US20170217923A1 - Therapeutic compounds and related methods of use - Google Patents

Therapeutic compounds and related methods of use Download PDF

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US20170217923A1
US20170217923A1 US15/456,927 US201715456927A US2017217923A1 US 20170217923 A1 US20170217923 A1 US 20170217923A1 US 201715456927 A US201715456927 A US 201715456927A US 2017217923 A1 US2017217923 A1 US 2017217923A1
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Masaki Suzuki
Kazumi Kondo
Muneaki Kurimura
Krishna Reddy Valluru
Akira Takahashi
Takeshi Kuroda
Haruka Takahashi
Tae Fukushima
Shin Miyamura
Indranath Ghosh
Abhishek Dogra
Geraldine Harriman
Amy Elder
Satoshi Shimizu
Kevin J. Hodgetts
Jason S. Newcom
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Otsuka Pharmaceutical Co Ltd
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Abstract

Methods of treating disorders using compounds that modulate striatal-enriched tyrosine phosphatase (STEP) are described herein. Exemplary disorders include schizophrenia and cognitive deficit.

Description

    RELATED APPLICATIONS
  • This application which claims the benefit under 35 U.S.C. §120 as a divisional application of U.S. patent application Ser. No. 14/692,434 titled “THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE,” filed on Apr. 21, 2015, which claims the benefit under 35 U.S.C. §120 as a continuation of U.S. patent application Ser. No. 13/520,018 titled “THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE,” filed on Sep. 25, 2012, which is a national stage application under 35 U.S.C. §371 of PCT Application No. PCT/US2010/062555 titled “THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE,” filed Dec. 30, 2010, which claims priority to U.S. Provisional Application Ser. No. 61/291,544, titled “THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE” filed on Dec. 31, 2009; 61/291,550, titled “THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE,” filed on Dec. 31, 2009; and 61/291,554, titled “THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE” filed on Dec. 31, 2009, all of which are herein incorporated by reference in their entireties.
    • BACKGROUND OF INVENTION
  • Tyrosine phosphorylation of synaptic receptors and signaling molecules regulates synaptic activity. A number of protein tyrosine phosphatases specifically expressed within the brain have been identified, including STEP (for STriatal-Enriched tyrosine Phosphatase, also known as PTPN5). Recent evidence suggests that STEP plays an important role in synaptic plasticity, for review see (Braithwaite S P, et al., (2006), Trends Neurosci, 29 (8): 452; Baum M L, et al., (2010), Commun Integr Biol, 3 (5): 419). STEP is specifically expressed within neurons of the central nervous system. As its name indicates, the highest expression level is within the striatum. However, more recent work has found that it is expressed at lower levels in multiple brain regions including the neocortex, amygdala, hippocampus, and embryonic spinal cord.
  • Four groups of proteins that STEP regulates have been identified: the mitogen-activated protein kinases (MAPKs), the tyrosine kinase Fyn, the N-methyl-D-aspartate (NMDA) receptor complex (specifically the NR2B subunit) and AMPA receptors (specifically, GluR2, (Zhang Y, et al., (2008), J Neurosci, 28 (42): 10561)). Three additional new substrates for STEP have also been recently discovered; proline-rich tyrosine kinase 2 (Pyk2; Xu J, et al., (2010), Abstracts of the Society for Neuroscience Meetings), the fragile X mental retardation protein (FMRP) (Goebel-Goody S M, et al., (2010), Abstracts of the Society for Neuroscience Meetings) and the cell-death mediator Bak (Fox J L, et al., (2010), EMBO J, 29 (22): 3853). Tyrosine phosphorylation of one member of the MAPK family, the extracellular signal regulated kinase (ERK), is necessary for the expression and maintenance of synaptic plasticity in many brain regions, and disruption of the ERK pathway leads to a disruption of learning and memory. One of the functions of these src and Pyk2 kinases is to phosphorylate NMDA receptors, thereby modulating their channel conductance properties and facilitating their movement toward the surface of neuronal plasma membranes. Pyk2 and Fyn tyrosine kinases are activated by phosphorylation on tyrosine residues. NR2B phosphorylation on Tyrosine 1452 inhibits the receptor endocytosis. STEP acts as direct or indirect brake of NMDAR mediated signaling by either respectively dephosphorylating NR2B or its associated kinases, Pyk2 and Fyn. Activation of AMPA, NMDA receptors and MAPKs are required for the induction of several forms of long-term potentiation (LTP) and long-term depression (LTD). Hippocampal LTP is increased in transgenic mice model of Alzheimer lacking STEP (Zhang Y, et al., (2010), Proc Natl Acad Sci USA, 107 (44): 19014). NR2B and AMPA receptor surface expression is increased in STEP KO mice. AMPA receptor endocytosis in group I metabotropic glutamate receptor I (mGluR) mediated LTD is mediated by a tyrosine phosphatase. AMPA receptor endocytosis induced by activation of group I mGLuR is blocked in STEP KO mice suggesting that STEP might also control mGluR mediated LTD.
  • Compounds that inhibit STEP activity should mimic the effects observed with the STEP KO and may be useful for treating conditions mediated by abnormal NMDA-receptor (NMDA-Rs) and/or MAP kinase pathway signaling. Both may mediate cognition, learning and memory, neurogenesis, and may also affect neuronal plasticity, pain perception, mood and anxiety, and neuroendocrine regulation.
  • Modulation of NMDA-Rs:
  • STEP decreases the tyrosine phosphorylation level of NMDA-Rs. Less phosphorylated NMDA-Rs have lower conductance states and thus will allow less current and fewer ions to pass. The NMDA-Rs will therefore be functionally less active (Alvestad R M, et al., (2003), J Biol Chem, 278 (13): 11020), which can lead to schizophrenic symptoms. Hypofunction of NMDA-Rs has been liked to schizophrenia. For example, phencyclidine, ketamine, and other noncompetitive antagonists at NMDA-type glutamate receptors can exacerbate symptoms in patients (Lahti A C, et al., (1995), Neuropsychopharmacology, 13 (1): 9) and may produce a range of psychotic symptoms in volunteers that are similar to those of schizophrenic patients. NMDA-R hypofunction is also linked to psychosis and drug addiction (Javitt D C and Zukin S R, (1991), Am J Psychiatry, 148 (10): 1301). Chronic treatment of atypical antipsychotic clozapine and risperidone in mice result in significant increase of phosphorylation of ERK, NR2B and Pyk2 on tyrosine residues recognized by STEP (Carty N C, et al., (2010), Abstracts of the Society for Neuroscience Meetings). Treatment of these anti-psychotics also enhances cAMP and STEP phosphorylation. Since PKA mediated phosphorylation of STEP is know to inactivate STEP, these results suggest that STEP inhibition mediates the beneficial effect of antipsychotic drugs. Recent studies have linked abnormal NMDA-R activity and expression of STEP to the cognitive decline observed in Alzheimer's disease or transgenic mice expressing mutant APP (Tg2576 mice) (Snyder E M, et al., (2005), Nat Neurosci, 8 (8): 1051; Hynd M R, et al., (2004), J Neurochem, 90 (4): 913; Kurup P, et al., (2010), Channels (Austin), 4 (5)). More specifically, STEP KO mice are less susceptible to PCP-induced hyperlocomotion and PCP-induced cognitive deficits in the object recognition tasks (Carty N C, et al., (2010), Abstracts of the Society for Neuroscience Meetings). Compared to the Tg2576 mice expressing STEP, Tg2576 lacking STEP gene showed rescue in their deficits in hyppocampal LTP and in different behavioral cognitive tasks. Altogether, these results suggest that STEP inhibitors might represent a novel class of drugs that can treat both positive symptoms and cognitive deficit associated with schizophrenia.
