WO2011112731A2 - Heterocyclic inhibitors of histamine receptors for the treatment of disease - Google Patents

Heterocyclic inhibitors of histamine receptors for the treatment of disease Download PDF

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WO2011112731A2
WO2011112731A2 PCT/US2011/027771 US2011027771W WO2011112731A2 WO 2011112731 A2 WO2011112731 A2 WO 2011112731A2 US 2011027771 W US2011027771 W US 2011027771W WO 2011112731 A2 WO2011112731 A2 WO 2011112731A2
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chosen
compound
hydrogen
recited
salt
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WO2011112731A3 (en
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Allen Borchardt
Robert Davis
Clay Beauregard
Daniel Becker
Daniel Gamache
Stewart A. Noble
Mark R. Hellberg
Peter G. Klimko
Qui Zhihai
Joseph E. Payne
John Yanni
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Kalypsys, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Histamine a low molecular weight biogenic amine
  • Histamine functions as a secreted signal in immune and inflammatory responses, as well as a neurotransmitter.
  • the functions of histamine are mediated through 4 distinct cell surface receptors (HiR, H 2 R, 3 ⁇ 4R and H 4 R). Histamine receptors vary in expression, signaling, function and histamine affinity, and therefore have different potential therapeutic applications (Zhang M, Thurmond RL, and Dunford PJ Pharmacology &
  • All 4 histamine receptors are G protein-coupled receptors (GPCRs). Upon histamine or other agonist binding, they activate distinct signaling pathways through different heterotrimeric G proteins.
  • the HiR couples to the G q family of G proteins, whose primary signaling cascade induces second messenger calcium mobilization from intracellular stores, followed by multiple downstream effects. HiR can also increase cyclic GMP (cGMP) production and activate NF B, a potent, positive transcriptional regulator of inflammation.
  • the H 2 R couples to the G s family of G proteins and increases cyclic AMP (cAMP) formation by stimulating adenylate cyclase, although it can also induce calcium mobilization in some cell types.
  • GPCRs G protein-coupled receptors
  • the 3 ⁇ 4R mediates its function through Gy 0 proteins and decreases cAMP formation by inhibiting adenylate cyclase. Like other Gj /0 -coupled receptors, 3 ⁇ 4R also activates the mitogen- activated protein/extracellular-signal regulated protein (MAP/ERK) kinase pathway. H 4 Rhas also been demonstrated to couple to Gj /o proteins, with canonical inhibition of cAMP formation and MAP kinase activation. However, H 4 R also couples to calcium mobilization in certain cell types. In fact, H 4 R signaling in mast cells is primarily through calcium
  • HiR is expressed in many cell types, including endothelial cells, most smooth muscle cells, cardiac muscle, central nervous system (CNS) neurons, and lymphocytes.
  • HiR signaling causes smooth muscle contraction (including bronchoconstriction), vasodilation, and increased vascular permeability, hallmarks of allergic and other immediate hypersensitivity reactions.
  • CNS central nervous system
  • HiR activation is associated with wakefulness. Its activation is also associated with pruritus and nociception in skin and mucosal tissues.
  • HiR antagonists have been utilized to treat acute and chronic allergic disorders and other histamine-mediated pathologies, such as itch and hives.
  • H 2 R is expressed similarly to the HiR, and can also be found in gastric parietal cells and neutrophils. H 2 R is best known for its central role in gastric acid secretion but has also been reported to be involved in increased vascular permeability and airway mucus production. Antagonists of H2R are widely used in treating peptic ulcers and gastroesophageal reflux disease. These drugs are also used extensively to reduce the risk of gastrointestinal (GI) bleeding associated with severe upper GI ulcers and GI stress in the inpatient setting.
  • GI gastrointestinal
  • the H 3 R is primarily found in the CNS and peripheral nerves innervating cardiac, bronchial, and GI tissue. H 3 R signaling regulates the release of multiple neurotransmitters, such as acetylcholine, dopamine, serotonin, and histamine itself (where it acts as a CNS autoreceptor). In the CNS, H 3 R participates in the processes of cognition, memory, sleep, and feeding behaviors. H 3 R antagonists may be used potentially for treating cognition disorders (such as Alzheimer's disease), sleep and wakefulness disorders, attention disorders, and metabolic disorders (especially related to obesity).
  • cognition disorders such as Alzheimer's disease
  • sleep and wakefulness disorders such as attention disorders, and metabolic disorders (especially related to obesity).
  • H 4 R Existence of the H 4 R was predicted in the early 1990s, but its cloning by multiple groups was not reported until 2000. In contrast to the other histamine receptors, the H 4 R has a distinctly selective expression profile in bone marrow and on certain types of hematopoietic cells. H 4 R signaling modulates the function of mast cells, eosinophils, dendritic cells, and subsets of T cells. The H 4 R appears to control multiple behaviors of these cells, such as activation, migration, and cytokine and chemokine production (Zhang M, Thurmond RL, and Dunford PJ
  • HiR histamine receptor
  • H 2 R histamine receptor
  • H 4 R histamine receptor
  • the HiR was the first described histamine receptor, and ligands targeting this receptor were initially developed in the 1930s and in widespread use by the 1940s.
  • HiR antagonist drugs currently approved for use include systemic agents such as diphenhydramine (Benadryl, also used topically), cetirizine (Zyrtec), fexofenadine (Allegra), loratadine (Claritin) and desloratadine (Clarinex), and topical agents such as olopatadine (Patanol, Pataday, Patanase), ketotifen, azelastine (Optivar, Astelin) and epinastine (Elestat).
  • Hi receptor antagonists have certain deficiencies as therapeutic agents in the treatment of diseases where histamine is an important mediator.
  • their effects are often only moderate and reduce allergic symptoms by only 40 to 50%.
  • Hi receptor antagonists, especially systemic agents have little to no effect in relieving nasal congestion.
  • Hi receptor antagonists In allergic asthma, despite the fact that histamine levels rapidly increase in the airways and in plasma (correlating with disease severity), Hi receptor antagonists have largely failed as a therapeutic strategy, though some effect is seen with administration during the priming phase as opposed to the challenge phase (Thurmond RL et al., Nat Rev Drug Discov, 2008, 7:41-53).
  • HiR antagonists are mostly ineffective in the treatment of atopic dermatitis-associated pruritus, with the only modest benefits derived from some first-generation compounds likely a consequence of their sedative properties (Sharpe, G. R. & Shuster, S. Br. I
  • HiR antagonists amenable to replacement by or
  • H 4 receptor As a therapeutic target. Given the ability of H 4 R to modulate the cellular function of eosinophils, mast cells, dendritic cells and T cells (M. Zhang et al., Pharmacol Ther 2007), it is natural to speculate that the H 4 R may be involved in various inflammatory diseases, and that H 4 R antagonists would have therapeutic potential (Jutel et al., 2006). Indeed, both in vitro and in vivo evidence has been demonstrated for the utility of H 4 R antagonists as anti-inflammatory agents in inflammatory bowel disease (IBD) (Sander LE et al., Gut 2006; 55:498-504).
  • IBD inflammatory bowel disease
  • H 4 receptor antagonists inhibit histamine-induced migration of mast cells and eosinophils in vitro and in vivo, both of which are important effector cells in the allergic response, raises the possibility that this class of compounds could reduce the allergic hyper-responsiveness developed upon repeated exposure to antigens, which is characterized by an increase in the number of mast cells and other inflammatory cells in the nasal and bronchial mucosa (Fung-Leung WP et al., Curr Opin Inves Drugs, 2004 5: 11 1174-1182).
  • HiR antagonists In contrast to some of the HiR antagonists, H 4 R antagonists given during the allergen challenge phase of a mouse model of asthma are equally effective to those given during sensitization
  • H4 receptor- deficient animals histamine or H 4 receptor agonist- induced itch was markedly attenuated in H4 receptor- deficient animals (Dunford, P. J. et al., /. Allergy Clin. Immunol, 2007, 119: 176-183).
  • the presence of the H 4 R in nasal tissue was first discovered by Nakaya et al. (Nakaya, M. et al., Ann Otol Rhinol Laryngol, 2004, 113: 552-557).
  • a more recent finding showed that there is a significant increase in the level of H 4 R in human nasal polyp tissue taken from patients with chronic rhinosinusitis (infection of the nose and nasal cavities) when compared to normal nasal mucosa.
  • H 4 R antagonists might be a new way to treat nasal polyps and chronic rhinosinusitis.
  • the administration of H 4 R antagonists may prevent the accumulation of eosinophils as a result of impaired cell chemotaxis toward polypous tissue (Jokuti, A. et al., Cell Biol Int, 2007, 31 : 1367).
  • H 4 R inverse agonist CZC- 13788
  • H 4 R antagonists or potentially, H 1 R/H 4 R dual antagonists, in the treatment of metabolic disorders such as obesity (Jorgensen E et al., Neuroendocrinology . 2007; 86(3):210-4), vascular or cardiovascular diseases such as atherosclerosis (Tanihide A et al., TCM 2006: 16(8): 280-4), inflammation and pain (Coruzzi G et al., Eur J Pharmacol. 2007 Jun l ;563(l-3):240-4), rheumatoid arthritis (Grzybowska-Kowalczyk A et al., Inflamm Res.
  • metabolic disorders such as obesity (Jorgensen E et al., Neuroendocrinology . 2007; 86(3):210-4), vascular or cardiovascular diseases such as atherosclerosis (Tanihide A et al., TCM 2006: 16(8): 280-4), inflammation and pain (Coruzzi G et al., Eur J Pharmacol. 2007 Jun
  • HiR antagonists antihistamines
  • HiR antagonists relieve edema and vasoconstriction, both important symptoms of the disease, but these drugs do not affect the underlying inflammatory responses.
  • H 3 R and H 4 R subtypes the traditional role for HiR antagonists in rhinitis has been reappraised.
  • H 3 R agonist (R)-a-methylhistamine can induce the dilatation of nasal blood vessels and that this effect can be counteracted by the 3 ⁇ 4R antagonist/H 4 R agonist clobenpropit (Taylor-Clark, T., et al, Pulm Pharm Ther, 2008, 21 : 455-460).
  • this 3 ⁇ 4R antagonist-mediated mechanism in nasal decongestion has certainly caught the attention of scientists from Pfizer Inc.
  • patient recruitment started for a Phase II clinical trial to test a H 3 R antagonist (PF-03654746, unpublished structure) as a novel nasal decongestant in patients with seasonal allergic rhinitis.
  • H1/H4 In view of the role of the H 4 R in allergic rhinitis, other potential treatment paradigms may also be considered, such as combining H1/H4, H3/H4 or even H1/H3/H4 antagonists/inverse agonist activity in the same molecule approach is being pursued by GSK that is currently recruiting patients to test a systemic H1/H3 antagonist (GSK835726, unpublished structure) for seasonal allergic rhinitis in a Phase I clinical trial. A second Phase I trial with another H1/H3 antagonist (GSK1004723, unpublished structure) for intranasal administration to treat rhinitis has recently been completed. With these compounds, the mode of action of the classical HiR antagonist is combined with the potential clinical benefit of added nasal decongestion by H 3 R blockade.
  • Novel compounds and pharmaceutical compositions certain of which have been found to inhibit the histamine type-1 receptor (HiR) and/or the histamine type-4 receptor (H 4 R) have been discovered, together with methods of synthesizing and using the compounds including methods for the treatment of histamine receptor-mediated diseases in a patient by administering the compounds.
  • HisR histamine type-1 receptor
  • H 4 R histamine type-4 receptor
  • A is an optionally substituted 5- or 6-membered, aromatic heterocycle
  • X 1 and X 5 are independently chosen from C, CH and N;
  • X 6 is chosen from CH and N;
  • Y 1 is chosen from a bond, lower alkyl, lower alkoxy, OR 15 , NR 16 R 17 , and lower aminoalkyl;
  • R 1 is selected from the group consisting of:
  • Y 1 when Y 1 is chosen from OR 15 , NR 16 R 17 , lower alkyl, lower alkoxy, or lower aminoalkyl;
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, C(0)OR 24 , acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 15 and R 16 are independently chosen from aminoalkyl, alkylaminoalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether, heterocycloalkyl, lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 17 is independently chosen from hydrogen, aminoalkyl, alkylaminoalkyl aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether, heterocycloalkyl, lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; and
  • R 24 is chosen from hydrogen and lower alkyl.
  • the ring comprising X 1 - X 5 is aromatic
  • X 1 and X 5 are independently chosen from C, CH and N;
  • X 2 is chosen from [C(R 6 )(R 7 )] n , NR 8 , O and S;
  • X 3 is chosen from [C(R 9 )(R 10 )] m , NR 11 , O, and S;
  • X 4 is chosen from [C(R 12 )(R 13 )], NR 14 , O and S;
  • n and m are each an integer from 1 to 2;
  • Y 1 is chosen from a bond, lower alkyl, lower alkoxy, OR 15 , NR 16 R 17 , and lower aminoalkyl;
  • R 1 is selected from the group consisting of:
  • Y 1 when Y 1 is chosen from OR 15 , NR 16 R 17 , lower alkyl, lower alkoxy, or lower aminoalkyl;
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl,
  • perhaloalkoxy amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 6 , R 7 , R 9 , R 10 , R 12 , and R 13 are independently chosen from null, hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 8 , R n , and R 14 are independently chosen from null, hydrogen, alkyl, heteroalkyl, alkoxy, haloalkyl, perhaloalkyl, aminoalkyl, C-amido, carboxyl, acyl, hydroxy, aryl, arylalkyl, cycloalkylalkylalkyl,
  • heterocycloalkylalkyl heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 15 and R 16 are independently chosen from aminoalkyl
  • alkylaminoalkyl aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether,
  • heterocycloalkyl lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 17 is independently chosen from hydrogen, aminoalkyl,
  • Certain compounds disclosed herein may possess useful histamine receptor inhibitory activity, and may be used in the treatment or prophylaxis of a disease or condition in which HiR and/or H 4 R plays an active role.
  • certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions.
  • Certain embodiments provide methods for inhibiting HiR and/or H 4 R.
  • Other embodiments provide methods for treating a HiR- and/or H 4 R- mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition according to the present invention.
  • certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the inhibition of HiR and/or H 4 R.
  • X 1 and X 5 are independently chosen from C and N;
  • X 2 is chosen from [C(R 6 )(R 7 )] n , NR 8 , and O;
  • X 3 is chosen from [C(R 9 )(R 10 )] m , NR 11 , and O;
  • X 4 is chosen from NR 14 , O, and S;
  • Y 1 is chosen from bond, OR 15 , and NR 16 R 17 ;
  • R 1 is selected from the group consisting of:
  • R 8 , R 11 , and R 14 are independently chosen from null, hydrogen, and C 1-C3 alkyl.
  • X 4 is NR 14 ;
  • R 1 is heterocycloalkyl
  • R 14 is null.
  • X 2 is selected from the group consisting of:
  • X 3 is selected from the group consisting of:
  • R 1 is chosen from heterocycloalkyl, which may be optionally substituted;
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl,
  • R 9 is chosen from hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; and R 9 is chosen from hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylal
  • R 9 is 2-furanyl
  • R 1 is chosen from piperazin-1- yl and 4-(2-hydroxyethyl)piperazin-l-yl; then R 2 , R 3 , R 4 , and R 5 are not all hydrogen; and
  • R 1 is chosen from 4-methylpiperazin-l-yl, piperazin- 1-yl, and 4-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl); and
  • p is an integer from 0 to 3;
  • R 18 is chosen from hydrogen and methyl
  • R 20 is chosen from hydrogen and chlorine
  • R 19 is independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; then R 19 are not all hydrogen; and
  • p is an integer from 0 to 3;
  • R 18 is methyl
  • R 20 is nitro
  • R 19 is independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; then R are not all hydrogen; and
  • R 26 is chosen from hydrogen and lower alkyl
  • q is an integer from 0 to 3.
  • R 21 is methyl
  • R 23 is chosen from hydrogen and methyl
  • R 22 is independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; then R 22 are not all hydrogen; and
  • R 21 and R 23 are hydrogen
  • R 22 is independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; then R 22 are not all hydrogen.
  • X 2 is CH
  • X 3 is N
  • R 1 is chosen from 4-methylpiperazin-l-yl and piperazin-l-yl.
  • X 2 is N
  • X 3 is CR 9 ; and R 9 is chosen from hydrogen, lower alkyl, halogen, haloalkyl, perhaloalkyl, amino, carboxyl, cyano, nitro, aryl, cycloalkyl, heterocycloalkyl, any of which may be optionally substituted.
  • X 2 and X 3 are N;
  • R 1 is chosen from 4-methylpiperazin-l-yl and piperazin-l-yl; and R 4 is chosen from cyano, halogen, haloalkyl, perhaloalkyl, and perhaloalkoxy.
  • the 5-membered ring comprising X 2 , X 3 , and X 5 is aromatic;
  • X 5 is chosen from C and N;
  • X 2 is selected from the group consisting of:
  • X 3 is chosen from CR 9 and O, when X 5 is C;
  • R 1 is heterocycloalkyl, which may be optionally substituted
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl,
  • perhaloalkoxy amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 6 and R 9 are independently chosen from hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 1 is chosen from 4-methylpiperazin-l-yl, piperazin- 1-yl and bicyclic heterocycloalkyl;
  • R 1 cannot be 4- morpholino, 4-piperidinyl, or 4-phenylpiperidin-4-ol;
  • X 5 is N.
  • X 2 is N
  • X 3 is CR 9 ;
  • R 4 is chosen from halogen, haloalkyl, lower alkenyl, perhaloalkyl, and perhaloalkoxy;
  • R 9 is chosen from hydrogen and lower alkyl.
  • X 5 is C.
  • X 2 is CR 6 ;
  • X 3 is O.
  • X 2 is O
  • X 3 is CR 9 ;
  • R 1 is chosen from a 5-membered heterocycloalkyl and a 6-membered heterocycloalkyl containing at least two nitrogens.
  • R is chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted.
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, Ci-Cio alkyl, Ci-Cio alkenyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, cyano, and nitro; and R 9 is chosen from hydrogen, Ci-Cio alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, carboxyl, cyano, nitro, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, any of which may be optionally substituted.
  • R 2 , R 3 , and R 5 are independently chosen from hydrogen, cyano, lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy;
  • R 4 is chosen from cyano, lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy.
  • R 2 , R 3 , and R 5 are independently chosen from hydrogen, cyano lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy;
  • R 4 is chosen from lower alkyl, cyano, lower alkenyl, bromine, fluorine, perhaloalkyl, haloalkyl, and perhaloalkoxy.
  • R 2 is chosen from lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy;
  • R 3 and R 5 are independently chosen from hydrogen, lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy;
  • R 4 is chosen from lower alkyl, cyano, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy.
  • R 2 and R 5 are independently chosen from hydrogen, lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy;
  • R 3 is chosen from lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy;
  • R 4 is chosen from lower alkyl, cyano lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy.
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, cyano, lower alkyl, halogen, haloalkyl, perhaloalkyl, and perhaloalkoxy.
  • R 2 , R 3 , and R 5 are
  • R 2 , R 3 and R 5 are independently chosen from hydrogen, halogen, haloalkyl, lower alkyl, perhaloalkyl, and perhaloalkoxy.
  • R 4 is chosen from cyano, halogen, lower alkyl, lower alkenyl, perhaloalkoxy, and perhaloalkyl.
  • R 4 is chosen from cyano, halogen, C1-C3 alkyl, and perhaloakyl.
  • R 4 is chosen from cyano, methyl, halogen, and perhaloalkyl.
  • R 4 is chosen from cyano, methyl, bromine, chlorine, and perhaloalkyl
  • R 4 is chosen from cyano, halogen, and perhaloalkyl.
  • R 4 is chosen from cyano, bromine, chlorine, and perhaloalkyl.
  • R 4 is perhaloalkyl
  • R 4 is halogen
  • R 4 is cyano
  • R 3 and R 4 are halogen.
  • R 2 and R 3 are independently chosen from hydrogen and halogen.
  • R 2 and R 3 are
  • R 2 and R 3 are hydrogen.
  • R 3 is chosen from hydrogen, C1-C3 alkyl, halogen, and perhaloalkyl.
  • R 3 is hydrogen
  • R 3 is halogen
  • R 2 and R 5 are independently chosen from hydrogen, lower alkyl, halogen, and perhaloalkyl.
  • R 2 and R 5 are independently chosen from hydrogen and halogen.
  • R 5 is hydrogen
  • R 2 is halogen.
  • R 2 is hydrogen.
  • R 1 is piperazin-l-yl
  • R 2 is hydrogen
  • R 4 is chosen from cyano, halogen, and perhaloalkyl.
  • R 2 is hydrogen
  • R 3 is halogen
  • R 4 is methyl
  • R 2 and R 4 are halogen
  • R 3 is hydrogen
  • R 2 and R 3 are hydrogen
  • R 4 is perhaloalkyl
  • R 9 is chosen from hydrogen and C1-C3 alkyl.
  • R 9 is chosen from hydrogen and methyl.
  • R 3 is hydrogen
  • R 9 is methyl
  • R 6 is hydrogen
  • R 1 is chosen from 4-methylpiperazin-l-yl and piperazin-l-yl.
  • R 1 is 4-methylpiperazin-l-yl.
  • R 1 is piperazin-l-yl.
  • X 1 and X 5 are independently chosen from C, CH and N;
  • X 2 is chosen from [C(R 6 )(R 7 )] n , NR 8 , and O;
  • X 3 is chosen from [C(R 9 )(R 10 )] m and NR 11 , and O;
  • X 4 is chosen from [C(R 12 )(R 13 )] and NR 14 ;
  • the ring comprising X 1 - X 5 is aromatic and comprises at least two heteroatoms;
  • R 1 is optionally substituted 4- to 7-membered monocyclic
  • R 4 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 2 , R 3 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 6°, R V', R 9 y , R 1 1 0 U , R 1 l 2 z , and R 1 1 3 J are independently chosen from null, hydrogen, lower alkyl, heteroalkyl, lower alkoxy, halogen, lower haloalkyl, lower amino, carboxyl, hydroxy, cyano, and nitro, any of which may be optionally substituted; and
  • R 8 , R n , and R 14 are independently chosen from null, hydrogen, lower alkyl, lower heteroalkyl, lower alkoxy, and lower haloalkyl, any of which may be optionally substituted;
  • R 10 is hydrogen
  • R 6 , R 8 , R 10 , and R 14 are independently chosen from null and hydrogen.
  • X 1 is chosen from C, CH and N;
  • X 2 is chosen from [C(R 6 )(R 7 )] n , NR 8 , and O;
  • X 3 is chosen from [C(R 9 )(R 10 )] m and NR 11 , and O;
  • the ring comprising X 1 - X 3 is aromatic
  • R 1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl
  • R 5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 2 , R 3 and R 4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 6 , R 7 , R 9 , and R 10 are independently chosen from null, hydrogen, lower alkyl, heteroalkyl, lower alkoxy, halogen, lower haloalkyl, lower amino, carboxyl, hydroxy, cyano, and nitro, any of which may be optionally substituted; and
  • R 8 , R 11 , and R 14 are independently chosen from null, hydrogen, lower alkyl, lower heteroalkyl, lower alkoxy, and lower haloalkyl, any of which may be optionally substituted;
  • R 1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl
  • R 5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 2 , R 3 and R 4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 6 , R 8 , R 10 , and R 14 are independently chosen from null and hydrogen;
  • R 9 and R n are independently chosen from null, hydrogen and lower alkyl.
  • R 1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl
  • R 5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano
  • R 2 , R 3 and R 4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 6 , R 8 , R 10 , and R 14 are independently chosen from null and hydrogen; and R 9 and R n are independently chosen from null, hydrogen and lower alkyl.
  • one of R 3 and R 4 is hydrogen.
  • R 5 is fluoro
  • R 4 is chosen from bromine, chlorine, and CF 3 .
  • R 4 is chosen from bromine, chlorine, and CF 3 ;
  • R 5 is fluoro.
  • R 1 is optionally substituted 4- to 7-membered monocyclic
  • R 5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 3 and R 4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 7 , R 9 , and R 11 are independently chosen from hydrogen and lower alkyl.
  • one of R 3 and R 4 is hydrogen.
  • R 5 is fluoro
  • R 4 is chosen from bromine, chlorine, and CF 3 .
  • R 3 is fluoro
  • R 4 is chosen from bromine, chlorine, and CF 3 ;
  • R 5 is fluoro.
  • X 3 and X 5 are each independently chosen from C(R 9 ) and N(R 10 );
  • R 1 is 4- to 7-membered monocyclic heterocycloalkyl optionally substituted with one to three substituents chosen from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cyano, lower amino, hydroxy, and nitro;
  • R 2 , R 3 , R 4 and R 5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 9 and R 10 are each independently chosen from null, hydrogen and lower alkyl; wherein
  • A is an optionally substituted monocyclic 4- to 7-membered heterocycloalkyl attached through a ring nitrogen to the core;
  • X 3 is chosen from C(R 9 ) and N;
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 9 is chosen from hydrogen and lower alkyl
  • X 3 is chosen from C(R 9 ) and N;
  • X 8 is chosen from CH and N;
  • n are each an integer chosen from 1 and 2;
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 9 is chosen from hydrogen and lower alkyl
  • R 24 is chosen from hydrogen, amino, and lower alkyl; wherein if R 5 is hydrogen, then X 3 must be N
  • X 8 is CH
  • n 1 ;
  • R 24 is chosen from hydrogen, amino, and lower alkyl. [092] In certain embodiments, R is lower amino.
  • R 24 is NHCH 3 .
  • X 8 is N
  • n 2;
  • R 24 is chosen from hydrogen and lower alkyl.
  • R 24 is chosen from hydrogen and methyl.
  • R 24 is methyl
  • X 8 is chosen from CH and N;
  • p and q are each an integer chosen from 1 and 2;
  • R 5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 3 and R 4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 9 is chosen from hydrogen and lower alkyl
  • R 24 is chosen from hydrogen, amino, and lower alkyl.
  • R 9 is chosen from hydrogen and methyl.
  • X 8 is CH
  • n 1 ;
  • R 24 is chosen from hydrogen, amino, and lower alkyl.
  • R 24 is lower amino
  • R 5 is fluoro
  • R 4 is chosen from bromine, chlorine, and CF 3 .
  • R 3 is fluoro
  • R is NHCH 3 .
  • X 8 is N
  • n 2;
  • R 24 is chosen from hydrogen and lower alkyl.
  • R 5 is fluoro
  • R 4 is chosen from bromine, chlorine, and CF 3 .
  • R 3 is fluoro
  • R 24 is chosen from hydrogen and methyl.
  • R 24 is methyl
  • X 1 and X 5 are independently chosen from C, CH and N;
  • X 2 is chosen from [C(R 6 )(R 7 )] n , NR 8 , O and S;
  • X 3 is chosen from [C(R 9 )(R 10 )] m , NR 11 , O, and S;
  • X 4 is chosen from [C(R 12 )(R 13 )], NR 14 , O and S;
  • n and m are each an integer from 1 to 2;
  • Y 1 is chosen from a bond, lower alkyl, lower alkoxy, OR 15 , NR 16 R 17 , and lower aminoalkyl;
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl,
  • perhaloalkoxy amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 6 , R 7 , R 9 , R 10 , R 12 , and R 13 are independently chosen from null, hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 8 , R n , and R 14 are independently chosen from null, hydrogen, alkyl, heteroalkyl, alkoxy, haloalkyl, perhaloalkyl, aminoalkyl, C-amido, carboxyl, acyl, hydroxy, aryl, arylalkyl, cycloalkylalkylalkyl,
  • heterocycloalkylalkyl heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 15 and R 16 are independently chosen from aminoalkyl
  • alkylaminoalkyl aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether,
  • heterocycloalkyl lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
  • R 17 is independently chosen from hydrogen, aminoalkyl,
  • X 1 and X 5 are independently chosen from C, CH and N;
  • X 2 is chosen from [C(R 6 )(R 7 )] n , NR 8 , and O;
  • X 3 is chosen from [C(R 9 )(R 10 )] m and NR 11 , and O;
  • X 4 is chosen from [C(R 12 )(R 13 )] and NR 14 ;
  • R 1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 6°, R V', R 9 y , R 1 1 0 U , R 1 l 2 z , and R 1 1 3 J are independently chosen from null, hydrogen, lower alkyl, heteroalkyl, lower alkoxy, halogen, lower haloalkyl, lower amino, carboxyl, hydroxy, cyano, and nitro, any of which may be optionally substituted;
  • R 8 , R n , and R 14 are independently chosen from null, hydrogen, lower alkyl, lower heteroalkyl, lower alkoxy, and lower haloalkyl, any of which may be optionally substituted; and
  • R 24 is chosen from hydrogen, lower amino, and lower alkyl; with the proviso that
  • R 5 is not chlorine
  • R 7 , R 9 , and R 11 are independently chosen from null, hydrogen, and lower alkyl
  • R 24 is chosen from hydrogen, lower amino, and lower alkyl.
  • R 24 is lower amino
  • R is NHCH 3 .
  • R 3 and R 5 are independently chosen from hydrogen and fluorine.
  • R 4 is chosen from cyano, bromine, chlorine, and CF 3 .
  • R 5 is fluoro
  • R 2 is hydrogen
  • R 3 and R 5 are hydrogen.
  • R is chosen from cyano, bromine, chlorine, and CF 3
  • R is cyano
  • R 24 is NHCH 3 .
  • R 2 is hydrogen
  • R 2 , R 3 , and R 5 are hydrogen.
  • X is chosen from C(R ) and N;
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
  • R 9 is chosen from hydrogen and lower alkyl
  • R is chosen from hydrogen, lower amino, and lower alkyl.
  • X 4 is chosen from CH and N;
  • R 1 is chosen from piperazin-l-yl and 4-methylpiperazin-l-yl;
  • R 3 is chosen from hydrogen, cyano, monocyclic heteroaryl, C(0)NHZ, C0 2 Z, CF 3 , NHC(0)Y, NHSO 2 Z, and S0 2 NHZ;
  • R 4 is different than R 3 and is chosen from cyano, monocyclic heteroaryl, C(0)NHZ, C0 2 Z, CF 3 , NHC(0)Y, NHS0 2 Z, and S0 2 NHZ;
  • Z is chosen from hydrogen, lower alkyl, phenyl, and benzyl
  • Y is chosen from lower alkyl, phenyl, benzyl, and lower alkoxy.
  • composition comprising a compound as disclosed herein, together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises at least one compound chosen from those recited in Examples 251-415 and 417-519 or a salt thereof, together with a pharmaceutically acceptable carrier.
  • composition comprising:
  • Another therapeutic agent chosen an HiR antagonist, an 3 ⁇ 4R antagonist, and an intranasal corticosteroid
  • the other therapeutic agent is chosen from acrivastine, alcaftadine, antazoline, azelastine, bromazine, brompheniramine, cetirizine, chlorpheniramine, clemastine, desloratidine, diphenhydramine, diphenylpyraline, ebastine, emedastine, epinastine, fexofenadine, hydroxyzine, ketotifen, levocabastine, levocetirizine, loratidine, methdilazine, mizolastine, promethazine, olopatadine, triprolidine, fluticasone, budesonide, beclomethasone, mometasone and ciclesonide.
  • Also provided herein is a method of treatment of an H 4 R-mediated disease comprising the administration, to a patient in need thereof, of a
  • said treatment is systemic.
  • said administration is topical.
  • said disease is chosen from an inflammatory disease, an autoimmune disease, an allergic disorder, and an ocular disorder.
  • disease is chosen from pruritus, eczema, atopic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, non-allergic rhinitis, rhinosinusitis, nasal inflammation, nasal congestion, sinus congestion, otic inflammation dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis.
  • COPD chronic obstructive pulmonary disease
  • said topical administration is to the skin.
  • said topical administration is to the eye.
  • said topical administration is intranasal, otic, or by inhalation.
  • Also provided herein is a method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as disclosed herein to a patient, wherein the effect is chosen from reduction in the number of mast cells, inhibition of eosiniphil migration optionally to the nasal mucosa, the eye, or the wound site, reduction in inflammatory markers, reduction in inflammatory cytokines, reduction in scratching, relief of symptoms and/or signs of nasal congestion from allergic and non-allergic causes, decreased watering or redness of the eyes, and reduction in ocular pain.
  • Also provided herein is a compound as recited herein for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of HiR and/or H 4 R.
  • Also provided herein is a compound as disclosed herein for use as a medicament.
  • Also provided herein is a compound as disclosed herein for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of HiR and/or H 4 R.
  • a compound as disclosed herein in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of H 4 R.
  • the medicament is formulated for systemic administration. In other embodiments, the medicament is formulated for topical administration.
  • a compound as disclosed herein in the manufacture of a combination medicament for reduction in the number of mast cells; inhibition of inflammatory cell (e.g., granulocytes including eosinophils, basophils, and neutrophils, mast cells, lymphocytes, and dendritic cells) migration to the nasal mucosa, the ear, the eye, or the wound site; reduction in inflammatory markers; reduction in inflammatory cytokines; reduction in scratching; relief of symptoms of nasal congestion from allergic or non-allergic causes; decreased watering or redness of the eyes; or reduction in ocular pain.
  • inflammatory cell e.g., granulocytes including eosinophils, basophils, and neutrophils, mast cells, lymphocytes, and dendritic cells
  • Also provided herein is use of a compound as disclosed herein in the manufacture of a medicament for the treatment of the pain or inflammation resulting from cataract surgery.
  • Also provided herein is use of a compound as disclosed herein in the manufacture of a combination medicament for the prevention or treatment of an H 4 R-mediated disease, together with another therapeutic agent.
  • a compound as disclosed herein together with another therapeutic agent, in the manufacture of a combination medicament for reduction in the number of mast cells; inhibition of inflammatory cell (e.g., granulocytes including eosinophils, basophils, and neutrophils, mast cells, lymphocytes, and dendritic cells) migration to the nasal mucosa, the ear, the eye, or the wound site; reduction in inflammatory markers; reduction in inflammatory cytokines; reduction in scratching; relief of symptoms of nasal congestion from allergic or non-allergic causes; decreased watering or redness of the eyes; or reduction in ocular pain.
  • inflammatory cell e.g., granulocytes including eosinophils, basophils, and neutrophils, mast cells, lymphocytes, and dendritic cells
  • the contacting causes inhibition which is competitive with histamine. .
  • acyl refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom attached to the carbonyl is carbon.
  • An “acetyl” group refers to a -C(0)CH 3 group.
  • An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.
  • alkenyl refers to a straight-chain or branched-chain hydrocarbon group having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms.
  • alkoxy refers to an alkyl ether group, wherein the term alkyl is as defined below.
  • suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, and the like.
  • alkyl refers to a straight-chain or branched-chain alkyl group containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl group will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl group will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like.
  • alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH 2 -). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.
  • alkylamino refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, ⁇ , ⁇ -dimethylamino, N,N- ethylmethylamino and the like.
  • alkylidene refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
  • alkylthio refers to an alkyl thioether (R-S-) group wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.
  • suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n- butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl,
  • alkynyl refers to a straight-chain or branched chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl group comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl group comprises from 2 to 4 carbon atoms.
  • alkynylene refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C ⁇ C-).
  • alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-l-yl, butyn-2-yl, pentyn-l-yl, 3-methylbutyn-l-yl, hexyn-2-yl, and the like.
  • alkynyl may include "alkynylene” groups.
  • acylamino as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group.
  • An example of an “acylamino” group is acetylamino (CH 3 C(0)NH-).
  • amino refers to— NRR , wherein R and R are independently chosen from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form heterocycloalkyl, either of which may be optionally substituted.
  • aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.
  • aryl embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
  • arylalkenyl or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
  • arylalkoxy or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
  • arylalkyl or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • arylalkynyl or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
  • arylalkanoyl or “aralkanoyl” or “aroyl,” as used herein, alone or in combination, refers to an acyl group derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.
  • aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.
  • carbamate refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
  • O-carbamyl as used herein, alone or in combination, refers to a -OC(0)NRR' group, with R and R' as defined herein.
  • N-carbamyl as used herein, alone or in combination, refers to a ROC(0)NR'- group, with R and R' as defined herein.
  • carbonyl when alone includes formyl [- C(0)H] and in combination is a -C(O)- group.
  • carboxyl or “carboxy,” as used herein, refers to -C(0)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt.
  • An "O- carboxy” group refers to a RC(0)0- group, where R is as defined herein.
  • a “C- carboxy” group refers to a -C(0)OR groups where R is as defined herein.
  • cyano as used herein, alone or in combination, refers to - CN.
  • cycloalkyl or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
  • said cycloalkyl will comprise from 5 to 7 carbon atoms.
  • cycloalkyl groups examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-lH-indenyl, adamantyl and the like.
  • "Bicyclic” and "tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene,
  • esters refers to a carboxy group bridging two moieties linked at carbon atoms.
  • ether refers to an oxy group bridging two moieties linked at carbon atoms.
  • halo or halogen
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups.
  • a monohaloalkyl group for one example, may have an iodo, bromo, chloro or fluoro atom within the group.
  • Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups.
  • haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and
  • Haloalkylene refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene
  • heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms chosen from O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH- OCH 3 .
  • heteroaryl refers to a 3 to 7 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from O, S, and N.
  • said heteroaryl will comprise from 5 to 7 carbon atoms.
  • heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.
  • heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl,
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • heterocycloalkyl and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently chosen from nitrogen, oxygen, and sulfur.
  • said heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members.
  • said heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members.
  • said heterocycloalkyl will comprise from 3 to 8 ring members in each ring.
  • said heterocycloalkyl and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently chosen from nitrogen, oxygen, and
  • heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said heterocycloalkyl will comprise from 5 to 6 ring members in each ring.
  • "Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,
  • dihydrocinnolinyl dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1 ,4-dioxanyl, 1,3- dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,
  • heterocycle groups may be optionally substituted unless specifically prohibited.
  • hydrazinyl as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.
  • hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
  • isocyanato refers to a -NCO group.
  • isothiocyanato refers to a -NCS group.
  • linear chain of atoms refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
  • lower means containing from 1 to and including 6 carbon atoms.
  • lower aryl as used herein, alone or in combination, means phenyl or naphthyl, which may be optionally substituted as provided.
  • lower heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of one to six atoms in which one to three may be heteroatoms chosen from O, N, and S, and the remaining atoms are carbon.
  • the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
  • the heteroatom(s) O, N and S may be placed at any interior or terminal position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 .
  • lower heteroaryl means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms chosen from O, S, and N, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms chosen from O, S, and N.
  • lower cycloalkyl as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include
  • lower heterocycloalkyl as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms chosen from O, S, and N.
  • lower heterocycloalkyls include pyrrolidinyl,
  • lower amino refers to— NRR , wherein R and R are independently chosen from hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R' of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.
  • mercaptyl as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.
  • nitro refers to - N0 2 .
  • perhaloalkoxy refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
  • perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • sulfonate refers to the -SO 3 H group and its anion as the sulfonic acid is used in salt formation.
  • thia and thio refer to a -S- group or an ether wherein the oxygen is replaced with sulfur.
  • the oxidized derivatives of the thio group namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
  • thiol as used herein, alone or in combination, refers to an - SH group.
  • thiocarbonyl when alone includes thioformyl -C(S)H and in combination is a -C(S)- group.
  • N-thiocarbamyl refers to an ROC(S)NR'- group, with R and R' as defined herein.
  • O-thiocarbamyl refers to a -OC(S)NRR' group with R and R' as defined herein.
  • thiocyanato refers to a -CNS group.
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • substituents of an "optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxy
  • Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
  • An optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., - CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in- between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ).
  • substituents are recited without qualification as to substitution, both substituted and
  • substituted the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, "optionally substituted with.”
  • R or the term R' refers to a moiety chosen from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted.
  • aryl, heterocycle, R, etc. occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence.
  • certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written.
  • unsymmetrical group such as -C(0)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.
  • bond refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • a bond may be single, double, or triple unless otherwise specified.
  • a dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
  • condition in medical condition, in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • inhibitor encompasses all forms of functional protein (enzyme, kinase, receptor, channel, etc., for example) inhibition, including neutral antagonism, inverse agonism, competitive inhibition, and non-competitive inhibition (such as allosteric inhibition). Inhibition may be phrased in terms of an IC 50 , defined below.
  • Compounds disclosed herein may be allosteric antagonists. Additionally, compounds disclosed herein may be agonists in one species and antagonists in another. Methods are known in the art, and are disclosed herein and can be adapted by those of skill in the art, to ascertain whether a compound is, for example, a suitable H 4 R antagonist in a species of interest.
  • HiR inhibitor is used herein to refer to a compound that exhibits an IC 50 with respect to the histamine type- 1 receptor of no more than about 100 ⁇ and more typically not more than about 50 ⁇ , as measured in the in vitro histamine receptor cell-based assays described generally hereinbelow.
  • H 3 R inhibitor is used herein to refer to a compound that exhibits an IC 50 with respect to the histamine type-3 receptor of no more than about 100 ⁇ and more typically not more than about 50 ⁇ , as measured in the in vitro histamine receptor cell-based assays described generally hereinbelow.
  • H 4 R inhibitor is used herein to refer to a compound that exhibits an IC 50 with respect to the histamine type-4 receptor of no more than about 100 ⁇ and more typically not more than about 50 ⁇ , as measured in the in vitro histamine receptor cell-based assays described generally hereinbelow.
  • EC 50 may also be used.
  • EC5 0 refers to the concentration of a compound required to achieve half of the maximal effect in an assay or protocol, typically as compared to a reference standard.
  • H1/H4 inhibitor is used herein to refer to a compound that exhibits an IC5 0 with respect to both the histamine type- 1 receptor and the histamine type-4 receptor of no more than about 100 ⁇ and more typically not more than about 50 ⁇ , as measured in the in vitro histamine receptor cell-based assays described generally hereinbelow; the amount of inhibition need not be equivalent at each receptor, but should not be negligible.
  • IC5 0 is that concentration of inhibitor which is required to displace a natural ligand or reference standard to a half-maximal level.
  • IC5 0 is that concentration of inhibitor which reduces the activity of a functional protein (e.g., HiR and/or H 4 R) to a half- maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibitory activity against HiR and/or H 4 R.
  • a functional protein e.g., HiR and/or H 4 R
  • compounds will exhibit an IC5 0 with respect to HiR and/or H 4 R of no more than about 10 ⁇ ; in further embodiments, compounds will exhibit an IC5 0 with respect to HiR and/or H 4 R of no more than about 5 ⁇ ; in yet further embodiments, compounds will exhibit an IC5 0 with respect to HiR and/or H 4 R of not more than about 1 ⁇ ; in yet further embodiments, compounds will exhibit an IC5 0 with respect to HiR and/or H 4 R of not more than about 200 nM, as measured in the HiR and/or H 4 R assay described herein.
  • the phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.
  • terapéuticaally acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • patient means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
  • prodrug refers to a compound that is made more active in vivo.
  • Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley- VHCA, Zurich, Switzerland 2003).
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound.
  • prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • a wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • the compounds disclosed herein can exist as therapeutically acceptable salts.
  • the present invention includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to
  • terapéuticaally acceptable salt represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L- ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylprop
  • basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion.
  • the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,
  • dicyclohexylamine procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1- ephenamine, and N,N-dibenzylethylenediamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g.
  • compositions disclosed herein may be manufactured in any manner known in the art, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual, ocular, intranasal and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • parenteral including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary
  • intraperitoneal transmucosal
  • transdermal rectal
  • topical including dermal, buccal, sublingual, ocular, intranasal and intraocular
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • fillers or diluents for use in oral pharmaceutical formulations such as capsules and tablets include, without limitation, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose (MCC), powdered cellulose, cornstarch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers such as polyethylene oxide, and hydroxypropyl methyl cellulose.
  • Fillers may have complexed solvent molecules, such as in the case where the lactose used is lactose monohydrate. Fillers may also be
  • PROSOLV is a proprietary, optionally high-density, silicified microcrystalline cellulose composed of 98% microcrystalline cellulose and 2% colloidal silicon dioxide. Silicification of the microcrystalline cellulose is achieved by a patented process, resulting in an intimate association between the colloidal silicon dioxide and microcrystalline cellulose.
  • ProSolv comes in different grades based on particle size, and is a white or almost white, fine or granular powder, practically insoluble in water, acetone, ethanol, toluene and dilute acids and in a 50g/l solution of sodium hydroxide.
  • disintegrants for use in oral pharmaceutical formulations include, without limitation, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, povidone, crospovidone (polyvinylpolypyrrolidone), methyl cellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxy propyl cellulose, starch, pregelatinized starch, and sodium alginate.
  • glidants and lubricants may be used in oral pharmaceutical formulations to ensure an even blend of excipients upon mixing.
  • lubricants include, without limitation, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • glidants include, without limitation, silicon dioxide (Si0 2 ), talc cornstarch, and poloxamers.
  • Poloxamers or LUTROL®, available from the BASF Corporation
  • A-B-A block copolymers in which the A segment is a hydrophilic polyethylene glycol homopolymer and the B segment is hydrophobic polypropylene glycol
  • Examples of tablet binders include, without limitation, acacia, alginic acid, carbomer, carboxymethyl cellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, copolyvidone, methyl cellulose, liquid glucose, maltodextrin, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch, sucrose, tragacanth, and zein.
  • the compounds may be formulated for parenteral administration by injection, e.g. , by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. , in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried
  • lyophilized condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen- free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen- free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, 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.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. , containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Certain compounds disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient for topical administration may comprise, for example, from 0.001 % to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 2% w/w of the formulation.
  • Topical ophthalmic, otic, and nasal formulations of the present invention may comprise excipients in addition to the active ingredient.
  • Excipients commonly used in such formulations include, but are not limited to, tonicity agents, preservatives, chelating agents, buffering agents, and surfactants.
  • Other excipients comprise solubilizing agents, stabilizing agents, comfort-enhancing agents, polymers, emollients, pH-adjusting agents and/or lubricants.
  • excipients may be used in formulations of the present invention including water, mixtures of water and water- miscible solvents, such as Cl-C7-alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% non-toxic water-soluble polymers, natural products, such as alginates, pectins, tragacanth, karaya gum, guar gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid and mixtures of those products.
  • concentration of the excipient is, typically, from 1 to 100,000 times the concentration of the excipient is, typically, from 1 to 100,000 times the concentration of the excipient is, typically, from 1 to 100,000 times the concentration of the excipient is, typically, from 1 to 100,000
  • the excipients to be included in the formulations are typically selected on the basis of their inertness towards the active ingredient component of the formulations.
  • suitable tonicity-adjusting agents include, but are not limited to, mannitol, dextrose, sodium chloride, glycerin, sorbitol and the like.
  • Suitable buffering agents include, but are not limited to, phosphates, citrates, borates, acetates and the like.
  • Suitable surfactants include, but are not limited to, ionic and nonionic surfactants (though nonionic surfactants are preferred), polysorbate 80, RLM 100, POE 20 cetylstearyl ethers such as Procol ® CS20 and poloxamers such as Pluronic ® F68.
  • Formulations may contain substances which increase the viscosity of the solution or suspension, such as sodium carboxymethyl cellulose, hypromellose, micro crystalline cellulose, sorbitol, or dextran.
  • the formulation may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions, including but not limited to ethanol, benzyl alcohol, polyethylene glycol, phenylethyl alcohol and glycerin.
  • formulations set forth herein may comprise one or more
  • preservatives examples include benzalkonium chloride, p- hydroxybenzoic acid ester, sodium perborate, sodium chlorite, alcohols such as chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives such as polyhexamethylene biguanide, sodium perborate, polyquaternium-1, amino alcohols such as AMP-95, or sorbic acid.
  • the formulation may be self -preserved so that no preservation agent is required.
  • the formulation may be a solution, a suspension or a gel.
  • the formulations for topical application to the eye or ear are in aqueous solution or suspension in the form of drops.
  • the formulations for topical application to the nose in aqueous solution or suspension are in the form of drops, spray or aerosol.
  • aqueous typically denotes an aqueous formulation wherein the formulation is >50 , more preferably >75 and in particular >90 by weight water.
  • the drops may be delivered from a multi-dose bottle which may preferably comprise a device which extracts any preservative from the formulation as it is delivered, such devices being known in the art.
  • Solution and suspension formulations may be nasally administered using a nebulizer. Intranasal delivery as a solution, suspension or dry powder may also facilitated by propellant-based aerosol systems, which include but are not limited to hydrofluoroalkane-based propellants.
  • components of the invention may be delivered to the eye as a concentrated gel or a similar vehicle, or as dissolvable inserts that are placed beneath the eyelids.
  • the formulations of the present invention that are adapted for topical administration to the eye are preferably isotonic, or slightly hypotonic in order to combat any hypertonicity of tears caused by evaporation and/or disease. This may require a tonicity agent to bring the osmolality of the formulation to a level at or near 210-320 milliosmoles per kilogram (mOsm/kg).
  • the formulations of the present invention generally have an osmolality in the range of 220-320 mOsm/kg, and preferably have an osmolality in the range of 235-300 mOsm/kg.
  • the ophthalmic formulations will generally be formulated as sterile aqueous solutions.
  • the compositions of the present invention are formulated with one or more tear substitutes.
  • tear substitutes include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; cellulose esters such hydroxypropylmethyl cellulose, carboxy methylcellulose sodium and hydroxy propylcellulose; dextrans such as dextran 70; vinyl polymers, such as polyvinyl alcohol; and carbomers, such as carbomer 934P, carbomer 941, carbomer 940 and carbomer 974P. Certain formulations of the present invention may be used with contact lenses or other ophthalmic products.
  • Preferred formulations are prepared using a buffering system that maintains the formulation at a pH of about 4.0 to a pH of about 8.
  • a most preferred formulation pH is from 6.5 to 7.5.
  • a formulation of the present invention is administered once a day.
  • the formulations may also be formulated for administration at any frequency of administration, including once a week, once every 5 days, once every 3 days, once every 2 days, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, every hour, or any greater frequency.
  • Such dosing frequency is also maintained for a varying duration of time depending on the therapeutic regimen.
  • the duration of a particular therapeutic regimen may vary from one-time dosing to a regimen that extends for months or years.
  • the formulations are administered at varying dosages, but typical dosages are one to two drops at each administration, or a comparable amount of a gel or other formulation.
  • One of ordinary skill in the art would be familiar with determining a therapeutic regimen for a specific indication.
  • Gels for topical or transdermal administration may comprise, generally, a mixture of volatile solvents, nonvolatile solvents, and water.
  • the volatile solvent component of the buffered solvent system may include lower (C1-C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers.
  • the volatile solvent is ethanol.
  • the volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates.
  • the nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used.
  • the nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system.
  • the amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess may result in a lack of bioavailability due to poor release of drug from solvent mixture.
  • the buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; in certain embodiments, water is used. A common ratio of ingredients is about 20% of the nonvolatile solvent, about 40% of the volatile solvent, and about 40% water.
  • chelators and gelling agents Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as
  • Lotions include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops or sprays may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and, in certain embodiments, including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98- 100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as hydrofluoroalkane, dichlorodifluoromethane,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations described above may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral or intranasal administration may include flavoring agents.
  • Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day.
  • the dose range for adult humans is generally from 5 mg to 2 g/day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compounds can be administered in various modes, e.g. orally, topically, or by injection.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity.
  • the compounds described herein may be administered in combination with another therapeutic agent.
  • another therapeutic agent such as a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • another therapeutic agent which also includes a therapeutic regimen
  • increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • Non-limiting examples of possible combination therapies include use of certain compounds of the invention with HiR antagonists, H 3 R antagonists and/or intranasal corticosteroids.
  • Specific, non-limiting examples of possible combination therapies include use of certain compounds of the invention with HiR antagonists such as acrivastine, alcaftadine, antazoline, azelastine, bromazine,
  • corticosteroids such as fluticasone, budesonide, beclomethasone, mometasone and ciclesonide.
  • the multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even
  • the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills).
  • One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses.
  • the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.
  • certain embodiments provide methods for treating HiR and/or H 4 R-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder that is known in the art.
  • certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of HiR and/or H 4 R-mediated disorders.
  • Specific diseases to be treated by the compounds, compositions, and methods disclosed herein include inflammation and related diseases, including autoimmune diseases.
  • the compounds are useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis.
  • the compounds are also useful in treating osteoporosis and other related bone disorders.
  • These compounds can also be used to treat gastrointestinal conditions such as reflux esophagitis, diarrhea, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.
  • the compounds may also be used in the treatment of upper respiratory inflammation, such as, but not limited to, seasonal allergic rhinitis, non-seasonal allergic rhinitis, acute non-allergic rhinitis, chronic non-allergic rhinitis, Sampter's triad, non-allergic rhinitis with eosinophilia syndrome, nasal polyposis, atrophic rhinitis, hypertrophic rhinitis, membranous rhinitis, vasomotor rhinitis, rhinosinusitis, chronic rhinopharyngitis, rhinorrhea, occupational rhinitis, hormonal rhinitis, drug-induced rhinitis, gustatory rhinitis, as well as pulmonary inflammation, such as that associated with
  • compounds disclosed herein may be used in the treatment of tendonitis, bursitis, skin-related conditions such as psoriasis, allergic dermatitis, atopic dermatitis and other variants of eczema, allergic contact dermatitis, irritant contact dermatitis, seborrhoeic eczema, nummular eczematous dermatitis, autosensitization dermatitis, Lichen Simplex Chronicus, dyshidrotic dermatitis, neurodermatitis, stasis dermatitis, generalized ordinary urticaria, acute allergic urticaria, chronic allergic urticaria, autoimmune urticaria, chronic idiopathic urticaria, drug-induced urticaria, cholinergic urticaria, chronic cold urticaria, dermatographic urticaria, solar urticaria, urticaria pigmentosa, mastocytosis, acute or chronic pruritis associated with skin-local
  • the compounds disclosed herein can be used to treat respiratory diseases, including therapeutic methods of use in medicine for preventing and treating a respiratory disease or condition including: asthmatic conditions including allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, cold- induced asthma, and viral-induced-asthma; chronic obstructive pulmonary diseases including chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous disease; and other pulmonary diseases involving inflammation including bronchioectasis cystic fibrosis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, pneumonia, aspiration or inhalation injury, fat embolism in the lung, acidosis inflammation of the lung, acute pulmonary edema, acute mountain sickness, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hy
  • the compounds disclosed herein are also useful in treating tissue damage in such diseases as vascular diseases, periarteritis nodosa, thyroiditis, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, periodontis, hypersensitivity, and swelling occurring after injury.
  • diseases as vascular diseases, periarteritis nodosa, thyroiditis, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, periodontis, hypersensitivity, and swelling occurring after injury.
  • the compounds disclosed herein can be used in the treatment of otic diseases and otic allergic disorders, including eustachian tube itching.
  • the compounds disclosed herein can be used in the treatment of ophthalmic diseases, such as ophthalmic allergic disorders, including allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis, dry eye, glaucoma, glaucomatous retinopathy, diabetic retinopathy, retinal ganglion degeneration, ocular ischemia, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue.
  • ophthalmic allergic disorders including allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis
  • dry eye glaucoma, glaucomatous retinopathy, diabetic retinopathy, retinal ganglion degeneration, ocular ischemia, retinitis,
  • the compounds of the present invention are used to treat an allergic eye disease chosen from allergic
  • Compounds disclosed herein are useful in treating patients with inflammatory pain such as reflex sympathetic dystrophy/causalgia (nerve injury), peripheral neuropathy (including diabetic neuropathy), and entrapment neuropathy (carpel tunnel syndrome).
  • the compounds are also useful in the treatment of pain associated with acute herpes zoster (shingles), postherpetic neuralgia (PHN), and associated pain syndromes such as ocular pain.
  • Pain indications include, but are not limited to, pain resulting from dermal injuriesand pain-related disorders such as tactile allodynia and hyperalgesia.
  • the pain may be somatogenic (either nociceptive or neuropathic), acute and/or chronic.
  • the present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatory therapies, such as together with steroids, NSAIDs, COX-2 selective inhibitors, 5 -lipoxygenase inhibitors, LTB 4 antagonists and LTA 4 hydrolase inhibitors.
  • the compounds disclosed herein may also be used to prevent tissue damage when therapeutically combined with antibacterial or antiviral agents.
  • certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • Example 7 The title compound was prepared as described in Example 7, except that 8-chloro-4-(piperazin-l-yl)-l,2-dihydroimidazo[l,2-a]quinoxaline (Example 7) was substituted for 8-chloro-4-(4-methylpiperazin- 1 -yl)-l ,2-dihydroimidazo[ 1 ,2- a]quinoxaline (Example 5) in step 1 of that route.

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Abstract

The present invention relates to compounds and methods which may be useful as inhibitors of H1R and/or H4R for the treatment or prevention of inflammatory, autoimmune, allergic, and ocular diseases.

Description

HETEROCYCLIC INHIBITORS OF HISTAMINE RECEPTORS FOR THE
TREATMENT OF DISEASE
[001] This application claims the benefit of United States Provisional
Applications No. 61/312,619, filed March 10, 2010 the disclosure of which is hereby incorporated by reference as if written herein in its entirety.
[002] Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibition of histamine receptor activity in a human or animal subject are also provided for the treatment of allergic diseases, inflammation, asthma, rhinitis, chronic obstructive pulmonary disease, conjunctivitis, rheumatoid arthritis, and general and localized pruritis.
[003] Histamine, a low molecular weight biogenic amine, is a potent chemical mediator of normal and pathological physiology. Histamine functions as a secreted signal in immune and inflammatory responses, as well as a neurotransmitter. The functions of histamine are mediated through 4 distinct cell surface receptors (HiR, H2R, ¾R and H4R). Histamine receptors vary in expression, signaling, function and histamine affinity, and therefore have different potential therapeutic applications (Zhang M, Thurmond RL, and Dunford PJ Pharmacology &
Therapeutics. 2007).
[004] All 4 histamine receptors are G protein-coupled receptors (GPCRs). Upon histamine or other agonist binding, they activate distinct signaling pathways through different heterotrimeric G proteins. The HiR couples to the Gq family of G proteins, whose primary signaling cascade induces second messenger calcium mobilization from intracellular stores, followed by multiple downstream effects. HiR can also increase cyclic GMP (cGMP) production and activate NF B, a potent, positive transcriptional regulator of inflammation. The H2R couples to the Gs family of G proteins and increases cyclic AMP (cAMP) formation by stimulating adenylate cyclase, although it can also induce calcium mobilization in some cell types. The ¾R mediates its function through Gy0 proteins and decreases cAMP formation by inhibiting adenylate cyclase. Like other Gj/0-coupled receptors, ¾R also activates the mitogen- activated protein/extracellular-signal regulated protein (MAP/ERK) kinase pathway. H4Rhas also been demonstrated to couple to Gj/o proteins, with canonical inhibition of cAMP formation and MAP kinase activation. However, H4R also couples to calcium mobilization in certain cell types. In fact, H4R signaling in mast cells is primarily through calcium
mobilization with little to no impact on cAMP formation.
[005] The HiR is expressed in many cell types, including endothelial cells, most smooth muscle cells, cardiac muscle, central nervous system (CNS) neurons, and lymphocytes. HiR signaling causes smooth muscle contraction (including bronchoconstriction), vasodilation, and increased vascular permeability, hallmarks of allergic and other immediate hypersensitivity reactions. In the CNS, HiR activation is associated with wakefulness. Its activation is also associated with pruritus and nociception in skin and mucosal tissues. For many years, the antiallergic and anti-inflammatory activities of HiR antagonists have been utilized to treat acute and chronic allergic disorders and other histamine-mediated pathologies, such as itch and hives.
[006] The H2R is expressed similarly to the HiR, and can also be found in gastric parietal cells and neutrophils. H2R is best known for its central role in gastric acid secretion but has also been reported to be involved in increased vascular permeability and airway mucus production. Antagonists of H2R are widely used in treating peptic ulcers and gastroesophageal reflux disease. These drugs are also used extensively to reduce the risk of gastrointestinal (GI) bleeding associated with severe upper GI ulcers and GI stress in the inpatient setting.
[007] The H3R is primarily found in the CNS and peripheral nerves innervating cardiac, bronchial, and GI tissue. H3R signaling regulates the release of multiple neurotransmitters, such as acetylcholine, dopamine, serotonin, and histamine itself (where it acts as a CNS autoreceptor). In the CNS, H3R participates in the processes of cognition, memory, sleep, and feeding behaviors. H3R antagonists may be used potentially for treating cognition disorders (such as Alzheimer's disease), sleep and wakefulness disorders, attention disorders, and metabolic disorders (especially related to obesity).
[008] Existence of the H4R was predicted in the early 1990s, but its cloning by multiple groups was not reported until 2000. In contrast to the other histamine receptors, the H4R has a distinctly selective expression profile in bone marrow and on certain types of hematopoietic cells. H4R signaling modulates the function of mast cells, eosinophils, dendritic cells, and subsets of T cells. The H4R appears to control multiple behaviors of these cells, such as activation, migration, and cytokine and chemokine production (Zhang M, Thurmond RL, and Dunford PJ
Pharmacology & Therapeutics. 2007).
[009] Of the 4 known histamine receptors, HiR, H2R and H4R have been shown clearly to affect inflammation and other immune responses and are proposed therapeutic targets for treating immune and inflammatory disorders (Jutel et al., 2002; Akdis & Simons, 2006). The HiR was the first described histamine receptor, and ligands targeting this receptor were initially developed in the 1930s and in widespread use by the 1940s. Common HiR antagonist drugs currently approved for use include systemic agents such as diphenhydramine (Benadryl, also used topically), cetirizine (Zyrtec), fexofenadine (Allegra), loratadine (Claritin) and desloratadine (Clarinex), and topical agents such as olopatadine (Patanol, Pataday, Patanase), ketotifen, azelastine (Optivar, Astelin) and epinastine (Elestat).
Traditional uses have included allergic diseases and reactions such as asthma, rhinitis, and other chronic obstructive pulmonary disorders, ocular disorders such as allergic conjunctivitis, and pruritis of varying etiologies.
[010] However, Hi receptor antagonists have certain deficiencies as therapeutic agents in the treatment of diseases where histamine is an important mediator. First, their effects are often only moderate and reduce allergic symptoms by only 40 to 50%. In particular, Hi receptor antagonists, especially systemic agents, have little to no effect in relieving nasal congestion. In allergic asthma, despite the fact that histamine levels rapidly increase in the airways and in plasma (correlating with disease severity), Hi receptor antagonists have largely failed as a therapeutic strategy, though some effect is seen with administration during the priming phase as opposed to the challenge phase (Thurmond RL et al., Nat Rev Drug Discov, 2008, 7:41-53). Additionally, although the efficacy of Hi receptor antagonists against pruritus in acute urticarias, associated with hives and insect stings, and in chronic idiopathic urticaria is well proven, HiR antagonists are mostly ineffective in the treatment of atopic dermatitis-associated pruritus, with the only modest benefits derived from some first-generation compounds likely a consequence of their sedative properties (Sharpe, G. R. & Shuster, S. Br. I
Dermatol. 1993, 129:575-9). Finally, sedation caused by HiR antagonists that cross the blood-brain barrier, among other side effects, limits the utility of many HiR antagonists in diseases for which they would otherwise be efficacious. These deficiencies render HiR antagonists amenable to replacement by or
supplementation with other agents.
[Oi l] Consequently, attention has focused on the more recently discovered H4 receptor as a therapeutic target. Given the ability of H4R to modulate the cellular function of eosinophils, mast cells, dendritic cells and T cells (M. Zhang et al., Pharmacol Ther 2007), it is natural to speculate that the H4R may be involved in various inflammatory diseases, and that H4R antagonists would have therapeutic potential (Jutel et al., 2006). Indeed, both in vitro and in vivo evidence has been demonstrated for the utility of H4R antagonists as anti-inflammatory agents in inflammatory bowel disease (IBD) (Sander LE et al., Gut 2006; 55:498-504). The finding that H4 receptor antagonists inhibit histamine-induced migration of mast cells and eosinophils in vitro and in vivo, both of which are important effector cells in the allergic response, raises the possibility that this class of compounds could reduce the allergic hyper-responsiveness developed upon repeated exposure to antigens, which is characterized by an increase in the number of mast cells and other inflammatory cells in the nasal and bronchial mucosa (Fung-Leung WP et al., Curr Opin Inves Drugs, 2004 5: 11 1174-1182). In contrast to some of the HiR antagonists, H4R antagonists given during the allergen challenge phase of a mouse model of asthma are equally effective to those given during sensitization
(Thurmond RL et al., Nat Rev Drug Discov, 2008, 7:41-53). In two recent mouse studies, a selective H4R agonist was shown to induce itch, whereas these responses, and those of histamine, were blocked by pretreatment with H4R antagonists.
Similarly, histamine or H4 receptor agonist- induced itch was markedly attenuated in H4 receptor- deficient animals (Dunford, P. J. et al., /. Allergy Clin. Immunol, 2007, 119: 176-183). The presence of the H4R in nasal tissue was first discovered by Nakaya et al. (Nakaya, M. et al., Ann Otol Rhinol Laryngol, 2004, 113: 552-557). In addition, a more recent finding showed that there is a significant increase in the level of H4R in human nasal polyp tissue taken from patients with chronic rhinosinusitis (infection of the nose and nasal cavities) when compared to normal nasal mucosa. Jokuti et al. suggest that the administration of H4R antagonists might be a new way to treat nasal polyps and chronic rhinosinusitis. The administration of H4R antagonists may prevent the accumulation of eosinophils as a result of impaired cell chemotaxis toward polypous tissue (Jokuti, A. et al., Cell Biol Int, 2007, 31 : 1367). Although scientific data on the role of the H4R in rhinitis is limited, at present, it is the only indication for which an H4R inverse agonist (CZC- 13788) is reported to be in preclinical development (Hale, R. A. et al., Drug News Perspect, 2007, 20: 593-600).
[012] Current research efforts include both a focus on H4R selective agents and an alternate path toward dual HiR/ H4R agents. Johnson & Johnson have developed a well-characterized H4R antagonist, JNJ-7777120, which is 1000-fold selective over Hi, ¾, and ¾ receptors, and equipotent across human and several nonhuman species. An exemplary HiR/ H4R dual agent has yet to publish as of the time of this writing, and the ideal proportion of HiR versus H4R antagonism is a nascent topic of debate. Nevertheless, the concept of dual activity via a single agent is well-precedented, and the design of multiply active ligands is a current topic in pharmaceutical discovery (Morphy R and Rankovic Z, J Med Chem. 2005;
48(21):6523-43). Additional reports have shown potential for H4R antagonists, or potentially, H1R/H4R dual antagonists, in the treatment of metabolic disorders such as obesity (Jorgensen E et al., Neuroendocrinology . 2007; 86(3):210-4), vascular or cardiovascular diseases such as atherosclerosis (Tanihide A et al., TCM 2006: 16(8): 280-4), inflammation and pain (Coruzzi G et al., Eur J Pharmacol. 2007 Jun l ;563(l-3):240-4), rheumatoid arthritis (Grzybowska-Kowalczyk A et al., Inflamm Res. 2007 Apr;56 Suppl l :S59-60) and other inflammatory and autoimmune diseases including systemic lupus erythematosus (Zhang M, Thurmond RL, and Dunford PJ Pharmacology & Therapeutics. 2007). What is clear is that a need still exists in the art for improved and varied antihistamines for the treatment of disease, and that compounds with H4R and/or H1R/H4R antagonist activity may fill this need.
[013] Histamine is reportedly implicated in allergic rhinitis by acting on three HR subtypes, the HiR, H3R and H4R. For many years, the classical application of HiR antagonists (antihistamines) has been the treatment of allergic rhinitis. HiR antagonists relieve edema and vasoconstriction, both important symptoms of the disease, but these drugs do not affect the underlying inflammatory responses. After the discovery of the H3R and H4R subtypes, the traditional role for HiR antagonists in rhinitis has been reappraised. It has been shown that the H3R agonist (R)-a-methylhistamine can induce the dilatation of nasal blood vessels and that this effect can be counteracted by the ¾R antagonist/H4R agonist clobenpropit (Taylor-Clark, T., et al, Pulm Pharm Ther, 2008, 21 : 455-460). Although a role for the H4R cannot be ruled out, this ¾R antagonist-mediated mechanism in nasal decongestion has certainly caught the attention of scientists from Pfizer Inc. Recently, patient recruitment started for a Phase II clinical trial to test a H3R antagonist (PF-03654746, unpublished structure) as a novel nasal decongestant in patients with seasonal allergic rhinitis. A dual target approach is being pursued by GSK that is currently recruiting patients to test a systemic H1/H3 antagonist (GSK835726, unpublished structure) for seasonal allergic rhinitis in a Phase I clinical trial. A second Phase I trial with another H1/H3 antagonist (GSK1004723, unpublished structure) for intranasal administration to treat rhinitis has recently been completed. With these compounds, the mode of action of the classical HiR antagonist is combined with the potential clinical benefit of added nasal decongestion by H3R blockade. The synergistic role of the HiR and H3R has been demonstrated in vivo in experiments performed at Schering-Plough. In view of the role of the H4R in allergic rhinitis, other potential treatment paradigms may also be considered, such as combining H1/H4, H3/H4 or even H1/H3/H4 antagonists/inverse agonist activity in the same molecule approach is being pursued by GSK that is currently recruiting patients to test a systemic H1/H3 antagonist (GSK835726, unpublished structure) for seasonal allergic rhinitis in a Phase I clinical trial. A second Phase I trial with another H1/H3 antagonist (GSK1004723, unpublished structure) for intranasal administration to treat rhinitis has recently been completed. With these compounds, the mode of action of the classical HiR antagonist is combined with the potential clinical benefit of added nasal decongestion by H3R blockade. The synergistic role of the HiR and H3R has been demonstrated in vivo in experiments performed at Schering-Plough. In view of the role of the H4R in allergic rhinitis, other potential treatment paradigms may also be considered, such as combining H1/H4, H3/H4 or even H1/H3/H4 antagonists/inverse agonist activity in the same molecule.
[014] Novel compounds and pharmaceutical compositions, certain of which have been found to inhibit the histamine type-1 receptor (HiR) and/or the histamine type-4 receptor (H4R) have been discovered, together with methods of synthesizing and using the compounds including methods for the treatment of histamine receptor-mediated diseases in a patient by administering the compounds. [015] Provided herein are compounds of structural Formula (I), or a salt thereof, wherein
Figure imgf000008_0001
(I)
or a salt thereof, wherein:
A is an optionally substituted 5- or 6-membered, aromatic heterocycle; X1 and X5 are independently chosen from C, CH and N;
X6 is chosen from CH and N;
Y1 is chosen from a bond, lower alkyl, lower alkoxy, OR15, NR16R17, and lower aminoalkyl;
R1 is selected from the group consisting of:
aryl, heterocycloalkyl, cycloalkyl, and heteroaryl, any of which may be optionally substituted, when Y1 is a bond; and
null, when Y1 is chosen from OR15, NR16R17, lower alkyl, lower alkoxy, or lower aminoalkyl;
R2, R3, R4, and R5 are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, C(0)OR 24 , acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
R15 and R16 are independently chosen from aminoalkyl, alkylaminoalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether, heterocycloalkyl, lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
R17 is independently chosen from hydrogen, aminoalkyl, alkylaminoalkyl aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether, heterocycloalkyl, lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; and
R 24 is chosen from hydrogen and lower alkyl. [016] Also provided herein are compounds of structural Formula (II), or a salt thereof, wherein
Figure imgf000009_0001
(Π)
the ring comprising X1 - X5 is aromatic;
X1 and X5 are independently chosen from C, CH and N;
X2 is chosen from [C(R6)(R7)]n, NR8, O and S;
X3 is chosen from [C(R9)(R10)]m, NR11, O, and S;
X4 is chosen from [C(R12)(R13)], NR14, O and S;
n and m are each an integer from 1 to 2;
Y1 is chosen from a bond, lower alkyl, lower alkoxy, OR15, NR16R17, and lower aminoalkyl;
R1 is selected from the group consisting of:
aryl, heterocycloalkyl, cycloalkyl, and heteroaryl, any of which may be optionally substituted, when Y1 is a bond; and
null, when Y1 is chosen from OR15, NR16R17, lower alkyl, lower alkoxy, or lower aminoalkyl;
R2, R3, R4, and R5 are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl,
perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
R6, R7, R9, R10, R12, and R13 are independently chosen from null, hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; R8, Rn, and R14 are independently chosen from null, hydrogen, alkyl, heteroalkyl, alkoxy, haloalkyl, perhaloalkyl, aminoalkyl, C-amido, carboxyl, acyl, hydroxy, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
R15 and R16 are independently chosen from aminoalkyl,
alkylaminoalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether,
heterocycloalkyl, lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; and
R17 is independently chosen from hydrogen, aminoalkyl,
alkylaminoalkyl aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether, heterocycloalkyl, lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted.
[017] Certain compounds disclosed herein may possess useful histamine receptor inhibitory activity, and may be used in the treatment or prophylaxis of a disease or condition in which HiR and/or H4R plays an active role. Thus, in broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for inhibiting HiR and/or H4R. Other embodiments provide methods for treating a HiR- and/or H4R- mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition according to the present invention. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the inhibition of HiR and/or H4R.
[018] In certain embodiments provided herein,
X1 and X5 are independently chosen from C and N;
X2 is chosen from [C(R6)(R7)]n, NR8, and O;
X3 is chosen from [C(R9)(R10)]m, NR11, and O;
X4 is chosen from NR14, O, and S; and
Y1 is chosen from bond, OR15, and NR16R17; R1 is selected from the group consisting of:
null, when Y1 is chosen from OR15 and NR16R17; and
optionally substituted heterocycloalkyl, when Y1 is a bond.
[019] In certain embodiments provided herein, R8, R11, and R14 are independently chosen from null, hydrogen, and C 1-C3 alkyl.
[020] In other embodiments provided herein,
Y1 is bond;
X4 is NR14;
R1 is heterocycloalkyl; and
R14 is null.
[021] Also provided herein are compounds of structural Formula (III), thereof, wherein,
Figure imgf000011_0001
(III)
X2 is selected from the group consisting of:
CH and N;
X3 is selected from the group consisting of:
CR9 and N;
with the proviso that at least one of X2 and X3 is N;
R1 is chosen from heterocycloalkyl, which may be optionally substituted;
R2, R3, R4, and R5 are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl,
perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; and R9 is chosen from hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
with the provisos that
when X3 is CR9; and R9 is 2-furanyl; and R1 is chosen from piperazin-1- yl and 4-(2-hydroxyethyl)piperazin-l-yl; then R2, R3, R4, and R5 are not all hydrogen; and
when X3 is N; then R1 is chosen from 4-methylpiperazin-l-yl, piperazin- 1-yl, and 4-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl); and
when compounds ha e structural Formula (Ilia), wherein:
Figure imgf000012_0001
(Ilia)
p is an integer from 0 to 3; and
R 18 is chosen from hydrogen and methyl; and
R20 is chosen from hydrogen and chlorine; and
R19 is independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; then R19 are not all hydrogen; and
when compounds have structural Formula (Ilia), wherein:
p is an integer from 0 to 3; and
R18 is methyl;
R20 is nitro;
R19 is independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; then R are not all hydrogen; and
R26 is chosen from hydrogen and lower alkyl; and
when compounds wherein:
Figure imgf000013_0001
(Illb)
q is an integer from 0 to 3; and
R21 is methyl; and
R23 is chosen from hydrogen and methyl; and
R 22 is independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; then R 22 are not all hydrogen; and
when compounds have structural Formula (Illb), wherein:
R21 and R23 are hydrogen; and
R22 is independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; then R 22 are not all hydrogen.
[022] In certain embodiments provided herein,
X2 is CH;
X3 is N; and
R1 is chosen from 4-methylpiperazin-l-yl and piperazin-l-yl.
[023] In certain embodiments provided herein,
X2 is N;
X3 is CR9; and R9 is chosen from hydrogen, lower alkyl, halogen, haloalkyl, perhaloalkyl, amino, carboxyl, cyano, nitro, aryl, cycloalkyl, heterocycloalkyl, any of which may be optionally substituted.
[024] In other embodiments provided herein,
X2 and X3 are N;
R1 is chosen from 4-methylpiperazin-l-yl and piperazin-l-yl; and R4 is chosen from cyano, halogen, haloalkyl, perhaloalkyl, and perhaloalkoxy.
[025] Provided herein are compounds of structural Formula (IV), or a salt thereof, wherein,
Figure imgf000014_0001
(IV)
or a salt, wherein:
the 5-membered ring comprising X2, X3, and X5 is aromatic;
X5 is chosen from C and N;
X2 is selected from the group consisting of:
N, when X5 is N; and
O and CR6, when X5 is C;
X3 is chosen from CR9 and O, when X5 is C; and
CR9, when X5 is N;
R1 is heterocycloalkyl, which may be optionally substituted;
R2, R3, R4, and R5 are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl,
perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; and
R6 and R9 are independently chosen from hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
with the provisos that
when X5 is N; then R1 is chosen from 4-methylpiperazin-l-yl, piperazin- 1-yl and bicyclic heterocycloalkyl;
when X2 is O; and X3 is CR9; and X5 is C; then R1 cannot be 4- morpholino, 4-piperidinyl, or 4-phenylpiperidin-4-ol;
when X2 is N; and X3 is CR9; and X5 is N; and R1 is 4-methylpiperazin- l-yl; and R4 is hydrogen; then R2, R3, R5, and R9 are not all hydrogen; and
when X2 is N; and X3 is CR9; and X5 is N; and R1 is piperazin-l-yl; and R4 is methyl; then R2, R3, R5, and R9 are not all hydrogen; and
when X2 is N; and X3 is CR9; and X5 is N; and R1 is 4-methylpiperazin- l-yl; and R4 is methoxy; then R3 cannot be methoxy.
