamino}methvl)phenyll-1 H-indole-7-carboxamide F O=S=0 O0 IOSz0 N N H 15 O NH2 305 WO 2007/005534 PCT/US2006/025402 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 H-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-[3-({f{1,2-dimethyl-1 H-imidazol-4-vl)sulfonyllaminolmethvl)phenyll 3-[1 -(ethylsulfonyll-4-piperidinyll-1 H-indole-7-carboxamide N N 0 N H N N H 10 0 NH2 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 H-indole 7-carboxamide substituting 1,2-dimethyl-1 H-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-[1-(ethylsulfonyl)-4-piperidinvll-5-(3 {[(phenvlsulfonvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide 306 WO 2007/005534 PCT/US2006/025402 O=S=O Oz NH 0 N N 9 H 0 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 H-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-[l-(ethylsulfonvl)-4-piperidinvll-5-[3-(ff(4 10 fluorophenvl)sulfonvilaminolmethvl)phenvll-1 H-indole-7-carboxamide F NHN IN1 N H 0 NH2 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 H-indole 7-carboxamide substituting 4-fluorobenzenesulfonyl chloride (69 mg, 0. 352 mmol) for 307 WO 2007/005534 PCT/US2006/025402 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 5 Example 381: 5-[3-(f(4-bromo-2-ethylphenvl)sulfonyllaminolmethvi)phenvil-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide Br O=S=0 O NHN N H 0
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 H-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 15 Example 382: 5-(3-fF(1-benzothien-3-vlsulfonyl)aminolmethyllphenyl)-3-[1 (ethylsulfonvl)-4-piperidinyll-1 H-indole-7-carboxamide 308 WO 2007/005534 PCT/US2006/025402 S O=s=0 O. NHN .N N H 0 NF-12 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 H-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-[(ff4-(1,1-dimethylethvl)phenvilsulfonvilamino)methyllphenv1-3 10 F1 -(ethylsulfonyl)-4-pi peridinyll-1 H-indole-7-carboxamide O=S=0 O0 NHN I N N H 0 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 H-indole 7-carboxamide substituting 4-(1,1 -dimethylethyl)benzenesulfonyl chloride (82 mg, 0. 352 309 WO 2007/005534 PCT/US2006/025402 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 5 Example 384: 5-r3-({f(3,4-difluorophenvl)sulfonvilaminolmethvl)phenvl1-3-[1 (ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide F F o=s=O NH N N N H 0
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 H-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 15 Example 385: 5-(3-f[(2,1,3-benzoxadiazol-4-vlsulfonvl)aminolmethyl}phenvl)-3-[l (ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide N 0, N H 0 NH 2 310 WO 2007/005534 PCT/US2006/025402 The title compound was prepared according to the general procedure of 5-[3-({[(2,5 dichloropheny)sulfonyl]amino}methyl)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 5 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-[1-(ethylsulfonyl)-4-piperidinvil-5-(3-{[(tetrahvdro-3 furanvlcarbonvl)aminolmethyllphenvl)-1 H-indole-7-carboxamide 00 10N H 10 0 NH2 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)pheny]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (40 mg, 15 0.096 mmol) in DMF (1.0 mL) and DIEA (33 pL, 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 20 Example 387: 5-{4-[(cyclopentvlsulfonyl)aminolphenvl}-3-[1-(ethylsulfonyl)-4 piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 311 WO 2007/005534 PCT/US2006/025402 Ozz O=S=O N HN F H F OH O N2 To 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-indole-7-carboxamide (20 mg, 0.048 mmol) was added chloro(di-2-norbornylphosphino)(2-dimethylaminomethyferrocen-1 yl)palladium (HI) (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 H 2 0 (1 mL). The reactin mixture was heated in a microwave at 1600 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 10 Example 388: 3-[1-(ethylsulfonvl)-4-piperidinyll-5-[4-(4-methyl-2-oxo-1 piperazinvl)phenvll-1 H-indole-7-carboxamide O z N"' O N N N H 0 NH 2 To 5-bromo-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 H 2 0 (1.0 mL), potassium carbonate (13 mg, 0.097 mmol) and 312 WO 2007/005534 PCT/US2006/025402 chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium (1l) (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 1600 C for 10 min. The reaction mixture was concentrated under Nitrogen and purified by Gilson Preparatory HPLC. The 5 desired fraction in CH 3 CN and H 2 0 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-pyridinvlI-3-fl-(ethVlsulfonvl)-4 10 pliperidinyll-1 H-indole-7-carboxamide trifluoroacetate 0 -N N F