  • Medications that modulate glutamatergic neurotransmission via NMDA-Rs may be also effective in treatment for mood and anxiety disorders. Administration of NMDA-R antagonists has anxiolytic effects in rodent models of anxiety (Falls W A, et al., (1992), J Neurosci, 12 (3): 854; Miserendino M J, et al., (1990), Nature, 345 (6277): 716). NMDA-Rs antagonist like ketamine has been shown to be effective in drug-resistant unipolar depression (Machado-Vieira R, et al., (2009), Pharmacol Ther, 123 (2): 143).
  • Abnormal balance between the activity of NMDA receptors at synaptic (prosurvival linked to ERK activation) and extrasynaptic (proapoptotic linked to p38 activation) sites has been proposed in cellular and mouse model of Huntington Disease (HD) (Milnerwood A J, et al., Neuron, 65 (2): 178). YAC128 mouse model (containing high number of glutamine repeat on huntingtin) of HD showed an increased activity of extrasynaptic NMDA receptors (NR2B subunit) and require p38 and caspase-6 cleavage activation. In YAC128 mice, NR2B synaptic expression is associated with high STEP expression and activity and a reduction in NR2B expression and phosphorylation (Gladding C M, et al., (2010), Abstracts of the Society for Neuroscience Meetings). Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP and activation of p38 (Xu J, et al., (2009), J Neurosci, 29 (29): 9330). Inhibiting STEP activity might therefore shift the balance toward the NMDA receptor/ERK synaptic prosurvival signaling pathway.
  • Modulation of ERK Pathway:
  • STEP inhibition may translate into activation of ERK1/2 kinases, for example, in the central nervous system (CNS). Activation of the ERK pathway in the CNS can mediate neurotrophic pathways involved in cellular resilience. ERK signaling directly affects Bak phosphorylation through inhibition of STEP to promote cell survival (Fox J L, et al., (2010), EMBO J, 29 (22): 3853). BDNF and other neurotrophins can block apoptosis and increase cell survival of different type of CNS neurons in vitro and in vivo via stimulation of the ERK pathway. Mood stabilizers effective in bipolar disorder like valproate and lithium may be potent activators of ERK activity. This effect on ERK activation is believed to be responsible for the neurotrophic effects of mood stabilizers observed in vitro or in brains of treated patients with bipolar disorder, for review see (Engel S R, et al., (2009), Mol Psychiatry, 14 (4): 448; Chen G and Manji H K, (2006), Curr Opin Psychiatry, 19 (3): 313; Machado-Vieira R, et al., (2009), Bipolar Disord, 11 Suppl 2 92). In vivo disruption of STEP activity was shown to activate MAPK pathway, leading to significant rescue from neuronal cell death after pilocarpine-induced status epilepticus (Choi Y S, et al., (2007), J Neurosci, 27 (11): 2999). Increasing cellular resilience could therefore limit or reduce neuronal loss in several neurologic disorders. Recent work has suggested a positive role for STEP inhibition in fragile X syndrome (FXS). This disorder results from the mutation of fmr1 gene coding for the fragile X mental retardation protein (FMRP). STEP binds to FMRP and its expression is dysregulated in FXS. FMR KO mice model displayed audiogenic seizures. FMR KO mice lacking STEP gene show a significant reduction of these seizures (Goebel-Goody S M, et al., (2010), Abstracts of the Society for Neuroscience Meetings), suggesting that STEP modulators might be therapeutic approach for FXS.
  • Various substituted heterocyclic compounds are disclosed in the art. For example, WO 02/062767 discloses quinazoline derivatives; WO 03/000188 discloses quinazolines and uses thereof; WO 2005/042501 discloses norepinephrine reuptake inhibitors for the treatment of central nervous system disorders; WO2006/058201 discloses heterocyclic and bicyclic compounds, compositions and methods; WO 2007/104560 discloses substituted 4-amino-quinazoline derivatives as regulators of metabotropic glutamate receptors and their use for producing drugs; WO 2007/133773 discloses CDKI pathway inhibitors; WO 2008/009078 discloses 4,6-DL- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections; WO 2009/000085 discloses quinoline and quinazoline derivatives useful as modulators of gated ion channels; US 2009/0143399 discloses protein kinase inhibitors; and Japan Publication Number 2007-084494A discloses substituted bicyclic compounds.
    • SUMMARY OF INVENTION
  • Described herein are compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds to treat a disorder, e.g., schizophrenia or cognitive deficit, in a subject. The compounds disclosed herein include quinoline- and quinazoline-containing compounds that modulate (e.g., inhibit) the activity of STEP.
  • The present invention provides therapeutic compounds, pharmaceutical composition comprising said compounds, use of said compounds and method for treating or preventing a disorder as descried in items 1 to 42 below.