[026] In certain embodiments provided herein, X5 is N.
[027] In other embodiments provided herein,
X2 is N;
X3 is CR9;
R4 is chosen from halogen, haloalkyl, lower alkenyl, perhaloalkyl, and perhaloalkoxy; and
R9 is chosen from hydrogen and lower alkyl.
[028] In further embodiments provided herein, X5 is C.
[029] In yet further embodiments provided herein,
X2 is CR6; and
X3 is O.
[030] In certain embodiments provided herein,
X2 is O;
X3 is CR9; and
R1 is chosen from a 5-membered heterocycloalkyl and a 6-membered heterocycloalkyl containing at least two nitrogens. [031] In certain embodiments provided herein, compounds of Formula I have a stru
Figure imgf000016_0001
wherein R is chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted.
[032] In certain embodiments provided herein,
R2, R3, R4, and R5 are independently chosen from hydrogen, Ci-Cio alkyl, Ci-Cio alkenyl, alkoxy, halogen, haloalkyl, perhaloalkyl, perhaloalkoxy, cyano, and nitro; and R9 is chosen from hydrogen, Ci-Cio alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, carboxyl, cyano, nitro, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, any of which may be optionally substituted.
[033] In other embodiments provided herein,
R2, R3, and R5 are independently chosen from hydrogen, cyano, lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy; and
R4 is chosen from cyano, lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy.
[034] In further embodiments provided herein,
R2, R3, and R5 are independently chosen from hydrogen, cyano lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy; and
R4 is chosen from lower alkyl, cyano, lower alkenyl, bromine, fluorine, perhaloalkyl, haloalkyl, and perhaloalkoxy.
[035] In certain embodiments provided herein,
R2 is chosen from lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy;
R3 and R5 are independently chosen from hydrogen, lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy; and
R4 is chosen from lower alkyl, cyano, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy.
[036] In certain embodiments provided herein,
R2 and R5 are independently chosen from hydrogen, lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy;
R3 is chosen from lower alkyl, lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy; and
R4 is chosen from lower alkyl, cyano lower alkenyl, halogen, perhaloalkyl, haloalkyl, and perhaloalkoxy.
[037] In other embodiments provided herein, R2, R3, R4, and R5 are independently chosen from hydrogen, cyano, lower alkyl, halogen, haloalkyl, perhaloalkyl, and perhaloalkoxy.
[038] In further embodiments provided herein, R2, R3, and R5 are
independently chosen from hydrogen, halogen, haloalkyl, lower alkyl, lower alkenyl, alkoxy, perhaloalkyl, and perhaloalkoxy. [039] In yet further embodiments provided herein, R2, R3 and R5 are independently chosen from hydrogen, halogen, haloalkyl, lower alkyl, perhaloalkyl, and perhaloalkoxy.
[040] In other embodiments provided herein, R4 is chosen from cyano, halogen, lower alkyl, lower alkenyl, perhaloalkoxy, and perhaloalkyl.
[041] In certain embodiments provided herein, R4 is chosen from cyano, halogen, C1-C3 alkyl, and perhaloakyl.
[042] In certain embodiments provided herein, wherein R4 is chosen from cyano, methyl, halogen, and perhaloalkyl.
[043] In other embodiments provided herein, wherein R4 is chosen from cyano, methyl, bromine, chlorine, and perhaloalkyl
[044] In further embodiments provided herein, R4 is chosen from cyano, halogen, and perhaloalkyl.
[045] In yet further embodiments provided herein, R4 is chosen from cyano, bromine, chlorine, and perhaloalkyl.
[046] In certain embodiments provided herein, R4 is perhaloalkyl.
[047] In other embodiments provided herein, R4 is halogen.
[048] In other embodiments provided herein, R4 is cyano.
[049] In other embodiments provided herein, R3 and R4 are halogen.
[050] In further embodiments provided herein, R2 and R3 are independently chosen from hydrogen and halogen.
[051] In yet further embodiments provided herein, R2 and R3 are
independently chosen from hydrogen, chlorine, and fluorine.
[052] In yet further embodiments provided herein, R2 and R3 are hydrogen.
[053] In certain embodiments provided herein, R3 is chosen from hydrogen, C1-C3 alkyl, halogen, and perhaloalkyl.
[054] In other embodiments provided herein, R3 is hydrogen.
[055] In other embodiments provided herein, R3 is halogen.
[056] In further embodiments provided herein, R2 and R5 are independently chosen from hydrogen, lower alkyl, halogen, and perhaloalkyl.
[057] In certain embodiments provided herein, R2 and R5 are independently chosen from hydrogen and halogen.
[058] In other embodiments provided herein, R5 is hydrogen.
[059] In other embodiments provided herein, R2 is halogen. [060] In further embodiments provided herein, R2 is hydrogen.
[061] In further embodiments provided herein,
R1 is piperazin-l-yl;
R2 is hydrogen; and
R4 is chosen from cyano, halogen, and perhaloalkyl.
[062] In yet further embodiments provided herein,
R2 is hydrogen;
R3 is halogen; and
R4 is methyl.
[063] In yet further embodiments provided herein,
R2 and R4 are halogen; and
R3 is hydrogen.
[064] In yet further embodiments provided herein,
R2 and R3 are hydrogen; and
R4 is perhaloalkyl.
[065] In certain embodiments provided herein, R9 is chosen from hydrogen and C1-C3 alkyl.
[066] In other embodiments provided herein, R9 is chosen from hydrogen and methyl.
[067] In other embodiments provided herein,
R3 is hydrogen; and
R9 is methyl.
[068] In certain embodiments provided herein, R6 is hydrogen.
[069] In certain embodiments, R1 is chosen from 4-methylpiperazin-l-yl and piperazin-l-yl.
[070] In other embodiments provided herein, R1 is 4-methylpiperazin-l-yl.
[071] In further embodiments provided herein, R1 is piperazin-l-yl.
[072] A compound chosen from Examples 251 -519, or a salt thereof. . [073] Provided herein are compounds of structural Formula (V):
Figure imgf000020_0001
or a salt thereof, wherein:
X1 and X5 are independently chosen from C, CH and N;
X2 is chosen from [C(R6)(R7)]n, NR8, and O;
X3 is chosen from [C(R9)(R10)]m and NR11, and O;
X4 is chosen from [C(R12)(R13)] and NR14;
the ring comprising X1 - X5 is aromatic and comprises at least two heteroatoms;
R1 is optionally substituted 4- to 7-membered monocyclic
heterocycloalkyl;
R4 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano; R2, R3, are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R 6°, R V', R 9y, R 110U, R 1l2z, and R 113J are independently chosen from null, hydrogen, lower alkyl, heteroalkyl, lower alkoxy, halogen, lower haloalkyl, lower amino, carboxyl, hydroxy, cyano, and nitro, any of which may be optionally substituted; and
R8, Rn, and R14 are independently chosen from null, hydrogen, lower alkyl, lower heteroalkyl, lower alkoxy, and lower haloalkyl, any of which may be optionally substituted;
and with the proviso that:
when X1 is C, X2 is NR8, R8 is null, X3 [C(R9)(R10)]m, m is 1, R9 is null, X4 is NR14, R14 is null, X5 is N, R1 is methylpiperazine, R4 is perfluoromethyl, and R5 is fluoro,
then R10 is hydrogen.
[074] In certain embodiments, R6, R8, R10, and R14 are independently chosen from null and hydrogen. ] A compound of structural Formula Va):
Figure imgf000021_0001
(Va)
or a salt thereof, wherein:
X1 is chosen from C, CH and N;
X2 is chosen from [C(R6)(R7)]n, NR8, and O;
X3 is chosen from [C(R9)(R10)]m and NR11, and O;
the ring comprising X1 - X3 is aromatic;
R1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl;
R5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
R2, R3 and R4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R6, R7, R9, and R10, are independently chosen from null, hydrogen, lower alkyl, heteroalkyl, lower alkoxy, halogen, lower haloalkyl, lower amino, carboxyl, hydroxy, cyano, and nitro, any of which may be optionally substituted; and
R8, R11, and R14 are independently chosen from null, hydrogen, lower alkyl, lower heteroalkyl, lower alkoxy, and lower haloalkyl, any of which may be optionally substituted;
and with the proviso that:
when X1 is C, X2 is NR8, R8 is null, X3 [C(R9)(R10)]m, m is 1, R9 is null, R1 is methylpiperazine, R4 is perfluoromethyl, and R5 is fluoro,
then R10 is hydrogen. [076] In certain embodiments provided herein, compounds of Formula V have
Figure imgf000022_0001
or a salt thereof, wherein:
R1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl;
R5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
R2, R3 and R4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R6, R8, R10, and R14 are independently chosen from null and hydrogen; and
R9 and Rn are independently chosen from null, hydrogen and lower alkyl. [077] In certain embodiments provided herein, compounds of Formula V have a struc
Figure imgf000023_0001
or a salt thereof, wherein:
R1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl; R5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano; R2, R3 and R4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R6, R8, R10, and R14 are independently chosen from null and hydrogen; and R9 and Rn are independently chosen from null, hydrogen and lower alkyl.
[078] In certain embodiments, one of R3 and R4 is hydrogen.
[079] In certain embodiments, R5 is fluoro.
[080] In certain embodiments, R4 is chosen from bromine, chlorine, and CF3.
[081] In certain embodiments :
R4 is chosen from bromine, chlorine, and CF3; and
R5 is fluoro. [082] In certain embodiments provided herein, compounds of Formula V have a structural formula chosen from:
Figure imgf000024_0001
or a salt thereof, wherein:
R1 is optionally substituted 4- to 7-membered monocyclic
heterocycloalkyl;
R5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano; R3 and R4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano; and
R7, R9, and R11 are independently chosen from hydrogen and lower alkyl.
[083] In certain embodiments, one of R3 and R4 is hydrogen.
[084] In certain embodiments, R5 is fluoro.
[085] In certain embodiments, R4 is chosen from bromine, chlorine, and CF3.
[086] In certain embodiments, R3 is fluoro.
[087] In certain embodiments,
R4 is chosen from bromine, chlorine, and CF3; and
R5 is fluoro. ] Provided herein are co al Formula (VI)
Figure imgf000025_0001
or a salt thereof, wherein:
X3 and X5 are each independently chosen from C(R9) and N(R10);
R1 is 4- to 7-membered monocyclic heterocycloalkyl optionally substituted with one to three substituents chosen from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cyano, lower amino, hydroxy, and nitro;
R2, R3, R4 and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano; and
R9 and R10 are each independently chosen from null, hydrogen and lower alkyl; wherein
if R5 is hydrogen, then X3 must be N; and
wherein the compound is not
8-chloro-2-methyl-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline;
8-chloro-2-methyl-4-(piperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline;
8-chloro-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline;
8-chloro-4-(piperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline;
4-(8-chloro-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-yl)- 1,1- dimethylpiperazin- 1 -ium;
2-methyl-4-(4-methylpiperazinyl)-8-(trifluoromethyl)pyrazolo[3,4- cjquinoline;
2-methyl-4-piperazinyl-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline HC1 salt; and
4-(4-methylpiperazinyl)-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline. [089] Provided herein are compounds of structural Formula (VII)
Figure imgf000026_0001
(VII)
or a salt thereof, wherein:
A is an optionally substituted monocyclic 4- to 7-membered heterocycloalkyl attached through a ring nitrogen to the core;
X3 is chosen from C(R9) and N;
R2, R3, R4, and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano; and
R9 is chosen from hydrogen and lower alkyl; wherein
if R5 is hydrogen, then X3 must be N.
[090] Provided herein are compounds of structural Formula (VIII)
Figure imgf000026_0002
(VIII)
or a salt thereof, wherein:
X3 is chosen from C(R9) and N;
X8 is chosen from CH and N;
m and n are each an integer chosen from 1 and 2;
R2, R3, R4, and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R9 is chosen from hydrogen and lower alkyl; and
R 24 is chosen from hydrogen, amino, and lower alkyl; wherein if R5 is hydrogen, then X3 must be N
[091] In certain embodiments :
X8 is CH;
m and n are each 1 ; and
R 24 is chosen from hydrogen, amino, and lower alkyl. [092] In certain embodiments, R is lower amino.
[093] In certain embodiments, R24 is NHCH3.
[094] In certain embodiments:
X8 is N;
m and n are each 2; and
R 24 is chosen from hydrogen and lower alkyl.
[095] In certain embodiments, R24 is chosen from hydrogen and methyl.
[096] In certain embodiments, R24 is methyl.
[097] Provided herein are compounds of structural Formula (FX)
Figure imgf000027_0001
(IX)
or a salt thereof, wherein:
X8 is chosen from CH and N;
p and q are each an integer chosen from 1 and 2;
R5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
R3 and R4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R9 is chosen from hydrogen and lower alkyl; and
R24 is chosen from hydrogen, amino, and lower alkyl.
[098] In certain embodiments, R9 is chosen from hydrogen and methyl.
[099] In certain embodiments:
X8 is CH;
m and n are each 1 ; and
R 24 is chosen from hydrogen, amino, and lower alkyl.
[0100] In certain embodiments, R 24 is lower amino.
[0101] In certain embodiments, R5 is fluoro.
[0102] In certain embodiments, R4 is chosen from bromine, chlorine, and CF3.
[0103] In certain embodiments, R3 is fluoro.
[0104] In certain embodiments, R is NHCH3. [0105] In certain embodiments :
X8 is N;
m and n are each 2; and
R 24 is chosen from hydrogen and lower alkyl.
[0106] In certain embodiments, R5 is fluoro.
[0107] In certain embodiments, R4 is chosen from bromine, chlorine, and CF3.
[0108] In certain embodiments, R3 is fluoro.
[0109] In certain embodiments, R24 is chosen from hydrogen and methyl.
[0110] In certain embodiments, R 24 is methyl.
[0111] Also provided Formula (X):
Figure imgf000028_0001
or a salt thereof, wherein:
X1 and X5 are independently chosen from C, CH and N;
X2 is chosen from [C(R6)(R7)]n, NR8, O and S;
X3 is chosen from [C(R9)(R10)]m, NR11, O, and S;
X4 is chosen from [C(R12)(R13)], NR14, O and S;
n and m are each an integer from 1 to 2;
Y1 is chosen from a bond, lower alkyl, lower alkoxy, OR15, NR16R17, and lower aminoalkyl;
R2, R3, R4, and R5 are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl,
perhaloalkoxy, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
R6, R7, R9, R10, R12, and R13 are independently chosen from null, hydrogen, alkyl, heteroalkyl, alkoxy, halogen, haloalkyl, perhaloalkyl, amino, aminoalkyl, amido, carboxyl, acyl, hydroxy, cyano, nitro, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; R8, Rn, and R14 are independently chosen from null, hydrogen, alkyl, heteroalkyl, alkoxy, haloalkyl, perhaloalkyl, aminoalkyl, C-amido, carboxyl, acyl, hydroxy, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted;
R15 and R16 are independently chosen from aminoalkyl,
alkylaminoalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether,
heterocycloalkyl, lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted; and
R17 is independently chosen from hydrogen, aminoalkyl,
alkylaminoalkyl aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, ether, heterocycloalkyl, lower alkylaminoheterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted.
[0112] In certain emb Formula (XI):
Figure imgf000029_0001
(XI)
or a salt thereof, wherein:
X1 and X5 are independently chosen from C, CH and N;
X2 is chosen from [C(R6)(R7)]n, NR8, and O;
X3 is chosen from [C(R9)(R10)]m and NR11, and O;
X4 is chosen from [C(R12)(R13)] and NR14;
R1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl;
R2, R3, R4, and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R 6°, R V', R 9y, R 110U, R 1l2z, and R 113J are independently chosen from null, hydrogen, lower alkyl, heteroalkyl, lower alkoxy, halogen, lower haloalkyl, lower amino, carboxyl, hydroxy, cyano, and nitro, any of which may be optionally substituted; R8, Rn, and R14 are independently chosen from null, hydrogen, lower alkyl, lower heteroalkyl, lower alkoxy, and lower haloalkyl, any of which may be optionally substituted; and
R 24 is chosen from hydrogen, lower amino, and lower alkyl; with the proviso that
when X1 is N, X2 is [C(R6)(R7)]n, X3 is NR11, X4 is NR14, X5 is C, R2 is hydrogen, R3 is hydrogen, R5 is hydrogen, R6-R10 and R12-R14 are chosen from null and hydrogen, and R24 is NH2,
then R5 is not chlorine.
[0113] In certain embodiments are provided compounds having a structural formula chosen from:
Figure imgf000030_0001
Figure imgf000031_0001
[0114] In certain embodiments :
R7, R9, and R11 are independently chosen from null, hydrogen, and lower alkyl; and
R 24 is chosen from hydrogen, lower amino, and lower alkyl.
[0115] In certain embodiments, R 24 is lower amino.
[0116] In certain embodiments, R is NHCH3.
[0117] In certain embodiments, R3 and R5 are independently chosen from hydrogen and fluorine.
[0118] In certain embodiments, R4 is chosen from cyano, bromine, chlorine, and CF3.
[0119] In certain embodiments, R5 is fluoro.
[0120] In certain embodiments :
R2 is hydrogen; and
at least one of R3 and R5 is hydrogen. [0121] In certain embodiments, R is chosen from cyano, bromine, chlorine, and CF3
[0122] In certain embodiments, R is cyano.
[0123] In certain embodiments, R 24 is NHCH3.
[0124] In certain embodiments, R2 is hydrogen.
[0125] In certain embodiments, R2, R3, and R5 are hydrogen.
[0126] Also provided are compounds having structural Formula (XII)
Figure imgf000032_0001
(XII)
or a salt thereof, wherein:
X is chosen from C(R ) and N;
R2, R3, R4, and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R9 is chosen from hydrogen and lower alkyl; and
R is chosen from hydrogen, lower amino, and lower alkyl.
[0127] Also provided are co ctural Formula (XIII):
Figure imgf000032_0002
(XIII)
or a salt thereof, wherein:
the ring comprising X4 is aromatic;
X4 is chosen from CH and N;
R1 is chosen from piperazin-l-yl and 4-methylpiperazin-l-yl;
R3 is chosen from hydrogen, cyano, monocyclic heteroaryl, C(0)NHZ, C02Z, CF3, NHC(0)Y, NHSO2Z, and S02NHZ;
R4 is different than R3 and is chosen from cyano, monocyclic heteroaryl, C(0)NHZ, C02Z, CF3, NHC(0)Y, NHS02Z, and S02NHZ;
Z is chosen from hydrogen, lower alkyl, phenyl, and benzyl; and
Y is chosen from lower alkyl, phenyl, benzyl, and lower alkoxy. [0128] In certain embodiments are provided compounds having a structural
Figure imgf000033_0001
[0129] In certain embodiments are provided compounds having a structural
Figure imgf000033_0002
Figure imgf000034_0001
[0130] Also provided herein is a pharmaceutical composition comprising a compound as disclosed herein, together with a pharmaceutically acceptable carrier.
[0131] In certain embodiments, the pharmaceutical composition comprises at least one compound chosen from those recited in Examples 251-415 and 417-519 or a salt thereof, together with a pharmaceutically acceptable carrier.
[0132] Also provided is a pharmaceutical composition comprising:
a compound as recited as recited herein;
another therapeutic agent chosen an HiR antagonist, an ¾R antagonist, and an intranasal corticosteroid; and
a pharmaceutically acceptable carrier.
[0133] In certain embodiments, the other therapeutic agent is chosen from acrivastine, alcaftadine, antazoline, azelastine, bromazine, brompheniramine, cetirizine, chlorpheniramine, clemastine, desloratidine, diphenhydramine, diphenylpyraline, ebastine, emedastine, epinastine, fexofenadine, hydroxyzine, ketotifen, levocabastine, levocetirizine, loratidine, methdilazine, mizolastine, promethazine, olopatadine, triprolidine, fluticasone, budesonide, beclomethasone, mometasone and ciclesonide.
[0134] Also provided herein is a method of treatment of an H4R-mediated disease comprising the administration, to a patient in need thereof, of a
therapeutically effective amount of a compound as disclosed herein.
[0135] In certain embodiments provided herein, said treatment is systemic.
[0136] In certain embodiments, said administration is topical.
[0137] In certain embodiments, said disease is chosen from an inflammatory disease, an autoimmune disease, an allergic disorder, and an ocular disorder.
[0138] In certain embodiments, disease is chosen from pruritus, eczema, atopic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, non-allergic rhinitis, rhinosinusitis, nasal inflammation, nasal congestion, sinus congestion, otic inflammation dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis.
[0139] In certain embodiments, said topical administration is to the skin.
[0140] In certain embodiments, said topical administration is to the eye.
[0141] In certain embodiments, said topical administration is intranasal, otic, or by inhalation.
[0142] Also provided herein is the use of a compound as disclosed herein in the manufacture of a medicament for the treatment of an H4R-mediated disease comprising the administration of:
a therapeutically effective amount of a compound as recited herein; and another therapeutic agent.
[0143] Also provided herein is a method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as disclosed herein to a patient, wherein the effect is chosen from reduction in the number of mast cells, inhibition of eosiniphil migration optionally to the nasal mucosa, the eye, or the wound site, reduction in inflammatory markers, reduction in inflammatory cytokines, reduction in scratching, relief of symptoms and/or signs of nasal congestion from allergic and non-allergic causes, decreased watering or redness of the eyes, and reduction in ocular pain.
[0144] Also provided herein is a compound as recited herein for use as a medicament.
[0145] Also provided herein is a compound as recited herein for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of HiR and/or H4R.
[0146] Also provided herein is a compound as disclosed herein for use as a medicament.
[0147] Also provided herein is a compound as disclosed herein for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of HiR and/or H4R.
[0148] Also provided herein is use of a compound as disclosed herein in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of H4R. [0149] In certain embodiments, the medicament is formulated for systemic administration. In other embodiments, the medicament is formulated for topical administration.
[0150] Also provided herein is use of a compound as disclosed herein in the manufacture of a combination medicament for reduction in the number of mast cells; inhibition of inflammatory cell (e.g., granulocytes including eosinophils, basophils, and neutrophils, mast cells, lymphocytes, and dendritic cells) migration to the nasal mucosa, the ear, the eye, or the wound site; reduction in inflammatory markers; reduction in inflammatory cytokines; reduction in scratching; relief of symptoms of nasal congestion from allergic or non-allergic causes; decreased watering or redness of the eyes; or reduction in ocular pain.
[0151] Also provided herein is use of a compound as disclosed herein in the manufacture of a medicament for the treatment of the pain or inflammation resulting from cataract surgery.
[0152] Also provided herein is use of a compound as disclosed herein in the manufacture of a combination medicament for the prevention or treatment of an H4R-mediated disease, together with another therapeutic agent.
[0153] Also provided herein is use of a compound as disclosed herein, together with another therapeutic agent, in the manufacture of a combination medicament for reduction in the number of mast cells; inhibition of inflammatory cell (e.g., granulocytes including eosinophils, basophils, and neutrophils, mast cells, lymphocytes, and dendritic cells) migration to the nasal mucosa, the ear, the eye, or the wound site; reduction in inflammatory markers; reduction in inflammatory cytokines; reduction in scratching; relief of symptoms of nasal congestion from allergic or non-allergic causes; decreased watering or redness of the eyes; or reduction in ocular pain.
[0154] Also provided herein is the use of a compound as disclosed herein in the inhibition of H4R comprising contacting H4R with a compound as recited herein.
[0155] In certain embodiments, the contacting causes inhibition which is competitive with histamine. .
[0156] As used herein, the terms below have the meanings indicated.
[0157] When ranges of values are disclosed, and the notation "from ni ... to n2" is used, where ni and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range "from 2 to 6 carbons" is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range "from 1 to 3 μΜ (micromolar)," which is intended to include 1 μΜ, 3 μΜ, and everything in between to any number of significant figures (e.g., 1.255 μΜ, 2.1 μΜ, 2.9999 μΜ, etc.).
[0158] The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.
[0159] The term "acyl," as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom attached to the carbonyl is carbon. An "acetyl" group refers to a -C(0)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.
[0160] The term "alkenyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon group having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(-CH=CH-),(-C::C-)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1 ,4-butadienyl and the like. Unless otherwise specified, the term "alkenyl" may include "alkenylene" groups.
[0161] The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether group, wherein the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, and the like.
[0162] The term "alkyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl group containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl group will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl group will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term "alkyl" may include "alkylene" groups.
[0163] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, Ν,Ν-dimethylamino, N,N- ethylmethylamino and the like.
[0164] The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
[0165] The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (R-S-) group wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n- butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl,
ethanesulfinyl, and the like.
[0166] The term "alkynyl," as used herein, alone or in combination, refers to a straight-chain or branched chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl group comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl group comprises from 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-l-yl, butyn-2-yl, pentyn-l-yl, 3-methylbutyn-l-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" may include "alkynylene" groups.
[0167] The terms "amido" and "carbamoyl," as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term "C-amido" as used herein, alone or in combination, refers to a -C(=0)-NR2 group with R as defined herein. The term "N-amido" as used herein, alone or in combination, refers to a RC(=0)NH- group, with R as defined herein. The term "acylamino" as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH3C(0)NH-).
[0168] The term "amino," as used herein, alone or in combination, refers to— NRR , wherein R and R are independently chosen from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form heterocycloalkyl, either of which may be optionally substituted.
[0169] The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
[0170] The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
[0171] The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
[0172] The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
[0173] The term "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
[0174] The term "arylalkanoyl" or "aralkanoyl" or "aroyl," as used herein, alone or in combination, refers to an acyl group derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like. [0175] The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.
[0176] The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent group C6H4= derived from benzene. Examples include benzothiophene and benzimidazole.
[0177] The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
[0178] The term "O-carbamyl" as used herein, alone or in combination, refers to a -OC(0)NRR' group, with R and R' as defined herein.
[0179] The term "N-carbamyl" as used herein, alone or in combination, refers to a ROC(0)NR'- group, with R and R' as defined herein.
[0180] The term "carbonyl," as used herein, when alone includes formyl [- C(0)H] and in combination is a -C(O)- group.
[0181] The term "carboxyl" or "carboxy," as used herein, refers to -C(0)OH or the corresponding "carboxylate" anion, such as is in a carboxylic acid salt. An "O- carboxy" group refers to a RC(0)0- group, where R is as defined herein. A "C- carboxy" group refers to a -C(0)OR groups where R is as defined herein.
[0182] The term "cyano," as used herein, alone or in combination, refers to - CN.
[0183] The term "cycloalkyl," or, alternatively, "carbocycle," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In certain embodiments, said cycloalkyl will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-lH-indenyl, adamantyl and the like. "Bicyclic" and "tricyclic" as used herein are intended to include both fused ring systems, such as decahydronaphthalene,
octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by bicyclo[l,l,l]pentane, camphor, adamantane, and bicyclo[3,2,l]octane. [0184] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.
[0185] The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.
[0186] The term "halo," or "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
[0187] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
[0188] The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for one example, may have an iodo, bromo, chloro or fluoro atom within the group. Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and
dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene
(-CFH-), difluoromethylene (-CF2 -), chloromethylene (-CHC1-) and the like.
[0189] The term "heteroalkyl," as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms chosen from O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH- OCH3.
[0190] The term "heteroaryl," as used herein, alone or in combination, refers to a 3 to 7 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from O, S, and N. In certain embodiments, said heteroaryl will comprise from 5 to 7 carbon atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
[0191] The terms "heterocycloalkyl" and, interchangeably, "heterocycle," as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently chosen from nitrogen, oxygen, and sulfur. In certain embodiments, said heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said
heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said heterocycloalkyl will comprise from 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,
dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1 ,4-dioxanyl, 1,3- dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,
tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.
[0192] The term "hydrazinyl" as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.
[0193] The term "hydroxy," as used herein, alone or in combination, refers to - OH.
[0194] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
[0195] The term "imino," as used herein, alone or in combination, refers to =N- [0196] The term "iminohydroxy," as used herein, alone or in combination, refers to =N(OH) and =N-0-.
[0197] The phrase "in the main chain" refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.
[0198] The term "isocyanato" refers to a -NCO group.
[0199] The term "isothiocyanato" refers to a -NCS group.
[0200] The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
[0201] The term "lower," as used herein, alone or in a combination, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.
[0202] The term "lower aryl," as used herein, alone or in combination, means phenyl or naphthyl, which may be optionally substituted as provided.
[0203] The term "lower heteroalkyl," as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of one to six atoms in which one to three may be heteroatoms chosen from O, N, and S, and the remaining atoms are carbon. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) O, N and S may be placed at any interior or terminal position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. [0204] The term "lower heteroaryl," as used herein, alone or in combination, means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four said members may be heteroatoms chosen from O, S, and N, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms chosen from O, S, and N.
[0205] The term "lower cycloalkyl," as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0206] The term "lower heterocycloalkyl," as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms chosen from O, S, and N. Examples of lower heterocycloalkyls include pyrrolidinyl,
imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.
[0207] The term "lower amino," as used herein, alone or in combination, refers to— NRR , wherein R and R are independently chosen from hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R' of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.
[0208] The term "mercaptyl" as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.
[0209] The term "nitro," as used herein, alone or in combination, refers to - N02.
[0210] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to -0-.
[0211] The term "oxo," as used herein, alone or in combination, refers to =0.
[0212] The term "perhaloalkoxy" refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
[0213] The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms. [0214] The terms "sulfonate," "sulfonic acid," and "sulfonic," as used herein, alone or in combination, refer to the -SO3H group and its anion as the sulfonic acid is used in salt formation.
[0215] The term "sulfanyl," as used herein, alone or in combination, refers to - S-.
[0216] The term "sulfinyl," as used herein, alone or in combination, refers to -S(O)-.
[0217] The term "sulfonyl," as used herein, alone or in combination, refers to - S(0)2-.
[0218] The term "N-sulfonamido" refers to a RS(=0)2NR' - group with R and R' as defined herein.
[0219] The term "S-sulfonamido" refers to a -S(=0)2NRR' , group, with R and R' as defined herein.
[0220] The terms "thia" and "thio," as used herein, alone or in combination, refer to a -S- group or an ether wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
[0221] The term "thiol," as used herein, alone or in combination, refers to an - SH group.
[0222] The term "thiocarbonyl," as used herein, when alone includes thioformyl -C(S)H and in combination is a -C(S)- group.
[0223] The term "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and R' as defined herein.
[0224] The term "O-thiocarbamyl" refers to a -OC(S)NRR' group with R and R' as defined herein.
[0225] The term "thiocyanato" refers to a -CNS group.
[0226] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
[0227] When a group is defined to be "null," what is meant is that said group is absent. [0228] The term "optionally substituted" means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(0)CH3, C02CH3, C02H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., - CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in- between fully substituted and monosubstituted (e.g., -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and
unsubstituted forms are encompassed. Where a substituent is qualified as
"substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, "optionally substituted with."
[0229] The term R or the term R' , appearing by itself and without a number designation, unless otherwise defined, refers to a moiety chosen from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R' and Rn where n=(l, 2, 3, ...n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an
unsymmetrical group such as -C(0)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.
[0230] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or
recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with
pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
[0231] The term "bond" refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
[0232] The term "disease" as used herein is intended to be generally synonymous, and is used interchangeably with, the terms "disorder" and
"condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
[0233] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
[0234] The term "inhibition" (and by extension, "inhibitor") as used herein encompasses all forms of functional protein (enzyme, kinase, receptor, channel, etc., for example) inhibition, including neutral antagonism, inverse agonism, competitive inhibition, and non-competitive inhibition (such as allosteric inhibition). Inhibition may be phrased in terms of an IC50, defined below.
Compounds disclosed herein may be allosteric antagonists. Additionally, compounds disclosed herein may be agonists in one species and antagonists in another. Methods are known in the art, and are disclosed herein and can be adapted by those of skill in the art, to ascertain whether a compound is, for example, a suitable H4R antagonist in a species of interest.
[0235] In certain embodiments, "HiR inhibitor" is used herein to refer to a compound that exhibits an IC50 with respect to the histamine type- 1 receptor of no more than about 100 μΜ and more typically not more than about 50 μΜ, as measured in the in vitro histamine receptor cell-based assays described generally hereinbelow. Similarly, "H3R inhibitor" is used herein to refer to a compound that exhibits an IC50 with respect to the histamine type-3 receptor of no more than about 100 μΜ and more typically not more than about 50 μΜ, as measured in the in vitro histamine receptor cell-based assays described generally hereinbelow. Also similarly, "H4R inhibitor" is used herein to refer to a compound that exhibits an IC50 with respect to the histamine type-4 receptor of no more than about 100 μΜ and more typically not more than about 50 μΜ, as measured in the in vitro histamine receptor cell-based assays described generally hereinbelow. In either of these scenarios, the term "EC 50" may also be used. In vitro or in vivo, "EC50" refers to the concentration of a compound required to achieve half of the maximal effect in an assay or protocol, typically as compared to a reference standard. A "H1/H4 inhibitor" is used herein to refer to a compound that exhibits an IC50 with respect to both the histamine type- 1 receptor and the histamine type-4 receptor of no more than about 100 μΜ and more typically not more than about 50 μΜ, as measured in the in vitro histamine receptor cell-based assays described generally hereinbelow; the amount of inhibition need not be equivalent at each receptor, but should not be negligible. In certain embodiments, such as, for example, in the case of an in vitro ligand-binding assay protocol, "IC50" is that concentration of inhibitor which is required to displace a natural ligand or reference standard to a half-maximal level. In other embodiments, such as, for example, in the case of certain cellular or in vivo protocols which have a functional readout, "IC50" is that concentration of inhibitor which reduces the activity of a functional protein (e.g., HiR and/or H4R) to a half- maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibitory activity against HiR and/or H4R. In certain embodiments, compounds will exhibit an IC50 with respect to HiR and/or H4R of no more than about 10 μΜ; in further embodiments, compounds will exhibit an IC50 with respect to HiR and/or H4R of no more than about 5 μΜ; in yet further embodiments, compounds will exhibit an IC50 with respect to HiR and/or H4R of not more than about 1 μΜ; in yet further embodiments, compounds will exhibit an IC50 with respect to HiR and/or H4R of not more than about 200 nM, as measured in the HiR and/or H4R assay described herein.
[0236] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.
[0237] The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
[0238] As used herein, reference to "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
[0239] The term "prodrug" refers to a compound that is made more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley- VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
[0240] The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to
Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley- VCHA, Zurich, Switzerland, 2002).
[0241] The term "therapeutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L- ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
[0242] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,
dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1- ephenamine, and N,N-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
[0243] While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g. , in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
[0244] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual, ocular, intranasal and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
[0245] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
[0246] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[0247] Examples of fillers or diluents for use in oral pharmaceutical formulations such as capsules and tablets include, without limitation, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose (MCC), powdered cellulose, cornstarch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers such as polyethylene oxide, and hydroxypropyl methyl cellulose. Fillers may have complexed solvent molecules, such as in the case where the lactose used is lactose monohydrate. Fillers may also be
proprietary, such in the case of the filler PROSOLV® (available from JRS Pharma). PROSOLV is a proprietary, optionally high-density, silicified microcrystalline cellulose composed of 98% microcrystalline cellulose and 2% colloidal silicon dioxide. Silicification of the microcrystalline cellulose is achieved by a patented process, resulting in an intimate association between the colloidal silicon dioxide and microcrystalline cellulose. ProSolv comes in different grades based on particle size, and is a white or almost white, fine or granular powder, practically insoluble in water, acetone, ethanol, toluene and dilute acids and in a 50g/l solution of sodium hydroxide.
[0248] Examples of disintegrants for use in oral pharmaceutical formulations such as capsules and tablets include, without limitation, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, povidone, crospovidone (polyvinylpolypyrrolidone), methyl cellulose, microcrystalline cellulose, powdered cellulose, low-substituted hydroxy propyl cellulose, starch, pregelatinized starch, and sodium alginate.
[0249] Additionally, glidants and lubricants may be used in oral pharmaceutical formulations to ensure an even blend of excipients upon mixing. Examples of lubricants include, without limitation, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. Examples of glidants include, without limitation, silicon dioxide (Si02), talc cornstarch, and poloxamers. Poloxamers (or LUTROL®, available from the BASF Corporation) are A-B-A block copolymers in which the A segment is a hydrophilic polyethylene glycol homopolymer and the B segment is hydrophobic polypropylene glycol
homopolymer.
[0250] Examples of tablet binders include, without limitation, acacia, alginic acid, carbomer, carboxymethyl cellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, copolyvidone, methyl cellulose, liquid glucose, maltodextrin, polymethacrylates, povidone, pregelatinized starch, sodium alginate, starch, sucrose, tragacanth, and zein. [0251 ] The compounds may be formulated for parenteral administration by injection, e.g. , by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. , in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen- free water, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[0252] Formulations for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, 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. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[0253] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0254] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
[0255] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. , containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
[0256] Certain compounds disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
[0257] Formulations suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001 % to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 2% w/w of the formulation.
[0258] Topical ophthalmic, otic, and nasal formulations of the present invention may comprise excipients in addition to the active ingredient. Excipients commonly used in such formulations include, but are not limited to, tonicity agents, preservatives, chelating agents, buffering agents, and surfactants. Other excipients comprise solubilizing agents, stabilizing agents, comfort-enhancing agents, polymers, emollients, pH-adjusting agents and/or lubricants. Any of a variety of excipients may be used in formulations of the present invention including water, mixtures of water and water- miscible solvents, such as Cl-C7-alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% non-toxic water-soluble polymers, natural products, such as alginates, pectins, tragacanth, karaya gum, guar gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid and mixtures of those products. The concentration of the excipient is, typically, from 1 to 100,000 times the
concentration of the active ingredient. In preferred embodiments, the excipients to be included in the formulations are typically selected on the basis of their inertness towards the active ingredient component of the formulations.
[0259] Relative to ophthalmic, otic, and nasal formulations, suitable tonicity- adjusting agents include, but are not limited to, mannitol, dextrose, sodium chloride, glycerin, sorbitol and the like. Suitable buffering agents include, but are not limited to, phosphates, citrates, borates, acetates and the like. Suitable surfactants include, but are not limited to, ionic and nonionic surfactants (though nonionic surfactants are preferred), polysorbate 80, RLM 100, POE 20 cetylstearyl ethers such as Procol® CS20 and poloxamers such as Pluronic® F68. Formulations may contain substances which increase the viscosity of the solution or suspension, such as sodium carboxymethyl cellulose, hypromellose, micro crystalline cellulose, sorbitol, or dextran. Optionally, the formulation may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions, including but not limited to ethanol, benzyl alcohol, polyethylene glycol, phenylethyl alcohol and glycerin.
[0260] The formulations set forth herein may comprise one or more
preservatives. Examples of such preservatives include benzalkonium chloride, p- hydroxybenzoic acid ester, sodium perborate, sodium chlorite, alcohols such as chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives such as polyhexamethylene biguanide, sodium perborate, polyquaternium-1, amino alcohols such as AMP-95, or sorbic acid. In certain embodiments, the formulation may be self -preserved so that no preservation agent is required.
[0261] For ophthalmic, otic, or nasal administration, the formulation may be a solution, a suspension or a gel. In preferred aspects, the formulations for topical application to the eye or ear are in aqueous solution or suspension in the form of drops. In preferred aspects, the formulations for topical application to the nose in aqueous solution or suspension are in the form of drops, spray or aerosol. The term "aqueous" typically denotes an aqueous formulation wherein the formulation is >50 , more preferably >75 and in particular >90 by weight water. These drops may be delivered from a single dose ampoule which may preferably be sterile and thus render bacteriostatic components of the formulation unnecessary. Alternatively, the drops may be delivered from a multi-dose bottle which may preferably comprise a device which extracts any preservative from the formulation as it is delivered, such devices being known in the art. Solution and suspension formulations may be nasally administered using a nebulizer. Intranasal delivery as a solution, suspension or dry powder may also facilitated by propellant-based aerosol systems, which include but are not limited to hydrofluoroalkane-based propellants.
[0262] For ophthalmic disorders, components of the invention may be delivered to the eye as a concentrated gel or a similar vehicle, or as dissolvable inserts that are placed beneath the eyelids.
[0263] The formulations of the present invention that are adapted for topical administration to the eye are preferably isotonic, or slightly hypotonic in order to combat any hypertonicity of tears caused by evaporation and/or disease. This may require a tonicity agent to bring the osmolality of the formulation to a level at or near 210-320 milliosmoles per kilogram (mOsm/kg). The formulations of the present invention generally have an osmolality in the range of 220-320 mOsm/kg, and preferably have an osmolality in the range of 235-300 mOsm/kg. The ophthalmic formulations will generally be formulated as sterile aqueous solutions.
[0264] In certain ophthalmic embodiments, the compositions of the present invention are formulated with one or more tear substitutes. A variety of tear substitutes are known in the art and include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; cellulose esters such hydroxypropylmethyl cellulose, carboxy methylcellulose sodium and hydroxy propylcellulose; dextrans such as dextran 70; vinyl polymers, such as polyvinyl alcohol; and carbomers, such as carbomer 934P, carbomer 941, carbomer 940 and carbomer 974P. Certain formulations of the present invention may be used with contact lenses or other ophthalmic products.
[0265] Preferred formulations are prepared using a buffering system that maintains the formulation at a pH of about 4.0 to a pH of about 8. A most preferred formulation pH is from 6.5 to 7.5.
[0266] In particular embodiments, a formulation of the present invention is administered once a day. However, the formulations may also be formulated for administration at any frequency of administration, including once a week, once every 5 days, once every 3 days, once every 2 days, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, every hour, or any greater frequency. Such dosing frequency is also maintained for a varying duration of time depending on the therapeutic regimen. The duration of a particular therapeutic regimen may vary from one-time dosing to a regimen that extends for months or years. The formulations are administered at varying dosages, but typical dosages are one to two drops at each administration, or a comparable amount of a gel or other formulation. One of ordinary skill in the art would be familiar with determining a therapeutic regimen for a specific indication.
[0267] Gels for topical or transdermal administration may comprise, generally, a mixture of volatile solvents, nonvolatile solvents, and water. In certain embodiments, the volatile solvent component of the buffered solvent system may include lower (C1-C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers. In further embodiments, the volatile solvent is ethanol. The volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates. The nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used. The nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. The amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess may result in a lack of bioavailability due to poor release of drug from solvent mixture. The buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; in certain embodiments, water is used. A common ratio of ingredients is about 20% of the nonvolatile solvent, about 40% of the volatile solvent, and about 40% water. There are several optional ingredients which can be added to the topical composition. These include, but are not limited to, chelators and gelling agents. Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as
hydroxypropylmethylcellulose) and synthetic polymers, galactomannan polymers (such as guar and derivatives thereof) and cosmetic agents. [0268] Lotions include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
[0269] Creams, ointments or pastes are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
[0270] Drops or sprays may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and, in certain embodiments, including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98- 100°C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
[0271] Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
[0272] For administration by inhalation, compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as hydrofluoroalkane, dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
[0273] Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
[0274] It should be understood that in addition to the ingredients particularly mentioned above, the formulations described above may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral or intranasal administration may include flavoring agents.
[0275] Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
[0276] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
[0277] The compounds can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity.
[0278] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for diabetes involving administration of one of the compounds described herein, increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
[0279] Non-limiting examples of possible combination therapies include use of certain compounds of the invention with HiR antagonists, H3R antagonists and/or intranasal corticosteroids. Specific, non-limiting examples of possible combination therapies include use of certain compounds of the invention with HiR antagonists such as acrivastine, alcaftadine, antazoline, azelastine, bromazine,
brompheniramine, cetirizine, chlorpheniramine, clemastine, desloratidine, diphenhydramine, diphenylpyraline, ebastine, emedastine, epinastine, fexofenadine, hydroxyzine, ketotifen, levocabastine, levocetirizine, loratidine, methdilazine, mizolastine, promethazine, olopatadine, and triprolidine, or intranasal
corticosteroids such as fluticasone, budesonide, beclomethasone, mometasone and ciclesonide.
[0280] In any case, the multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even
simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.
[0281] Thus, in another aspect, certain embodiments provide methods for treating HiR and/or H4R-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder that is known in the art. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of HiR and/or H4R-mediated disorders.
[0282] Specific diseases to be treated by the compounds, compositions, and methods disclosed herein include inflammation and related diseases, including autoimmune diseases. The compounds are useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis. The compounds are also useful in treating osteoporosis and other related bone disorders. These compounds can also be used to treat gastrointestinal conditions such as reflux esophagitis, diarrhea, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds may also be used in the treatment of upper respiratory inflammation, such as, but not limited to, seasonal allergic rhinitis, non-seasonal allergic rhinitis, acute non-allergic rhinitis, chronic non-allergic rhinitis, Sampter's triad, non-allergic rhinitis with eosinophilia syndrome, nasal polyposis, atrophic rhinitis, hypertrophic rhinitis, membranous rhinitis, vasomotor rhinitis, rhinosinusitis, chronic rhinopharyngitis, rhinorrhea, occupational rhinitis, hormonal rhinitis, drug-induced rhinitis, gustatory rhinitis, as well as pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. In addition, compounds disclosed herein are also useful in organ transplant patients either alone or in combination with conventional immunomodulators.
[0283] Moreover, compounds disclosed herein may be used in the treatment of tendonitis, bursitis, skin-related conditions such as psoriasis, allergic dermatitis, atopic dermatitis and other variants of eczema, allergic contact dermatitis, irritant contact dermatitis, seborrhoeic eczema, nummular eczematous dermatitis, autosensitization dermatitis, Lichen Simplex Chronicus, dyshidrotic dermatitis, neurodermatitis, stasis dermatitis, generalized ordinary urticaria, acute allergic urticaria, chronic allergic urticaria, autoimmune urticaria, chronic idiopathic urticaria, drug-induced urticaria, cholinergic urticaria, chronic cold urticaria, dermatographic urticaria, solar urticaria, urticaria pigmentosa, mastocytosis, acute or chronic pruritis associated with skin-localized or systemic diseases and disorders, such as pancreatitis, hepatitis, burns, sunburn, and vitiligo.
[0284] Further, the compounds disclosed herein can be used to treat respiratory diseases, including therapeutic methods of use in medicine for preventing and treating a respiratory disease or condition including: asthmatic conditions including allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, cold- induced asthma, and viral-induced-asthma; chronic obstructive pulmonary diseases including chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous disease; and other pulmonary diseases involving inflammation including bronchioectasis cystic fibrosis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, pneumonia, aspiration or inhalation injury, fat embolism in the lung, acidosis inflammation of the lung, acute pulmonary edema, acute mountain sickness, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reactions, sepsis, status asthamticus and hypoxia.
[0285] The compounds disclosed herein are also useful in treating tissue damage in such diseases as vascular diseases, periarteritis nodosa, thyroiditis, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, periodontis, hypersensitivity, and swelling occurring after injury.
[0286] The compounds disclosed herein can be used in the treatment of otic diseases and otic allergic disorders, including eustachian tube itching.
[0287] The compounds disclosed herein can be used in the treatment of ophthalmic diseases, such as ophthalmic allergic disorders, including allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis, dry eye, glaucoma, glaucomatous retinopathy, diabetic retinopathy, retinal ganglion degeneration, ocular ischemia, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with acute injury to the eye tissue. The compounds can also be used to treat post-operative
inflammation or pain as from ophthalmic surgery such as cataract surgery and refractive surgery. In preferred embodiments, the compounds of the present invention are used to treat an allergic eye disease chosen from allergic
conjunctivitis; vernal conjunctivitis; vernal keratoconjunctivitis; and giant papillary conjunctivitis.
[0288] Compounds disclosed herein are useful in treating patients with inflammatory pain such as reflex sympathetic dystrophy/causalgia (nerve injury), peripheral neuropathy (including diabetic neuropathy), and entrapment neuropathy (carpel tunnel syndrome). The compounds are also useful in the treatment of pain associated with acute herpes zoster (shingles), postherpetic neuralgia (PHN), and associated pain syndromes such as ocular pain. Pain indications include, but are not limited to, pain resulting from dermal injuriesand pain-related disorders such as tactile allodynia and hyperalgesia. The pain may be somatogenic (either nociceptive or neuropathic), acute and/or chronic.
[0289] The present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatory therapies, such as together with steroids, NSAIDs, COX-2 selective inhibitors, 5 -lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors. The compounds disclosed herein may also be used to prevent tissue damage when therapeutically combined with antibacterial or antiviral agents. [0290] Besides being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
[0291] All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties. Where any inconsistencies arise, material literally disclosed herein controls.
General methods for preparing compounds:
[0292] The following schemes can be used to practice the present invention.
[0293] The invention is further illustrated by the following examples, which may be made my methods known in the art and/or as shown below. Additionally, these compounds may be commercially available.
SCHEME 1: [l,2,4]triazolo[4,3-a]quinoxalines
Figure imgf000066_0001
EXAMPLE 1
8-chloro-4-(l,2,3,6-tetrahydropyridin-4-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000067_0001
6-Chloroquinoxaline-2,3(lH,4H)-dione:
[0294] A 100 mL round bottom flask was charged with 4-chlorobenzene-l ,2- diamine (5.3 g, 37 mmol) and diethyl oxalate (31 mL). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC
(EtO Ac/Petroleum ether = 1 :10). Work-up: the precipitate was collected by filtration, washed with EtOH (20 mL) and dried, to afford 7.0 g (96%) of the product as light yellow solid. *H NMR (300 MHz, DMSO-d6) δ: 11.96 (br, 2H), 7.11 (m, 3H). MS m/z: 195 (M-H+).
Step 2
Figure imgf000067_0002
2,3,6-Trichloroquinoxaline:
[0295] A 50 mL round bottom flask was charged with 6-chloroquinoxaline- 2,3(lH,4H)-dione (7.0 g, 36 mmol) and phosphorus oxychloride (16 mL). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :10). Work-up: the reaction mixture was cooled to room temperature and cautiously poured over ice water. The solid was collected by filtration and re-dissolved in EtOAc (150 mL) then washed with brine (100 mL), dried over anhydrous Na2S04, and concentrated in vacuo, to afford 7.4 g (89%) of the product as light yellow solid. *H NMR (300 MHz, DMSO-d6) δ: 8.23 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.7, 2.4 Hz, 1H).
Step 3
Figure imgf000068_0001
2,6-Dichloro-3-hydrazinylquinoxaline:
[0296] A 250 mL round bottom flask was charged with 2,3,6- trichloroquinoxaline (4.6 g, 20 mmol) and EtOH (150 mL). To the above was added dropwise hydrazine hydrate (2.2 g, 44 mmol). The resulting solution was stirred overnight at room temperature. Reaction progress was monitored by TLC
(EtO Ac/Petroleum ether = 1 :2). Work-up: the resulting light yellow solid was collected by filtration, washed with water (50 mL) then ethyl acetate (50 mL), and dried, to give 1.5 g (34%) of the product as pink solid. *H NMR (300 MHz, DMSO- d6) δ: 9.14 (br, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.66 (s, 1H), 7.39 (d, J = 8.7 Hz, 1H). MS m/z: 229 (M+H+).
Step 4
Figure imgf000068_0002
4,8-Dichloro-[l,2,4]triazolo[4,3-a]quinoxaline:
[0297] A 50 mL round bottom flask was charged with 2,6-dichloro-3- hydrazinylquinoxaline (1.5 g, 6.6 mmol) and triethyl orthoformate (18 mL). The resulting mixture was stirred at 100 °C for 1 h. Reaction progress was monitored by TLC (EtOAc/Petroleum ether = 1 :2). Work-up: the resulting solid was collected by filtration, washed with MeOH (20 mL x 2), and dried, to give 1.5 g (96%) of the product as light yellow powder. *H NMR (300 MHz, DMSO-d6) δ: 10.20 (s, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.78 (dd, J = 9.0, 2.1 Hz, 1H ). MS m/z: 239 (M+H+).
Step 5
Figure imgf000069_0001
tert-Butyl 4-(8-chloro-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)-5,6- dihydr opyr idine- 1 (2H) -carboxylate :
[0298] A 250 mL 3-necked round bottom flask was charged with 4,8-dichloro- [l,2,4]triazolo[4,3-a]quinoxaline (Example 1, 1.5 g, 6.27 mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)- carboxylate (2.1 g, 6.90 mmol), K2C03 (2.6 g, 6.52 mmol), (1, 1 '- bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.51 g, 0.63 mmol), 1,4- dioxane (45 mL) and water (15 mL). The resulting mixture was stirred at 80 °C for 2 h under N2 atmosphere. Reaction progress was monitored by TLC
(EtO Ac/Petroleum ether = 1 : 1). Work-up: the reaction mixture was diluted with EtOAc (150 mL) and washed with brine (100 mL). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10-40% EtO Ac in petroleum ether, to afford 1.8 g (74%) of the product as light yellow crystals. !H NMR (300 MHz, DMSO-d6) δ: 10.11 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.28 (br, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.69 (dd, J = 9.0, 2.1 Hz, 1H), 4.23 (d, J = 9.6 Hz, 2H), 3.64-3.59 (m, 2H), 2.77 (br, 2H), 1.45 (s, 9H). MS m/z: 386 (M+H+). Step 6
Figure imgf000070_0001
8-chloro-4-(l,2,3,6-tetrahydropyridin-4-yl)-[l,2,4]triazolo[4,3-a]quinoxaline:
[0299] A 50 mL round bottom flask was charged with tert-butyl 4-(8-chloro- [l,2,4]triazolo[4,3-a]quinoxalin-4-yl)-5,6-dihydropyridine-l(2H)-carboxylate (1.05 g, 2.72 mmol) and CH2CI2 (25 mL). To the above was added dropwise
trifluoroacetic acid (2 mL) at 0 °C. The resulting solution was stirred at room temperature for 4 h. Reaction progress was monitored by TLC (MeOH/CH2Cl2 = 1 :10). Work-up: the reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with a 1:10 MeOH/CH2Cl2, to afford 0.67 g (82%) of the product as light yellow crystals. *H NMR (300 MHz, DMSO-d6) δ: 10.11 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 8.34 (t, J = 3.3 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.70 (dd, J = 8.7, 2.4 Hz, 1H), 3.64 (m, 2H), 3.01 (m, 2H), 2.66 (m, 2H). MS m/z: 286 (M+H+).
EXAMPLE 2
8-Chloro-4-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000070_0002
[0300] A 10 mL round bottom flask was charged with 8-chloro-4-(l ,2,3,6- tetrahydropyridin-4-yl)-[l,2,4]triazolo[4,3-a]quinoxaline (140 mg, 0.489 mmol), HCHO (38%, 78 mg, 0.979 mmol), AcOH (35 mg, 0.587 mmol), CH2C12 (2 mL) and MeOH (2 mL). To the above was added NaB(OAc)3H (160 mg, 0.734 mmol) in several batches. The resulting mixture was stirred at room temperature for 1.5 h. Reaction progress was monitored by TLC (MeOH/CI^Ck = 1 :10). Work-up: the reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with a 1:10 MeOH/CH2Cl2, to afford 75 mg (55%) of the product as light yellow solid. *H NMR (300 MHz, CDC13) δ: 9.24 (s, 1H), 8.46 (t, J = 3.6 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 8.7, 2.1 Hz, 1H), 3.63 (br, 2H), 3.04 (br, 4H), 2.66 (s, 3H). MS m/z: 300 (M+H+).
EXAMPLE 3
8-Chloro-4-(piperidin-4-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000071_0001
[0301] A 50 mL round bottom flask was charged with tert-butyl 4-(8-chloro- [l,2,4]triazolo[4,3-a]quinoxalin-4-yl)-5,6-dihydropyridine-l(2H)-carboxylate (prepared as in Example 1, 80 mg, 0.21 mmol) and CH2CI2 (4 mL). To the above was added dropwise trifluoroacetic acid (0.48 g, 4.14 mmol) at 0 °C, followed by addition of triethylsilane (150 mg, 1.24 mmol). The resulting solution was stirred room temperature for 3 days. Reaction progress was monitored by TLC
(MeOH/CH2Ci2 = 1 :10). Work-up: the reaction solution was concentrated under reduced pressure. The residue was recrystallized from a 1:3 ethyl acetate/hexane, to afford 45 mg (53%) of the product as light yellow solid. *H NMR (300 MHz, CD3OD) δ: 9.91 (d, J = 0.9 Hz, 1H), 8.46 (t, J = 2.1 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.71 (m, 1H), 3.91 (m, 1H), 3.60 (m, 2H), 3.35-3.29 (m, 2H), 2.47-2.29 (m, 4H). MS m/z: 288 (M+H+). EXAMPLE 4
8-Chloro-4-(l-methylpiperidin-4-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000072_0001
[0302] The title compound was prepared as described in Example 2, except that 8-chloro-4-(piperidin-4-yl)-[l,2,4]triazolo[4,3-a]quinoxaline was substituted for 8- chloro-4-(l,2,3,6-tetrahydropyridin-4-yl)-[l,2,4]triazolo[4,3-a]quinoxaline in step 1 of that route. *H NMR (300 MHz, CD3OD) δ: 9.90 (s, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 8.4, 2.1 Hz, 1H), 3.90 (m, 1H), 3.68 (m, 2H), 3.35 (m, 2H), 2.96 (s, 3H), 2.52-2.44 (m, 4H). MS m/z: 302 (M+H+).
SCHEME 2
Figure imgf000072_0002
Et0H Ν :Ι chc|3
Figure imgf000072_0003
EXAMPLE 5
8-Chloro-4-(4-methylpiperazin-l-yl)-l,2-dihydroimidazo[l,2-a]quinoxaline
Figure imgf000072_0004
Step 1
Figure imgf000073_0001
2-(3,7-Dichloroquinoxalin-2-ylamino)ethanol:
[0303] A 250 mL 3-necked round bottom flask was charged with 2,3,6- trichloroquinoxaline (described in step 2 of Example 1, 4.46 g, 19.1 mmol) and EtOH (50 mL). To the above was added dropwise a solution of 2-aminoethanol (2.44 g, 40.1 mmol) in EtOH (20 mL) with the temperature maintained below 35 °C. The resulting mixture was stirred at room temperature for 4 h and then cooled to 0 °C. The precipitate was collected by filtration, washed with a 1 : 1 n- hexane/EtOAc and dried, to afford 4.0 g (81 %) of the product.
Step 2
Figure imgf000073_0002
4,8-Dichloro-l,2-dihydroimidazo[l,2-a]quinoxaline:
[0304] A 100 mL round bottom flask was charged with 2-(3,7- dichloroquinoxalin-2-ylamino)ethanol (4.0 g, 15.5 mmol), SOCi2 (20 mL) and CHCI3 (20 mL). The resulting solution was heated at reflux for 2 h then concentrated in vacuo. The residue was co-evaporated several times with CHCI3 then EtOAc. The crude product thus obtained was washed with EtOAc to afford 2.4 g (65 %) of the product. Step 3
Figure imgf000074_0001
8-Chloro-4-(4-methylpiperazin-l-yl)-l,2-dihydroimidazo[l,2-a]quinoxaline:
[0305] A 50 mL round bottom flask was charged with 4,8-dichloro- 1 ,2- dihydroimidazo[l ,2-a]quinoxaline (500 mg, 2.1 mmol), N-methylpiperazine (700 mg, 7.0 mmol) and EtOH (3 mL). The resulting solution was heated at reflux for 16 h then concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel to afford 500 mg (79%) of the product. 1H NMR (300 MHz, CDC13) δ: 7.24 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 4.21-4.09 (m, 6H), 3.92 (m, 2H), 2.54 (m, 4H), 2.34 (s, 3H). MS m/z: 304 (M+H+).
EXAMPLE 6
8-Chloro-4-(piperazin-l-yl)-l,2-dihydroimidazo[l,2-a]quinoxaline
Figure imgf000074_0002
[0306] The title compound was prepared as described in Example 5, except that piperazine was substituted for N-methylpiperazine in step 3 of that route. JH NMR (300 MHz, CD3OD/D2O) δ: 7.82 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.7, 2.1 Hz, 1H), 4.81 (m, 2H), 4.32 (m, 2H), 3.79 (m, 4H), 3.47 (m, 4H). MS m/z: 290 (M+H+). EXAMPLE 7
8-Chloro-4-(4-methylpiperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000075_0001
[0307] A 250 mL round bottom flask was charged with 8-chloro-4-(4- methylpiperazin-l-yl)-l,2-dihydroimidazo[l,2-a]quinoxaline (Example 5, 300 mg, 0.99 mmol), chloranil (1 g, 4 mmol) and xylene (100 mL). The resulting solution was heated at reflux for 16 h then cooled to room temperature. The reaction mixture was washed several times with diluted aqueous NaOH solution until the aqueous phase became colorless. The organic layer was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel to afford
220 mg (74%) of the product. *H NMR (300 MHz, CDC13) δ: 7.90 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.62-7.58 (m, 2H), 7.34 (dd, J = 8.7, 2.1 Hz, 1H), 4.42 (m, 4H), 2.61 (m, 4H), 2.37 (s, 3H). MS m/z: 302 (M+H+).
EXAMPLE 8
8-Chloro-4-(piperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000075_0002
[0308] The title compound was prepared as described in Example 7, except that 8-chloro-4-(piperazin-l-yl)-l,2-dihydroimidazo[l,2-a]quinoxaline (Example 7) was substituted for 8-chloro-4-(4-methylpiperazin- 1 -yl)-l ,2-dihydroimidazo[ 1 ,2- a]quinoxaline (Example 5) in step 1 of that route. *H NMR (300 MHz, D20) δ: 8.01 (d, J = 1.2 Hz, 1H), 7.58 (m, 2H), 7.32 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H), 4.24 (m, 4H), 3.41 (m, 4H). MS m/z: 288 (M+H+).
Figure imgf000076_0001
EXAMPLE 9
8-Chloro-2-methyl-4-(4-methylpiperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000076_0002
Mixture of 2-(3,7-dichloroquinoxalin-2-ylamino)propan-l-ol and 2-(3,6- dichloroquinoxalin-2-ylamino)propan-l-ol:
[0309] A 500 mL 3-necked round bottom flask was charged with 2,3,6- trichloroquinoxaline (described in step 2 of Example 1, 5.0 g, 21.4 mmol) and EtOH (100 mL). To the above was added dropwise a solution of 2-aminopropan- 1- ol (3.7 mL, 47.5 mmol) in EtOH (50 mL). The resulting solution was heated at reflux for 4 h then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 2.5 g (54%) of the product as a mixture of two isomers.
Step 2
Figure imgf000077_0001
4,8-Dichloro-2-methyl-l,2-dihydroimidazo[l,2-a]quinoxaline and 4,7-dichloro-2- methyl- 1 ,2-dihydroimidazo[ 1 ,2-a]quinoxaline:
[0310] A 50 mL round bottom flask was charged with the mixture of 2-(3,7- dichloroquinoxalin-2-ylamino)propan- 1 -ol and 2-(3 ,6-dichloroquinoxalin-2- ylamino)propan-l-ol (1.8 g, 6.6 mmol), SOC12 (10 mL) and CHC13 (10 mL). The resulting solution was heated at reflux for 2 h then concentrated in vacuo. The residue was poured into saturated aqueous Na2C03 and extracted with CH2C12. The combined organic layers were dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% EtOAc in petroleum ether to afford 1.08 g (64%) of 4,8-dichloro-2-methyl-l ,2- dihydroimidazo[l ,2-a]quinoxaline (*H NMR (300 MHz, CDC13) δ: 8.15 (d, J = 8.7 Hz, 1H), 7.00 (dd, J = 8.4, 2.1 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 4.50 (m, 1H), 4.16 (m, 1H), 3.60 (m, 1H), 1.44 (d, J = 6.6 Hz, 3H)), and 270 mg (0.16%) of 4,7- dichloro-2-methyl-l ,2-dihydroimidazo[l ,2-a]quinoxaline (!H NMR (300 MHz, CDCI3) δ: 7.57 (d, J = 1.8 Hz, 1H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.52 (m, 1H), 4.20 (m, 1H), 3.62 (m, 1H), 1.45 (d, J = 6.9 Hz, 3H)) as yellow solids. Step 3
Figure imgf000078_0001
8-Chloro-2-methyl-4-(4-methylpiperazin-l-yl)-l ,2-dihydroimidazo[l ,2- ajquinoxaline:
[0311 ] A 50 mL round bottom flask was charged with 4,8-dichloro-2-methyl- l,2-dihydroimidazo[l,2-a]quinoxaline (300 mg, 1.2 mmol), N-methylpiperazine (0.16 mL, 1.4 mmol), Et3N (0.35 mL, 2.5 mmol) and anhydrous EtOH (20 mL). The resulting solution was heated at reflux for 2 h then concentrated in vacuo. The residue was dissolved in CH2CI2, washed with brine, dried over MgS04, and concentrated in vacuo, to afford 360 mg (96%) of the product as yellow oil. JH
NMR (300 MHz, DMSO-d6) δ: 7.15 (d, J = 8.7 Hz, 1H), 6.92 (dd, J = 8.4, 2.4 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 4.77 (m, 1H), 4.35 (m, 1H), 3.99 (m, 4H), 3.49 (m, 1H), 2.37 (m, 4H), 2.19 (s, 3H), 1.28 (d, J = 6.0 Hz, 1H). MS m/z: 317 (M+H+).
Step 4
Figure imgf000078_0002
8-Chloro-2-methyl-4-(4-methylpiperazin-l-yl)imidazo[l,2-a]quinoxaline:
[0312] A 50 mL round bottom flask was charged with 8-chloro-2-methyl-4-(4- methylpiperazin-l-yl)-l ,2-dihydroimidazo[l,2-a]quinoxaline (360 mg, 1.13 mmol), 2,3-dichloro-5,6-dicyano-p-benzoquinone (515 mg, 2.26 mmol) and xylene (lOmL). The resulting solution was heated at reflux for 3 h then concentrated in vacuo. The residue was dissolved in 1 M aqueous NaOH (10 mL) and extracted with CH2CI2. The organic layer was dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 3% MeOH in CH2C12, to afford 95 mg (26%) of the product as white solid. *H NMR (300 MHz, CDC13) δ: 7.60 (m, 3H), 7.31 (dd, J = 8.7, 2.4 Hz, 1H), 4.40 (br, 4H), 2.62 (m, 4H), 2.46 (d, J = 0.6 Hz, 3H), 2.38 (s, 3H). MS m/z: 315 (M+H+).
EXAMPLE 10
8-Chloro-2-methyl-4-(piperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000079_0001
[0313] The title compound was prepared as described in Example 9, except that piperazine was substituted for N-methylpiperazine in step 3 of that route. JH NMR (300 MHz, CD3OD) δ: 8.17 (s, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 8.7, 2.4 Hz, 1H), 4.51 (t, J = 5.4 Hz, 4H), 3.40 (t, J = 5.4 Hz, 4H), 2.45 (s, 3H). MS m/z: 301 (M+H+).
EXAMPLE 11
7-Chloro-2-methyl-4-(4-methylpiperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000079_0002
[0314] The title compound was prepared as described in Example 9, except that
4.7- dichloro-2-methyl-l,2-dihydroimidazo[l,2-a]quinoxaline was substituted for
4.8- dichloro-2-methyl-l,2-dihydroimidazo[l,2-a]quinoxaline in step 3 of that route. *H NMR (300 MHz, CD3OD) δ: 8.06 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 9.0, 2.4 Hz, 1H), 4.33 (m, 4H), 2.62 (t, J = 5.4 Hz, 4H), 2.43 (s, 3H), 2.35 (s, 3H). MS m/z: 315 (M+H+).
Figure imgf000080_0001
EXAMPLE 12
9-Chloro-5-(piperazin-l-yl)tetrazolo[l,5-c]quinazoline
Figure imgf000080_0002
6-Chloroquinazoline-2,4(lH,3H)-dione:
[0315] A 250 mL round bottom flask was charged with 2-amino-5- chlorobenzoic acid (17.2 g, 0.1 mol) and urea (30 g, 0.5 mol). The resulting mixture was heated to 200 °C for 3 h. Work up: the reaction mixture was washed by water and filtered. The solid was dried to give 18.5 g (94%) of the product. MS m/z: 196 (M+H+). Step 2
Figure imgf000081_0001
2,4,6-Trichloroquinazoline:
[0316] The title compound was prepared as described in Example 1, except that 6-chloroquinazoline-2,4(lH,3H)-dione was substituted for 6-chloroquinoxaline- 2,3(lH,4H)-dione in step 2 of that route. *H NMR (300 MHz, CDC13) δ: 8.24 (d, J = 2.1 Hz, 1H), 7.99-7.90 (m, 2H).
Step3
Figure imgf000081_0002
2,6-Dichloro-4-hydrazinylquinazoline:
[0317] A 100 mL round bottom flask was charged with 2,4,6- trichloroquinazoline (1 g, 4.3 mmol) and ethanol (50 mL). To the above was added dropwise hydrazine hydrate (0.492 g, 9.8 mmol) at 0-5 °C. The resulting mixture was stirred for 0.5 h below 10 °C then 2 h at room temperature. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1:4, Rf = 0.3). Work-up: the resulting solid was collected by filtration, washed with ethanol and dried, to give 0.94 g (96%) of the product. *H NMR (300 MHz, DMSO-d6) δ: 8.34 (s, 1H), 7.76 (m, 1H), 7.58 (m, 1H). MS m/z: 229 (M+H+).
Step 4
Figure imgf000082_0001
6-Chloro-4-hydrazinyl-2-(piperazin-l-yl)quinazoline:
[0318] A 250 mL round bottom flask was charged with 2,6-dichloro-4- hydrazinylquinazoline (1 g, 4.4 mmol), piperazine (1.13 g, 13.1 mmol) and absolute ethanol (100 mL). The resulting mixture was heated at reflux for 8 h. Work-up: the reaction mixture was concentrated under reduced pressure. The resulting solid was collected by filtration, washed with ethanol and dried, to give 0.9 g (74%) of the product. MS m/z: 279 (M+H+).
Step 5
Figure imgf000082_0002
9-Chloro-5-(piperazin-l-yl)tetrazolo[l,5-c]quinazoline:
[0319] A 250 mL round bottom flask was charged with 6-chloro-4-hydrazinyl- 2-(piperazin-l-yl)quinazoline (1.6 g, 5.75 mmol) and 0.2 M HC1 (80 mL). To the above was added dropwise a solution of NaN02 (0.6 g, 8.62 mmol) in water (2 mL) at 0-5 °C. The resulting mixture was stirred at 5 °C for 1 h. Work up: the reaction mixture was washed with ethyl acetate (50 mL x 3). The aqueous layer was basified to PH 8 by saturated aqueous Na2C03. The precipitate was collected by filtration, washed with water and dried, to give 670 mg (40%) of the product. *H NMR (300 MHz, DMSO-d6) δ: 8.36 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 9.0, 2.4 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 3.98 (m, 4H), 2.92 (m, 4H). MS m/z: 290 (M+H+). EXAMPLE 13
9-chloro-5-(4-methylpiperazin-l-yl)tetrazolo[l,5-c]quinazoline
Figure imgf000083_0001
[0320] The title compound was prepared as described in Example 12, except that N-methylpiperazine was substituted for piperazine in step 4 of that route. MS m/z: 304 (M+H+).
EXAMPLE 14
9-chloro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-c]quinazoline
Figure imgf000083_0002
[0321] The title compound was prepared as described in Collection of
Czechoslovak Chemical Communications (1984), 49(8), 1795-9, using 6-chloro-4- hydrazinyl-2-(4-methylpiperazin-l-yl)quinazoline described in step 3 of Example 12. MS m/z: 303 (M+H+).
EXAMPLE 15
8-methyl-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000083_0003
[0322] The title compound was obtained from a commercial source. EXAMPLE 16
7-Chloro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000084_0001
Step 1
Figure imgf000084_0002
4,7-Dichlorotetrazolo[l,5-a]quinoxaline:
[0323] A 100 mL round bottom flask was charged with 2,3,6- trichloroquinoxaline (described in step 2 of Example 1, 1.0 g, 4.27 mmol), NaN3 (2.5 g, 38.46 mmol) and EtOH (50 mL). The resulting mixture was stirred at 60 °C overnight. Reaction progress was monitored by TLC (EtOAc/Petroleum ether = 1 : 10). Work-up: the reaction mixture was concentrated under reduced pressure. The residue was mixed with water (30 mL) and extracted with EtOAc (50 and 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4, concentrated in vacuo, to afford 1.0 g (quantitative) of the product as yellow amorphous powder. !H NMR (300 MHz, CDC13) δ: 8.76 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 9.0 Hz, 1H), 7.96 (dd, J = 9.0, 2.1 Hz, 1H).
Step 2
Figure imgf000085_0001
7-Chloro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline:
[0324] A 5 mL microwave reaction tube was charged with 4,7- dichlorotetrazolo[l,5-a]quinoxaline (0.27 g, 1.13 mmol), piperazine (0.15 g, 1.69 mmol), CS2CO3 (1.14 g, 3.39 mmol) and DMF (4 mL). The resulting mixture was heated at 140 °C for 1 h in a Biotage microwave reactor. Work-up: the reaction mixture was diluted with EtOAc (30 mL) and washed with Η20 (30 mL). The organic layer was dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 5-10% MeOH in CH2CI2 to provide 0.25 g of yellow solid. It was further purified by recrystallization from EtOAc, to afford 120 mg (37%) of the product as light yellow solid. *H NMR (300 MHz, CD3OD) δ: 8.29 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 8.7, 2.4 Hz, 1H), 4.37 (br, 4H), 3.02 (m, 4H). MS m/z: 290
(M+H+).
EXAMPLE 17
7-Chloro-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000085_0002
[0325] The title compound was prepared as described in Example 16, except that N-methylpiperazine was substituted for piperazine in step 2 of that route. JH NMR (300 MHz, CDC13) δ: 8.29 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.7, 2.1 Hz, 1H), 4.50 (br, 4H), 2.61 (t, J = 5.1 Hz, 4H), 2.34 (s, 3H). MS m/z: 304 (M+H+).
Figure imgf000086_0001
Figure imgf000086_0002
EXAMPLE 18
8-Methyl-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000086_0003
6-Methylquinoxaline-2,3(lH,4H)-dione:
[0326] A 250 mL round bottom flask was charged with 4-methylbenzene-l,2- diamine (9.76 g, 0.08 mol) and diethyl oxalate (86 mL, 0.64 mol). The resulting mixture was heated at 140 °C overnight. Work-up: the reaction mixture was filtered and the solid was washed with ethanol and dried to give 13 g (92%) of the product. MS m/z: 175 (M+H+).
Figure imgf000087_0001
2,3-Dichloro-6-methylquinoxaline:
[0327] The title compound was prepared as described in Example 1, except that 6-methylquinoxaline-2,3(lH,4H)-dione was substituted for 6-chloroquinoxaline- 2,3(lH,4H)-dione in step 2 of that route. *H NMR (300 MHz, CDC13) δ: 7.92 (m, 1H), 7.79 (s, 1H), 7.54 (m, 1H), 2.59 (s, 3H).
Step 3
Figure imgf000087_0002
2-Chloro-3-hydrazinyl-6-methylquinoxaline:
[0328] The title compound was prepared as described in Example 12, except that 2,3-dichloro-6-methylquinoxaline was substituted for 2,4,6- trichloroquinazoline in step 3 of that route. MS m/z: 209 (M+H+).
Step 4
Figure imgf000087_0003
3-Hydrazinyl-6-methyl-2-(piperazin-l-yl)quinoxaline:
[0329] The title compound was prepared as described in Example 12, except that 2-chloro-3-hydrazinyl-6-methylquinoxaline was substituted for 2,6-dichloro-4- hydrazinylquinazoline in step 4 of that route. MS m/z: 259 (M+H+). Step 5
Figure imgf000088_0001
8-Methyl-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline:
[0330] The title compound was prepared as described in Example 12, except that 3-hydrazinyl-6-methyl-2-(piperazin-l-yl)quinoxaline was substituted for 6- chloro-4-hydrazinyl-2-(piperazin-l-yl)quinazoline in step 5 of that route. JH NMR
(300 MHz, CD3OD) δ: 8.04 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.38 (m, 1H), 4.28 (m, 4H), 3.03 (m, 4H), 2.50 (s, 3H). MS m/z: 270 (M+H+).
EXAMPLE 19
8-Chloro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000088_0002
Step 1
Figure imgf000088_0003
6-Chloro-3-hydrazinyl-2-(piperazin-l-yl)quinoxaline:
[0331] The title compound was prepared as described in Example 12, except that 2,6-dichloro-3-hydrazinylquinoxaline (prepared in Example 1) was substituted for 2,6-dichloro-4-hydrazinylquinazoline in step 4 of that route. MS m/z: 279 (M+H+). Step 2
Figure imgf000089_0001
8-Chloro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline:
[0332] The title compound was prepared as described in Example 12, except that 6-chloro-3-hydrazinyl-2-(piperazin-l-yl)quinoxaline was substituted for 6- chloro-4-hydrazinyl-2-(piperazin-l-yl)quinazoline in step 5 of that route. JH NMR (300 MHz, CD3OD) δ: 8.42 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.68 (dd, J = 9.0, 2.4 Hz, 1H), 4.64 (m, 4H), 3.46 (m, 4H). MS m/z: 290 (M+H+).