F
F OH H 0 NH2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperazinyl)-3-pyridinyl]-1 H indole-7-carboxamide (40 mg, 0.080 mmol) in dicloromethane at 00 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 H 2 0. 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-[l-(ethylsulfonvll-4-piperidinvil-5-(4 20 ff(methyloxv)aminolmethyllphenvi)-1H-indole-7-carboxamide 313 WO 2007/005534 PCT/US2006/025402 U"NH N N H H2N O To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1 H-indole-7 carboxamide (50 mg, 0.114 mmol) in DCM (1.5 mL) and MeOH (1.5 mL) was added 0 5 methyihydroxylamine (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-i -(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)imino]methyl}phenyl)-1 H-indole-7 carboxamide (76%). 10 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)imino]methyl}phenyl) 1 H-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 00 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 15 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 00 C and stirred till room temperature was achieved. Mixture was quenched with H 2 0. 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%). 20 LC/MS = m/z 471.6 [M+H] Ret. Time: 1.67 min Example 391:-3-[1-(ethylsulfonyl)-4-piperidinvll-5-(3 f{(methyloxv)aminolmethyllphenyl)-1 H-indole-7-carboxamide 314 WO 2007/005534 PCT/US2006/025402 0 O-I IH / O NH N N H H2N O To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1 H-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. 5 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 H-indole-7-carboxamide (56%). 10 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)imino]methyl}phenyl) 1 H-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 00 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%). 15 LC/MS = m/z 471.6 [M+H] Ret. Time: 1.75 min Example 392: 3-r1-(ethylsulfonyl)-4-piperidinvil-5-(5-ff4-(1-pyrrolidinvi)-1 piperidinyllmethyl}-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate 315 WO 2007/005534 PCT/US2006/025402 N N S F F+ N F OH H 0 NH2 To a solution of 3-[l -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-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 10 Example 393: 3-[1-(ethylsulfonyl)-4-piperdinil-5-(5-{[(2S)-2-(trifluoromethyl)-1 pyrrolidinyllmethyl}-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate
O
F N/ F N S F IF O IF N F OH H 0 NH2 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 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 316 WO 2007/005534 PCT/US2006/025402 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 5 Example 394: 5-(5-ff(2R)-2-(hydroxVmethyl)-1-pyrrolidinvllmethyl}-3-thienyl)-3-{1 (1 -methylethvl)sulfonvll-4-piperidi nyl-1 H-indole-7-carboxamide /O ' HO g N H H2N O To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H 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-ff(3S)-3-hydroxy-1-pyrrolidinvilmethyll-3-thienyl)-3-f1-[(1 methylethvl)sulfonvll-4-piperidinvl}-1 H-indole-7-carboxamide 20 317* HO N N H H 2N O 20 317 WO 2007/005534 PCT/US2006/025402 The title compound was prepared according to the general procedure of 5-(5-{[(2R)-2 (hydroxymethyl)-1 -pyrrolidinyl]methy}-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-ffcvclopentyl(methvl)aminolmethyl}-3-thienvl)-3-f1-[(1 methylethvl)sulfonvll-4-piperdinvl}-1 H-indole-7-carboxamide H H2N O 10 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 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-f[(2-hydroxvethyl)(methvl)aminolmethyll-3-thienvi)-3-f1-[(1 methylethyl)sulfonyll-4-pi peridinyll-1 H-indole-7-carboxamide O m' N ON S N H2N O 20 318 WO 2007/005534 PCT/US2006/025402 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-ff(2-amino-2-oxoethyl)(methvl)aminolmethyll-3-thienvl)-3-fl-(1 methylethvi)sulfonvil-4-piperidinyl}-1 H-indole-7-carboxamide 0 _ H 2N NS N H H2N O 10 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 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-[1-(ethylsulfonvl)-4-piperidinyll-5-(5-f{methvl(2-propen-1 yl)aminolmethyl}-3-thienyl)-1 H-indole-7-carboxamide zo N N s N H 20 0 NH 2 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)-1 H-indole-7 carboxamide (20 mg, 0.0449 mmol) in DMSO (0.5 mL) in a 1-dram vial. NaBH(OAc) 3 (95 319 WO 2007/005534 PCT/US2006/025402 mg, 0.449 mmol) was then added, the vial was capped and the reaction was stirred at room temperature for 15 h. NaCNBH 3 (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 NH/MeOH (9 mL). The NH/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% CH 3