    • Item 1. A compound of formula (I):
  • Figure US20170217923A1-20170803-C00001
      • or a salt thereof,
      • wherein:
      • A is CR4 or N;
      • B is aryl, cyclyl or a 5- or 6-membered heteroaryl;
      • m is 0, 1, 2, 3, 4 or 5;
      • E is aryl or a 5-membered heteroaryl;
      • n is 0, 1, 2, 3 or 4;
      • when E is aryl, n is 0, 1, 2, 3 or 4; and when E is a 5-membered heteroaryl, n is 0, 1, 2 or 3;
      • L is NR5, S, O or a direct bond;
      • one of X and Z is N and the other is CH;
      • p is 0, 1, 2, 3 or 4;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl, silylalkoxy, silylalkoxyalkyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRc(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6;
      • R5 is hydrogen; or when m is not 0, R5 and one R1 may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;
      • each R6 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R7;
      • each R7 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R9;
      • each R9 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • Y is O or S;
      • q is 1 or 2 and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy or silylalkoxyalkyl;
      • wherein when B is phenyl, two R1 are not taken together to form a pyrazole ring; and
      • when B is phenyl, R2 is not
  • Figure US20170217923A1-20170803-C00002
  • a compound of formula (II):
  • Figure US20170217923A1-20170803-C00003
      • or a salt thereof,
      • wherein:
      • L is CR4R5, O, C(O), NR6C(O) or NR7;
      • A is N;
      • each X1, X2, X3, X4 and X5 is independently CH or N, provided that at least two of X1, X2, X3, X4 and X5 are N;
      • n is 0, 1, 2, 3 or 4;
      • p is 0, 1, 2 or 3;
      • R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl or heterocyclylalkyl, each of which is optionally substituted with 1-5 R9; wherein R1 or R9 is optionally taken together with one of R4, R5, R6 or R7, and the atoms to which they are attached, to form a cyclyl, heterocyclyl, aryl or heteroaryl ring that is optionally substituted with 1-3 R10;
      • each R2 and R3 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRc(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf; each of which is optionally substituted with 1-3 R11;
      • each R4, R5, R6 and R7 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each R9, R10 and R11 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12;
      • wherein, two R9, two R10 or two R11 is optionally taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R12 is —ORd;
      • Y is O or S;
      • q is 1 or 2 and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl and
        a compound of formula (III):
  • Figure US20170217923A1-20170803-C00004
  • or a salt thereof,
    wherein:
    • A is CH or N;
  • L is O, a direct bond or NR6;
    one of X1, X2, X3, X4 and X5 is N and the others are CH;
    m is 1, 2 or 3;
    n is 1, 2, 3 or 4;
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl, hydroxyalkyl, heteroaryl, heteroarylalkyl, arylalkyl, —C(Y)Re, cyclyl, cyclylalkyl or heterocyclyl, each of which is optionally substituted with 1-3 R7;
      • R2 is aryl or heteroaryl, each of which is optionally substituted with 1-5 R9;
      • each R3 or R4 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRc(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R10;
      • R6 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11;
      • each R7, R9 and R10 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; wherein two R7, two R9 or two R10 are optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • each R11 and R12 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)Rf, each of which is optionally substituted with 1-3 R13;
      • R13 is independently C1-C8 alkyl, haloalkyl, halo, heterocyclyl, cyclyl, oxo or —C(Y)NRbRb′;
      • Y is independently O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, haloalkyl alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
      • with proviso R9 is not
  • Figure US20170217923A1-20170803-C00005
    • Item 2. The compound according to item 1 represented by general formula (I) or a salt thereof,
      • wherein:
      • A is CR4 or N;
      • B is aryl, cyclyl or a 5- or 6-membered heteroaryl;
      • m is O, 1, 2, 3, 4 or 5;
      • n is 0, 1, 2, 3 or 4;
      • E is aryl or a 5-membered heteroaryl;
      • when E is aryl, n is 0, 1, 2, 3 or 4; and when E is a 5-membered heteroaryl, n is 0, 1, 2 or 3;
      • L is NR5, S, O or a direct bond;
      • one of X and Z is N and the other is CH;
      • p is 0, 1, 2, 3 or 4;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl, silylalkoxy, silylalkoxyalkyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6;
      • R5 is hydrogen; or when m is not 0, R5 and one R1 may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;
      • each R6 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R7;
      • each R7 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)Rf, each of which is optionally substituted with 1-3 R9;
      • each R9 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • Y is O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy or silylalkoxyalkyl;
      • wherein when B is phenyl, two R1 are not taken together to form a pyrazole ring; and
      • when B is phenyl, R is not
  • Figure US20170217923A1-20170803-C00006
    • Item 3. The compound according to item 2 represented by general formula (I) or a salt thereof,
      • wherein:
      • A is CH or N;
      • B is aryl, cyclyl or a 5- or 6-membered heteroaryl;
      • m is 0, 1, 2, 3 or 4;
      • E is aryl or a 5-membered heteroaryl;
      • n is 0, 1 or 2;
      • when E is aryl, n is 0, 1 or 2 and when E is a 5-membered heteroaryl, n is 0 or 1;
      • p is 0, 1 or 2;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRbRb′, —OC(O)NRbRb′, —NRcC(Y)Rc′, —SO2NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • each R6 is independently C1-C8 alkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —ORd or —C(Y)Re, each of which is optionally substituted with 1-3 R7;
      • each R7 is oxo; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, haloalkyl, dialkylaminoalkyl, hydroxyalkyl or alkoxyalkyl.
    • Item 4. The compound according to item 3 represented by general formula (I) or a salt thereof,
      • wherein:
      • B or two R1 and B are taken together to form a group is phenyl, dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl, tetrahydroquinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, quinolyl, isoquinolinyl, tetrahydroquinazolinyl, indolinyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, isoindolinyl, dihydroisobenzofuranyl, benzofuryl, benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, dihydrocyclopentathiophenyl, tetrahydrobenzothiophenyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl or pyridyl;
      • E is phenyl, thienyl or pyrrolyl;
      • when E is phenyl, n is 1 or 2; and when E is thienyl, n is 0 or 1;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkynyl, phenyl, thienyl, pyrrolyl, oxadiazolyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, C3-C8 cycloalkyl, piperidyl, pyrrolidinyl, morpholinyl, dioxolanyl, phenylalkyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperidylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO2, oxo, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —SO2NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6;
        each R6 is independently C1-C8 alkyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, morpholinylalkyl, dialkylaminoalkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —NRcC(Y)Rc′, —C(Y)NRbRb′, —NRbRb′, alkoxyalkyl, —ORd or —C(Y)Re; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, phenyl, pyridyl, dihydroindenyl, morpholinyl, tetrahydropyranyl, piperidyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, phenylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl, hydroxyalkyl, thiazolylalkyl, pyrazolylalkyl, morpholinylalkyl, pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl, benzodioxolylalkyl, dihydrobenzodioxinylalkyl, benzothienylalkyl, C3-C8 cycloalkylalkyl, oxazolidinylalkyl, haloalkyl or alkoxyalkyl.
    • Item 5. The compound according to item 3 represented by general formula (I) or a salt thereof,
      • wherein:
      • B or two R1 and B are taken together to form a group is phenyl, dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl, tetrahydroquinoxalinyl, tetrahydroisoquinolyl, tetrahydroquinolinyl, dihydroquinolyl, quinolyl, isoquinolyl, tetrahydroquinazolinyl, indolinyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, isoindolinyl, dihydroisobenzofuranyl, benzofuryl, benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, dihydrocyclopentathiophenyl, tetrahydrobenzothienyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl or pyridyl;
      • E is phenyl, thienyl or pyrrolyl;
      • when E is phenyl, n is 0, 1 or 2; and when E is thienyl, n is 0 or 1;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkynyl, phenyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C3-C8 cycloalkyl, piperidyl, pyrrolidinyl, morpholinyl, dioxolanyl, phenylalkyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperidylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO2, oxo, —C(O)ORa, —C(Y)NRbRb′, —NRbRb′, —NRcC(Y)Rc′, —OC(O)NRbRb′, —SO2NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6;
      • each R6 is independently C1-C8 alkyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, morpholinylalkyl, dialkylaminoalkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —NRcC(Y)Rc′, —C(Y)NRbRb′, —NRbRb′, alkoxyalkyl, —ORd or —C(Y)Re, each of which is optionally substituted with 1-3 R7;
      • R7 is oxo; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, phenyl, pyridyl, dihydroindenyl, morpholinyl, tetrahydropyranyl, piperidyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, phenylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl, hydroxyalkyl, thiazolylalkyl, pyrazolylalkyl, morpholinylalkyl, pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl, benzodioxolilalkyl, dihydrobenzodioxinylalkyl, benzothienylalkyl, C3-C8 cycloalkylalkyl, oxazolidinylalkyl, haloalkyl, or alkoxyalkyl.