EXAMPLE 20
8-Chloro-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000089_0002
[0333] The title compound was prepared as described in Example 19, except that N-methylpiperazine was substituted for piperazine in step 1 of that route. JH NMR (300 MHz, CDC13) δ: 8.37 (d, J = 2.7 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 8.7, 2.4 Hz, 1H), 4.43 (br, 4H), 2.62 (m, 4H), 2.38 (s, 3H). MS m/z: 304 (M+H+).
EXAMPLE 21
8-Methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000089_0003
Step 1
Figure imgf000090_0001
4-Chloro-8-methyl-[l,2,4]triazolo[4,3-a]quinoxaline:
[0334] A 100 mL round bottom flask was charged with 2-chloro-3-hydrazinyl- 6-methylquinoxaline (prepared in Example 18 step 1-3, 2.39 g, 11.4 mmol) and trimethyl orthoformate (40 mL). The resulting mixture was heated at reflux for 1.5 h. Work-up: the reaction mixture was filtered and the solid was washed with ethanol and dried to give 1.55 g (62%) of the product. MS m/z: 219 (M+H+).
Step 2
Figure imgf000090_0002
8-Methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline:
[0335] The title compound was prepared as described in Example 12, except that 4-chloro-8-methyl-[l,2,4]triazolo[4,3-a]quinoxaline was substituted for 2,6- dichloro-4-hydrazinylquinazoline, and N-methylpiperazine for piperazine in step 4 of that route. 'H NMR (300 MHz, CDC13) δ: 9.15 (s, 1H), 7.56 (m, 2H), 7.28 (m, 1H), 4.42 (br, 4H), 2.59 (m, 4H), 2.48 (s, 3H), 2.35 (s, 3H). MS m/z: 283 (M+H+).
EXAMPLE 22
8-Methyl-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000091_0001
[0336] The title compound was prepared as described in Example 21, except that piperazine was substituted for N-methylpiperazine in step 2 of that route. NMR (300 MHz, CDC13) δ: 9.14 (s, 1H), 7.55 (m, 2H), 7.29 (m, 1H), 4.41 (br, 4H), 3.10 (m, 4H), 2.50 (s, 3H). MS m/z: 269 (M+H+).
SCHEME 6
F3C¾(NH2 Et° °Et- F3°^3C¾ OCi3) ^0^^^' H N N~,
2 H
Figure imgf000091_0002
EXAMPLE 23
4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000091_0003
Step 1
Figure imgf000092_0001
6-(Trifluoromethyl)-l,4-dihydroquinoxaline-2,3-dione:
[0337] A 100 mL round bottom flask was charged with 4- (trifluoromethyl)benzene- 1 ,2-diamine (5.3 g, 37 mmol) and diethyl oxalate (31 mL). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :10). Work-up: the precipitate was collected by filtration, washed with EtOH (20 mL) and dried, to afford 7.0 g (96%) of the product as light yellow solid.
Step 2
Figure imgf000092_0002
2,3-Dichloro-6-(trifluoromethyl)quinoxaline:
[0338] A 100 mL round bottom flask was charged with 6-(trifluoromethyl)-l ,4- dihydroquinoxaline-2,3-dione (7.0 g, 36 mmol) and phosphorus oxychloride (16 mL). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :10). Work-up: the reaction mixture was cooled to room temperature and cautiously poured into ice water. The solid was collected by filtration and re-dissolved in EtO Ac (150 mL) then washed with brine (100 mL), dried over anhydrous Na2S04, and concentrated in vacuo, to afford 7.4 g (89%) of the product as light yellow solid. Step 3
Figure imgf000093_0001
3-Chloro-2-(4-methylpiperazinyl)-6-(trifluoromethyl)quinoxaline:
[0339] A 250 mL round bottom flask was charged with 2,3-dichloro-6- (trifluoromethyl)quinoxaline (4.6 g, 17.2 mmol) and EtOH (50 mL). To the above was added dropwise N-methylpiperazine (1.7 g, 17.2 mmol). The resulting solution was stirred overnight at room temperature. Reaction progress was monitored by TLC (EtOAc/Petroleum ether = 1 :2). Work-up: the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtOAc (50 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10-20% EtOAc in petroleum ether, to afford 3.0 g (52%) of the product as white solid. MS m/z: 331 (M+H+).
Step 4
Figure imgf000093_0002
3-hydrazinyl-2-(4-methylpiperazin-l-yl)-6-(trifluoromethyl)quinoxaline:
[0340] A 100 mL round bottom flask was charged with 3-chloro-2-(4- methylpiperazinyl)-6-(trifluoromethyl)quinoxaline (3.0 g, 9.1 mmol), hydrazine hydrate (9.0 g, 182 mmol) and EtOH (50 mL). The resulting solution was refluxed for 0.5 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was re-dissolved in CH2C12 (50 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with a 1 : 10 MeOH/CH2Cl2, to afford 1.5 g (50%) of the product as light yellow crystals. MS m/z: 327 (M+H+). Step 5
Figure imgf000094_0001
4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline:
[0341] A 100 mL round bottom flask was charged with 3-hydrazinyl-2-(4- methylpiperazin-l-yl)-6-(trifluoromethyl)quinoxaline (1.3 g, 3.9 mmol) and triethyl orthoformate (20 mL). The resulting mixture was stirred at 100 °C for 1 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 2:1). Work-up: the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtO Ac (50 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10-40% EtO Ac in petroleum ether, to afford 0.7 g (54%) of the product as white solid. *H NMR (300 MHz,
CD3OD) δ: 9.91 (s, 1H), 8.45 (s, 1H), 7.73 (m, 2H), 4.49 (m, 4H), 2.69 (m, 4H), 2.39 (s, 3H). MS m/z: 337 (M+H+).
EXAMPLE 24
4-(piperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000094_0002
[0342] The title compound was prepared as described in Example 23, except that piperazine was substituted for N-methylpiperazine in step 3 of that route. JH NMR (300 MHz, CD3OD) δ: 10.10 (s, 1H), 8.57 (s, 1H), 7.82 (m, 2H), 4.73 (m, 4H), 3.46 (m, 4H). MS m/z: 323 (M+H+). EXAMPLE 25
4-(4-methylpiperazin-l-yl)-7-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000095_0001
[0343] The title compound was prepared as described in Examples 50 and 21, except that 4-(trifluoromethyl)benzene-l,2-diamine was substituted for 4- methylbenzene-l,2-diamine as the starting material of that route. JH NMR (300 MHz, CD3OD) δ: 9.81 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.7, 2.1 Hz, 1H), 4.46 (m, 4H), 2.67 (m, 4H), 2.37 (s, 3H). MS m/z: 337 (M+H+).
EXAMPLE 26
4-(piperazin-l-yl)-7-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000095_0002
[0344] The title compound was prepared as described in Example 25, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CD3OD) δ: 9.87 (s, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 1.5 Hz, 1H), 7.64 (dd, J = 8.7, 1.8 Hz, 1H), 4.60 (m, 4H), 2.67 (m, 4H). MS m/z: 323 (M+H+). SCHEME 7
Figure imgf000096_0001
EXAMPLE 27
4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline
Figure imgf000096_0002
[0345] The title compound was prepared as described in Examples 23 and 16, except that 3-chloro-2-(4-methylpiperazinyl)-6-(trifluoromethyl)quinoxaline (prepared as described in Example 90 step 3) was substituted for 2,3,6- trichloroquinoxaline in step 1 of Example 16. *H NMR (300 MHz, CD3OD) δ: 8.62 (s, 1H), 7.88 (m, 2H), 4.49-4.46 (m, 4H), 2.68 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H). MS m/z: 338 (M+H+).
EXAMPLE 28
4-(4-methylpiperazin-l-yl)-7-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline
Figure imgf000096_0003
[0346] The title compound was prepared as described in Example 27, except that 2-chloro-3-(4-methylpiperazinyl)-6-(trifluoromethyl)quinoxaline was obtained in step 1 of that route. *H NMR (300 MHz, CD3OD) δ: 8.35 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 0.9 Hz, 1H), 7.63 (dd, J = 8.7, 0.9 Hz, 1H), 4.42-4.38 (br, 4H), 2.67 (t, J = 5.1 Hz, 4H), 2.39 (s, 3H). MS m/z: 338 (M+H+).
Figure imgf000097_0001
EXAMPLE 29
4-(piperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline
hydrochloride
Figure imgf000097_0002
[0347] The title compound was prepared as described in Example 27, except that tert-butyl piperazinecarboxylate was substituted for N-methylpiperazine and tert-butyl 4- [3-chloro-6-(trifluoromethyl)quinoxalin-2-yl]piperazinecarboxylate was obtained in step 1 of that route. BOC group was then removed by methanolic HCl in EtOAc. *H NMR (300 MHz, CD3OD) δ: 8.70 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.93 (dd, J = 9.0, 2.1 Hz, 1H), 4.74-4.70 (br, 4H), 3.48 (t, J = 5.1 Hz, 4H). MS m/z: 324 (M+H+).
EXAMPLE 30
4-(piperazin-l-yl)-7-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline
hydrochloride
Figure imgf000097_0003
[0348] The title compound was prepared as described in Example 29, except that tert-butyl 4-[3-chloro-7-(trifluoromethyl)quinoxalin-2-yl]piperazinecarboxylate was obtained in step 1 of that route. *H NMR (300 MHz, CD3OD) δ: 8.61 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.83 (dd, J = 8.4, 1.8 Hz, 1H), 4.70 (t, J = 5.1 Hz, 4H), 3.48 (t, J = 5.1 Hz, 4H). MS m/z: 324 (M+H+).
Figure imgf000098_0001
EXAMPLE 31
8-chloro-7-fluoro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000098_0002
[0349] The title compound was prepared as described in Example 23, except that 4-chloro-5-fluorobenzene-l,2-diamine was substituted for 4- (trifluoromethyl)benzene- 1 ,2-diamine in step 1 of that route. 1H NMR (300 MHz, CD3OD) δ: 9.80 (s, 1H), 8.36 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 9.9 Hz, 1H), 5.45- 3.28 (m, 8H), 2.97 (s, 3H). MS m/z: 321 (M+H+). EXAMPLE 32
8-chloro-7-fluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000099_0001
[0350] The title compound was prepared as described in Example 31, except that piperazine was substituted for N-methylpiperazine in step 3 of that route. JH NMR (300 MHz, CD3OD) δ: 9.86 (s, 1H), 8.39 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 9.9 Hz, 1H), 4.67 (t, J = 5.1 Hz, 4H), 3.42 (t, J = 5.1 Hz, 4H). MS m/z: 307 (M+H+).
SCHEME 10
Figure imgf000099_0002
EXAMPLE 33
7-chloro-8-fluoro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000099_0003
[0351] The title compound was prepared as described in Examples 50 and 21, except that 5-chloro-4-fluorobenzene-l,2-diamine was substituted for 4- methylbenzene-l,2-diamine as the starting material of that route. JH NMR (300 MHz, DMSO-d6) δ: 9.93 (s, 1H), 8.38 (d, J = 9.9 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 4.30-4.27 (m, 4H), 3.34-3.31 (m, 4H), 2.23 (s, 3H). MS m/z: 321 (M+H+).
Figure imgf000100_0001
EXAMPLE 34
7-fluoro-8-methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000100_0002
N-(4-Fluoro-3-methylphenyl)acetamide:
[0352] A 100 mL round bottom flask was charged with 4-fluoro-3- methylaniline (9.0 g, 0.072 mol) and acetyl acetate (32 mL). The resulting mixture was stirred 1 h at 0 °C. Reaction progress was monitored by TLC
(EtO Ac/Petroleum ether = 1 :2). Work-up: the reaction solution was diluted with H20 (100 mL) and neutralized with ammonia. The precipitate was collected by filtration, washed with H20, and dried under vacuum, to afford 12 g (quantitative yield) of product as white solids. MS m/z: 168 (M+H+). Step 2
Figure imgf000101_0001
N-(4-Fluoro-5-methyl-2-nitrophenyl)acetamide:
[0353] A 100 mL round bottom flask was charged with N-(4-fluoro-3- methylphenyl)acetamide (10.5 g, 0.063 mol) and nitric acid (68%, 15 mL). To the solution was added dropwise fuming nitric acid (12 mL). The reaction solution was stirred 1 h at room temperature. Work-up: the reaction solution was diluted with H20 (100 mL). The precipitate was collected by filtration, washed with H20, and dried under vacuum. It was further purified by column chromatography on silica gel with a 1 :20 EtOAc/CH2Cl2, giving 8.47 g (64%) of the product as yellow solids. !H NMR (300 MHz, CDC13) δ: 10.28 (s, 1H), 8.65 (d, J = 6.6 Hz, 1H), 7.87 (d, J = 9.3 Hz, 1H), 2.36 (d, J = 2.1 Hz, 3H), 2.28 (s, 3 H).
Step 3
Figure imgf000101_0002
4-Fluoro-5-methyl-2-nitrophenylamine:
[0354] A 250 mL round bottom flask was charged with N-(4-fluoro-5-methyl- 2-nitrophenyl)acetamide (4.0 g, 0.019 mol), KOH (1.06 g, 0.019 mol), H20 (30 mL) and MeOH (80 mL). The solution was kept in a 60 °C water-bath for 15 min. H20 (30 mL) was added and the reaction mixture was kept in the bath for another 15 min before it was cooled in an ice-bath. The precipitates were collected by filtration, washed with cold water, and dried under vacuum, giving 3.15 g (98%) of the product as orange solids. Step 4
Figure imgf000102_0001
5-Fluoro-4-methylbenzene-l,2-diamine:
[0355] A 250 mL round bottom flask was charged with 4-fluoro-5-methyl-2- nitrophenylamine (3.12 g, 0.018 mol), Na2S204 (9.58 g, 0.055 mol), H20 (45 mL) and EtOH (90 mL). The mixture was heated at reflux for 1 h. Work-up: the solvent was evaporated. The residue was suspended in triethylamine (15 mL) and ethyl acetate (300 mL), and then filtered. The filtrate was concentrated in vacuo, giving 2.1 g (82%) of the product as pale-red solids.
Steps 5-9
Figure imgf000102_0002
7-fluoro-8-methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline:
[0356] The title compound was prepared as described in Example 23, except that 5-fluoro-4-methylbenzene- l ,2-diamine was substituted for 4- (trifluoromethyl)benzene- 1 ,2-diamine in step 1 of that route. JH NMR (300 MHz, CD3OD) δ: 9.68 (s, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.25 (d, J = 10.8 Hz, 1H), 4.38 (m, 4H), 2.64 (t, J = 4.9 Hz, 4H), 2.39 (s, 3H), 2.37 (s, 3H). MS m/z: 301 (M+H+).
EXAMPLE 35
7-fluoro-8-methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000102_0003
[0357] The title compound was prepared as described in Example 34, except that piperazine was substituted for N-methylpiperazine in step 7 of that route. 1H NMR (300 MHz, D20) δ: 8.40 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 10.5 Hz, 1H), 3.92 (t, J = 5.1 Hz, 4H), 3.35 (t, J = 5.1 Hz, 4H), 2.19 (s, 3H). MS m/z: 287 (M+H+).
SCHEME 12
Figure imgf000103_0001
EXAMPLE 36
8-fluoro-7-methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000103_0002
[0358] The title compound was prepared as described in Examples 50 and 21, except that 5-fluoro-4-methylbenzene-l,2-diamine (prepared in Example 34 step 1- 4) was substituted for 4-methylbenzene-l,2-diamine as the starting material of that route. *H NMR (300 MHz, CDC13) δ: 9.05 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 4.42 (m, 4H), 2.60 (t, J = 4.8 Hz, 4H), 2.37 (s, 6H). MS m/z: 301 (M+H+). EXAMPLE 37
7,8-difluoro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000104_0001
[0359] The title compound was prepared as described in Examples 50 and 21, except that 4,5-difluorobenzene-l,2-diamine was substituted for 4-methylbenzene- 1,2-diamine as the starting material of that route. !H NMR (300 MHz, CD3OD) δ: 9.67 (s, 1H), 8.08 (dd, J = 10.5, 7.5 Hz, 1H), 7.45 (dd, J = 11.4, 7.8, 1H), 4.38 (m, 4H), 2.63 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 305 (M+H+).
EXAMPLE 38
7,8-difluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000104_0002
[0360] The title compound was prepared as described in Example 37, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CD3OD) δ: 9.68 (s, 1H), 8.09 (dd, J = 10.5, 7.8 Hz, 1H), 7.46 (dd, J = 11.7, 7.8 Hz, 1H), 4.35 (t, J = 4.8 Hz, 4H), 2.99 (t, J = 5.1 Hz, 4H). MS m/z: 291 (M+H+).
Figure imgf000104_0003
EXAMPLE 39
7,8-dichloro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000105_0001
[0361] The title compound was prepared as described in Example 23, except that 4,5-dichlorobenzene-l,2-diamine was substituted for 4- (trifluoromethyl)benzene- 1 ,2-diamine in step 1 of that route. 1H NMR (300 MHz, CDC13) δ: 9.09 (s, 1H), 7.80 (s, 1H), 7.76 (s, 1H), 4.50-4.47 (m, 4H), 2.59 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 337 (M+H+).
SCHEME 14
Figure imgf000105_0002
Figure imgf000105_0003
EXAMPLE 40
8-fluoro-4-(4-methylpiperazin-l-yl)-7-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000105_0004
[0362] The title compound was prepared as described in Example 34, except that 4-fluoro-3-trifluoromethylaniline was substituted for 4-fluoro-3-methylaniline in step 1 of that route. *H NMR (300 MHz, CD3OD) δ: 9.95 (s, 1H), 8.54 (d, J = 6.0 Hz, 1H), 7.56 (d, J = 12.0 Hz, 1H), 4.88-4.82 (m, 4H), 3.52-3.47 (m, 4H), 2.97 (s, 3H). MS m/z: 355 (M+H+).
Figure imgf000106_0001
EXAMPLE 41
7-Fluoro-4-(piperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000106_0002
[0363] The title compound was prepared as described in Example 40, except that N-BOC piperazine was substituted for N-methylpiperazine. JH NMR (300 MHz, CD3OD) δ: 9.86 (s, 1H), 8.44 (d, J = 6.0 Hz, 1H), 7.41 (d, J = 12.0 Hz, 1H), 4.47-4.43 (m, 4H), 3.02-2.99 (m, 4H). MS m/z: 341 (M+H+).
SCHEME 17
Figure imgf000106_0003
EXAMPLE 42
8-fluoro-4-(4-methylpiperazin-l-yl)-7-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000107_0001
[0364] The title compound was prepared as described in Examples 50 and 21, except that 5-fluoro-4-trifluoromethylbenzene-l,2-diamine (prepared in Example 40 step 1-4) was substituted for 4-methylbenzene-l,2-diamine as the starting material of that route. *H NMR (300 MHz, CD3OD) δ: 9.77 (s, 1H), 8.14 (d, J = 12.0 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 4.43-4.40 (m, 4H), 2.67-2.64 (m, 4H), 2.38 (s, 3H). MS m/z: 355 (M+H+).
EXAMPLE 43
8-Fluoro-4-(piperazin-l-yl)-7-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000107_0002
[0365] The title compound was prepared as described in Example 42, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CD3OD) δ: 9.75 (s, 1H), 8.11 (d, J = 12.0 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 4.39-4.36 (m, 4H), 3.00-2.96 (m, 4H). MS m/z: 341 (M+H+).
Figure imgf000108_0001
EXAMPLE 44
7-Chloro-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000108_0002
4-Chloro-5-(trifluoromethyl)benzene-l,2-diamine:
[0366] The title compound was prepared as described in Example 34 step 1-4, except that 4-chloro-3-trifluoromethylaniline was substituted for 4-fluoro-3- methylaniline as the starting material of that route. Steps 5-9
Figure imgf000109_0001
7-Chloro-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
[0367] The title compound was prepared as described in Examples 50 and 21, except that 4-chloro-5-(trifluoromethyl)benzene-l,2-diamine was substituted for 4- methylbenzene-l,2-diamine as the starting material of that route. JH NMR (300 MHz, CD3OD) δ: 9.81 (s, 1H), 8.39 (s, 1H), 7.95 (s, 1H), 4.46 (m, 4H), 2.64 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 371 (M+H+).
EXAMPLE 45
7-Chloro-4-(piperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000109_0002
[0368] The title compound was prepared as described in Example 44, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CD3OD) δ: 10.12 (s, 1H), 8.73 (s, 1H), 7.96 (s, 1H), 4.58 (m, 4H), 3.28 (m, 4H). MS m/z: 357 (M+H+).
SCHEME 19
Figure imgf000110_0001
EXAMPLE 46
8-Chloro-4-(4-methylpiperazin-l-yl)-7-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000110_0002
[0369] The title compound was prepared as described in Example 23, except that 4-chloro-5-(trifluoromethyl)benzene-l,2-diamine (prepared in Example 44 step 1-4) was substituted for 4-(trifluoromethyl)benzene-l,2-diamine as the starting material of that route. !H NMR (300 MHz, CD3OD) δ: 9.89 (s, 1H), 8.49 (s, 1H), 7.71 (s, 1H), 4.50 (m, 4H), 2.64 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 371 (M+H+).
EXAMPLE 47
8-Chloro-4-(piperazin-l-yl)-7-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000110_0003
[0370] The title compound was prepared as described in Example 46, except that piperazine was substituted for N-methylpiperazine in step 3 of that route. 1H NMR (300 MHz, CD3OD) δ: 10.22 (s, 1H), 8.76 (s, 1H), 7.80 (s, 1H), 4.64 (m, 4H), 3.21 (m, 4H). MS m/z: 357 (M+H+).
SC
Figure imgf000111_0001
EXAMPLE 48
6-Fluoro-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000111_0002
[0371] The title compound was prepared as described in Example 34, except that 2-fluoro-4-trifluoromethylaniline was substituted for 4-fluoro-3-methylaniline in step 1 of that route. *H NMR (300 MHz, CD3OD) δ: 9.89 (s, 1H), 8.29 (s, 1H), 7.53 (d, J = 9.3 Hz, 1H), 4.52 (m, 4H), 2.66 (d, J = 4.8 Hz, 4H), 2.37 (s, 3H). MS m/z: 355 (M+H+). EXAMPLE 49
6-Fluoro-4-(piperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000112_0001
[0372] The title compound was prepared as described in Example 48, except that piperazine was substituted for N-methylpiperazine in step 7 of that route. 1H NMR (300 MHz, CD3OD) δ: 9.86 (s, 1H), 8.24 (s, 1H), 7.48 (d, J = 9.9 Hz, 1H), 4.45 (m, 4H), 3.00 (m, 4H). MS m/z: 341 (M+H+).
Figure imgf000112_0002
EXAMPLE 50
4-(4-methylpiperazin-l-yl)-8-(trifluoromethoxy)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000112_0003
[0373] The title compound was prepared as described in Examples 50 and 21, except that 4-(trifluoromethoxy)benzene-l,2-diamine was substituted for 4- methylbenzene-l,2-diamine as the starting material of that route. JH NMR (300 MHz, DMSO-d6) δ: 10.03 (s, 1H), 8.34 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.45 (dd, J = 9.0, 1.2 Hz, 1H), 4.31 (br, 4H), 2.49-2.46 (m, 4H), 2.22 (s, 3H). MS m/z: 353 (M+H+).
EXAMPLE 51
4-(piperazin-l-yl)-8-(trifluoromethoxy)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000113_0001
[0374] The HCl salt of the title compound was prepared as described in
Example 50, except that piperazine was substituted for N-methylpiperazine in step 5 of that route. *H NMR (300 MHz, DMSO-d6) δ: 10.01 (s, 1H), 8.32 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 4.25 (br, 4H), 2.84 (br, 4H). MS m/z: 339 (M+H+).
SCHEME 22
Figure imgf000113_0002
EXAMPLE 52
8-bromo-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000113_0003
Steps 1-5
Figure imgf000114_0001
tert-butyl 4-(8-bromo-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)piperazine-l- carboxylate
[0375] The title compound was prepared as described in Examples 50 and 21, except that 4-bromobenzene-l,2-diamine was substituted for 4-methylbenzene- 1 ,2- diamine as the starting material, and N-BOC piperazine for N-methylpiperazine in the last step of that route. It was separated from the other regio-isomer by column chromatography on silica gel with a 1 :1 :2 EtOAc/CI^CVpetroleum ether. JH NMR
(300 MHz, CDC13) δ: 9.14 (s, 1H), 7.88 (m, 1H), 7.56 (m, 2H), 4.42 (m, 4H), 3.63 (m, 4H), 1.50 (s, 9H).
Figure imgf000114_0002
tert-butyl 4-(7-bromo-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)piperazine-l- carboxylate
[0376] The title compound was prepared as described in Examples 50 and 21, except that 4-bromobenzene-l,2-diamine was substituted for 4-methylbenzene- 1 ,2- diamine as the starting material, and N-BOC piperazine for N-methylpiperazine in the last step of that route. It was separated from the other regio-isomer by column chromatography on silica gel with a 1 :1 :2 EtOAc/CH2Cl2/petroleum ether. JH NMR (300 MHz, CDCI3) δ: 9.14 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 8.7, 2.1 Hz, 1H), 4.44 (m, 4H), 3.63 (t, J = 5.1 Hz, 4H), 1.50 (s, 9H). Step 6
Figure imgf000115_0001
8-bromo-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
[0377] A 50 mL round bottom flask was charged with tert-butyl 4-(8-bromo- 10-hydro-l,2,4-triazolo[4,3-a]quinoxalin-4-yl)piperazinecarboxylate (0.13 g, 0.28 mmol), THF (15 mL) and concentrate HC1 (0.5 mL). The reaction mixture was heated at reflux for 1 h. Work-up: the solid was collected by filtration, washed with THF, and dried under vacuum, giving 0.11 g (99%) of the product as white solids. *H NMR (300 MHz, D20) δ: 9.19 (s, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.15 (dd, J = 6.6, 2.1 Hz, 1H), 6.98 (d, J = 5.7 Hz, 1H), 4.27 (t, J = 5.1 Hz, 4H), 3.37 (t, J = 5.1 Hz, 4H). MS m/z: 333 (M+H+).
EXAMPLE 53
7-bromo-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000115_0002
[0378] The HC1 salt of the title compound was prepared as described in Example 52, except that tert-butyl 4-(7-bromo-10-hydro-l,2,4-triazolo[4,3- a]quinoxalin-4-yl)piperazinecarboxylate was substituted for tert-butyl 4-(8-bromo- 10-hydro-l,2,4-triazolo[4,3-a]quinoxalin-4-yl)piperazinecarboxylate in the last step of that route. *H NMR (300 MHz, D20) δ: 9.30 (s, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.22 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.29 (t, J = 5.4 Hz, 4H), 3.36 (t, J = 5.1 Hz, 4H). MS m/z: 333 (M+H+). EXAMPLE 54
8-bromo-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000116_0001
[0379] A 100 mL round bottom flask was charged with 8-bromo-4-piperazinyl- 10-hydro-l ,2,4-triazolo[4,3-a]quinoxaline HC1 salt (1.30 g, 3.6 mmol), formaldehyde (40%, 6 mL), CH2C12 (20 mL), MeOH (20 mL) and NaBH3(CN) (0.68 g, 0.011 mol). The resulting mixture was stirred at room temperature for 1 h. Work-up: the reaction mixture was diluted with H20 (100 mL) and extracted with CH2C12 (50 mL x 2). The combined organic layers was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by column chromatography on silica gel with 3% MeOH in CH2C12, giving 0.94g (77%) of the product as white solids. *H NMR (300 MHz, CDC13) δ: 9.12 (s, 1H), 7.89 (m, 1H), 7.63 (m, 2H), 4.46 (m, 4H), 2.60 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 347 (M+H+).
EXAMPLE 55
8-chloro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000116_0002
[0380] The title compound was obtained from commercial sources. EXAMPLE 56
tert-butyl 4-(8-chloro-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)piperazine-l- carboxylate
Figure imgf000117_0001
[0381] The title compound was prepared analogously to Example 54. MS m/z: 389 (M+H+).
EXAMPLE 57
8-chloro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000117_0002
[0382] The title compound was prepared analogously to Example 54. MS m/z: 289 (M+H+).
EXAMPLE 58
4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000117_0003
[0383] The title compound was prepared analogously to Example 54. MS m/z: 269 (M+H+). EXAMPLE 59
l-(8-chloro-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)pyrrolidin-3-
Figure imgf000118_0001
[0384] The title compound was prepared analogously to Example 54. MS m/z: 289 (M+H+).
EXAMPLE 60
l-(8-chloro-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)-N-methylpyrrolidin-3-amine
Figure imgf000118_0002
[0385] The title compound was prepared analogously to Example 54. MS m/z: 303 (M+H+).
EXAMPLE 61
-4-(tetrahydro-lH-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)- [l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000118_0003
[0386] The title compound was prepared analogously to Example 54. MS m/z: 329 (M+H+). EXAMPLE 62
8-chloro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)- [l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000119_0001
[0387] The title compound was prepared analogously to Example 54. MS m/z: 329 (M+H+).
EXAMPLE 63
l-(8-chloro-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)azetidin-3-amine
Figure imgf000119_0002
[0388] The title compound was prepared analogously to Example 54. MS m/z: 275 (M+H+).
EXAMPLE 64
8-chloro-4-(4-cyclopropylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000119_0003
[0389] The title compound was prepared analogously to Example 54. MS m/z: 329 (M+H+). EXAMPLE 65
8-chloro-4-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)-[l,2,4]triazolo[4,3- a]quinoxaline
Figure imgf000120_0001
[0390] The title compound was prepared analogously to Example 54. MS m/z: 329 (M+H+).
EXAMPLE 66
8-chloro-4-(l,4-diazepan-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000120_0002
[0391] The title compound was prepared analogously to Example 54. MS m/z: 303 (M+H+).
EXAMPLE 67
4-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-8-chloro-[l,2,4]triazolo[4,3- a]quinoxaline
Figure imgf000120_0003
[0392] The title compound was prepared analogously to Example 54. MS m/z: 301 (M+H+). EXAMPLE 68
8-chloro-4-(4-methyl-l,4-diazepan-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000121_0001
[0393] The title compound was prepared analogously to Example 54. MS m/z: 317 (M+H+).
EXAMPLE 69
8-chloro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-[l,2,4]triazolo[4,3- a]quinoxaline
Figure imgf000121_0002
[0394] The title compound was prepared analogously to Example 54. MS m/z: 315 (M+H+).
EXAMPLE 70
Afl-(8-chloro-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)ethane-l,2-diamine
Figure imgf000121_0003
[0395] The title compound was prepared analogously to Example 54. MS m/z: 263 (M+H+). EXAMPLE 71
8-chloro-N-(2-morpholinoethyl)-[l,2,4]triazolo[4,3-a]quinoxalin-4-amine
Figure imgf000122_0001
[0396] The title compound was prepared analogously to Example 54. MS m/z: 333 (M+H+).
EXAMPLE 72
4-(azetidin-3-yloxy)-8-chloro-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000122_0002
[0397] The title compound was prepared analogously to Example 54. MS m/z: 276 (M+H+).
EXAMPLE 73
8-chloro-N-(piperidin-4-yl)-[l,2,4]triazolo[4,3-a]quinoxalin-4-amine
Figure imgf000122_0003
[0398] The title compound was prepared analogously to Example 54. MS m/z: 303 (M+H+). EXAMPLE 74
8-chloro-4-(piperidin-4-yloxy)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000123_0001
[0399] The title compound was prepared analogously to Example 54. MS m/z: 304 (M+H+).
EXAMPLE 75
4-(azetidin-3-ylmethoxy)-8-chloro-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000123_0002
[0400] The title compound was prepared analogously to Example 54. MS m/z: 290 (M+H+).
EXAMPLE 76
(S)-8-chloro-4-((l-methylpyrrolidin-3-yl)methoxy)-[l,2,4]triazolo[4,3- a]quinoxaline
Figure imgf000123_0003
[0401] The title compound was prepared analogously to Example 54. MS m/z: 318 (M+H+). EXAMPLE 77
V1-(8-chloro-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)-N1,N2-dimethylethane-l,2- diamine
Figure imgf000124_0001
[0402] The title compound was prepared analogously to Example 54. MS m/z: 291 (M+H+).
EXAMPLE 78
/V1-(8-chloro-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)-N1,N2,N2-trimethylethane-
1,2-diamine
Figure imgf000124_0002
[0403] The title compound was prepared analogously to Example 54. MS m/z: 305 (M+H+).
EXAMPLE 79
^-(S-chloro-tl^^ltriazolo^^-alquinoxalin^-y -Nl-methylethane-l^- diamine
Figure imgf000124_0003
[0404] The title compound was prepared analogously to Example 54. MS m/z: 277 (M+H+). EXAMPLE 80
2-(8-chloro-[l,2,4]triazolo[4 -a]quinoxalin-4-yloxy)-N-methylethanamine
Figure imgf000125_0001
[0405] The title compound was prepared analogously to Example 54. MS M/Z: 278 (M+H+).
EXAMPLE 81
l-(8-chloro-[l,2,4]triazolo[4,3-a]quinoxalin-4-yl)piperidin-4-amine
Figure imgf000125_0002
[0406] The title compound was prepared analogously to Example 54. MS M/Z: 303 (M+H+).
EXAMPLE 82
8-chloro-4-(3,3-dimethylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000125_0003
The title compound was prepared analogously to Example 54. MS M/Z: EXAMPLE 83
8-chloro-4-((3S,5R)-3,5-dimethylpiperazin-l-yl)-[l,2,4]triazolo[4,3- a]quinoxaline
Figure imgf000126_0001
[0408] The title compound was prepared analogously to Example 54. MS M/Z: 317 (M+H+).
EXAMPLE 84
8-chloro-l-methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000126_0002
[0409] The title compound was prepared analogously to Example 54. MS M/Z: 317 (M+H+).
EXAMPLE 85
8-chloro-l-methyl-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000126_0003
[0410] The title compound was prepared analogously to Example 54. MS M/Z: 303 (M+H+). EXAMPLE 86
8-chloro-l-ethyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000127_0001
[0411] The title compound was prepared analogously to Example 54. MS M/Z: 331 (M+H+).
EXAMPLE 87
8-chloro-l-isopropyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3- a]quinoxaline
Figure imgf000127_0002
[0412] The title compound was prepared analogously to Example 54. MS M/Z: 345 (M+H+).
EXAMPLE 88
4-(4-methylpiperazin-l-yl)-8-vinyl-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000127_0003
[0413] A 100 mL round bottom flask was charged with 8-bromo-4-(4- methylpiperazinyl)-10-hydro- l,2,4-triazolo[4,3-a]quinoxaline (Example 54, 0.86 g, 2.48 mmol), LiCl (0.21 g, 5.0 mmol), tri-n-butyl(vinyl)tin (0.94 g, 3.0 mmol), bis(triphenyphosphine)palladium(II) chloride (0.12 g, 0.2 mmol) and DMF (25 mL). The mixture was heated at 90 °C overnight. Work-up: the reaction solution was diluted with H20 (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by column chromatography on silica gel with 4% MeOH in CH2C12, giving 0.48 g (66%) of the product as white solids. !H NMR (300 MHz, CDC13) δ: 9.17 (s, 1H), 7.68-7.61 (m, 3H), 6.78 (dd, J = 17.4, 11.1 Hz, 1H), 5.82 (d, J = 17.4 Hz, 1H), 5.34 (d, J = 11.1 Hz, 1H), 4.46 (m, 4H), 2.60 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 295 (M+H+).
Figure imgf000128_0001
EXAMPLE 89
4-(piperazin-l-yl)-8-vinyl-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000128_0002
[0414] The HCI salt of the title compound was prepared as described in Example 52, except that tert-butyl 4-(8-vinyl-10-hydro-l,2,4-triazolo[4,3- a]quinoxalin-4-yl)piperazinecarboxylate (prepared as described in Example 88 from tert-butyl 4-(8-bromo-10-hydro-l ,2,4-triazolo[4,3-a]quinoxalin-4- yl)piperazinecarboxylate) was substituted for tert-butyl 4-(8-bromo-10-hydro- 1,2,4- triazolo[4,3-a]quinoxalin-4-yl)piperazinecarboxylate in step 6 of that route. 1H NMR (300 MHz, D20) δ: 8.89 (s, 1H), 6.68 (m, 3H), 6.08 (dd, J = 17.4, 10.8 Hz, 1H), 5.36 (d, J = 17.4 Hz, 1H), 5.06 (d, J = 10.8 Hz, 1H), 4.07 (t, J = 5.1 Hz, 4H), 3.28 (t, J = 5.1 Hz, 4H). MS m/z: 281 (M+H+). EXAMPLE 90
8-ethyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000129_0001
[0415] A 100 mL round bottom flask was charged with 4-(4- methylpiperazinyl)-8-vinyl- 10-hydro- 1 ,2,4-triazolo[4,3-a]quinoxaline (Example 88, 0.26 g, 0.88 mol), Pd/C (0.10 g) and THF (30 mL). The mixture was stirred under ¾ atmosphere for 1 h. Work-up: The reaction mixture was filtered. The filtrate was concentrated in vacuo, giving 0.18 g (69%) of the product as white solids. *H NMR (300 MHz, CDC13) δ: 9.17 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 8.4, 1.8 Hz, 1H), 4.43 (m, 4H), 2.79 (q, J = 7.5 Hz, 2H), 2.60 (t, J = 6.0 Hz, 4H), 2.37 (s, 3H), 1.32 (t, J = 7.5 Hz, 3H). MS m/z: 297 (M+H+).
EXAMPLE 91
8-ethyl-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000129_0002
[0416] The HC1 salt of the title compound was prepared as described in Example 52, except that tert-butyl 4-(8-ethyl- 10-hydro- l,2,4-triazolo[4,3- a]quinoxalin-4-yl)piperazinecarboxylate (prepared as described in Example 90 and 88 from tert-butyl 4-(8-bromo-10-hydro-l,2,4-triazolo[4,3-a]quinoxalin-4- yl)piperazinecarboxylate) was substituted for tert-butyl 4-(8-bromo- 10-hydro- 1,2,4- triazolo[4,3-a]quinoxalin-4-yl)piperazinecarboxylate in step 6 of that route. 1H
NMR (300 MHz, D20) δ: 9.17 (s, 1H), 7.10-6.98 (m, 3H), 4.19 (t, J = 4.8 Hz, 1H), 3.37 (t, J = 5.4 Hz, 4H), 2.45 (q, J = 7.5 Hz, 2H), 1.05 (t, J = 7.5 Hz, 3H). MS m/z: 283 (M+H+).
Figure imgf000130_0001
EXAMPLE 92
9-Chloro-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000130_0002
Methyl 4-chloro-2-cyanophenylcarbamate:
[0417] A 100 mL round bottom flask was charged with 2-amino-5- chlorobenzonitrile (0.76 g, 5.0 mmol), methyl chloroformate (0.43 mL, 5.40 mmol), NaHCC>3 (0.5 g, 6.0 mmol) and 2-butanone (25 mL). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC
(EtO Ac/Petroleum ether = 1 : 10). Work-up: the reaction mixture was filtered and the solid was washed more 2-butanone (20 mL x 2). The filtrate was concentrated in vacuo, to give 0.95 g (97%) of the product as white solid. Step 2
Figure imgf000131_0001
9-Chloro-[l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one:
[0418] A 100 mL round bottom flask was charged with methyl 4-chloro-2- cyanophenylcarbamate (0.9 g, 4.26 mmol), formic hydrazide (0.3 g, 5.12 mmol) and l-methyl-2-pyrrolidone (25 mL). The resulting mixture was heated at 180 °C for 1.5 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :2). Work-up: the solvent was evaporated under reduced pressure and the residue was poured into EtO Ac (20 mL) and well-mixed by stirring. The solid was collected by filtration, washed with EtOAc (20 mL) and dried, to give 0.88 g (85%) of the product as light yellow crystalline solid. *H NMR (300 MHz, DMSO-d6) δ: 12.45 (s, 1H), 8.55 (s, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.75 (dd, J = 9.0, 2.4 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H). MS m/z: 219 (M-H+).
Step 3
Figure imgf000131_0002
5,9-Dichloro- [ l,2,4]triazolo [1 ,5-c] quinazoline :
[0419] A 50 mL round bottom flask was charged with 9-chloro- [l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one (0.88 g, 4.0 mmol) and phosphorus oxychloride (15 mL). To the above was added dropwise N,N-diisopropylethylamine (1.38 g, 8.0 mmol). The resulting mixture was heated at reflux for 8 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :8). Work-up: the solvent was evaporated under reduced pressure and the residue was poured into EtOAc (20 mL) and well-mixed by stirring. The solid was collected by filtration, washed with CH2CI2 (20 mL), and dried, to give 0.77 g (81 ) of the product as light yellow crystalline solid. *H NMR (300 MHz, CDC13) δ: 8.51 (dd, J = 2.4, 0.3 Hz, 1H), 8.48 (s, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.81 (dd, J = 9.0, 2.4 Hz, 1H). MS m/z: 239 (M+H+).
Step 4
Figure imgf000132_0001
9-Chloro-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline:
[0420] A 5 mL microwave reaction tube was charged with 5,9-dichloro- [l,2,4]triazolo[l,5-c]quinazoline ( 0.12 g, 0.50 mmol), piperazine (0.103 g, 0.55 mmol) and EtOH (4 mL). The resulting mixture was heated at 130 °C for 1.5 h in a Biotage microwave reactor. Work-up: the solvent was evaporated under reduced pressure. The solid was collected by filtration, washed with H20 (10 mL) and dried, to give 0.18 g (92%) of the product as light yellow crystalline solid. !H NMR (300 MHz, CD3OD) δ: 8.52 (s, 1H), 8.32 (m, 1H), 7.75 (m, 2H), 4.33 (t, J = 5.1 Hz, 4H), 3.48 (t, J = 5.4 Hz, 4H). MS m/z: 289 (M+H+).
Figure imgf000132_0002
EXAMPLE 93
8,9-Dichloro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000133_0001
Step 1
Figure imgf000133_0002
2-Amino-4,5-dichlorobenzonitrile:
[0421] A 10 mL round bottom flask was charged with 2-amino-4- chlorobenzonitrile (0.2 g, 1.31 mmol), N-chlorosuccinimide (0.19 g, 1.44 mmol) and DMF (5 mL). The resulting mixture was stirred at 25 °C overnight. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 : 10). Work-up: the reaction mixture was diluted with EtO Ac (40 mL) and washed with brine (40 mL). The organic layer was dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a 1 : 10
EtOAc/Petroleum ether, to afford 170 mg (47%) of the product as white solid. NMR (300 MHz, CDC13) δ: 7.45 (s, 1H), 6.88 (s, 1H), 4.48 (br, 2H).
Steps 2-5
Figure imgf000133_0003
8,9-Dichloro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline: [0422] The title compound was prepared as described in Example 92, except that N-methylpiperazine was substituted for piperazine in step 4, 2-amino-4,5- dichlorobenzonitrile for 2-amino-5-chlorobenzonitrile in step 1, and acetic hydrazide for formic hydrazide in step 2. *H NMR (300 MHz, CD3OD) δ: 8.26 (s, 1H), 7.77 (s, 1H), 4.12 (t, J = 5.1 Hz, 4H), 2.67 (t, J = 5.1 Hz, 4H), 2.58 (s, 3H), 2.38 (s, 3H). MS m/z: 351 (M+H+).
EXAMPLE 94
8,9-Dichloro-2-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000134_0001
[0423] The title compound was prepared as described in Example 93, except that piperazine was substituted for N-methylpiperazine in step 5 of that route. JH NMR (300 MHz, CD3OD) δ: 8.22 (s, 1H), 7.73 (s, 1H), 4.08 (m, 4H), 3.06 (m, 4H), 2.58 (s, 3H). MS m/z: 337 (M+H+).
Figure imgf000134_0002
EXAMPLE 95
9-Chloro-8-fluoro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000135_0001
[0424] The title compound was prepared as described in Example 93, except that 2-amino-4-fluorobenzonitrile was substituted for 2-amino-4-chlorobenzonitrile in step 1 of that route. *H NMR (300 MHz, CD3OD) δ: 8.22 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 10.5 Hz, 1H), 4.12 (t, J = 4.8 Hz, 4H), 2.66 (t, J = 4.8 Hz, 4H), 2.57 (s, 3H), 2.37 (s, 3H). MS m/z: 335 (M+H+).
EXAMPLE 96
9-Chloro-8-fluoro-2-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000135_0002
[0425] The title compound was prepared as described in Example 95, except that piperazine was substituted for N-methylpiperazine in step 5 of that route.
NMR (300 MHz, CD3OD) δ: 8.26 (d, J = 7.8 Hz, 1H), 7.46 (d, J
4.08 (m, 4H), 3.03 (m, 4H), 2.58 (s, 3H). MS m/z: 321 (M+H+).
Figure imgf000136_0001
EXAMPLE 97
8,9-Difluoro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000136_0002
4,5-Difluoro-2-nitrobenzamide:
[0426] A 100 mL round bottom flask was charged with 4,5-difluoro-2- nitrobenzoic acid (5.08 g, 25 mmol) and SOCl2 (15 mL). The mixture was refluxed for 1 h then concentrated in vacuo. To the residue was added slowly 25% aqueous ammonia (30 mL) at 0 °C and the reaction mixture was stirred for further 2 h at 0 °C. The reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 : 1, Rf = 0.4). Work-up: the solid was collected by filtration and dried to afford 4.06 g (80%) of the product as brown solid.
Step 2
Figure imgf000137_0001
4,5-Difluoro-2-nitrobenzonitrile:
[0427] A 250 mL round bottom flask was charged with 4,5-difluoro-2- nitrobenzamide (4.06 g, 20 mmol), (CF3CO)20 (5.6 mL, 40 mmol), Et3N (5.6 mL, 40 mmol) and CH2CI2 (120 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :4, Rf = 0.7). Work-up: the reaction mixture was diluted with more CH2CI2 (120 mL), washed with saturated aqueous NaHCC>3 (250 mL). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo. The oil residue solidified after 1 h at room temperature, to afford 4.5 g (quantitative yield) of the product as orange solid. *H NMR (300 MHz, DMSO-d6) δ: 8.70 (dd, J = 10.3, 7.3 Hz, 1H), 8.58 (dd, J = 10.1, 7.5 Hz, 1H).
Step 3
Figure imgf000137_0002
2-Amino-4,5-difluorobenzonitrile:
[0428] A 250 mL round bottom flask was charged with 4,5-difluoro-2- nitrobenzonitrile (3.68 g, 20 mmol), Na2S204 (85% purity, 8.19 g, 40 mmol), EtOH (150 mL) and ¾0 (20 mL). The resulting mixture was stirred at reflux overnight and then concentrated to dryness under reduced pressure. The residue was suspended in saturated aqueous NaHC03 (200 mL) and extracted with ethyl ether (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04 then concentrated in vacuo, to afford 1.2 g (39%) of the product as yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 7.64 (dd, J
7.1 Hz, 1H), 6.24 (br, 2H).
Step 4
Figure imgf000138_0001
Ethyl 2-cyano-4,5-difluorophenylcarbamate:
[0429] A 100 mL round bottom flask was charged with 2-amino-4,5- difluorobenzonitrile (1.1 g, 7.1 mmol), ethyl chloroformate (25 mL, 260 mmol) and NaHCC>3 (0.72 g, 8.6 mmol). The resulting mixture was refluxed overnight (16 h) then cooled to room temperature. It was diluted with CH2CI2 (200 mL) then filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with 10% AcOEt in petroleum ether, to afford 1.36 g (84%) of the product as white solid. *H NMR (300 MHz, DMSO-d6) δ: 9.91 (s, 1H), 8.11 (dd, J = 10.4, 8.5 Hz, 1H), 7.65 (dd, J = 12.1, 7.4 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).
Step 5
Figure imgf000138_0002
8,9-Difluoro-2-methyl-[l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one:
[0430] A 50 mL round bottom flask was charged with ethyl 2-cyano-4,5- difluorophenylcarbamate (1.36 g, 6.0 mmol), acetic hydrazide (0.535 g, 7.2 mmol) and l-methyl-2-pyrrolidone (15 mL). The resulting solution was refluxed for 2 h. The l-methyl-2-pyrrolidone was then removed under reduced pressure, to afford 1.42 g (quantitative) of the product as orange solid. It was used directly in the next step. Step 6
Figure imgf000139_0001
5-Chloro-8,9-difluoro-2-methyl-[l,2,4]triazolo[l,5-c]quinazoline:
[0431] A 100 mL round bottom flask was charged with 8,9-difluoro-2-methyl- [l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one (1.42 g, 6.0 mmol) and POCl3 (20 mL). After N,N-diisopropylethylamine (2.1 mL, 12 mmol) was added dropwise at 0 °C, the resulting mixture was refluxed overnight (16 h) and then concentrated under reduced pressure. The residue was carefully diluted with saturated aqueous NaHC03 (150 mL), then extracted with CH2C12 (150 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2S04 then concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel with 20-50% AcOEt in CH2C12 (containing 1% Et3N), to afford 0.96 g (63%) of the product as light-orange solid. *H NMR (300 MHz, CDC13) δ: 8.19 (dd, J = 9.4, 8.1 Hz, 1H), 7.75 (dd, J = 10.3, 7.1 Hz, 1H), 2.66 (s,
3H).
Step 7
Figure imgf000139_0002
8,9-Difluoro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline:
[0432] A 100 mL round bottom flask was charged with 5-chloro-8,9-difluoro-2- methyl-[l,2,4]triazolo[l,5-c]quinazoline (0.2 g, 0.8 mmol), N-methylpiperazine (0.1 mL, 0.9 mmol), Et3N (0.5 mL, 3.6 mmol), DMF (10 mL) and THF (10 mL). The resulting solution was stirred at room temperature for 1 h, and then was concentrated under reduced pressure. The residue was mixed with saturated aqueous NaHC03 (100 mL), then extracted with CHC13 (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2-4% MeOH in CH2C12 (saturated with NH3), to afford 0.085 g (34%) of the product as off-white solid. *H NMR (300 MHz, CDC13) δ: 8.05 (dd, J = 9.8, 8.5 Hz, 1H), 7.46 (dd, J = 11.4, 7.2 Hz, 1H), 4.09 (t, J = 4.8 Hz, 4H), 2.66 (t, J = 4.8 Hz, 4H), 2.62 (s, 3H), 2.40 (s, 3H). MS m/z: 319 (M+H+).
EXAMPLE 98
8,9-Difluoro-2-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000140_0001
[0433] The title compound was prepared as described in Example 97, except that piperazine was substituted for N-methylpiperazine in step 7 of that route. 1H NMR (300 MHz, CDC13) δ: 8.05 (dd, J = 9.9, 8.4 Hz, 1H), 7.46 (dd, J = 11.4, 7.1 Hz, 1H), 4.01 (t, J = 5.1 Hz, 4H), 3.10 (t, J = 5.1 Hz, 4H), 2.62 (s, 3H). MS m/z: 305 (M+H+).
Figure imgf000140_0002
EXAMPLE 99
2,9-Dimethyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000141_0001
Methyl 2-cyano-4-methylphenylcarbamate:
[0434] A 100 mL round bottom flask was charged with 2-amino-5- methylbenzonitrile (3.5 g, 26.5 mmol), Na2C03 (5.8 g, 54.7 mmol) and methyl chloroformate (50 mL). The resulting solution was heated at reflux overnight. The reaction mixture was concentrated. The resulting precipitate was collected by filtration, to afford 2.6 g (52%) of the product as yellow solid.
Step 2
Figure imgf000141_0002
2,9-Dimethyl-[l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one:
[0435] A 100 mL round bottom flask was charged with methyl 2-cyano-4- methylphenylcarbamate (2.6 g, 13.7 mmol), acetic hydrazide (1.2 g, 16.2 mmol) and l-methyl-2-pyrrolidone (50 mL). The resulting solution was heated at 180 °C for 1 h then concentrated in vacuo. The resulting precipitate was collected by filtration, washed with EtOAc and dried, to afford 2 g (68%) of the product. Step 3
Figure imgf000142_0001
5-Chloro-2,9-dimethyl-[l,2,4]triazolo[l,5-c]quinazoline:
[0436] A 100 mL round bottom flask was charged with 2,9-dimethyl- [l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one (1 g, 1.07mmol), N,N-dimethylanaline (0.26 mL, 2.14 mmol) and POCI3 (10 mL). The resulting solution was heated at reflux for 3 h then concentrated in vacuo. The residue was poured into saturated aqueous Na2CC>3 and extracted with CH2CI2. The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 300 mg (27%) of the product as white solid. MS m/z: 233 (M+H+).
Step 4
Figure imgf000142_0002
2,9-Dimethyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline:
[0437] A 20 mL microwave reaction tube was charged with 5-chloro-2,9- dimethyl-[l,2,4]triazolo[l,5-c]quinazoline (150 mg, 0.64 mmol), N- methylpiperazine (0.22 mL, 1.98 mmol) and anhydrous EtOH (10 mL). The resulting solution was heated at 130 °C for 1 h in a Biotage microwave reactor. The solvent was evaporated and the residue was purified by flash column
chromatography on silica gel with 10% MeOH in CH2C12 to afford 110 mg (57%) of the product as white solid. *H NMR (300 MHz, CD3OD) δ: 8.00 (s, 1H), 7.53 (m, 2H), 3.99 (br, 4H), 2.66 (t, J = 5.1 Hz, 4H), 2.57 (s, 3H), 2.48 (s, 3H), 2.37 (s, 3H). MS m/z: 297 (M+H+). EXAMPLE 100
2,9-Dimethyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000143_0001
[0438] The title compound was prepared as described in Example 99, except that piperazine was substituted for N-methylpiperazine in step 4 of that route.1H NMR (300 MHz, CD3OD) δ: 8.06 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 8.4, 1.5 Hz, 1H), 3.93 (m, 4H), 3.04 (m, 4H), 2.59 (s, 3H), 2.50 (s, 3H). MS m/z: 283 (M+H+).
Figure imgf000143_0002
EXAMPLE 101
9-Methoxy-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000143_0003
Step 1
Figure imgf000144_0001
5-Methoxy-2-nitrobenzamide:
[0439] A 100 mL round bottom flask was charged with 5-methoxy-2- nitrobenzoic acid (1.5 g, 7.61 mmol), DMF (1 mL) and SOCl2 (15 mL). The resulting mixture was heated at reflux for 1 h then concentrated in vacuo. The residue was re-dissolved in DMF (3 mL) and the solution was added dropwise to aqueous ammonia (25%, 15 mL) at 0 °C with vigorous stirring. Work-up: the resulting solid was collected by filtration, washed with H20 (20 mL) and dried, to give 1.2 g (80%) of the product as white solid.
Step 2
Figure imgf000144_0002
5-Methoxy-2-nitrobenzonitrile:
[0440] A 100 mL round bottom flask was charged with 5-methoxy-2- nitrobenzamide (2.1 g, 0.01 mol), trifluoroacetic anhydride (2.2 mL), triethylamine (2.9 mL) and CH2C12 (30 mL). The resulting solution was stirred at room temperature for 1 h. Work-up: the reaction solution was washed with H20 (30 mL x 2). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo, to give 1.75 g (92%) of the product as white solid. MS m/z: 179 (M+H+).
Step 3
Figure imgf000144_0003
2-Amino-5-methoxybenzonitrile: [0441] A 100 mL round bottom flask was charged with 5-methoxy-2- nitrobenzonitrile (1.7 g, 9.55 mmol), sodium dithionite (4.99 g, 29 mmol), water (15 mL) and EtOH (50 mL). The resulting mixture was heated at reflux for 1 h. Work-up: the reaction mixture was concentrated in vacuo to remove ethanol then extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo, to afford 1.4 g (quantitative) of the product as yellow oil. It was used in the next step without further purification.
Steps 4-7
Figure imgf000145_0001
9-Methoxy-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline:
[0442] The title compound was prepared as described in Examples 92, except that N-methylpiperazine was substituted for piperazine in step 4, 2-amino-5- methoxybenzonitrile for 2-amino-5-chlorobenzonitrile in step 1, and acetic hydrazide for formic hydrazide in step 2. *H NMR (300 MHz, CDC13) δ: 7.67 (m, 2H), 7.29 (dd, J = 9.0, 2.7 Hz, 1H), 3.99 (m, 4H), 3.93 (s, 3H), 2.68 (m, 4H), 2.65 (s, 3H), 2.40 (s, 3H). MS m/z: 313 (M+H+).
EXAMPLE 102
9-Methoxy-2-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000145_0002
[0443] The title compound was prepared as described in Example 101, except that piperazine was substituted for N-methylpiperazine in step 7 of that route. JH NMR (300 MHz, CD3OD) δ: 7.66 (m, 2H), 7.32 (dd, J = 9.0, 3.0 Hz, 1H), 3.96-3.92 (m, 7H), 3.12 (t, J = 5.1 Hz, 4H), 2.59 (s, 3H). MS m/z: 299 (M+H+).
Figure imgf000146_0001
EXAMPLE 103
2-Methyl-5-(4-methylpiperazin-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000146_0002
[0444] The title compound was prepared as described in Examples 92, except that N-methylpiperazine was substituted for piperazine in step 4, 2-amino-5- (trifluoromethyl)benzonitrile for 2-amino-5-chlorobenzonitrile in step 1, and acetic hydrazide for formic hydrazide in step 2. *H NMR (300 MHz, CD3OD) δ: 8.52 (s, 1H), 7.89 (dd, J =9.0, 2.4 Hz, 1H), 7.78 (dd, J = 9.0, 0.6 Hz, 1H), 4.19 (t, J = 5.1 Hz, 4H), 2.67 (t, J = 5.1 Hz, 4H), 2.60 (s, 3H), 2.37 (s, 3H). MS m/z: 351 (M+H+). EXAMPLE 104
2-Methyl-5-(piperazin-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000147_0001
[0445] The title compound was prepared as described in Example 103, except that piperazine was substituted for N-methylpiperazine in step 4 of that route. 1H NMR (300 MHz, CD3OD) δ: 8.45 (d, J = 0.3 Hz, 1H), 7.85 (dd, J = 8.7, 2.4 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 4.11 (m, 4H), 3.02 (t, J = 4.8 Hz, 4H), 2.57 (s, 3H). MS m/z: 337 (M+H+).
Figure imgf000147_0002
EXAMPLE 105
8-Chloro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000147_0003
[0446] The title compound was prepared as described in Examples 92, except that N-methylpiperazine was substituted for piperazine in step 4, 2-amino-4- chlorobenzonitrile for 2-amino-5 -chlorobenzonitrile in step 1, and acetic hydrazide for formic hydrazide in step 2. *H NMR (300 MHz, CDC13) δ: 8.23 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.37 (dd, J = 8.7, 2.1 Hz, 1H), 4.12 (m, 4H), 2.63 (m, 7H), 2.38 (s, 3H). MS m/z: 317 (M+H+).
EXAMPLE 106
8-Chloro-2-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000148_0001
[0447] The title compound was prepared as described in Example 105, except that piperazine was substituted for N-methylpiperazine in step 4 of that route. JH NMR (300 MHz, CDC13) δ: 8.23 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.38 (dd, J = 8.7, 2.1 Hz, 1H), 4.17 (t, J = 4.8 Hz, 4H), 3.20 (t, J = 4.8 Hz, 4H), 2.63 (s, 3H). MS m/z: 303 (M+H+). a2S204
Figure imgf000148_0002
EXAMPLE 107
8-Fluoro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000149_0001
[0448] The title compound was prepared as described in Example 101, except that 4-fluoro-2-nitrobenzoic acid was substituted for 5-methoxy-2-nitrobenzoic acid in step 1 of that route. *H NMR (300 MHz, CD3OD) δ: 8.26 (dd, J = 8.7, 6.0 Hz, 1H), 7.35 (dd, J = 10.5, 2.4 Hz, 1H), 7.24 (m, 1H), 4.12 (m, 4H), 2.68 (m, 4H), 2.58 (s, 3H), 2.37 (s, 3H). MS m/z: 301 (M+H+).
EXAMPLE 108
8-Fluoro-2-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000149_0002
[0449] The title compound was prepared as described in Example 107, except that piperazine was substituted for N-methylpiperazine in step 7 of that route. JH NMR (300 MHz, CD3OD) δ: 8.25 (dd, J = 9.0, 6.0 Hz, 1H), 7.33 (dd, J = 10.5, 2.7 Hz, 1H), 7.22 (m, 1H), 4.05 (m, 4H), 3.30 (m, 4H), 2.58 (s, 3H). MS m/z: 287
(M+H+).
Figure imgf000150_0001
EXAMPLE 109
2-Methyl-5-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000150_0002
[0450] The title compound was prepared as described in Example 101, except that 2-nitro-4-(trifluoromethyl)benzoic acid was substituted for 5-methoxy-2- nitrobenzoic acid in step 1 of that route. *H NMR (300 MHz, CDC13) δ: 8.40 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 4.14 (br, 4H), 2.65 (m, 7H), 2.38 (s, 3H). MS m/z: 351 (M+H+).
EXAMPLE 110
2-Methyl-5-(piperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000151_0001
[0451] The title compound was prepared as described in Example 109, except that piperazine was substituted for N-methylpiperazine in step 7 of that route. 1H NMR (300 MHz, CD3OD) δ: 8.35 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.63 (dd, J = 8.4, 1.5 Hz, 1H), 4.08 (m, 4H), 3.04 (m, 4H), 2.60 (s, 3H). MS m/z: 337 (M+H+).
Figure imgf000151_0002
EXAMPLE 111
9-chloro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000151_0003
[0452] The title compound was prepared as described in Examples 92, except that N-methylpiperazine was substituted for piperazine in step 4. 1H NMR (300 MHz, CDCI3) δ: 8.29 (d, J = 2.4 Hz, 1H), 7.61 (m, 2H), 4.08 (br, 4H), 2.64 (m, 7H), 2.38 (s, 3H). MS m/z: 317 (M+H+).
EXAMPLE 112
9-Chloro-2-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000152_0001
[0453] The title compound was prepared as described in Example 111, except that piperazine was substituted for N-methylpiperazine in step 4 of that route. MS m/z: 317 (M+H+).
EXAMPLE 113
9-chloro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000152_0002
[0454] The title compound was prepared as described in Example 111, except that 5,9-dichloro-2-methyl-[l,2,4]triazolo[l,5-c]quinazoline was substituted for 5,9- dichloro-[l,2,4]triazolo[l,5-c]quinazoline in the final step of that route.1H NMR (300 MHz, CD3OD) δ: 8.19 (s, 1H), 7.67 (m, 2H), 4.01 (m, 4H), 3.03 (t, J = 5.1 Hz, 4H), 2.59 (s, 3H). MS m/z: 303 (M+H+).
Figure imgf000153_0001
EXAMPLE 114
9-Chloro-2-ethyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000153_0002
[0455] The title compound was prepared as described in Examples 92, except that N-methylpiperazine was substituted for piperazine in step 4, and propionic hydrazide for formic hydrazide in step 2. *H NMR (300 MHz, CDC13) δ: 8.30 (d, J = 2.1 Hz, 1H), 7.60 (m, 2H), 4.09 (br, 4H), 2.97 (q, J = 7.5 Hz, 2H), 2.65 (t, J = 4.8 Hz, 4H), 2.38 (s, 3H), 1.44 (t, J = 7.8 Hz, 3H). MS m/z: 331 (M+H+).
EXAMPLE 115
9-Chloro-2-ethyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000153_0003
[0456] The title compound was prepared as described in Example 114, except that piperazine was substituted for N-methylpiperazine in step 4 of that route. 1H NMR (300 MHz, CD3OD) δ: 8.15 (s, 1H), 7.59 (s, 2H), 4.01 (t, J = 5.1 Hz, 4H), 3.03 (t, J = 4.8 Hz, 4H), 2.94 (q, J = 7.5 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). MS m/z: 317 (M+H+).
Figure imgf000154_0001
EXAMPLE 116
9-Chloro-2-isopropyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000154_0002
[0457] The title compound was prepared as described in Example 92, except that N-methylpiperazine was substituted for piperazine in step 4, and isobutyric hydrazide for formic hydrazide in step 2. *H NMR (300 MHz, CD3OD) δ: 8.25 (t, J = 1.5 Hz, 1H), 7.63 (d, J = 1.5 Hz, 2H), 4.09 (t, J = 4.5 Hz, 4H), 3.29 (m, 1H), 2.67 (t, J = 4.5 Hz, 4H), 2.37 (s, 3H), 1.45 (d, J = 6.9 Hz, 6H). MS m/z: 345 (M+H+). EXAMPLE 117
9-Chloro-2-isopropyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000155_0001
[0458] The title compound was prepared as described in Example 116, except that piperazine was substituted for N-methylpiperazine in step 4 of that route. JH NMR (300 MHz, CD3OD) δ: 8.27 (m, 1H), 7.65 (m, 2H), 4.04 (m, 4H), 3.29 (m, 1H), 3.03 (m, 4H), 1.45 (d, J = 6.9 Hz, 6H). MS m/z: 331 (M+H+).
Figure imgf000155_0002
EXAMPLE 118
2-Benzyl-9-chloro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000155_0003
Step 1
Figure imgf000156_0001
Methyl 4-chloro-2-cyanophenylcarbamate:
[0459] A 100 mL round bottom flask was charged with 2-amino-5- chlorobenzonitrile (0.76 g, 5.0 mmol), methyl chloroformate (0.43 mL, 5.40 mmol), NaHCC>3 (0.5 g, 6.0 mmol) and 2-butanone (25 mL). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC
(EtO Ac/Petroleum ether = 1 : 10). Work-up: the reaction mixture was filtered and the solid was washed more 2-butanone (20 mL x 2). The filtrate was concentrated in vacuo, to give 0.95 g (97%) of the product as white solid.
Step 2
2-Benzyl-9-chloro-[l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one:
[0460] A 50 mL round bottom flask was charged with methyl 4-chloro-2- cyanophenylcarbamate (500 mg, 2.38 mmol), 2-phenylacetic hydrazide (430 mg, 2.86 mmol) and l-methyl-2-pyrrolidone (20 mL). The resulting solution was heated at 180 °C for 1.5 h then concentrated in vacuo. The resulting precipitate was collected by filtration, washed with EtO Ac and dried, to afford 610 mg (82%) of the product. Step 3
Figure imgf000157_0001
2-Benzyl-5,9-dichloro-[l,2,4]triazolo[l,5-c]quinazoline:
[0461] A 50 mL round bottom flask was charged with 2-benzyl-9-chloro- [l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one (610 mg, 1.97 mmol) and POCl3 (15 mL). The resulting solution was heated at reflux for 1 h then concentrated in vacuo. The residue was poured into saturated aqueous Na2CC>3 and extracted with CH2CI2. The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 330 mg (51 ) of the product as white solid.
Step 4
Figure imgf000157_0002
2-Benzyl-9-chloro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline:
[0462] A 50 mL round bottom flask was charged with 2-benzyl-5,9-dichloro- [l,2,4]triazolo[l,5-c]quinazoline (160 mg, 0.488 mmol), Et3N (0.14 mL, 1.0 mmol), N-methylpiperazine (0.07 ml, 0.65 mmol) and anhydrous EtOH (15 mL). The resulting solution stirred at room temperature for 1.5 h then concentrated in vacuo. The resulting solid was washed with H20 to give 115 mg (60%) of the product as white solid. *H NMR (300 MHz, CDC13) δ: 8.31 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 9.0, 2.4 Hz, 1H), 7.43-7.24 (m, 5H), 4.29 (s, 2H), 4.08 (m, 4H), 2.64 (t, J = 4.8 Hz, 4H), 2.38 (s, 3H). MS m/z: 393 (M+H+). EXAMPLE 119
2-Benzyl-9-chloro-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000158_0001
[0463] The title compound was prepared as described in Example 118, except that piperazine was substituted for N-methylpiperazine in step 4 of that route. 1H NMR (300 MHz, CD3OD) δ: 8.23 (s, 1H), 7.64 (m, 2H), 7.38-7.21 (m, 5H), 4.27 (s, 2H), 4.02 (t, J = 4.8 Hz, 4H), 3.02 (t, J = 4.8 Hz, 4H). MS m/z: 379 (M+H+).
Figure imgf000158_0002
EXAMPLE 120
5-(4-methylpiperazin-l-yl)-2,9-bis(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000158_0003
Step 1
Figure imgf000159_0001
Ethyl 2-cyano-4-(trifluoromethyl)phenylcarbamate:
[0464] A 25 mL round bottom flask was charged with 2-amino-5- (trifluoromethyl)benzenecarbonitrile (1.0 g, 5.4 mmol), Na2C03 (1.14 g, 10.8 mmol) and ethyl chloroformate (15 mL). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :6). Work-up: the mixture was filtered and the filter cake was washed 2- butanone (20 mL x 2). The filtrate was concentrated to dryness, giving 1.35 g (98%) of the product as light yellow solids.
Step 2
Figure imgf000159_0002
3-amino-4-imino-6-(trifluoromethyl)-3,4-dihydroquinazolin-2(lH)-one:
[0465] A 25 mL round bottom flask was charged with N-[2-cyano-4- (trifluoromethyl) phenyl]ethoxycarboxamide (0.3 g, 1.2 mmol), hydrazine hydrate (0.07 g, 1.4 mmol) and THF (7 mL). The resulting mixture was heated at 60 °C overnight. Work-up: the precipitate was collected by filtration and washed with THF (20 mL x 2), to afford 0.15 g (52 %) of the product as light yellow solids. The filtrate was recovered and heated again at 60 °C, to get another batch of 50 mg of the product in the same manner. MS m/z: 245 (M+H+). Step 3
Figure imgf000160_0001
2,9-bis(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one:
[0466] A 15 mL tube was charged with 3-amino-4-imino-6-(trifluoromethyl)- 3,4-dihydroquinazolin-2(lH)-one (0.24 g, 1.0 mmol) and trifluoroacetic anhydride (3 mL). The tube was sealed and the reaction mixture was heated at 85 °C overnight. Reaction progress was monitored by TLC (EtOAc/Petroleum ether = 2:1). Work-up: the solvent was evaporated under reduced pressure. The crude material was purified by flash column chromatography on silica gel with a 1 :40 MeOH/CH2Cl2, to afford 0.29 g (91 ) of the product as light yellow crystals. *H NMR (300 MHz, DMSO-d6) δ: 11.14 (s, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.00 (dd, J = 8.7, 1.8 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H). MS m/z: 321 (M-H+).
Step 4
Figure imgf000160_0002
5-chloro-2,9-bis(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazoline:
[0467] A 25 mL round bottom flask was charged with 2,9-bis(trifluoromethyl)- 5,7-dihydro-l,2,4-triazolo[l,5-c]quinazolin-6-one (0.16 g, 0.50 mmol) and phosphorus oxychloride (4 mL). To the resulting solution was added N,N- diisopropylethylamine (0.17 mL, 1.0 mmol). The mixture was heated at reflux for 1.5 h. Reaction progress was monitored by TLC (EtOAc/Petroleum ether = 2:1). Work-up: the solvent was evaporated under reduced pressure. The crude material was purified by flash column chromatography on silica gel with a 1 : 15 EtOAc/Petroleum ether, to afford 0.16 g (95%) of the product as light yellow solids.
Step 5
Figure imgf000161_0001
5-(4-methylpiperazin-l-yl)-2,9-bis(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline:
[0468] A 25 mL round bottom flask was charged with N-methylpiperazine (0.11 mL, 0.94 mmol) and acetonitrile (2 mL). To the resulting solution was added dropwise a solution of 5-chloro-2,9-bis(trifluoromethyl)-[l,2,4]triazolo[l,5- cjquinazoline (0.16 g, 0.47 mmol) in acetonitrile (2 mL). The mixture was stirred at room temperature for 30 minutes. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :8). Work-up: the solvent was evaporated under reduced pressure. The residue was mixed with water (10 mL) and stirred for 20 minutes at room temperature. The solid was collected by filtration, washed with water (5 mL), and dried, to give 0.17 g (90%) of the product as light yellow crystals. *H NMR (300 MHz, CD3OD) δ: 8.63 (d, J = 1.8 Hz, 1H), 7.99 (dd, J = 9.0, 1.8 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 4.19 (t, J = 4.5 Hz, 4H), 2.70 (t, J = 4.5 Hz, 4H), 2.38 (s, 3H). MS m/z: 405 (M+H+).
EXAMPLE 121
5-(piperazin-l-yl)-2,9-bis(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000161_0002
[0469] The title compound was prepared as described in Example 120, except that piperazine was substituted for N-methylpiperazine in step 5 of that route. 1H NMR (300 MHz, CD3OD) δ: 8.61 (d, J = 0.6 Hz, 1H), 7.95 (dd, J = 8.7, 0.6 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 4.14 (t, J = 4.8 Hz, 4H), 3.07 (t, J = 4.8 Hz, 4H). MS m/z: 391 (M+H+).
Figure imgf000162_0001
EXAMPLE 122
8-chloro-2-methyl-5-(4-methylpiperazin-l-yl)-9-(trifluoromethyl)- [l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000162_0002
5-Chloro-2-iodo-4-(trifluoromethyl)phenylamine:
[0470] A 250 mL 3-necked round bottom flask was charged with 3-chloro-4- (trifluoromethyl)aniline (4.5 g, 0.02 mol) and MeOH (50 mL). To the above was added dropwise a solution of ICl (4.8 g, 0.03 mol) in CH2C12 (100 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :20, Rf = 0.6). Work-up: the mixture was concentrated in vacuo. The residue was re-dissolved in CH2C12, washed with water, dried over anhydrous Na2SC>4 and concentrated in vacuo, to give 6.9 g (93%) of the product. MS m/z: 320 (M-H+).
Step 2
Figure imgf000163_0001
2-Amino-4-chloro-5-(trifluoromethyl)benzenecarbonitrile:
[0471] A 250 mL round bottom flask was charged with 5-chloro-2-iodo-4- (trifluoromethyl)aniline (6.9 g, 0.02 mol), CuCN (3.85 g, 0.04 mol) and DMF (100 mL). The resulting mixture was stirred at 130 °C overnight. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :4, Rf = 0.5). Work-up: the mixture was concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel with 20 % EtO Ac in petroleum ether, to afford 3 g (63%) of the product. MS m/z: 221 (M+H+).
Steps 3-6
Figure imgf000163_0002
8-chloro-2-methyl-5-(4-methylpiperazin-l-yl)-9-(trifluoromethyl)- [l,2,4]triazolo[l,5-c]quinazoline:
[0472] The HC1 salt of the title compound was prepared as described in Example 93, except that 2-amino-4-chloro-5-(trifluoromethyl)benzenecarbonitrile was substituted for 2-amino-4,5-dichlorobenzonitrile in steps 2-5 of that route. NMR (300 MHz, D20) δ: 7.87 (s, 1H), 7.36 (s, 1H), 4.94-4.91 (m, 2H), 3.53-3.51 (m, 4H), 3.25-3.22 (m, 2H), 2.90 (s, 3H), 2.45 (s, 3H). MS m/z: 385 (M+H+). EXAMPLE 123
8-chloro-2-methyl-5-(piperazin-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000164_0001
[0473] The HCI salt of the title compound was prepared as described in Example 122, except that piperazine was substituted for N-methylpiperazine in step 6 of that route. *H NMR (300 MHz, D20) δ: 7.83 (s, 1H), 7.32 (s, 1H), 4.18 (t, J = 5.4 Hz, 4H), 3.04 (t, J = 4.8 Hz, 4H), 2.45 (s, 3H). MS m/z: 371 (M+H+).
Figure imgf000164_0002
EXAMPLE 124
8-fluoro-2-methyl-5-(4-methylpiperazin-l-yl)-9-(trifluoromethyl)- [l,2,4]triazolo[l,5-c]quinazoline hydrochloride
Figure imgf000164_0003
[0474] The title compound was prepared as described in Example 122, except that 3-fluoro-4-(trifluoromethyl)aniline was substituted for 3-chloro-4- (trifluoromethyl)aniline in step 1 of that route. !H NMR (300 MHz, DMSO-d6) δ: 11.65 (s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 12.6 Hz, 1H), 5.08 (d, J = 12.9 Hz, 2H), 3.75-3.24 (m, 6H), 2.78 (s, 3H), 2.55 (s, 3H). MS m/z: 369 (M+H+).
EXAMPLE 125
8-fluoro-2-methyl-5-(piperazin-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline hydrochloride
Figure imgf000165_0001
[0475] The title compound was prepared as described in Example 124, except that piperazine was substituted for N-methylpiperazine in step 6 of that route. JH NMR (300 MHz, DMSO-d6) δ: 9.45 (s, 2H), 8.47 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 12.3 Hz, 1H), 4.35 (t, J = 4.5 Hz, 4H), 3.30 (t, J = 4.5 Hz, 4H), 2.55 (s, 3H). MS m/z: 355 (M+H+).
Figure imgf000165_0002
EXAMPLE 126
10-fluoro-2-methyl-5-(4-methylpiperazin-l-yl)-9-(trifluoromethyl)- [l,2,4]triazolo[l,5-c]quinazoline hydrochloride
Figure imgf000166_0001
[0476] The title compound was prepared as described in Example 124, except that 3-fluoro-2-iodo-4-(trifluoromethyl)aniline, which was also obtained as the other isomer in step 1, was substituted for 5-fluoro-2-iodo-4- (trifluoromethyl)aniline in step 2 of that route. !H NMR (300 MHz, CD3OD) δ: 7.94 (t, J = 8.4 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 5.35 (d, J = 14.4 Hz, 2H), 3.73- 3.62 (m, 4H), 3.43-3.35 (m, 2H), 2.99 (s, 3H), 2.64 (s, 3H). MS m/z: 369 (M+H+).