CN/H
2 0 (0.1% NH 4 0H) to 70% CH 3
CN/H
2 0 (0.1%
NH
4 0H) 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. 15 Example 400: 5-(5-fif(3,5-dimethvl-1H-pyrazol-4-vl)methyll(methvl)aminolmethvl}-3 thienvl)-3-[1-(ethylsulfonvl)-4-piperidinvll-1 H-indole-7-carboxamide O O=,S N H N S N H O NH12 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-indole-7 carboxamide (45 mg, 100 pmol) in dimethyl sulfoxide (1.0 mL) was added 1-(3,5 20 dimethy-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%). 25 LC/MS = m/z 569.3 [M+H] Ret. Time: 1.42 min. Example 401: 5-(5-{fr(cyanomethyl)(methvI)aminolmethyl}-3-thienvl)-3-l (ethylsulfonVl)-4-piperidinyll-1 H-indole-7-carboxamide 320 WO 2007/005534 PCT/US2006/025402 O O=S N N S N\ N H O NH2 The title compound was prepared according to the general procedure of 5-(5-{[[(3,5 dimethyl-1 H-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. 10 Example 402: 3-[1-(ethylsulfonVl)-4-piperidinvll-5-(5-ffmethvl(1 methylpropyl)aminolmethyl}-3-thienI)-1 H-indole-7-carboxamide 0 O=,S N -N S N H O NH2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyll-5-(5-formyl-3-thienyl)-1 H-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 NH 3 in methanol. Further 20 purification was performed by Gilson Preparatory HPLC. XBridge C18 Column (P/N 321 WO 2007/005534 PCT/US2006/025402 186002978) using a gradient of 10% acetonitrile to 70% acetronile in water with 0.1%
NH
4 0H to give 14.4 mg of the title compound (27.9%). LC/MS = m/z 517.3 [M+H] Ret. Time: 1.58 min. 5 Example 403: 5-(5-{[[2-(ethyloxv)ethyll(methvl)aminolmethyl}-3-thienyl)-3-f1 (ethylsulfonyl)-4-piperidi nyl-1 H-indole-7-carboxamide O -- N S N H O NH 2 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. 15 Example 404: 5-(5-{[cvclobutyl(methyl)aminolmethyll-3-thienvl)-3-1-(ethylsulfonyl) 4-piperidinyll-1 H-indole-7-carboxamide trif luoroacetate Om, / NN S F O F OH H2N O 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 322 WO 2007/005534 PCT/US2006/025402 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. 5 Example 405: 3-l-(ethylsulfonvl)-4-piperidinyll-5-[5-({2-[(methyloxv)methVll-1 pyrrolidinvlmethyl)-3-thienvll-1 H-indole-7-carboxamide trifluoroacetate 0 OZ~ IN N S F O N F \ H F OH 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 5 mg of the title compound (7.6%). LC/MS = m/z 545.3 [M+H] Ret. Time: 1.65 min. 15 Example 406: 5-(5-{[(1,1-dimethylethyl)(methvl)aminolmethyl}-3-thienyl)-3-[1 (ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate O
O=S
N -N S F 0 F I /N \H H F OH O NH2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1 -methylpropyl)aminomethyl}-3-thienyl)-1 H 20 indole-7-carboxamide 323 WO 2007/005534 PCT/US2006/025402 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. 5 Example 407: 3-[1-(ethylsulfonyl)-4-piperidinyll-5-(5-f[3-(trifluoromethyl)-1 piperidinvllmethyll-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate F F F Oz O N N F N 44 H F OH
H
2 N 0 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 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. 15 Example 408: 3-F1 -(ethylsulfonyl)-4-piperidi nyll-5-(5-[F(1 S)-2-hydroxy-1 methylethyll(methvl)aminolmethyll-3-thienvl)-1 H-indole-7-carboxamide trifluoroacetate N HO/ \---N S F N F OH H2N O To a vial containing (2R)-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 H-indole-7-carboxamide (30 mg, 0.067 mmol) in DMSO (300 pL) and acetic acid (50 pL). The resulting mixture was shaken for 5 min followed by an addition of sodium triacetoxyborohydride (250 mg, 1.20 324 WO 2007/005534 PCT/US2006/025402 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. 10 Example 409: 5-(5-f[(cyclopropvlmethyl)(methvl)aminolmethyll-3-thienyl)-3-[1 (ethylsulfonvl)-4-piperidi nyl-1 H-indole-7-carboxamide trifluoroacetate NS N F O F N F OH H2N O 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)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting (cyclopropylmethyl)amine (1.20 mmol) for (2R)-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. 