    • Item 6. The compound according to item 5 represented by general formula (I) or a salt thereof,
      • wherein:
      • R1 is C1-C8 alkyl, phenyl, thienyl, pyrrolyl, oxazolyl, C3-C8 cycloalkyl, dioxolanyl, phenylalkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —SO2NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6;
      • R2 is C1-C8 alkyl, C2-C8 alkynyl, phenyl, thienyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C3-C8 cycloalkyl, pyrrolidinyl, morpholinyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperiridylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRbRb′, —OC(O)NRbRb′, —ORd or —C(Y)Re, each of which is optionally substituted with 1-3 R6;
      • R3 is C1-C8 alkyl, halo, haloalkyl, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R6.
    • Item 7. The compound according to item 4 or 6 represented by general formula (I) or a salt thereof,
      • wherein:
      • R1 is C1-C8 alkyl, phenyl, thienyl, pyrrolyl, oxazolyl, C3-C8 cycloalkyl, dioxolanyl, phenylalkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —SO2NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • R2 is C1-C8 alkyl, C2-C8 alkynyl, phenyl, thienyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C3-C8 cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperiridinylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRbRb′, —OC(O)NRbRb′, —ORd, —C(Y)Re or —S(O)qRf;
      • R3 is C1-C8 alkyl, halo, haloalkyl, —NRbRb′ or —ORd.
    • Item 8. The compound according to item 7 represented by general formula (I) or a salt thereof,
      • wherein:
      • B or two R1 and B are taken together to form a group is phenyl, dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl, tetrahydroisoquinolyl, tetrahydroquinolinyl, dihydroquinolyl, quinolyl, tetrahydroquinazolinyl, indolinyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, isoindolinyl, benzofuryl, benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, tetrahydrobenzothienyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, thiadiazolyl or pyridyl;
      • m is 1, 2, 3 or 4;
        R1 is C1-C8 alkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —SO2NRbRb′, —ORd, or —S(O)qRf;
      • R2 is C1-C8 alkyl, C3-C8 cycloalkyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRbRb′, —ORd, —C(Y)Re or —S(O)qRf;
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, phenyl, dihydroindenyl, morpholinyl, tetrahydropyranyl, piperidyl, pyrrolidinyl, thiomorpholinyl, phenylalkyl, thienylalkyl, pyridylalkyl, tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl, hydroxyalkyl, morpholinylalkyl, pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl, benzodioxolilalkyl, dihydrobenzodioxinylalkyl, C3-C8 cycloalkylalkyl, haloalkyl or alkoxyalkyl.
    • Item 9. The compound according to item 1 represented by general formula (II) or a salt thereof,
      • wherein:
      • L is CR4R5, O, C(O), NR6C(O) or NR7;
      • A is N;
      • each X1, X2, X3, X4 and X5 is independently CH or N, provided that at least two of X1, X2, X3, X4 and X5 are N;
      • n is 0, 1, 2, 3 or 4;
      • p is 0, 1, 2 or 3;
      • R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl or heterocyclylalkyl, each of which is optionally substituted with 1-5 R9; wherein R1 or R9 is optionally taken together with one of R4, R5, R6 or R7, and the atoms to which they are attached to form a cyclyl, heterocyclyl, aryl or heteroaryl ring that is optionally substituted with 1-3 R10;
      • each R2 and R3 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R11;
      • each R4, R5, R6 and R7 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each R9, R10 and R11 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; wherein two R8, two R9, two R10 or two R11 is optionally taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R12 is —ORd;
      • Y is O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, arylalkyl, or heteroarylalkyl.
    • Item 10. The compound according to item 9 represented by general formula (II) or a salt thereof,
      • L is NR7;
      • n is 0, 1 or 2;
      • p is 0;
      • R1 is C1-C8 alkyl, aryl or heteroaryl;
      • each R2 and R3 is independently hydrogen, C1-C8 alkyl, aryl, halo, heterocyclylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R11;
      • R7 is hydrogen; and
      • each R9, R10 and R11 is independently C1-C8 alkyl, heterocyclyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)ORa, —C(Y)NRbRb′, —ORd or —C(Y)Re; Y is O;
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, cyclyl, heterocyclyl, aryl, or heteroaryl.
    • Item 11. The compound according to item 10 represented by general formula (II) or a salt thereof,
      • wherein:
      • R1 is C1-C8 alkyl, phenyl or benzodioxolyl;
      • each R2 and R3 is independently hydrogen, C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd;
      • R9 is independently C1-C8 alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)ORa, —C(Y)NRbRb′, —ORd or —C(Y)Re; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, tetrahydropyranyl, phenyl, or pyridyl.
    • Item 12. The compound according to item 10 represented by general formula (II) or a salt thereof,
      • wherein:
      • R1 is C1-C8 alkyl, phenyl or benzodioxolyl;
      • each R2 and R3 is independently hydrogen, C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R11;
      • each R9, R10 and R11 is independently C1-C8 alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)ORa, —C(Y)NRbRb′, —ORd or —C(Y)Re; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′, and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, tetrahydropyranyl, phenyl, or pyridyl.
    • Item 13. The compound according to item 12 represented by general formula (II) or a salt thereof, wherein:
      • R2 is C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R11;
      • R3 is hydrogen;
      • R9 is halo, haloalkoxy, —CN, —C(O)ORa or —C(Y)NRbRb′; and
      • R11 is C1-C8 alkyl, morpholinyl, tetrahydropyranyl, halo, —CN, —ORd or —C(Y)Re;
    • Item 14. The compound according to item 11 or 13 represented by general formula (II) or a salt thereof, wherein:
      • R2 is C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd;
      • R3 is hydrogen; and
      • R9 is halo, haloalkoxy, —CN, —C(O)ORa or —C(Y)NRbRb′.
    • Item 15. The compound according to item 1 represented by general formula (III) or a salt thereof,
      • wherein:
      • A is CH or N;
      • L is O, a direct bond or NH;
      • one of X1, X2, X3, X4 and X5 is N and the others are CH;
      • m is 1, 2 or 3;
      • n is 1, 2, 3 or 4;
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl, hydroxyalkyl, heteroaryl, heteroarylalkyl, arylalkyl, —C(Y)Re, cyclyl, cyclylalkyl or heterocyclyl, each of which is optionally substituted with 1-3 R7;
      • R2 is aryl or heteroaryl, each of which is optionally substituted with 1-5 R9;
      • each R3 or R4 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R10;
      • each R7, R9 and R10 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; wherein two R7 or two R9 are optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R12 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R13;
      • R13 is independently C1-C8 alkyl, haloalkyl, halo, heterocyclyl, cyclyl, oxo or —C(Y)NRbRb′;
      • Y is O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cyclylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl.
    • Item 16. The compound according to item 15 represented by general formula (III) or a salt thereof,
      • wherein:
      • m is 1;
      • n is 1;
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, heteroaryl, heterocyclyl, arylalkyl, cyclylalkyl, heteroarylalkyl, alkoxyalkyl, hydroxyalkyl or —C(O)Re, each of which is optionally substituted with 1-3 R7;
      • R2 is aryl, heteroaryl or benzofuryl, each of which is optionally substituted with 1-5 R9;
      • each R3 or R4 is independently hydrogen, C1-C8 alkyl, halo, haloalkyl or —ORd;
      • R6 is hydrogen or C1-C8 alkyl;
      • each R7 and R9 is independently C1-C8 alkyl, aryl, heteroaryl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —C(O)NRbRb′, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12;
      • R12 is independently C1-C8 alkyl, oxo, halo, haloalkyl, —CN, —C(O)NRbRb′ or —C(O)Re each of which is optionally substituted with 1-3 R13;
      • R13 is independently C1-C8 alkyl, halo or heterocyclyl; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, cyclyl, heterocyclyl, arylalkyl, alkoxyalkyl, heterocyclylalkyl, heteroarylalkyl, alkylaminoalkyl, dialkylaminoalkyl or phenyl.