Figure imgf000166_0002
EXAMPLE 127
7-fluoro-2-methyl-5-(4-methylpiperazin-l-yl)-9-(trifluoromethyl)- [l,2,4]triazolo[l,5-c]quinazoline hydrochloride
Figure imgf000167_0001
[0477] The title compound was prepared as described in Example 122, except that 2-fluoro-4-(trifluoromethyl)aniline was substituted for 3-chloro-4- (trifluoromethyl)aniline in step 1 of that route. !H NMR (300 MHz, D20) δ: 7.68 (s, 1H), 7.49 (d, J = 10.5 Hz, 1H), 4.97 (d, J = 14.4 Hz, 2H), 3.65 (d, J = 12.8 Hz, 2H), 3.55-3.46 (m, 2H), 3.30-3.22 (m, 2H), 2.92 (s, 3H), 2.46 (s, 3H). MS m/z: 369 (M+H+).
EXAMPLE 128
7-fluoro-2-methyl-5-(piperazin-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline hydrochloride
Figure imgf000167_0002
[0478] The title compound was prepared as described in Example 127, except that piperazine was substituted for N-methylpiperazine in step 6 of that route. JH NMR (300 MHz, D20) δ: 7.70 (s, 1H), 7.49 (d, J = 10.5 Hz, 1H), 4.20 (br, 4H), 3.41 (br, 4H), 2.46 (s, 3H). MS m/z: 355 (M+H+).
Figure imgf000168_0001
EXAMPLE 129
9-fluoro-2-methyl-5-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)- [l,2,4]triazolo[l,5-c]quinazoline hydrochloride
Figure imgf000168_0002
[0479] The title compound was prepared as described in Example 122, except that 4-fluoro-3-(trifluoromethyl)aniline was substituted for 3-chloro-4- (trifluoromethyl)aniline in step 1 of that route. !H NMR (300 MHz, D20) δ: 7.61 (d, J = 6.0 Hz, 1H), 7.37 (d, J = 12.0 Hz, 1H), 4.76-4.68 (m, 2H), 3.65-3.23 (m, 6H), 2.91 (s, 3H), 2.45 (s, 3H). MS m/z: 369 (M+H+).
EXAMPLE 130
9-fluoro-2-methyl-5-(piperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline hydrochloride
Figure imgf000168_0003
[0480] The title compound was prepared as described in Example 129, except that piperazine was substituted for N-methylpiperazine in step 6 of that route. 1H NMR (300 MHz, D20) δ: 7.61 (d, J = 6.0 Hz, 1H), 7.39 (d, J = 12.0 Hz, 1H), 4.07- 4.04 (m, 4H), 3.40-3.36 (m, 4H), 2.46 (s, 3H). MS m/z: 355 (M+H+).
Figure imgf000169_0001
EXAMPLE 131
9-chloro-2-methyl-5-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)- [l,2,4]triazolo[l,5-c]quinazoline hydrochloride
Figure imgf000169_0002
[0481] The title compound was prepared as described in Example 122, except that 4-chloro-3-(trifluoromethyl)aniline was substituted for 3-chloro-4- (trifluoromethyl)aniline in step 1 of that route. !H NMR (300 MHz, D20) δ: 7.57 (s, 1H), 7.56 (s, 1H), 4.83 (d, J = 14.4 Hz, 2H), 3.62 (d, J = 12.8 Hz, 2H), 3.51-3.41 (m, 2H), 3.29-3.24 (m, 2H), 2.90 (s, 3H), 2.46 (s, 3H). MS m/z: 385 (M+H+).
EXAMPLE 132
9-chloro-2-methyl-5-(piperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline hydrochloride
Figure imgf000170_0001
[0482] The title compound was prepared as described in Example 131, except that piperazine was substituted for N-methylpiperazine in step 6 of that route.1H NMR (300 MHz, D20) δ: 7.60 (br, 2H), 4.11 (br, 4H), 3.40 (br, 4H), 2.47 (s, 3H). MS m/z: 371 (M+H+).
Figure imgf000170_0002
EXAMPLE 133
2-methyl-5-(4-methylpiperazin-l-yl)-9-(trifluoromethoxy)-[l,2,4]triazolo[l,5- c]quinazoline hydrochloride
Figure imgf000170_0003
[0483] The title compound was prepared as described in Example 122, except that 4-(trifluoromethoxy)aniline was substituted for 3-chloro-4- (trifluoromethyl)aniline in step 1 of that route. !H NMR (300 MHz, CD3OD) δ: 8.19 (dd, J = 2.4, 1.2 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.72-7.68 (m, 1H), 5.17 (dd, J = 14.1, 2.1 Hz, 2H), 3.72-3.58 (m, 4H), 3.46-3.42 (m, 2H), 2.99 (s, 3H), 2.65 (s, 3H). MS m/z: 367 (M+H+).
EXAMPLE 134
2-methyl-5-(piperazin-l-yl)-9-(trifluoromethoxy)-[l,2,4]triazolo[l,5- c]quinazoline hydrochloride
Figure imgf000171_0001
[0484] The title compound was prepared as described in Example 133, except that piperazine was substituted for N-methylpiperazine in step 6 of that route. 1H NMR (300 MHz, DMSO-d6) δ: 9.50 (br, 2H), 8.10 (d, J = 0.6 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H), 7.73 (dd, J = 9.3, 0.6 Hz, 1H), 4.23 (t, J = 5.1 Hz, 4H), 3.29 (br, 4H), 2.55 (s, 3H). MS m/z: 353 (M+H+).
Figure imgf000171_0002
EXAMPLE 135
9-bromo-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000172_0001
[0485] The HC1 salt of the title compound was prepared as described in Example 93, except that 2-amino-5-bromobenzonitrile was substituted for 2-amino- 4,5-dichlorobenzonitrile in steps 2-5 of that route. *H NMR (300 MHz, CD3OD) δ: 8.31 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 8.7, 2.1 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 5.18-5.13 (m, 2H), 3.70-3.58 (m, 4H), 3.43-3.39 (m, 2H), 2.98 (s, 3H), 2.63 (s, 3H). MS m/z: 361 (M+H+).
EXAMPLE 136
9-bromo-2-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000172_0002
[0486] The HC1 salt of the title compound was prepared as described in Example 135, except that piperazine was substituted for N-methylpiperazine in step 4 of that route. *H NMR (300 MHz, CD3OD) δ: 8.42-8.40 (m, 1H), 7.88 (dd, J = 8.7, 2.4 Hz, 1H), 7.67-7.64 (m, 1H), 4.32 (t, J = 5.1 Hz, 4H), 3.49-3.31 (m, 4H), 2.64 (s, 3H). MS m/z: 347 (M+H+). EXAMPLE 137
2-methyl-5-(4-methylpiperazin-l-yl)-9-vinyl-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000173_0001
[0487] The HC1 salt of the title compound was prepared as described in Example 88, except that 9-bromo-2-methyl-5-(4-methylpiperazin-l-yl)- [l,2,4]triazolo[l,5-c]quinazoline was substituted for 8-bromo-4-(4- methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline, in step 1 of that route.1H NMR (300 MHz, CD3OD) δ: 8.27 (d, J = 1.8 Hz, 1H), 8.02 (dd, J = 8.7, 2.1 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 17.7, 11.1 Hz, 1H), 5.99 (d, J = 17.4 Hz, 1H), 5.44 (d, J = 11.4 Hz, 1H), 5.10-5.05 (m, 2H), 3.73-3.66 (m, 4H), 3.45-3.37 (m, 2H), 2.99 (s, 3H), 2.71 (s, 3H). MS m/z: 309 (M+H+).
EXAMPLE 138
2-methyl-5-(piperazin-l-yl)-9-vinyl-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000173_0002
[0488] The HC1 salt of the title compound was prepared as described in
Example 89, except that piperazine was substituted for N-methylpiperazine in step 4 of that route. *H NMR (300 MHz, CD3OD) δ: 8.28 (d, J = 1.8 Hz, 1H), 8.01 (dd, J = 8.4, 2.1 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 17.7, 11.1 Hz, 1H), 5.98 (d, J = 17.4 Hz, 1H), 5.44 (d, J = 10.8 Hz, 1H), 4.31 (t, J = 5.1 Hz, 4H), 3.49 (t, J = 5.1 Hz, 4H), 2.70 (s, 3H). MS m/z: 295 (M+H+). EXAMPLE 139
9-ethyl-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000174_0001
[0489] The HC1 salt of the title compound was prepared as described in Example 90, except that 2-methyl-5-(4-methylpiperazin-l-yl)-9-vinyl- [l,2,4]triazolo[l,5-c]quinazoline was substituted for 4-(4-methylpiperazin-l-yl)-8- vinyl-[l,2,4]triazolo[4,3-a]quinoxaline, in step 1 of that route. !H NMR (300 MHz, CD3OD) δ: 8.14 (s, 1H), 7.80 (m, 2H), 5.05-5.00 (m, 2H), 3.72-3.58 (m, 4H), 3.46- 3.37 (m, 2H), 2.99 (s, 3H), 2.88 (q, J = 7.8 Hz, 2H), 2.71 (s, 3H), 1.35 (t, J = 7.8 Hz, 3H). MS m/z: 311 (M+H+).
EXAMPLE 140
9-ethyl-2-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000174_0002
[0490] The HC1 salt of the title compound was prepared as described in
Example 91, except that piperazine was substituted for N-methylpiperazine in step 4 of that route. *H NMR (300 MHz, CD3OD) δ: 8.15 (s, 1H), 7.83 (m, 2H), 4.29 (t, J = 4.8 Hz, 4H), 3.49 (t, J = 5.1 Hz, 4H), 2.89 (q, J = 7.5 Hz, 2H), 2.85 (s, 3H), 1.35 (t, J = 7.8 Hz, 3H). MS m/z: 297 (M+H+).
Figure imgf000175_0001
EXAMPLE 141
8-chloro-4-(4-methylpiperazin-l-yl)oxazolo[4,5-c]quinoline
Figure imgf000175_0002
6-Chloro-lH-benzo[d]l,3-oxazine-2,4-dione:
[0491] A 500 mL 3-necked round bottom flask was charged with 2-amino-5- chlorobenzoic acid (17 g, 0.1 mol) and 1 ,2-dichloroethane (200 mL). To the above was added dropwise a solution of triphosgene (21 g, 0.21 mol) in 1,2- dichloroethane (100 mL) at 80 °C. The resulting mixture was heated at 80 °C for further 3 h then cooled in ice- water. The precipitate was collected by filtration and dried to afford 19 g (97%) of the product as white solid. *H NMR (300 MHz, DMSO-d6) δ: 11.85 (br, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.7, 2.4 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H). Step 2
Figure imgf000176_0001
6-Chloro-4-hydroxy-3-nitrohydroquinolin-2-one:
[0492] A 500 mL 3-necked round bottom flask was charged with ethyl nitroacetate (16 mL, 144 mmol), Et3N (20 mL, 144 mmol) and anhydrous THF (400 mL). To the above was added dropwise a solution of 6-chloro-lH- benzo[d]l,3-oxazine-2,4-dione (19 g, 96 mmol) in THF (100 mL). The resulting solution was heated at 55 °C overnight then concentrated under reduced pressure. The residue was washed with Et20 then dissolved in water and acidified with 6 M HCl. The precipitate was collected by filtration and dried to afford 8 g (34%) of the product as yellow solid. *H NMR (300 MHz, DMSO-d6) δ: 11.85 (br, 1H), 8.00 (d, J = 2.7 Hz, 1H), 7.64 (dd, J = 8.4, 2.1 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H).
Step 3
Figure imgf000176_0002
3-Amino-6-chloro-4-hydroxyhydroquinolin-2-one hydrochloride salt:
[0493] A 250 mL round bottom flask was charged with 6-chloro-4-hydroxy-3- nitrohydroquinolin-2-one (2.4 g, 10 mmol) and 1 M NaOH aqueous solution (100 mL). To the above was added Na2S204 (12 g, 59 mmol) portion-wise. The resulting solution was stirred in the dark for 30 min. It was then cooled to 0 °C and acidified with 6 M HCl. The precipitate was collected by filtration, washed with small amount of acetone, and dried, to afford 2 g (83%) of the product as white solid. 1H
NMR (300 MHz, DMSO-d6) δ: 12.06 (br, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.54 (dd, J = 9.3, 2.4 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 5.0 (br, 3H). MS m/z: 211 (M+H+). Step 4
Figure imgf000177_0001
8-chlorooxazolo[4,5-c]quinolin-4(5H)-one:
[0494] A 100 mL round bottom flask was charged with 3-amino-6-chloro-4- hydroxyhydroquinolin-2-one hydrochloride salt (2 g, 8.1 mmol) and
triethylorthoformate (30 mL). The resulting solution was heated at reflux for 30 min then cooled in ice-water. The precipitate was collected by filtration, washed with
CH2C12, and dried, to afford 1.5 g (84%) of the product as yellow solid. *H NMR (300 MHz, DMSO-d6) δ: 12.15 (br, 1H), 8.87 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.62 (dd, J = 8.7, 2.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H). MS m/z: 221 (M+H+).
Step 5
Figure imgf000177_0002
4,8-dichlorooxazolo[4,5-c]quinoline:
[0495] A 100 mL round bottom flask was charged with 8-chloro-5 -hydro- 1 ,3- oxazolo[4,5-c]quinolin-4-one (1.7 g, 7.7 mmol) and POCI3 (20 mL). The resulting solution was heated at reflux for 20 min then concentrated in vacuo. The residue was mixed with saturated aqueous Na2CC>3 and extracted with CH2CI2. The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. It was further purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 480 mg (26%) of the product as white solid. *H NMR (300 MHz, CDC13) δ: 9.19 (s, 1H), 8.38 (dd, J = 2.4, 0.3 Hz, 1H), 8.15 (dd, J =9.0, 0.3 Hz, 1H), 7.91 (dd, J = 8.7, 2.4 Hz, 1H). MS m/z: 239 (M+H+) Step 6
Figure imgf000178_0001
8-chloro-4-(4-methylpiperazin-l-yl)oxazolo[4,5-c]quinoline:
[0496] A 20 mL microwave reaction tube was charged with 4,8- dichlorooxazolo[4,5-c]quinoline (320 mg, 1.3 mmol), N-methylpiperazine (0.16 mL, 1.4 mmol), Et3N (0.6 mL, 4.3 mmol) and anhydrous EtOH (15 mL). The resulting solution was heated at 130 °C for 1 h in a Biotage microwave reactor. The solvent was evaporated and the residue was purified by flash column
chromatography on silica gel with 10% MeOH in CH2C12, to afford 100 mg (25%) of the product as white solid. *H NMR (300 MHz, CD3OD) δ: 8.51 (s, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.49 (dd, J = 9.0, 2.7 Hz, 1H), 4.26 (t, J = 5.1 Hz, 4H), 2.65 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H). MS m/z: 303 (M+H+).
EXAMPLE 142
8-Chloro-4-piperazinyl-l,3-oxazolo[4,5-c]quinoline
Figure imgf000178_0002
[0497] The title compound was prepared as described in Example 141, except that piperazine was substituted for N-methylpiperazine in step 6 of that route. JH
NMR (300 MHz, CD3OD) δ: 8.60 (s, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.58 (dd, J = 9.0, 2.4 Hz, 1H), 4.47 (t, J = 5.4 Hz, 4H), 3.36 (t, J = 5.4 Hz, 4H). MS m/z: 289 (M+H+).
Figure imgf000179_0001
EXAMPLE 143
8-chloro-2-methyl-4-(4-methylpiperazin-l-yl)oxazolo[4,5-c]quinoline
Figure imgf000179_0002
N-(6-Chloro-4-hydroxy-2-oxo-3-hydroquinolyl)acetamide:
[0498] A 500 mL round bottom flask was charged with 3-amino-6-chloro-4- hydroxyhydroquinolin-2-one hydrochloride salt (prepared in Example 141 step 1-3, 6.8 g, 28 mmol) and anhydrous THF (150 mL). To the above were added dropwise anhydrous Et3N (9.6 mL, 69 mmol) and acetyl chloride (3 mL, 42 mmol). The resulting solution was heated at reflux for 6 h, cooled to room temperature, diluted with H20 and acidified with 6N HCl. The precipitate was collected by filtration and washed with H20, to afford 6 g (86%) of the product as yellow solid. !H NMR (300 MHz, DMSO-d6) δ: 12.07 (br, 1H), 11.94 (br, 1H), 9.76 (br, 1H), 7.79 (d, J = 2.7 Hz, 1H), 7.54 (dd, J = 8.7, 2.4 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 2.23 (s, 3H). Step 2
Figure imgf000180_0001
8-chloro-2-methyloxazolo[4,5-c]quinolin-4(5H)-one:
[0499] A 500 mL round bottom flask was charged with N-(6-chloro-4-hydroxy- 2-oxo-3-hydroquinolyl)acetamide (3 g, 12 mmol) and xylene (250 mL). The resulting solution was heated at 190 °C for 4 h. The solvent was evaporated under reduced pressure and the residue was re-dissolved in EtOAc and washed with H20. The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo, to afford 1 g (36%) of the product which was used as such in the next step. 1H NMR
(300 MHz, DMSO-d6) δ: 12.06 (br, 1H), 7.89 (d, J
2.4 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), 2.65 (s, 3H).
Step 3
Figure imgf000180_0002
4,8-dichloro-2-methyloxazolo[4,5-c]quinoline:
[0500] A 50 mL round bottom flask was charged with 8-chloro-2- methyloxazolo[4,5-c]quinolin-4(5H)-one (1.0 g, 4.3 mmol) and POCI3 (20 mL). The resulting solution was heated at reflux for 20 min. After evaporation of the solvent, the residue was poured into saturated aqueous Na2CC>3 and extracted with CH2C12. The combined organic layers were dried over Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 730 mg (68%) of the product as white solid. MS m/z: 328 (M+H+). Step 4
Figure imgf000181_0001
8-chloro-2-methyl-4-(4-methylpiperazin-l-yl)oxazolo[4,5-c]quinoline:
[0501] A 20 mL microwave reaction tube was charged with 4,8-dichloro-2- methyloxazolo[4,5-c]quinoline (300 mg, 1.2 mmol), N-methylpiperazine (0.16 mL, 1.4 mmol), Et3N (0.31 ml, 2.2 mmol) and anhydrous EtOH (15 mL). The resulting solution was heated at 100 °C for 1 h in a Biotage microwave reactor. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 10% MeOH in CH2C12, to afford 110 mg (29%) of the product as white solid. *H NMR (300 MHz, CD3OD) δ: 7.81 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.44 (dd, J = 9.0, 2.4 Hz, 1H), 4.19 (t, J = 4.5 Hz, 4H), 2.67 (s, 3H), 2.60 (t, J = 4.8 Hz, 4H), 2.35 (s, 3H). MS m/z: 316 (M+H+).
EXAMPLE 144
8-chloro-2-methyl-4-(piperazin-l-yl)oxazolo[4,5-c]quinoline
Figure imgf000181_0002
[0502] The title compound was prepared as described in Example 143, except that piperazine was substituted for N-methylpiperazine in step 4 of that route.
NMR (300 MHz, CD3OD) δ: 7.87 (d, J = 2.7 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.46 (dd, J = 9.0, 2.4 Hz, 1H), 4.16 (t, J = 5.4 Hz, 4H), 2.97 (t, J = 5.1 Hz, 4H), 2.69 (s, 3H). MS m/z: 302 (M+H+).
Figure imgf000182_0001
EXAMPLE 145
7,8-difluoro-2-methyl-4-(4-methylpiperazin-l-yl)oxazolo[4,5-c]quinoline
Figure imgf000182_0002
[0503] The title compound was prepared as described in Example 141, except that 2-amino-4,5-difluorobenzoic acid was substituted for 2-amino-5-chlorobenzoic acid in step 1 , and ethyl orthoacetate was substituted for ethyl orthoformate in step 4 of that route. *H NMR (300 MHz, CD3OD) δ: 7.65-7.63 (m, 1H), 7.45-7.43 (m, 1H), 4.18 (t, J = 4.8 Hz, 4H), 2.67 (s, 3H), 2.59 (t, J = 5.1 Hz, 4H), 2.35 (s, 3H). MS m/z: 319 (M+H+).
EXAMPLE 146
7,8-difluoro-2-methyl-4-(piperazin-l-yl)oxazolo[4,5-c]quinoline
Figure imgf000182_0003
[0504] The title compound was prepared as described in Example 145, except that piperazine was substituted for N-methylpiperazine in step 6 of that route. 1H NMR (300 MHz, DMSO-d6) δ: 7.87-7.85 (m, 1H), 7.56-7.54 (m, 1H), 4.04 (t, J = 4.8 Hz, 4H), 2.82 (t, J = 5.1 Hz, 4H), 2.69 (s, 3H). MS m/z: 305 (M+H+).
Figure imgf000183_0001
EXAMPLE 147
8-Chloro-4-(4-methylpiperazin-l-yl)furo[2,3-c]quinoline
Figure imgf000183_0002
Step 1
Figure imgf000183_0003
N-(4-Chloro-2-iodophenyl)furan-2-carboxamide:
[0505] A 100 mL round bottom flask was charged with furan-2-carboxylic acid (1.0 g, 7.8 mmol) and SOCl2 (15 mL). The resulting mixture was stirred at reflux for 2.5 h then concentrated in vacuo. The residue was dissolved in CH2CI2 (10 mL) and to the solution was added dropwise a solution of 4-chloro-2-iodophenylamine (1.8 g, 7.1 mmol) and Et3N (1.3 mL, 9.2 mmol) in CH2C12 (20mL) at 0 °C. The resulting solution was stirred at room temperature for 18 h, then diluted with CH2CI2 (200 mL) and washed with H20 (100 mL). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 4% EtOAc in petroleum ether, to afford 2.0 g (71 %) of the product. MS m/z: 347 (M+H+). Step 2
Figure imgf000184_0001
tert-Butyl 4-chloro-2-iodophenyl(furan-2-carbonyl)carbamate:
[0506] A 100 mL round bottom flask was charged with N-(4-chloro-2- iodophenyl)furan-2-carboxamide (3.70 g, 10.6 mmol), 4-dimethylaminopyridine (1.30 g, 10.6 mmol) and DMF (30 mL). To the above was added dropwise a solution of di-tert-butyl dicarbonate (7.0 g, 31.8 mmol) in DMF (10 mL) at 0 °C. The resulting solution was stirred at 60 °C for 18 h then cooled to room
temperature. It was diluted with H20 (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a 1 : 16 EtO Ac/Petroleum ether, to give 2.50 g (53%) of the product as white solid. *H NMR (300 MHz, CDC13) δ: 7.90 (d, J = 2.3 Hz, 1H), 7.56 (dd, J = 1.8, 0.8 Hz, 1H), 7.38 (dd, J = 8.3, 2.3 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.14 (dd, J = 3.5, 0.8 Hz, 1H), 6.54 (dd, J = 3.5, 1.8 Hz, 1H), 1.40 (s, 9H).
Step 3
Figure imgf000184_0002
8-Chlorofuro[2,3-c]quinolin-4(5H)-one:
[0507] A 20 mL microwave reaction tube was charged with tert-butyl 4-chloro- 2-iodophenyl(furan-2-carbonyl)carbamate (0.45 g, 1.0 mmol), palladium(II) acetate (0.023 g, 0.1 mmol), tricyclohexylphosphine (0.028 g, 0.1 mmol), K2C03 (0.28 g, 2.0 mmol) and N,N-dimethylacetamide (10 mL). After the air was purged by bubbling argon into the reaction solution, the tube was sealed and heated at 140 °C for 1 h in a Biotage microwave reactor. It was diluted with H20 (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 20-100% EtOAc in petroleum ether, to afford 0.10 g (53%) of the product as white solid.
Step 4
Figure imgf000185_0001
4,8-Dichlorofuro[2,3-c]quinoline:
[0508] A 100 mL round bottom flask was charged with 8-chlorofuro[2,3- c]quinolin-4(5H)-one (100 mg, 0.46 mmol) and POCI3 (20 mL). The resulting solution was heated at reflux for 2 h then concentrated under reduced pressure. The residue was mixed with saturated aqueous Na2CC>3 and extracted with EtOAc (50 mL x 4). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The resulting solid was washed with EtOH to afford 100 mg (93%) of the product as white solid. *H NMR (300 MHz, CDC13) δ: 8.10-8.05 (m, 2H), 7.95 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 9.1, 2.1 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H).
Step 5
Figure imgf000185_0002
8-Chloro-4-(4-methylpiperazin-l-yl)furo[2,3-c]quinoline:
[0509] A 20 mL microwave reaction tube was charged with 4,8- dichlorofurano[2,3-c]quinoline (110 mg, 0.46 mmol), N-methylpiperazine (0.15 mL, 1.4 mmol) and anhydrous iPrOH (10 mL). The resulting solution was heated at 130 °C for 1 h in a Biotage microwave reactor. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 10% MeOH in CH2C12 to afford 100 mg (72%) of the product as white solid. *H NMR (300 MHz, CDC13) δ: 7.85 (d, J = 2.4 Hz, 1H), 7.75 (m, 2H), 7.53 (dd, J = 6.3, 2.4 Hz, 1H), 7.13 (d, J = 1.8 Hz, 1H), 4.06 (t, J = 5.1 Hz, 4H), 2.61 (t , J = 5.1 Hz, 4H), 2.38 (s, 3H). MS m/z: 302 (M+H+).
EXAMPLE 148
8-Chloro-4-(piperazin-l-yl)furo[2,3-c]quinoline
Figure imgf000186_0001
[0510] The title compound was prepared as described in Example 147, except that piperazine was substituted for N-methylpiperazine in step 5 of that route.1H NMR (300 MHz, D20) δ: 8.14 (d, J = 1.5 Hz, 1H), 8.00 (s, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.59 (m, 1H), 7.35(s, 1H), 4.31 (t, J = 5.1 Hz, 4H), 3.48 (t, J = 5.1 Hz, 4H). MS m/z: 288 (M+H+).
EXAMPLE 149
8-Chloro-4-(4-methylpiperazin-l-yl)thieno[2,3-c]quinoline
Figure imgf000186_0002
[0511] The title compound was prepared as described in Example 147, except that thiophene-2-carboxylic acid was substituted for furan-2-carboxylic acid in step 1 of that route. *H NMR (300 MHz, CDC13) δ: 8.07 (d, J = 2.1 Hz, 1H), 7.83 (m, 2H), 7.73 (d, J = 5.4 Hz, 1H), 7.50 (m, 1H), 3.85 (t, J = 5.1 Hz, 4H), 2.66 (t, J = 4.8 Hz, 4H), 2.40 (s, 3H). MS m/z: 318 (M+H+).
Figure imgf000187_0001
EXAMPLE 150
8-Chloro-2-methyl-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline
Figure imgf000187_0002
Ethyl 2-(5-chloro-lH-indol-3-yl)-2-oxoacetate:
[0512] A 500 mL 3-necked round bottom flask was charged with 5- chloroindole (15.2 g, 0.10 mol), pyridine (10.5 mL) and anhydrous ethyl ether (200 mL). To the above was added dropwise a solution of ethyl oxalylchloride (16.4 g, 0.12 mol) in anhydrous ethyl ether (50 mL) at 0-5 °C. The resulting mixture was stirred at 0 °C for 1 h. Reaction progress was monitored by TLC (EtOAc/Petroleum ether = 1 : 1, Rf = 0.3). Work-up: the mixture was concentrated in vacuo. The resulting solid was washed with a small amount of ethyl ether, then with water, and dried, to give 19.3 g (77%) of the product. MS m/z: 252 (M+H+). Step 2
Figure imgf000188_0001
8-Chloro-2-methyl-2H-pyrazolo[3,4-c1quinolin-4(5H)-one:
[0513] A 250 mL round bottom flask was charged with ethyl 2-(5-chloro-lH- indol-3-yl)-2-oxoacetate (3 g, 12 mmol), methylhydrazine hydrochloride salt (3 g, 16 mmol), absolute ethanol (150 mL) and acetic acid (3 mL). The resulting mixture was heated at reflux for 24 h. Work-up: the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel with a 1 :40 MeOH/CH2Cl2, to give 2.2 g (79%) of the product. *H NMR (300 MHz,
DMSO-d6) δ: 11.43 (s, 1H), 8.68 (s, 1H), 7.99 (s,lH), 7.39-7.30 (m, 2H), 4.12 (s, 3H). MS m/z: 234 (M+H+).
Step 3
Figure imgf000188_0002
4,8-Dichloro-2-methyl-2H-pyrazolo[3,4-c]quinoline:
[0514] A 100 mL round bottom flask was charged with 8-chloro-2-methyl-2H- pyrazolo[3,4-c]quinolin-4(5H)-one (2.2 g, 9.4 mmol), PC15 (0.28 g, 1.9 mmol) and POCI3 (40 mL). The resulting mixture was heated at reflux for 2 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 : 10, Rf = 0.3). Workup: POCI3 was evaporated under reduced pressure. The residue was carefully poured into ice-cooled saturated aqueous NaHCC>3 (100 mL) and extracted with CH2C12 (50 mL x 4). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a 1 :4 EtOAC/Petroleum ether, to give 1.67 g (70%) of the product. MS m/z: 253 (M+H+). Step 4
Figure imgf000189_0001
8-Chloro-2-methyl-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline:
[0515] A 100 mL round bottom flask was charged with 4,8-dichloro-2-methyl- 2H-pyrazolo[3,4-c]quinoline (0.504 g, 2 mmol), N-methylpiperazine (0.6 g, 6 mmol), Et3N (0.84 mL, 6.1 mmol) and absolute ethanol (35 mL). The resulting mixture was heated at reflux for 24 h. Work-up: the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with a 1 :20 MeOH/CILC^, to give 300 mg (47%) of the product. *H NMR (300 MHz, CD3OD) δ: 8.44 (s, 1H), 7.84 (d, J = 2.7 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.30 (dd, J = 8.7, 2.4 Hz, 1H), 4.36 (br, 4H), 4.18 (s, 3H), 2.91 (t, J = 5.1 Hz, 4H), 2.57 (s, 3H). MS m/z: 316 (M+H+).
EXAMPLE 151
8-Chloro-2-methyl-4-(piperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline
Figure imgf000189_0002
[0516] The HC1 salt of the title compound was prepared as described in Example 150, except that tert-butyl piperazine-l-carboxylate was substituted for N- methylpiperazine in step 4 of that route. The resulting tert-butyl 4-(8-chloro-2- methyl-2H-pyrazolo[3,4-c]quinolin-4-yl)piperazine-l-carboxylate was treated with 3 M HC1 in methanol solution overnight at room temperature. The solid was collected by filtration, washed with methanol, and dried, to afford the HC1 salt of the title compound as white solid. *H NMR (300 MHz, DMSO-d6) δ: 9.83 (br, 2H), 9.04 (s, 1H), 8.35 (m, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.57 (dd, J = 8.7, 2.1 Hz, 1H), 4.72 (br, 4H), 4.22 (s, 3H), 3.78 (m, 4H). MS m/z: 288 (M+H+). SCHEME 52
Figure imgf000190_0001
EXAMPLE 152
8-Chloro-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline
Figure imgf000190_0002
(4-Methoxybenzyl)hydrazine HC1 salt:
A 500 mL 3 -necked round bottom flask was charged with hydrazine hydrate (40 g, 0.80 mol) and EtOH (280 mL). To the above solution was added dropwise a solution of 4-methoxybenzylchloride (12.5 g, 0.080 mol) in EtOH (30 mL) at room temperature. The resulting mixture was stirred at 90 °C for 2 h. Work-up: the reaction mixture was concentrated in vacuo then re-dissolved in EtOH (150 mL). The solution was acidified with 5 M HCl (120 mL) at 0 °C. The resulting precipitate was collected by filtration and dried to afford 8.72 g (72%) of the product as white solid. MS m/z: 153 (M+H+).
Steps 2-3
Figure imgf000191_0001
8-Chloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinolin-4(5H)-one:
[0517] The title compound was prepared as described in Example 150, except that (4-methoxybenzyl)hydrazine HCl salt was substituted for methylhydrazine HCl salt in step 2 of that route. *H NMR (300 MHz, DMSO-d6) δ: 11.43 (s, 1H), 8.77 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.38-7.29 (m, 4H), 6.96-6.93 (m, 2H), 5.52 (s, 2H), 3.74 (s, 3H). MS m/z: 340 (M+H+).
Step 4
Figure imgf000191_0002
4,8-Dichloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinoline:
[0518] The title compound was prepared as described in Example 150, except that 8-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinolin-4(5H)-one was substituted for 8-chloro-2-methyl-2H-pyrazolo[3,4-c]quinolin-4(5H)-one in step 3 of that route. MS m/z: 359 (M+H+). Step 5
Figure imgf000192_0001
8-Chloro-2-(4-methoxybenzyl)-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4- c]quinoline:
[0519] The title compound was prepared as described in Example 150, except that 4,8-dichloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinoline was substituted for 4,8-dichloro-2-methyl-2H-pyrazolo[3,4-c]quinoline in step 4 of that route. *H NMR (300 MHz, DMSO-d6) δ: 8.20 (s, 1H), 7.83 (s, 1H), 7.52 (m, 1H), 7.38-7.22 (m, 3H), 6.88 (m, 2H), 5.52 (s, 2H), 4.29 (m, 4H), 3.74 (s, 3H), 2.66 (m, 4H), 2.38 (s, 3H). MS m/z: 422 (M+H+).
Step 6
Figure imgf000192_0002
8-Chloro-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline:
[0520] A 50 mL 3-necked round bottom flask was charged with 8-chloro-2-(4- methoxybenzyl)-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline (1.28 g, 3.0 mmol), trifluoroacetic acid (30 mL), anisole (881 mg, 8.2 mmol) and concentrated H2SO4 (0.45 mL). The resulting mixture was stirred at 0 °C for 2 h and then at 50 °C overnight. Work-up: the reaction solution was added dropwise to an ice-cooled saturated aqueous Na2CC>3 (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a 1 :20 MeOH/CH2Cl2, to afford 400 mg (44%) of the product. *H NMR (300 MHz, CD3OD) δ: 8.57 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.33 (dd, J = 8.7, 2.4 Hz, 1H), 4.22 (m, 4H), 2.64 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 302 (M+H+).
Figure imgf000193_0001
EXAMPLE 153
8-Chloro-4-(piperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline
Figure imgf000193_0002
[0521] The title compound was prepared as described in Example 152, except that tert-butyl piperazine-l-carboxylate was substituted for N-methylpiperazine in step 5 of that route. *H NMR (300 MHz, CD3OD) δ: 8.93 (s, 1H). 8.24 (d, J = 2.1 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.60 (dd, J = 8.7, 2.1 Hz, 1H), 3.62 (m, 4H), 3.30 (m, 4H). MS m/z: 288 (M+H+).
SCHEME 54
Figure imgf000193_0003
EXAMPLE 154
4-(8-Chloro-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-yl)-l,l-dimethylpiperazin-
1-ium
Figure imgf000194_0001
4-(8-Chloro-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-yl)-l,l-dimethylpiperazin- 1-ium:
[0522] A 25 rriL 3-necked round bottom flask was charged with 8-chloro-4-(4- methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline (152, 200 mg, 0.664 mmol) and KOH (372 mg, 6.64 mmol) and H20 (10 rriL). To the above was added drop wise a solution of dimethyl sulfate (418 mg, 3.32 mmol) in acetone (2 mL). The resulting mixture was stirred at room temperature for 0.5 h. Reaction progress was monitored by TLC (MeOH/CH2Cl2 = 10:1, Rf = 0.3). Work-up: the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 100 mg (46%) of the product. *H NMR (300 MHz, DMSO-d6) δ: 8.91 (s, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 8.7, 2.4 Hz, 1H), 4.55 (br, 4H), 4.22 (s, 3H), 3.60 (m., 4H), 3.24 (s, 6H). MS m/z: 330 (M+H+).
Figure imgf000195_0001
EXAMPLE 155
2-Methyl-4-(4-methylpiperazinyl)-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline
Figure imgf000195_0002
[0523] The title compound was prepared as described in Example 150, except that 5-trifluoromethylindole was substituted for 5-chloroindole in step 1 of that route. *H NMR (300 MHz, CD3OD) δ: 8.57 (s, 1H), 8.18 (s, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 4.36-4.32 (m, 4H), 4.21 (s, 3H), 2.64-2.61 (m, 4H), 2.36 (s, 3H). MS m/z: 350 (M+H+).
EXAMPLE 156
2-Methyl-4-piperazinyl-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline HCl salt
Figure imgf000195_0003
[0524] The title compound was prepared as described in Example 155, except that piperazine was substituted for N-methylpiperazine in step 4 of that route.1H NMR (300 MHz, CD3OD) δ: 8.98 (s, 1H), 8.51 (s, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 4.34 (s, 3H), 3.66-3.63 (m, 4H), 3.31-3.29 (m, 4H). MS m/z: 336 (M+H+).
Figure imgf000196_0001
EXAMPLE 157
4-(4-Methylpiperazinyl)-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline
Figure imgf000196_0002
(4-Methoxybenzyl)hydrazine:
[0525] The HCl salt of the title compound was prepared as described in Example 152. Step 2
Figure imgf000197_0001
2-Iodo-4-(trifluoromethyl)aniline:
[0526] A 500 mL 3-necked round bottom flask was charged with 4- (trifluoromethyl)aniline (22.5 g, 0.14 mol) and MeOH (100 mL). To the above was added dropwise a solution of ICl (25 g, 0.15 mol) in CH2C12 (100 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 : 10, Rf = 0.5). Work-up: the mixture was concentrated in vacuo. The residue was re-dissolved in CH2C12, washed with water, dried over anhydrous Na2S04 and concentrated in vacuo, to give 37.8 g (97%) of the product. *H NMR (300 MHz, CDC13) δ: 7.86 (d, J = 1.2 Hz, 1H), 7.36 (dd, J = 8.4, 1.8 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 4.41 (br, 2H).
Step 3
Figure imgf000197_0002
Ethoxy-N-[2-iodo-4-(trifluoromethyl)phenyl]carboxamide:
[0527] A 500 mL 3-necked round bottom flask was charged with 2-iodo-4- (trifluoromethyl)aniline (63 g, 0.22 mol) and pyridine (300 mL). To the above was added dropwise ethyl chloroformate (36 g, 0.33 mol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :20, Rf = 0.5). Work-up: the mixture was concentrated in vacuo. The residue was re-dissolved in CH2C12, washed with saturated NH4C1, dried over anhydrous Na2S04 and concentrated in vacuo, to give 43.5 g (55%) of the product. MS m/z: 358 (M-H+). Step 4
Figure imgf000198_0001
N-[2-(3,3-Dimethyl-3-silabut-l-ynyl)-4- (trifluoromethyl)phenyl]ethoxycarboxamide:
[0528] A 250 mL 3-necked round bottom flask was charged with ethoxy-N-[2- iodo-4-(trifluoromethyl)phenyl]carboxamide (50 g, 0.14 mol), Cul (1.5 g, 7.87 mmol), (l,l '-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (5.0 g, 7.2 mmol), Et3N (200 mL) and THF (400 mL). To the above was added dropwise 2,2- dimethyl-2-silabut-3-yne (21.7 mL, 0.15 mol). The resulting mixture was stirred at room temperature for 0.5 h under N2 atmosphere. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :20). Work-up: the mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 5% EtOAc in petroleum ether, to afford 31.5 g (74%) of the product. !H NMR (300 MHz, DMSO-d6) δ: 8.28 (d, J = 8.7 Hz, 1H), 7.64 (m, 1H), 7.55 (m, 2H), 4.26 (q, J = 6.9 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H), 0.31 (s, 9H).
Step 5
Figure imgf000198_0002
5- (Trifluoromethyl)indole :
[0529] A 250 mL 3-necked round bottom flask was charged with N-[2-(3,3- dimethyl-3-silabut-l-ynyl)-4-(trifluoromethyl)phenyl]ethoxycarboxamide (31.5 g, 0.1 mol), EtONa (32.5 g, 0.48 mol) and ethanol (200 mL). The resulting mixture was heated at reflux for 2 h. Work-up: the mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 25% EtOAc in petroleum ether, to afford 14 g (77%) of the product. !H NMR (300 MHz, DMSO-d6) δ: 8.36 (s, IH), 7.96-7.94 (m, IH), 7.46-7.44 (m, 2H), 7.32-7.30 (m, IH), 6.66-6.64 (m, IH).
Steps 6-9
Figure imgf000199_0001
4-(4-Methylpiperazinyl)-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline:
[0530] The HC1 salt of the title compound was prepared as described in Example 152, except that 5-(trifluoromethyl)indole was substituted for 5- chloroindole in step 2 of that route. *H NMR (300 MHz, D20) δ: 8.52-8.50 (m, IH), 8.12-8.10 (m, IH), 7.72-7.69 (m, IH), 7.62-7.59 (m, IH), 5.38-5.35 (m, 2H), 3.74- 3.71 (m, 4H), 3.32-3.28 (m, 2H), 2.87 (s, 3H). MS m/z: 336 (M+H+).
Figure imgf000199_0002
EXAMPLE 158
8-Chloro-l-methyl-4-(piperazin-l-yl)-lH-imidazo[4,5-c]quinoline
Figure imgf000200_0001
Step 1
Figure imgf000200_0002
5-Chloro-2-(2-nitroethylideneamino)benzoic acid:
[0531] A 100 mL round bottom flask was charged with NaOH (2.33 g, 0.058 mol) and H20 (10 mL). To the above was added dropwise nitromethane (3.1 mL, 3.56 g, 0.058 mol) at room temperature. The resulting solution was slowly warmed to 45 °C for 5 min then cooled to 0 °C and acidified with concentrated HCl. It was added to a suspension of 2-amino-5-chlorobenzoic acid (5.0 g, 0.029 mol) in concentrated HCl (50 mL) and H20 (20 mL). The reaction solution was allowed to stand overnight at room temperature. The solid was collected by filtration, washed with H20, and dried, to afford 4.7 g (66%) of the product.
Step 2
Figure imgf000200_0003
6-Chloro-3-nitroquinolin-4-ol:
[0532] A 500 mL round bottom flask was charged with 5-chloro-2-(2- nitroethylideneamino)benzoic acid (25 g, 0.10 mol), K2CO3 (42.6 g, 0.30 mol) and acetic anhydride (250 mL). The resulting mixture was heated to 90 °C for 1 h. Work-up: the resulting solid was collected by filtration, washed with water and dried to give 17.5 g (76%) of the product as grey solid. !H NMR (300 MHz, DMSO-d6) δ: 9.12 (s, 1H), 8.15 (s, 1H), 7.72 (s, 2H). MS m/z: 224 (M+H+).
Step 3
Figure imgf000201_0001
4,6-Dichloro-3-nitroquinoline:
[0533] A 500 mL round bottom flask was charged with 6-chloro-3- nitroquinolin-4-ol (2.41 g, 10.8 mmol), acetonitrile (50 mL), N,N- diisopropylethylamine (2.49 g, 21.6 mmol) and POCI3 (1.5 mL, 16.2 mmol). The resulting solution was heated at reflux for 1 h. Work-up: the solvent was removed, and the residue was purified by flash column chromatography on silica gel with a 1 : 15 EtO Ac/Petroleum ether, to give 2.0 g (77%) of the product as white solid. JH NMR (300 MHz, CDC13) δ: 9.23 (s, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.89 (dd, J = 9.0, 2.4 Hz, 1H).
Step 4
Figure imgf000201_0002
6-Chloro-N-methyl-3-nitroquinolin-4-amine:
[0534] A 100 mL round bottom flask was charged with 4,6-dichloro-3- nitroquinoline (2.0 g, 8.3 mmol) and THF (50 mL). To the above was added methylamine (2 M in THF, 6.2 mL) at 0 °C. The resulting solution was stirred at room temperature for 1 h. Work-up: the solvent was removed. The residue was dissolved in CH2CI2 (300 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo. It was further purified by flash column chromatography on silica gel with a 1 :2:2 EtO Ac/Petroleum ether/CH2Cl2, to give 1.8 g (91 ) of the product as yellow solid. MS m/z: 238 (M+H+).
Step 5
Figure imgf000202_0001
6-Chloro-N4-methylquinoline-3,4-diamine:
[0535] A 100 mL round bottom flask was charged with 6-chloro-N-methyl-3- nitroquinolin-4-amine (1.1 g, 4.6 mmol), sodium dithionite (1.62 g, 9.2 mmol), water (10 mL) and EtOH (50 mL). The resulting mixture was heated at reflux for 1 h. Work-up: the solvent was removed and the residue was washed with water (5 mL) and dried to afford 0.96 g (quantitative) of the product, which was used as such for the next step. MS m/z: 208 (M+H+).
Step 6
Figure imgf000202_0002
8-Chloro-l-methyl-lH-imidazo[4,5-c]quinoline:
[0536] A 100 mL round bottom flask was charged with 6-chloro-N4- methylquinoline-3,4-diamine (0.96 g, 4.6 mmol), HCOOH (30 mL) and concentrated HC1 (5 mL). The resulting mixture was heated at reflux for 30 min. Work-up: the solvent was removed. The residue was poured into 50% aqueous NaOH at 0 °C and extracted with CH2C12 (100 mL x 4). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. It was further purified by flash column chromatography on silica gel with 33% EtOAc in petroleum ether then 3% MeOH in CH2C12, to give 0.47 g (46%) of the product as white solid. *H NMR (300 MHz, CDC13) δ: 9.30 (s, 1H), 8.23 (d, J = 4.2 Hz, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.63 (d, J = 6.6 Hz, 1H), 4.28 (s, 3H). MS m/z: 218 (M+H+).
Step 7
Figure imgf000203_0001
8-Chloro-l-methyl-lH-imidazo[4,5-c]quinolin-4(5H)-one:
[0537] A 50 mL round bottom flask was charged with 8-chloro-l-methyl-lH- imidazo[4,5-c]quinoline (1.4 g, 6.46 mmol), 30% H2O2 (1.5 mL) and acetic acid (20 mL). The reaction mixture was stirred at 80 °C overnight then concentrated under reduced pressure. The residue was neutralized with saturated aqueous NaHCC>3 and the resulting precipitate was collected by filtration and dried. It was re-suspended in acetic anhydride (15 mL) and heated at reflux for 1 h. The solvent was removed and methanol (10 mL) was added to the residue, followed by dropwise addition of a solution of 28% sodium methoxide in methanol until PH 10. The solid was collected by filtration and dried to give 0.40 g (27%) of the product as yellow solid. *H NMR (300 MHz, DMSO-d6) δ: 11.70 (s, 1H), 8.12 (s, 1H), 8.05 (s, 1H), 7.53-7.44 (m, 2H), 4.17 (s, 3H). MS m/z: 234 (M+H+).
Step 8
Figure imgf000203_0002
4,8-Dichloro-l-methyl-lH-imidazo[4,5-c]quinoline:
[0538] A 50 mL round bottom flask was charged with 8-chloro-l-methyl-lH- imidazo[4,5-c]quinolin-4(5H)-one (0.20 g, 0.86 mmol) and POCl3 (5 mL). The mixture was heated at reflux for 1 h. Work-up: the solvent was removed under reduced pressure. The residue was treated with saturated aqueous Na2C03 at 0 °C, extracted with CH2CI2 (50 mL x 2), concentrated in vacuo and further purified by flash column chromatography on silica gel with 5% MeOH in CH2CI2, to give 0.12 g (56%) of the product as yellow solid. MS m/z: 252 (M+H+).
Step 9
Figure imgf000204_0001
8-Chloro-l-methyl-4-(piperazin-l-yl)-lH-imidazo[4,5-c]quinoline:
[0539] A 20 mL microwave reaction tube was charged with 4,8-dichloro-l- methyl-lH-imidazo[4,5-c]quinoline (0.21 g, 0.84 mmol), piperazine (0.14 g, 1.68 mmol) and EtOH (10 mL). The resulting mixture was heated at 140 °C for 2 h in a Biotage microwave reactor. Work-up: the solvent was removed. The residue was diluted with CH2CI2 (50 mL) and washed with water (30 mL x 2). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was then treated with 3 M HC1 (2.0 mL) and THF (20 mL). The resulting white solid was collected by filtration and dried, to give 160 mg (57%) of the HC1 salt of the product as white solid. *H NMR (300 MHz, D20) δ: 8.17 (s, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 9.3 Hz, 1H), 7.44 (dd, J = 9.0, 2.1 Hz, 1H), 4.53 (t, J = 5.4 Hz, 4H), 4.03 (s, 3H), 3.50 (t, J = 5.4 Hz, 4H). MS m/z: 302 (M+H+).
EXAMPLE 159
8-Chloro-l-methyl-4-(4-methylpiperazin-l-yl)-lH-imidazo[4,5-c]quinoline
Figure imgf000204_0002
[0540] The title compound was prepared as described in Example 158, except that N-methylpiperazine was substituted for piperazine in step 9 of that route. JH NMR (300 MHz, DMSO-d6) δ: 8.32 (s, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 8.7 Hz, IH), 7.54 (dd, J
MS m/z: 316 (M+H+).
Figure imgf000205_0001
EXAMPLE 160
8-Chloro-4-(4-methylpiperazin-l-yl)-lH-imidazo[4,5-c]quinoline
Figure imgf000205_0002
6-Chloro-N-(2,4-dimethoxybenzyl)-3-nitroquinolin-4-amine:
[0541] The title compound was prepared as described in Example 158, except that 2,4-dimethoxybenzylamine was substituted for methylamine in step 4 of that route. MS m/z: 373 (M+H+).
Step 2
Figure imgf000206_0001
6-Chloro-N4-(2,4-dimethoxybenzyl)quinoline-3,4-diamine:
[0542] The title compound was prepared as described in Example 158, except that 6-chloro-N-(2,4-dimethoxybenzyl)-3-nitroquinolin-4-amine was substituted for 6-chloro-N-methyl-3-nitroquinolin-4-amine in step 5 of that route.
Step 3
Figure imgf000206_0002
8-Chloro-l-(2,4-dimethoxybenzyl)-lH-imidazo[4,5-c1auinoline:
[0543] The title compound was prepared as described in Example 158, except that 6-chloro-N4-(2,4-dimethoxybenzyl)quinoline-3,4-diamine was substituted for 6-chloro-N4-methylquinoline-3,4-diamine, and methyl orthoformate for HCOOH and concentrated HC1 in step 6 of that route. Step 4
Figure imgf000207_0001
8-Chloro-l-(2,4-dimethoxybenzyl)-lH-imidazo[4,5-c]quinolin-4(5H)-one:
[0544] A 100 mL round bottom flask was charged with 8-chloro-l-(2,4- dimethoxybenzyl)-lH-imidazo[4,5-c]quinoline (2.10 g, 5.94 mmol), 3- chloroperbenzoic acid (1.23 g, 7.13 mmol) and CH2CI2 (50 mL). The resulting solution was stirred at room temperature for 3 h. Reaction progress was monitored by TLC (MeOH/CH2Cl2 = 1:20, Rf = 0.4). Work-up: the mixture was concentrated and the residue was purified by flash column chromatography on silica gel with a 1 :20 MeOH/CH2Cl2, to give 1.7 g (77%) of white solid, which was suspended in acetic anhydride (20 mL) and stirred at reflux for 1 h. The mixture was
concentrated and the residue was diluted with methanol (5 mL), followed by dropwise addition of a solution of 28% sodium methoxide in methanol until PH 10. The solid was collected by filtration and dried to give 1.5 (68%) of the product as white solid. *H NMR (300 MHz, DMSO-d6) δ: 8.17 (s, 1H), 7.60 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.68 (s, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 9.0 Hz, 1H), 5.61 (s, 2H), 3.94 (s, 3H), 3.71 (s, 3H).
Step 5
Figure imgf000207_0002
4,8-Dichloro-lH-imidazo[4,5-c]quinoline:
[0545] A 50 mL round bottom flask was charged with 8-chloro-l-(2,4- dimethoxybenzyl)-lH-imidazo[4,5-c]quinolin-4(5H)-one (0.80 g, 2.17 mmol), POCI3 (15 mL) and N,N-diisopropylethylamine (0.50 g, 4.34 mmol). The resulting mixture was stirred overnight at reflux. Work-up: the mixture was concentrated and the residue was purified by flash column chromatography on silica gel with a 1 :20 MeOH/CH2Cl2, to give 0.20 g (40%) of the product as white solid. MS m/z: 238 (M+H+).
Step 6
Figure imgf000208_0001
8-Chloro-4-(4-methylpiperazin-l-yl)-lH-imidazo[4,5-c]quinoline:
[0546] The title compound was prepared as described in Example 158, except that 4,8-dichloro-lH-imidazo[4,5-c]quinoline was substituted for 4,8-dichloro-l- methyl-lH-imidazo[4,5-c]quinoline, and N-methylpiperazine for piperazine in step 9 of that route. *H NMR (300 MHz, DMSO-d6) δ: 8.33 (s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 9.0, 2.7 Hz, 1H), 4.24 (br, 4H), 2.49 (m, 4H), 2.22 (s, 3H). MS m/z: 302 (M+H+).
EXAMPLE 161
8-Chloro-4-(piperazin-l-yl)-lH-imidazo[4,5-c]quinoline
Figure imgf000208_0002
[0547] The title compound was prepared as described in Example 160, except that piperazine was substituted for N-methylpiperazine in step 6 of that route. 1H NMR (300 MHz, CD3OD) δ: 8.18 (s, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 9.0, 2.4 Hz, 1H), 4.15 (t, J = 5.0 Hz, 4H), 3.03 (t, J = 5.1 Hz, 4H). MS m/z: 288 (M+H+).
Figure imgf000209_0001
EXAMPLE 162
8-Chloro-2-methyl-4-(4-methylpiperazinyl)imidazo[4,5-c]quinoline
Figure imgf000209_0002
[0548] The title compound was prepared as described in Example 160, except that triethyl orthoacetate was substituted for triethyl orthoformate in step 3 of that route. *H NMR (300 MHz, CD3OD) δ: 7.97 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.45 (dd, J = 9.0, 2.4 Hz, 1H), 4.88 (m, 4H), 3.39 (m, 4H), 2.92 (s, 3H), 2.64 (s, 3H). MS m/z: 316 (M+H+).
EXAMPLE 163
8-Chloro-2-methyl-4-piperazinylimidazo[4,5-c]quinoline
Figure imgf000210_0001
[0549] The title compound was prepared as described in Example 162, except that piperazine was substituted for N-methylpiperazine in step 6 of that route. 1H NMR (300 MHz, D20) δ: 7.49 (d, J = 9.0 Hz, 1H), 7.24 (dd, J = 9.0, 2.1 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 4.42 (t, J = 5.1 Hz, 4H), 3.45 (t, J = 5.1 Hz, 4H), 2.45 (s, 3 H). MS m/z: 302 (M+H+).
Figure imgf000210_0002
EXAMPLE 164
8-chloro-2-methyl-4-(piperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline
Figure imgf000211_0001
5-Chloro-2-nitrophenylhydrazine:
[0550] A 500 mL round bottom flask was charged with 5-chloro-2-nitroaniline (17.25 g, 0.1 mol) and 6 N HCl (100 mL). To the above was added dropwise a solution of NaN02 (7.7 g, 0.105 mol) in water (30 mL) at 0-5 °C and the resulting mixture was stirred for 1 h. The diazotized solution was filtered and added slowly with stirring to an ice cold solution of SnCl2 (56.4 g, 0.25 mol) in concentrated HCl (70 mL). The reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :4, Rf = 0.3). Work up: the yellow precipitate was collected by filtration, then partitioned between EtOAc (300 mL) and saturated aqueous NaOAc solution (200 mL). The organic layer was separated, dried over anhydrous MgS04, and concentrated in vacuo, to give 8.4 g (45 ) of the product. !H NMR (300 MHz, CDC13) δ: 8.94 (s, 1H), 8.06 (d, J = 10.8 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 6.66- 6.62 (m, 1H), 3.81 (s, 2H).
Step 2
Figure imgf000212_0001
((lZ)-2-Amino-l-azaprop-l-enyl)(5-chloro-2-nitrophenyl)amine:
[0551] A 250 mL round bottom flask was charged with 5-chloro-2- nitrophenylhydrazine (8.06 g, 0.043 mol), ethyl acetimidate hydrochloride (5.3 g, 0.043 mol) and pyridine (120 mL). The resulting mixture was stirred at room temperature overnight. The reaction progress was monitored by TLC
(EtO Ac/Petroleum ether = 1 :1, Rf = 0.4). Work up: the solvent was evaporated under reduced pressure. The residue was partitioned between EtO Ac (200 mL) and saturated aqueous Na2C03 solution (200 mL). The organic layer was separated, dried over anhydrous MgS04, and concentrated in vacuo, to give 6.4 g (65 ) of the product. *H NMR (300 MHz, CDC13) δ: 9.56 (s, 1H), 8.07 (d, J = 9.0 Hz 7.54 (d, J = 2.4 Hz, 1H), 6.66 (dd, J = 9.0, 2.1 Hz, 1H), 4.73 (s, 2H), 2.10 (s, MS m/z: 229 (M+H+).
Step 3
Figure imgf000212_0002
Ethyl (N-{(lZ)-2-[(5-chloro-2-nitrophenyl)amino]-l-methyl-2- azavinyl}carbamoyl)formate:
[0552] A 500 mL round bottom flask was charged with (lZ)-2-amino-l- azaprop-l-enyl)(5-chloro-2-nitrophenyl)amine (6.4 g, 28 mmol) and ethyl ether (25 mL). To the above was added dropwise a solution of ethyl 2- (chlorocarbonyl)acetate (7.65 g, 56 mmol) in ethyl ether (20 mL) at room temperature. The resulting mixture turned yellow from red. The reaction mixture was stirred at room temperature for 1 h, then mixed with anhydrous toluene (200 mL) and heated at reflux for 1 h. Work up: the reaction mixture was filtered. The filtrate was concentrated in vacuo, to give 4.2 g of the product, which was used directly in the next step without further purification.
Step 4
Figure imgf000213_0001
Ethyl l-(5-chloro-2-nitrophenyl)-3-methyl-l,2,4-triazole-5-carboxylate:
[0553] A 50 mL round bottom flask was charged with ethyl (N-{ (1Ζ)-2-[(5- chloro-2-nitrophenyl)amino]-l-methyl-2-azavinyl}carbamoyl)formate (4.2 g). It was heated at 180 °C for 1 h under N2. The reaction progress was monitored by TLC (EtOAc/Petroleum ether = 1 : 1 , Rf = 0.3). Work up: the cooled mass was dissolved in CH2C12 (100 mL), washed with 0.5 N KOH solution (20mL) and brine (30 mL) subsequently. The organic layer was dried over anhydrous MgS04 and concentrated in vacuo. The residue was further purified by flash column
chromatography on silica gel with a 1 :6 EtO Ac/Petroleum ether, to give 1.8 g of the product. *H NMR (300 MHz, CDC13) δ: 8.20 (d, J = 8.7 Hz, 1H), 7.66 (dd, J = 9.3, 2.4 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 4.38-4.31 (m, 2H), 2.53 (s, 3H), 1.37-1.25 (m, 3H).
Step 5
Figure imgf000213_0002
8-chloro-2-methyl-[l,2,4]triazolo[l,5-a]quinoxalin-4(5H)-one:
[0554] A 100 mL round bottom flask was charged with ethyl l-(5-chloro-2- nitrophenyl)-3-methyl-l,2,4-triazole-5-carboxylate (1.8 g, 5.8 mmol), iron powder (5.87 g, 87 mmol) and HO Ac (40 mL). The resulting mixture was heated at 90 °C for 1 h. Work up: the reaction mixture was filtered. The filtrate was concentrated in vacuo and mixed with 6 N HC1 (50 mL). The precipitate formed was collected by filtration and dried, to give 0.8 g of the product which was used directly in the next step without further purification. MS m/z: 233 (M-H+).
Step 6
Figure imgf000214_0001
4,8-dichloro-2-methyl-[l,2,4]triazolo[l,5-a]quinoxaline:
[0555] The title compound was prepared as described in Example 92, except that 8-chloro-2-methyl-[l,2,4]triazolo[l,5-a]quinoxalin-4(5H)-one was substituted for 9-chloro-[l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one in step 3 of that route. 1H NMR (300 MHz, CDC13) δ: 8.39 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.65 (dd, J = 9.0, 2.4 Hz, 1H), 2.75 (s, 3H).
Step 7
Figure imgf000214_0002
8-chloro-2-methyl-4-(piperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline:
[0556] The title compound was prepared as described in Example 92, except that 4,8-dichloro-2-methyl-[l ,2,4]triazolo[l,5-a]quinoxaline was substituted for 5,9-dichloro-[l,2,4]triazolo[l,5-c]quinazoline in step 1 of that route. !H NMR (300 MHz, CD3OD) δ: 8.16-8.15 (m, 1H), 7.62-7.59 (m, 1H), 7.41-7.37 (m, 1H), 4.33- 4.30 (m, 4H), 3.07-3.04 (m, 4H), 2.64 (s, 3H). MS m/z: 303 (M+H+). EXAMPLE 165
8-chloro-2-methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline
Figure imgf000215_0001
[0557] The title compound was prepared as described in Example 164, except that N-methylpiperazine was substituted for piperazine in step 7 of that route. 1H NMR (300 MHz, CD3OD) δ: 8.17 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.40 (dd, J = 8.7, 2.4 Hz, 1H), 4.38-4.35 (m, 4H), 2.64 (s, 3H), 2.61-2.58 (m, 4H), 2.37 (s, 3H). MS m/z: 317 (M+H+).
SCHEME 61
Figure imgf000215_0002
EXAMPLE 166
8-Chloro-4-(4-methylpiperazin-l-yl)isoxazolo[3,4-c]quinoline
Figure imgf000216_0001
Step 1
Figure imgf000216_0002
Ethyl chlorooximidoacetate:
[0558] A 250 mL round bottom flask was charged with glycine ethyl ester hydrochloride (40 g, 0.29 mol), concentrated HCl (24 mL, 0.29 mol) and water (55 mL). To the above was added dropwise a solution of sodium nitrite (20 g, 0.29 mol) in water (30 mL) at -5 °C. A second equivalent of hydrochloric acid and sodium nitrite were then added in the same manner. The resulting mixture was stirred at -5 °C for 20 min then extracted with ethyl ether (250 mL). The extract was dried over anhydrous MgS04 and concentrated in vacuo. The yellowish oil residue was crystallized from hexane to afford 17 g (39%) of the product as white crystals. JH
NMR (300 MHz, CDC13) δ: 9.92 (br, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDC13) δ: 158.5, 132.9, 63.8, 13.9.
Step 2
Figure imgf000216_0003
Ethyl 2-(5-chloro-2-nitrophenyl)acetate:
[0559] A 500 mL round bottom flask was charged with potassium t-butoxide (17.8 g, 0.16 mol) and dry DMF (200 mL). To the above was added dropwise a solution of 1 -chloro-4-nitrobenzene (10 g, 0.063 mol) and ethyl chloroacetate (7.1 mL, 0.067 mol) in dry DMF (50 mL) at -5 °C. The resulting dark-blue mixture was stirred at -5 °C for further 20 min then poured into 1 M HCl (500 mL) and extracted with ethyl ether (100 mL x 5). The combined organic layers were washed with saturated aqueous NaHCC>3 (250 mL) and brine (250 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 2-4% ethyl ether in petroleum ether, to afford 11.8 g (76%) of the product as orange oil. *H NMR (300 MHz, CDC13) δ: 8.06 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.8, 2.3 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.98 (s, 2H), 1.24 (t, J = 7.1 Hz, 3H). MS m/z: 242 (M-
H+).
Step 3
Figure imgf000217_0001
2-(5-Chloro-2-nitrophenyl)acetaldehyde:
[0560] A 250 mL 3-necked round bottom flask was charged with ethyl 2-(5- chloro-2-nitrophenyl)acetate (2.0 g, 8.2 mmol) and dry ethyl ether (50 mL). To the above was added drop wise a solution of 1.5 M diisobutylaluminum hydride in toluene (11 ml, 16.5 mmol) at -78 °C. The resulting mixture was stirred at -78 °C for further 1 h then quenched by slow addition of methanol (10 mL). The mixture was poured into 1 M HCl (200 mL) and extracted with ethyl ether (100 mL x 2). The combined organic layers were washed with saturated aqueous NaHCC>3 (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 4-20% ethyl ether in petroleum ether, to afford 1.1 g (70%) of the product as orange oil. *H NMR (300 MHz, CDC13) δ: 9.83 (t, J = 0.7 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 8.8, 2.3 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 4.13 (s, 2H). MS m/z: 198 (M-H+). Steps 4-6
Figure imgf000218_0001
Ethyl 4-(5-chloro-2-nitrophenyl)isoxazole-3-carboxylate:
[0561] A I L round bottom flask was charged with 2-(5-chloro-2- nitrophenyl)acetaldehyde (8.5 g, 43 mmol), pyrrolidine (4.3 mL, 51 mmol), crushed 4A molecular sieves (18 g) and dry toluene (50 mL). The reaction mixture was stirred for 2 h at room temperature under N2 and developed a dark-red color.
[0562] To the above dark-red mixture were added Et3N (12 mL, 86 mmol) and THF (150 mL), followed by a very slow addition in the dark of a solution of ethyl chlorooximidoacetate (13 g, 86 mmol) in THF (250 mL). The resulting mixture was stirred in the dark overnight at room temperature, and then filtered and concentrated in vacuo.
[0563] The residue was added to EtOH (150 mL) and concentrated HC1 (36 mL, 0.43 mol). The resulting mixture was stirred at 50 °C overnight then concentrated in vacuo. It was poured into saturated aqueous NaHCC>3 (300 mL) and extracted with CHCI3 (100 mL x 5). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 40-100% CH2C12 in petroleum ether, to afford 8.8 g (70%) of the product as dark-red oil. *H NMR (300 MHz, CDCI3) δ: 8.59 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.8, 2.2 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ: 159.3, 157.3, 152.9, 146.6, 139.7, 132.6, 129.9, 126.6, 125.2, 118.1, 62.5, 13.8. Step 7
Figure imgf000219_0001
8-Chloroisoxazolo[3,4-c]quinolin-4(5H)-one:
[0564] A 250 mL round bottom flask was charged with ethyl 4-(5-chloro-2- nitrophenyl)isoxazole-3-carboxylate (3.4 g, 11 mmol), Na2S204 (85% purity, 4.7 g, 23 mmol), EtOH (120 mL) and H20 (50 mL). The resulting mixture was stirred at reflux overnight and then concentrated in vacuo. The residue was mixed with saturated aqueous NaHC03 (200 mL) and extracted with CHC13 (100 mL x 5). The combined organic layers were dried over anhydrous Na2S04 then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 5-20% MeOH in CH2C12, to afford 1.2 g (47%) of the product as white solid. *H NMR (300 MHz, DMSO-d6) δ: 11.83 (br, 1H), 10.05 (s, 1H), 8.14 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H).
Step 8
Figure imgf000219_0002
4,8-Dichloroisoxazolo[3,4-c]quinoline:
[0565] A 100 mL round bottom flask was charged with 8-chloroisoxazolo[3,4- c]quinolin-4(5H)-one (1.2 g, 5.5 mmol) and POCI3 (50 mL). After N,N- diisopropylethylamine (0.95 mL, 5.5 mmol) was added dropwise at 0 °C, the resulting mixture was refluxed overnight (16 h) and then concentrated under reduced pressure. The residue was carefully diluted with saturated aqueous NaHC03 (150 mL), then extracted with CH2C12 (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04 then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with CH2C12 (containing 1% Et3N), to afford 0.50 g (38%) of the product as light- yellow solid. *H NMR (300 MHz, CDC13) δ: 9.47 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 8.9, 2.4 Hz, 1H).
Step 9
Figure imgf000220_0001
8-Chloro-4-(4-methylpiperazin-l-yl)isoxazolo[3,4-c]quinoline:
[0566] A 20 mL microwave reaction tube was charged with 4,8- dichloroisoxazolo[3,4-c]quinoline (200 mg, 0.84 mmol), N-methylpiperazine (0.28 mL, 2.5 mmol) and THF (10 mL). The tube was sealed and heated at 90 °C for 1 h in a Biotage microwave reactor. Work-up: the reaction mixture was poured into saturated aqueous NaHC03 (100 mL) and extracted with CH2C12 (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with CH2C12 (saturated with N¾), to afford 150 mg (59%) of the product as tan solid. *H NMR (300 MHz, CD3OD) δ: 9.73 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 4.23 (m, 4H), 2.62 (m, 4H), 2.36 (s, 3H). MS m/z: 303 (M+H+).
EXAMPLE 167
8-Chloro-4-(piperazin-l-yl)isoxazolo[3,4-c]quinoline
Figure imgf000220_0002
[0567] The title compound was prepared as described in Example 166, except that piperazine was substituted for N-methylpiperazine in step 9 of that route. JH NMR (300 MHz, CD3OD) δ: 9.72 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 4.18 (m, 4H), 2.97 (m, 4H). MS m/z: 289 (M+H+).
EXAMPLE 168
7,8-dichloro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000221_0001
[0568] The title compound was prepared as described in Example 39, except that piperazine was substituted for N-methylpiperazine in step 3 of that route.
NMR (300 MHz, CD3OD) δ: 9.70 (s, 1H), 8.22 (s, 1H), 7.62 (s, 1H), 4.41-4.38 (m, 4H), 3.08 (t, J = 5.4 Hz, 4H). MS m/z: 323 (M+H+).
EXAMPLE 169
9-fluoro-4-(piperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000221_0002
[0569] The title compound was prepared as described in Example 236, except that piperazine was substituted for N-methylpiperazine in step 8 of that route.
NMR (300 MHz, CDC13) δ: 9.40 (d, J = 2.4 Hz, 1H), 7.61 (t, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.55 (br, 4H), 3.08 (t, J = 5.4 Hz, 4H). MS m/z: 341 (M+H+).
Figure imgf000222_0001
EXAMPLE 170
6-fluoro-4-(4-methylpiperazin-l-yl)-7-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline:
Figure imgf000222_0002
[0570] The title compound was prepared as described in Example 21, except that 2,3-dichloro-5-fluoro-6-(trifluoromethyl)quinoxaline (prepared as described in Example 132, step 7) was substituted for 2,3-dichloro-6-methylquinoxaline as the starting material. *H NMR (300 MHz, DMSO-d6) δ: 10.08 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.64 (t, J = 6.9 Hz, 1H), 4.34 (br, 4H), 2.52 (m, 4H), 2.23 (s, 3H). MS m/z: 355 (M+H+).
Figure imgf000222_0003
EXAMPLE 171
9-Fluoro-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5- ajquinoxaline
Figure imgf000223_0001
[0571] The title compound was prepared as described in Example 27, except that 2,3-dichloro-5-fluoro-6-(trifluoromethyl)quinoxaline (prepared as described in Example 132, step 7) was substituted for 2,3-dichloro-6-
(trifluoromethyl)quinoxaline as the starting material. JH NMR (300 MHz, DMSO- d6) δ: 7.89 (t, J = 8.7 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 4.46 (br, 4H), 2.53 (t, J = 5.4 Hz, 4H), 2.24 (s, 3H). MS m/z: 356 (M+H+).
EXAMPLE 172
9-fluoro-4-(piperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline:
Figure imgf000223_0002
[0572] The title compound was prepared as described in Example 171, except that piperazine was substituted for N-methylpiperazine in step 1 of that route.
NMR (300 MHz, DMSO-d6) δ: 7.77 (t, J = 8.4 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 4.56 (m, 4H), 3.44 (m, 4H). MS m/z: 342 (M+H+).
EXAMPLE 173
8-isopropyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline:
Figure imgf000224_0001
[0573] The title compound was prepared as described in Examples 88 and 90, except that 2-(tributylstannyl)propene was substituted for tri-n-butyl(vinyl)tin as the coupling reactant. *H NMR (300 MHz, CDC13) δ: 9.17 (s, IH), 7.62 (d, J = 8.4 Hz, IH), 7.53 (s, IH), 7.37 (d, J = 8.7 Hz, IH), 4.44 (br, 4H), 3.06 (m, IH), 2.61 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H), 1.33 (d, J = 6.9 Hz, 6H). MS m/z: 310 (M+H+).
EXAMPLE 174
(E)-4-(4-methylpiperazin-l-yl)-8-(prop-l-enyl)-[l,2,4]triazolo[4,3- ajquinoxaline:
Figure imgf000224_0002
[0574] The title compound was prepared as described in Example 88, except that 1 -propenyltributyltin was substituted for tri-n-butyl(vinyl)tin as the coupling reactant. *H NMR (300 MHz, CDC13) δ: 9.14 (s, IH), 7.64-7.57 (m, 2H), 7.48 (m, IH), 6.53-6.45 (m, IH), 6.39-6.27 (m, 0.5 H), 5.95-5.84 (m, 0.5H), 4.48 (br, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.40 (s, 3H), 1.98-1.92 (m, 3H). MS m/z: 308 (M+H+).
EXAMPLE 175
4-(4-methylpiperazin-l-yl)-8-propyl-[l,2,4]triazolo[4,3-a]quinoxaline:
Figure imgf000225_0001
[0575] The title compound was prepared as described in Example 90, except that (E)-4-(4-methylpiperazin-l-yl)-8-(prop-l-enyl)-[l ,2,4]triazolo[4,3- ajquinoxaline (Example 174) was substituted for 4-(4-methylpiperazin-l-yl)-8- vinyl-[l,2,4]triazolo[4,3-a]quinoxaline (Example 88) as the starting material. JH NMR (300 MHz, CDC13) δ: 9.15 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 4.43 (br, 4H), 2.71 (t, J = 7.6 Hz, 2H), 2.60 (t, J = 4.8 Hz, 4H), 2.36 (s, 3H), 1.71 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). MS m/z: 310 (M+H+).
EXAMPLE 176
N-isopropyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxalin-8- amine:
Figure imgf000225_0002
[0576] A 50 mL round bottom flask was charged with 8-bromo-4-(4- methylpiperazin-l-yl)-[l ,2,4]triazolo[4,3-a]quinoxaline (Example 54, 0.20 g, 0.6 mmol), isopropylamine (1 mL), L-proline (0.13 g, 1.13 mmol), Cul (0.11 g, 0.6 mmol), K3PO4 (0.1 lg, 1.2 mmol) and DMSO (20 mL). The resulting mixture was heated at 90 °C overnight. Work-up: the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 5% MeOH in
CH2CI2, to afford 80 mg (43%) of the product as yellow solid. *H NMR (300 MHz, CDCI3) δ: 9.05 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 6.77 (s, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.31 (t, J = 4.8 Hz, 4H), 3.72 (m, 1H), 2.63 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H), 1.28 (d, J = 6.0 Hz, 6H). MS m/z: 326 (M+H+).
EXAMPLE 177
4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)imidazo[l,2-a]quinoxaline:
Figure imgf000226_0001
[0577] The title compound was prepared as described in Example 54, except that 4-(piperazin- 1 -yl)-8-(trifluoromethyl)imidazo[ 1 ,2-a]quinoxaline hydrochloride (EXAMPLE 178) was substituted for 8-bromo-4-piperazinyl-10-hydro- 1,2,4- triazolo[4,3-a]quinoxaline HCl salt (Example 52). *H NMR (300 MHz, CDC13) δ: 8.00 (d, J = 1.5 Hz, 1H), 7.90 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.65-7.59 (m, 2H), 4.52 (br, 4H), 2.63 (t, J = 4.8 Hz, 4H), 2.39 (s, 3H). MS m/z: 336 (M+H+).
EXAMPLE 178
4-(piperazin-l-yl)-8-(trifluoromethyl)imidazo[l,2-a]quinoxaline
hydrochloride:
Figure imgf000226_0002
[0578] The title compound was prepared as described as in Example 180, except that 4-(trifluoromethyl)benzene-l,2-diamine was substituted for 4-chloro-5- fluorobenzene- 1 ,2-diamine as the starting material.1H NMR (300 MHz, D20) δ:
8.10 (d, J = 1.5 Hz, 1H), 7.88 (s, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.54-7.47 (m, 2H), 4.34 (t, J = 5.1 Hz, 4H), 3.42 (t, J = 5.1 Hz, 4H). MS m/z: 322 (M+H+). EXAMPLE 179
8-chloro-7-fluoro-4-(piperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000227_0001
[0579] The title compound was prepared as described in Example 54, except that 8-chloro-7-fluoro-4-(piperazin-l-yl)imidazo[l,2-a]quinoxaline HCl salt (Example 180) was substituted for 8-bromo-4-piperazinyl-10-hydro- 1,2,4- triazolo[4,3-a]quinoxaline HCl salt (Example 52). *H NMR (300 MHz, CDC13) δ: 7.85 (d, J = 1.5 Hz, 1H), 7.67 (d, J = 6.9 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 10.2 Hz, 1H), 4.44 (t, J = 4.5 Hz, 4H), 2.58 (t, J = 5.1 Hz, 4H), 2.35 (s, 3H). MS m/z: 320 (M+H+).
Figure imgf000227_0002
EXAMPLE 180
8-chloro-7-fluoro-4-(piperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000228_0001
tert-butyl 4-(6-chloro-3-(2,2-diethoxyethylamino)-7-fluoroquinoxalin-2- yl)piperazine-l-carboxylate:
[0580] A 50 mL round bottom flask was charged with tert-butyl 4-(3,6- dichloro-7-fluoroquinoxalin-2-yl)piperazinecarboxylate (prepared as described in Example 31, 1.5 g, 3.6 mmol) and 2,2-diethoxyethylamine (10 mL). The resulting mixture was stirred at reflux for 1 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :5). Work-up: the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtO Ac (200 mL) and washed with brine (100 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo to afford the title compound.