20 Example 410: 5-(5-flI2-(acetylamino)ethyll(methvl)aminolmethyl}-3-thienvl)-3-[1 (ethylsulfonyl)-4-piperidinyll-1 H-indole-7-carboxamide trifluoroacetate 325 WO 2007/005534 PCT/US2006/025402 N SN 0 F F N F OHH H2N O The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1 -methylethyl](methyl)amino]methyl} 3-thienyl)-1 H-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-[1 -(ethylsulfonvl)-4-piperidinvil-5-(5-f{F(1 R,2R)-2 10 hydroxvcvclopentyl](methvl)aminolmethyl}-3-thienvi)-1 H-indole-7-carboxamide trifluoroacetate Chiral OZ~ OH N S F F OH H2N O 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)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting (1 R,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. 20 Example 412: 5-(5-f[(1,1-dimethylpropyl)(methyl)aminolmethyl}-3-thienvi)-3-f1 (ethylsulfonyl)-4-pi peridi nyll-1 H-indole-7-carboxamide trifluoroacetate 326 WO 2007/005534 PCT/US2006/025402 O N F O F \N F OH H 2N O The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1 -methylethyl](methyl)amino]methyl} 5 3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting (1,1 dimethylpropyl)amine (1.20 mmol) for (2R)-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. 10 Example 413: 3-[1-(ethylsulfonvl)-4-piperidinvil-5-(5-f[F(2S)-2 hydroxvpropyll(methvl)aminolmethyll-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate Chiral Ozm N N O N S F N -H . H F OH 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)-1 H-indole-7-carboxamide trifluoroacetate (salt), substituting (2S)-1 -amino-2 propanol (1.20 mmol) for (2R)-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. 20 Example 414: 3-fl-(ethylsulfonyl)-4-piperidinvl-5-[5-(fmethvl[(2R)-tetrahvdro-2 furanvimethyllamino}methyl)-3-thienvll-1 H-indole-7-carboxamide trifluoroacetate 327 WO 2007/005534 PCT/US2006/025402 'O 01N N SN F F N F OHH H2N O The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1 -methylethyl](methyl)amino]methyl} 5 3-thienyl)-1 H-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. 10 Example 415: 3-ri-(ethvlsulfonvi)-4-piperidinyll-5-(5-fif2-l(2 hydroxvethvl)oxylethyl}(methvl)aminolmethyll-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate HO N 0\ N S F F OH H2N 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)-1 H-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. 20 Example 416: 3-[1-(ethylsulfonyl)-4-piperidinVil-5-r5-(1-{methyll2 (methyloxv)ethyllaminolethyl)-3-thienvll-1 H-indole-7-carboxamide trifluoroacetate 328 WO 2007/005534 PCT/US2006/025402 0 N -- N S F N F H F OH H2N O To a solution of 5-(5-acetyl-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 1209 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-[1-(ethylsulfonvl)-4-piperidinvll-5-(5-f1-[methyl(propvl)aminolethyll 15 3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate N -- N S F 0 H F O H H2N O To a solution of 5-(5-acetyl-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H-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 ZO 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 120L C for 120 min. All 329 WO 2007/005534 PCT/US2006/025402 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. 5 Example 418: 5-(2.3-dihydro-1 H-isoindol-5-yl)-3-1 -(ethylsulfonyl)-4-piperidinyll-1 H indole-7-carboxamide 0 N HN N H O NH 2 To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2 10 dioxaborolan-2-y)-1 H-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 H-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 150Q 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-ethyl-2,3-dihydro-1 H-isoindol-5-yl)-3-1 -(ethylsulfonyl)-4 20 piperidinyll-1 H-indole-7-carboxamide N 0 \N N H O NH 2 330 WO 2007/005534 PCT/US2006/025402 To a solution of 5-(2,3-dihydro-1 H-isoindol-5-yl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 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 1009 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-[l-(ethylsulfonyl)-4-piperidinvll-5-[2-(1-methylethyl)-2,3-dihvdro-1H 10 isoindol-5-yll-1 H-indole-7-carboxamide 0" N N N H 0 NH 2 To a solution of 5-(2,3-dihydro-1 H-isoindol-5-yl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 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. 