    • Item 17. The compound according to Item 16 represented by general formula (III) or a salt thereof,
      • wherein:
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl, hydroxyalkyl, imidazolyl, pyridylalkyl, phenylalkyl, oxazolylalkyl, thienylalkyl, thiazolidinyl isoindolyl, —C(O)Re, dihydroindenyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-3 R7;
      • R2 is phenyl, naphthyl, benzofuryl, indazolyl, benzothienyl, pyridyl, pyrimidinyl, dihydrobenzodioxinyl, benzodioxolyl, benzoimidazolyl, isoxazolyl, pyrazolyl, indolinyl or benzoisoxazolyl, each of which is optionally substituted with 1-5 R9;
      • each R3 or R4 is independently hydrogen, C1-C8 alkyl, halo, haloalkyl or —ORd;
      • R6 is hydrogen or C1-C8 alkyl;
        each R7 and R9 is independently C1-C8 alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —C(O)NRbRb′, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl, alkoxyalkyl, morholinylalkyl, oxazolidinylalkyl, imidazolylalkyl, tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl, thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl, dihydrobenzoxazinylalkyl, tetrahydrofurylalkyl, tetrahydrofuryl, alkylaminoalkyl, dialkylaminoalkyl or phenyl.
    • Item 18. The compound according to item 16 represented by general formula (III) or a salt thereof,
      • wherein:
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl, hydroxyalkyl, imidazolyl, furylalkyl, pyridylalkyl, phenylalkyl, oxazolylalkyl, thienylalkyl, thiazolidinyl, isoindolyl, —C(O)Re, dihydroindenyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-3 R7;
      • R2 is phenyl, naphthyl, benzofuryl, indazolyl, benzothienyl, pyridyl, pyrimidinyl, dihydrobenzodioxinyl, benzodioxolyl, benzoimidazolyl, isoxazolyl, pyrazolyl, indolinyl or benzisoxazolyl, each of which is optionally substituted with 1-5 R9;
      • each R3 or R4 is independently hydrogen, C1-C8 alkyl, halo, haloalkyl or —ORd;
      • R6 is hydrogen or C1-C8 alkyl;
      • each R7 and R9 is independently C1-C8 alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —C(O)NRbRb′, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12;
      • R12 is independently C1-C8 alkyl, oxo, halo, haloalkyl, —CN, —C(O)NRbRb′ or —C(O)Re, each of which is optionally substituted with 1-3 R13;
        R13 is independently C1-C8 alkyl, halo or pyrrolidinyl; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl, alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl, tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl, thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl, dihydrobenzoxazinylalkyl, tetrahydrofurylalkyl, tetrahydrofuryl, alkylaminoalkyl, dialkylaminoalkyl or phenyl.
    • Item 19. The compound according to item 18 represented by general formula (III) or a salt thereof,
      • wherein:
      • A is N;
      • R3 is hydrogen, C1-C8 alkyl, halo, haloalkyl, or —ORd;
      • R4 is hydrogen, C1-C8 alkyl, halo, or —ORd;
      • R7 is C1-C8 alkyl, phenyl, halo, haloalkyl, oxo, —C(O)ORa, —C(O)NRbRb′ or —ORd each of which is optionally substituted with 1-3 R12;
      • R9 is C1-C8 alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, —CN, —NO2, —C(O)NRbRb′, —C(O)ORa, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl, alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl, tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl, thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl, tetrahydrofurylalkyl, dihydrobenzoxazinylalkyl, tetrahydrofuryl, alkylaminoalkyl, dialkylaminoalkyl or phenyl.
    • Item 20. The compound according to item 17 or 19 represented by general formula (III) or a salt thereof,
      • wherein:
      • A is N;
      • R3 is hydrogen, C1-C8 alkyl, halo, haloalkyl, or —ORd;
      • R4 is hydrogen, C1-C8 alkyl, halo, or —ORd;
      • R7 is C1-C8 alkyl, phenyl, halo, haloalkyl, oxo, —C(O)ORa, —C(O)NRbRb′ or —ORd;
      • R9 is C1-C8 alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, —CN, —NO2, —C(O)NRbRb′, —C(O)ORa, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl, alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl, tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl, thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl, tetrahydrofurylalkyl, tetrahydrofuryl, dihydrobenzoxazinylalkyl, alkylaminoalkyl, dialkylaminoalkyl or phenyl.
    • Item 21. The compound according to item 20 represented by general formula (III) or a salt thereof,
      • wherein:
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl, hydroxyalkyl, imidazolyl, furylalkyl, pyridylalkyl, phenylalkyl, oxazolylalkyl, thienylalkyl, isoindolyl, —C(O)Re, dihydroindenyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-3 R7;
      • R2 is phenyl, which is optionally substituted with 1-5 R9; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, alkoxyalkyl, morpholinylalkyl, tetrahydropyranylalkyl, pyridylalkyl, thiazolylalkyl, pyrrolylalkyl, tetrahydrofuryl, alkylaminoalkyl or phenyl.
    • Item 22. A pharmaceutical composition comprising the compound according to any one of items 1 to 21 or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
    • Item 23. The pharmaceutical composition according to item 22 for preventing or treating central nervous system diseases.
    • Item 24. The pharmaceutical composition according to item 23 for treating or preventing central nervous system disorders selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type disorder; depression; endogenous depression; major depression; melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorder; adjustment disorder; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism; anhedonia; iatrogenic anhedonia; anhedonia of a psychic or mental cause; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease; Parkinson's disease and associated neurodegenerative diseases; cognitive impairment of schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain (ache); mental retardation; autism disorder (autism); Tourette's disorder; tic disorder; attention-deficit/hyperactivity disorder; conduct disorder; and Down's syndrome.
    • Item 25. A process for producing a pharmaceutical composition comprising mixing a compound of the formula (I), (II), or (III) or a salt thereof according to any one of items 1 to 21 with a pharmaceutically acceptable carrier.
    • Item 26. Use of a compound of the formula (I), (II) or (III) or a salt thereof according to any one of items 1 to 21 as a drug.
    • Item 27. Use of the compound according to any one of items 1 to 21 represented by general formula (I), (II) or (III) or a salt thereof as a STEP inhibitor.
    • Item 28. A method of treating a disorder that would benefit by the modulation of STEP (e.g., by activation of inhibition of STEP) in a subject, the method comprising administering to a compound of formula (I), (II) or (III) or a salt thereof according to any one of items 1 to 21.
    • Item 29. The method of item 28, wherein the disorder is schizophrenia.
    • Item 30. The method of item 28, wherein the disorder is cognitive deficit.
    • Item 31. The method of item 28, wherein the compound of formula (I), (II), or (III) is administered in combination with an additional therapeutic agent.