Step 5
Figure imgf000228_0002
tert-butyl 4-(8-chloro-7-fluoroimidazo[l,2-a]quinoxalin-4-yl)piperazine-l- carboxylate: [0581] A 50 mL round bottom flask was charged with tert-butyl 4-{ 3-[(2,2- diethoxyethyl)amino]-6-chloro-7-fluoroquinoxalin-2-yl}piperazinecarboxylate from step 4, p-toluenesulfonic acid (1.37 g, 7.3 mmol) and isopropanol (25 mL). The resulting mixture was stirred at reflux for 1 h. Reaction progress was monitored by TLC (EtOAc/Petroleum ether = 1 :3). Work-up: the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtO Ac (200 mL) and washed with brine (100 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with a 1 :3 EtO Ac/Petroleum ether to afford the title compound.
Step 6
Figure imgf000229_0001
8-chloro-7-fluoro-4-(piperazin-l-yl)imidazo[l,2-a]quinoxaline:
[0582] The HC1 salt of the title compound was prepared as described in Example 52 step 6, except that tert-butyl 4-(8-chloro-7-fluoro-10- hydroimidazo[l,2-a]quinoxalin-4-yl)piperazinecarboxylate was substituted for tert- butyl 4-(8-bromo-10-hydro-l,2,4-triazolo[4,3-a]quinoxalin-4- yl)piperazinecarboxylate. *H NMR (300 MHz, CDC13) δ: 7.83 (d, J = 5.4 Hz, 1H), 7.66 (d, J = 6.9 Hz, 1H), 7.59 (s, 1H), 7.38 (d, J = 9.9 Hz, 1H), 4.34 (br, 4H), 3.02 (br, 4H). MS m/z: 306 (M+H+).
Figure imgf000230_0001
EXAMPLE 181
7,8-difluoro-4-(4-methylpiperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000230_0002
[0583] The title compound was prepared as described in Examples 37 and 179, except that 2,3-dichloro-6,7-difluoroquinoxaline was substituted for 2,3,7-trichloro- 6-fluoroquinoxaline in step 3 of that route. *H NMR (300 MHz, DMSO-d6) δ: 8.61 (d, J = 1.5 Hz, 1H), 8.38 (dd, J = 11.1, 7.8 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.56 (dd, J = 12.0, 8.1 Hz, 1H), 4.31 (br, 4H), 2.49 (m, 4H), 2.23 (s, 3H). MS m/z: 304 (M+H+).
EXAMPLE 182
7,8-difluoro-4-(piperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000230_0003
[0584] The title compound was prepared as described in Example 181, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CD3OD) δ: 8.29 (d, J = 1.5 Hz, 1H), 7.98 (dd, J = 11.1, 7.8 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.46 (dd, J = 11.7, 8.1 Hz, 1H), 4.29 (t, J = 5.1 Hz, 4H), 3.00 (t, J = 5.1 Hz, 4H). MS m/z: 290 (M+H+).
Figure imgf000231_0001
EXAMPLE 183
4-(piperazin-l-yl)-7-(trifluoromethyl)imidazo[l,2-a]quinoxaline hydrochloride
Figure imgf000231_0002
[0585] The title compound was prepared as described as in Example 178. It was separated from the other regio-isomer by flash column chromatography. JH NMR (300 MHz, DMSO-d6) δ: 9.60 (br, 2H), 8.83 (d, J = 1.8 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 1.5 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.70 (dd, J = 8.4, 1.8 Hz, 1H), 4.62 (br, 4H), 3.28 (br, 4H). MS m/z: 322 (M+H+).
Figure imgf000232_0001
EXAMPLE 184
8-bromo-7-fluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000232_0002
[0586] The HC1 salt of the title compound was prepared as described in Example 34, except that 4-bromo-3-fluoroaniline was substituted for 4-fluoro-3- methylaniline as the starting material. !H NMR (300 MHz, DMSO-d6) δ: 9.97 (s, 1H), 8.65 (d, J = 6.6 Hz, 1H), 7.46 (d, J = 10.5 Hz, 1H), 4.37 (br, 4H), 3.01 (t, J = 5.1 Hz, 4H). MS m/z: 351 (M+H+).
EXAMPLE 185
8-bromo-7-fluoro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000233_0001
[0587] The title compound was prepared as described in Example 54, except that 8-bromo-7-fluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline HCl salt (Example 184) was substituted for 8-bromo-4-piperazinyl-10-hydro- 1,2,4- triazolo[4,3-a]quinoxaline HCl salt (Example 52). *H NMR (300 MHz, DMSO-d6) δ: 9.95 (s, 1H), 8.62 (d, J = 6.6 Hz, 1H), 7.45 (d, J = 10.2 Hz, 1H), 4.32 (br, 4H), 3.29 (m, 4H), 2.22 (s, 3H). MS m/z: 365 (M+H+).
SCHEME 68
Figure imgf000233_0002
EXAMPLE 186
7-fluoro-4-(piperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline
Figure imgf000234_0001
[0588] The HCl salt of the title compound was prepared as described in Example 29, except that 5-fluoro-4-(trifluoromethyl)benzene-l,2-diamine (prepared according to Example 34) was substituted for 4-(trifluoromethyl)benzene-l,2- diamine as the starting material. *H NMR (300 MHz, DMSO-d6) δ: 9.59 (br, 1H), 8.64 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 11.7 Hz, 1H), 4.65-4.33 (m, 8H). MS m/z: 342 (M+H+).
EXAMPLE 187
7-fluoro-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5- a]quinoxaline
Figure imgf000234_0002
[0589] The title compound was prepared as described in Example 54, except that 7 -fluoro-4- (piperazin- 1 -yl)- 8- (trifluoromethyl)tetrazolo [ 1 , 5 - a] quinoxaline HCl salt was substituted for 8-bromo-4-piperazinyl-10-hydro-l,2,4-triazolo[4,3- a]quinoxaline HCl salt as the starting material. !H NMR (300 MHz, CDC13) δ: 8.62 (d, J = 6.9 Hz, 1H), 7.50 (d, J = 11.4 Hz, 1H), 4.80-4.22 (m, 4H), 2.63 (m, 4H), 2.40 (s, 3H). MS m/z: 356 (M+H+). SCHEME 69
Figure imgf000235_0001
EXAMPLE 188
8-chloro-7-fluoro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000235_0002
[0590] The HCl salt of the title compound was prepared as described in Examples 29 and 180, except that 4-chloro-5-fluorobenzene-l,2-diamine was substituted for 4-(trifluoromethyl)benzene- 1 ,2-diamine as the starting material.1H NMR (300 MHz, DMSO-d6) δ: 8.48 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 10.8 Hz, 1H), 4.23 (br, 4H), 2.86 (m, 4H). MS m/z: 307 (M+H+).
EXAMPLE 189
8-chloro-7-fluoro-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000235_0003
[0591] The title compound was prepared as described in Example 54, except that 8-chloro-7-fluoro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline HCl salt (Example 188) was substituted for 8-bromo-4-piperazinyl-10-hydro- 1,2,4- triazolo[4,3-a]quinoxaline HCI salt (Example 52). *H NMR (300 MHz, DMSO-d6) δ: 8.52 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 10.2 Hz, 1H), 4.30 (br, 4H), 2.57 (br, 4H), 2.28 (s, 3H). MS m/z: 321 (M+H+).
Figure imgf000236_0001
EXAMPLE 190
7,8-difluoro-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000236_0002
[0592] The title compound was prepared as described in Examples 37 and 27, except that 2,3-dichloro-6,7-difluoroquinoxaline was substituted for 2,3-dichloro-6- (trifluoromethyl)quinoxaline as the starting material of that route. 1H NMR (300 MHz, DMSO-d6) δ: 8.02 (dd, J =10.2, 7.8 Hz, 1H), 7.78 (dd, J = 11.4, 7.8 Hz, 1H), 4.26 (br, 4H), 2.50 (m, 4H), 2.24 (s, 3H). MS m/z: 306 (M+H+).
Figure imgf000236_0003
EXAMPLE 191
7,8-difluoro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000237_0001
[0593] The HCI salt of the title compound was prepared as described in Examples 37 and 29, except that 2,3-dichloro-6,7-difluoroquinoxaline was substituted for 2,3-dichloro-6-(trifluoromethyl)quinoxaline as the starting material of that route. *H NMR (300 MHz, DMSO-d6) δ: 9.65 (br, 3H), 8.55 (dd, J =10.2, 7.8 Hz, 1H), 7.87 (dd, J = 11.7, 7.8 Hz, 1H), 4.50 (br, 4H), 3.30 (m, 4H). MS m/z: 292 (M+H+).
EXAMPLE 192
7-chloro-9-fluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000237_0003
[0594] The HCI salt of the title compound was prepared as described in Examples 23 and 196, except that 5-chloro-3-fluorobenzene-l,2-diamine was substituted for 4-(trifluoromethyl)benzene- 1 ,2-diamine. Ή NMR (300 MHz, DMSO-d6) δ: 9.59 (s, 1H), 7.46-7.39 (m, 2H), 4.29 (br, 4H), 2.87 (br, 4H). MS m/z: 307 (M+H+).
EXAMPLE 193
7-bromo-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000238_0001
[0595] The title compound was prepared as described in Example 54, except that 7-bromo-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline HCl salt
(Example 53) was substituted for 8-bromo-4-piperazinyl-10-hydro- 1,2,4- triazolo[4,3-a]quinoxaline HCl salt (Example 52). *H NMR (300 MHz, CDC13) δ: 9.12 (s, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.38 (dd, J = 8.7, 2.1 Hz, 1H), 4.48 (br, 4H), 2.60 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 347 (M+H+).
EXAMPLE 194
7-bromo-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline hydrochloride
Figure imgf000238_0002
[0596] The title compound was prepared as described in Examples 29 and 52, except that 4-bromobenzene-l,2-diamine was substituted for 4- (trifluoromethyl)benzene- 1 ,2-diamine as the starting material. JH NMR (300 MHz, DMSO-d6) δ: 9.58 (s, 2H), 8.30 (d, J = 9.0 Hz, 1H), 7.96 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 4.52 (br, 4H), 3.29 (br, 4H). MS m/z: 334 (M+H+). EXAMPLE 195
7-bromo-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000239_0001
[0597] The title compound was prepared as described in Example 54, except that 7-bromo-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline hydrochloride (Example 194) was substituted for 8-bromo-4-piperazinyl-10-hydro-l,2,4-triazolo[4,3- ajquinoxaline HCl salt (Example 52). *H NMR (300 MHz, CDC13) δ: 8.21 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 4.44 (br, 4H), 2.61 (t, J = 4.8 Hz, 4H), 2.37 (s, 3H). MS m/z: 348 (M+H+).
Figure imgf000239_0002
EXAMPLE 196
8-chloro-6-fluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000240_0001
Step 1
Figure imgf000240_0002
4-Chloro-2-fluoro-6-iodoaniline:
[0598] The title compound was prepared as described in Example 122 step 1, except that 4-chloro-2-fluoroaniline was substituted for 3-chloro-4- (trifluoromethyl)aniline.
Step 2
Figure imgf000240_0003
5-chloro-3-fluorobenzene-l,2-diamine:
[0599] The title compound was prepared as described in Example 236 step 5, except that 4-chloro-2-fluoro-6-iodoaniline was substituted for 6-bromo-2-fluoro-3- (trifluoromethyl)aniline.
Steps 3-8
Figure imgf000240_0004
8-chloro-6-fluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
[0600] The HCl salt of the title compound was prepared as described in Example 21, except that 5-chloro-3-fluorobenzene-l,2-diamine was substituted for 4-methylbenzene-l,2-diamine as the starting material. JH NMR (300 MHz, DMSO- d6) δ: 9.99 (s, 1H), 8.23 (s, 1H), 7.49 (d, J = 10.8 Hz, 1H), 4.26 (br, 4H), 2.85 (br, 4H). MS m/z: 307 (M+H+).
EXAMPLE 197
8-chloro-6-fluoro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000241_0001
[0601] The title compound was prepared as described in Example 54, except that 8-chloro-6-fluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline HCl salt (Example 196) was substituted for 8-bromo-4-piperazinyl-10-hydro- 1,2,4- triazolo[4,3-a]quinoxaline HCl salt (Example 52). *H NMR (300 MHz, DMSO-d6) δ: 9.99 (s, 1H), 8.24 (s, 1H), 7.53 (d, J = 10.5 Hz, 1H), 4.33 (br, 4H), 3.30 (br, 4H), 2.23 (s, 3H). MS m/z: 321 (M+H+).
Figure imgf000241_0002
EXAMPLE 198
7-bromo-8-fluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000242_0001
[0602] The HCl salt of the title compound was prepared as described in Examples 21 and 184, except that 4-bromo-5-fluorobenzene-l,2-diamine was substituted for 4-methylbenzene- 1 ,2-diamine. !H NMR (300 MHz, DMSO-d6) δ: 9.86 (s, 1H), 8.27 (d, J = 9.3 Hz, 1H), 7.73 (d, J = 6.6 Hz, 1H), 4.21 (br, 4H), 2.80 (br, 4H). MS m/z: 351 (M+H+).
EXAMPLE 199
7-bromo-8-fluoro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000242_0002
[0603] The title compound was prepared as described in Example 54, except that 7-bromo-8-fluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline HCl salt (Example 198) was substituted for 8-bromo-4-piperazinyl-10-hydro- 1,2,4- triazolo[4,3-a]quinoxaline HCl salt (Example 52). *H NMR (300 MHz, DMSO-d6) δ: 9.90 (s, 1H), 8.31 (d, J = 9.6 Hz, 1H), 7.79 (d, J = 6.6 Hz, 1H), 4.27 (br, 4H), 2.46 (br, 4H), 2.22 (s, 3H). MS m/z: 365 (M+H+).
SCHEME 75
Figure imgf000242_0003
EXAMPLE 200
8-fluoro-4-(piperazin-l-yl)-7-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline
Figure imgf000243_0001
[0604] The HCl salt of the title compound was prepared as described in Examples 18 and 186, except that 5-fluoro-4-(trifluoromethyl)benzene-l,2-diamine (prepared according to Example 34) was substituted for 4-methylbenzene-l,2- diamine as the starting material. *H NMR (300 MHz, CDC13) δ: 8.19 (d, J = 9.3 Hz, 1H), 8.04 (d, J = 6.6 Hz, 1H), 4.41 (br, 4H), 3.09 (m, 4H). MS m/z: 342 (M+H+).
EXAMPLE 201
8-fluoro-4-(4-methylpiperazin-l-yl)-7-(trifluoromethyl)tetrazolo[l,5- a]quinoxaline
Figure imgf000243_0002
[0605] The title compound was prepared as described in Example 54, except that 8-fluoro-4-(piperazin-l-yl)-7-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline HCl salt was substituted for 8-bromo-4-piperazinyl-10-hydro-l,2,4-triazolo[4,3- a]quinoxaline HCl salt as the starting material. *H NMR (300 MHz, CDC13) δ: 8.19 (d, J = 9.3 Hz, 1H), 8.04 (d, J = 6.3 Hz, 1H), 4.44 (br, 4H), 2.62 (m, 4H), 2.38 (s, 3H). MS m/z: 356 (M+H+). EXAMPLE 202
7-chloro-8-fluoro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000244_0001
[0606] The title compound was prepared as described in Example 18, except that 4-chloro-5-fluorobenzene- 1,2-diamine was substituted for 4-methylbenzene- 1,2-diamine as the starting material of that route. !H NMR (300 MHz, CDC13) δ: 8.14 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 4.38 (br, 4H), 3.08 (t, J = 5.1 Hz, 4H). MS m/z: 308 (M+H+).
EXAMPLE 203
7-chloro-8-fluoro-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000244_0002
[0607] The title compound was prepared as described in Example 54, except that 7-chloro-8-fluoro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline (Example 202) was substituted for 8-bromo-4-piperazinyl-10-hydro-l,2,4-triazolo[4,3- a]quinoxaline HCl salt (Example 52). *H NMR (300 MHz, CDC13) δ: 8.14 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 6.9 Hz, 1H), 4.42 (br, 4H), 2.61 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H). MS m/z: 322 (M+H+).
EXAMPLE 204
8-bromo-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000245_0001
[0608] The title compound was prepared as described in Example 18, except that 4-bromobenzene- 1 ,2-diamine was substituted for 4-methylbenzene-l,2-diamine as the starting material and N-methylpiperazine for piperazine in step 4 of that route. *H NMR (300 MHz, CDC13) δ: 8.52 (d, J = 2.1 Hz, 1H), 7.68 (dd, J = 8.7, 2.1 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 4.43 (br, 4H), 2.62 (t, J = 5.3 Hz, 4H), 2.38 (s, 3H). MS m/z: 348 (M+H+).
EXAMPLE 205
8-bromo-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000245_0002
[0609] The title compound was prepared as described in Example 18, except that 4-bromobenzene- 1 ,2-diamine was substituted for 4-methylbenzene-l,2-diamine as the starting material of that route. *H NMR (300 MHz, CDC13) δ: 8.50 (d, J = 2.1 Hz, 1H), 7.67 (dd, J = 8.7, 2.1 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 4.38 (br, 4H), 3.08 (m, 4H). MS m/z: 334 (M+H+).
EXAMPLE 206
6-fluoro-4-(piperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline hydrochloride
Figure imgf000246_0001
[0610] The title compound was prepared as described in Example 29, except that 3-fluoro-5-(trifluoromethyl)benzene-l,2-diamine (prepared as described in Example 48 steps 1-4) was substituted for 4-(trifluoromethyl)benzene-l,2-diamine as the starting material of that route. *H NMR (300 MHz, DMSO-d6) δ: 9.58 (br, 2H), 8.48 (s, 1H), 8.07 (dd, J = 10.8, 1.8 Hz, 1H), 4.61 (br, 4H), 3.33 (t, J = 5.1 Hz, 4H). MS m/z: 342 (M+H+).
EXAMPLE 207
6-fluoro-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5- ajquinoxaline hydrochloride
Figure imgf000246_0002
[0611] The title compound was prepared as described in Example 54, except that 6-fluoro-4-(piperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline hydrochloride (Example 206) was substituted for 8-bromo-4-piperazinyl-10-hydro- l,2,4-triazolo[4,3-a]quinoxaline HCI salt (Example 52). *H NMR (300 MHz, DMSO-d6) δ: 8.38 (s, 1H), 7.97 (dd, J = 10.8, 2.1 Hz, 1H), 4.37 (br, 4H), 2.54 (t, J = 5.1 Hz, 4H), 2.25 (s, 3H). MS m/z: 356 (M+H+).
Figure imgf000247_0001
EXAMPLE 208
8-bromo-6-fluoro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000247_0002
[0612] The title compound was prepared as described in Example 196, except that 4-bromo-2-fluoroaniline was substituted for 4-chloro-2-fluoroaniline in step 1 , and N-methylpiperazine for N-BOC piperazine in step 7 of that route. 1H NMR (300 MHz, CD3OD) δ: 9.75 (s, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 9.6, 1.8 Hz, 1H), 4.45 (br, 4H), 2.64 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 365 (M+H+)
EXAMPLE 209
8-bromo-6-fluoro-4-(piperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000247_0003
[0613] The title compound was prepared as described in Example 208, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CD3OD) δ: 9.75 (s, 1H), 8.13 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 9.6, 1.8 Hz, 1H), 4.41 (br, 4H), 3.01 (t, J = 5.1 Hz, 4H). MS m/z: 351 (M+H+).
EXAMPLE 210
8-bromo-6-fluoro-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000248_0001
[0614] The title compound was prepared as described in Example 18, except that 5-bromo-3-fluorobenzene-l,2-diamine (prepared as described in Example 208, steps 1-2) was substituted for 4-methylbenzene-l,2-diamine as the starting material of that route. *H NMR (300 MHz, CD3OD) δ: 8.34 (t, J = 1.8 Hz, 1H), 7.50 (dd, J = 9.9, 1.8 Hz, 1H), 4.47 (br, 4H), 2.63 (t, J = 5.1 Hz, 4H), 2.39 (s, 3H). MS m/z: 366 (M+H+).
EXAMPLE 211
8-bromo-7-fluoro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000248_0002
[0615] The HC1 salt of the title compound was prepared as described in Example 29, except that 4-bromo-5-fluorobenzene-l,2-diamine (prepared as described in Example 184 steps 1-4) was substituted for 4-
(trifluoromethyl)benzene- 1 ,2-diamine as the starting material of that route. JH NMR (300 MHz, DMSO-d6) δ: 9.45 (br, 2H), 8.70 (d, J = 6.6 Hz, 1H), 7.75 (d, J = 9.9 Hz, 1H), 4.52 (br, 4H), 3.30 (t, J = 5.7 Hz, 4H). MS m/z: 352 (M+H+). EXAMPLE 212
8-bromo-7-fluoro-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000249_0001
[0616] The title compound was prepared as described in Example 54, except that 8-bromo-7-fluoro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline HC1 salt (Example 211) was substituted for 8-bromo-4-piperazinyl-10-hydro- 1,2,4- triazolo[4,3-a]quinoxaline HC1 salt (Example 52). *H NMR (300 MHz, CDC13) δ: 8.57 (d, J = 6.9 Hz, 1H), 7.46 (d, J = 9.3 Hz, 1H), 4.46 (br, 4H), 2.61 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H). MS m/z: 366 (M+H+).
EXAMPLE 213
8-chloro-4-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)tetrazolo[l,5- ajquinoxaline
Figure imgf000249_0002
4,8-dichlorotetr azolo [1 ,5-a] quinoxaline :
[0617] A 25 mL round bottom flask was charged with 2,6-dichloro-3- hydrazinylquinoxaline (prepared as described in Example 1, steps 1-3, 0.1 g, 0.44 mmol) and IN aqueous HC1 solution (2 mL). To the suspension was added dropwise a solution of sodium nitrite (45 mg, 0.44 mmol) in water (0.5 mL) at 0 °C. The resulting mixture was stirred at 0-5 °C for further 0.5 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :1). Work-up: the precipitate was collected by filtration and washed with water to afford 100 mg (95%) of the product as light yellow solids. *H NMR (300 MHz, DMSO-d6) δ: 8.70 (d, J = 2.1 Hz, 1H), 8.27 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 8.7, 2.1 Hz, 1H).
Step 2
Figure imgf000250_0001
8-chloro-4-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)tetrazolo[l,5- ajquinoxaline:
[0618] The title compound was prepared as described in Example 19, except that octahydropyrrolo[l,2-a]pyrazine was substituted for piperazine in that route.1H NMR (300 MHz, DMSO-d6) δ: 8.33 (d, J = 2.1 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.66 (dd, J = 8.7, 2.1 Hz, 1H), 5.44-5.37 (m, 2H), 3.33-3.16 (m, 2H), 3.08-2.92 (m, 2H), 2.29-2.21 (m, 1H), 2.14-2.05 (m, 2H), 1.90-1.66 (m, 3H), 1.50-1.41 (m, 1H). MS m/z: 330 (M+H+).
EXAMPLE 214
2-methyl-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)oxazolo[4,5- c]quinoline
Figure imgf000250_0002
[0619] The title compound was prepared as described in Example 141, except that 2-amino-5-(trifluoromethyl)benzoic acid was substituted for 2-amino-5- chlorobenzoic acid as the starting material, and ethyl orthoacetate was substituted for ethyl orthoformate in step 4 of that route. !H NMR (300 MHz, DMSO-d6) δ: 8.21 (s, 1H), 7.79 (m, 2H), 4.21 (br, 4H), 2.73 (s, 3H), 2.49 (m, 4H), 2.24 (s, 3H). MS m/z: 351 (M+H+).
EXAMPLE 215
2-methyl-4-(piperazin-l-yl)-8-(trifluoromethyl)oxazolo[4,5-c]quinoline
Figure imgf000251_0001
[0620] The title compound was prepared as described in Example 214, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, DMSO-d6) δ: 8.19 (s, 1H), 7.77 (m, 2H), 4.15 (m, 4H), 2.85 (m, 4H), 2.72 (s, 3H). MS m/z: 337 (M+H+).
Figure imgf000251_0002
EXAMPLE 216
8-chloro-7-fluoro-2-methyl-4-(4-methylpiperazin-l-yl)oxazolo[4,5-c]quinoline
Figure imgf000252_0001
2-Amino-5-chloro-4-fluorobenzoic acid:
[0621] A 500 mL 3-necked round bottom flask was charged with 2-amino-4- fluorobenzoic acid (5.0 g, 32.3 mmol) and anhydrous DMF (75 mL). To the above was added N-chlorosuccinimide (4.3 g, 32.3 mmol) in several portions at room temperature. The resulting mixture was heated at 50 °C for 2.5 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 : 1 , Rf = 0.4). Workup: the mixture was poured into water and filtered. The solid collected was washed with water and dried, to afford 4.53 g (74%) of the product, which was used in the next step without further purification.
Steps 2-7
Figure imgf000252_0002
8-chloro-7-fluoro-2-methyl-4-(4-methylpiperazin-l-yl)oxazolo[4,5-c]quinoline:
[0622] The title compound was prepared as described in Example 141, except that 2-amino-5-chloro-4-fluorobenzoic acid was substituted for 2-amino-5- chlorobenzoic acid in step 1 , and ethyl orthoacetate was substituted for ethyl orthoformate in step 4 of that route. *H NMR (300 MHz, DMSO-d6) δ: 8.07 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 11.4 Hz, 1H), 4.15 (t, J = 4.8 Hz, 4H), 2.70 (s, 3H), 2.46 (t, J = 4.8 Hz, 4H), 2.23 (s, 3H). MS m/z: 335 (M+H+).
EXAMPLE 217
8-chloro-7-fluoro-2-methyl-4-(piperazin-l-yl)oxazolo[4,5-c]quinoline
Figure imgf000253_0001
[0623] The title compound was prepared as described in Example 216, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, DMSO-d6) δ: 8.02 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 11.7 Hz, 1H), 4.08 (t, J = 4.8 Hz, 4H), 2.83 (t, J = 4.5 Hz, 4H), 2.69 (s, 3H). MS m/z: 321 (M+H+).
Figure imgf000253_0002
EXAMPLE 218
4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)isoxazolo[3,4-c]quinoline
Figure imgf000254_0001
[0624] The title compound was prepared as described in Example 166, except that 4-nitrobenzotrifluoride was substituted for l-chloro-4-nitrobenzene as the starting material. *H NMR (300 MHz, CDC13) δ: 9.33 (s, 1H), 8.02 (s, 1H), 7.66 (s, 2H), 4.35 (t, J = 3.3 Hz, 4H), 2.61 (t, J = 4.5 Hz, 4H), 2.38 (s, 3H). MS m/z: 337 (M+H+).
EXAMPLE 219
4-Piperazinyl-8-(trifluoromethyl)isoxazolo[3,4-c]quinoline
Figure imgf000254_0002
[0625] The title compound was prepared as described in Example 218, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CDC13) δ: 9.33 (s, 1H), 8.02 (s, 1H), 7.66 (s, 2H), 4.33 (t, J = 3.3 Hz, 4H), 3.09 (t, J = 4.2 Hz, 4H). MS m/z: 323 (M+H+).
EXAMPLE 220
4-(4-Methylpiperazinyl)-7-(trifluoromethyl)isoxazolo[3,4-c]quinoline
Figure imgf000254_0003
[0626] The title compound was prepared as described in Example 166, except that 3-nitrobenzotrifluoride was substituted for l-chloro-4-nitrobenzene as the starting material. *H NMR (300 MHz, CDC13) δ: 9.32 (s, 1H), 7.85 (m, 2H), 7.42 (dd, J = 8.1, 1.2 Hz, 1H), 4.32 (m, 4H), 2.60 (m, 4H), 2.37 (s, 3H). MS m/z: 337 (M+H+).
EXAMPLE 221
4-(piperazin-l-yl)-7-(trifluoromethyl)isoxazolo[3,4-c]quinoline
Figure imgf000255_0001
[0627] The title compound was prepared as described in Example 220, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CDC13) δ: 9.33 (s, 1H), 7.86 (m, 2H), 7.42 (dd, J = 7.8, 1.5 Hz, 1H), 4.27 (m, 4H), 3.06 (m, 4H). MS m/z: 323 (M+H+).
Figure imgf000255_0002
EXAMPLE 222
8-bromo-4-(4-methylpiperazin-l-yl)isoxazolo[3,4-c]quinoline
Figure imgf000256_0001
[0628] The title compound was prepared as described in Example 166, except that 1 -bromo-4-nitrobenzene was substituted for l-chloro-4-nitrobenzene as the starting material. *H NMR (300 MHz, CDC13) δ: 9.24 (s, 1H), 7.79 (d, J = 1.8 Hz, 1H), 7.48 (m, 2H), 4.28 (t, J = 4.8 Hz, 4H), 2.59 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 347 (M+H+).
EXAMPLE 223
8-bromo-4-(piperazin-l-yl)isoxazolo[3,4-c]quinoline
Figure imgf000256_0002
[0629] The title compound was prepared as described in Example 222, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CDC13) δ: 9.24 (s, 1H), 7.89 (d, J = 2.1, 1H), 7.48 (m, 2H), 4.24 (t, J = 4.8 Hz, 4H), 3.06 (t, J = 5.1 Hz, 4H). MS m/z: 333 (M+H+).
Figure imgf000257_0001
EXAMPLE 224
7-chloro-4-(4-methylpiperazin-l-yl)isoxazolo[3,4-c]quinoline
Figure imgf000257_0002
(E)-2-(4-chloro-2-nitrophenyl)-N,N-dimethylethenamine:
[0630] A 250 mL round bottom flask was charged with 4-chloro-2-nitrotoluene (10.0 g, 58.3 mmol), Ν,Ν-dimethylformamide dimethyl acetal (23 mL) and DMF (100 mL). The resulting mixture was stirred at reflux overnight. Work-up: the reaction mixture was concentrated in vacuo. The residue was used as such for the next step. *H NMR (300 MHz, CDC13) δ: 7.85 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.26 (m, 1H), 6.93 (d, J = 16.2 Hz, 1H), 5.83 (d, J = 13.5 Hz, 1H), 2.91 (s, 6H).
Steps 2-6
Figure imgf000258_0001
7-chloro-4-(4-methylpiperazin-l-yl)isoxazolo[3,4-c]quinoline:
[0631 ] The title compound was prepared as described in Example 166, except that (E)-2-(4-chloro-2-nitrophenyl)-N,N-dimethylethenamine was substituted for [(lE)-2-(5-chloro-2-nitrophenyl)vinyl]pyrrolidine in step 4 of that route.1H NMR (300 MHz, CDC13) δ: 9.23 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.18 (dd, J = 8.4, 2.1 Hz, 1H), 4.23 (t, J = 4.8 Hz, 1H), 2.58 (t, J = 5.1 Hz, 1H), 2.36 (s, 3H). MS m/z: 303 (M+H+).
EXAMPLE 225
7-chloro-4-(piperazin-l-yl)isoxazolo[3,4-c]quinoline
Figure imgf000258_0002
[0632] The title compound was prepared as described in Example 224, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, DMSO-d6) δ: 10.15 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.26 (dd, J = 8.1, 2.1 Hz, 1H), 4.09 (t, J = 4.5 Hz, 1H), 2.83 (t, J = 5.1 Hz, 1H). MS m/z: 289 (M+H+). EXAMPLE 226
7,8-difluoro-4-(4-methylpiperazin-l-yl)isoxazolo[3,4-c]quinoline
Figure imgf000259_0001
[0633] The title compound was prepared as described in Example 224, except that 4,5-difluoro-2-nitrotoluene was substituted for 4-chloro-2-nitrotoluene as the starting material. *H NMR (300 MHz, CDC13) δ: 9.19 (s, 1H), 7.51 (dd, J = 10.0, 8.2 Hz, 1H), 7.37 (dd, J = 12.0, 7.8 Hz, 1H), 4.26 (t, J = 5.1 Hz, 4H), 2.59 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 305 (M+H+).
EXAMPLE 227
7,8-difluoro-4-(piperazin-l-yl)isoxazolo[3,4-c]quinoline
Figure imgf000259_0002
[0634] The title compound was prepared as described in Example 226, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, D20) δ: 9.70 (s, 1H), 7.76 (m, 1H), 7.53 (m, 1H), 4.55 (br, 4H), 3.55 (t, J = 5.1 Hz, 4H). MS m/z: 291 (M+H+).
Figure imgf000260_0001
EXAMPLE 228
7-bromo-4-(4-methylpiperazin-l-yl)isoxazolo[3,4-c]quinoline
Figure imgf000260_0002
[0635] The title compound was prepared as described in Example 224, except that 4-bromo-2-nitrotoluene was substituted for 4-chloro-2-nitrotoluene as the starting material. *H NMR (300 MHz, CDC13) δ: 9.24 (s, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.31 (dd, J = 8.1, 1.8 Hz, 1H), 4.29 (t, J = 4.8 Hz, 4H), 2.58 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 347 (M+H+). EXAMPLE 229
7-bromo-4-(piperazin-l-yl)isoxazolo[3,4-c]quinoline
Figure imgf000261_0001
[0636] The title compound was prepared as described in Example 228, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CDC13) δ: 9.25 (s, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.1, 1.8 Hz, 1H), 4.26 (t, J = 5.1 Hz, 4H), 3.06 (m, 4H). MS m/z: 333 (M+H+).
EXAMPLE 230
8-chloro-4-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)isoxazolo[3,4-c]quinoline
Figure imgf000261_0002
[0637] The HC1 salt of the title compound was prepared as described in Example 166, except that l,4-diazabicyclo[4.3.0]nonane was substituted for N- methylpiperazine in the last step. *H NMR (300 MHz, CD3OD) δ: 9.85 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 9.0, 2.4 Hz, 1H), 5.52 (br, 1H), 4.57 (br 1H), 3.60 (br, 6H), 2.35-1.90 (m, 5H). MS: m/z 329 (M+H+).
EXAMPLE 231
4-(piperazin-l-yl)-8-(trifluoromethyl)-3H-pyrazolo[3,4-c]quinoline
Figure imgf000261_0003
[0638] The HC1 salt of the title compound was prepared as described in Example 157, except that piperazine was substituted for N-methylpiperazine in step 9 of that route. *H NMR (300 MHz, D20) δ: 8.60 (s, 1H), 8.20 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 4.60 (br, 4H), 3.54 (t, J = 4.8 Hz, 4H). MS m/z: 322 (M+H+).
EXAMPLE 232
8-bromo-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline
Figure imgf000262_0001
[0639] The title compound was prepared as described in Example 152, except that 5-bromoindole was substituted for 5-chloroindole as the starting material of that route. *H NMR (300 MHz, CD3OD) δ: 8.56 (s, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 8.7, 2.1 Hz, 1H), 4.22 (m, 4H), 2.64 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 346 (M+H+).
EXAMPLE 233
8-bromo-4-(piperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline
Figure imgf000262_0002
[0640] The HC1 salt of the title compound was prepared as described in Example 153, except that 5-bromoindole was substituted for 5-chloroindole as starting material of that route. *H NMR (300 MHz, D20) δ: 8.46 (s, 1H), 7.83 ( 1H), 7.45 (s, 2H), 4.65 (br, 4H), 3.54 (m, 4H). MS m/z: 332 (M+H+). EXAMPLE 234
8-bromo-2-methyl-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline
Figure imgf000263_0001
[0641] The title compound was prepared as described in Example 150, except that 5-bromoindole was substituted for 5-chloroindole as the starting material of that route. *H NMR (300 MHz, CD3OD) δ: 8.44 (s, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.43 (dd, J = 4.8, 2.1 Hz, 1H), 4.27 (t, J = 5.1 Hz, 4H), 4.18 (s, 3H), 2.61 (t, J = 5.1 Hz, 4H), 2.35 (s, 3H). MS m/z: 360 (M+H+).
EXAMPLE 235
8-bromo-2-methyl-4-(piperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline
Figure imgf000263_0002
[0642] The title compound was prepared as described in Example 234, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CD3OD) δ: 8.42 (s, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 4.8 Hz, 1H), 7.43 (dd, J = 4.8, 2.1 Hz, 1H), 4.22 (t, J = 5.1 Hz, 4H), 4.17 (s, 3H), 2.98 (t, J = 5.1 Hz, 4H). MS m/z: 346 (M+H+).
Figure imgf000264_0001
EXAMPLE 236
9-fluoro-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000264_0002
Step 1
Figure imgf000264_0003
tert-Butyl {(tert-butoxy)-N-[2-fluoro-3-(trifluoromethyl)phenyl]- carbonylaminojformate :
[0643] A I L round bottom flask was charged with 2-fluoro-3- (trifluoromethyl)aniline (25 g, 0.14 mol), di-tert-butyl dicarbonate (91 g, 0.42 mol), 4-(dimethylamino)pyridine (1.7 g, 14 mmol) and THF (500 mL). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 : 10). Work-up: the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtO Ac (500 mL) and washed with brine (100 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo, to afford 43 g (81 ) of the product as white oil.
Step 2
Figure imgf000265_0001
tert-butyl 2-fluoro-3-(trifluoromethyl)phenylcarbamate:
[0644] A I L round bottom flask was charged with tert-butyl { (tert-butoxy)-N- [2-fluoro-3-(trifluoromethyl)phenyl]carbonylamino}formate (43 g, 0.11 mol), K2CO3 (31 g, 0.22 mol) and MeOH (300 mL). The resulting mixture was stirred at reflux for 2 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :30). Work-up: the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtOAc (200 mL) and washed with 0.5 N HCl (50 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 2% EtOAc in petroleum ether, to afford 16 g (52 ) of the product as white oil. 1H
NMR (300 MHz, CDC13) δ: 8.34-8.29 (m, 1H), 7.25-7.16 (m, 2H), 6.78 (s, 1H), 1.53 (s, 9H).
Step 3
Figure imgf000265_0002
tert-butyl 6-bromo-2-fluoro-3-(trifluoromethyl)phenylcarbamate:
[0645] A I L 3-necked round bottom flask was charged with tert-butyl 2-fluoro- 3-(trifluoromethyl)phenylcarbamate (10 g, 35.8 mmol) and dry THF (300 mL). To the above was added dropwise t-BuLi solution (1.3 M, 55.2 mL, 71.8 mmol) at -70 °C. The resulting mixture was stirred at -50 °C for 1 h, followed by dropwise addition of a solution of CBr4 (13.1 g, 39.5 mmol) in THF (50 mL) at -70 °C. The reaction mixture was stirred at room temperature for further 1 h. It was then carefully mixed with ice water and extracted with Et20. The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 2-5% EtOAc in petroleum ether, to afford 9.4 g (73%) of the product as yellow solid. 1H
NMR (300 MHz, CDC13) δ: 7.49 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 6.07 (s, 1H), 1.50 (s, 9H).
Step 4
Figure imgf000266_0001
6-Bromo-2-fluoro-3-(trifluoromethyl)aniline:
[0646] A I L 3-necked round bottom flask was charged with tert-butyl 6- bromo-2-fluoro-3-(trifluoromethyl)phenylcarbamate (9.4 g, 26 mmol),
trifluoroacetic acid (40 mL) and CH2C12 (50 mL). The resulting mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC
(EtO Ac/Petroleum ether = 1 : 10). Work-up: the reaction mixture was concentrated in vacuo. The residue was re-dissolved in EtOAc (200 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 5% EtOAc in petroleum ether, to afford 6.2 g (91%) of the product.
Step 5
Figure imgf000266_0002
3-Fluoro-4-(trifluoromethyl)benzene-l,2-diamine:
[0647] A 200 mL pressure tube was charged with 6-bromo-2-fluoro-3- (trifluoromethyl)aniline (7.0 g, 27 mmol), Cu20 (1.0 g, 7.0 mmol), CuCl (1.0 g, 10 mmol) and saturated methanolic ammonia solution (100 mL). The tube was sealed and the resulting mixture was stirred at 150 °C overnight. Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 30 % EtOAc in petroleum ether, to afford 2.8 g
(53%) of the product. *H NMR (300 MHz, CDC13) δ: 6.91 (t, J
(d, J = 8.4 Hz, 1H), 3.80 (s, 2H), 3.36 (s, 2H).
Steps 6-10
Figure imgf000267_0001
9-fluoro-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- ajquinoxaline:
[0648] The title compound was prepared as described in Example 23, except that 3-fluoro-4-(trifluoromethyl)benzene-l,2-diamine was substituted for 4- (trifluoromethyl)benzene- 1 ,2-diamine in step 1 of that route. 1H NMR (300 MHz, CDCI3) δ: 9.40 (d, J = 2.4 Hz, 1H), 7.63 (t, J = 8.1 Hz, 1H), 7.48 (d, J = 10.2 Hz, 1H), 4.58 (br, 4H), 2.62 (t, J = 4.8 Hz, 4H), 2.38 (s, 3H). MS m/z: 355 (M+H+).
S
Figure imgf000268_0001
EXAMPLE 237
8-bromo-7-fluoro-2-methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- ajquinoxaline
Figure imgf000268_0002
(5-bromo-4-fluoro-2-nitrophenyl)hydrazine:
[0649] A 250 mL round bottom flask was charged with l-bromo-2,5-difluoro- 4-nitrobenzene (5.0 g, 21 mmol) and ethanol (70 mL). To the solution was added dropwise hydrazine hydrate (2.1 mL, 42 mmol) at 0 °C. The resulting mixture was stirred overnight at room temperature. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :3). Work-up: the reaction mixture was partitioned between EtOAc (200 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SC>4 then concentrated in vacuo to afford 5.2 g (quantitative yield) of the product, which was fairly pure and used in next step without further purification.
Steps 2-7
Figure imgf000269_0001
8-bromo-7-fluoro-2-methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- ajquinoxaline:
[0650] The title compound was prepared as described in Example 165 steps 2- 7, except that (5-bromo-4-fluoro-2-nitrophenyl)hydrazine was substituted for 5- chloro-2-nitrophenylhydrazine in step 2 of that route. !H NMR (300 MHz, DMSO- d6) δ: 8.36 (d, J = 7.2 Hz, 1H), 7.40 (d, J = 9.6 Hz, 1H), 4.39 (br, 4H), 2.63 (s, 3H), 2.58 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 379 (M+H+).
EXAMPLE 238
8-bromo-7-fluoro-2-methyl-4-(piperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline
Figure imgf000269_0002
[0651] The title compound was prepared as described in Example 237, except that piperazine was substituted for N-methylpiperazine in the last step of that route.
*H NMR (300 MHz, DMSO-d6) δ: 8.35 (d, J = 6.9 Hz, 1H), 7.39 (d, J = 9.6 Hz, 1H), 4.34 (t, J = 5.1 Hz, 4H), 3.05 (t, J = 5.1 Hz, 4H), 2.63 (s, 3H). MS m/z: 365 (M+H+). EXAMPLE 239
7-fluoro-2,8-dimethyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- ajquinoxaline
Figure imgf000270_0001
[0652] The title compound was prepared as described in Example 237, except that 2,5-difluoro-4-nitrotoluene was substituted for l-bromo-2,5-difluoro-4- nitrobenzene as the starting material of that route. !H NMR (300 MHz, CD3OD) δ: 7.93 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 10.8 Hz, 1H), 4.30 (t, J = 4.8 Hz, 4H), 2.62 (t, J = 5.1 Hz, 4H), 2.58 (s, 3H), 2.39 (d, J = 1.5 Hz, 3H), 2.36 (s, 3H). MS m/z: 315 (M+H+).
EXAMPLE 240
7-fluoro-2,8-dimethyl-4-(piperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline
Figure imgf000270_0002
[0653] The title compound was prepared as described in Example 239, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CD3OD) δ: 7.89 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 10.8 Hz, 1H), 4.31 (t, J = 4.8 Hz, 4H), 3.09 (t, J = 5.4 Hz, 4H), 2.57 (s, 3H), 2.38 (d, J = 2.1 Hz, 3H). MS m/z: 301 (M+H+). EXAMPLE 241
8-bromo-2-methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline
Figure imgf000271_0001
[0654] The title compound was prepared as described in Example 237, except that l-bromo-3-fluoro-4-nitrobenzene was substituted for l-bromo-2,5-difluoro-4- nitrobenzene as the starting material of that route. !H NMR (300 MHz, CDC13) δ: 8.33 (m, 1H), 7.55 (m, 2H), 4.37 (t, J = 4.8 Hz, 4H), 2.64 (s, 3H), 2.60 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 361 (M+H+).
EXAMPLE 242
8-bromo-2-methyl-4-(piperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline
Figure imgf000271_0002
[0655] The title compound was prepared as described in Example 241, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CDC13) δ: 8.33 (m, 1H), 7.54 (m, 2H), 4.32 (t, J = 5.1 Hz, 4H), 3.06 (t, J = 4.8 Hz, 4H), 2.64 (s, 3H). MS m/z: 347 (M+H+).
SC
Figure imgf000272_0001
EXAMPLE 243
8-chloro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline
Figure imgf000272_0002
Step 1
Figure imgf000272_0003
(Z)-ethyl 2-chloro-2-(2-(5-chloro-2-nitrophenyl)hydrazono)acetate:
[0656] A 500 mL round bottom flask was charged with 5-chloro-2-nitroaniline (14.8 g, 0.086 mol), concentrated HCl (40 mL), ethanol (20 mL) and water (20 mL). To the above was added dropwise a solution of NaN02 (6.5 g, 0.094 mol) in water (50 mL) at 0-5 °C, followed by the addition of a cold solution of ethyl 2- chloroacetoacetate (12.7 g, 0.086 mol) and sodium acetate (8.08 g, 0.097 mol) in ethanol (370 mL) and water (40 mL). The reaction mixture was stirred at -5 °C for 4 h. Work up: The reaction was quenched with water (1.5 L) and stirred for further 2 h. The solid was collected and recrystallized from ethanol to give 20.5 g (78%) of the product. *H NMR (300 MHz, CDC13) δ: 11.39 (s, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.06-7.02 (m, 1H), 4.48-4.40 (m, 2H), 1.46-1.41 (m, 3H).
Step 2
Figure imgf000273_0001
(Z)-ethyl 2-amino-2-(2-(5-chloro-2-nitrophenyl)hydrazono)acetate:
[0657] A 500 mL round bottom flask was charged with (Z)-ethyl 2-chloro-2-(2- (5-chloro-2-nitrophenyl)hydrazono)acetate (20.5 g, 0.067 mol) and THF (250 mL). Ammonia gas was introduced by bubbling through the reaction solution for 4 h. The reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :4, Rf = 0.5). Work up: The reaction solution was concentrated in vacuo to give 19.1 g (quantitative yield) of the product. MS m/z: 286 (M+H+).
Steps 3-5
Figure imgf000273_0002
Ethyl 8-chloro-4-oxo-4,5-dihydro-[l,2,4]triazolo[l,5-a]quinoxaline-2- carboxylate:
[0658] The title compound was prepared as described in Example 164 steps 3- 5, except that (Z)-ethyl 2-amino-2-(2-(5-chloro-2-nitrophenyl)hydrazono)acetate was substituted for ((lZ)-2-amino-l-azaprop-l-enyl)(5-chloro-2-nitrophenyl)amine in step 3 of that route. MS m/z: 293 (M+H+).
Step 6
Figure imgf000274_0001
8-chloro-4-oxo-4,5-dihydro-[l,2,4]triazolo[l,5-a]quinoxaline-2-carboxylic acid:
[0659] A 500 mL round bottom flask was charged with ethyl 8-chloro-4-oxo- 4,5-dihydro-[l,2,4]triazolo[l,5-a]quinoxaline-2-carboxylate (1.5 g, 5.1 mmol), NaOH (4.0 g, 0.1 mol), water (85 mL) and ethanol (85 mL). The resulting mixture was heated at reflux for 3 h. The reaction progress was monitored by LC-MS. Work up: the solid was collected and dissolved in water (20 mL). To the aqueous solution was added dropwise 6N HC1 (2 mL). The precipitate was collected by filtration, washed with water and dried, to afford 1.35 g (99%) of the product. JH NMR (300 MHz, DMSO-d6) δ: 12.52 (s, 1H), 8.07 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.46 (d, J= 8.1 Hz, 1H). MS m/z: 263 (M-H+).
Step 7
Figure imgf000274_0002
8-chloro-[l,2,4]triazolo[l,5-a]quinoxalin-4(5H)-one:
[0660] A 50 mL round bottom flask was charged with 8-chloro-4-oxo-4,5- dihydro-[l,2,4]triazolo[l,5-a]quinoxaline-2-carboxylic acid (1.35 g, 5.1 mmol), Cu20 (20 mg, 0.13 mmol) and HO(CH2CH20)2H (30 mL). The resulting mixture was heated at 135 °C overnight. The reaction progress was monitored by LC-MS. Work up: the solid was collected by filtration, washed with 0.5 M aqueous NaHCC>3 (10 mL) and then with a few drops of ammonia/ammonium chloride buffer (PH 9), and dried, to afford 0.84 g (75%) of the product. MS m/z: 219 (M-H+).
Steps 8-9
Figure imgf000275_0001
8-chloro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline:
[0661] The title compound was prepared as described in Example 164 steps 6- 7, except that 8-chloro-[l,2,4]triazolo[l,5-a]quinoxalin-4(5H)-one was substituted for 8-chloro-2-methyl-[l,2,4]triazolo[l,5-a]quinoxalin-4(5H)-one in step 6 and N- methylpiperazine for piperazine in step 7 of that route.1H NMR (300 MHz, CDCI3) δ: 8.37 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.44 (dd, J = 9.0, 2.1 Hz, 1H), 4.38 (t, J = 5.0 Hz, 4H), 2.60 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 303 (M+H+).
Figure imgf000275_0002
EXAMPLE 244
Ethyl 8-chloro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline-2- carboxylate
Figure imgf000275_0003
[0662] The title compound was prepared as described in Example 164 steps 6- 7, except that ethyl 8-chloro-4-oxo-4,5-dihydro-[l,2,4]triazolo[l,5-a]quinoxaline-2- carboxylate (prepared as described in Example 243, steps 1-5) was substituted for 8-chloro-2-methyl-[l,2,4]triazolo[l,5-a]quinoxalin-4(5H)-one in step 6 and N- methylpiperazine for piperazine in step 7 of that route. JH NMR (300 MHz, CDCI3) δ: 8.36 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.48 (dd, J = 9.0, 2.1 Hz, 1H), 4.58 (q, J = 7.2 Hz, 2H), 4.41 (br, 4H), 2.60 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H). MS m/z: 375 (M+H+).
Figure imgf000276_0001
EXAMPLE 245
9-chloro-5-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)-2-methyl- [l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000276_0002
[0663] The title compound was prepared as described in Example 111, except that l,4-diazabicyclo[4.3.0]nonane was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, DMSO-d6) δ: 8.12 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.7, 2.4 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 4.90 (m, 2H), 3.28-2.99 (m, 3H), 2.85 (m, 1H), 2.52 (s, 3H), 2.34-2.27 (m, 1H), 2.14-2.05 (m, 2H), 1.83-1.64 (m, 3H), 1.40-1.35 (m, 1H). MS m/z: 343 (M+H+). EXAMPLE 246
9-chloro-7-fluoro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000277_0001
[0664] The title compound was prepared as described in Example 122, except that 4-chloro-2-fluoroaniline was substituted for 3-chloro-4-(trifluoromethyl)aniline as the starting material of that route. *H NMR (300 MHz, CDC13) δ: 8.08 (dd, J = 2.1, 1.2 Hz, 1H), 7.37 (dd, J = 10.2, 2.4 Hz, 1H), 4.17 (t, J = 4.8 Hz, 4H), 2.64 (t, J = 5.4 Hz, 4H), 2.64 (s, 3H), 2.38 (s, 3H). MS m/z: 335 (M+H+).
EXAMPLE 247
9-chloro-7-fluoro-2-methyl-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000277_0002
[0665] The title compound was prepared as described in Example 246, except that piperazine was substituted for N-methylpiperazine in the last step of that route. *H NMR (300 MHz, CD3OD) δ: 7.92 (dd, J = 2.4, 1.8 Hz, 1H), 7.46 (dd, J = 10.2, 2.4 Hz, 1H), 4.12 (t, J = 5.1 Hz, 4H), 3.09 (t, J = 5.1 Hz, 4H), 2.59 (s, 3H). MS m/z: 321 (M+H+). EXAMPLE 248
9-bromo-7-fluoro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000278_0001
[0666] The title compound was prepared as described in Example 122, except that 4-bromo-2-fluoroaniline was substituted for 3-chloro-4-(trifluoromethyl)aniline as the starting material of that route. *H NMR (300 MHz, CDC13) δ: 8.25 (dd, J = 2.1, 1.5 Hz, 1H), 7.50 (dd, J = 9.9, 2.1 Hz, 1H), 4.23 (t, J = 4.8 Hz, 4H), 2.72 (t, J = 5.1 Hz, 4H), 2.63 (s, 3H), 2.43 (s, 3H). MS m/z: 379 (M+H+).
Figure imgf000278_0002
EXAMPLE 249
8-chloro-5-(4-methylpiperazin-l-yl)benzo[f][l,7]naphthyridine
Figure imgf000278_0003
Step 1
Figure imgf000279_0001
3-(4-chloro-2-fluorophenyl)picolinonitrile:
[0667] A 20 mL microwave reaction tube was charged with 3-chloro-2- cyanopyridine (1.00 g, 7.2 mmol), 4-chloro-2-fluorophenylboronic acid (1.51 g, 8.7 mmol), Pd(PPh3)4 (417 mg, 0.36 mmol), K3P04 (3.8 g, 18 mmol) and DMF (15 mL). After 02 was purged by bubbling N2 into the reaction solution, the tube was sealed and heated at 150 °C for 0.5 h in a Biotage microwave reactor. Work-up: the reaction mixture was poured into water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 50% CH2C12 in petroleum ether, to afford 0.53 g
(32%) of the product as white solids. *H NMR (300 MHz, CDC13) δ: 8.73 (dd, J = 4.8, 1.6 Hz, 1H), 7.85 (dt, J = 8.0, 1.4 Hz, 1H), 7.60 (dd, J = 8.0, 4.7 Hz, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.33-7.26 (m, 2H).
Step 2
Figure imgf000279_0002
8-chlorobenzo[f][l,7]naphthyridin-5(6H)-one:
[0668] A 20 mL microwave reaction tube was charged with 3-(4-chloro-2- fluorophenyl)picolinonitrile (0.44 g, 1.9 mmol), KOH (0.53 g, 9.5 mol) and methanol (10 mL). The tube was sealed and heated at 120 °C for 1 h in a Biotage microwave reactor. Work-up: the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 4). The combined organic layers were dried over anhydrous Na2S04 and then concentrated in vacuo, to afford 0.24 g (55%) of the product as white solids. *H NMR (300 MHz, DMSO-d6) δ: 11.94 (br, 1H), 8.93- 8.87 (m, 2H), 8.41 (d, J = 8.8 Hz, 1H), 7.83 (dd, J = 8.2, 4.4 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 8.8, 2.0 Hz, 1H).
Step 3
Figure imgf000280_0001
5,8-dichlorobenzo[f][l,7]naphthyridine:
[0669] A 100 mL round bottom flask was charged with 8- chlorobenzo[f][l,7]naphthyridin-5(6H)-one (0.24 g, 1.0 mmol) and POCl3 (50 mL). The resulting mixture was refluxed for 3 h and then concentrated in vacuo. The residue was carefully diluted with saturated aqueous NaHCC>3 (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04 then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 0-2% CH3OH in CH2CI2, to afford 0.20 g (77%) of the product as white solids. *H NMR (300 MHz, CDC13) δ: 9.16 (dd, J = 4.4, 1.5 Hz, 1H), 8.86 (dd, J = 8.5, 1.5 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.85 (dd, J = 8.5, 4.4 Hz, 1H), 7.69 (dd, J = 8.8, 2.2 Hz, 1H).
Step 4
Figure imgf000280_0002
8-chloro-5-(4-methylpiperazin-l-yl)benzo[f][l,7]naphthyridine:
[0670] A 20 mL microwave reaction tube was charged with 5,8- dichlorobenzo[f][l,7]naphthyridine (0.24 g, 0.96 mmol), N-methylpiperazine (0.33 mL, 3.0 mmol) and THF (10 mL). The tube was sealed and heated at 90 °C for 1 h in a Biotage microwave reactor. Work-up: the reaction mixture was poured into saturated aqueous NaHCC>3 (60 mL) and extracted with CH2CI2 (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with CH2C12 (saturated with NH3), to afford 0.26 g (86%) of the product as off- white solids. *H NMR (300 MHz, CDC13) δ: 8.91 (dd, J = 4.3, 1.7 Hz, 1H), 8.74 (dd, J = 8.4, 1.7 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.66 (dd, J = 8.4, 4.3 Hz, 1H), 7.36 (dd, J = 8.7, 2.1 Hz, 1H), 4.13 (t, J = 4.7 Hz, 4H), 2.70 (t, J = 5.0 Hz, 4H), 2.39 (s, 3H). MS: m/z 313 (M+H+).
EXAMPLE 250
8-chloro-5-(4-methylpiperazin-l-yl)pyrazino[2,3-c]quinoline
Figure imgf000281_0001
[0671] The title compound was prepared as described in Example 229, except that 2-chloro-3-cyanopyrazine was substituted for 3-chloro-2-cyanopyridine as the starting material. *H NMR (300 MHz, CDC13) δ: 8.96 (d, J = 1.9 Hz, 1H), 8.82 (d, J = 1.9 Hz, 1H), 8.71 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.39 (dd, J = 8.7, 2.1 Hz, 1H), 4.14 (t, J = 5.0 Hz, 4H), 2.68 (t, J = 5.0 Hz, 4H), 2.39 (s, 3H). MS: m/z 314 (M+H+).
Figure imgf000281_0002
EXAMPLE 251
8-Chloro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoline
Figure imgf000282_0001
Step 1
Figure imgf000282_0002
3-Ethoxyacryloyl chloride:
[0672] A 50 mL round bottom flask was charged with ethyl 3,3- diethoxypropionate (1.7 g, 8.9 mmol), LiOH (0.75 g, 18 mmol), THF (5 mL) and H20 (10 mL). The mixture was heated at 80 °C for 1 h then cooled to room temperature and acidified with concentrated HC1. The product was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo, to afford 1.43 g of the product as bright yellow oil. It was then treated with thionyl chloride (7 mL) at 80 °C for 1 h. Evaporation of the solvent provided the title compound as yellow oil with quantitative yield, which was used in next step without further purification.
Step 2
Figure imgf000282_0003
N-(3-Chlorophenyl)-3-ethoxyacrylamide:
[0673] A 50 mL round bottom flask was charged with 3-chloroaniline (1.12 g, 8.80 mmol), pyridine (1.5 mL, 8.8 mmol) and dichloromethane (15 mL). To the mixture was added dropwise a solution of 3-ethoxyacryloyl chloride (2.2 g, 16 mmol) in dichloromethane (5 mL). The resulting solution was stirred overnight at room temperature. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :4). Work-up: the reaction mixture was diluted with EtO Ac (50 mL). The organic solution was washed with brine (40 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash chromatography on silica gel with 10% EtO Ac in petroleum ether, to afford 1.5 g (74%) of the product as light yellow crystals.
Step 3
Figure imgf000283_0001
7- Chloroquinolin-2( 1H) -one :
[0674] A 50 mL round bottom flask was charged with concentrated sulfuric acid (15 mL). To the above was added in portions N-(3-chlorophenyl)-3- ethoxyacrylamide (1.5 g, 13 mmol). The resulting mixture was stirred at room temperature for 1.5 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 : 1). Work-up: the reaction mixture was poured into ice water and stirred for 15 min. The white precipitate was collected by filtration and washed with more water. It was recrystallized from acetic acid, to afford 0.94 g (40%) of the product as white crystals.
Step 4
Figure imgf000283_0002
3-Bromo-7-chloroquinolin-2(lH)-one:
[0675] A 50 mL round bottom flask was charged with 7-chloroquinolin-2(lH)- one (0.37 g, 2.1 mmol) and DMF (15 mL). To the solution was added N- bromosuccinimide (0.56 g, 3.1 mmol). The resulting mixture was heated at 60 °C for 3 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :1). Work-up: the reaction mixture was poured into water and extracted with EtO Ac. The organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 50% EtOAc in petroleum ether, to afford 0.38 g (68%) of the product as light yellow crystals.
Step 5
Figure imgf000284_0001
3-Bromo-2,7-dichloroquinoline:
[0676] A 50 mL round bottom flask was charged with 3-bromo-7- chloroquinolin-2(lH)-one (0.40 g, 1.6 mmol) and phosphorus oxychloride (10 mL). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 : 10). Work-up: after the reaction mixture was cooled to room temperature, it was cautiously poured into ice water. The precipitate was collected by filtration and re-dissolved in EtO Ac (20 mL). The organic solution was washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated in vacuo, to afford 0.31 g (72%) of the product as white solid.
Step 6
Figure imgf000284_0002
3-Bromo-7-chloro-2-hydrazinylquinoline:
[0677] A 50 mL round bottom flask was charged with 3-bromo-2,7- dichloroquinoline (0.31 g, 1.1 mmol) and EtOH (10 mL). To the solution was added dropwise hydrazine hydrate (0.10 g, 2.8 mmol). The solution was heated at 60 °C overnight. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :2). Work-up: the reaction mixture was filtered. The filtrate was concentrated then petroleum ether (20 mL) was added. The resulting solid was collected by filtration and dried, to afford 0.23 g (77%) of the product as light yellow solid. Step 7
Figure imgf000285_0001
4-Bromo-8-chloro-[l,2,4]triazolo[4,3-a]quinoline:
[0678] A 50 mL round bottom flask was charged with 3-bromo-7-chloro-2- hydrazinylquinoline (0.34 g, 1.3 mmol) and triethyl orthoformate (10 mL). The resulting mixture was stirred at 130 °C for 1 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :2). Work-up: the resulting solid was collected by filtration, washed with EtOH (10 mL x 2) and dried, to afford 0.27 g (78%) of the product as light yellow powder.
Step 8
Figure imgf000285_0002
8-Chloro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoline:
[0679] A 50 mL round bottom flask was charged with 4-bromo-8-chloro- [l,2,4]triazolo[4,3-a]quinoline (0.15 g, 0.53 mmol), N-methylpiperazine (0.11 g, 1.1 mmol), Cul (0.20 g, 1.1 mmol), L-proline (0.061 g, 0.53 mmol), K3P04 (0.23 g, 1.1 mmol) and DMSO (5 mL). The resulting mixture was heated at 120 °C for 1 h under N2 atmosphere. Work-up: the reaction mixture was poured into brine (20 mL) and extracted with CH2CI2 (30 mL). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash chromatography on silica gel with 5% MeOH in CH2C12, to afford 30 mg (21 %) of the product as light yellow crystals. *H NMR (300 MHz, CDC13) δ: 9.15 (s, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 1.8 Hz, 1H), 6.59 (s, 1H), 3.69 (t, J = 4.5 Hz, 4H), 2.71 (t, J = 5.1 Hz, 4H), 2.39 (s, 3H). MS m/z: 302 (M+H+).
Figure imgf000286_0001
EXAMPLE 252
9-Chloro-5-(piperazin-l-yl)pyrimido[4,5-c]quinoline
Figure imgf000286_0002
tert-Butyl 4-(8-chloroisoxazolo[3,4-c]quinolin-4-yl)piperazine-l-carboxylate:
[0680] The title compound was prepared as described in Example 166, except that N-BOC-piperazine was substituted for N-methylpiperazine in the last step of that route.
Step 9
Figure imgf000287_0001
tert-Butyl 4-(3-amino-6-chloro-4-(hydroxymethyl)quinolin-2-yl)piperazine-l- carboxylate:
[0681] A 250 mL 3-necked round bottom flask was charged with tert-butyl 4- (8-chloroisoxazolo[3,4-c]quinolin-4-yl)piperazine-l-carboxylate (~7 mmol, crude) and ethanol (100 mL). The reaction mixture was refluxed for 6 h and NaBH4 (0.89 g x 4, 94 mmol) was added in portions. It was cooled to room temperature and poured into 0.2 M HCl (150 mL). The resulting mixture was stirred for 10 min and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated aqueous NaHCC^ (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 20-60% ethyl acetate in petroleum ether, to afford 1.0 g (36%) of the product as light-brown solid. !H NMR (300
MHz, CDC13) δ: 7.73 (d, J = 1.8 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.30 (dd, J = 8.7, 2.1 Hz, 1H), 5.03 (s, 2H), 4.70 (br, 2H), 3.61 (t, J = 5.2 Hz, 4H), 3.19 (t, J = 5.2 Hz, 4H), 1.48 (s, 9H). Step 10
Figure imgf000288_0001
tert-Butyl 4-(3-amino-6-chloro-4-formylquinolin-2-yl)piperazine-l- carboxylate:
[0682] A 250 mL round bottom flask was charged with tert-butyl 4-(3-amino-6- chloro-4-(hydroxymethyl)quinolin-2-yl)piperazine-l-carboxylate (1.0 g, 2.5 mmol), Mn02 (5.5 g, freshly prepared from MnS04 and KMn04, 63 mmol) and CHC13 (100 mL). The suspension was stirred for 20 h at 40 °C under N2. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :2). Work-up: the mixture was filtered through Celite and the solids were washed with EtOAc (500 mL). The combined solutions were concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with 10-20% ethyl acetate in petroleum ether, to afford 0.78 g (78%) of the product as orange solid. *H NMR (300 MHz,
CDCI3) δ: 10.78 (s, 1H), 8.19 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 3.67 (br, 4H), 3.28 (br, 4H), 1.49 (s, 9H).
Step 11
Figure imgf000288_0002
tert-Butyl 4-(9-chloropyrimido[4,5-c]quinolin-5-yl)piperazine-l-carboxylate:
[0683] Each of two 20 mL microwave reaction tubes was charged with tert- butyl 4-(3-amino-6-chloro-4-formylquinolin-2-yl)piperazine-l-carboxylate (0.39 g, 1.0 mmol), formamide (15 mL) and acetic acid (2 mL). Both tubes were sealed and heated at 100 °C for 4 h in a Biotage microwave reactor. Work-up: the reaction mixtures were combined and poured into saturated aqueous NaHCC>3 (150 mL) and extracted with ethyl aceate (150 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 4-20% ethyl acetate in CH2C12, to afford 0.31 g (39%) of the product as light-brown solid.
*H NMR (300 MHz, CDC13) δ: 9.96 (s, 1H), 9.46 (s, 1H), 8.35 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 8.7, 2.1 Hz, 1H), 4.08 (t, J = 5.1 Hz, 4H), 3.69 (t, J = 5.1 Hz, 4H), 1.50 (s, 9H).
Step 12
Figure imgf000289_0001
9-Chloro-5-(piperazin-l-yl)pyrimido[4,5-c]quinoline:
[0684] A 100 mL round bottom flask was charged with tert-butyl 4-(9- chloropyrimido[4,5-c]quinolin-5-yl)piperazine-l-carboxylate (0.30 g, 0.75 mmol) and THF (25 mL). To the solution was added concentrated HC1 (5 mL) and the resulting slurry was refluxed for 20 min. The reaction mixture was then allowed to cool to room temperature and neutralized with Na2CC>3. It was diluted with water and extracted with CH2C12 (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with CH2C12, to afford 0.11 g (49%) of the product as yellow solid. *H NMR (300 MHz, CD3OD/CDCI3) δ: 10.04 (s, 1H), 9.40 (s, 1H), 8.47 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.60 (dd, J = 9.0, 2.2 Hz, 1H), 4.06 (t, J = 5.1 Hz, 4H), 3.09 (t, J = 5.1 Hz, 4H). MS m/z: 300 (M+H+). EXAMPLE 253
9-Chloro-5-(4-methylpiperazin-l-yl)pyrimido[4,5-c]quinoline
Figure imgf000290_0001
[0685] The title compound was prepared as described in Example 252, except that N-methylpiperazine was substituted for N-BOC-piperazine in step 8 of that route. *H NMR (300 MHz, CDC13) δ: 9.91 (s, 1H), 9.44 (s, 1H), 8.29 (d, J = 0.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.7, 1.2 Hz, 1H), 4.21 (br, 4H), 2.81 (br, 4H), 2.47 (s, 3H). MS m/z: 314 (M+H+).
Figure imgf000290_0002
EXAMPLE 254
8-Chloro-4-(4-methylpip 3]triazolo[4,5-c]quinoline
Figure imgf000290_0003
Step 1
Figure imgf000290_0004
6-Chloro-4-hydroxy-3-nitroquinolin-2(lH)-one:
[0686] A I L 3-necked round bottom flask was charged with ethyl nitroacetate (16 mL, 144 mmol), Et3N (20 mL, 144 mmol) and anhydrous THF (400 mL). To the above was added dropwise a solution of 6-chloro-lH-benzo[d] l ,3-oxazine-2,4- dione (19 g, 96 mmol) in THF (100 mL). The resulting solution was heated at 55 °C overnight then concentrated under reduced pressure. The residue was washed with Et20 then dissolved in water and acidified with 6 M HC1. The precipitate was collected by filtration, washed with H20 and dried, to afford 16 g (90%) of the product as yellow solid. *H NMR (300 MHz, DMSO-d6) δ: 11.85 (br, 1H), 8.00 (d, J = 2.7 Hz, 1H), 7.64 (dd, J = 8.4, 2.1 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H).
Step 2
Figure imgf000291_0001
2,4,6-Trichloro-3-nitroquinoline:
[0687] A 100 mL round bottom flask was charged with 6-chloro-4-hydroxy-3- nitroquinolin-2(lH)-one (5.0 g, 21 mmol) and pyridine (5 mL). To the mixture was added dropwise POCI3 (25 mL) over a period of 1 h while keeping the temperature below 50°C. The suspension was heated at reflux for 2.5 h then cooled to room temperature and concentrated in vacuo. The residue was poured into saturated aqueous NaHCC>3 and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash chromatography on silica gel with 2.5% EtOAc in petroleum ether, to afford 3.5 g (70%) of the product as white solid.
Step 3
Figure imgf000291_0002
2,6-Dichloro-3-nitroquinolin-4-amine:
[0688] A 250 mL round bottom flask was charged with 2,4,6-trichloro-3- nitroquinoline (3.5 g, 13 mmol) and ammonia in 1.4-dioxane solution (150 mL). The mixture was heated at 30 °C for 4 h then concentrated in vacuo. The residue was poured into saturated aqueous NaHCC>3 and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 3.0 g (86%) of the product as white solid. MS m/z: 258 (M+H+).
Step 4
Figure imgf000292_0001
6-Chloro-2-(4-methylpiperazin-l-yl)-3-nitroquinolin-4-amine:
[0689] A 20 mL microwave reaction tube was charged with 2,6-dichloro-3- nitroquinolin-4-amine (1.0 g, 3.9 mmol), N-methylpiperazine (0.78 g, 7.8 mmol) and EtOH (15 mL). The resulting solution was heated at 130 °C for 1 h in a Biotage microwave reactor. The solvent was evaporated and the residue was purified by flash chromatography on silica gel with 10% MeOH in CH2CI2, to afford 0.8 g (80%) of the product as white solid. MS m/z: 321 (M+H+).
Step 5
Figure imgf000292_0002
6-Chloro-2-(4-methylpiperazin-l-yl)quinoline-3,4-diamine:
[0690] A 250 mL round bottom flask was charged with 6-chloro-2-(4- methylpiperazin-l-yl)-3-nitroquinolin-4-amine (3.2 g, 10 mmol), Na2S204 (8.0 g, 45 mmol), H20 (45 mL) and EtOH (90 mL). The mixture was heated at reflux for 1 h. Work-up: the solvent was evaporated. The residue was suspended in
triethylamine (15 mL) and ethyl acetate (300 mL), and then filtered. The filtrate was concentrated in vacuo, to afford 2.3 g (72%) of the product as pale-red solid. MS m/z: 292 (M+H+).
Step 6
Figure imgf000293_0001
8-Chloro-4-(4-methylpiperazin-l-yl)-lH-[l,2,3]triazolo[4,5-c]quinoline:
[0691] A 50 mL round bottom flask was charged with 6-chloro-2-(4- methylpiperazin-l-yl)quinoline-3,4-diamine (0.30 g, 1.0 mmol) and CH3COOH (10 mL). To the above was added dropwise a solution of NaN02 (0.10 g, 1.5 mmol) in water (1 mL) at 10 °C. The resulting mixture was stirred at 10 °C for 1 h. Work up: the reaction mixture was neutralized with saturated aqueous Na2CC>3 and extracted with ethyl acetate (20 mL x 3). The combined organic layers were concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with 10% MeOH in CH2C12, to afford 0.10 g (33%) of the product as white solid. *H NMR (300 MHz, CD3OD) δ: 8.14 (d, J = 3.3 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.51 (dd, J = 9.0, 2.4 Hz, 1H), 4.50 (br, 4H), 3.30 (t, J = 5.1 Hz, 4H), 2.65 (s, 3H). MS m/z: 303 (M+H+).
EXAMPLE 255
8-Chloro-4-(piperazin-l-yl)-lH-[l,2,3]triazolo[4,5-c]quinoline
Figure imgf000293_0002
[0692] The title compound was prepared as described in Example 254, except that piperizine was substituted for N-methylpiperazine in step 4 of that route. 1H NMR (300 MHz, CD3OD) δ: 7.52 (m, 2H), 7.41 (m, 1H), 4.52 (m, 4H), 3.47 (m, 4H). MS m/z: 289 (M+H+).
[0693] The following examples were prepared analogously to previously illustrated examples, as indicated in Table 1, but using appropriate starting materials.
Table 1.
Figure imgf000294_0001
Mass Prepared
Example Overall
Structure Spectrum analogously to
# Yield
(M+H+) Example #
Example
321 5.0% 224 256
Example
307 4.0% 224 257
Example
347 7.0% 243 258
Example
333 5.7% 243 259
Example
367 14.2% 224 260
Example
353 12.1% 224 261
Example
365 21.3% 92 262
Figure imgf000296_0001
N-(4-
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Mass Prepared
Example Overall
Structure Spectrum analogously to
# Yield
(M+H+) Example #
Example
337 36.1% 34 303
Example
377 35.9% 34 304
Example
328 10.1% 34 305
Example
314 10.3% 34 306
Example
328 9.8% 201 307
Example
314 9.6% 201 308
Example
365 56.9% 92 309
Figure imgf000303_0001
step:
Figure imgf000304_0001
Figure imgf000305_0001
of Example 325. Mass Prepared
Example Overall
Structure Spectrum analogously to
# Yield
(M+H+) Example #
Example
361 0.8% 34 330
Example
347 0.3% 34 331
Example
332 18.0% 16 332
Example
361 0.7% 34 333
Comment to Example 333: Isomer isolated by preprative HPLC in the purification of Example 330.
Example
347 0.2% 34 334
Comment to Example 334: Isomer isolated by preprative HPLC in the purification of Example 331.
Example
355 2.4% 243 335
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
the
Figure imgf000315_0001
Figure imgf000316_0001
difluoroaniline to N02: WO2007/36715 A2 step:
Figure imgf000317_0001
Figure imgf000318_0001
aldehyde then converted into CF2H- group. Mass Prepared
Example Overall
Structure Spectrum analogously to
# Yield
(M+H+) Example #
Example
298 9.7% 23 414
Comment to Examole 414: From the product of Example 411, ester was reduced to primary alcohol.
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
EXAMPLE 415
4-(piperazin-l-yl)-4,5-dihydrotetrazolo[l,5-a]quinoxaline-8-carbonitrile trifluoroacetate
Figure imgf000332_0002
Step 1
Figure imgf000333_0001
2,3-dioxo-l,2,3,4-tetrahydroquinoxaline-6-carbonitrile
[0694] A suspension of 3,4-diaminobenzonitrile (6.28 g, 47.2 mmol, 100 mol %) and oxalic acid (6.15 g, 68.3 mmol, 145 mol%) in 4M aqueous HC1 (60 mL) was refluxed for 3 h. The reaction was cooled to room temperature and filtered. The solid was washed with water and azeotropically dried with 3 x 10 mL portions of toluene to afford the title compound as a light tan solid (8.44 g, 96%). MS, m/z = 188 for [M+H]+. *H NMR (400 MHz, DMSO-d6) δ: 12.21 (s, 1H), 12.02 (s, 1H), 7.51 (dd, J = 8 Hz, 2 Hz, 1H), 7.40 (d, J = 2 Hz, 1H), 7.22 (d, J = 8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 155.06 (C), 154.70 (C), 129.79 (C), 126.80 (CH), 126.31 (CH), 118.63 (C), 118.26 (CH), 115.96 (CH). 104.55 (C). Both the !H and 13C NMR spectra indicated the presence of tautomeric 2,3-dihydroxyquinoxaline-6- carbonitrile (shown below) as a minor component (-10%).
Figure imgf000333_0002
2,3-dihydroxyquinoxaline-6- carbonitrile
Step 2
Figure imgf000333_0003
2,3-dichloroquinoxaline-6-carbonitrile
[0695] A suspension of 2,3-dioxo-l ,2,3,4-tetrahydroquinoxaline-6-carbonitrile (8.40 g, 44.9 mmol, 100 mol%), SOCl2 (9.2 mL, 15 g, 130 mol%), Ν,Ν,- dimethylformamide (0.52 mL, 490 mg, 6.7 mmol, 15 mol%), and 1,2- dichloroethane (60 mL) was refluxed for 5 h, cooled to room temperature, and added to 150 mL of ice water. The precipitate was filtered, washed with water and CH2CI2, and azeotropically dried with toluene to afford the title compound (10.92 g, > 100% nominal yield), which contained residual toluene by 1H NMR analysis. 1H NMR (400 MHz, CDC13) δ: 8.40 (dd, J = 2 Hz, 1 Hz, 1H), 8.15 (dd, J = 9 Hz, 1 Hz, 1H), 7.97 (dd, J = 9 Hz, 2 Hz, 1H). 13C NMR (100 MHz, CDC13) δ: 148.57 (C), 147.85 (C), 141.87 (C), 139.66 (C), 133.78 (CH), 132.16 (CH), 129.85 (CH), 117.20 (C), 114.86 (C).