20 Example 421: 5-[2-(1,2-dimethylpropyl)-2,3-dihydro-1 H-isoindol-5-yll-3-1 (ethylsulfonvi)-4-piperidinyll-1 H-indole-7-carboxamide 331 WO 2007/005534 PCT/US2006/025402 O N N N H 0 NH 2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl]-1 H-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-[1-(ethylsulfonvi)-4-piperidinyll-5-[2-(1-methylpropyl)-2,3-dihvdro 10 1 H-isoindol-5-vil-1 H-indole-7-carboxamide O" SCO N N N H 0 NH 2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyll-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-y]-1 H-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-[2-(1 -ethyl propyl)-2,3-di hydro-1 H-isoindol-5-yil-3-[1 -(ethylsulfonyl) 20 4-piperidinyll-1 H-indole-7-carboxamide 332 WO 2007/005534 PCT/US2006/025402 O S-O N N N H 0 NH 2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-y]-1 H-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-cyclopentyl-2,3-dihydro-1 H-isoindol-5-yI)-3-[1 -(ethylsulfonyl)-4 10 piperidinvll-1 H-indole-7-carboxamide :Or N C>N N H 0 NH 2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl]-1 H-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-f2-(cyclopropylmethyl)-2.3-dihydro-1 H-isoindol-5-vll-3-1 20 (ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide 333 WO 2007/005534 PCT/US2006/025402 z:O N NN H 0 NH 2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl]-1 H-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-[2-(2,2-dimethVlpropyl)-2,3-dihvdro-1 H-isoindol-5-Vll-3-[1 10 (ethylsulfonyl)-4-piperidinvIl-1 H-indole-7-carboxamide 0" ZZO N -N N H O NH 2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl]-1 H-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-[1-(ethylsulfonvl)-4-piperidinyll-5-(2-methyl-2,3-dihydro-1H-isoindol 20 5-yl)-1 H-indole-7-carboxamide 334 WO 2007/005534 PCT/US2006/025402 2 /SO N -- N N H 0 NH2 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl]-1 H-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-[1-(ethylsulfonvi)-4-piperidinvil-5-(2 10 ff(phenvlsulfonvl)aminolcarbonyll-23-dihvdro-1 H-isoindol-5-yl)-1 H-indole-7 carboxamide Or N 0 - N 0 O N H O NH2 To a solution of 5-(2,3-dihydro-1 H-isoindol-5-yl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1 H 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. 20 335 WO 2007/005534 PCT/US2006/025402 Example 429: 5-(5-{[(2R)-2-(aminocarbonyl)-1-pyrrolidinvllmethyll-3-thienvl)-3-fl [(1-methylethyl)sulfonyll-4-piperidi nyl-1 H-indole-7-carboxamide HNN H2N NN 0 N H r H2N O 5 To a solution of 5-(5-formyl-3-thienyl)-3-{1 -[(1 -methylethyl)sulfonyl]-4-piperidinyl}-1 H 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-[1-(ethylsulfonvl)-4-piperdinyll-5-(5-ff2 15 (ethylthio)ethyll(methvl)aminolmethyI}-3-thienvl)-1H-indole-7-carboxamide om N S -\\N S N H H2N 0 20 To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H 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 p L), 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 pL, 1.2 mmol). The mixture was 336 WO 2007/005534 PCT/US2006/025402 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. 5 Example 431: 3-[1-(ethylsulfonyl)-4-piperidinyll-5-(5-fff2-[(2 hydroxvethvl)thiolethyl}(methvl)aminolmethyll-3-thienvl)-1 H-indole-7-carboxamide HO H2N O 10 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 H 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. 15 Example 432: 3-[1-(ethylsulfonvi)-4-piperidinvil-5-(5-{[F2-hydroxy-1 (hydroxymethvl)ethyll(methvl)aminolmethyll-3-thienvl)-1 H-indole-7-carboxamide OH HO N S 0 N 0O
H
2 N N 0 H 20 The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[2-(ethylthio)ethyl](methyl)aminolmethyl}-3-thienyl)-1 H 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. 337 WO 2007/005534 PCT/US2006/025402 LC/MS = m/z 535 [M+H] Ret. Time: 1.44 min. Example 433: ethyl [(4-{7-(ami nocarbonyl)-3-1 -(ethylsulfonvl)-4-piperdinyll-1 H indol-5-vl-2-thienyl)methyllmethvlcarbamate 00 N 0 S /_O 'kN N H 5 0 NH 2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl} 1 H-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 10 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 N-R(4-{7-(aminocarbonyl)-3-[1 -(ethylsulfonyl)-4-piperidinyll-1 H indol-5-vl}-2-thienvl)methyll-N-methylglycinate 0 0 = / \ 4-N H 15 0 NH2 To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-indole-7 carboxamide (45 mg, 100 pmol) in dimethyl sulfoxide (1.0 mL) was added ethyl N methylglycinate (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 20 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. 338 WO 2007/005534 PCT/US2006/025402 Example 435: 3-[1-(ethylsulfonvl)-4-piperidinvll-5-(5-ff (1S)-2-hydroxy-1 methylethyll(methvl)aminolmethyl-3-thienyl)-1 H-indole-7-carboxamide trifluoroacetate (salt) 0-o N 0 / N S N H F c0
H