    • Item 32. The method of item 28, wherein the additional therapeutic agent is an atypical antipsychotic.
    • Item 33. The method of item 28, wherein the additional therapeutic agent is selected from the group consisting of aripiprazole, clozapine, ziprasidone, risperidone, quetiapine, olanzapine, amisulpride, asenapine, iloperidone, melperone, paliperidone, perospirone, sertindole and sulpiride.
    • Item 34. The method of item 28, wherein the additional therapeutic agent is a typical antipsychotic.
    • Item 35. The method of item 28, wherein the additional therapeutic agent is selected from the group consisting of haloperidol, molindone, loxapine, thioridazine, molindone, thiothixene, pimozide, fluphenazine, trifluoperazine, mesoridazine, chlorprothixene, chlorpromazine, perphenazine, triflupromazine and zuclopenthixol.
    • Item 36. A kit comprising a composition comprising a compound of formula (I), (II), or (III) or a salt thereof according to any one of items 1 to 21 and an acceptable carrier.
    • Item 37. A kit comprising a pharmaceutical composition comprising a compound of formula (I), (II), or (III) or a salt thereof according to any one of items 1 to 21 and a pharmaceutically acceptable carrier.
    • Item 38. A compound of formula (IV):
  • Figure US20170217923A1-20170803-C00007
      • wherein:
      • A is CH, CR4 or N;
      • B is aryl or a 5- or 6-membered heteroaryl;
      • m is 0, 1, 2, 3, 4 or 5;
      • E is aryl or a 5-membered heteroaryl;
      • when E is aryl, n is 1, 2, 3 or 4; and when E is a 5-membered heteroaryl, n is 0, 1, 2 or 3;
      • L is NR5 or O;
      • one of X and Z is N and the other is CH;
      • p is 0, 1, 2, 3 or 4;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRc(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6;
      • R5 is hydrogen; or when m is not 0, R5 and 1 R1 may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;
      • each R6 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R7;
      • each R7 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each Y is independently O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy and silylalkoxyalkyl, each of which may be optionally substituted with 1-3 R6, wherein Rb and Rb′, together with the atoms to which they are attached, may form an optionally substituted cyclyl or heterocyclyl ring;
      • or a pharmaceutically acceptable derivative or prodrug thereof,
      • wherein when B is phenyl, two R1 are not taken together to form a pyrazole ring;
      • when B is phenyl, R2 is not
  • Figure US20170217923A1-20170803-C00008
      • and where in the compound is not:
  • Figure US20170217923A1-20170803-C00009
    • Item 39. A compound of formula (IV):
  • Figure US20170217923A1-20170803-C00010
      • wherein:
      • A is CH, CR4 or N;
      • B is aryl or a 5-membered heteroaryl;
      • E is aryl or a 5-membered heteroaryl;
      • L is NR5 or O;
      • one of X and Z is N and the other is CH;
      • m is 0, 1, 2, 3, 4 or 5;
      • n is 1, 2, 3 or 4;
      • p is 0, 1, 2, 3 or 4;
      • each R1 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, or aryl ring;
      • each R2 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRc(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6; wherein two R1, together with the carbons to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6;
      • R5 is hydrogen; or when m is not 0, R5 and 1 R1 may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;
      • each R6 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRc(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R7;
      • each R7 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • Y is O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of which may be optionally further substituted with 1-3 R6, wherein Rb and Rb′, together with the atoms to which they are attached, may form an optionally substituted cyclyl or heterocyclyl ring;
      • wherein when B is phenyl, two R1 are not taken together to form a pyrazole ring; and
      • when B is phenyl, R2 is not
  • Figure US20170217923A1-20170803-C00011
    • Item 40. A compound of formula (V):
  • Figure US20170217923A1-20170803-C00012
      • wherein:
      • L is CR4R5, O, C(O), NR6C(O), or NR7;
      • A is CR8, CH or N;
      • each X1, X2, X3, X4 and X5 is independently CH or N, provided that at least two of X1, X2, X3, X4 and X5 are N;
      • n is 0, 1, 2, 3 or 4;
      • p is 0, 1, 2 or 3;
      • R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl or heterocyclylalkyl, each of which may be optionally substituted with 1-5 R9; wherein R1 or R9 may optionally be taken together with one of R4, R5, R6 or R7, and the atoms to which they are attached, to form a cyclyl, heterocyclyl, aryl or heteroaryl ring that is optionally substituted with 1-3 R10;
      • each R2 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRc(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf; each of which is optionally substituted with 1-3 R11;
      • each R4, R5, R6 and R7 is independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each R8, R9, R10 and R11 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally further substituted; wherein two R8, two R9, two R10 or two R11 may optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • each Y is independently O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of which may be optionally substituted with 1-3 R8,
      • or a pharmaceutically acceptable derivative or prodrug thereof.
    • Item 41. A compound of formula (VI):
  • Figure US20170217923A1-20170803-C00013
      • wherein:
      • A is CR5, CH or N;
      • L is O or NR6;
      • 1, 2 or 3 of X1, X2, X3, X4 and X5 are N and the others are CH;
      • m is 0, 1, 2 or 3;
      • n is 0, 1, 2, 3 or 4;
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R7; or when L is NR6, R1 or R7 may be taken together with R6 and the atoms to which they are attached to form a heterocyclyl or heteroaryl ring that is optionally substituted with 1-3 R8;
      • R2 is aryl or heteroaryl, each of which is optionally substituted with 1-5 R9;
      • each R3, R4 and R5 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R10;
      • R6 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11;
      • each R7, R8, R9 and R10 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; wherein two R7, two R8, two R9 or two R10 may optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • each R11 and R12 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each Y is independently O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of which may be optionally substituted with 1-3 R7;
      • or a pharmaceutically acceptable derivative or prodrug thereof,
      • wherein when R1 is cyclopropyl, R9 is not:
  • Figure US20170217923A1-20170803-C00014
    • Item 42. A compound of formula (VI):
  • Figure US20170217923A1-20170803-C00015
      • wherein:
      • A is CR5, CH or N;
      • L is O or NR6;
      • 1, 2 or 3 of X1, X2, X3, X4 and X5 are N and the others are CH;
      • m is 0, 1, 2 or 3;
      • n is 0, 1, 2, 3 or 4;
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R7; or when L is NR6, R1 or R7 may be taken together with R6 and the atoms to which they are attached to form a heterocyclyl or heteroaryl ring that is optionally substituted with 1-3 R8;
      • R2 is aryl or heteroaryl, each of which is optionally substituted with 1-5 R9;
      • each R3, R4 and R5 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R10;
      • R6 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11;
      • each R7, R8, R9 and R10 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; wherein two R7, two R8, two R9 or two R10 may optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • each R11 and R12 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each Y is independently O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of which may be optionally substituted with 1-3 R7;
      • wherein R9 is not:
  • Figure US20170217923A1-20170803-C00016
    • Compounds of Formula (I)
  • The following aspects and embodiments relate to compounds of formula (I).