Step 3
Figure imgf000334_0001
tert-butyl 4-(3-chloro-6-cyanoquinoxalin-2-yl)piperazine-l-carboxylate
[0696] A suspension of2,3-dichloroquinoxaline-6-carbonitrile (2.73 g, 12.2 mmol, 100 mol ) and tert-butyl piperazine-l-carboxylate (3.25 g, 17.4 mmmol, 143 mol ) in absolute ethanol (50 mL) was stirred at room temperature for 18 h. Water (50 mL) was added and the suspension was filtered to afford a solid (2.25 g) and a filtrate. The filtrate was extracted with ethyl acetate (2 x 100 mL), dried (MgS04), and filtered. This filtrate was combined with the previously isolated solid and concentrated on silica gel (6.5 g). The residue was chromatographed on silica gel (100 g) eluting with a 10 →25 →40 gradient of ethyl acetate in hexanes to afford the title compound as a yellow solid (2.73 g, 59%). MS, m/z = 274 for [M+H-C02Bu ]+. *H NMR (400 MHz, DMSO-d6) δ: 8.46 (d, J = 2 Hz, 1H), 8.01 (dd, J = 8 Hz, 2 Hz, 1H), 7.88 (dd, J = 8 Hz, 1 Hz, 1H), 3.64 -3.62 (br m, 4H), 3.55-3.53 (br m, 4H), 1.44 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ: 153.94 (C), 152.92 (C), 142.67 (C), 141.72 (C), 136.26 (C), 132.96 (CH), 131.86 (CH), 127.80 (CH), 118.36 (C), 108.78 (C), 79.16 (C), 48.15 (CH2), 42.5 (br, CH2), 28.03 (CH3).
Step 4
Figure imgf000334_0002
tert-butyl 4-(8-cyanotetrazolo[l,5-a]quinoxalin-4-yl)piperazine-l-carboxylate
[0697] A suspension of tert-butyl 4-(3-chloro-6-cyanoquinoxalin-2- yl)piperazine-l-carboxylate (1.67 g, 4.47 mmol, 100 mol%), sodium azide (2.46 g, 37.8 mmol, 846 mol ), and absolute ethanol (47 mL) was refluxed for 20 h. After cooling to room temperature, 70 mL of a 1 :1 v:v mixture of watenethyl acetate was added to the suspension, which was then filtered to afford the title compound as an ivory solid (1.00 g, 59%). MS, m/z = 281 for [M+H-C02Bu ]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.83 (d, J = 2 Hz, 1H), 8.01 (d, J = 8 Hz, 1H), 7.80 (d, J = 8 Hz, 1H), 4.4 (br s, 4H), 3.59 (t, J = 5 Hz, 4H), 1.46 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ: 153.54 (C), 144.89 (C), 139.36 (C), 138.04 (C), 131.42 (CH), 126.50 (CH), 120.83 (C), 119.52 (CH), 116.89 (C), 106.45 (C), 79.64 (C), 42.87 (CH2), 27.84 (CH3).
Step 5
Figure imgf000335_0001
4-(piperazin-l-yl)-4,5-dihydrotetrazolo[l,5-a]quinoxaline-8-carbonitrile trifluoroacetate
[0698] To a 0 °C solution of tert-butyl 4-(8-cyanotetrazolo[l,5-a]quinoxalin-4- yl)piperazine-l-carboxylate (940 mg, 2.47 mmol) in CH2C12 (33 mL) was added trifluoroacetic acid (6 mL). After 30 min the reaction was warmed to room temperature. After an additional 2.5 h the reaction was concentrated to afford a viscous orange oil. Addition of warm MeOH (15 mL) afforded a white precipitate, which was filtered to afford the title compound (582 mg, 60%). MS, m/z = 281 for
[M+H]+ of free base. *H NMR (400 MHz, DMSO-d6) δ: 9.28 (br s, 2H), 8.91 (d, J = 2 Hz, 1H), 8.07 (dd, J = 8 Hz, 2 Hz, 1H), 7.87 (d, J = 8 Hz, 1H), 4.58 (br s, 4H), 3.38 (t, J = 5 Hz, 4H). 13C NMR (100 MHz, DMSO-d6) δ: 158.28 (q, J = 31 Hz, C), 146.58 (C), 139.89 (C), 139.55 (C), 132.61 (CH), 127.14 (CH), 122.04 (C), 120.54 (CH), 118.12 (C), 106.40 (C), 43.0 (very br, CH2), 42.50 (CH2). Elemental analysis for Ci3H12N8-CF3C02H: calculated, C 45.69%, H 3.32%, N 28.42%; found, C 45.56%, H 3.21%, N 28.43%. EXAMPLE 416
4-(4-methylpiperazin- -yl)tetrazolo[l,5-a]quinoxaline-8-carbonitrile
Figure imgf000336_0001
[0699] To a mixture of 4-(piperazin-l-yl)-4,5-dihydrotetrazolo[l,5- a]quinoxaline-8-carbonitrile trifluoroacetate (192 mg, 0.487 mmol, 100 mol ), 37% aqueous formaldehyde (1.2 mL = 440 mg of active formaldehyde, 15 mmol, 3000 mol%), MeOH (3 mL), and CH2C12 (3 mL) was added NaCNBH3 (93 mg, 1.5 mmol, 310 mol%). After 2 h aqueous saturated NaHCC>3 was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with saturated aqueous NaCl (2 x 5 mL), dried (MgS04), filtered, and concentrated to afford a yellow oil. Addition of warm MeOH (10 mL) precipated the title compound as an ivory solid (78 mg after filtration, 55%). MS, m/z = 295 for {M+H]+. *H NMR (400 MHz, DMSO-d6) δ: 8.81 (d, J = 2 Hz, 1H), 8.00 (dd, J = 9 Hz, 2 Hz, 1H), 7.79 (d, J = 9 Hz, 1H), 4.38 (very br s, 4H), 2.55 (t, J = 5 Hz, 4H), 2.27 (s, 3H). 13C NMR (100 MHz, DMSO- d6) δ: 146.36 (C), 140.54 (C), 139.56 (C), 132.38 (CH), 126.75 (C), 121.85 (C), 120.38 (CH), 118.29 (C), 105.35 (C), 54.33 (CH2), 45.50 (CH3).
EXAMPLE 417
7-Fluoro-2-methyl-4-(4-methylpiperazin-l-yl)oxazolo[4,5-c]quinoline-8- carbonitrile
Figure imgf000336_0002
[0700] The title compound was prepared analogously to Example 145. JH NMR (300 MHz, CDC13) δ: 8.17 (d, J = 6.9 Hz, 1H), 7.42 (d, J = 10.8 Hz, 1H), 4.37 (br, 4H), 2.71 (s, 3H), 2.58 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 326 (M+H+).
Figure imgf000337_0001
EXAMPLE 418
9-Bromo-10-fluoro-5-(pip triazolo[l,5-c]quinazoline
Figure imgf000337_0002
Step 1
Figure imgf000337_0003
6-Amino-3-bromo-2-fluorobenzonitrile:
[0701] A 100 mL round bottom flask was charged with 2-amino-6- fluorobenzonitrile (6.8 g, 50 mmol), N-bromosuccinimide (8.9 g, 50 mmol), and DMF (70 mL). The resulting solution was stirred at room temperature for 20 minutes. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1:4). Work-up: the reaction mixture was poured into ice water. The white precipitate was collected by filtration and washed with water. It was further purified by recrystallization from 5% MeOH in petroleum ether to afford 8.7 g (61%) of the product. *H NMR (400 MHz, CDC13) δ: 7.42 (t, J = 8.8 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 4.62 (br, 2H).
Step 2
Figure imgf000337_0004
Ethyl (4-bromo-2-cyano-3-fluorophenyl)carbamate:
[0702] A 100 mL round bottom flask was charged with 6-amino-3-bromo-2- fluorobenzonitrile (4.3 g, 20 mmol), Na2CC>3 (4.2 g, 40 mmol) and ethyl chloroformate (70 mL). The resulting solution was stirred overnight at reflux.
Work-up: the reaction mixture was concentrated in vacuo. The residue was re- dissolved in dichloromethane (150 mL) and filtered. The filtrate was concentrated in vacuo, to afford 5.6 g (98%) of the product. MS m/z: 287 (M+H+).
Step 3
Figure imgf000338_0001
9-Bromo-10-fluoro-[l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one:
[0703] A 100 mL round bottom flask was charged with ethyl (4-bromo-2- cyano-3-fluorophenyl)carbamate (2.87 g, 10 mmol), formic hydrazide (0.72 g, 12 mmol) and l-methyl-2-pyrrolidone (70 mL). The resulting mixture was heated at 180 °C for 1.5 h. Work-up: the reaction mixture was poured into ice water. The precipitate was collected by filtration and dried to afford 2.8 g (92%) of the product. *H NMR (400 MHz, DMSO-d6) δ: 12.61 (br, 1H), 8.60 (s, 1H), 7.96 (dd, J = 8.8, 8.0 Ηζ,ΙΗ), 7.21 (d, J = 8.8 Hz, 1H). MS m/z: 281 (M-H+).
Step 4
Figure imgf000338_0002
9-Bromo-5-chloro-10-fluoro-[l,2,4]triazolo[l,5-c]quinazoline:
[0704] A 100 mL round bottom flask was charged with 9-bromo-10-fluoro- [l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one (2.8 g, 9.9 mmol) and POCl3 (50 mL). After N,N-diisopropylethylamine (1.9 g, 15.0 mmol) was added dropwise at 0 °C, the resulting solution was heated at reflux for 3 days then concentrated in vacuo. The residue was carefully mixed with saturated aqueous Na2C03 and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2S04 and then concentrated in vacuo. It was further purified by recrystallization from 20% EtOAc in petroleum ether to afford 1.66 g (55%) of the product. MS m/z: 299 (M-H+). Step 5
Figure imgf000339_0001
tert-Butyl 4-(9-bromo-10-fluoro-[l,2,4]triazolo[l,5-c]quinazolin-5- yl)piperazine-l-carboxylate:
[0705] A 50 mL round bottom flask was charged with 9-bromo-5-chloro-10- fluoro-[l,2,4]triazolo[l,5-c]quinazoline (301 mg, 1.0 mmol), N-Boc-piperazine (372 mg, 2.0 mmol) and EtOH (5 mL). The resulting solution was stirred at room temperature for 1 h then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 208 mg (46%) of the product. 1H NMR (400 MHz, CDC13) δ: 8.43 (s, 1H), 7.78 (dd, J = 8.8, 7.6 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 4.10 (t, J = 4.8 Hz, 4H), 3.68 (t, J = 4.8 Hz, 4H), 1.51 (s, 9H). MS m/z: 451 (M+H+).
Step 6
Figure imgf000339_0002
9- Bromo-10-fluoro-5-(piperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline HCl salt:
[0706] A 25 mL round bottom flask was charged with tert-butyl 4-(9-bromo-
10- fluoro-[l,2,4]triazolo[l,5-c]quinazolin-5-yl)piperazine-l-carboxylate (100 mg, 0.22 mmol), trifluoroacetic acid (2 mL) and dichloromethane (5 mL). The resulting solution was stirred at room temperature for 2 h. Work-up: the reaction solution was neutralized with saturated aqueous Na2CC>3 and extracted with
dichloromethane (10 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and then concentrated in vacuo, to afford 70 mg (90%) of the product. It was then converted into the corresponding HCl salt by treating with the HCl in EtOAc solution. *H NMR (400 MHz, D20) δ: 8.58 (s, 1H), 7.90 (dd, J = 8.8, 7.6 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 4.27 (t, J = 5.2 Hz, 4H), 3.57 (t, J = 5.2 Hz, 4H). MS m/z: 351 (M+H+).
Figure imgf000340_0001
EXAMPLE 419
10-Fluoro-5-(piperazin-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000340_0002
tert-Butyl (3-fluoro-4-(trifluoromethyl)phenyl)carbamate:
[0707] A 2 L round bottom flask was charged with 3-fluoro-4- (trifluoromethyl)aniline (150 g, 0.84 mol), di-tert-butyl dicarbonate (850 g, 3.89 mol), triethylamine (423 g, 4.19 mol) and THF (1.5 L). The resulting mixture was stirred overnight at reflux. Reaction progress was monitored by TLC
(EtO Ac/Petroleum ether = 1 :10). Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a 1 :100 EtO Ac/Petroleum ether, to afford 328 g (quantitative) of the di-Boc protected aniline product. [0708] A 2 L round bottom flask was charged with the above di-Boc protected aniline product (100 g, 0.26 mol), K2C03 (73 g, 0.53 mol) and MeOH (1 L). The resulting mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :20). Work-up: the reaction mixture was filtered. The filtrate was concentrated in vacuo. The solid obtained was rinsed with water, and dried to afford 70 g (97 %) of the product. *H NMR (300 MHz, CDC13) δ: 7.52-7.43 (m, 2H), 7.03 (m, 1H), 6.68 (br, 1H), 1.52 (s, 9H).
Step 3
Figure imgf000341_0001
tert-Butyl (3-fluoro-2-iodo-4-(trifluoromethyl)phenyl)carbamate:
[0709] A 2 L 3-necked round bottom flask was charged with tert-butyl (3- fluoro-4-(trifluoromethyl)phenyl)carbamate (90 g, 0.32 mol) and dry THF (500 mL). To the above was added dropwise n-BuLi solution (2.5 M, 0.9 L, 2.25 mol) with the inner temperature kept below -65 °C. The resulting mixture was stirred at - 78 °C for 1 h, followed by dropwise addition of a solution of I2 (571 g, 2.25 mmol) in dry THF (1.3 L) with the inner temperature kept below -65 °C. The reaction mixture was allowed to warm to room temperature and stirred at that temperature overnight. Saturated aqueous NH4CI (100 mL) was added slowly, followed by the addition of saturated aqueous NaHSC>3 (1 L). The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to remove 90% of the solvent. To the hot residue was added MeOH (300 mL). The precipitate was collected by filtration and dried, to afford 50 g (38%) of the product as a white solid. The remained crude product from the filtrate was purified by flash column chromatography on silica gel, to afford 21 g (16%) more of the product. *H NMR (300 MHz, CDC13) δ: 8.06 (d, J = 8.7 Hz, 1H), 7.54 (t, J = 8.7 Hz, 1H), 7.13 (br, 1H), 1.55 (s, 9H). Step 4
Figure imgf000342_0001
3-Fluoro-2-iodo-4-(trifluoromethyl)aniline:
[0710] A 500 mL round bottom flask was charged with tert-butyl (3-fluoro-2- iodo-4-(trifluoromethyl)phenyl)carbamate (64 g, 0.16 mol), THF (300 mL) and 12 M HC1 (80 mL). The resulting mixture was stirred at 60 °C overnight. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :10). Work-up: the solvent was evaporated to dryness, to afford 47 g (97%) of the product as a white solid. *H NMR (300 MHz, CDC13) δ: 7.32 (t, J = 8.4 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 4.61 (br, 2H).
Step 5
Figure imgf000342_0002
6-Amino-2-fluoro-3-(trifluoromethyl)benzonitrile:
[0711] A 500 mL round bottom flask was charged with 3-fluoro-2-iodo-4- (trifluoromethyl)aniline (40 g, 0.13 mol), CuCN (22 g, 0.25 mol), Pd(PPh3)4 (6.6 g, 5.7 mmol) and DMF (200 mL). The resulting mixture was heated at 110 °C overnight. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel, to afford 17 g (63%) of the product as a white solid. MS m/z: 203 (M-H+).
Step 6
Figure imgf000342_0003
Ethyl (2-cyano-3-fluoro-4-(trifluoromethyl)phenyl)carbamate:
[0712] A I L round bottom flask was charged with 6-amino-2-fluoro-3- (trifluoromethyl)benzonitrile (17 g, 83 mmol), Na2C03 (26 g, 250 mmol) and ethyl chloroformate (300 mL). The resulting mixture was heated at reflux for 24 h. Workup: the reaction mixture was filtered. The filtrate was concentrated in vacuo to remove 90% of the solvent. To the hot residue was added EtOAc (90 mL). The precipitate was collected by filtration and dried, to afford 12 g (52%) of the product as a yellow solid. The remained crude product from the filtrate was purified by flash column chromatography on silica gel, to afford 10 g (43%) more of the product. MS m/z: 275 (M-H+).
Step 7
Figure imgf000343_0001
10-Fluoro-9-(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one:
[0713] A 500 mL round bottom flask was charged with ethyl (2-cyano-3- fluoro-4-(trifluoromethyl)phenyl)carbamate (22 g, 80 mmol), formic hydrazide (7.1 g, 120 mmol) and 1 -methyl-2-pyrrolidinone (150 mL). The resulting mixture was heated at 180 °C for 1.5 h. Work-up: the reaction mixture was cooled to room temperature and poured into water (300 mL). The precipitate was collected by filtration, washed with EtOH, and dried, to afford 12 g (55%) of the product as a white solid.
Step 8
Figure imgf000343_0002
5-Chloro-10-fluoro-9-(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazoline:
[0714] A 500 mL round bottom flask was charged with lO-fluoro-9- (trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazolin-5(6H)-one (20 g, 73 mmol) and POCI3 (150 mL). To the above was added dropwise N,N-diisopropylethylamine (25 mL). The resulting mixture was heated at 120 °C overnight. Work-up: the solvent was evaporated. The residue was washed with EtOAc and the solid was collected by filtration and dried, to afford 10 g (47%) of the product. The remained crude product from the filtrate was purified by flash column chromatography on silica gel, to afford 2 g (9%) more of the product. Step 9
Figure imgf000344_0001
tert-Butyl 4-(10-fluoro-9-(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazolin-5- yl)piperazine-l-carboxylate:
[0715] A 250 mL round bottom flask was charged with 5-chloro-10-fluoro-9- (trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazoline (10 g, 34 mmol), N-Boc piperizine (8.2 g, 44 mmol), triethylamine (11 g, 0.11 mol) and EtOH (100 mL). The resulting solution was stirred at room temperature for 1 h and a white precipitate was developed. The solid was collected by filtration and dried, to afford 16 g (quantitative) of the product.
Step 10
Figure imgf000344_0002
10-Fluoro-5-(piperazin-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline:
[0716] A 250 mL round bottom flask was charged with tert-butyl 4-(10-fluoro- 9-(trifluoromethyl)- [ 1 ,2,4]triazolo[ 1 ,5-c]quinazolin-5-yl)piperazine- 1 -carboxylate (16 g, 34 mmol), dichloromethane (100 mL) and trifluoroacetic acid (40 mL). The resulting solution was stirred at room temperature overnight. Work-up: the solvent was evaporated. The residue was neutralized with saturated aqueous NaHCC>3 and extracted with EtOAc (150 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel, to afford 12 g (quantitative) of the product as a white solid. *H NMR (300 MHz, CD3OD) δ: 8.57 (s, 1H), 7.93 (t, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 4.31 (t, J = 5.1 Hz, 4H), 3.22 (t, J = 5.1 Hz, 4H), MS m/z: 341 (M+H+). EXAMPLE 420
10-Fluoro-5-(4-methylpiperazin-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000345_0001
[0717] The title compound was prepared as described in Example 419, except that N-methylpiperazine was substituted for N-Boc-piperazine in step 9 of that route. *H NMR (300 MHz, DMSO-d6) δ: 8.75 (s, 1H), 7.97 (t, J = 8.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 4.15 (t, J = 4.8 Hz, 4H), 2.55 (t, J = 4.8 Hz, 4H), 2.25 (s, 3H). MS m/z: 355 (M+H+).
EXAMPLE 421
9-Bromo-10-fluoro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000345_0002
[0718] The HC1 salt of the title compound was prepared as described in Example 418, except that N-methylpiperazine was substituted for N-Boc-piperazine in step 5 of that route. The compound was converted into the corresponding HC1 salt by treatment with HCl/EtOAc. *H NMR (400 MHz, D20) δ: 8.53 (s, 1H), 7.78 (t, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 4.96 (d, J = 14.0 Hz, 2H), 3.79 (d, J = 12.8 Hz, 2H), 3.64 (t, J = 13.2 Hz, 2H), 3.47 (t, J = 11.6 Hz, 2H), 3.06 (s, 3H). MS m/z: 365 (M+H+).
EXAMPLE 422
l-(10-Fluoro-9-(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazolin-5-yl)-N- methylazetidin-3-amine
Figure imgf000345_0003
[0719] The title compound was prepared as described in Example 419, except that 3-(N-tert-butoxycarbonyl-N-methylamino)azetidine was substituted for N-Boc- piperazine in step 9 of that route. *H NMR (300 MHz, CD3OD) δ: 8.42 (s, 1H), 7.76 (t, J = 8.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 4.73 (br, 2H), 4.32 (br, 2H), 3.78- 3.70 (m, 1H), 2.41 (s, 3H). MS m/z: 341 (M+H+).
Figure imgf000346_0001
EXAMPLE 423
l-(9-Bromo-8-fluoro-[l,2,4]triazolo[l,5-c]quinazolin-5-yl)-N-methylazetidin-3- amine
Figure imgf000346_0002
[0720] The title compound was prepared as described in Example 418, except that 2-amino-4-fluorobenzonitrile was substituted for 2-amino-6-fluorobenzonitrile as the starting material, and 3-(N-tert-butoxycarbonyl-N-methylamino)azetidine for N-Boc-piperazine in step 5 of that route. *H NMR (300 MHz, CDC13) δ: 8.49 (d, J = 7.5 Hz, 1H), 8.24 (s, 1H), 7.36 (d, J = 9.9 Hz, 1H), 4.80-4.74 (m, 2H), 4.33-4.28 (m, 2H), 3.83-3.77 (m, 1H), 2.48 (s, 3H). MS m/z: 351 (M+H+).
Figure imgf000346_0003
EXAMPLE 424
l-(9-Bromo-[l,2,4]triazolo[ -c]quinazolin-5-yl)-N-methylazetidin-3-
Figure imgf000347_0001
[0721] The title compound was prepared as described in Example 418, except that 2-amino-5-bromobenzonitrile was substituted for 6-amino-3-bromo-2- fluorobenzonitrile in step 2, and 3-(N-tert-butoxycarbonyl-N- methylamino)azetidine for N-Boc-piperazine in step 5 of that route. JH NMR (300 MHz, CDC13) δ: 8.43 (dd, J = 2.4, 0.6 Hz, 1H), 8.26 (s, 1H), 7.70 (dd, J = 8.8, 2.4 Hz, 1H), 7.52 (dd, J = 8.8, 0.6 Hz, 1H), 4.76 (br, 2H), 4.30 (br, 2H), 3.81-3.76 (m, 1H), 2.48 (s, 3H). MS m/z: 333 (M+H+).
EXAMPLE 425
9-Chloro-10-fluoro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000347_0002
[0722] The HC1 salt of the title compound was prepared as described in Example 419, except that 4-chloro-3-fluoroaniline was substituted for 3-fluoro-4- (trifluoromethyl)aniline as the starting material, N-methylpiperazine for N-Boc- piperazine in Step 9 of that route. *H NMR (300 MHz, CD3OD) δ: 8.59 (s, 1H), 7.82 (dd, J = 9.0, 7.8 Hz, 1H), 7.60 (dd, J = 9.0, 1.2 Hz, 1H), 5.30-5.00 (br, 2H), 3.60-3.50 (br, 6H), 3.00 (s, 3H). MS m/z: 321 (M+H+).
Figure imgf000347_0003
EXAMPLE 426
N-methyl-l-(9-(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazolin-5-yl)azetidin- -amine
Figure imgf000348_0001
[0723] The title compound was prepared as described in Example 418, except that 2-amino-5-(trifluoromethyl)benzonitrile was substituted for 6-amino-3-bromo- 2-fluorobenzonitrile in Step 2, and 3-(N-tert-butoxycarbonyl-N- methylamino)azetidine for N-Boc-piperazine in Step 5 of that route. 1H NMR (300 MHz, CDC13) δ: 8.58-8.57 (m, 1H), 8.28 (s, 1H), 7.80 (dd, J = 8.7, 1.8 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 4.83-4.77 (m, 2H), 4.37-4.31 (m, 2H), 3.83-3.77 (m, 1H), 2.49 (s, 3H). MS m/z: 323 (M+H+).
Figure imgf000348_0002
EXAMPLE 427
l-(8-Fluoro-9-(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazolin-5-yl)-N- methylazetidin-3-amine
Figure imgf000348_0003
[0724] The title compound was prepared as described in Example 418, except that 2-amino-4-fluoro-5-(trifluoromethyl)benzonitrile (prepared from 3-fluoro-4- (trifluoromethyl)aniline as described in Example 122) was substituted for 6-amino- 3-bromo-2-fluorobenzonitrile in step 2, and 3-(N-tert-butoxycarbonyl-N- methylamino)azetidine for N-Boc-piperazine in step 5 of that route. JH NMR (300 MHz, CDC13) δ: 8.56 (d, J = 7.5 Hz, 1H), 8.26 (s, 1H), 7.36 (d, J = 12.0 Hz, 1H), 4.91-4.75 (m, 2H), 4.42-4.25 (m, 2H), 3.90-3.76 (m, 1H), 2.49 (s, 3H). MS m/z: 341 (M+H+).
Figure imgf000349_0001
EXAMPLE 428
l-(9-Chloro-[l,2,4]triazolo[ -c]quinazolin-5-yl)-N-methylazetidin-3-
Figure imgf000349_0002
[0725] The title compound was prepared as described in Example 418, except that 2-amino-5-chlorobenzonitrile was substituted for 6-amino-3-bromo-2- fluorobenzonitrile in Step 2, and 3-(N-tert-butoxycarbonyl-N- methylamino)azetidine for N-Boc-piperazine in Step 5 of that route. 1H NMR (300 MHz, CDCI3) δ: 8.28-8.26 (m, 2H), 7.61-7.53 (m, 2H), 4.76 (dd, J = 9.6, 7.2 Hz, 2H), 4.30 (dd, J = 9.6, 4.8 Hz, 2H), 3.81-3.76 (m, 1H), 2.48 (s, 3H). MS m/z: 289 (M+H+). EXAMPLE 429
2-Methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline-9- carbonitrile
Figure imgf000350_0001
[0726] The HC1 salt of the title compound was prepared analogously to Example 122. *H NMR (300 MHz, CD3OD) δ: 7.82 (s, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 4.94 (d, J = 14.7 Hz, 2H), 3.64 (d, J = 12.9 Hz, 2H), 3.56-3.46 (m, 2H), 3.35-3.26 (m, 2H), 2.91 (s, 3H), 2.46 (s, 3H). MS m/z: 308 (M+H+).
EXAMPLE 430
8-Fluoro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline-9- carbonitrile
Figure imgf000350_0002
[0727] The title compound was prepared analogously to Example 122. 1H NMR (300 MHz, CDC13) δ: 8.64 (d, J = 7.2 Hz, 1H), 8.33 (s, 1H), 7.39 (d, J = 10.5 Hz, 1H), 4.32 (t, J = 5.1 Hz, 4H), 2.64 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H). MS m/z: 312 (M+H+).
EXAMPLE 431
8-Fluoro-5-(4-methylpiperazin-l-yl)-9-(trifluoromethoxy)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000350_0003
[0728] The title compound was prepared analogously to Example 97. 1H NMR (300 MHz, D20) δ: 8.37 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 11.1 Hz, 1H), 4.84 (d, J = 14.4 Hz, 2H), 3.63 (d, J = 12.6 Hz, 2H), 3.53-3.43 (m, 2H), 3.32-3.25 (m, 2H), 2.90 (s, 3H). MS m/z: 371 (M+H+). EXAMPLE 432
2-Ethyl-5-(4-methylpiperazin-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5 c]quinazoline
Figure imgf000351_0001
[0729] The title compound was prepared analogously to Example 114. 1H NMR (300 MHz, DMSO-d6) δ: 8.42 (d, J = 1.8 Hz, 1H), 7.95 (dd, J = 8.4, 1.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 4.09 (t, J = 5.1 Hz, 4H), 2.91 (q, J = 7.6 Hz, 2H), 2.55-2.48 (m, 4H), 2.24 (s, 3H), 1.36 (t, J = 7.6 Hz, 3H). MS m/z: 365 (M+H+).
EXAMPLE 433
5-(4-Methylpiperazin-l-yl) quinazoline-9-carbonitrile
Figure imgf000351_0002
[0730] The title compound was prepared analogously to Example 122. 1H NMR (300 MHz, CDC13) δ: 8.68 (d, J = 1.8 Hz, 1H), 8.36 (s, 1H), 7.80 (dd, J = 8.4, 1.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 4.30-4.27 (m, 4H), 2.68 (t, J = 5.1 Hz, 4H), 2.41 (s, 3H). MS m/z: 294 (M+H+).
EXAMPLE 434
8,9-Difluoro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000351_0003
[0731] The title compound was prepared analogously to Example 97. 'll NlVIR (300 MHz, CDCI3) δ: 8.31 (s, 1H), 8.11 (dd, J = 9.9, 8.4 Hz, 1H), 7.50 (dd, J = 11.1, 7.2 Hz, 1H), 4.11 (t, J = 4.8 Hz, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.39 (s, 3H). MS m/z: 305 (M+H+). EXAMPLE 435
8-Bromo-9-fluoro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000352_0001
[0732] The HC1 salt of the title compound was prepared analogously to Example 97. *H NMR (300 MHz, DMSO-d6) δ: 10.91 (br, 1H), 8.74 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 6.6 Hz, 1H), 4.93 (d, J = 14.7 Hz, 2H), 3.62-3.57 (m, 4H), 3.30-3.24 (m, 2H), 2.83 (d, J = 4.5 Hz, 3H). MS m/z: 365 (M+H+).
EXAMPLE 436
7-Fluoro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline- -carbonitrile
Figure imgf000352_0002
[0733] The title compound was prepared analogously to Example 127. 1H NMR (300 MHz, CDC13) δ: 8.41 (s, 1H), 7.52 (dd, J = 10.2, 1.5 Hz, 1H), 4.34 (br, 4H), 2.64 (br, 4H), 2.39 (s, 3H), 1.81 (s, 3H). MS m/z: 326 (M+H+).
EXAMPLE 437
8-Chloro-9-fluoro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000352_0003
[0734] The HC1 salt of the title compound was prepared analogously to Example 122. *H NMR (400 MHz, D20) δ: 8.52 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 6.4 Hz, 1H), 4.87 (d, J = 14.0 Hz, 2H), 3.78 (d, J = 12.8 Hz, 2H), 3.58 (t, J = 12.8 Hz, 2H), 3.47-3.40 (m, 2H), 3.06 (s, 3H). MS m/z: 321 (M+H+). EXAMPLE 438
9-Chloro-10-fluoro-5-(p iazolo[l,5-c]quinazoline
Figure imgf000353_0001
[0735] The HC1 salt of the title compound was prepared as described in Example 419, except that 4-chloro-3-fluoroaniline was substituted for 3-fluoro-4- (trifluoromethyl)aniline as the starting material of that route. 1H NMR (300 MHz, D20) δ: 8.28 (s, 1H), 7.30 (t, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.06 (t, J = 5.1 Hz, 4H), 3.42 (t, J = 5.1 Hz, 4H). MS m/z: 307 (M+H+).
EXAMPLE 439
5-(3-(Methylamino)azetidin-l-yl)-[l,2,4]triazolo[l,5-c]quinazoline-9- carbonitrile
Figure imgf000353_0002
[0736] The title compound was prepared analogously to Example 122. JH NMR (300 MHz, DMSO-d6) δ: 8.62 (s, 1H), 8.57 (d, J = 1.8 Hz, 1H), 7.96 (dd, J = 8.7, 1.8 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 4.68 (br, 2H), 4.25 (br, 2H), 3.69-3.61 (m, 1H), 2.29 (s, 3H). MS m/z: 280 (M+H+).
EXAMPLE 440
8-Fluoro-5-(piperazin-l-yl) ]quinazoline-9-carbonitrile
Figure imgf000353_0003
[0737] The HC1 salt of the title compound was prepared analogously to
Example 122. *H NMR (300 MHz, D20/DMSO-d6) δ: 8.77 (d, J = 6.9 Hz, 1H), 8.67 (s, 1H), 7.70 (d, J = 10.5 Hz, 1H), 4.50 (t, J = 4.8 Hz, 4H), 3.51 (t, J = 4.8 Hz, 4H). MS m/z: 298 (M+H+).
Figure imgf000354_0001
EXAMPLE 441
9-Chloro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- -7-carbonitrile
Figure imgf000354_0002
2-Amino-5-chloro-3-iodobenzonitrile:
[0738] The title compound was prepared as described in Example 122 step 1, except that 2-amino-5-chlorobenzonitrile was substituted for 3-chloro-4- (trifluoromethyl)aniline. -5
Figure imgf000354_0003
9-Chloro-7-iodo-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline:
[0739] The title compound was prepared as described in Example 92, except that 2-amino-5-chloro-3-iodobenzonitrile was substituted for 2-amino-5- chlorobenzonitrile, ethyl chloroformate for methyl chloroformate in step 1 , acetic hydrazide for formic hydrazide in step 2, and 1 -methylpiperazine for piperazine in step 4 of that route.
Step 6
Figure imgf000355_0001
9-Chloro-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline-7-carbonitrile:
[0740] Reference for introducing cyano group: DM Tschaen et al, Synth.
Commun. 1994, 24(6), 887-890. The title compound was obtained as the corresponding HC1 salt. *H NMR (300 MHz, D20) δ: 7.77 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 5.09 (d, J = 14.7 Hz, 2H), 3.68-3.53 (m, 4H), 3.32-3.23 (m, 2H), 2.92 (s, 3H), 2.52 (s, 3H). MS m/z: 342 (M+H+).
EXAMPLE 442
8-Bromo-9-methyl-5-(pi iazolo[l,5-c]quinazoline
Figure imgf000355_0002
[0741] The HC1 salt of the title compound was prepared analogously to Example 122. *H NMR (300 MHz, D20) δ: 11.33 (br, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 4.91 (d, J = 14.4 Hz, 2H), 3.75-3.50 (m, 4H), 3.30-3.20 (m, 2H), 2.81 (d, J = 4.5 Hz, 3H), 2.54 (s, 3H). MS m/z: 361 (M+H+).
EXAMPLE 443
8-Fluoro-5-(piperazin-l-yl)-9-(trifluoromethoxy)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000355_0003
[0742] The HC1 salt of the title compound was prepared analogously to
Example 97. *H NMR (300 MHz, D20) δ: 8.40 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 11.4 Hz, 1H), 4.15 (t, J = 5.1 Hz, 4H), 3.42 (t, J = 5.1 Hz, 4H). MS m/z: 357 (M+H+).
EXAMPLE 444
9-Chloro-5-(4-methylpiperazin-l-yl)-2-(thiophen-3-ylmethyl)- [l,2,4] oline
Figure imgf000356_0001
[0743] The title compound was prepared analogously to Example 118. 1H NMR (300 MHz, CDC13) δ: 8.32 (dd, J = 2.4, 0.6 Hz, 1H), 7.63 (dd, J = 8.7, 0.6 Hz, 1H), 7.57 (dd, J = 8.7, 2.4 Hz, 1H), 7.28 (dd, J = 4.8, 3.0 Hz, 1H), 7.21 (dd, J = 3.0, 1.2 Hz, 1H), 7.15 (dd, J = 4.8, 1.2 Hz, 1H), 4.31 (s, 2H), 4.11-4.07 (m, 4H), 2.64 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H). MS m/z: 399 (M+H+).
EXAMPLE 445
2-Methyl-5-(piperazin-l-yl) quinazoline-9-carbonitrile
Figure imgf000356_0002
[0744] The title compound was prepared analogously to Example 122. 1H NMR (300 MHz, CD3OD) δ: 8.51-8.48 (m, 1H), 7.88-7.84 (m, 1H), 7.71-7.67 (m, 1H), 4.18 (t, J = 5.1 Hz, 4H), 3.03 (t, J = 5.1 Hz, 4H), 2.60 (s, 3H). MS m/z: 294 (M+H+).
EXAMPLE 446
5-(Piperazin-l-yl)-[l,2 azoline-9-carbonitrile
Figure imgf000356_0003
[0745] The title compound was prepared analogously to Example 122. JH NMR (300 MHz, CD3OD) δ: 8.73 (dd, J = 2.1, 0.6 Hz, 1H), 8.57 (s, 1H), 7.99 (dd, J = 8.7, 2.1 Hz, IH), 7.86 (dd, J = 8.7, 0.6 Hz, IH), 4.46 (t, J = 5.1 Hz, 4H), 3.46 (t, J = 5.1 Hz, 4H). MS m/z: 280 (M+H+).
EXAMPLE 447
9-Chloro-5-(4-methylpiperazin-l-yl)-2-(thiophen-2- [l,2,4] oline
Figure imgf000357_0001
[0746] The title compound was prepared analogously to Example 118. JH NMR (300 MHz, CDC13) δ: 8.32 (dd, J = 2.4, 0.6 Hz, IH), 7.63 (dd, J = 8.7, 0.6 Hz, IH), 7.58 (dd, J = 8.7, 2.4 Hz, IH), 7.20 (dd, J = 5.1, 1.2 Hz, IH), 7.04 (dd, J = 3.3, 1.2 Hz, IH), 6.96 (dd, J = 5.1, 3.3 Hz, IH), 4.50 (s, 2H), 4.12-4.08 (m, 4H), 2.65 (t, J = 5.1 Hz, 4H), 2.39 (s, 3H). MS m/z: 399 (M+H+).
EXAMPLE 448
8-Bromo-9-fluoro-5-(pip iazolo[l,5-c]quinazoline
Figure imgf000357_0002
[0747] The HC1 salt of the title compound was prepared analogously to
Example 97. *H NMR (300 MHz, DMSO-d6) δ: 9.27 (br, IH), 8.72 (s, IH), 8.20 (d, J = 8.4 Hz, IH), 8.11 (d, J = 6.6 Hz, IH), 4.22 (t, J = 5.1 Hz, 4H), 3.33 (br, 4H). MS m/z: 351 (M+H+).
EXAMPLE 449
8,9-Difluoro-5-(pipera lo[l,5-c]quinazoline
Figure imgf000357_0003
[0748] The title compound was prepared analogously to Example 97. 1H NMR (300 MHz, CDCI3) δ: 8.31 (s, IH), 8.11 (dd, J = 9.9, 8.7 Hz, IH), 7.50 (dd, J = 11.4, 7.5 Hz, 1H), 4.05 (t, J = 5.1 Hz, 4H), 3.11 (t, J = 5.1 Hz, 4H). MS m/z: 291 (M+H+).
EXAMPLE 450
8-Chloro-9-fluoro-5-(pip iazolo[l,5-c]quinazoline
Figure imgf000358_0001
[0749] The HC1 salt of the title compound was prepared analogously to
Example 122. *H NMR (400 MHz, D20) δ: 8.54 (s, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H), 4.22 (t, J = 5.0 Hz, 4H), 3.60 (t, J = 5.0 Hz, 4H). MS m/z: 307 (M+H+).
EXAMPLE 451
2-Ethyl-5-(piperazin-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000358_0002
[0750] The HC1 salt of the title compound was prepared analogously to
Example 115. *H NMR (400 MHz, DMSO-d6) δ: 9.58 (s, 2H), 8.50 (s, 1H), 8.03 (dd, J = 8.8, 2.4 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 4.36-4.33 (m, 4H), 3.33 (br, 4H), 2.94 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H). MS m/z: 351 (M+H+).
EXAMPLE 452
9-Chloro-5-(piperazin-l-yl)-2-(thiophen-3-ylmethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000358_0003
[0751] The title compound was prepared analogously to Example 119. 1H NMR (300 MHz, CDC13) δ: 8.32 (dd, J = 2.1, 0.6 Hz, 1H), 7.63 (dd, J = 9.0, 0.6 Hz, 1H), 7.57 (dd, J = 9.0, 2.1 Hz, 1H), 7.28 (dd, J = 4.8, 3.0 Hz, 1H), 7.21 (dd, J = 3.0, 1.5 Hz, 1H), 7.16 (dd, J = 4.8, 1.5 Hz, 1H), 4.31 (s, 2H), 4.04-4.00 (m, 4H), 3.12- 3.08 (m, 4H). MS m/z: 385 (M+H+).
EXAMPLE 453
9-Chloro-5-(piperazin-l-yl)-2-(thiophen-2-ylmethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000359_0001
[0752] The title compound was prepared analogously to Example 119. JH NMR (300 MHz, CDC13) δ: 8.33 (dd, J = 2.4, 0.6 Hz, 1H), 7.63 (dd, J = 8.7, 0.6 Hz, 1H), 7.58 (dd, J = 8.7, 2.4 Hz, 1H), 7.20 (dd, J = 5.1, 1.2 Hz, 1H), 7.04 (dd, J = 3.3, 1.2 Hz, 1H), 6.96 (dd, J = 5.1, 3.3 Hz, 1H), 4.50 (s, 2H), 4.05-4.01 (m, 4H), 3.12- 3.08 (m, 4H). MS m/z: 385 (M+H+).
EXAMPLE 454
2-(9-Chloro-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-c]quinazolin-2-yl)-
N,N-dimethylethanamine
Figure imgf000359_0002
[0753] The HCl salt of the title compound was prepared analogously to
Example 116. *H NMR (300 MHz, DMSO-d6) δ: 8.25 (d, J = 1.8 Hz, 1H), 7.85- 7.74 (m, 2H), 3.60 (t, J = 7.2 Hz, 2H), 3.42 (br, 8H), 3.08 (br, 2H), 2.87 (s, 6H), 2.76 (s, 3H). MS m/z: 374 (M+H+). EXAMPLE 455
9-Chloro-5-(7,7-difluorohexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)-2-methyl-
[l,2, ine
Figure imgf000360_0001
[0754] The title compound was prepared analogously to Example 113. 7,7- difluorooctahydropyrrolo[l,2-a]pyrazine was prepared according to
WO2008/124083 A2 Example 385. *H NMR (400 MHz, CDC13) δ: 8.32 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.0 Hz, 1H), 5.04-4.97 (m, 2H), 3.31-3.52 (m, 2H), 3.14-3.00 (m, 2H), 2.74-2.56 (m, 3H), 2.65 (s, 3H), 2.43-2.38 (m, 1H), 2.12-2.04 (m, 1H). MS m/z: 379 (M+H+).
EXAMPLE 456
N-Methyl-l-(2-methyl-9-(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazolin-5- yl)azetidin-3-amine
Figure imgf000360_0002
[0755] The HC1 salt of the title compound was prepared as described in Example 418, except that 2-amino-5-(trifluoromethyl)benzonitrile was substituted for 6-amino-3-bromo-2-fluorobenzonitrile in step 2, acetic hydrazide for formic hydrazide in step 3, and 3-(N-tert-butoxycarbonyl-N-methylamino)azetidine for N- Boc-piperazine in step 5 of that route, as well as the Boc group was removed by HC1/THF without neutralization during the work-up. *H NMR (300 MHz, CD3OD) δ: 8.55 (s, 1H), 7.94 (dd, J = 8.7, 1.8 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 5.03-4.93 (m, 2H), 4.85-4.67 (m, 2H), 4.30-4.22 (m, 1H), 2.82 (s, 3H), 2.62 (s, 3H). MS m/z: 337 (M+H+). EXAMPLE 457
8-bromo-2,9-dimethyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000361_0001
[0756] The HCl salt of the title compound was prepared analogously to
Example 122. *H NMR (300 MHz, D20) δ: 7.21 (s, 1H), 7.13 (s, 1H), 4.70-4.60 (m, 2H), 3.64 (d, J = 11.1 Hz, 2H), 3.50-3.20 (m, 4H), 2.92 (s, 3H), 2.46 (s, 3H), 2.02 (s, 3H). MS m/z: 377 (M+H+).
EXAMPLE 458
8-Fluoro-9-iodo-2-methyl-5-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5- c]quinazoline
[0757] The title compound was prepared analogously to Example 418. 1H NMR (300 MHz, CDC13) δ: 8.72 (dd, J = 7.2, 0.3 Hz, 1H), 7.32 (dd, J = 9.3, 0.3 Hz, 1H), 4.14 (t, J = 4.8 Hz, 4H), 2.63 (t, J = 4.8 Hz, 4H), 2.61 (s, 3H), 2.38 (s, 3H). MS m/z: 427 (M+H+).
EXAMPLE 459
5-(4-Methyl-l,4-diazepan-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5- c]quinazoline
Figure imgf000361_0003
[0758] The HCl salt of the title compound was prepared analogously to
Example 111. *H NMR (400 MHz, CD3OD) δ: 8.62 (s, 1H), 8.60 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 4.74 (dd, J = 16.4, 3.2 Hz, 1H), 4.41-4.36 (m, IH), 4.36-4.19 (m, 2H), 3.94-3.89 (m, IH), 3.73-3.63 (m, 2H), 3.62-3.49 (m, IH), 2.99 (s, 3H), 2.49-2.43 (m, 2H). MS m/z: 351 (M+H+).
EXAMPLE 460
5-(l,4-Diazepan-l-yl)-9-(trifluoromethyl)-[l,2,4]triazolo[l,5-c]quinazoline
Figure imgf000362_0001
[0759] The title compound was prepared analogously to Example 92. 1H NMR (400 MHz, DMSO-d6) δ: 8.65 (s, IH), 8.41 (s, IH), 7.92 (d, J = 8.2 Hz, IH), 7.69 (d, J = 8.2 Hz, IH), 4.23-4.19 (m, 4H), 3.01-2.98 (m, 2H), 2.79-2.75 (m, 2H), 2.36 (br, IH), 1.91-1.87 (m, 2H). MS m/z: 337 (M+H+).
EXAMPLE 461
5-(5-Methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-9-(trifluoromethyl)- [l,2, line
Figure imgf000362_0002
[0760] The title compound was prepared analogously to Example 111. JH NMR (400 MHz, CDC13) δ: 8.59 (s, IH), 8.29 (s, IH), 7.79 (dd, J = 8.4, 1.6 Hz, IH), 7.69 (d, J = 8.4 Hz, IH), 4.34-4.18 (m, 4H), 3.05 (br, 2H), 2.74-2.59 (m, 4H), 2.36 (s, 3H). MS m/z: 363 (M+H+).
EXAMPLE 462
5-(Hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-9-(trifluoromethyl)- [l,2, line
Figure imgf000362_0003
[0761] The title compound was prepared analogously to Example 92. 'll NlVIR
(400 MHz, CDC13) δ: 8.60 (s, IH), 8.29 (s, IH), 7.80 (dd, J = 8.8, 1.6 Hz, IH), 7.70 (d, J = 8.8 Hz, IH), 4.36-4.14 (m, 4H), 3.22-3.19 (m, 2H), 3.01-2.92 (m, 4H). MS m/z: 349 (M+H+).
EXAMPLE 463
8-Chloro-6-methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000363_0001
[0762] The title compound was prepared analogously to Example 36. JH NMR (300 MHz, CDC13) δ: 9.10 (s, IH), 7.57 (dd, J = 0.9 Hz, IH), 7.32 (dd, J = 1.1 Hz, IH), 4.46-4.47 (m, 4H), 2.60-2.63 (m, 4H), 2.59 (s, 3H), 2.38 (s, 3H). MS m/z: 317 (M+H+).
EXAMPLE 464
6-Methyl-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- a]quinoxaline
Figure imgf000364_0001
[0763] The title compound was prepared as described in Example 34, except that 2-bromo-4-(trifluoromethyl)aniline was substituted for 4-fluoro-3- methylaniline as the starting material, tert-butyl piperazine-l-carboxylate for 1- methylpiperazine in step 7 of that route, and one extra step (step 10, described below) was included in that route. *H NMR (300 MHz, DMSO-d6) δ: 10.13 (s,
1H), 8.49 (s, 1H), 7.67 (s, 1H), 4.38 (br, 4H), 2.56 (s, 3H), 2.53-2.48 (m, 4H), 2.46 (s, 3H). MS m/z: 351 (M+H+).
Step 10
Figure imgf000364_0002
tert-Butyl 4-(6-methyl-8-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]quinoxalin-4- yl)piperazine-l-carboxylate:
[0764] A 35 rriL pressure tube was charged with tert-butyl 4-(6-bromo-8- (trifluoromethyl)- [ 1 ,2,4]triazolo[4,3-a]quinoxalin-4-yl)piperazine- 1 -carboxylate (1.90 g, 3.8 mmol), trimethylboroxine (1.0 g, 8.3 mmol), Pd(dppf)Cl2 (310 mg, 0.38 mmol), K2CO3 (1.0 g, 7.8 mmol) and DMF (15 mL). After 02 was purged by bubbling N2 into the reaction solution, the tube was sealed and heated at 100 °C for 2 days. Work-up: the reaction mixture was poured into water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 1.2 g (72%) of the product as a yellow solid. *H NMR (300 MHz, CDC13) δ: 9.21 (s, 1H), 7.83 (s, 1H), 7.58 (s, 1H), 4.54-4.22 (br, 4H), 3.67-3.63 (m, 4H), 2.64 (s, 3H), 1.50 (s, 9H). MS m/z: 437 (M+H+). EXAMPLE 465
6,7-Difluoro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000365_0001
[0765] The title compound was prepared analogously to Example 34. JH NMR (300 MHz, DMSO-d6) δ: 10.00 (s, IH), 8.06-8.00 (m, IH), 7.41 (dd, J = 17.4, 9.9 Hz, IH), 4.38 (br, 4H), 2.53-2.49 (m, 4H), 2.24 (s, 3H). MS m/z: 305 (M+H+).
EXAMPLE 466
4-(4-Methylpipera -l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3-
Figure imgf000365_0002
[0766] The title compound was prepared as described in Example 192, except that 2-amino-5-(trifluoromethyl)benzonitrile was substituted for 4-chloro-2- fluoroaniline in step 1 of that route. *H NMR (300 MHz, CDC13) δ: 9.25 (s, IH), 8.10 (d, J = 1.4 Hz, IH), 7.98 (d, J = 1.4 Hz, IH), 4.99 (br, 2H), 4.32 (br, 2H), 2.64 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H). MS m/z: 362 (M+H+).
EXAMPLE 467
8,9-Difluoro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[4,3-a]quinoxaline
Figure imgf000365_0003
[0767] The title compound was prepared analogously to Example 36. 1H NMR (300 MHz, DMSO-d6) δ: 9.67 (d, J = 2.4 Hz, IH), 7.55 (dd, J = 18.6, 9.3 Hz, IH), 7.43-7.38 (m, IH), 4.32 (br, 4H), 2.50 (br, 4H), 2.24 (s, 3H). MS m/z: 305 (M+H+). EXAMPLE 468
4-(Piperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]quinoxaline-6- carbonitrile
Figure imgf000366_0001
[0768] The HC1 salt of the title compound was prepared as described in Example 192, except that 2-amino-5-(trifluoromethyl)benzonitrile was substituted for 4-chloro-2-fluoroaniline in step 1 of that route. *H NMR (300 MHz, CDC13) δ: 9.24 (s, IH), 8.09 (s, IH), 7.98 (s, IH), 4.97 (br, 2H), 4.30 (br, 2H), 3.11 (t, J = 5.1 Hz, 4H). MS m/z: 348 (M+H+).
EXAMPLE 469
8-Chloro-6-methyl-4-(pi riazolo[4,3-a]quinoxaline
Figure imgf000366_0002
[0769] The HC1 salt of the title compound was prepared analogously to
Example 36. *H NMR (300 MHz, DMSO-d6) δ: 10.04 (s, IH), 8.28 (d, J = 2.2 Hz, IH), 7.45 (d, J = 2.2 Hz, IH), 4.53 (br, 4H), 3.29 (br, 4H), 2.53 (s, 3H). MS m/z: 303 (M+H+).
EXAMPLE 470
6-Methyl-4-(piperazin-l-yl)-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- a]quinoxaline
Figure imgf000366_0003
[0770] The HC1 salt of the title compound was prepared as described in Example 464 step 11. *H NMR (300 MHz, DMSO-d6) δ: 10.20 (s, IH), 9.54 (br, 2H), 8.56 (s, IH), 7.72 (s, IH), 6.01-5.93 (br, 4H), 4.62-4.58 (br, 4H), 2.60 (s, 3H). MS m/z: 337 (M+H+).
Figure imgf000367_0001
EXAMPLE 471
8-Chloro-4-(4-methylpiperazin-l-yl)-l-(thiophen-2- -a]quinoxaline
Figure imgf000367_0002
2,6-Dichloro-3-hydrazinylquinoxaline:
[0771] The title compound was prepared as described in Example 1 steps 1-3.
Step 4
Figure imgf000367_0003
N'-(3,7-Dichloroquinoxalin-2-yl)-2-(thiophen-2-yl)acetohydrazide:
[0772] A 100 mL round bottom flask was charged with 2,6-dichloro-3- hydrazinylquinoxaline (1.2 g, 5.2 mmol), triethylamine (0.77 g, 7.8 mmol) and THF (30 mL). To the mixture was added dropwise 2-(thiophen-2-yl)acetyl chloride (0.92 g, 5.7 mmol) at 0 °C. The resulting solution was stirred at room temperature for 15 minutes. Reaction progress was monitored by TLC (EtO Ac/petroleum ether = 1:1). Work-up: the reaction mixture was diluted with EtOAc (80 mL). The organic solution was washed with brine (60 mL), dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 20% EtOAc in petroleum ether, to afford 1.2 g (65%) of the product.
Step 5
Figure imgf000368_0001
4,8-Dichloro-l-(thiophen-2-ylmethyl)-[l,2,4]triazolo[4,3-a]quinoxaline:
[0773] A 100 mL round bottom flask was charged with POCl3 (30 mL). To the above was added N'-(3,7-dichloroquinoxalin-2-yl)-2-(thiophen-2-yl)acetohydrazide (1.2 g, 3.4 mmol). The resulting mixture was heated at 120 °C for 30 minutes. Reaction progress was monitored by TLC (EtOAc/petroleum ether = 1 :3). Workup: the reaction mixture was concentrated in vacuo. The residue was poured into ice-water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 15% EtOAc in petroleum ether, to afford 1.0 g (80%) of the product.
Step 6
Figure imgf000368_0002
8-Chloro-4-(4-methylpiperazin-l-yl)-l-(thiophen-2-ylmethyl)- [l,2,4]triazolo[4,3-a]quinoxaline:
[0774] A 100 mL round bottom flask was charged with 4,8-dichloro-l- (thiophen-2-ylmethyl)-[l,2,4]triazolo[4,3-a]quinoxaline (0.2 g, 0.6 mmol), 1- methylpiperazine (0.18 g, 1.8 mmol) and THF (60 mL). The resulting solution was stirred at room temperature for 1 h. Reaction progress was monitored by TLC (methanol/dichloromethane = 1:20). Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 10% MeOH in dichloromethane, to afford 0.21 g (85%) of the product. *H NMR (300 MHz, CDC13) δ: 7.85 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 8.8, 2.1 Hz, 1H), 7.23 (dd, J = 5.1, 1.2 Hz, 1H), 6.94 (dd, J = 5.1, 3.6 Hz, 1H), 6.84 (dd, J = 3.6, 1.2 Hz, 1H), 4.98 (s, 2H), 4.46 (br, 4H), 2.63 (t, J = 5.1 Hz, 4H), 2.39 (s, 3H). MS m/z: 399 (M+H+).
EXAMPLE 472
8-Chloro-4-(4-methylpiperazin-l-yl)-l-(thiophen-3-ylmethyl)- [l,2,4] ne
Figure imgf000369_0001
[0775] The title compound was prepared as described in Example 471, except that 2-(thiophen-3-yl)acetyl chloride was substituted for 2-(thiophen-2-yl)acetyl chloride in step 4 of that route. *H NMR (300 MHz, CDC13) δ: 7.80 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.36-7.31 (m, 2H), 7.05-6.95 (m, 2H), 4.80 (s, 2H), 4.46 (br, 4H), 2.62 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H). MS m/z: 399 (M+H+).
EXAMPLE 473
8-Chloro-4-(piperazin-l-yl)-l-(thiophen-2-ylmethyl)-[l,2,4]triazolo[4,3- ajquinoxaline
Figure imgf000369_0002
[0776] The title compound was prepared as described in Example KLP-471 , except that piperazine was substituted for 1 -methylpiperazine in step 6 of that route. *H NMR (300 MHz, CDC13) δ: 7.85 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 7.23 (dd, J = 5.1, 1.2 Hz, 1H), 6.94 (dd, J = 5.1, 3.6, 1H), 6.85 (dd, J = 3.6, 1.2 Hz, 1H), 4.98 (s, 2H), 4.44 (br, 4H), 3.10 (t, J = 5.1 Hz, 4H). MS m/z: 385 (M+H+). EXAMPLE 474
8-Chloro-4-(piperazin-l-yl)-l-(thiophen-3-ylmethyl)-[l,2,4]triazolo[4,3- a]quinoxaline
Figure imgf000370_0001
[0777] The title compound was prepared as described in Example 471, except that 2-(thiophen-3-yl)acetyl chloride was substituted for 2-(thiophen-2-yl)acetyl chloride in step 4, piperazine for 1 -methylpiperazine in step 6 of that route.
NMR (300 MHz, CDC13) δ: 7.80 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.35- 7.30 (m, 2H), 7.05-6.95 (m, 2H), 4.81 (s, 2H), 4.42 (br, 4H), 3.08 (t, J = 5.1 Hz, 4H). MS m/z: 385 (M+H+).
EXAMPLE 475
8-Chloro-6-fluoro-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline
Figure imgf000370_0002
[0778] The title compound was prepared analogously to Example 243. 1H NMR (300 MHz, CD3OD) δ: 8.51 (s, 1H), 8.02 (t, J = 2.1 Hz, 1H), 7.37 (dd, J = 10.2, 2.4 Hz, 1H), 4.42 (br, 4H), 2.64 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 321 (M+H+).
EXAMPLE 476
2-Methyl-4-(4-methylpiperazin-l-yl)-[l,2,4]triazolo[l,5-a]quinoxaline-8- carbonitrile
Figure imgf000370_0003
[0779] The title compound was prepared analogously to Example 241. JH NMR (300 MHz, CDC13) δ: 8.45 (dd, J = 1.8, 0.6 Hz, 1H), 7.69 (dd, J = 8.7, 0.6 Hz, IH), 7.64 (dd, J = 8.7, 1.8 Hz, IH), 4.48 (br, 4H), 2.65 (s, 3H), 2.61 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H). MS m/z: 308 (M+H+).
EXAMPLE 477
8-Chloro-6-fluoro-4-(pi azolo[l,5-a]quinoxaline
Figure imgf000371_0001
[0780] The title compound was prepared analogously to Example 243. JH NMR (300 MHz, DMSO-d6) δ: 8.72 (s, IH), 7.94 (t, J = 2.0 Hz, IH), 7.59 (dd, J 10.8, 2.0 Hz, IH), 4.18 (br, 4H), 2.87-2.81 (m, 4H). MS m/z: 307 (M+H+).
EXAMPLE 478
8-Bromo-4-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)-[l,2,4]triazolo[l,5 a]quinoxaline
Figure imgf000371_0002
[0781] The title compound was prepared analogously to Example 243. JH NMR (300 MHz, CDC13) δ: 8.39-8.37 (m, 2H), 7.58 (s, 2H), 5.67-5.56 (m, 2H), 3.36-3.14 (m, 3H), 2.99-2.90 (m, IH), 2.42-2.34 (m, IH), 2.24-2.02 (m, 2H), 2.01- 1.70 (m, 3H), 1.60-1.52 (m, IH). MS m/z: 373 (M+H+).
EXAMPLE 479
8-Bromo-4-(pip l,2-a]quinoxaline
Figure imgf000371_0003
[0782] The HC1 salt of the title compound was prepared as described in Example 181, except that 4-bromobenzene- 1 ,2-diamine was substituted for 4- chlorobenzene- 1 ,2-diamine as the starting material of that route. 1H NMR (300 MHz, CD3OD) δ: 8.44 (d, J = 1.6 Hz, IH), 8.28-8.26 (m, IH), 7.65 (d, J = 1.6 Hz, 1H), 7.59-7.58 (m, 2H), 4.50 (t, J = 5.4 Hz, 4H), 3.33-3.31 (m, 4H). MS m/z: 332 (M+H+).
EXAMPLE 480
8-Bromo-4-(4-methylpiperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000372_0001
[0783] The HC1 salt of the title compound was prepared as described in Example 181, except that 4-bromobenzene- 1 ,2-diamine was substituted for 4- chlorobenzene- 1 ,2-diamine as the starting material of that route. 1H NMR (300 MHz, CD3OD) δ: 8.69 (d, J = 1.5 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 7.88 (d, J = 1.5 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.73 (dd, J = 9.0, 2.1 Hz, 1H), 5.57-5.51 (m, 2H), 3.82-3.73 (m, 4H), 3.46-3.42 (m, 2H), 3.00 (s, 1H). MS m/z: 346 (M+H+).
EXAMPLE 481
4-(4-Methylpiperazin-l-yl)imidazo[l,2-a]quinoxaline-8-carbonitrile
Figure imgf000372_0002
[0784] The title compound was prepared analogously to Example 180. JH NMR (300 MHz, CDC13) δ: 7.96-7.94 (m, 2H), 7.69-7.60 (m, 3H), 4.54 (br, 4H), 2.60 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H). MS m/z: 293 (M+H+).
EXAMPLE 482
8-Chloro-4-(4-ethylpipe idazo[l,2-a]quinoxaline
Figure imgf000372_0003
[0785] The HC1 salt of the title compound was prepared analogously to
Example 180. *H NMR (300 MHz, CD3OD) δ: 8.60 (d, J = 2.7 Hz, 1H), 8.41 (d, J = 6.9 Hz, 1H), 7.83 (d, J = 2.7 Hz, 1H), 7.67 (d, J = 9.9 Hz, 1H), 5.59 (d, J = 14.4 Hz, 2H), 3.80-3.68 (m, 4H), 3.34-3.26 (m, 4H), 1.42 (t, J = 7.5 Hz, 3H). MS m/z: 334 (M+H+).
EXAMPLE 483
8-Bromo-2-methyl-4-(4-methylpiperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000373_0001
[0786] The HC1 salt of the title compound was prepared analogously to Example 9. *H NMR (300 MHz, DMSO-d6) δ: 10.56 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 7.59-7.56 (m, 2H), 5.60-5.51 (m, 2H), 3.59-3.49 (m, 4H), 3.25-3.11 (m, 2H), 2.79 (s, 3H), 2.40 (s, 3H). MS m/z: 360 (M+H+).
EXAMPLE 484
7-Bromo-4-(4-methylpiperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000373_0002
[0787] The HC1 salt of the title compound was prepared as described in Example 180, except that 4-bromobenzene- 1 ,2-diamine was substituted for 4- chlorobenzene- 1 ,2-diamine as the starting material, and the other regio-isomer in the reaction with 2-aminoethanol was isolated, of that route. *H NMR (300 MHz, CD3OD) δ: 8.61 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 1.4 Hz, 1H), 7.65 (dd, J = 8.7, 2.1 Hz, 1H), 5.62-5.56 (m, 2H), 3.75-3.66 (m, 4H), 3.43-3.37 (m, 2H), 3.00 (s, 3H). MS m/z: 346 (M+H+).
EXAMPLE 485
7-Bromo-4-(pip ,2-a]quinoxaline
Figure imgf000373_0003
[0788] The HC1 salt of the title compound was prepared as described in Example 180, except that 4-bromobenzene- 1 ,2-diamine was substituted for 4- chlorobenzene- 1 ,2-diamine as the starting material, and the other regio-isomer in the reaction with 2-aminoethanol was isolated, of that route. *H NMR (300 MHz, CD3OD) δ: 8.50 (d, J = 1.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.57 (dd, J = 8.4, 2.1 Hz, 1H), 4.62 (t, J = 5.4 Hz, 4H), 3.46 (t, J = 5.4 Hz, 4H). MS m/z: 332 (M+H+).
EXAMPLE 486
7-Bromo-2-methyl-4-(piperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000374_0001
[0789] The HC1 salt of the title compound was prepared analogously to Example 11. *H NMR (400 MHz, DMSO-d6) δ: 10.94 (br, 1H), 8.48 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 5.60 (d, J = 13.6 Hz, 2H), 3.62-3.55 (m, 4H), 3.20-3.15 (m, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.41 (s, 3H). MS m/z: 346 (M+H+).
EXAMPLE 487
8-Bromo-2-methyl-4-(piperazin-l-yl)imidazo[l,2-a]quinoxaline
Figure imgf000374_0002
[0790] The HC1 salt of the title compound was prepared analogously to Example 9. *H NMR (300 MHz, DMSO-d6) δ: 9.56 (br, 1H), 8.53 (s, 1H), 8.43- 8.42 (m, 1H), 7.58-7.57 (m, 2H), 4.54 (br, 4H), 3.26 (br, 4H), 2.40 (s, 3H). MS m/z: 346 (M+H+). EXAMPLE 488
7-Bromo-2-methyl-4-(4-methylpiperazin-l-yl)imidazo[l,2-a]quinoxaline
. BrJCC N N
[0791] The HC1 salt of the title compound was prepared analogously to
Example 11. *H NMR (400 MHz, DMSO-d6) δ: 9.23 (br, 1H), 8.47 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.53 (dd, J = 8.8, 1.8 Hz, 1H), 4.54 (br, 4H), 3.28 (br, 4H), 2.40 (s, 3H). MS m/z: 360 (M+H+).
Figure imgf000375_0001
EXAMPLE 489
5-(4-Methylpiperazin-l-yl)tetrazolo[l,5-c]quinazoline-9-carbonitrile
Figure imgf000375_0002
[0792] The title compound was prepared as described in Example 12, except that 2-amino-5-iodobenzoic acid was substituted for 2-amino-5-chlorobenzoic acid as the starting material and N-methylpiperazine for piperazine (Reference for introducing cyano group in step 2: DM Tschaen et al, Synth. Commun. 1994, 24(6), 887-890). The compound exists as a mixture of cyclic tetrazolo structure and linear azido structure. !H NMR (300 MHz, CD3OD) δ: 8.76 (d, J = 1.8 Hz, 0.33H), 8.16 (d, J = 1.8 Hz, 0.67H), 8.02 (dd, J = 8.7, 1.8 Hz, 0.33 H), 7.80 (dd + d, J = 8.7, 1.8 Hz, 0.67H + 0.33H), 7.51 (d, J = 8.7 Hz, 0.67H), 4.33 (t, J = 5.1 Hz, 1.33H), 4.04 (t, J = 5.1 Hz, 2.67H), 2.76 (t, J = 5.1 Hz, 1.33H), 2.69 (t, J = 5.1 Hz, 2.67H), 2.46 (s, 2.00H), 2.43 (s, 1.00H). *H NMR (300 MHz, CDC13) δ: 8.79 (d, J = 1.8 Hz, 0.2H), 8.12 (d, J = 1.8 Hz, 0.8H), 7.90 (dd, J = 8.8, 1.8 Hz, 0.2H), 7.77 (d, J = 8.8 Hz, 0.2H), 7.70 (dd, J = 8.8, 1.8 Hz, 0.8H), 7.47 (d, J = 8.8 Hz, 0.8H), 4.36 (t, J = 5.1 Hz, 0.8H), 4.00 (t, J = 5.1 Hz, 3.2H), 2.67 (t, J = 5.1 Hz, 0.8H), 2.50 (t, J = 5.1 Hz, 3.2H), 2.40 (s, 0.6H), 2.36 (s, 2.4H). MS m/z: 295 (M+H+).
EXAMPLE 490
8-Chloro-6-methyl-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000376_0001
[0793] The title compound was prepared analogously to Example 201. JH NMR (300 MHz, CDC13) δ: 8.24 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 4.42 (br, 4H), 2.65-2.62 (m, 4H), 2.61 (s, 3H), 2.39 (s, 3H). MS m/z: 318 (M+H+).
EXAMPLE 491
6-Fluoro-4-(4-methylpiperaz -l-yl)tetrazolo[l,5-a]quinoxaline-8-carbonitrile
Figure imgf000376_0002
[0794] The title compound was prepared as described in Example 27, except that 3,4-diamino-5-fluorobenzonitrile (prepared as described in Example 196 steps 1-2, except that 4-amino-3-fluorobenzonitrile was substituted for 4-chloro-2- fluoroaniline) was substituted for 4-(trifluoromethyl)benzene-l,2-diamine as the starting material of that route. *H NMR (300 MHz, CDC13) δ: 8.47 (t, J = 1.6 Hz, 1H), 7.56 (dd, J = 9.4, 1.6 Hz, 1H), 4.83 (br, 2H), 4.26 (br, 2H), 2.66-2.62 (m, 4H), 2.39 (s, 3H). MS m/z: 313 (M+H+).
EXAMPLE 492
6,7-Difluoro-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000376_0003
[0795] The title compound was prepared analogously to Example 187. 1H NMR (300 MHz, DMSO-d6) δ: 8.17-8.11 (m, IH), 7.57-7.47 (m, IH), 4.33 (br, 4H), 2.56-2.48 (m, 4H), 2.26 (s, 3H). MS m/z: 306 (M+H+).
EXAMPLE 493
4-(4-Methylpiperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline-6- carbonitrile
Figure imgf000377_0001
[0796] The title compound was prepared as described in Example 27, except that 2,3-diamino-5-(trifluoromethyl)benzonitrile (prepared as described in Example 196 steps 1-2, except that 2-amino-5-(trifluoromethyl)benzonitrile was substituted for 4-chloro-2-fluoroaniline) was substituted for 4-(trifluoromethyl)benzene-l,2- diamine as the starting material of that route. !H NMR (300 MHz, CDC13) δ: 8.78 (s, IH), 8.11 (s, IH), 4.89 (br, 2H), 4.35 (br, 2H), 2.68-2.64 (m, 4H), 2.39 (s, 3H). MS m/z: 363 (M+H+).
SCHEME 103
Figure imgf000377_0002
EXAMPLE 494
6-Methyl-4-(4-methylpiperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5- ajquinoxaline
Figure imgf000378_0001
[0797] The title compound was prepared as described in Example 187, except that 2-bromo-4-(trifluoromethyl)aniline was substituted for 4-fluoro-3- (trifluoromethyl)aniline as the starting material of that route, and one extra step (step 9, as described in Example 464 step 10, except that tert-butyl 4-(6-bromo-8- (trifluoromethyl)tetrazolo[l,5-a]quinoxalin-4-yl)piperazine-l-carboxylate was substituted for tert-butyl 4-(6-bromo-8-(trifluoromethyl)-[l,2,4]triazolo[4,3- a]quinoxalin-4-yl)piperazine-l-carboxylate) was included in that route. 1H NMR (300 MHz, CDC13) δ: 8.51 (s, 1H), 7.68 (s, 1H), 4.53-4.48 (br, 4H), 2.68 (s, 3H), 2.64 (t, J = 5.4 Hz, 4H), 2.39 (s, 3H). MS m/z: 352 (M+H+).
EXAMPLE 495
8,9-Difluoro-4-(4-methylpiperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000378_0002
[0798] The title compound was prepared analogously to Example 201. 1H NMR (300 MHz, DMSO-d6) δ: 7.81-7.71 (m, 1H), 7.61-7.55 (m, 1H), 4.28 (br, 4H), 2.55-2.48 (m, 4H), 2.26 (s, 3H). MS m/z: 306 (M+H+).
EXAMPLE 496
6-Fluoro-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline-8-carbonitrile
Figure imgf000378_0003
[0799] The HC1 salt of the title compound was prepared as described in Example 27, except that 3,4-diamino-5-fluorobenzonitrile (prepared as described in Example 196 steps 1-2, except that 4-amino-3-fluorobenzonitrile was substituted for 4-chloro-2-fluoroaniline) was substituted for 4-(trifluoromethyl)benzene-l,2- diamine as the starting material, and tert-butyl piperazine-l-carboxylate for 1- methylpiperazine of that route. *H NMR (300 MHz, CD3OD/DMSO-d6) δ: 7.96 (s, 1H), 7.20 (d, J = 7.5 Hz, 1H), 4.00 (br, 4H), 2.75-2.70 (m, 4H). MS m/z: 299 (M+H+).
EXAMPLE 497
6-Fluoro-4-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)tetrazolo[l,5- a]q ile
Figure imgf000379_0001
[0800] The title compound was prepared as described in Example 27, except that 3,4-diamino-5-fluorobenzonitrile (prepared as described in Example 196 steps 1-2, except that 4-amino-3-fluorobenzonitrile was substituted for 4-chloro-2- fluoroaniline) was substituted for 4-(trifluoromethyl)benzene-l,2-diamine as the starting material, and octahydropyrrolo[l,2-a]pyrazine for 1-methylpiperazine of that route. *H NMR (300 MHz, CDC13) δ: 8.48 (t, J = 1.5 Hz, 1H), 7.56 (dd, J = 9.6, 1.5 Hz, 1H), 6.22-6.08 (m, 1H), 5.46-5.30 (m, 1H), 3.66-2.35 (m, 5H), 2.27- 1.79 (m, 6H). MS m/z: 339 (M+H+).
EXAMPLE 498
8-Chloro-6-methyl-4-(piperazin-l-yl)tetrazolo[l,5-a]quinoxaline
Figure imgf000379_0002
[0801] The HC1 salt of the title compound was prepared analogously to
Example 201. *H NMR (300 MHz, DMSO-d6) δ: 8.26 (s, 1H), 7.70 (s, 1H), 4.49 (br, 4H), 3.33 (br, 4H), 2.60 (s, 3H). MS m/z: 304 (M+H+). EXAMPLE 499
4-(Piperazin-l-yl)-8-(trifluoromethyl)tetrazolo[l,5-a]quinoxaline-6- carbonitrile
Figure imgf000380_0001
[0802] The HC1 salt of the title compound was prepared as described in Example 27, except that 2,3-diamino-5-(trifluoromethyl)benzonitrile (prepared as described in Example 196 steps 1-2, except that 2-amino-5- (trifluoromethyl)benzonitrile was substituted for 4-chloro-2-fluoroaniline) was substituted for 4-(trifluoromethyl)benzene- 1 ,2-diamine as the starting material, and tert-butyl piperazine-l-carboxylate for 1-methylpiperazine of that route. 1H NMR (300 MHz, DMSO-d6) δ: 9.73 (br, 2H), 8.90 (s, IH), 8.67 (s, IH), 4.92 (br, 2H), 4.42 (br, 2H), 3.37 (br, 4H). MS m/z: 349 (M+H+).
EXAMPLE 500
6-Methyl-4-(piperazin-l-yl)- -(trifluoromethyl)tetrazolo[l,5-a]quinoxaline
Figure imgf000380_0002
[0803] The HC1 salt of the title compound was prepared as described in
Example 494 step 10. *H NMR (300 MHz, DMSO-d6) δ: 9.41-9.39 (br, 2H), 8.48 (s, IH), 7.96 (s, IH), 4.61-4.54 (br, 4H), 3.42-3.31 (br, 4H), 2.68 (s, 3H). MS m/z: 338 (M+H+).
Figure imgf000381_0001
EXAMPLE 501
9-Chloro-5-(4-methylpiperazin-l-yl)pyrazolo[l,5-c]quinazoline
Figure imgf000381_0002
l-(5-Chloro-2-nitrophenyl)ethanone:
[0804] A 250 mL round bottom flask was charged with fuming HNO3 (17 mL) and concentrated H2SO4 (2.5 mL) at -20 °C. To the above was added in portions 1- (3-chlorophenyl)ethanone (5.0 g, 32.3 mmol) over 15 minutes. The mixture was allowed to warm to -10 °C and stirred for 5 h at this temperature, after which ice- water (75 mL) was added and the reaction mixture was extracted with
dichloromethane (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 2% EtOAc in petroleum ether, to afford 5.0 g (78%) of the product as an off-white crystal. Step 2
Figure imgf000382_0001
l-(5-Chloro-2-nitrophenyl)-3-(dimethylamino)prop-2-en-l-one:
[0805] A 100 mL round bottom flask was charged with l-(5-chloro-2- nitrophenyl)ethanone (4.00 g, 20.2 mmol), Ν,Ν-dimethylformamide dimethyl acetal (2.65 g, 22.3 mmol) and DMF (25 mL). The mixture was heated at 100 °C for 2 h under N2. It was then concentrated under reduced pressure to dryness. The residue was mixed with ethyl ether (20 mL). The solid was collected by filtration, washed with more ethyl ether (10 mL x 2), and dried to afford 3.15 g (62%) of the product as a yellow solid.
Step 3
Figure imgf000382_0002
5-(5-Chloro-2-nitrophenyl)-lH-pyrazole:
[0806] A 100 mL round bottom flask was charged with l-(5-chloro-2- nitrophenyl)-3-(dimethylamino)prop-2-en-l-one (3.15 g, 12.5 mmol), hydrazine hydrate (0.69 g, 13.8 mmol) and ethanol (32 mL). The mixture was stirred at 90 °C for 9.5 h under N2. It was then concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 2.3 g (83%) of the product as an off-white crystal.
Step 4
Figure imgf000382_0003
4-Chloro-2-(lH-pyrazol-5-yl)aniline:
[0807] A 100 mL round bottom flask was charged with 5-(5-chloro-2- nitrophenyl)-lH-pyrazole (2.3 g, 10.4 mmol), Na2S2C>4 (5.4 g, 31.0 mmol), methanol (23 mL) and water (10 mL). The mixture was heated at reflux for 0.5 h under N2. It was then concentrated in vacuo. The residue was basified with saturated aqueous NaHCC>3 (20 mL) to pH 9 and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated in vacuo, to afford 0.76 g (38%) of the product as a yellow crystal.