2 N 0 F o F OH 5 To a vial containing (2S)-2-amino-1-propanol (91 mg, 1.2 mmol) was added a solution of 3-[l-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.067 mmol) in DMSO (300 pL) and acetic acid (50 pL). The resulting mixture was shaken for 5 min followed by an addition of sodium triacetoxyborohydride (250 mg, 1.20 mmol) in DMSO (800 pL). The mixture was shaken overnight. Sodium cyanoborohydride 10 (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 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 15 using Gilson Preparatory HPLC to afford 18.7 mg of the title compound. LC/MS = m/z 519.3 [M+HJ Ret. Time: 1.49 min. Example 436: 5-(5-ff(1,1-dioxidotetrahvdro-3-thienvI)(methvl)aminolmethyl}-3 thienvl)-3-[l-(ethylsulfonyl)-4-piperidinvll-1 H-indole-7-carboxamide trifluoroacetate oms N 0 0::S N s N H
H
2 N 0 F F o 20 F OH The title compound was prepared according to the general procedure of 3-[1 (ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S)-2-hydroxy-1 -methylethyl](methyl)amino]methyl} 339 WO 2007/005534 PCT/US2006/025402 3-thienyl)-1H-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. 5 Biological Data IKK2 Assay Recombinant human IKKB (residues 1-737) was expressed in baculovirus as a C-terminal GST-tagged fusion protein, and its activity was assessed using a time-resolved 10 fluorescence resonance energy transfer (TR-FRET) assay. Briefly, IKK2 (0.5 nM - 5nM final) diluted in assay buffer (50 mM HEPES, 10 mM MgCl 2 , 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 pM final), in a total volume of 6 pl. The reaction 15 was incubated for 15 minutes at room temperature, then terminated by the addition of 3 pl 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-1 024 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. 25 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 plC 50 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 plC 0 of less than 5.0. Monocyte Assay 5 Effect of IKK-s 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 340 WO 2007/005534 PCT/US2006/025402 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) for 2h. 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 pM in this assay. 20 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 pM (top dose tested). 25 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. 30 Variable results were obtain in the monocyte assay for Examples 38, 64, 82, 215, 297, 344, 364, and 369. 341 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. 341A

Claims (7)

1. 3-[1 -(ethylsulfony)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl] 1H-indole-7-carboxamide of formula (1) 5 N N N H S NH2() or a pharmaceutically acceptable salt thereof.
2. 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl] 10 1H-indole-7-carboxamide of formula (1) 0" O N N N H S NH2 ().
3. A pharmaceutical composition comprising 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-( 1 15 methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
4. A pharmaceutical composition according to claim 3, which further comprises one 20 or more additional pharmaceutically active compounds. 342 C.WURPonb\DCCJXT\4183624_LDOC-29AI2/21112
5. 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl] 1H-indole-7-carboxamide, or a pharmaceutically acceptable salt thereof, for use in therapy. 5 6. 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl] 1 H-indole-7-carboxamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of asthma or chronic obstructive pulmonary disease (COPD).
7. Use of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H 10 isoindol-5-yl]-1H-indole-7-carboxamide, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of asthma or chronic obstructive pulmonary disease (COPD).
8. A method of treating asthma or chronic obstructive pulmonary disease (COPD), 15 comprising administering a safe and effective amount of 3-[1-(ethylsulfonyl)-4 piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl]-1 H-indole-7 carboxamide, or a pharmaceutically acceptable salt thereof to a patient in need thereof. 20 9. 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[2-(1 -methylethyl)-2,3-dihydro-1 H-isoindol-5-yl] 1H-indole-7-carboxamide according to claim 1, a pharmaceutical composition according to claim 3, a use according to claim 7, or a method according to claim 8, substantially as hereinbefore described and/or exemplified. 343
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