    • Item 2. The compound according to item 1 represented by general formula (I) or a salt thereof,
      • wherein:
      • A is CR4 or N;
      • B is aryl, cyclyl or a 5- or 6-membered heteroaryl;
      • m is 0, 1, 2, 3, 4 or 5;
      • n is 0, 1, 2, 3 or 4;
      • E is aryl or a 5-membered heteroaryl;
      • when E is aryl, n is 0, 1, 2, 3 or 4; and when E is a 5-membered heteroaryl, n is 0, 1, 2 or 3;
      • L is NR5, S, O or a direct bond;
      • one of X and Z is N and the other is CH;
      • p is 0, 1, 2, 3 or 4;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl, silylalkoxy, silylalkoxyalkyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6;
      • R5 is hydrogen; or when m is not 0, R5 and one R1 may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;
      • each R6 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R7;
      • each R7 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)Rf, each of which is optionally substituted with 1-3 R9;
      • each R9 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • Y is O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy or silylalkoxyalkyl;
      • wherein when B is phenyl, two R1 are not taken together to form a pyrazole ring; and
      • when B is phenyl, R2 is not
  • Figure US20170217923A1-20170803-C00017
    • Item 3. The compound according to item 2 represented by general formula (I) or a salt thereof,
      • wherein:
      • A is CH or N;
      • B is aryl, cyclyl or a 5- or 6-membered heteroaryl;
      • m is 0, 1, 2, 3 or 4;
      • E is aryl or a 5-membered heteroaryl;
      • n is 0, 1 or 2;
      • when E is aryl, n is 0, 1 or 2 and when E is a 5-membered heteroaryl, n is 0 or 1;
      • p is 0, 1 or 2;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRbRb′, —OC(O)NRbRb′, —NRcC(Y)Rc′, —SO2NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • each R6 is independently C1-C8 alkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —ORd or —C(Y)Re, each of which is optionally substituted with 1-3 R7;
      • each R7 is oxo; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, haloalkyl, dialkylaminoalkyl, hydroxyalkyl or alkoxyalkyl.
    • Item 4. The compound according to item 3 represented by general formula (I) or a salt thereof,
      • wherein:
      • B or two R1 and B are taken together to form a group is phenyl, dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl, tetrahydroquinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, quinolyl, isoquinolinyl, tetrahydroquinazolinyl, indolinyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, isoindolinyl, dihydroisobenzofuranyl, benzofuryl, benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, dihydrocyclopentathiophenyl, tetrahydrobenzothiophenyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl or pyridyl;
      • E is phenyl, thienyl or pyrrolyl;
      • when E is phenyl, n is 1 or 2; and when E is thienyl, n is 0 or 1;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkynyl, phenyl, thienyl, pyrrolyl, oxadiazolyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, C3-C8 cycloalkyl, piperidyl, pyrrolidinyl, morpholinyl, dioxolanyl, phenylalkyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperidylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO2, oxo, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —SO2NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6;
        each R6 is independently C1-C8 alkyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, morpholinylalkyl, dialkylaminoalkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —NRcC(Y)Rc′, —C(Y)NRbRb′, —NRbRb′, alkoxyalkyl, —ORd or —C(Y)Re; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, phenyl, pyridyl, dihydroindenyl, morpholinyl, tetrahydropyranyl, piperidyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, phenylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl, hydroxyalkyl, thiazolylalkyl, pyrazolylalkyl, morpholinylalkyl, pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl, benzodioxolylalkyl, dihydrobenzodioxinylalkyl, benzothienylalkyl, C3-C8 cycloalkylalkyl, oxazolidinylalkyl, haloalkyl, or alkoxyalkyl.
    • Item 5. The compound according to item 3 represented by general formula (I) or a salt thereof,
      • wherein:
      • B or two R1 and B are taken together to form a group is phenyl, dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl, tetrahydroquinoxalinyl, tetrahydroisoquinolyl, tetrahydroquinolinyl, dihydroquinolyl, quinolyl, isoquinolyl, tetrahydroquinazolinyl, indolinyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, isoindolinyl, dihydroisobenzofuranyl, benzofuryl, benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, dihydrocyclopentathiophenyl, tetrahydrobenzothienyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyrrolyl or pyridyl;
      • E is phenyl, thienyl or pyrrolyl;
      • when E is phenyl, n is 0, 1 or 2; and when E is thienyl, n is 0 or 1;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkynyl, phenyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C3-C8 cycloalkyl, piperidyl, pyrrolidinyl, morpholinyl, dioxolanyl, phenylalkyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperidylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO2, oxo, —C(O)ORa, —C(Y)NRbRb′, —NRbRb′, —NRcC(Y)Rc′, —OC(O)NRbRb′, —SO2NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6;
      • each R6 is independently C1-C8 alkyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, morpholinylalkyl, dialkylaminoalkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —NRcC(Y)Rc′, —C(Y)NRbRb′, —NRbRb′, alkoxyalkyl, —ORd or —C(Y)Re, each of which is optionally substituted with 1-3 R7;
      • R7 is oxo; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, phenyl, pyridyl, dihydroindenyl, morpholinyl, tetrahydropyranyl, piperidyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, phenylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl, hydroxyalkyl, thiazolylalkyl, pyrazolylalkyl, morpholinylalkyl, pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl, benzodioxolilalkyl, dihydrobenzodioxinylalkyl, benzothienylalkyl, C3-C8 cycloalkylalkyl, oxazolidinylalkyl, haloalkyl, or alkoxyalkyl.
    • Item 6. The compound according to item 5 represented by general formula (I) or a salt thereof,
      • wherein:
      • R1 is C1-C8 alkyl, phenyl, thienyl, pyrrolyl, oxazolyl, C3-C8 cycloalkyl, dioxolanyl, phenylalkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —SO2NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R6;
      • R2 is C1-C8 alkyl, C2-C8 alkynyl, phenyl, thienyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C3-C8 cycloalkyl, pyrrolidinyl, morpholinyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperiridylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRbRb′, —OC(O)NRbRb′, —ORd or —C(Y)Re, each of which is optionally substituted with 1-3 R6;
      • R3 is C1-C8 alkyl, halo, haloalkyl, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R6.
    • Item 7. The compound according to item 4 or 6 represented by general formula (I) or a salt thereof,
      • wherein:
      • R1 is C1-C8 alkyl, phenyl, thienyl, pyrrolyl, oxazolyl, C3-C8 cycloalkyl, dioxolanyl, phenylalkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —SO2NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • R2 is C1-C8 alkyl, C2-C8 alkynyl, phenyl, thienyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C3-C8 cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperiridinylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRbRb′, —OC(O)NRbRb′, —ORd, —C(Y)Re or —S(O)qRf;
      • R3 is C1-C8 alkyl, halo, haloalkyl, —NRbRb′ or —ORd.