Step 5
Figure imgf000383_0001
9-Chloropyrazolo[l,5-c]quinazolin-5(6H)-one:
[0808] A 100 mL round bottom flask was charged with 4-chloro-2-(lH- pyrazol-5-yl)aniline (0.76 g, 3.9 mmol), K2C03 (0.81 g, 5.9 mmol) and THF (40 mL). To the above was added in portions triphosgene (1.39 g, 4.7 mmol). The mixture was heated at reflux for 4 h under N2. It was then concentrated under reduced pressure to dryness. The solid residue was washed with water (20 mL) and dichloromethane (20 mL x 2) and dried, to afford 0.63 g (74%) of the product as an off-white solid.
Step 6
Figure imgf000383_0002
5,9-Dichloropyrazolo[l,5-c]quinazoline:
[0809] A 50 mL round bottom flask was charged with 9-chloropyrazolo[l ,5- c]quinazolin-5(6H)-one (0.41 g, 1.87 mmol), phosphorus oxychloride (10 mL) and diisopropylethylamine (2 mL). The resulting mixture was heated at reflux for 3 h under N2. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :5). Work-up: the mixture was concentrated in vacuo. The residue was cautiously poured into ice water, neutralized with saturated aqueous NaHCC>3 (20 mL) and extracted with EtO Ac (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 0.30 g (68%) of the product as a white solid. Step 7
Figure imgf000384_0001
9-Chloro-5-(4-methylpiperazin-l-yl)pyrazolo[l,5-c]quinazoline:
[0810] A 50 mL round bottom flask was charged with 5,9- dichloropyrazolo[l,5-c]quinazoline (0.30 g, 1.27 mmol), 1 -methylpiperazine (0.14 g, 1.40 mmol), triethylamine (0.38 g, 3.81 mmol) and THF (10 mL). The mixture was heated at 60 °C for 0.5 h under N2. It was then concentrated in vacuo. The residue was mixed with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SC>4 and concentrated in vacuo, to afford 0.38 g (99%) of the product as an off-white solid. To the solution of the product in EtOAc (20 mL) was added a solution (2 mL) of HC1 in EtOAc with stirring. The precipitate was collected by filtration, washed with ethyl ether (10 mL x 2) and dried, to afford 0.39 g (92%) of the corresponding HC1 salt as an off-white solid. *H NMR (300 MHz, D20) δ: 7.97 (d, J = 2.1 Hz, 1H), 7.47 (s, 1H), 7.30-7.10 (m, 2H), 6.76 (s, 1H), 4.60-4.40 (m, 2H), 3.75-3.55 (m, 2H), 3.45-3.25 (m, 4H), 2.96 (s, 3H). MS m/z: 302 (M+H+).
Figure imgf000384_0002
EXAMPLE 502
5-(4-Methylpiperazin-l-yl)-9-(trifluoromethyl)-[l,2,3]triazolo[l,5- c]quinazoline
Figure imgf000385_0001
Step 1
Figure imgf000385_0002
2-Iodo-4-(trifluoromethyl)aniline:
[0811] A I L round bottom flask was charged with 4-(trifluoromethyl)aniline (50.0 g, 0.31 mol), ICl (60.0 g, 0.37 mol), methanol (100 mL) and dichloromethane (300 mL). The resulting mixture was stirred for 1 h at room temperature. Reaction progress was monitored by TLC (EtO Ac/petroleum ether = 1 :20). Work-up: the reaction solution was diluted with saturated Na2SC>3 (500 mL) and then extracted with CH2CI2 (600 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with petroleum ether, to afford 60.0 g (67%) of the product as a light-red oil. MS m/z: 288 (M+H+).
Step 2
Figure imgf000385_0003
4-(Trifluoromethyl)-2-((trimethylsilyl)ethynyl)aniline:
[0812] A I L round bottom flask was charged with 2-iodo-4- (trifluoromethyl)aniline (60 g, 0.21 mol) and triethylamine (300 mL). To the above solution was added trimethylsilylacetylene (88 mL, 0.62 mol), followed by the addition of PdCl2(PPh3)2 (4.4 g, 6.3 mmol) and cuprous iodide (1.6 g, 8.4 mmol). The resulting mixture was stirred for 1 h at room temperature under N2 atmosphere. Reaction progress was monitored by TLC (EtOAc/petroleum ether = 1 :20). Workup: the reaction solution was diluted with saturated aqueous NaHCC>3 (300 mL) and then extracted with EtO Ac (400 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with petroleum ether, to afford 50.0 g (93%) of the product as a light-red oil. MS m/z: 258 (M+H+).
Step 3
Figure imgf000386_0001
2-Ethynyl-4-(trifluoromethyl)aniline:
[0813] A I L round bottom flask was charged with 4-(trifluoromethyl)-2- ((trimethylsilyl)ethynyl)aniline (50.0 g, 0.19 mol) and methanol (300 mL). To the above solution was added K2CO3 (29 g, 0.21 mol). The resulting mixture was stirred for 0.5 h at room temperature. Reaction progress was monitored by TLC (EtO Ac/petroleum ether = 1 :20). Work-up: the reaction solution was diluted with saturated aqueous NaHCC>3 (300 mL) and then extracted with EtO Ac (400 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with petroleum ether, to afford 30.0 g (83%) of the product as a light-red oil. MS m/z: 186 (M+H+).
Step 4
Figure imgf000386_0002
2-(lH-l,2,3-Triazol-5-yl)-4-(trifluoromethyl)aniline:
[0814] A 300 mL pressure vessel was charged with 2-ethynyl-4- (trifluoromethyl)aniline (12.0 g, 65 mmol), Cul (0.35 g, 1.8 mmol),
azidotrimethylsilane (8.2 g, 71 mmol), methanol (8 mL) and DMF (72 mL). The vessel was sealed and the reaction mixture was magnetically stirred at 100 °C for 12 h. Reaction progress was monitored by TLC (EtO Ac/petroleum ether = 1 :10). Work-up: the reaction solution was diluted with saturated aqueous NaHC03 (100 mL) and then extracted with EtO Ac (150 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with petroleum ether, to afford 9.0 g (61%) of the product as a light-red oil. MS m/z: 229 (M+H+).
Step 5
Figure imgf000387_0001
9-(Trifluoromethyl)-[l,2,3]triazolo[l,5-c]quinazoline-5(6H)-thione:
[0815] A 1 L round bottom flask was charged with 2-(lH-l,2,3-triazol-5-yl)-4- (trifluoromethyl)aniline (20.0 g, 88 mmol) and THF (300 mL). To the above solution were added K2CO3 (18.2 g, 0.13 mol) and thiophosgene (15.1 g, 0.13 mol). The resulting mixture was stirred for 10 h at reflux. Reaction progress was monitored by TLC (EtO Ac/petroleum ether = 3:1). Work-up: the reaction solution was concentrated in vacuo. The resulting crystalline solid was collected by filtration, washed with water (50 mL) and ethyl ether (100 mL), and dried to afford 16.0 g (68%) of the product as a red solid. MS m/z: 271 (M+H+).
Step 6
Figure imgf000387_0002
5-(4-Methylpiperazin-l-yl)-9-(trifluoromethyl)-[l,2,3]triazolo[l,5- c]quinazoline:
[0816] A I L round bottom flask was charged with 9-(trifluoromethyl)- [l,2,3]triazolo[l,5-c]quinazoline-5(6H)-thione (16.0 g, 59 mmol), 1- methylpiperazine (11.9 g, 0.12 mol) and 1,4-dioxane (500 mL). To the above solution was added 30% aqueous H2O2 (5 mL) at 0 °C. The resulting mixture was stirred for 0.5 h at that temperature. Reaction progress was monitored by TLC (EtO Ac/petroleum ether = 3:1). Work-up: the reaction solution was diluted with saturated aqueous Na2S03 (200 mL) and then extracted with CH2C12 (300 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 4% MeOH in CH2C12, to afford 8.0 g (40%) of the product as a light-orange solid. *H NMR (300 MHz, CDC13) δ: 8.39 (s, 1H), 8.19 (s, 1H), 7.78 (s, 2H), 4.28 (t, J = 4.8 Hz, 4H), 2.68 (t, J = 4.8 Hz, 4H), 2.40 (s, 3H). MS m/z: 337 (M+H+).
EXAMPLE 503
9-Bromo-8-fluoro-5-(4-methylpiperazin-l-yl)-[l,2,3]triazolo[l,5-c]quinazoline
Figure imgf000388_0001
[0817] The title compound was prepared as described in Example 502, except that 4-bromo-3-fluoroaniline was substituted for 4- (trifluoromethyl) aniline in step 1 of that route. *H NMR (300 MHz, CDC13) δ: 8.27 (s, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 9.6 Hz, 1H), 4.22 (t, J = 4.8 Hz, 4H), 2.67 (t, J = 4.8 Hz, 4H), 2.39 (s, 3H). MS m/z: 365 (M+H+).
EXAMPLE 504
9-Chloro-5-(4-methylpip iazolo[l,5-c]quinazoline
Figure imgf000388_0002
[0818] The title compound was prepared analogously to Example 502. JH NMR (300 MHz, CDC13) δ: 8.32 (s, 1H), 7.92 (dd, J = 2.4, 0.3 Hz, 1H), 7.65 (dd, J = 8.7, 0.3 Hz, 1H), 7.54 (dd, J = 8.7, 2.4 Hz, 1H), 4.17 (t, J = 5.1 Hz, 4H), 2.68 (t, J = 5.1 Hz, 4H), 2.40 (s, 3H). MS m/z: 303 (M+H+).
EXAMPLE 505
5-(4-Methylpiperazin-l-yl)- ]quinazoline-9-carbonitrile
Figure imgf000388_0003
[0819] The title compound was prepared analogously to Example 502. 1H NMR (400 MHz, CDC13) δ: 8.38 (s, 1H), 8.25 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 4.33 (br, 4H), 2.68 (br, 4H), 2.40 (s, 3H). MS m/z: 294 (M+H+). EXAMPLE 506
9-Bromo-5-(4-methylpiperazin-l-yl)pyrazolo[l,5-c]quinazoline
Figure imgf000389_0001
[0820] The title compound was prepared analogously to Example 501. 1H NMR (300 MHz, CDC13) δ: 8.03 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.59 (dd, J = 8.7, 2.1 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 4.04 (br, 4H), 2.67 (t, J = 5.1 Hz, 4H), 2.39 (s, 3H). MS m/z: 346 (M+H+).
EXAMPLE 507
9-Bromo-5-(pip l,5-c]quinazoline
Figure imgf000389_0002
[0821] The HC1 salt of the title compound was prepared analogously to
Example 501. *H NMR (300 MHz, D20) δ: 7.90 (d, J = 2.1 Hz, 1H), 7.41 (d, J 2.1 Hz, 1H), 7.22 (dd, J = 8.7, 2.1 Hz ,1H), 6.98 (d, J = 8.7 Hz, 1H), 6.62 (d, J = Hz, 1H), 3.84 (br, 4H), 3.48-3.42 (m, 4H). MS m/z: 332 (M+H+).
EXAMPLE 508
9-Bromo-8-fluoro-5-(4-methylpiperazin-l-yl)pyrazolo[l,5-c]quinazoline
Figure imgf000389_0003
[0822] The HC1 salt of the title compound was prepared as described in Example 501, except that l-(3-bromo-4-fluorophenyl)ethanone was substituted for l-(3-chlorophenyl)ethanone in step 1, and Ν,Ν-dimethylformamide di-tert-butyl acetal for Ν,Ν-dimethylformamide dimethyl acetal in step 2 of that route. JH NMR (300 MHz, DMSO-d6) δ: 11.16 (s, 1H), 8.66 (d, J = 7.5 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.56 (d, J = 9.9 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 4.97 (d, J = 14.1 Hz, 2H), 3.65-3.55 (m, 4H), 3.33-3.25 (m, 2H), 2.81 (d, J = 4.8 Hz, 3H). MS m/z: 364 (M+H+). EXAMPLE 509
2-Methyl-5-(4-methylpiperaz -l-yl)pyrazolo[l,5-c]quinazoline-9-carbonitrile
Figure imgf000390_0001
[0823] The title compound was prepared analogously to Example 501. 1H NMR (300 MHz, CDC13) δ: 8.14 (d, J = 1.5 Hz, 1H), 7.68 (dd, J = 8.7, 1.5 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 6.75 (s, 1H), 4.23 (br, 4H), 2.74 (br, 4H), 2.52 (s, 3H), 2.44 (s, 3H). MS m/z: 307 (M+H+).
EXAMPLE 510
9-Bromo-8-fluoro-5-(piperazin-l-yl)pyrazolo[l,5-c]quinazoline
Figure imgf000390_0002
[0824] The HC1 salt of the title compound was prepared as described in Example 501, except that l-(3-bromo-4-fluorophenyl)ethanone was substituted for l-(3-chlorophenyl)ethanone in step 1, Ν,Ν-dimethylformamide di-tert-butyl acetal for Ν,Ν-dimethylformamide dimethyl acetal in step 2, and piperazine for 1- methylpiperazine in step 7 of that route. *H NMR (300 MHz, DMSO-d6) δ: 8.62 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 10.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 4.20 (t, J = 5.1 Hz, 4H), 3.32 (t, J = 5.1 Hz, 4H). MS m/z: 350 (M+H+).
EXAMPLE 511
9-Bromo-2-methyl-5-(4-methylpiperazin-l-yl)pyrazolo[l,5-c]quinazoline
Figure imgf000390_0003
[0825] The title compound was prepared as described in Example 501, except that l-(3-bromophenyl)ethanone was substituted for l-(3-chlorophenyl)ethanone in step 1, and Ν,Ν-dimethylacetamide dimethyl acetal for N,N-dimethylformamide dimethyl acetal in step 2 of that route. *H NMR (300 MHz, CDC13) δ: 7.96 (d, J = 2.1 Hz, 1H), 7.57 (dd, J = 7.8, 2.1 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 6.68 (s, 1H), 4.02 (br, 4H), 2.66 (t, J = 5.1 Hz, 4H), 2.51 (s, 3H), 2.38 (s, 3H). MS m/z: 360 (M+H+).
EXAMPLE 512
9-Chloro-2-methyl-5-(4-methylpiperazin-l-yl)pyrazolo[l,5-c]quinazoline
Figure imgf000391_0001
[0826] The title compound was prepared analogously to Example 501, except that Ν,Ν-dimethylacetamide dimethyl acetal was substituted for N,N- dimethylformamide dimethyl acetal in step 2 of that route. JH NMR (300 MHz, DMSO-d6) δ: 8.19 (dd, J = 2.1, 1.2 Hz, 1H), 7.57-7.50 (m, 2H), 7.16 (s, 1H), 3.92 (t, J = 4.8 Hz, 4H), 2.53-2.48 (m, 4H), 2.44 (s, 3H), 2.24 (s, 3H). MS m/z: 316 (M+H+).
EXAMPLE 513
2-Methyl-5-(4-methylpiperazin-l-yl)-9-(trifluoromethyl)pyrazolo[l,5- c]quinazoline
Figure imgf000391_0002
[0827] The HC1 salt of the title compound was prepared analogously to
Example 501. *H NMR (300 MHz, D20) δ: 7.86 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 6.59 (s, 1H), 4.60-4.55 (m, 2H), 3.62-3.57 (m, 2H), 3.36- 3.28 (m, 4H), 2.90 (s, 3H), 2.33 (s, 3H). MS m/z: 350 (M+H+).
Figure imgf000392_0001
EXAMPLE 514
-Chloro-4-(4-methylpiperazin-l-yl)imidazo[l,5-a]quinoxaline
Figure imgf000392_0002
Dimethyl l-(5-chloro-2-nitrophenyl)-lH-imidazole-4,5-dicarboxylate:
[0828] A 50 mL round bottom flask was charged with 4-chloro-2-fluoro-l- nitrobenzene (2.0 g, 11.4 mmol), dimethyl lH-imidazole-4,5-dicarboxylate (2.3 g, 12.5 mmol), CS2CO3 (4.5 g, 13.7 mmol) and DMF (30 mL). The mixture was heated at 80 °C for 12 h then cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 1% methanol in dichloromethane, to afford 3.1 g (81 ) of the product as a yellow crystal. Step 2
Figure imgf000393_0001
Methyl 8-chloro-4-oxo-4,5-dihydroimidazo[l,5-a]quinoxaline-3-carboxylate:
[0829] A 50 mL round bottom flask was charged with dimethyl l-(5-chloro-2- nitrophenyl)-lH-imidazole-4,5-dicarboxylate (1.5 g, 4.40 mmol), iron powder (0.99 g, 17.2 mmol) and acetic acid (15 mL). The mixture was heated at 100 °C for 12 h and then concentrated under reduced pressure to dryness. 1 M HC1 (50 mL) was then added slowly to remove any unreacted iron. The solid remained was collected by filtration and dried to afford 2.2 g of the product as a gray solid, which was used in the next step without further purification.
Step 3
Figure imgf000393_0002
8-Chloro-4-oxo-4,5-dihydroimidazo[l,5-a]quinoxaline-3-carboxylic acid:
[0830] A 100 mL round bottom flask was charged with methyl 8-chloro-4-oxo- 4,5-dihydroimidazo[l,5-a]quinoxaline-3-carboxylate (2.2 g crude from last step, 4.40 mmol), LiOH (0.92 g, 22.0 mmol), THF (30 mL) and water (30 mL). The mixture was stirred at 25 °C for 12 h and then concentrated in vacuo. The solid was collected by filtration and dried, to afford 1.0 g (86% for 2 steps) of the product as an off-white solid.
Figure imgf000393_0003
8- Chloroimidazo [ l,5-a]quinoxalin-4(5H) -one :
[0831] A 50 mL round bottom flask was charged with 8-chloro-4-oxo-4,5- dihydroimidazo[l,5-a]quinoxaline-3-carboxylic acid (0.60 g, 2.27 mmol) and diphenyl ether (20 mL). The mixture was heated at 250 °C for 2.5 h under N2 then cooled to room temperature. It was diluted with petroleum ether (50 mL). The solid was collected by filtration and dried, to afford 0.41 g (82%) of the product as a gray solid.
Step 5
Figure imgf000394_0001
4,8-Dichloroimidazo[l,5-a]quinoxaline:
[0832] A 50 mL round bottom flask was charged with 8-chloroimidazo[l,5- a]quinoxalin-4(5H)-one (0.41 g, 1.86 mmol), phosphorus oxychloride (10 mL) and diisopropylethylamine (2 mL). The resulting mixture was stirred at reflux overnight. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :2). Work-up: the mixture was concentrated in vacuo. The residue was cautiously poured into ice water, neutralized with saturated aqueous NaHCC>3 (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 0.60 g of the product as a yellow solid.
Step 6
Figure imgf000394_0002
8-Chloro-4-(4-methylpiperazin-l-yl)imidazo[l,5-a]quinoxaline HC1 salt:
[0833] A 50 mL round bottom flask was charged with 4,8-dichloroimidazo[l,5- a]quinoxaline (0.60 g, 2.52 mmol), 1-methylpiperazine (0.76 g, 7.55 mmol) and THF (15 mL). The mixture was heated at 60 °C for 12 h and then cooled to room temperature. It was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 0.16 g (29% for 2 steps) of the free base of the product as an off-white solid. To its solution in THF (15 mL) was added slowly a solution (2 mL) of HC1 in EtOAc with stirring. The precipitate was collected by filtration, washed with ethyl ether (10 mL x 2), and dried, to afford 0.12 g of the corresponding HC1 salt as an off-white solid. *H NMR (300 MHz, D20) δ: 9.42 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 4.60-4.40 (m, 2H), 3.75-3.50 (m, 4H), 3.40-3.20 (m, 2H), 2.90 (s, 3H). MS m/z: 302 (M+H+).
Figure imgf000395_0001
EXAMPLE 515
-Chloro-4-(4-methylpiperazin-l-yl)pyrrolo[l,2-a]quinoxaline
Figure imgf000395_0002
Methyl l-(5-chloro-2-nitrophenyl)-lH-pyrrole-2-carboxylate:
[0834] A 50 mL round bottom flask was charged with 4-chloro-2-fluoro-l- nitrobenzene (2.0 g, 11.4 mmol), methyl lH-pyrrole-2-carboxylate (1.4 g, 11.4 mmol), CS2CO3 (4.5 g, 13.7 mmol) and DMF (35 mL). The mixture was heated at 60 °C for 24 h and then cooled to room temperature. It was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 1% EtOAc in petroleum ether, to afford 2.8 g (88%) of the product as a yellow crystal. Step 2
Figure imgf000396_0001
8- Chloropyrrolo [1 ,2-a]quinoxalin-4(5H) -one :
[0835] A 50 mL round bottom flask was charged with methyl l-(5-chloro-2- nitrophenyl)-lH-pyrrole-2-carboxylate (1.2 g, 4.30 mmol), iron powder (0.96 g, 17.2 mmol) and AcOH (12 mL). The mixture was heated at 100 °C for 12 h and then concentrated under reduced pressure to dryness. 1 M HC1 (50 mL) was then added slowly to remove any unreacted iron. The solid remained was collected by filtration and dried to afford 0.86 g (92%) of the product as a gray solid.
Step 3
Figure imgf000396_0002
4,8-Dichloropyrrolo[l,2-a]quinoxaline:
[0836] A 50 mL round bottom flask was charged with 8 -chloropyrrolo [1 ,2- a]quinoxalin-4(5H)-one (0.86 g, 3.94 mmol), phosphorus oxychloride (10 mL) and diisopropylethylamine (2 mL). The resulting mixture was heated at reflux for 1 h under N2. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :20). Work-up: the mixture was concentrated in vacuo. The residue was cautiously poured into ice water, neutralized with saturated aqueous NaHCC>3 (50 mL) and extracted with EtO Ac (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SC>4 and concentrated in vacuo, to afford 0.87 g (94%) of the product as a gray solid.
Step 4
Figure imgf000396_0003
8-Chloro-4-(4-methylpiperazin-l-yl)pyrrolo[l,2-a]quinoxaline:
[0837] A 50 mL round bottom flask was charged with 4,8-dichloropyrrolo[l,2- a]quinoxaline (0.40 g, 1.7 mmol), 1 -methylpiperazine (0.51 g, 5.1 mmol) and THF (10 mL). The mixture was heated at 60 °C for 12 h and then cooled to room temperature. It was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 1 % methanol in dichloromethane, to afford 0.47 g (92%) of the product as an off-white solid. *H NMR (300 MHz, CDC13) δ: 7.73 (dd, J = 2.7, 1.5 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.26 (dd, J = 8.7, 2.1 Hz, 1H), 6.90-6.60 (m, 2H), 3.83 (t, J = 5.1 Hz, 4H), 2.61 (t, J = 5.1 Hz, 4H), 2.38 (s, 3H). MS m/z: 301 (M+H+).
EXAMPLE 516
8-Chloro-4-(pipe l,2-a]quinoxaline
Figure imgf000397_0001
[0838] The HC1 salt of the title compound was prepared as described in Example 515, except that 1-Boc-piperazine was substituted for 1 -methylpiperazine in step 4 of that route. The Boc group was removed by HC1/THF solution. 1H NMR (300 MHz, D20) δ: 7.91 (dd, J = 2.7, 1.2 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.44 (dd, J = 4.5, 1.2 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.15 (dd, J = 8.7, 2.1 Hz, 1H), 6.93 (dd, J = 4.5, 2.7 Hz, 1H), 4.19 (t, J = 5.4 Hz, 4H), 3.53 (t, J = 5.4 Hz, 4H). MS m/z: 287 (M+H+).
Figure imgf000397_0002
EXAMPLE 517
9-Chloro-5-(4-methylpiperazin-l-yl)pyrrolo[l,2-c]quinazoline
Figure imgf000398_0001
tert-Butyl (4-chloro-2-iodophenyl)carbamate:
[0839] A 50 mL round bottom flask was charged with 4-chloro-2-iodoaniline (1.01 g, 4.0 mmol), di-tert-butyl dicarbonate (1.04 g, 4.8 mmol), 4- dimethylaminopyridine (0.49 g, 4.0 mmol) and pyridine (15 mL). The mixture was stirred at 70 °C for 2 h. Reaction progress was monitored by TLC
(EtO Ac/petroleum ether = 1 :20, Rf = 0.7). Work-up: the solvent was evaporated. The residue was mixed with brine and extracted with EtO Ac. The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo, to afford 1.08 g (76%) of the product. MS m/z: 354 (M+H+).
Step 2
Figure imgf000398_0002
tert-Butyl (4-chloro-2-(lH-pyrrol-2-yl)phenyl)carbamate:
[0840] A 100 mL round bottom flask was charged with tert-butyl (4-chloro-2- iodophenyl)carbamate (1.24 g, 3.5 mmol), Pd(PPh3)4 (202 mg, 0.17 mmol), Cs2C03 (1.15 g, 3.5 mmol), 1,4-dioxane (36 mL), water (12 mL) and (l-(tert- butoxycarbonyl)-lH-pyrrol-2-yl)boronic acid (886 mg, 4.2 mmol). The resulting mixture was stirred under N2 atmosphere at 90 °C overnight. Reaction progress was monitored by TLC (EtO Ac/petroleum ether = 1:10). Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel with 5-10% EtOAc in petroleum ether, to afford 0.324 g (31%) of the product, together with 0.665 g (48%) of tert-butyl 2-(2-((tert- butoxycarbonyl)amino)-5-chlorophenyl)-lH-pyrrole-l-carboxylate. Step 3
Figure imgf000399_0001
4-Chloro-2-(lH-pyrrol-2-yl)aniline:
[0841] A 50 mL round bottom flask was charged with tert-butyl (4-chloro-2- (lH-pyrrol-2-yl)phenyl)carbamate (0.324 g, 1.1 mmol) and trifluoroacetic acid (15 mL). The solution was stirred at 25 °C for 2 h. Reaction progress was monitored by TLC (EtO Ac/petroleum ether = 1 :4). Work-up: the solvent was evaporated. The residue was mixed with saturated aqueous NaHCC>3 and extracted with EtO Ac (30 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo, to afford 0.21 g (quantitative) of the product. MS m/z: 193 (M+H+).
Step 4
Figure imgf000399_0002
9- Chloropyrrolo [1 ,2-c]quinazolin-5(6H) -one :
[0842] A 50 mL round bottom flask was charged with 4-chloro-2-(lH-pyrrol-2- yl)aniline (210 mg, 1.09 mmol), K2CO3 (228 mg, 1.65 mmol), triphosgene (420 mg, 1.42 mmol) and THF (20 mL). The mixture was stirred at 75 °C for 20 h. Reaction progress was monitored by TLC (MeOH/CH2Cl2 = 1 :20, Rf = 0.3). Work-up: the solvent was evaporated. The residue was washed with water and dried to afford 166 mg (70%) of the product as a solid. MS m/z: 219 (M+H+).
Step 5
Figure imgf000399_0003
5,9-Dichloropyrrolo[l,2-c]quinazoline:
[0843] A 50 mL round bottom flask was charged with 9 -chloropyrrolo [1 ,2- c]quinazolin-5(6H)-one (166 mg, 0.76 mmol), phosphorus oxychloride (15 mL) and diisopropylethylamine (100 mg, 0.76 mmol). The resulting mixture was heated at reflux overnight. Work-up: the reaction mixture was concentrated in vacuo. The residue was cautiously poured into ice water, neutralized with saturated aqueous NaHCC>3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 10% EtOAc in petroleum ether, to afford 60 mg (33%) of the product. MS m/z: 237 (M+H+).
Step 6
Figure imgf000400_0001
9-Chloro-5-(4-methylpiperazin-l-yl)pyrrolo[l,2-c]quinazoline:
[0844] A 50 mL round bottom flask was charged with 5,9-dichloropyrrolo[l,2- cjquinazoline (60 mg, 0.25 mmol), 1-methylpiperazine (76 mg, 0.76 mmol) and THF (10 mL). The mixture was stirred at 60 °C for 1 h. Reaction progress was monitored by TLC. Work-up: the solvent was evaporated. The residue was purified by preparative-TLC, to afford 14 mg (18%) of the product. *H NMR (300 MHz, CDC13) δ: 7.84 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.34 (dd, J = 3.0, 1.5 Hz, 1H), 7.31 (dd, J = 8.7, 2.4 Hz, 1H), 6.88 (dd, J = 3.6, 1.5 Hz, 1H), 6.76 (dd, J = 3.6, 3.0 Hz, 1H), 3.48 (t, J = 5.0 Hz, 4H), 2.66 (t, J = 5.0 Hz, 4H), 2.40 (s, 3H). MS m/z: 301 (M+H+).
Figure imgf000400_0002
EXAMPLE 518
9-Chloro-5-(4-methylpiperazin-l-yl)imidazo[l,5-c]quinazoline
Figure imgf000401_0001
2,4,6-Trichloroquinazoline:
[0845] The title compound was prepared as described in Example 12.
Step 3-4
Figure imgf000401_0002
Diethyl 2-acetamido-2-(6-chloro-2-(4-methylpiperazin-l-yl)quinazolin-4- yl)malonate:
[0846] A 100 mL 3-necked round bottom flask was charged with NaH (383 mg, 9.42 mmol) and THF (20 mL). To the above suspension was added dropwise a solution of diethyl 2-acetamidomalonate (1.40 g, 6.42 mmol) in THF (10 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 0.5 h at that temperature. A solution of 2,4,6-trichloroquinazoline (1.00 g, 4.28 mmol) in THF (10 mL) was then added dropwise at 0 °C. The resulting solution was stirred at room temperature for 2 h, followed by the addition of N-methylpiperazine (556 mg, 5.56 mmol) and triethylamine (1.55 g, 12.8 mmol). The reaction solution was stirred at room temperature for another 2 h. Work-up: the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% methanol in CH2CI2, to afford 1.18 g (57%) of the product as a red solid. Step 5
Figure imgf000402_0001
(6-Chloro-2-(4-methylpiperazin-l-yl)quinazolin-4-yl)methanamine:
[0847] A 25 mL round bottom flask was charged with diethyl 2-acetamido-2- (6-chloro-2-(4-methylpiperazin-l-yl)quinazolin-4-yl)malonate (0.86 g, 1.80 mmol), 8 M aqueous NaOH (0.90 mL, 7.20 mmol) and ethanol (3 mL). The resulting mixture was stirred at room temperature for 2 h then cooled to 5 °C and acidified to pH 2 with 6 M aqueous HC1. Ethanol was evaporated and to the residue was added more 6 M aqueous HC1 (1.3 mL). The resulting suspension was stirred at 80 °C for 4 h then room temperature overnight. Work-up: the reaction mixture was basified to pH 10 and extracted with (¾(¾. The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 5 ~20 methanol in CH2CI2, to afford 250 mg (47%) of the product as a solid. *H NMR (300 MHz, CDC13) δ: 7.72-7.71 (m, 1H), 7.57-7.50 (m, 2H), 4.31 (s, 2H), 4.02 (t, J = 5.2 Hz, 4H), 2.52 (t, J = 5.2 Hz, 4H), 2.36 (s, 3H).
Step 6
Figure imgf000402_0002
N-((6-Chloro-2-(4-methylpiperazin-l-yl)quinazolin-4-yl)methyl)formamide:
[0848] A 10 mL round bottom flask was charged with formic acid (0.5 mL) and acetic anhydride (0.5 mL). The resulting solution was heated at 50 °C for 0.5 h then cooled to room temperature. It was then added into a solution of (6-chloro-2-(4- methylpiperazin-l-yl)quinazolin-4-yl)methanamine (230 mg, 0.788 mmol) in dichloromethane (5 mL). The reaction solution was stirred at room temperature overnight. Work-up: the solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 2%~5% methanol in CH2CI2, to afford 107 mg (42%) of the product as a light yellow solid. Step 7
Figure imgf000403_0001
9-Chloro-5-(4-methylpiperazin-l-yl)imidazo[l,5-c]quinazoline:
[0849] A 10 mL round bottom flask was charged with N-((6-chloro-2-(4- methylpiperazin-l-yl)quinazolin-4-yl)methyl)formamide (0.100 g, 0.313 mmol) and POCI3 (5 mL). The resulting solution was heated at reflux for 1 h. Work-up: the solvent was evaporated and the residue was purified by flash column
chromatography on silica gel with 10% methanol in (¾(¾, to afford 8 mg (8%) of the product as a light yellow solid. *H NMR (400 MHz, CDC13) δ: 8.17 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 8.6, 2.4 Hz, 1H), 3.55 (t, J = 4.6 Hz, 4H), 2.69 (t, J = 4.6 Hz, 4H), 2.42 (s, 3H). MS m/z: 302 (M+H+).
EXAMPLE 519
2-Methyl-5-(piperazin-l-yl -9-(trifluoromethyl)pyrazolo[l,5-c]quinazoline
Figure imgf000403_0002
[0850] The HC1 salt of the title compound was prepared analogously to Example 501. *H NMR (300 MHz, D20/DMSO-d6) δ: 8.53 (s, 1H), 7.86-7.74 (m, 2H), 7.34 (s, 1H), 4.28 (br, 4H), 3.34 (br, 4H), 2.40 (s, 3H). MS m/z: 336 (M+H+).
[0851] The following compounds, represented as structures or as SMILES strings below, can generally be made using the methods known in the art and/or as shown above. It is expected that these compounds when made will have activity similar to those that have been made in the examples above. Some of these compounds may have been made and tested, and if so, are represented above in the Examples; if any discrepancy in nomenclature occurs, the Examples control.
Figure imgf000404_0001
403
Figure imgf000405_0001
404
Figure imgf000406_0001
[0852] The following compounds are represented herein using the Simplified Molecular Input Line Entry System, or SMILES. SMILES is a modern chemical notation system, developed by David Weininger and Daylight Chemical Information Systems, Inc., that is built into all major commercial chemical structure drawing software packages. Software is not needed to interpret SMILES text strings, and an explanation of how to translate SMILES into structures can be found in Weininger, D., /. Chem. Inf. Comput. Sci. 1988, 28, 31-36. All SMILES strings used herein, as well as numerous IUPAC names, were generated using
CambridgeSoft's ChemDraw ChemBioDraw Ultra 11.0.
C 1 CN(CCN1 )C3=NC2=CC(=CC=C2N4N=NN=C34)C1
FC(F)(F)C= 1 C=CC=2N=C(C3=NN=NN3(C=2(C=1 )))N4CCNCC4
CC2=NC=3C(=NC=lC=C(F)C(=CC=lC=3(02))Br)N4CCN(C)CC4
CC2=NC=3C(=NC=lC=C(F)C(=CC=lC=3(02))Br)N4CCNCC4
C 1 CN(CCN1 )C3=NC2=CC=C(C=C2N4N=CN=C34)C1
FC4=CC(=CCl=C4(N=C(C2=NN=NN12)N3CCNCC3))Br
CN1CCN(CC1)C3=NC=2C(F)=CC(=CC=2N4N=NN=C34)C1
FC4=CC(=CC1=C4(N=C(C2=NN=NN12)N3CCNCC3))C1
CC=2N=C3C=4C=C(C=C(F)C=4(N=C(NlCCNCCl)N3(N=2)))Br
CC2=NC=3C(=NCl=CC=C(C=ClC=3(02))Br)N4CCN(C)CC4
CC2=NC=3C(=NC 1 =CC=C(C=C 1 C=3(02))Br)N4CCNCC4
CC0C(=0)C=2N=C3C(=NC1=CC=C(C=C1N3(N=2))C1)N4CCNCC4
CN1CCN(CC1)C4=NC=2C=C(F)C(=CC=2C3=C0N=C34)C1
FC 1 =CC=2N=C(C3=NOC=C3(C=2(C=C 1 C1)))N4CCNCC4
C=1C=NC2=C(C=1)C=4C=C(C=CC=4(N=C2N3CCNCC3))C1
CN1 CCN(CC 1)C4=NC=2C=CC(=CC=2C=3N=CC=NC=34)C1
CN1 CCN(CC 1)C4=NC=2C=CC(=CC=2C=3C=CC=NC=34)C1
C=1C=NC2=C(N=1)C=4C=C(C=CC=4(N=C2N3CCNCC3))C1
CN1 CCN(CC 1)C4=NC=2C=CC(=CC=2C=3C=NC=NC=34)C1
C1CN(CCN1)C4=NC=2C=CC(=CC=2C=3C=NC=NC=34)C1
CC=2N=C3C(=NC 1 =CC(F)=C(C=C 1 N3(N=2))C1)N4CCN(C)CC4
CC=2N=C3C(=NC 1 =CC(F)=C(C=C 1 N3(N=2))C1)N4CCNCC4
CNlCCN(CCl)C4=NC=2C=C(F)C(=CC=2C3=CON=C34)Br
FC 1 =CC=2N=C(C3=NOC=C3(C=2(C=C 1 Br)))N4CCNCC4
CC=2N=C3C=4C=C(C(F)=CC=4(N=C(NlCCN(C)CCl)N3(N=2)))Br
CC=2N=C3C=4C=C(C(F)=CC=4(N=C(NlCCNCCl)N3(N=2)))Br
CC=2N=C3C(=NC 1 =C(F)C=C(C=C 1 N3(N=2))Br)N4CCN(C)CC4 CC=2N=C3 C(=NC 1 =C(F)C=C(C=C 1 N3 (N=2))Br)N4CCNCC4
CNlCCN(CCl)C3=NC4=C(F)C=C(C=C4(C2=CON=C23))Br
FC=2C=C(C=C3Cl=CON=ClC(=NC=23)N4CCNCC4)Br
CN1CCN(CC1)C3=NC2=CC=C(C=C2N4N=C(N=C34)C(=0)0)C1
0=C(0)C=2N=C3C(=NC1=CC=C(C=C1N3(N=2))C1)N4CCNCC4
CN(CC4)CCN4C(C2=NN=CN23)=NC1=C3C=C(C(F)(F)C(F)(F)F)C=C1
FC(C(F)(F)F)(F)C1=CC3=C(N=C(N4CCNCC4)C2=NN=CN23)C=C1
CC=2N=C3C(=NC1=CC=C(C=C1N3(N=2))C(F)(F)F)N4CCN(C)CC4
CC=2N=C3C(=NC1=CC=C(C=C1N3(N=2))C(F)(F)F)N4CCNCC4
CNlCCN(CCl)C4=NC=2C=CC(=CC=2C3=C4(N=CS3))Br
ClCN(CCNl)C4=NC=2C=CC(=CC=2C3=C4(N=CS3))Br
ClCC2CN(CCN2(Cl))C5=NC=3C=CC(=CC=3C4=C5(N=CS4))Br
CNlCCN(CCl)C4=NC=2C=C(F)C(=CC=2C3=C4(N=CS3))Br
FCl=CC=2N=C(C=3N=CSC=3(C=2(C=ClBr)))N4CCNCC4
FCl=CC=2N=C(C=3N=CSC=3(C=2(C=ClBr)))N4CCN5CCCC5(C4)
CNlCCN(CCl)C4=NC=2C(F)=CC(=CC=2C3=C4(N=CS3))Br
FC4=CC(=CCl=C4(N=C(C=2N=CSCl=2)N3CCNCC3))Br
FC5=CC(=CCl=C5(N=C(C=2N=CSCl=2)N3CCN4CCCC4(C3)))Br
CNlCCN(CCl)C4=NC=2C(F)=C(F)C(=CC=2C3=C4(N=CS3))Br
FC4=C(F)C(=CCl=C4(N=C(C=2N=CSCl=2)N3CCNCC3))Br
FC5=C(F)C(=CCl=C5(N=C(C=2N=CSCl=2)N3CCN4CCCC4(C3)))Br
CN1CCN(CC1)C4=NC=2C=CC(=CC=2C3=C4(N=CS3))C1
C1CN(CCN1)C4=NC=2C=CC(=CC=2C3=C4(N=CS3))C1
C1CC2CN(CCN2(C1))C5=NC=3C=CC(=CC=3C4=C5(N=CS4))C1
CN1CCN(CC1)C4=NC=2C=C(F)C(=CC=2C3=C4(N=CS3))C1
FC 1 =CC=2N=C(C=3N=CSC=3(C=2(C=C 1 C1)))N4CCNCC4
FC1=CC=2N=C(C=3N=CSC=3(C=2(C=C1C1)))N4CCN5CCCC5(C4)
CN1CCN(CC1)C4=NC=2C(F)=CC(=CC=2C3=C4(N=CS3))C1
FC4=CC(=CC1=C4(N=C(C=2N=CSC1=2)N3CCNCC3))C1
FC5=CC(=CC1=C5(N=C(C=2N=CSC1=2)N3CCN4CCCC4(C3)))C1
CN1CCN(CC1)C4=NC=2C(F)=C(F)C(=CC=2C3=C4(N=CS3))C1
FC4=C(F)C(=CC1=C4(N=C(C=2N=CSC1=2)N3CCNCC3))C1
FC5=C(F)C(=CC1=C5(N=C(C=2N=CSC1=2)N3CCN4CCCC4(C3)))C1
CN1CCN(CC1)C4=NC=2C=CC(=CC=2C3=C4(N=CS3))C(F)(F)F FC(F)(F)C=1C=CC=2N=C(C=3N=CSC=3(C=2(C=1)))N4CCNCC4
FC(F)(F)C=1C=CC=2N=C(C=3N=CSC=3(C=2(C=1)))N4CCN5CCCC5(C4)
CN1CCN(CC1)C4=NC=2C=C(F)C(=CC=2C3=C4(N=CS3))C(F)(F)F
FC1=CC=2N=C(C=3N=CSC=3(C=2(C=C1C(F)(F)F)))N4CCNCC4
FC1=CC=2N=C(C=3N=CSC=3(C=2(C=C1C(F)(F)F)))N4CCN5CCCC5(C4)
CN1CCN(CC1)C4=NC=2C(F)=CC(=CC=2C3=C4(N=CS3))C(F)(F)F
FC4=CC(=CC1=C4(N=C(C=2N=CSC1=2)N3CCNCC3))C(F)(F)F
FC5=CC(=CC1=C5(N=C(C=2N=CSC1=2)N3CCN4CCCC4(C3)))C(F)(F)F
CN1CCN(CC1)C4=NC=2C(F)=C(F)C(=CC=2C3=C4(N=CS3))C(F)(F)F
FC4=C(F)C(=CC1=C4(N=C(C=2N=CSC1=2)N3CCNCC3))C(F)(F)F
FC5=C(F)C(=CC1=C5(N=C(C=2N=CSC1=2)N3CCN4CCCC4(C3)))C(F)(F)F
CN1CCN(CC1)C4=NC=2C=C(C(=CC=2C3=C4(N=CS3))C(F)(F)F)C1
FC(F)(F)C 1 =CC2=C(C=C 1 C1)N=C(C=3N=CSC2=3)N4CCNCC4
FC(F)(F)C1=CC2=C(C=C1C1)N=C(C=3N=CSC2=3)N4CCN5CCCC5(C4)
CNlCCN(CCl)C4=NC=2C=C(F)C(=CC=2C3=CC=NN34)Br
FC2=CC=3N=C(N1 CCNCC 1 )N4N=CC=C4(C=3(C=C2Br))
FC3=CC=4N=C(NlCCN2CCCC2(Cl))N5N=CC=C5(C=4(C=C3Br))
CNlCCN(CCl)C4=NC=2C=CC(=CC=2C3=CC=NN34)Br
C=2C=C3C=4C=C(C=CC=4(N=C(NlCCNCCl)N3(N=2)))Br
C 1 CC2CN(CCN2(C 1 ))C5=NC=3C=CC(=CC=3C4=CC=NN45)Br
CNlCCN(CCl)C3=NC=4C(F)=CC(=CC=4(C2=CC=NN23))Br
FC2=CC(=CC=3Cl=CC=NNlC(=NC2=3)N4CCNCC4)Br
FC2=CC(=CC=3Cl=CC=NNlC(=NC2=3)N4CCN5CCCC5(C4))Br
CNlCCN(CCl)C3=NC=4C(F)=C(F)C(=CC=4(C2=CC=NN23))Br
FC2=C(F)C(=CC=3C 1 =CC=NN1 C(=NC2=3)N4CCNCC4)Br
FC2=C(F)C(=CC=3Cl=CC=NNlC(=NC2=3)N4CCN5CCCC5(C4))Br
CN1CCN(CC1)C4=NC=2C=C(F)C(=CC=2C3=CC=NN34)C1
FC2=CC=3N=C(N1 CCNCC 1 )N4N=CC=C4(C=3(C=C2C1))
FC3=CC=4N=C(N1CCN2CCCC2(C1))N5N=CC=C5(C=4(C=C3C1))
CN1CCN(CC1)C4=NC=2C=CC(=CC=2C3=CC=NN34)C1
C=2C=C3C=4C=C(C=CC=4(N=C(N1CCNCC1)N3(N=2)))C1
C1CC2CN(CCN2(C1))C5=NC=3C=CC(=CC=3C4=CC=NN45)C1
CN1CCN(CC1)C3=NC=4C(F)=CC(=CC=4(C2=CC=NN23))C1
FC2=CC(=CC=3C1=CC=NN1C(=NC2=3)N4CCNCC4)C1 FC2=CC(=CC=3C1=CC=NN1C(=NC2=3)N4CCN5CCCC5(C4))C1
CN1CCN(CC1)C3=NC=4C(F)=C(F)C(=CC=4(C2=CC=NN23))C1
FC2=C(F)C(=CC=3C 1 =CC=NN1 C(=NC2=3)N4CCNCC4)C1
FC2=C(F)C(=CC=3C1=CC=NN1C(=NC2=3)N4CCN5CCCC5(C4))C1
CN1CCN(CC1)C4=NC=2C=C(F)C(=CC=2C3=CC=NN34)C(F)(F)F
FC2=CC=3N=C(N1CCNCC1)N4N=CC=C4(C=3(C=C2C(F)(F)F))
FC3=CC=4N=C(N1CCN2CCCC2(C1))N5N=CC=C5(C=4(C=C3C(F)(F)F))
CN1CCN(CC1)C4=NC=2C=CC(=CC=2C3=CC=NN34)C(F)(F)F
FC(F)(F)C=2C=CC=3N=C(N1CCNCC1)N4N=CC=C4(C=3(C=2))
FC(F)(F)C=3C=CC=4N=C(N1CCN2CCCC2(C1))N5N=CC=C5(C=4(C=3))
CN1CCN(CC1)C3=NC=4C(F)=C(F)C(=CC=4(C2=CC=NN23))C(F)(F)F
FC2=C(F)C(=CC=3C1=CC=NN1C(=NC2=3)N4CCNCC4)C(F)(F)F
FC1=C(F)C3=C(C2=CC=NN2C(N4CCN(CCC5)C5C4)=N3)C=C1C(F)(F)F
CN1CCN(CC1)C3=NC=4C(F)=CC(=CC=4(C2=CC=NN23))C(F)(F)F
FC2=CC(=CC=3C1=CC=NN1C(=NC2=3)N4CCNCC4)C(F)(F)F
FC2=CC(=CC=3C1=CC=NN1C(=NC2=3)N4CCN5CCCC5(C4))C(F)(F)F
CN1CCN(CC1)C4=NC=2C=C(C(=CC=2C3=CC=NN34)C(F)(F)F)C1
FC(F)(F)C1=CC3=C(C=C1C1)N=C(N2CCNCC2)N4N=CC=C34
FC(F)(F)C1=CC4=C(C=C1C1)N=C(N2CCN3CCCC3(C2))N5N=CC=C45
Cl=CC=2C=4C=C(C=CC=4(N=C(C=2(N=Nl))N3CCNCC3))Br
CNlCCN(CCl)C4=NC=2C=CC(=CC=2C=3C=CN=NC=34)Br
C 1 CC2CN(CCN2(C 1 ))C5=NC=3C=CC(=CC=3C=4C=CN=NC=45)Br
FC 1 =CC=2N=C(C=3N=NC=CC=3(C=2(C=C 1 Br)))N4CCNCC4
CNlCCN(CCl)C4=NC=2C=C(F)C(=CC=2C=3C=CN=NC=34)Br
FC 1 =CC=2N=C(C=3N=NC=CC=3(C=2(C=C 1 Br)))N4CCN5CCCC5(C4)
FC2=CC(=CC=3C=lC=CN=NC=lC(=NC2=3)N4CCNCC4)Br
CNlCCN(CCl)C3=NC=4C(F)=CC(=CC=4(C=2C=CN=NC=23))Br
FC2=CC(=CC=3C=lC=CN=NC=lC(=NC2=3)N4CCN5CCCC5(C4))Br
FC2=C(F)C(=CC=3C= 1 C=CN=NC= 1 C(=NC2=3)N4CCNCC4)Br
CNlCCN(CCl)C3=NC=4C(F)=C(F)C(=CC=4(C=2C=CN=NC=23))Br
FC2=C(F)C(=CC=3C=lC=CN=NC=lC(=NC2=3)N4CCN5CCCC5(C4))Br
C1=CC=2C=4C=C(C=CC=4(N=C(C=2(N=N1))N3CCNCC3))C1
CN1CCN(CC1)C4=NC=2C=CC(=CC=2C=3C=CN=NC=34)C1
C 1 CC2CN(CCN2(C 1 ))C5=NC=3C=CC(=CC=3C=4C=CN=NC=45)C1 FC 1 =CC=2N=C(C=3N=NC=CC=3(C=2(C=C 1 C1)))N4CCNCC4
CN1CCN(CC1)C4=NC=2C=C(F)C(=CC=2C=3C=CN=NC=34)C1
FC1=CC=2N=C(C=3N=NC=CC=3(C=2(C=C1C1)))N4CCN5CCCC5(C4)
FC2=CC(=CC=3C=1C=CN=NC=1C(=NC2=3)N4CCNCC4)C1
CN1CCN(CC1)C3=NC=4C(F)=CC(=CC=4(C=2C=CN=NC=23))C1
FC2=CC(=CC=3C=1C=CN=NC=1C(=NC2=3)N4CCN5CCCC5(C4))C1
FC2=C(F)C(=CC=3C= 1 C=CN=NC= 1 C(=NC2=3)N4CCNCC4)C1
CN1CCN(CC1)C3=NC=4C(F)=C(F)C(=CC=4(C=2C=CN=NC=23))C1
FC2=C(F)C(=CC=3C=1C=CN=NC=1C(=NC2=3)N4CCN5CCCC5(C4))C1
FC(F)(F)C 1 =CC2=C(C=C 1 C1)N=C(C=3N=NC=CC2=3)N4CCNCC4
CN1CCN(CC1)C4=NC=2C=C(C(=CC=2C=3C=CN=NC=34)C(F)(F)F)C1
FC(F)(F)C1=CC2=C(C=C1C1)N=C(C=3N=NC=CC2=3)N4CCN5CCCC5(C4)
FC(F)(F)C(F)(F)C1=CC=C2N=C(C3=NN=CN3(C2(=C1)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC=C(C=C2N4C=NN=C34)C(F)(F)C(F)(F)F
FC(F)(F)C(F)(F)C1=CC=C2N=C(C3=NN=CN3(C2(=C1)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C3=NN=CN3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(F)=C(C=C2N4C=NN=C34)C(F)(F)C(F)(F)F
FC=1C=C2N=C(C3=NN=CN3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCN5CCCC5(C4
)
FC=4C=C(C=C1C=4(N=C(C2=NN=CN12)N3CCNCC3))C(F)(F)C(F)(F)F CN1CCN(CC1)C3=NC2=C(F)C=C(C=C2N4C=NN=C34)C(F)(F)C(F)(F)F FC=5C=C(C=C1C=5(N=C(C2=NN=CN12)N3CCN4CCCC4(C3)))C(F)(F)C(F)(F) F
FC=4C(F)=C(C=C1C=4(N=C(C2=NN=CN12)N3CCNCC3))C(F)(F)C(F)(F)F CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2N4C=NN=C34)C(F)(F)C(F)(F)F FC=5C(F)=C(C=C1C=5(N=C(C2=NN=CN12)N3CCN4CCCC4(C3)))C(F)(F)C(F) (F)F
N#CC1=CC=C2N=C(C3=NN=CN3(C2(=C1)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC=C(C#N)C=C2N4C=NN=C34
N#CC1=CC=C2N=C(C3=NN=CN3(C2(=C1)))N4CCN5CCCC5(C4)
N#CC=1C=C2C(=CC=1(F))N=C(C3=NN=CN23)N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(F)=C(C#N)C=C2N4C=NN=C34
N#CC=1C=C2C(=CC=1(F))N=C(C3=NN=CN23)N4CCN5CCCC5(C4)
N#CC=4C=C1C(N=C(C2=NN=CN12)N3CCNCC3)=C(F)C=4(F) CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C#N)C=C2N4C=NN=C34
N#CC=5C=C1C(N=C(C2=NN=CN12)N3CCN4CCCC4(C3))=C(F)C=5(F)
FC=4C(F)=C(C=ClC=4(N=C(C2=NN=CN12)N3CCNCC3))Br
CNlCCN(CCl)C3=NC2=C(F)C(F)=C(C=C2N4C=NN=C34)Br
FC=5C(F)=C(C=ClC=5(N=C(C2=NN=CN12)N3CCN4CCCC4(C3)))Br
FC=4C(F)=C(C=C1C=4(N=C(C2=NN=CN12)N3CCNCC3))C1
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2N4C=NN=C34)C1
FC=5C(F)=C(C=C1C=5(N=C(C2=NN=CN12)N3CCN4CCCC4(C3)))C1
FC=4C(F)=C(C=C1C=4(N=C(C2=NN=CN12)N3CCNCC3))C(F)(F)F
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2N4C=NN=C34)C(F)(F)F
FC=5C(F)=C(C=C1C=5(N=C(C2=NN=CN12)N3CCN4CCCC4(C3)))C(F)(F)F
CC1=CC(F)=C2N=C(C3=NN=CN3(C2(=C1)))N4CCNCC4
CC1=CC(F)=C2N=C(C3=NN=CN3(C2(=C1)))N4CCN(C)CC4
CC1=CC(F)=C2N=C(C3=NN=CN3(C2(=C1)))N4CCN5CCCC5(C4)
CC=4C=C1C(N=C(C2=NN=CN12)N3CCNCC3)=C(F)C=4(F)
CC=4C=C1C(N=C(C2=NN=CN12)N3CCN(C)CC3)=C(F)C=4(F)
CC=5C=C1C(N=C(C2=NN=CN12)N3CCN4CCCC4(C3))=C(F)C=5(F)
FC=4C=C1C(N=C(C2=NN=CN12)N3CCNCC3)=C(F)C=4(F)
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(F)C=C2N4C=NN=C34
FC=5C=C1C(N=C(C2=NN=CN12)N3CCN4CCCC4(C3))=C(F)C=5(F)
FC(F)(F)C=1C=C2N=C(C3=NN=CN3(C2(=CC=1C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(=C(C=C2N4C=NN=C34)C(F)(F)F)C(F)(F)F
FC(F)(F)C=1C=C2N=C(C3=NN=CN3(C2(=CC=1C(F)(F)F)))N4CCN5CCCC5(C4
)
FC2(F)(C=1C=C3N=C(C4=NN=CN4(C3(=CC=1C(F)(F)C2(F)(F))))N5CCNCC5) CN1CCN(CC1)C3=NC2=CC5=C(C=C2N4C=NN=C34)C(F)(F)C(F)(F)C5(F)(F) FC2(F)(C=1C=C3N=C(C4=NN=CN4(C3(=CC=1C(F)(F)C2(F)(F))))N5CCN6CCC C6(C5))
CC=2N=C3C4=CC(=CC=C4(N=C(N1CCNCC1)N3(N=2)))C(F)(F)C(F)(F)F CC=2N=C3C4=CC(=CC=C4(N=C(N1CCN(C)CC1)N3(N=2)))C(F)(F)C(F)(F)F CC=3N=C4C5=CC(=CC=C5(N=C(N1CCN2CCCC2(C1))N4(N=3)))C(F)(F)C(F)( F)F
CC=2N=C3C4=CC(=C(F)C=C4(N=C(N1CCNCC1)N3(N=2)))C(F)(F)C(F)(F)F CC=2N=C3C4=CC(=C(F)C=C4(N=C(N1CCN(C)CC1)N3(N=2)))C(F)(F)C(F)(F)F CC=3N=C4C5=CC(=C(F)C=C5(N=C(N1CCN2CCCC2(C1))N4(N=3)))C(F)(F)C( F)(F)F
CC=2N=C3C4=CC(=CC(F)=C4(N=C(N1CCNCC1)N3(N=2)))C(F)(F)C(F)(F)F CC=2N=C3C4=CC(=CC(F)=C4(N=C(N1CCN(C)CC1)N3(N=2)))C(F)(F)C(F)(F)F CC=3N=C4C5=CC(=CC(F)=C5(N=C(N1CCN2CCCC2(C1))N4(N=3)))C(F)(F)C( F)(F)F
CC=2N=C3C4=CC(=C(F)C(F)=C4(N=C(N1CCNCC1)N3(N=2)))C(F)(F)C(F)(F)F CC=2N=C3C4=CC(=C(F)C(F)=C4(N=C(N1CCN(C)CC1)N3(N=2)))C(F)(F)C(F)( F)F
CC=3N=C4C5=CC(=C(F)C(F)=C5(N=C(N1CCN2CCCC2(C1))N4(N=3)))C(F)(F) C(F)(F)F
CC=2N=C3C4=CC(C#N)=C(F)C=C4(N=C(N1CCNCC1)N3(N=2))
CC=2N=C3C4=CC(C#N)=C(F)C=C4(N=C(N1CCN(C)CC1)N3(N=2))
CC=3N=C4C5=CC(C#N)=C(F)C=C5(N=C(N1CCN2CCCC2(C1))N4(N=3))
CC=2N=C3C4=CC(C#N)=CC=C4(N=C(N1CCNCC1)N3(N=2))
CC=2N=C3C4=CC(C#N)=CC=C4(N=C(N1CCN(C)CC1)N3(N=2))
CC=3N=C4C5=CC(C#N)=CC=C5(N=C(N1CCN2CCCC2(C1))N4(N=3))
CC=2N=C3C4=CC(C#N)=CC(F)=C4(N=C(N1CCNCC1)N3(N=2))
CC=2N=C3C4=CC(C#N)=CC(F)=C4(N=C(N1CCN(C)CC1)N3(N=2))
CC=3N=C4C5=CC(C#N)=CC(F)=C5(N=C(N1CCN2CCCC2(C1))N4(N=3))
CC=2N=C3C4=CC(C#N)=C(F)C(F)=C4(N=C(N1CCNCC1)N3(N=2))
CC=2N=C3C4=CC(C#N)=C(F)C(F)=C4(N=C(N 1 CCN(C)CC 1 )N3(N=2))
CC=3N=C4C5=CC(C#N)=C(F)C(F)=C5(N=C(N1CCN2CCCC2(C1))N4(N=3))
CC=2N=C3C4=CC(=C(F)C(F)=C4(N=C(NlCCNCCl)N3(N=2)))Br
CC=2N=C3C4=CC(=C(F)C(F)=C4(N=C(NlCCN(C)CCl)N3(N=2)))Br
CC=3N=C4C5=CC(=C(F)C(F)=C5(N=C(NlCCN2CCCC2(Cl))N4(N=3)))Br
CC=2N=C3C4=CC(=C(F)C(F)=C4(N=C(N1CCNCC1)N3(N=2)))C1
CC=2N=C3C4=CC(=C(F)C(F)=C4(N=C(N1CCN(C)CC1)N3(N=2)))C1
CC=3N=C4C5=CC(=C(F)C(F)=C5(N=C(N1CCN2CCCC2(C1))N4(N=3)))C1
CC=2N=C3C4=CC(=C(F)C(F)=C4(N=C(N1CCNCC1)N3(N=2)))C(F)(F)F
CC=2N=C3C4=CC(=C(F)C(F)=C4(N=C(N1CCN(C)CC1)N3(N=2)))C(F)(F)F
CC=3N=C4C5=CC(=C(F)C(F)=C5(N=C(N1CCN2CCCC2(C1))N4(N=3)))C(F)(F)
F
CC=2N=C3C4=CC(C)=C(F)C=C4(N=C(N1CCNCC1)N3(N=2)) CC=2N=C3C4=CC(C)=C(F)C=C4(N=C(N1CCN(C)CC1)N3(N=2))
CC=3N=C4C5=CC(C)=C(F)C=C5(N=C(N1CCN2CCCC2(C1))N4(N=3))
CC2=CC(F)=C3N=C(N1CCNCC1)N4N=C(C)N=C4(C3(=C2))
CC2=CC(F)=C3N=C(N1CCN(C)CC1)N4N=C(C)N=C4(C3(=C2))
CC3=CC(F)=C4N=C(N1CCN2CCCC2(C1))N5N=C(C)N=C5(C4(=C3))
CC=2N=C3C4=CC(C)=C(F)C(F)=C4(N=C(N1CCNCC1)N3(N=2))
CC=2N=C3C4=CC(C)=C(F)C(F)=C4(N=C(N1CCN(C)CC1)N3(N=2))
CC=3N=C4C5=CC(C)=C(F)C(F)=C5(N=C(N1CCN2CCCC2(C1))N4(N=3))
CC=2N=C3C4=CC(F)=C(F)C(F)=C4(N=C(N1CCNCC1)N3(N=2))
CC=2N=C3C4=CC(F)=C(F)C(F)=C4(N=C(N1CCN(C)CC1)N3(N=2))
CC=3N=C4C5=CC(F)=C(F)C(F)=C5(N=C(N1CCN2CCCC2(C1))N4(N=3))
CC=2N=C3C4=CC(=C(C=C4(N=C(N1CCNCC1)N3(N=2)))C(F)(F)F)C(F)(F)F
CC=2N=C3C4=CC(=C(C=C4(N=C(N1CCN(C)CC1)N3(N=2)))C(F)(F)F)C(F)(F)F
CC=3N=C4C5=CC(=C(C=C5(N=C(N1CCN2CCCC2(C1))N4(N=3)))C(F)(F)F)C(
F)(F)F
CC=2N=C3C4=CC5=C(C=C4(N=C(N1CCNCC1)N3(N=2)))C(F)(F)C(F)(F)C5(F) (F)
CC=2N=C3C4=CC5=C(C=C4(N=C(N1CCN(C)CC1)N3(N=2)))C(F)(F)C(F)(F)C5 (F)(F)
CC=3N=C4C5=CC6=C(C=C5(N=C(N1CCN2CCCC2(C1))N4(N=3)))C(F)(F)C(F) (F)C6(F)(F)
FC(F)(F)C(F)(F)C1=CC=C2N=C(C3=NN=NN3(C2(=C1)))N4CCNCC4
FC=1C=C2N=C(C3=NN=NN3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCNCC4
FC=4C=C(C=C1C=4(N=C(C2=NN=NN12)N3CCNCC3))C(F)(F)C(F)(F)F
CN1CCN(CC1)C3=NC2=CC=C(C=C2N4N=NN=C34)C(F)(F)C(F)(F)F
CN1CCN(CC1)C3=NC2=CC(F)=C(C=C2N4N=NN=C34)C(F)(F)C(F)(F)F
CN1CCN(CC1)C3=NC2=C(F)C=C(C=C2N4N=NN=C34)C(F)(F)C(F)(F)F
FC(F)(F)C(F)(F)C1=CC=C2N=C(C3=NN=NN3(C2(=C1)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C3=NN=NN3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCN5CCCC5(C4
)
FC=5C=C(C=C1C=5(N=C(C2=NN=NN12)N3CCN4CCCC4(C3)))C(F)(F)C(F)(F) F
FC=4C(F)=C(C=C1C=4(N=C(C2=NN=NN12)N3CCNCC3))C(F)(F)C(F)(F)F CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2N4N=NN=C34)C(F)(F)C(F)(F)F FC=5C(F)=C(C=C1C=5(N=C(C2=NN=NN12)N3CCN4CCCC4(C3)))C(F)(F)C(F) (F)F
CN1CCN(CC1)C3=NC2=CC=C(C#N)C=C2N4N=NN=C34
N#CC=1C=C2C(=CC=1(F))N=C(C3=NN=NN23)N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(F)=C(C#N)C=C2N4N=NN=C34
N#CC=1C=C2C(=CC=1(F))N=C(C3=NN=NN23)N4CCN5CCCC5(C4)
N#CC 1 =CC(F)=C2N=C(C3=NN=NN3(C2(=C 1 )))N4CCNCC4
CN1CCN(CC1)C3=NC2=C(F)C=C(C#N)C=C2N4N=NN=C34
N#CC1=CC(F)=C2N=C(C3=NN=NN3(C2(=C1)))N4CCN5CCCC5(C4)
N#CC=4C=C1C(N=C(C2=NN=NN12)N3CCNCC3)=C(F)C=4(F)
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C#N)C=C2N4N=NN=C34
N#CC=5C=C1C(N=C(C2=NN=NN12)N3CCN4CCCC4(C3))=C(F)C=5(F)
FC=4C(F)=C(C=ClC=4(N=C(C2=NN=NN12)N3CCNCC3))Br
CNlCCN(CCl)C3=NC2=C(F)C(F)=C(C=C2N4N=NN=C34)Br
FC=5C(F)=C(C=ClC=5(N=C(C2=NN=NN12)N3CCN4CCCC4(C3)))Br
CC1=CC(F)=C2N=C(C3=NN=NN3(C2(=C1)))N4CCNCC4
CC=4C=C1C(N=C(C2=NN=NN12)N3CCNCC3)=C(F)C=4(F)
FC=4C=C1C(N=C(C2=NN=NN12)N3CCNCC3)=C(F)C=4(F)
FC2(F)(C=1C=C3N=C(C4=NN=NN4(C3(=CC=1C(F)(F)C2(F)(F))))N5CCNCC5)
FC(F)(F)0C1=CC=C2N=C(C3=NN=NN3(C2(=C1)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC=C(C=C2N4N=NN=C34)0C(F)(F)F
FC(F)(F)0C1=CC=C2N=C(C3=NN=NN3(C2(=C1)))N4CCN5CCCC5(C4)
FC(F)(F)C 1 =CC=C2N=C(C3=NN=NN3(C2(=C 1 )))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC=C(C=C2N4N=NN=C34)C(F)(F)F
FC(F)(F)C1=CC=C2N=C(C3=NN=NN3(C2(=C1)))N4CCN5CCCC5(C4)
CN1CCN(CC1)C3=NC2=CC5=C(C=C2N4N=NN=C34)C(F)(F)C(F)(F)C5(F)(F)
FC2(F)(C=1C=C3N=C(C4=NN=NN4(C3(=CC=1C(F)(F)C2(F)(F))))N5CCN6CCC
C6(C5))
CC1=CC(F)=C2N=C(C3=NN=NN3(C2(=C1)))N4CCN(C)CC4
CC=4C=C1C(N=C(C2=NN=NN12)N3CCN(C)CC3)=C(F)C=4(F)
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(F)C=C2N4N=NN=C34
CC1=CC(F)=C2N=C(C3=NN=NN3(C2(=C1)))N4CCN5CCCC5(C4)
CC=5C=C1C(N=C(C2=NN=NN12)N3CCN4CCCC4(C3))=C(F)C=5(F)
FC=5C=C1C(N=C(C2=NN=NN12)N3CCN4CCCC4(C3))=C(F)C=5(F) FC=4C(F)=C(C=C1C=4(N=C(C2=NN=NN12)N3CCNCC3))C1
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2N4N=NN=C34)C1
FC=5C(F)=C(C=C1C=5(N=C(C2=NN=NN12)N3CCN4CCCC4(C3)))C1
FC=4C(F)=C(C=C1C=4(N=C(C2=NN=NN12)N3CCNCC3))C(F)(F)F
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2N4N=NN=C34)C(F)(F)F
FC=5C(F)=C(C=C1C=5(N=C(C2=NN=NN12)N3CCN4CCCC4(C3)))C(F)(F)F
CC=1C=C2C(=CC=1(F))N=C(C3=NN=NN23)N4CCNCC4
CC=1C=C2C(=CC=1(F))N=C(C3=NN=NN23)N4CCN(C)CC4
CC=1C=C2C(=CC=1(F))N=C(C3=NN=NN23)N4CCN5CCCC5(C4)
CC=2N=C3C(=NC1=CC=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCNCC4
CC=2N=C3C(=NC1=CC=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCN(C)CC4
CC=2N=C3C(=NC1=CC=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCN5CCCC5(C
4)
CC=2N=C3C(=NC1=CC(F)=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCNCC4 CC=2N=C3C(=NC1=CC(F)=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCN(C)CC4 CC=2N=C3C(=NC1=CC(F)=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCN5CCCC5 (C4)
CC=2N=C3C(=NC1=C(F)C=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCNCC4 CC=2N=C3C(=NC1=C(F)C=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCN(C)CC4 CC=2N=C3C(=NC1=C(F)C=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCN5CCCC5 (C4)
CC=2N=C3C(=NC1=C(F)C(F)=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCNCC4
CC=2N=C3C(=NC1=C(F)C(F)=C(C=C1N3(N=2))C(F)(F)C(F)(F)F)N4CCN(C)CC
4
CC=2N=C3C(=NC 1 =CC=C(C#N)C=C 1 N3(N=2))N4CCNCC4
CC=2N=C3 C(=NC 1 =C(F)C=C(C#N)C=C 1 N3 (N=2))N4CCNCC4
CC=2N=C3C(=NC 1 =C(F)C(F)=C(C=C 1 N3(N=2))Br)N4CCNCC4
CC=2N=C3C(=NC 1 =C(F)C(F)=C(C=C 1 N3(N=2))Br)N4CCN(C)CC4
CC=2N=C3C(=NCl=C(F)C(F)=C(C=ClN3(N=2))Br)N4CCN5CCCC5(C4) CC=2N=C3C(=NC 1 =C(F)C(F)=C(C=C 1 N3(N=2))C1)N4CCNCC4
CC=2N=C3C(=NC 1 =C(F)C(F)=C(C=C 1 N3(N=2))C1)N4CCN(C)CC4
CC=2N=C3C(=NC1=C(F)C(F)=C(C=C1N3(N=2))C1)N4CCN5CCCC5(C4) CC=2N=C3C(=NC 1 =C(F)C(F)=C(C=C 1 N3(N=2))C(F)(F)F)N4CCNCC4 CC=2N=C3C(=NC 1 =C(F)C(F)=C(C=C 1 N3(N=2))C(F)(F)F)N4CCN(C)CC4 CC=2N=C3C(=NC1=C(F)C(F)=C(C=C1N3(N=2))C(F)(F)F)N4CCN5CCCC5(C4)
CC=2N=C3 C(=NC 1 =CC(F)=C(C=C 1 N3 (N=2))C(F)(F)F)N4CCNCC4
CC=2N=C3C(=NC 1 =CC(F)=C(C=C 1 N3(N=2))C(F)(F)F)N4CCN(C)CC4
CC=2N=C3C(=NC1=CC(F)=C(C=C1N3(N=2))C(F)(F)F)N4CCN5CCCC5(C4)
FC(F)(F)C(F)(F)C1=CC=C2N=C(C3=NC=NN3(C2(=C1)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC=C(C=C2N4N=CN=C34)C(F)(F)C(F)(F)F
FC(F)(F)C(F)(F)C1=CC=C2N=C(C3=NC=NN3(C2(=C1)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C3=NC=NN3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(F)=C(C=C2N4N=CN=C34)C(F)(F)C(F)(F)F
FC=1C=C2N=C(C3=NC=NN3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCN5CCCC5(C4
)
FC=4C=C(C=C1C=4(N=C(C2=NC=NN12)N3CCNCC3))C(F)(F)C(F)(F)F CN1CCN(CC1)C3=NC2=C(F)C=C(C=C2N4N=CN=C34)C(F)(F)C(F)(F)F FC=5C=C(C=C1C=5(N=C(C2=NC=NN12)N3CCN4CCCC4(C3)))C(F)(F)C(F)(F) F
N#CC1=CC=C2N=C(C3=NC=NN3(C2(=C1)))N4CCNCC4
N#CC=1C=C2C(=CC=1(F))N=C(C3=NC=NN23)N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(F)=C(C#N)C=C2N4N=CN=C34
N#CC=1C=C2C(=CC=1(F))N=C(C3=NC=NN23)N4CCN5CCCC5(C4)
N#CC 1 =CC(F)=C2N=C(C3=NC=NN3(C2(=C 1 )))N4CCNCC4
CN1CCN(CC1)C3=NC2=C(F)C=C(C#N)C=C2N4N=CN=C34
N#CC1=CC(F)=C2N=C(C3=NC=NN3(C2(=C1)))N4CCN5CCCC5(C4)
N#CC=4C=C1C(N=C(C2=NC=NN12)N3CCNCC3)=C(F)C=4(F)
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C#N)C=C2N4N=CN=C34
N#CC=5C=C1C(N=C(C2=NC=NN12)N3CCN4CCCC4(C3))=C(F)C=5(F)
FC=4C(F)=C(C=ClC=4(N=C(C2=NC=NN12)N3CCNCC3))Br
CNlCCN(CCl)C3=NC2=C(F)C(F)=C(C=C2N4N=CN=C34)Br
FC=5C(F)=C(C=ClC=5(N=C(C2=NC=NN12)N3CCN4CCCC4(C3)))Br
FC=lC=C2N=C(C3=NC=NN3(C2(=CC=lBr)))N4CCNCC4
CNlCCN(CCl)C3=NC2=CC(F)=C(C=C2N4N=CN=C34)Br
FC=lC=C2N=C(C3=NC=NN3(C2(=CC=lBr)))N4CCN5CCCC5(C4)
FC=4C=C(C=ClC=4(N=C(C2=NC=NN12)N3CCNCC3))Br
CNlCCN(CCl)C3=NC2=C(F)C=C(C=C2N4N=CN=C34)Br
FC=5C=C(C=ClC=5(N=C(C2=NC=NN12)N3CCN4CCCC4(C3)))Br FC=4C(F)=C(C=ClC=4(N=C(C2=NC=NN12)N3CCNCC3))Br
CNlCCN(CCl)C3=NC2=C(F)C(F)=C(C=C2N4N=CN=C34)Br
FC=5C(F)=C(C=ClC=5(N=C(C2=NC=NN12)N3CCN4CCCC4(C3)))Br
FC=1C=C2N=C(C3=NC=NN3(C2(=CC=1C1)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(F)=C(C=C2N4N=CN=C34)C1
FC=1C=C2N=C(C3=NC=NN3(C2(=CC=1C1)))N4CCN5CCCC5(C4)
FC=4C=C(C=C1C=4(N=C(C2=NC=NN12)N3CCNCC3))C1
CN1CCN(CC1)C3=NC2=C(F)C=C(C=C2N4N=CN=C34)C1
FC=5C=C(C=C1C=5(N=C(C2=NC=NN12)N3CCN4CCCC4(C3)))C1
FC=4C(F)=C(C=C1C=4(N=C(C2=NC=NN12)N3CCNCC3))C1
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2N4N=CN=C34)C1
FC=5C(F)=C(C=C1C=5(N=C(C2=NC=NN12)N3CCN4CCCC4(C3)))C1
FC(F)(F)C 1 =CC=C2N=C(C3=NC=NN3(C2(=C 1 )))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC=C(C=C2N4N=CN=C34)C(F)(F)F
FC(F)(F)C 1 =CC=C2N=C(C3=NC=NN3(C2(=C 1 )))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C3=NC=NN3(C2(=CC=1C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(F)=C(C=C2N4N=CN=C34)C(F)(F)F
FC=1C=C2N=C(C3=NC=NN3(C2(=CC=1C(F)(F)F)))N4CCN5CCCC5(C4)
FC=4C=C(C=C1C=4(N=C(C2=NC=NN12)N3CCNCC3))C(F)(F)F
CN1CCN(CC1)C3=NC2=C(F)C=C(C=C2N4N=CN=C34)C(F)(F)F
FC=5C=C(C=C1C=5(N=C(C2=NC=NN12)N3CCN4CCCC4(C3)))C(F)(F)F
FC=4C(F)=C(C=C1C=4(N=C(C2=NC=NN12)N3CCNCC3))C(F)(F)F
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2N4N=CN=C34)C(F)(F)F
FC=5C(F)=C(C=C1C=5(N=C(C2=NC=NN12)N3CCN4CCCC4(C3)))C(F)(F)F
FC(F)(F)C= 1 C=C2C(=CC=1 C1)N=C(C3=NC=NN23)N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(=C(C=C2N4N=CN=C34)C(F)(F)F)C1
FC(F)(F)C=1C=C2C(=CC=1C1)N=C(C3=NC=NN23)N4CCN5CCCC5(C4)
FC=lC=C2N=C(C3=NOC=C3(C2(=CC=lBr)))N4CCNCC4
CNlCCN(CCl)C4=NC2=CC(F)=C(C=C2C3=CON=C34)Br
FC=lC=C2N=C(C3=NOC=C3(C2(=CC=lBr)))N4CCN5CCCC5(C4)
FC=2C=C(C=C3Cl=CON=ClC(=NC=23)N4CCNCC4)Br
CNlCCN(CCl)C3=NC4=C(F)C=C(C=C4(C2=CON=C23))Br
FC=2C=C(C=C3Cl=CON=ClC(=NC=23)N4CCN5CCCC5(C4))Br
FC=lC(F)=C2N=C(C3=NOC=C3(C2(=CC=lBr)))N4CCNCC4 CNlCCN(CCl)C3=NC4=C(F)C(F)=C(C=C4(C2=CON=C23))Br
FC=lC(F)=C2N=C(C3=NOC=C3(C2(=CC=lBr)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C3=N0C=C3(C2(=CC=1C1)))N4CCNCC4
FC=1C=C2N=C(C3=N0C=C3(C2(=CC=1C1)))N4CCN5CCCC5(C4)
FC=2C=C(C=C3C1=C0N=C1C(=NC=23)N4CCNCC4)C1
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C2=C0N=C23))C1
FC=2C=C(C=C3C1=C0N=C1C(=NC=23)N4CCN5CCCC5(C4))C1
FC=1C(F)=C2N=C(C3=N0C=C3(C2(=CC=1C1)))N4CCNCC4
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C2=C0N=C23))C1
FC=1C(F)=C2N=C(C3=N0C=C3(C2(=CC=1C1)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C3=N0C=C3(C2(=CC=1C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=C0N=C34)C(F)(F)F
FC=1C=C2N=C(C3=N0C=C3(C2(=CC=1C(F)(F)F)))N4CCN5CCCC5(C4)
FC=2C=C(C=C3C1=C0N=C1C(=NC=23)N4CCNCC4)C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C2=C0N=C23))C(F)(F)F
FC=2C=C(C=C3C1=C0N=C1C(=NC=23)N4CCN5CCCC5(C4))C(F)(F)F
FC=1C(F)=C2N=C(C3=N0C=C3(C2(=CC=1C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C2=C0N=C23))C(F)(F)F
FC=1C(F)=C2N=C(C3=N0C=C3(C2(=CC=1C(F)(F)F)))N4CCN5CCCC5(C4)
FC(F)(F)C= 1 C=C2C(=CC=1 Cl)N=C(C3=NOC=C23)N4CCNCC4
CN1CCN(CC1)C4=NC2=CC(=C(C=C2C3=C0N=C34)C(F)(F)F)C1
FC(F)(F)C=1C=C2C(=CC=1C1)N=C(C3=N0C=C23)N4CCN5CCCC5(C4)
FC(F)(F)C(F)(F)C2=CC=C3N=C(N1CCNCC1)N4N=CN=C4(C3(=C2))
CN1CCN(CC1)C4=NC2=CC=C(C=C2C3=NC=NN34)C(F)(F)C(F)(F)F
FC(F)(F)C(F)(F)C3=CC=C4N=C(N1CCN2CCCC2(C1))N5N=CN=C5(C4(=C3))
FC=2C=C3N=C(N1CCNCC1)N4N=CN=C4(C3(=CC=2C(F)(F)C(F)(F)F))
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=NC=NN34)C(F)(F)C(F)(F)F
FC=3C=C4N=C(N1CCN2CCCC2(C1))N5N=CN=C5(C4(=CC=3C(F)(F)C(F)(F)F)
)
FC=4C=C(C=C2C=4(N=C(N1CCNCC1)N3N=CN=C23))C(F)(F)C(F)(F)F CN1CCN(CC1)C4=NC2=C(F)C=C(C=C2C3=NC=NN34)C(F)(F)C(F)(F)F FC=5C=C(C=C3C=5(N=C(N1CCN2CCCC2(C1))N4N=CN=C34))C(F)(F)C(F)(F) F
FC=4C(F)=C(C=C2C=4(N=C(N1CCNCC1)N3N=CN=C23))C(F)(F)C(F)(F)F CN1CCN(CC1)C4=NC2=C(F)C(F)=C(C=C2C3=NC=NN34)C(F)(F)C(F)(F)F
FC=5C(F)=C(C=C3C=5(N=C(N1CCN2CCCC2(C1))N4N=CN=C34))C(F)(F)C(F)
(F)F
N#CC2=CC=C3N=C(N1CCNCC1)N4N=CN=C4(C3(=C2))
N#CC=1C=C3C(=CC=1(F))N=C(N2CCNCC2)N4N=CN=C34
N#CC2=CC(F)=C3N=C(N1CCNCC1)N4N=CN=C4(C3(=C2))
C 1 CN(CCN1 )C4=NC2=CC=C(C=C2C3=NC=NN34)Br
CNlCCN(CCl)C4=NC2=CC=C(C=C2C3=NC=NN34)Br
C 1 CC2CN(CCN2(C 1 ))C5=NC3=CC=C(C=C3C4=NC=NN45)Br
FC=2C=C3N=C(N1 CCNCC 1 )N4N=CN=C4(C3(=CC=2Br))
CNlCCN(CCl)C4=NC2=CC(F)=C(C=C2C3=NC=NN34)Br
FC=3C=C4N=C(NlCCN2CCCC2(Cl))N5N=CN=C5(C4(=CC=3Br))
FC=4C=C(C=C2C=4(N=C(N1 CCNCC 1 )N3N=CN=C23))Br
CNlCCN(CCl)C4=NC2=C(F)C=C(C=C2C3=NC=NN34)Br
FC=5C=C(C=C3C=5(N=C(NlCCN2CCCC2(Cl))N4N=CN=C34))Br
FC=4C(F)=C(C=C2C=4(N=C(NlCCNCCl)N3N=CN=C23))Br
CNlCCN(CCl)C4=NC2=C(F)C(F)=C(C=C2C3=NC=NN34)Br
FC=5C(F)=C(C=C3C=5(N=C(NlCCN2CCCC2(Cl))N4N=CN=C34))Br
C 1 CN(CCN1 )C4=NC2=CC=C(C=C2C3=NC=NN34)C1
C 1 CC2CN(CCN2(C 1 ))C5=NC3=CC=C(C=C3C4=NC=NN45)C1
FC=2C=C3N=C(N1 CCNCC 1 )N4N=CN=C4(C3(=CC=2C1))
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=NC=NN34)C1
FC=3C=C4N=C(N1CCN2CCCC2(C1))N5N=CN=C5(C4(=CC=3C1))
FC=4C=C(C=C2C=4(N=C(N1 CCNCC 1 )N3N=CN=C23))C1
CN1CCN(CC1)C4=NC2=C(F)C=C(C=C2C3=NC=NN34)C1
FC=5C=C(C=C3C=5(N=C(N1CCN2CCCC2(C1))N4N=CN=C34))C1
FC=4C(F)=C(C=C2C=4(N=C(N1CCNCC1)N3N=CN=C23))C1
CN1CCN(CC1)C4=NC2=C(F)C(F)=C(C=C2C3=NC=NN34)C1
FC=5C(F)=C(C=C3C=5(N=C(N1CCN2CCCC2(C1))N4N=CN=C34))C1
FC(F)(F)C2=CC=C3N=C(N1CCNCC1)N4N=CN=C4(C3(=C2))
CN1CCN(CC1)C4=NC2=CC=C(C=C2C3=NC=NN34)C(F)(F)F
FC(F)(F)C3=CC=C4N=C(N1CCN2CCCC2(C1))N5N=CN=C5(C4(=C3))
FC=2C=C3N=C(N1CCNCC1)N4N=CN=C4(C3(=CC=2C(F)(F)F))
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=NC=NN34)C(F)(F)F FC=3C=C4N=C(N1CCN2CCCC2(C1))N5N=CN=C5(C4(=CC=3C(F)(F)F))
FC=4C=C(C=C2C=4(N=C(N1 CCNCC 1 )N3N=CN=C23))C(F)(F)F
CN1CCN(CC1)C4=NC2=C(F)C=C(C=C2C3=NC=NN34)C(F)(F)F
FC=5C=C(C=C3C=5(N=C(N1CCN2CCCC2(C1))N4N=CN=C34))C(F)(F)F
FC=4C(F)=C(C=C2C=4(N=C(N1CCNCC1)N3N=CN=C23))C(F)(F)F
CN1CCN(CC1)C4=NC2=C(F)C(F)=C(C=C2C3=NC=NN34)C(F)(F)F
FC=5C(F)=C(C=C3C=5(N=C(N1CCN2CCCC2(C1))N4N=CN=C34))C(F)(F)F
CC2=CC=C3N=C(N1 CCNCC 1 )N4N=CN=C4(C3(=C2))
CC2=CC=C3N=C(N1CCN(C)CC1)N4N=CN=C4(C3(=C2))
CC3=CC=C4N=C(N1CCN2CCCC2(C1))N5N=CN=C5(C4(=C3))
CC=1C=C3C(=CC=1(F))N=C(N2CCNCC2)N4N=CN=C34
CC=1C=C3C(=CC=1(F))N=C(N2CCN(C)CC2)N4N=CN=C34
CC=1C=C4C(=CC=1(F))N=C(N2CCN3CCCC3(C2))N5N=CN=C45
CC2=CC(F)=C3N=C(N1CCNCC1)N4N=CN=C4(C3(=C2))
CC2=CC(F)=C3N=C(N1CCN(C)CC1)N4N=CN=C4(C3(=C2))
CC3=CC(F)=C4N=C(N1CCN2CCCC2(C1))N5N=CN=C5(C4(=C3))
FC(F)(F)C=1C=C3C(=CC=1C1)N=C(N2CCNCC2)N4N=CN=C34
CN1CCN(CC1)C4=NC2=CC(=C(C=C2C3=NC=NN34)C(F)(F)F)C1
FC(F)(F)C=1C=C4C(=CC=1C1)N=C(N2CCN3CCCC3(C2))N5N=CN=C45
C 1 CN(CCN1 )C4=NC2=CC=C(C=C2C3=NN=NN34)Br
CNlCCN(CCl)C4=NC2=CC=C(C=C2C3=NN=NN34)Br
C 1 CC2CN(CCN2(C 1 ))C5=NC3=CC=C(C=C3C4=NN=NN45)Br
FC=2C=C3N=C(N1 CCNCC 1 )N4N=NN=C4(C3(=CC=2Br))
CNlCCN(CCl)C4=NC2=CC(F)=C(C=C2C3=NN=NN34)Br
FC=3C=C4N=C(NlCCN2CCCC2(Cl))N5N=NN=C5(C4(=CC=3Br))
FC=4C=C(C=C2C=4(N=C(N1 CCNCC 1 )N3N=NN=C23))Br
CNlCCN(CCl)C4=NC2=C(F)C=C(C=C2C3=NN=NN34)Br
FC=5C=C(C=C3C=5(N=C(NlCCN2CCCC2(Cl))N4N=NN=C34))Br
FC=4C(F)=C(C=C2C=4(N=C(NlCCNCCl)N3N=NN=C23))Br
CNlCCN(CCl)C4=NC2=C(F)C(F)=C(C=C2C3=NN=NN34)Br
FC=5C(F)=C(C=C3C=5(N=C(NlCCN2CCCC2(Cl))N4N=NN=C34))Br
FC=2C=C3N=C(N1 CCNCC 1 )N4N=NN=C4(C3(=CC=2C1))
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=NN=NN34)C1
FC=3C=C4N=C(N1CCN2CCCC2(C1))N5N=NN=C5(C4(=CC=3C1)) FC=4C=C(C=C2C=4(N=C(N1 CCNCC 1 )N3N=NN=C23))C1
CN1CCN(CC1)C4=NC2=C(F)C=C(C=C2C3=NN=NN34)C1
FC=5C=C(C=C3C=5(N=C(N1CCN2CCCC2(C1))N4N=NN=C34))C1
FC=4C(F)=C(C=C2C=4(N=C(N1CCNCC1)N3N=NN=C23))C1
CN1CCN(CC1)C4=NC2=C(F)C(F)=C(C=C2C3=NN=NN34)C1
FC=5C(F)=C(C=C3C=5(N=C(N1CCN2CCCC2(C1))N4N=NN=C34))C1
FC(F)(F)C2=CC=C3N=C(N1CCNCC1)N4N=NN=C4(C3(=C2))
CN1CCN(CC1)C4=NC2=CC=C(C=C2C3=NN=NN34)C(F)(F)F
FC(F)(F)C3=CC=C4N=C(N1CCN2CCCC2(C1))N5N=NN=C5(C4(=C3))
FC=2C=C3N=C(N1CCNCC1)N4N=NN=C4(C3(=CC=2C(F)(F)F))
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=NN=NN34)C(F)(F)F
FC=3C=C4N=C(N1CCN2CCCC2(C1))N5N=NN=C5(C4(=CC=3C(F)(F)F))
FC=4C=C(C=C2C=4(N=C(N1 CCNCC 1 )N3N=NN=C23))C(F)(F)F
CN1CCN(CC1)C4=NC2=C(F)C=C(C=C2C3=NN=NN34)C(F)(F)F
FC=5C=C(C=C3C=5(N=C(N1CCN2CCCC2(C1))N4N=NN=C34))C(F)(F)F
FC=4C(F)=C(C=C2C=4(N=C(N1CCNCC1)N3N=NN=C23))C(F)(F)F
CN1CCN(CC1)C4=NC2=C(F)C(F)=C(C=C2C3=NN=NN34)C(F)(F)F
FC=5C(F)=C(C=C3C=5(N=C(N1CCN2CCCC2(C1))N4N=NN=C34))C(F)(F)F
CC=1C=C3C(=CC=1(F))N=C(N2CCNCC2)N4N=NN=C34
CC=1C=C3C(=CC=1(F))N=C(N2CCN(C)CC2)N4N=NN=C34
CC=1C=C4C(=CC=1(F))N=C(N2CCN3CCCC3(C2))N5N=NN=C45
CC2=CC(F)=C3N=C(N1CCNCC1)N4N=NN=C4(C3(=C2))
CC2=CC(F)=C3N=C(N1CCN(C)CC1)N4N=NN=C4(C3(=C2))
CC3=CC(F)=C4N=C(N1CCN2CCCC2(C1))N5N=NN=C5(C4(=C3))
CC2= =NC= =3C(= =NC1: =CC(F)=C(C=ClC=3(02))Br)N4CCNCC4
CC2= =NC= =3C(= =NC1: =CC(F)=C(C=ClC=3(02))Br)N4CCN(C)CC4
CC2= =NC= =3C(= =NC1: =CC(F)=C(C=ClC=3(02))Br)N4CCN5CCCC5(C4)
CC2= =NC= =3C(= =NC1: =C(F)C=C(C=ClC=3(02))Br)N4CCNCC4
CC2= =NC= =3C(= =NC1: =C(F)C=C(C=ClC=3(02))Br)N4CCN(C)CC4
CC2= =NC= =3C(= =NC1: =C(F)C=C(C=ClC=3(02))Br)N4CCN5CCCC5(C4)
CC2= =NC= =3C(= =NC1: =C(F)C(F)=C(C=ClC=3(02))Br)N4CCNCC4
CC2= =NC= =3C(= =NC1: =C(F)C(F)=C(C=ClC=3(02))Br)N4CCN(C)CC4
CC2= =NC= =3C(= =NC1: =C(F)C(F)=C(C=ClC=3(02))Br)N4CCN5CCCC5(C4)
CC2= =NC= =3C(= =NC1: =CC(F)=C(C=C1C=3(02))C1)N4CCNCC4 CC2=NC=3C(=NC1=CC(F)=C(C=C1C=3(02))C1)N4CCN(C)CC4
CC2=NC=3C(=NC1=CC(F)=C(C=C1C=3(02))C1)N4CCN5CCCC5(C4)
CC2=NC=3C(=NC1=C(F)C=C(C=C1C=3(02))C1)N4CCNCC4
CC2=NC=3C(=NC1=C(F)C=C(C=C1C=3(02))C1)N4CCN(C)CC4
CC2=NC=3C(=NC1=C(F)C=C(C=C1C=3(02))C1)N4CCN5CCCC5(C4)
CC2=NC=3C(=NC 1 =C(F)C(F)=C(C=C 1 C=3(02))C1)N4CCNCC4
CC2=NC=3C(=NC 1 =C(F)C(F)=C(C=C 1 C=3(02))C1)N4CCN(C)CC4
CC2=NC=3C(=NC1=C(F)C(F)=C(C=C1C=3(02))C1)N4CCN5CCCC5(C4)
FC(F)(F)C(F)(F)C1=CC=C2N=C(C=3N=C0C=3(C2(=C1)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC=C(C=C2C=40C=NC3=4)C(F)(F)C(F)(F)F
FC(F)(F)C(F)(F)C1=CC=C2N=C(C=3N=C0C=3(C2(=C1)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C=3N=C0C=3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(F)=C(C=C2C=40C=NC3=4)C(F)(F)C(F)(F)F
FC=1C=C2N=C(C=3N=C0C=3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCN5CCCC5(C
4)
FC=4C=C(C=C1C=4(N=C(C=2N=C0C1=2)N3CCNCC3))C(F)(F)C(F)(F)F CN1CCN(CC1)C3=NC2=C(F)C=C(C=C2C=40C=NC3=4)C(F)(F)C(F)(F)F FC=5C=C(C=C1C=5(N=C(C=2N=C0C1=2)N3CCN4CCCC4(C3)))C(F)(F)C(F)(F )F
FC=lC=C2N=C(C=3N=COC=3(C2(=CC=lBr)))N4CCNCC4
CNlCCN(CCl)C3=NC2=CC(F)=C(C=C2C=40C=NC3=4)Br
FC=lC=C2N=C(C=3N=COC=3(C2(=CC=lBr)))N4CCN5CCCC5(C4)
FC=4C=C(C=C 1 C=4(N=C(C=2N=COC 1 =2)N3CCNCC3))Br
CNlCCN(CCl)C3=NC2=C(F)C=C(C=C2C=40C=NC3=4)Br
FC=5C=C(C=ClC=5(N=C(C=2N=COCl=2)N3CCN4CCCC4(C3)))Br
FC=lC(F)=C2N=C(C=3N=COC=3(C2(=CC=lBr)))N4CCNCC4
CNlCCN(CCl)C3=NC2=C(F)C(F)=C(C=C2C=40C=NC3=4)Br
FC=lC(F)=C2N=C(C=3N=COC=3(C2(=CC=lBr)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C=3N=C0C=3(C2(=CC=1C1)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(F)=C(C=C2C=40C=NC3=4)C1
FC=1C=C2N=C(C=3N=C0C=3(C2(=CC=1C1)))N4CCN5CCCC5(C4)
FC=4C=C(C=C 1 C=4(N=C(C=2N=COC 1 =2)N3CCNCC3))C1
CN1CCN(CC1)C3=NC2=C(F)C=C(C=C2C=40C=NC3=4)C1
FC=5C=C(C=C1C=5(N=C(C=2N=C0C1=2)N3CCN4CCCC4(C3)))C1 FC=1C(F)=C2N=C(C=3N=C0C=3(C2(=CC=1C1)))N4CCNCC4
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2C=40C=NC3=4)C1
FC=1C(F)=C2N=C(C=3N=C0C=3(C2(=CC=1C1)))N4CCN5CCCC5(C4)
C 1 CN(CCN1 )C3=NC2=CC=C(C=C2N4C=CN=C34)Br
CNlCCN(CCl)C3=NC2=CC=C(C=C2N4C=CN=C34)Br
ClCC2CN(CCN2(Cl))C4=NC3=CC=C(C=C3N5C=CN=C45)Br
FC=lC=C2N=C(C3=NC=CN3(C2(=CC=lBr)))N4CCNCC4
CNlCCN(CCl)C3=NC2=CC(F)=C(C=C2N4C=CN=C34)Br
FC=lC=C2N=C(C3=NC=CN3(C2(=CC=lBr)))N4CCN5CCCC5(C4)
FC=4C=C(C=ClC=4(N=C(C2=NC=CN12)N3CCNCC3))Br
CNlCCN(CCl)C3=NC2=C(F)C=C(C=C2N4C=CN=C34)Br
FC=5C=C(C=ClC=5(N=C(C2=NC=CN12)N3CCN4CCCC4(C3)))Br
FC=4C(F)=C(C=ClC=4(N=C(C2=NC=CN12)N3CCNCC3))Br
CNlCCN(CCl)C3=NC2=C(F)C(F)=C(C=C2N4C=CN=C34)Br
FC=5C(F)=C(C=ClC=5(N=C(C2=NC=CN12)N3CCN4CCCC4(C3)))Br
FC=4C=C(C=C1C=4(N=C(C2=NC=CN12)N3CCNCC3))C1
CN1CCN(CC1)C3=NC2=C(F)C=C(C=C2N4C=CN=C34)C1
FC=5C=C(C=C1C=5(N=C(C2=NC=CN12)N3CCN4CCCC4(C3)))C1
FC=4C(F)=C(C=C1C=4(N=C(C2=NC=CN12)N3CCNCC3))C1
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2N4C=CN=C34)C1
FC=5C(F)=C(C=C1C=5(N=C(C2=NC=CN12)N3CCN4CCCC4(C3)))C1
FC(F)(F)C1=CC=C2N=C(C3=NC=CN3(C2(=C1)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C3=NC=CN3(C2(=CC=1C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(F)=C(C=C2N4C=CN=C34)C(F)(F)F
FC=1C=C2N=C(C3=NC=CN3(C2(=CC=1C(F)(F)F)))N4CCN5CCCC5(C4)
FC=4C=C(C=C1C=4(N=C(C2=NC=CN12)N3CCNCC3))C(F)(F)F
CN1CCN(CC1)C3=NC2=C(F)C=C(C=C2N4C=CN=C34)C(F)(F)F
FC=5C=C(C=C1C=5(N=C(C2=NC=CN12)N3CCN4CCCC4(C3)))C(F)(F)F
FC=4C(F)=C(C=C1C=4(N=C(C2=NC=CN12)N3CCNCC3))C(F)(F)F
CN1CCN(CC1)C3=NC2=C(F)C(F)=C(C=C2N4C=CN=C34)C(F)(F)F
FC=5C(F)=C(C=C1C=5(N=C(C2=NC=CN12)N3CCN4CCCC4(C3)))C(F)(F)F
CC1=CC=C2N=C(C3=NC=CN3(C2(=C1)))N4CCNCC4
CC 1=CC=C2N=C(C3=NC=CN3(C2(=C 1)))N4CCN(C)CC4
CC1=CC=C2N=C(C3=NC=CN3(C2(=C1)))N4CCN5CCCC5(C4) CC=1C=C2C(=CC=1(F))N=C(C3=NC=CN23)N4CCNCC4
CC=1C=C2C(=CC=1(F))N=C(C3=NC=CN23)N4CCN(C)CC4
CC=1C=C2C(=CC=1(F))N=C(C3=NC=CN23)N4CCN5CCCC5(C4)
FC(F)(F)C=1C=C2C(=CC=1C1)N=C(C3=NC=CN23)N4CCNCC4
CN1CCN(CC1)C3=NC2=CC(=C(C=C2N4C=CN=C34)C(F)(F)F)C1
FC(F)(F)C=1C=C2C(=CC=1C1)N=C(C3=NC=CN23)N4CCN5CCCC5(C4)
FC=1C=C2C(=CC=1C(F)(F)F)N=C(C3=NC=CN23)N4CCNCC4
FC2(F)(C=1C=C3N=C(C4=NC=CN4(C3(=CC=1C(F)(F)C2(F)(F))))N5CCNCC5)
FC(F)(F)0C1=CC=C2N=C(C3=NC=CN3(C2(=C1)))N4CCNCC4
FC(F)(F)C(F)(F)C1=CC=C2N=C(C3=NNC=C3(C2(=C1)))N4CCNCC4
CN1CCN(CC1)C4=NC2=CC=C(C=C2C3=CNN=C34)C(F)(F)C(F)(F)F
FC(F)(F)C(F)(F)C1=CC=C2N=C(C3=NNC=C3(C2(=C1)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C3=NNC=C3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=CNN=C34)C(F)(F)C(F)(F)F
FC=1C=C2N=C(C3=NNC=C3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCN5CCCC5(C4
)
FC=2C=C(C=C3C1=CNN=C1C(=NC=23)N4CCNCC4)C(F)(F)C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C2=CNN=C23))C(F)(F)C(F)(F)F
FC=2C=C(C=C3C1=CNN=C1C(=NC=23)N4CCN5CCCC5(C4))C(F)(F)C(F)(F)F
N#CC1=CC(F)=C2N=C(C3=NNC=C3(C2(=C1)))N4CCNCC4
CN1CCN(CC1)C3=NC4=C(F)C=C(C#N)C=C4(C2=CNN=C23)
N#CC1=CC(F)=C2N=C(C3=NNC=C3(C2(=C1)))N4CCN5CCCC5(C4)
FC=lC=C2N=C(C3=NNC=C3(C2(=CC=lBr)))N4CCNCC4
CNlCCN(CCl)C4=NC2=CC(F)=C(C=C2C3=CNN=C34)Br
FC=lC=C2N=C(C3=NNC=C3(C2(=CC=lBr)))N4CCN5CCCC5(C4)
FC=2C(F)=C(C=C3C 1 =CNN=C 1 C(=NC=23)N4CCNCC4)Br
CNlCCN(CCl)C3=NC4=C(F)C(F)=C(C=C4(C2=CNN=C23))Br
FC=2C(F)=C(C=C3C 1 =CNN=C 1 C(=NC=23)N4CCN5CCCC5(C4))Br
FC=1C=C2N=C(C3=NNC=C3(C2(=CC=1C1)))N4CCNCC4
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=CNN=C34)C1
FC=1C=C2N=C(C3=NNC=C3(C2(=CC=1C1)))N4CCN5CCCC5(C4)
FC=2C=C(C=C3C1=CNN=C1C(=NC=23)N4CCNCC4)C1
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C2=CNN=C23))C1
FC=2C=C(C=C3C1=CNN=C1C(=NC=23)N4CCN5CCCC5(C4))C1 FC=2C(F)=C(C=C3C 1 =CNN=C 1 C(=NC=23)N4CCNCC4)C1
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C2=CNN=C23))C1
FC=2C(F)=C(C=C3C 1 =CNN=C 1 C(=NC=23)N4CCN5CCCC5(C4))C1
FC=1C=C2N=C(C3=NNC=C3(C2(=CC=1C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=CNN=C34)C(F)(F)F
FC=1C=C2N=C(C3=NNC=C3(C2(=CC=1C(F)(F)F)))N4CCN5CCCC5(C4)
FC=2C=C(C=C3C1=CNN=C1C(=NC=23)N4CCNCC4)C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C2=CNN=C23))C(F)(F)F
FC=2C=C(C=C3C1=CNN=C1C(=NC=23)N4CCN5CCCC5(C4))C(F)(F)F
FC=2C(F)=C(C=C3C 1 =CNN=C 1 C(=NC=23)N4CCNCC4)C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C2=CNN=C23))C(F)(F)F
FC=2C(F)=C(C=C3C1=CNN=C1C(=NC=23)N4CCN5CCCC5(C4))C(F)(F)F
FC(F)(F)C=1C=C2C(=CC=1C1)N=C(C3=NNC=C23)N4CCNCC4
CN1CCN(CC1)C4=NC2=CC(=C(C=C2C3=CNN=C34)C(F)(F)F)C1
FC(F)(F)C=1C=C2C(=CC=1C1)N=C(C3=NNC=C23)N4CCN5CCCC5(C4)
CN1CCN(CC1)C4=NC2=CC=C(C=C2C3=CN(C)N=C34)C(F)(F)C(F)(F)F
CN1C=C2C5=CC(=CC=C5(N=C(C2(=N1))N3CCN4CCCC4(C3)))C(F)(F)C(F)(F)
F
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=CN(C)N=C34)C(F)(F)C(F)(F)F
CN1C=C2C5=CC(=C(F)C=C5(N=C(C2(=N1))N3CCN4CCCC4(C3)))C(F)(F)C(F)
(F)F
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C2=CN(C)N=C23))C(F)(F)C(F)(F)F
CN1C=C2C5=CC(=CC(F)=C5(N=C(C2(=N1))N3CCN4CCCC4(C3)))C(F)(F)C(F)
(F)F
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C2=CN(C)N=C23))C(F)(F)C(F)(F)F CN1C=C2C5=CC(=C(F)C(F)=C5(N=C(C2(=N1))N3CCN4CCCC4(C3)))C(F)(F)C (F)(F)F
CN1CCN(CC1)C4=NC2=CC=C(C#N)C=C2C3=CN(C)N=C34
CN1C=C2C5=CC(C#N)=CC=C5(N=C(C2(=N1))N3CCN4CCCC4(C3))
CN1CCN(CC1)C4=NC2=CC(F)=C(C#N)C=C2C3=CN(C)N=C34
CN1C=C2C5=CC(C#N)=C(F)C=C5(N=C(C2(=N1))N3CCN4CCCC4(C3))
CN1CCN(CC1)C3=NC4=C(F)C=C(C#N)C=C4(C2=CN(C)N=C23)
CN1C=C2C5=CC(C#N)=CC(F)=C5(N=C(C2(=N1))N3CCN4CCCC4(C3))
CNlCCN(CCl)C4=NC2=CC(F)=C(C=C2C3=CN(C)N=C34)Br CNlC=C2C5=CC(=C(F)C=C5(N=C(C2(=Nl))N3CCN4CCCC4(C3)))Br
CNlCCN(CCl)C3=NC4=C(F)C=C(C=C4(C2=CN(C)N=C23))Br
CNlC=C2C5=CC(=CC(F)=C5(N=C(C2(=Nl))N3CCN4CCCC4(C3)))Br
CNlCCN(CCl)C3=NC4=C(F)C(F)=C(C=C4(C2=CN(C)N=C23))Br
CNlC=C2C5=CC(=C(F)C(F)=C5(N=C(C2(=Nl))N3CCN4CCCC4(C3)))Br
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=CN(C)N=C34)C1
CN1C=C2C5=CC(=C(F)C=C5(N=C(C2(=N1))N3CCN4CCCC4(C3)))C1
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C2=CN(C)N=C23))C1
CN1C=C2C5=CC(=CC(F)=C5(N=C(C2(=N1))N3CCN4CCCC4(C3)))C1
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C2=CN(C)N=C23))C1
CN1C=C2C5=CC(=C(F)C(F)=C5(N=C(C2(=N1))N3CCN4CCCC4(C3)))C1
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C3=CN(C)N=C34)C(F)(F)F
CN1C=C2C5=CC(=C(F)C=C5(N=C(C2(=N1))N3CCN4CCCC4(C3)))C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C2=CN(C)N=C23))C(F)(F)F
CN1C=C2C5=CC(=CC(F)=C5(N=C(C2(=N1))N3CCN4CCCC4(C3)))C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C2=CN(C)N=C23))C(F)(F)F
CN1C=C2C5=CC(=C(F)C(F)=C5(N=C(C2(=N1))N3CCN4CCCC4(C3)))C(F)(F)F
CC1=CC=C2N=C(C3=NN(C)C=C3(C2(=C1)))N4CCN(C)CC4
CC1=CC=C2N=C(C3=NN(C)C=C3(C2(=C1)))N4CCN5CCCC5(C4)
CC=1C=C2C(=CC=1(F))N=C(C3=NN(C)C=C23)N4CCN(C)CC4
CC=1C=C2C(=CC=1(F))N=C(C3=NN(C)C=C23)N4CCN5CCCC5(C4)
CC1=CC(F)=C2N=C(C3=NN(C)C=C3(C2(=C1)))N4CCN(C)CC4
CC1=CC(F)=C2N=C(C3=NN(C)C=C3(C2(=C1)))N4CCN5CCCC5(C4)
C 1 CN(CCN1 )C4=NC2=CC=C(C=C2C=3NC=NC=34)Br
CN1 CCN(CC l)C4=NC2=CC=C(C=C2C=3NC=NC=34)Br
C 1 CC2CN(CCN2(C 1 ))C5=NC3=CC=C(C=C3C=4NC=NC=45)Br
FC=lC=C2N=C(C=3N=CNC=3(C2(=CC=lBr)))N4CCNCC4
CNlCCN(CCl)C4=NC2=CC(F)=C(C=C2C=3NC=NC=34)Br
FC=lC=C2N=C(C=3N=CNC=3(C2(=CC=lBr)))N4CCN5CCCC5(C4)
FC=4C=C(C=C 1 C=4(N=C(C=2N=CNC 1 =2)N3CCNCC3))Br
CNlCCN(CCl)C4=NC2=C(F)C=C(C=C2C=3NC=NC=34)Br
FC=5C=C(C=ClC=5(N=C(C=2N=CNCl=2)N3CCN4CCCC4(C3)))Br
FC=1C=C2N=C(C=3N=CNC=3(C2(=CC=1C1)))N4CCNCC4
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C=3NC=NC=34)C1 FC=1C=C2N=C(C=3N=CNC=3(C2(=CC=1C1)))N4CCN5CCCC5(C4)
FC=4C=C(C=C 1 C=4(N=C(C=2N=CNC 1 =2)N3CCNCC3))C1
CN1CCN(CC1)C4=NC2=C(F)C=C(C=C2C=3NC=NC=34)C1
FC=5C=C(C=C1C=5(N=C(C=2N=CNC1=2)N3CCN4CCCC4(C3)))C1
CN1CCN(CC1)C4=NC2=CC=C(C=C2C=3NC=NC=34)C(F)(F)F
FC(F)(F)C 1 =CC=C2N=C(C=3N=CNC=3(C2(=C 1 )))N4CCN5CCCC5(C4)
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C=3NC=NC=34)C(F)(F)F
FC=1C=C2N=C(C=3N=CNC=3(C2(=CC=1C(F)(F)F)))N4CCN5CCCC5(C4)
CN1CCN(CC1)C4=NC2=C(F)C=C(C=C2C=3NC=NC=34)C(F)(F)F
FC=5C=C(C=C1C=5(N=C(C=2N=CNC1=2)N3CCN4CCCC4(C3)))C(F)(F)F
FC(F)(C(C 1 =CC=C(N=C(N4CCNCC4)C3=C2C=NC=N3)C2=C 1 )(F)F)F
FC(F)(F)C(F)(F)C 1 =CC=C2N=C(C=3N=CC=NC=3(C2(=C 1 )))N4CCNCC4
FC(F)(F)C(F)(F)C1=CC=C2N=C(C=3N=CC=CC=3(C2(=C1)))N4CCNCC4
CN(CC4)CCN4C2=NC1=CC=C(C(F)(C(F)(F)F)F)C=C1C3=C2N=CN=C3
CN1CCN(CC1)C4=NC2=CC=C(C=C2C=3N=CC=NC=34)C(F)(F)C(F)(F)F
CN1CCN(CC1)C4=NC2=CC=C(C=C2C=3C=CC=NC=34)C(F)(F)C(F)(F)F
FC(F)(C(C1=CC=C(N=C(N4CCN(CCC5)C5C4)C3=C2C=NC=N3)C2=C1)(F)F)F
FC(F)(F)C(F)(F)C1=CC=C2N=C(C=3N=CC=NC=3(C2(=C1)))N4CCN5CCCC5(
C4)
FC(F)(F)C(F)(F)C1=CC=C2N=C(C=3N=CC=CC=3(C2(=C1)))N4CCN5CCCC5(C 4)
FC1=C(C(F)(C(F)(F)F)F)C=C2C(N=C(N4CCNCC4)C3=C2C=NC=N3)=C1
FC=1C=C2N=C(C=3N=CC=NC=3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCNCC4
FC=1C=C2N=C(C=3N=CC=CC=3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCNCC4
CN(CC4)CCN4C2=NC1=CC(F)=C(C(F)(C(F)(F)F)F)C=C1C3=C2N=CN=C3
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C=3N=CC=NC=34)C(F)(F)C(F)(F)F
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C=3C=CC=NC=34)C(F)(F)C(F)(F)F
FC1=C(C(F)(C(F)(F)F)F)C=C2C(N=C(N4CCN(CCC5)C5C4)C3=C2C=NC=N3)=
CI
FC=1C=C2N=C(C=3N=CC=NC=3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCN5CCCC 5(C4)
FC=1C=C2N=C(C=3N=CC=CC=3(C2(=CC=1C(F)(F)C(F)(F)F)))N4CCN5CCCC 5(C4)
FC1=C(N=C(N4CCNCC4)C3=C2C=NC=N3)C2=CC(C(C(F)(F)F)(F)F)=C1 FC=4C=C(C=C1C=4(N=C(C=2N=CC=NC1=2)N3CCNCC3))C(F)(F)C(F)(F)F
FC=2C=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCNCC4)C(F)(F)C(F)(F)F
CN(CC4)CCN4C2=NC1=C(F)C=C(C(C(F)(F)F)(F)F)C=C1C3=C2N=CN=C3
CN1CCN(CC1)C4=NC2=C(F)C=C(C=C2C=3N=CC=NC=34)C(F)(F)C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C=2C=CC=NC=23))C(F)(F)C(F)(F)F
FC1=C(N=C(N4CCN(CCC5)C5C4)C3=C2C=NC=N3)C2=CC(C(F)(C(F)(F)F)F)=
CI
FC=5C=C(C=C1C=5(N=C(C=2N=CC=NC1=2)N3CCN4CCCC4(C3)))C(F)(F)C(F )(F)F
FC=2C=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCN5CCCC5(C4))C(F)(F)C(F)( F)F
FC1=C(C(C(F)(F)F)(F)F)C=C2C(N=C(N4CCNCC4)C3=C2C=NC=N3)=C1F
FC=4C(F)=C(C=C1C=4(N=C(C=2N=CC=NC1=2)N3CCNCC3))C(F)(F)C(F)(F)F
FC=2C(F)=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCNCC4)C(F)(F)C(F)(F)F
CN(CC4)CCN4C2=NC1=C(F)C(F)=C(C(F)(C(F)(F)F)F)C=C1C3=C2N=CN=C3
CN1CCN(CC1)C4=NC2=C(F)C(F)=C(C=C2C=3N=CC=NC=34)C(F)(F)C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C=2C=CC=NC=23))C(F)(F)C(F)(F)
F
FC1=C(C(F)(C(F)(F)F)F)C=C2C(N=C(N4CCN(CCC5)C5C4)C3=C2C=NC=N3)= C1F
FC=5C(F)=C(C=C1C=5(N=C(C=2N=CC=NC1=2)N3CCN4CCCC4(C3)))C(F)(F) C(F)(F)F
FC=2C(F)=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCN5CCCC5(C4))C(F)(F)C( F)(F)F
N#CC 1 =CC=C2N=C(C=3N=CN=CC=3(C2(=C 1 )))N4CCNCC4
N#CC 1 =CC=C2N=C(C=3N=CC=NC=3(C2(=C 1 )))N4CCNCC4
N#CC1=CC=C2N=C(C=3N=CC=CC=3(C2(=C1)))N4CCNCC4
CN1CCN(CC1)C4=NC2=CC=C(C#N)C=C2C=3C=NC=NC=34
CN1CCN(CC1)C4=NC2=CC=C(C#N)C=C2C=3N=CC=NC=34
CN1CCN(CC1)C4=NC2=CC=C(C#N)C=C2C=3C=CC=NC=34
N#CC1=CC=C2N=C(C=3N=CN=CC=3(C2(=C1)))N4CCN5CCCC5(C4)
N#CC1=CC=C2N=C(C=3N=CC=NC=3(C2(=C1)))N4CCN5CCCC5(C4)
N#CC1=CC=C2N=C(C=3N=CC=CC=3(C2(=C1)))N4CCN5CCCC5(C4)
N#CC=1C=C2C(=CC=1(F))N=C(C=3N=CN=CC2=3)N4CCNCC4 N#CC=1C=C2C(=CC=1(F))N=C(C=3N=CC=NC2=3)N4CCNCC4
N#CC=1C=C2C(=CC=1(F))N=C(C=3N=CC=CC2=3)N4CCNCC4
CN1CCN(CC1)C4=NC2=CC(F)=C(C#N)C=C2C=3C=NC=NC=34
CN1CCN(CC1)C4=NC2=CC(F)=C(C#N)C=C2C=3N=CC=NC=34
CN1CCN(CC1)C4=NC2=CC(F)=C(C#N)C=C2C=3C=CC=NC=34
N#CC=1C=C2C(=CC=1(F))N=C(C=3N=CN=CC2=3)N4CCN5CCCC5(C4)
N#CC=1C=C2C(=CC=1(F))N=C(C=3N=CC=NC2=3)N4CCN5CCCC5(C4)
N#CC=1C=C2C(=CC=1(F))N=C(C=3N=CC=CC2=3)N4CCN5CCCC5(C4)
FC=2C=C(C=C3C=1C=NC=NC=1C(=NC=23)N4CCNCC4)C1
FC=4C=C(C=C 1 C=4(N=C(C=2N=CC=NC 1 =2)N3CCNCC3))C1
FC=2C=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCNCC4)C1
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C=2C=NC=NC=23))C1
CN1CCN(CC1)C4=NC2=C(F)C=C(C=C2C=3N=CC=NC=34)C1
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C=2C=CC=NC=23))C1
FC=2C=C(C=C3C=1C=NC=NC=1C(=NC=23)N4CCN5CCCC5(C4))C1
FC=5C=C(C=C1C=5(N=C(C=2N=CC=NC1=2)N3CCN4CCCC4(C3)))C1
FC=2C=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCN5CCCC5(C4))C1
FC=2C(F)=C(C=C3C= 1 C=NC=NC= 1 C(=NC=23)N4CCNCC4)C1
FC=4C(F)=C(C=C 1 C=4(N=C(C=2N=CC=NC 1 =2)N3CCNCC3))C1
FC=2C(F)=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCNCC4)C1
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C=2C=NC=NC=23))C1
CN1CCN(CC1)C4=NC2=C(F)C(F)=C(C=C2C=3N=CC=NC=34)C1
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C=2C=CC=NC=23))C1
FC=2C(F)=C(C=C3C=1C=NC=NC=1C(=NC=23)N4CCN5CCCC5(C4))C1
FC=5C(F)=C(C=C 1 C=5(N=C(C=2N=CC=NC 1 =2)N3CCN4CCCC4(C3)))C1
FC=2C(F)=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCN5CCCC5(C4))C1
FC(F)(F)C 1 =CC=C2N=C(C=3N=CN=CC=3(C2(=C 1 )))N4CCNCC4
FC(F)(F)C 1 =CC=C2N=C(C=3N=CC=NC=3(C2(=C 1 )))N4CCNCC4
FC(F)(F)C1=CC=C2N=C(C=3N=CC=CC=3(C2(=C1)))N4CCNCC4
CN1CCN(CC1)C4=NC2=CC=C(C=C2C=3C=NC=NC=34)C(F)(F)F
CN1CCN(CC1)C4=NC2=CC=C(C=C2C=3N=CC=NC=34)C(F)(F)F
CN1CCN(CC1)C4=NC2=CC=C(C=C2C=3C=CC=NC=34)C(F)(F)F
FC(F)(F)C 1 =CC=C2N=C(C=3N=CN=CC=3(C2(=C 1 )))N4CCN5CCCC5(C4)
FC(F)(F)C 1 =CC=C2N=C(C=3N=CC=NC=3(C2(=C 1 )))N4CCN5CCCC5(C4) FC(F)(F)C1=CC=C2N=C(C=3N=CC=CC=3(C2(=C1)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C=3N=CN=CC=3(C2(=CC=1C(F)(F)F)))N4CCNCC4
FC=1C=C2N=C(C=3N=CC=NC=3(C2(=CC=1C(F)(F)F)))N4CCNCC4
FC=1C=C2N=C(C=3N=CC=CC=3(C2(=CC=1C(F)(F)F)))N4CCNCC4
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C=3C=NC=NC=34)C(F)(F)F
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C=3N=CC=NC=34)C(F)(F)F
CN1CCN(CC1)C4=NC2=CC(F)=C(C=C2C=3C=CC=NC=34)C(F)(F)F
FC=1C=C2N=C(C=3N=CN=CC=3(C2(=CC=1C(F)(F)F)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C=3N=CC=NC=3(C2(=CC=1C(F)(F)F)))N4CCN5CCCC5(C4)
FC=1C=C2N=C(C=3N=CC=CC=3(C2(=CC=1C(F)(F)F)))N4CCN5CCCC5(C4)
FC=2C=C(C=C3C=1C=NC=NC=1C(=NC=23)N4CCNCC4)C(F)(F)F
FC=4C=C(C=C 1 C=4(N=C(C=2N=CC=NC 1 =2)N3CCNCC3))C(F)(F)F
FC=2C=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCNCC4)C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C=2C=NC=NC=23))C(F)(F)F
CN1CCN(CC1)C4=NC2=C(F)C=C(C=C2C=3N=CC=NC=34)C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C=C(C=C4(C=2C=CC=NC=23))C(F)(F)F
FC=2C=C(C=C3C=1C=NC=NC=1C(=NC=23)N4CCN5CCCC5(C4))C(F)(F)F
FC=5C=C(C=C1C=5(N=C(C=2N=CC=NC1=2)N3CCN4CCCC4(C3)))C(F)(F)F
FC=2C=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCN5CCCC5(C4))C(F)(F)F
FC=2C(F)=C(C=C3C=1C=NC=NC=1C(=NC=23)N4CCNCC4)C(F)(F)F
FC=4C(F)=C(C=C1C=4(N=C(C=2N=CC=NC1=2)N3CCNCC3))C(F)(F)F
FC=2C(F)=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCNCC4)C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C=2C=NC=NC=23))C(F)(F)F
CN1CCN(CC1)C4=NC2=C(F)C(F)=C(C=C2C=3N=CC=NC=34)C(F)(F)F
CN1CCN(CC1)C3=NC4=C(F)C(F)=C(C=C4(C=2C=CC=NC=23))C(F)(F)F
FC=2C(F)=C(C=C3C=1C=NC=NC=1C(=NC=23)N4CCN5CCCC5(C4))C(F)(F)F
FC=5C(F)=C(C=C1C=5(N=C(C=2N=CC=NC1=2)N3CCN4CCCC4(C3)))C(F)(F)
F
FC=2C(F)=C(C=C3C=1C=CC=NC=1C(=NC=23)N4CCN5CCCC5(C4))C(F)(F)F FC(F)(F)C= 1 C=C2C(=CC=1 C1)N=C(C=3N=CN=CC2=3)N4CCNCC4
FC(F)(F)C= 1 C=C2C(=CC=1 C1)N=C(C=3N=CC=NC2=3)N4CCNCC4
FC(F)(F)C= 1 C=C2C(=CC=1 C1)N=C(C=3N=CC=CC2=3)N4CCNCC4
CN1CCN(CC1)C4=NC2=CC(=C(C=C2C=3C=NC=NC=34)C(F)(F)F)C1 CN1CCN(CC1)C4=NC2=CC(=C(C=C2C=3N=CC=NC=34)C(F)(F)F)C1 CN1CCN(CC1)C4=NC2=CC(=C(C=C2C=3C=CC=NC=34)C(F)(F)F)C1
FC(F)(F)C=1C=C2C(=CC=1C1)N=C(C=3N=CN=CC2=3)N4CCN5CCCC5(C4) FC(F)(F)C=1C=C2C(=CC=1C1)N=C(C=3N=CC=NC2=3)N4CCN5CCCC5(C4) FC(F)(F)C=1C=C2C(=CC=1C1)N=C(C=3N=CC=CC2=3)N4CCN5CCCC5(C4) CN1 CCN(C(C3=NN=CN34)=NC2=C4C=C(C#N)C=C2)CC 1
[0853] The activity of the compounds in Examples 1-519 as HiR and/or H4R inhibitors is illustrated in the following assay. The other compounds listed above, which have not yet been made and/or tested, are predicted to have activity in these assays as well.
Biological Activity Assay
In vitro histamine receptor cell-based assays
[0854] The cell-based assays utilize an aequorin dependent bioluminescence signal. Doubly-transfected, stable CHO-K1 cell lines expressing human H4, or Hi, mitochondrion-targeted aequorin, and (H4 only) human G protein Gal 6 are obtained from Perkin-Elmer. Cells are maintained in F12 (Ham's) growth medium, containing 10% (vol./vol.) fetal bovine serum, penicillin (100 IU/mL), streptomycin (0.1 mg/mL), zeocin (0.25 mg/mL) and geneticin (0.40 mg/mL). Cell media components are from Invitrogen, Inc. One day prior to assay, the growth medium is replaced with the same, excluding zeocin and geneticin. In some assays, cells previously frozen at "ready to use density" are thawed and immediately available for loading with coelenterazine-h dye as described below.
[0855] For assay preparation, growth medium is aspirated, and cells are rinsed with calcium-free, magnesium-free phosphate-buffered saline, followed by two to three minute incubation in Versene (Invitrogen, Inc.) at 37 °C. Assay medium (DMEM:F12 [50:50], phenol-red free, containing 1 mg/mL protease-free bovine serum albumin) is added to collect the released cells, which are then centrifuged.. The cell pellet is re-suspended in assay medium, centrifuged once more, and re- suspended in assay medium to a final density of 5 x 106 cells/mL. Coelenterazine-h dye (500 μΜ in ethanol) is added to a final concentration of 5 μΜ, and mixed immediately. The conical tube containing the cells is then wrapped with foil to protect the light-sensitive dye. The cells are incubated for four hours further at room temperature (approximately 21°C) with end-over-end rotation to keep them in suspension.
[0856] Just before assay, the dye-loaded cells are diluted to 1.5 x 106 cells/mL (H4 receptor) or 0.75 x 106 cells/mL (Hi receptor) with additional assay medium. Cells are dispensed to 1536 well micro-titer plates at 3
Figure imgf000433_0001
To assay receptor antagonism 60 nl of 100X concentration test compounds in 100% dimethyl sulfoxide (DMSO) are dispensed to the wells, one compound per well in concentration response array by passive pin transfer, and the plates are incubated for 15 minutes at room temperature. Assay plates are then transferred to a Lumilux bioluminescence plate reader (Perkin-Elmer) equipped with an automated 1536 disposable tip pipette. The pipette dispenses 3 μίΛ βΙΙ of agonist (histamine, at twice the final concentration, where final concentration is a previously determined EC8o) in assay medium, with concurrent bioluminescence detection. Potential agonist activity of test compounds is measured by separate assays that measure response to test compounds alone, without added histamine agonist. CCD image capture on the Lumilux includes a 5 second baseline read and generally a 40 second read per plate after agonist (or test compound only in agonist mode assay) addition. A decrease in bioluminescence signal (measured either as area-under-the-curve, or maximum signal amplitude minus minimum signal amplitude) correlates with receptor antagonism in a dose dependent manner. The negative control is DMSO lacking any test compound. For antagonist assays, the positive controls are JNJ7777120 (l-[(5-Chloro-lH-indol-2-yl)carbonyl]-4-methyl-piperazine, 10 μΜ final concentration, ¾ receptor) and diphenhydramine (2-Diphenylmethoxy-N,N- dimethylethylamine, 10 μΜ final concentration, Hi receptor) . For agonist assays, the positive control is histamine (10 μΜ final concentration). Efficacy is measured as a percevtage of positive control activity.
[0857] Data reported as NT refers to the example having been not tested. It is expected that these compounds when tested will be active and will have utility similar to those that have been tested. In the antagonist assays in Table 2 below, "+" indicates EC50 < 10 μΜ and "-" indicates EC 50 > 10 μΜ. In the agonist assay, "+" indicates EC50 < 10 μΜ, "-" indicates EC50 > 10 μΜ but < 100 μΜ, "W" indicates no activity to 10 μΜ, and "NA" indicates no activity to 100 μΜ. Table 2. Biological Activity
Figure imgf000434_0001
Figure imgf000435_0001
Figure imgf000436_0001
Figure imgf000437_0001
Figure imgf000438_0001
Figure imgf000439_0001
Figure imgf000440_0001
Figure imgf000441_0001
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
In Vivo Assay Number One
Assessment of H4 Antagonism - Model of Scratching Induced by Histamine in CD-I mice.
Animals
[0858] Female CD-I mice (Charles River, Hollister, CA), approximately 10 weeks old were housed under controlled conditions (12 h light: 12 h dark, 21 ° C) and allowed ad libitum access to food (Purina LabDiet 5P14) and water. Animals were deprived of access to food and water for 1 hour during the experimental itch protocol. All studies were performed under the guidelines of the Institutional Animal Care and Use Committee of Kalypsys, Inc.
Induction and Measurement of Itch
[0859] At least 24 hours prior to study initiation, the hair on the rostral dorsum of the animal was clipped to clear a location for intradermal (i.d.) injection of pruritogen (histamine, dissolved in Dulbecco's PBS [pH 7.4] at a concentration of 10 μιηοΐ per 20 μί). Animals were dosed by oral gavage with vehicle (9/0.5/0.5/90 PEG-400/Tween-80/PVP-K30/l carboxymethylcellulose in water) or test compounds (formulated as suspensions in vehicle) at 30 mg/kg in 200 μL· by means of a 20 gauge 1.5" feeding needle affixed to a 1 mL syringe. There were 8 mice per study group. Thirty minutes after oral dosing, animals were injected i.d. with 20 μL· of histamine. Immediately afterward animals were placed into individual sections of a standard acrylic cage for observation, which was recorded digitally for a 20 minute period by video cameras (Panasonic SDR-S70/PC) for later review.
[0860] Quantitation of induced itch was measured as described previously (Bell, J.K. et al., British Journal of Pharmacology , 142:374-380, 2004) by counting the number of scratching bouts per animal in the 20 minute period after i.d.
injection. A scratching bout was defined as three rapid scratch movements of the hind paw in the area of the injection site. Activity with the fore paws was deemed to be grooming and not scratching, and thus was not counted. All data were analyzed using GraphPad Prism (San Diego, CA) software, and reported as mean percentage reduction in scratching bouts versus vehicle control. The significance of antagonist effect on agonist-induced itching was analyzed using the nonparametric Mann-Whitney test with P values < 0.05 being designated as statistically significant.
[0861] Data reported as NT refers to the example having been not tested. It is expected that these compounds when tested will be active and will have utility similar to those that have been tested. In Table 3 below, entries with superscript "1" are statistically significant according to the criteria outlined in the protocol above. Entries with superscript "2" are examples that have been tested on two separate days and the results reported below are the mean of the two experiments.
Table 3. In Vivo Activity
Figure imgf000447_0001
In Vivo Assay Number Two
Allergic Conjunctivitis in Passively Sensitized Guinea Pigs
[0862] Male Hartley VAF outbred guinea pigs were passively sensitized to ovalbumin by a single OD subconjunctival injection of undiluted guinea pig anti- ovalbumin antiserum 24 hours before OD topical challenge with 500 μg ovalbumin in saline. Control animals were injected with saline only and challenged with ovalbumin. To determine acute phase drug efficacy, 30 min after challenge animals were clinically scored by a masked observer for severity of signs of conjunctivitis based on a standard scale. Test compounds were administered topically 1 hour prior to challenge (QD protocol), or 1 hour prior to challenge and again 8 hours after challenge (BID protocol). Twenty-four hours after challenge, animals were euthanized and conjunctivae were harvested for determination of tissue eosinophil peroxidase (EPO) concentration as a marker of allergic inflammation.
Homogenates of freshly collected tissues were prepared by shaking the tissues in 2 mL round-bottom tubes containing 0.5 mL of homogenization buffer (50 mM Tris HC1, pH 8.0, 6 mM KBr) and one 5-mm stainless steel bead on a Qiagen
TissueLyser at 30 Hz for 5 min. Homogenates were frozen and thawed once, then centrifuged at 10,000 rpm for 5 min. EPO activity in supernatants was measured by reacting diluted homogenates with a solution of 6 mM o-phenylenediamine substrate and 8.8 mM H202 in homogenization buffer for 3 min. The reaction was stopped with 4M H2S04 and absorbances were measured at 490 nM on a spectrophotometric plate reader. Total EPO in samples was calculated from a standard curve of recombinant human EPO in each assay. EPO activity was normalized to total protein concentration (Pierce BCA assay) in supernatants. Background EPO activity was determined from the unsensitized, antigen- challenged control group. Percent inhibition was calculated from the sensitized, antigen-challenged, vehicle-treated control group in each experiment. Ovalbumin- injected animals dosed topically with 0.1% w/v dexamethasone (dex) served as positive control. Groups were compared by ANOVA with Dunnett's or Tukey's post-hoc tests where appropriate with significance assigned at the 95% confidence level.
[0863] Table 4 below summarizes the results. In the column labeled "BID activity", a test compound was assigned a "+" if a 0.01% bid dose was statistically equivalent to dexamethasone with respect to reduction of EPO activity, while a "-" was assigned if the compound was statistically inferior to dexamethasone and not different than vehicle. In the column labeled "QD activity", a test compound was assigned a "+" if a < 0.1 % qd dose was statistically equivalent to dexamethasone with respect to reduction of EPO activity, while a "-" was assigned if the compound was statistically inferior to dexamethasone and not different than vehicle.
[0864] Data reported as NT refers to the example having been not tested. It is expected that these compounds when tested will be active and will have utility similar to those that have been tested.
Table 4. In Vivo Activity
Figure imgf000449_0001
Example # BID activity QD activity
57 + +
66 NT -
95 - NT
99 + -
103 NT +
104 NT -
109 - NT
113 - NT
124 NT -
125 NT -
126 NT +
127 NT +
129 NT -
133 NT -
136 NT -
143 + -
145 NT -
150 - NT
152 - NT
153 - NT
160 - NT
161 + NT
165 + +
166 + +
In Vivo Assay Number Three
Assessment of H4 Antagonism - Model of Allergic Rhinitis in Balb/C mice.
Animals
[0865] Female BALB/c mice, 6-12 weeks of age, were obtained from Jackson Laboratories (Bar Harbor, ME). All experimental animals used in this work were under a protocol approved by the Institutional Animal Care and Use Committee of the National Jewish Medical and Research Center, Denver, CO.
Induction and Measurement of Allergic Rhinitis
[0866] The assay protocol is similar to that described in Miyahara, S. et al. (2005), J Allergy Clin Immunol , 116: 1020-1027. The role of the H4 receptor in this model has been validated [Shiraishi, Y. et al. (2009), J Allergy Clin Immunol. , 123:S561. Briefly, mice received intraperitoneal injections of 20 μg ovalbumin (OVA, Grade V; Sigma-Aldrich, St. Louis, MO), previously emulsified in 2.25 mg of alum (Alumlmuject; Pierce, Rockford, IL) in a total volume of 100 \L
(sensitization phase). Injections occurred on days 0 and 14. Starting on day 28 onward (challenge phase), mice received daily intranasal instillation of OVA (25 mg/ml in phosphate-buffered saline), 15 μΐ in each nostril without anesthesia. Instillations occurred for 6 days to evoke allergic nasal inflammation and congestion. Compounds were tested for the ability to prevent induction of nasal inflammation and congestion by intranasal instillation 2.5 hours prior to OVA instillation. Instillations of compounds were performed using 10 μΐ (0.03 to 0.1 % weight/volume [0.3 to 1 mg/ml]) in each nostril without anesthesia, in formulation vehicle: either (a) unbuffered saline, [pH approximately 6.0], 0.2% v/v Tween-80 (Sigma-Aldrich, St. Louis, MO), or (b) 50 mM sodium acetate [pH 5.0], 100 mM sodium chloride, 0.2% v/v Tween-80. On day 4 (early phase) and day 7 (late phase) after starting OVA challenges, respiratory frequency (RF) was measured in conscious animals by single chamber restrained whole-body plethysmography (WBP) [Buxco Research Systems, Troy, New York]. Because mice are obligate nasal breathers, OVA induced nasal inflammation and congestion results in decreased breathing frequency. Compounds that block OVA-induced nasal inflammation and congestion prevent the decrease in RF compared to positive control (instillation with formulation vehicle only prior to OVA challenge). The assay negative control measures baseline RF, where challenge is performed with phosphate-buffered saline lacking OVA. Compounds were also tested without OVA challenge to demonstrate no effect on RF alone. After whole-body plethysmography on day 7, nasal airflow impedance was measured as described (RNAJ see Methods section for Miyahara S. et al. [above] in the online supplemental material at the Journal of Allergy and Clinical Immunology: www.j acionline.org), using a custom-designed ventilator (Flexivent; Scireq, Montreal, Quebec, Canada). After airflow impedance measurement, the study was terminated and animals were euthanized.
[0867] It is expected that many of these compounds when tested will be active and will have utility similar to those that have been tested. In Table 5 below, entries with a " + " are active and statistically significant compared to positive control. Entries with a " - " are either weakly active, or inactive (statistically indistinguishable from positive control).
Table 5. In Vivo Activity
WBP, Day 4
Example # Dosage "+: increase in RF over positive control
"-: no increase in RF over positive control
19 0.1 , w/v +
23 0.1 , w/v +
24 0.1 , w/v +
29 0.1 , w/v -
45 0.1 , w/v +
57 0.1 , w/v +
57 0.02 % w/v -
95 0.1 % w/v +
103 0.1 % w/v -
113 0.1 % w/v +
127 0.1 % w/v -
129 0.1 % w/v -
135 0.1 % w/v +
143 0.1 % w/v -
145 0.1 % w/v -
206 0.1 , w/v -
246 0.1 % w/v +
281 0.1 % w/v +
309 0.1 % w/v -
311 0.1 % w/v -
351 0.1 % w/v +
358 0.1 % w/v -
365 0.1 , w/v +
373 0.1 % w/v +
376 0.1 % w/v -
377 0.1 % w/v -
391 0.1 % w/v + 418 0.1 % w/v -
419 0.1 % w/v -
422 0.1 % w/v +
424 0.1 % w/v -
425 0.1 % w/v -
426 0.1 % w/v -
427 0.1 % w/v -
428 0.1 % w/v +
429 0.1 % w/v +
433 0.1 % w/v +
Compositions
[0868] The following are examples of compositions which may be used to orally deliver compounds disclosed herein as a capsule.
[0869] A solid form of a compound of Formula (I) may be passed through one or more sieve screens to produce a consistent particle size. Excipients, too, may be passed through a sieve. Appropriate weights of compounds, sufficient to achieve the target dosage per capsule, may be measured and added to a mixing container or apparatus, and the blend is then mixed until uniform. Blend uniformity may be done by, for example, sampling 3 points within the container (top, middle, and bottom) and testing each sample for potency. A test result of 95-105% of target, with an RSD of 5%, would be considered ideal; optionally, additional blend time may be allowed to achieve a uniform blend. Upon acceptable blend uniformity results, a measured aliquot of this stock formulation may be separated to manufacture the lower strengths. Magnesium stearate may be passed through a sieve, collected, weighed, added to the blender as a lubricant, and mixed until dispersed. The final blend is weighed and reconciled. Capsules may then be opened and blended materials flood fed into the body of the capsules using a spatula. Capsules in trays may be tamped to settle the blend in each capsule to assure uniform target fill weight, and then sealed by combining the filled bodies with the caps.
COMPOSITION EXAMPLE 1
[0870] 10 mg Capsule: Total fill weight of capsule is 300 mg, not including capsule weight. Target compound dosage is 10 mg per capsule, but may be adjusted to account for the weight of counterions and/or solvates if given as a salt or solvated polymorph thereof. In such a case the weight of the other excipients, typically the filler, is reduced.
Figure imgf000454_0001
COMPOSITION EXAMPLE 2
[0871] 20 mg Capsule: Total fill weight of capsule is 300 mg, not including capsule weight. Target compound dosage is 20 mg per capsule, but may be adjusted to account for the weight of counterions and/or solvates if given as a salt or solvated polymorph thereof. In such a case the weight of the other excipients, typically the filler, is reduced.
Figure imgf000454_0002
[0872] The following are examples of compositions which may be used to topically deliver compounds disclosed herein, for example to the eye or nasal passages.
COMPOSITION EXAMPLE 3
Figure imgf000454_0003
Sodium chloride 0.5%
Disodium EDTA (Edetate disodium) 0.01%
Polysorbate 80 0.05%
Benzalkonium chloride 0.01%
Sodium hydroxide / Hydrochloric acid For adjusting pH to 7.3 - 7.4
Purified water q.s. to 100%
COMPOSITION EXAMPLE 4
Figure imgf000455_0001
[0873] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

CLAIMS What is claimed is:
1. A compound chosen from any one of Examples 251-415 and 417-519, or a salt thereof. .
2. A compound of structural Formula Va):
Figure imgf000456_0001
(Va)
or a salt thereof, wherein:
X1 is chosen from C, CH and N;
X2 is chosen from [C(R6)(R7)]n, NR8, and O;
X3 is chosen from [C(R9)(R10)]m and NR11, and O;
the ring comprising X1 - X3 is aromatic;
R1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl;
R5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
R2, R3 and R4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R6, R7, R9, and R10, are independently chosen from null, hydrogen, lower alkyl, heteroalkyl, lower alkoxy, halogen, lower haloalkyl, lower amino, carboxyl, hydroxy, cyano, and nitro, any of which may be optionally substituted; and
R8, R11, and R14 are independently chosen from null, hydrogen, lower alkyl, lower heteroalkyl, lower alkoxy, and lower haloalkyl, any of which may be optionally substituted;
and with the proviso that:
when X1 is C, X2 is NR8, R8 is null, X3 [C(R9)(R10)]m, m is 1, R9 is null, R1 is methylpiperazine, R4 is perfluoromethyl, and R5 is fluoro,
then R10 is hydrogen.
3. The compound as recited in Claim 2, wherein R6, R8, R10, and R14 are
independently chosen from null and hydrogen.
4. A compound having a structural formula chosen from:
Figure imgf000457_0001
or a salt thereof, wherein:
R1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl;
R5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
R2, R3 and R4 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R6, R8, R10, and R14 are independently chosen from null and hydrogen; and
R9 and Rn are independently chosen from null, hydrogen and lower alkyl.
5. The compound as recited in Claim 4, or a salt thereof wherein one of R3 and R4 is hydrogen.
6. The compound as recited in Claim 5, or a salt thereof wherein R5 is fluoro.
7. The compound as recited in Claim 5, or a salt thereof wherein R4 is chosen from bromine, chlorine, and CF3.
8. The compound as recited in Claim 5, or a salt thereof wherein:
R4 is chosen from bromine, chlorine, and CF3; and
R5 is fluoro.
9. A compound of structural fo
Figure imgf000458_0001
or a salt thereof, wherein:
X3 and X5 are each independently chosen from C(R9) and N(R10);
R1 is 4- to 7-membered monocyclic heterocycloalkyl optionally substituted with one to three substituents chosen from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cyano, lower amino, hydroxy, and nitro;
R2, R3, R4 and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano; and
R9 and R10 are each independently chosen from null, hydrogen and lower alkyl; wherein
if R5 is hydrogen, then X3 must be N; and
wherein the compound is not
8-chloro-2-methyl-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline;
8-chloro-2-methyl-4-(piperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline;
8-chloro-4-(4-methylpiperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline;
8-chloro-4-(piperazin-l-yl)-2H-pyrazolo[3,4-c]quinoline;
4-(8-chloro-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-yl)- 1,1- dimethylpiperazin- 1 -ium;
2-methyl-4-(4-methylpiperazinyl)-8-(trifluoromethyl)pyrazolo[3,4- cjquinoline;
2-methyl-4-piperazinyl-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline HC1 salt; or
4-(4-methylpiperazinyl)-8-(trifluoromethyl)pyrazolo[3,4-c]quinoline.
10. The compound as recited in Claim 9, having structural formula (VII)
Figure imgf000459_0001
(VII)
or a salt thereof, wherein:
A is an optionally substituted monocyclic 4- to 7-membered heterocycloalkyl attached through a ring nitrogen to the core;
X3 is chosen from C(R9) and N;
R2, R3, R4, and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano; and
R9 is chosen from hydrogen and lower alkyl; wherein
if R5 is hydrogen, then X3 must be N.
11. The compound as recited in Claim 10, having structural formula (VIII)
Figure imgf000459_0002
(VIII)
or a salt thereof, wherein:
X3 is chosen from C(R9) and N;
X8 is chosen from CH and N;
m and n are each an integer chosen from 1 and 2;
R2, R3, R4, and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R9 is chosen from hydrogen and lower alkyl; and
R 24 is chosen from hydrogen, amino, and lower alkyl; wherein if R5 is hydrogen, then X3 must be N.
12. The compound as recited in Claim 11, or a salt thereof, wherein:
X8 is CH;
m and n are each 1 ; and
R 24 is chosen from hydrogen, amino, and lower alkyl.
13. The compound as recited in Claim 12, or a salt thereof, wherein R is lower amino.
14. The compound as recited in Claim 13, or a salt thereof, wherein R 24 is NHCH3.
15. The compound as recited in Claim 11, or a salt thereof, wherein:
X8 is N;
m and n are each 2; and
R24 is chosen from hydrogen and lower alkyl.
16. The compound as recited in Claim 15, or a salt thereof, wherein R24 is chosen from hydrogen and methyl.
17. The compound as recited in Claim 16, or a salt thereof, wherein R24 is methyl.
18. The compound as recited in Claim 3, having structural formula (IX)
Figure imgf000460_0001
(IX)
or a salt thereof, wherein:
X8 is chosen from CH and N;
p and q are each an integer chosen from 1 and 2;
R5 is chosen from halogen, perhalomethyl, perhalomethoxy, and cyano;
R3 and R4 are independently chosen from hydrogen, halogen,
perhalomethyl, perhalomethoxy, and cyano;
R9 is chosen from hydrogen and lower alkyl; and
R24 is chosen from hydrogen, amino, and alkyl.
19. The compound as recited in Claim 18, or a salt thereof wherein R4 is chosen from bromine, chlorine, and CF3.
20. The compound as recited in Claim 19, wherein R9 is chosen from hydrogen and methyl.
21. The compound as recited in Claim 20, or a salt thereof, wherein:
X8 is CH;
m and n are each 1 ; and
R 24 is chosen from hydrogen, lower amino, and lower alkyl.
22. The compound as recited in Claim 21, or a salt thereof, wherein R is lower amino.
23. The compound as recited in Claim 22, or a salt thereof, wherein R 24 is NHCH3.
24. The compound as recited in Claim 23, or a salt thereof wherein R5 is fluoro.
25. The compound as recited in Claim 20, or a salt thereof, wherein:
X8 is N;
m and n are each 2; and
R24 is chosen from hydrogen and lower alkyl.
26. The compound as recited in Claim 25, or a salt thereof wherein R5 is fluoro.
27. The compound as recited in Claim 26, or a salt thereof wherein R4 is chosen from bromine, chlorine, and CF3.
28. The compound as recited in Claim 26, or a salt thereof wherein R3 is fluoro.
29. The compound as recited in Claim 26, or a salt thereof, wherein R 24 is chosen from hydrogen and methyl.
30. The compound as recited in Claim 29, or a salt thereof, wherein R 24 is methyl.
31. A compound of structu
Figure imgf000461_0001
(XI)
or a salt thereof, wherein:
X1 and X5 are independently chosen from C, CH and N;
X2 is chosen from [C(R6)(R7)]n, NR8, and O;
X3 is chosen from [C(R9)(R10)]m and NR11, and O;
X4 is chosen from [C(R12)(R13)] and NR14;
R1 is optionally substituted 4- to 7-membered monocyclic heterocycloalkyl; R2, R3, R4, and R5 are independently chosen from hydrogen, halogen, perhalomethyl, perhalomethoxy, and cyano;
R 6°, R V', R 9y, R 110U, R 1l2z, and R 113J are independently chosen from null, hydrogen, lower alkyl, heteroalkyl, lower alkoxy, halogen, lower haloalkyl, lower amino, carboxyl, hydroxy, cyano, and nitro, any of which may be optionally substituted; R8, R11, and R14 are independently chosen from null, hydrogen, lower alkyl, lower heteroalkyl, lower alkoxy, and lower haloalkyl, any of which may be optionally substituted; and
R 24 is chosen from hydrogen, lower amino, and lower alkyl;
with the proviso that
when X1 is N, X2 is [C(R6)(R7)]n, X3 is NR11, X4 is NR14, X5 is C, R2 is hydrogen, R3 is hydrogen, R5 is hydrogen, R6-R10 and R12-R14 are chosen from null and hydrogen, and R24 is NH2,
then R5 is not chlorine.
32. A compound as recited in claim 31, or a salt thereof, having a structural formula chosen from:
Figure imgf000462_0001
Figure imgf000463_0001
33. The compound as recited in Claim 32, or a salt thereof, wherein:
R7, R9, and R11 are independently chosen from null, hydrogen, and lower alkyl; and
R24 is chosen from hydrogen, lower amino, and lower alkyl.
34. The compound as recited in Claim 33, or a salt thereof, wherein R 24 is lower amino.
35. The compound as recited in Claim 34, or a salt thereof, wherein R 24 is NHCH3.
36. The compound as recited in Claim 35, or a salt thereof wherein R3 and R5 are independently chosen from hydrogen and fluorine.
37. The compound as recited in Claim 36, or a salt thereof wherein R4 is chosen from cyano, bromine, chlorine, and CF3.
38. The compound as recited in Claim 37, or a salt thereof wherein R5 is fluoro.
39. The compound as recited in Claim 38, or a salt thereof wherein
R2 is hydrogen; and
at least one of R3 and R5 is hydrogen.
40. The compound as recited in Claim 34, or a salt thereof wherein R4 is chosen from cyano, bromine, chlorine, and CF3.
41. The compound as recited in Claim 40, or a salt thereof wherein R4 is cyano.
42. The compound as recited in Claim 41, or a salt thereof, wherein R24 is NHCH3.
43. The compound as recited in Claim 42, or a salt thereof wherein R2 is hydrogen.
44. The compound as recited in Claim 43, or a salt thereof wherein R2, R3, and R5 are hydrogen.
45. A compound of structural Formula (XIII):
Figure imgf000464_0001
(XIII)
or a salt thereof, wherein:
the ring comprising X4 is aromatic;
X4 is chosen from CH and N;
R1 is chosen from piperazin-l-yl and 4-methylpiperazin-l-yl;
R3 is chosen from hydrogen, cyano, monocyclic heteroaryl, C(0)NHZ, C02Z, CF3, NHC(0)Y, NHSO2Z, and S02NHZ;
R4 is different than R3 and is chosen from cyano, monocyclic heteroaryl, C(0)NHZ, C02Z, CF3, NHC(0)Y, NHS02Z, and S02NHZ;
Z is chosen from hydrogen, lower alkyl, phenyl, and benzyl; and
Y is chosen from lower alkyl, phenyl, benzyl, and lower alkoxy.
46.
Figure imgf000464_0002
47
Figure imgf000465_0001
48. A pharmaceutical composition comprising at least one compound chosen from those recited in Examples 251-415 and 417-519 or a salt thereof, together with a pharmaceutically acceptable carrier.
49. A pharmaceutical composition comprising a compound as recited any one of Claims 1, 2, 4, 31, 32 and 45, together with a pharmaceutically acceptable carrier.
50. A pharmaceutical composition comprising:
a compound as recited in any one of Claims 1, 2, 4, 31, 32 and 45;
another therapeutic agent chosen an HiR antagonist, an ¾R antagonist, and an intranasal corticosteroid; and
a pharmaceutically acceptable carrier.
51. The pharmaceutical composition comprising as recited in Claim 50, wherein the other therapeutic agent is chosen from acrivastine, alcaftadine, antazoline, azelastine, bromazine, brompheniramine, cetirizine, chlorpheniramine, clemastine, desloratidine, diphenhydramine, diphenylpyraline, ebastine, emedastine, epinastine, fexofenadine, hydroxyzine, ketotifen, levocabastine, levocetirizine, loratidine, methdilazine, mizolastine, promethazine, olopatadine, triprolidine, fluticasone, budesonide, beclomethasone, mometasone and ciclesonide.
52. A compound as recited in Claim 1 for use as a medicament.
53. Use of a compound as recited in Any one of Claims 1, 2, 4, 31, 32 and 45 in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of H4R.
54. The use as recited in Claim 53, wherein the medicament is formulated for
systemic administration.
55. The use as recited in Claim 53, wherein the medicament is formulated for
topical administration.
56. The use as recited in Claim 53, wherein the disease is chosen from an
inflammatory disease, an autoimmune disease, an allergic disorder, and an ocular disorder.
57. The use as recited in Claim 53, wherein disease is chosen from pruritus,
eczema, atopic dermatitis, asthma, chronic obstructive pulmonary disease, allergic rhinitis, non-allergic rhinitis, rhinosinusitis, nasal inflammation, nasal congestion, sinus congestion, otic inflammation dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis..
58. The use as recited in Claim 53, wherein the topical administration is to the skin.
59. The use as recited in Claim 53, wherein the topical administration is to the eye.
60. The use as recited in Claim 53, wherein the topical administration is intranasal, otic, or by inhalation.
61. A method of inhibition of H4R comprising contacting H4R with a compound as recited in any one of Claims 1, 2, 4, 31, 32 and 45.
62. The method as recited in claim 61, wherein the contacting causes inhibition which is competitive with histamine.
63. Use of a compound as recited in any one of Claims 1, 2, 4, 31, 32 and 45 in the manufacture of a combination medicament for:
reduction in the number of mast cells;
inhibition of inflammatory cell migration to the nasal mucosa, the ear, the eye, or the wound site; reduction in inflammatory markers;
reduction in inflammatory cytokines;
reduction in scratching;
relief of symptoms of nasal congestion from allergic or non-allergic causes; decreased watering or redness of the eyes; or
reduction in ocular pain.
64. Use of a compound as recited in any one of Claims 1, 2, 4, 31, 32 and 45 in the manufacture of a medicament for the treatment of the pain or inflammation resulting from cataract surgery.
65. Use of a compound as recited in any one of Claims 1, 2, 4, 31, 32 and 45 in the manufacture of a combination medicament for the prevention or treatment of an H4R-mediated disease, together with another therapeutic agent.
66. Use of a compound as recited in any one of Claims 1, 2, 4, 31, 32 and 45
together with another therapeutic agent, in the manufacture of a combination medicament for:
reduction in the number of mast cells,
inhibition of inflammatory cell migration to the nasal mucosa, the ear, the eye, or the wound site,
reduction in inflammatory markers;
reduction in inflammatory cytokines;
reduction in scratching;
relief of symptoms of nasal congestion from allergic or non-allergic causes; decreased watering or redness of the eyes; or
reduction in ocular pain.
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