    • Item 8. The compound according to item 7 represented by general formula (I) or a salt thereof,
      • wherein:
      • B or two R1 and B are taken together to form a group is phenyl, dihydroindenyl, dihydrobenzoxazinyl, dihydrobenzodioxinyl, chromenyl, tetrahydroisoquinolyl, tetrahydroquinolinyl, dihydroquinolyl, quinolyl, tetrahydroquinazolinyl, indolinyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, isoindolinyl, benzofuryl, benzothienyl, benzodioxolyl, indolyl, indazolyl, benzoimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, tetrahydrobenzothienyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, thiadiazolyl or pyridyl;
      • m is 1, 2, 3 or 4;
      • R1 is C1-C8 alkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —SO2NRbRb′, —ORd, or —S(O)qRf;
      • R2 is C1-C8 alkyl, C3-C8 cycloalkyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRbRb′, —ORd, —C(Y)Re or —S(O)qRf;
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, phenyl, dihydroindenyl, morpholinyl, tetrahydropyranyl, piperidyl, pyrrolidinyl, thiomorpholinyl, phenylalkyl, thienylalkyl, pyridylalkyl, tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl, hydroxyalkyl, morpholinylalkyl, pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl, benzodioxolilalkyl, dihydrobenzodioxinylalkyl, C3-C8 cycloalkylalkyl, haloalkyl or alkoxyalkyl.
  • In some embodiments, A is N. In some embodiments, A is CH. In some embodiments, A is CR4.
  • In some embodiments, B is aryl (e.g., phenyl).
  • In some embodiments, m is 0.
  • In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.
  • In some embodiments, R1 is in the ortho position. In some embodiments, R1 is in the meta position. In some embodiments, R1 is in the para position.
  • In some embodiments, R1 is C1-C8 alkyl (e.g., methyl or tert-butyl). In some embodiments, R1 is heteroaryl (e.g., oxazolyl, oxadiazolyl or quinazolinyl).
  • In some embodiments, R1 is heteroaryl substituted with 1-3 R6 (e.g., 1 R6).
  • In some embodiments, R1 is oxadiazolyl substituted with 1 R6. some embodiments, R6 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R1 is heteroaryl substituted with 2 R6. In some embodiments, R1 is quinazolinyl substituted with 2 R6. In some embodiments, one R6 is halo (e.g., bromo) and the other is heteroaryl (e.g., pyridyl).
  • In some embodiments, m is 1 and R1 is halo (e.g., fluoro, chloro or bromo). In some embodiments, m is 2 and each R1 is halo (e.g., fluoro, chloro or bromo). In some embodiments, m is 3 and each R1 is halo (e.g., fluoro, chloro or bromo). In some embodiments, R1 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R1 is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).
  • In some embodiments, R1 is haloalkoxy substituted with 1 R6. In some embodiments, R1 is —O—CF2—R6. In some embodiments, R6 is —C(Y)NRbRb′. In some embodiments, Y is O, Rb is hydrogen and Rb′ is C1-C8 alkyl (e.g., methyl). In some embodiments, R1 is —O—CF2—CH2—R6. In some embodiments, R6 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R6 is —NRbRb′. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, R6 is heterocyclyl (e.g., morpholino).
  • In some embodiments, R1 is aminoalkyl. In some embodiments, R1 is —CH2NH2. In some embodiments, R1 is alkylaminoalkyl. In some embodiments, R1 is —CH2NHCH2CH2CH3. In some embodiments, R1 is dialkylaminoalkyl. In some embodiments, R1 is —CH2N(CH(CH3)2)2.
  • In some embodiments, R1 is hydroxyalkyl. In some embodiments, R1 is —CH2OH.
  • In some embodiments, R1 is —CN.
  • In some embodiments, R1 is —NO2.
  • In some embodiments, R1 is —C(O)ORa. In some embodiments, Ra is hydrogen. In some embodiments, Ra is C1-C8 alkyl (e.g., methyl or ethyl).
  • In some embodiments, R1 is —NRcC(Y)Rc′. In some embodiments, one of Rc and Rc′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R1 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl or ethyl).
  • In some embodiments, R1 is —SO2NRbRb′. In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, R1 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is C1-C8 alkyl (e.g., methyl). In some embodiments, Re is heterocyclyl (e.g., pyrrolidinyl, piperidinyl or morpholino).
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, Y is S. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rb is hydrogen. In some embodiments, Rb is hydrogen and Rb′ is aralkyl. In some embodiments, Rb is hydrogen and Rb′ is optionally substituted benzyl. In some embodiments, Rb′ is C1-C8 alkyl, e.g., methyl, ethyl, C3 alkyl (e.g., n-propyl or isopropyl), C4 alkyl (e.g., n-butyl, sec-butyl or tert-butyl), C5 alkyl (e.g., n-pentyl, isopentyl or pentan-3-yl), C6 alkyl (e.g., n-hexyl or 3,3-dimethylbutan-2-yl), or C7 alkyl (e.g., n-heptyl or 2-heptyl).
  • In some embodiments, Rb′ is bicyclyl (e.g., indanyl). In some embodiments, Rb′ is heterocyclyl, e.g., a 6-membered heterocyclyl. In some embodiments, Rb′ is a 6-membered oxygen-containing heterocyclyl (e.g., tetrahydropyranyl). In some embodiments, Rb′ is a 6-membered nitrogen-containing heterocyclyl (e.g., piperidinyl).
  • In some embodiments, Rb′ is aralkyl. In some embodiments, the alkyl is a C1-C8 alkyl (e.g., C1, C2, C3 or C4 alkyl). In some embodiments, the alkyl is a straight-chain alkyl. In some embodiments, the alkyl is a branched alkyl. In some embodiments, the aryl is phenyl. In some embodiments, Rb′ is benzyl. In some embodiments, Rb′ is phenylethyl.
  • In some embodiments, Rb′ is heteroaralkyl. In some embodiments, the alkyl is a C1-C8 alkyl (e.g., C1, C2 or C3 alkyl). In some embodiments, the alkyl is a straight-chain alkyl. In some embodiments, the alkyl is a branched alkyl. In some embodiments, the heteroaryl is pyridyl. In some embodiments, the heteroaryl is furanyl. In some embodiments, the heteroaryl is thiazolyl. In some embodiments, the heteroaryl is thienyl.
  • In some embodiments, Rb′ is cyclylalkyl. In some embodiments, the alkyl is a C1-C8 alkyl (e.g., C1 alkyl). In some embodiments, the cyclyl group is cyclopropyl. In some embodiments, the cyclyl group is cyclopentyl. In some embodiments, the cyclyl group is a bicyclic group. In some embodiments, the bicyclic group is indanyl. In some embodiments, Rb′ is heterocyclylalkyl. In some embodiments, the alkyl is a C1-C8 alkyl (e.g., C1 alkyl). In some embodiments, the heterocyclyl group is tetrahydropyranyl.
  • In some embodiments, Rb′ is haloalkyl (e.g., fluoroethyl, difluoroethyl, trifluoroethyl or trifluoropropyl).
  • In some embodiments, Rb′ is alkoxyalkyl. In some embodiments, the alkyl is a C1-C8 alkyl (e.g., C1, C2, C3 or C4 alkyl). In some embodiments, the alkyl is a straight-chain alkyl. In some embodiments, the alkyl is a branched alkyl. In some embodiments, the alkoxy is methoxy.
  • In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl, both ethyl, or both isopropyl).
  • In some embodiments, two R1 and B are taken together to form a bicyclic heteroaryl or heterocyclic ring.
  • In some embodiments, two R1 and B are taken together to form
  • Figure US20170217923A1-20170803-C00018
  • In some embodiments, R1 is halo. In some embodiments, R1 is at the 6, 7, or 8 position.
  • In some embodiments, two R1 and B are taken together to form a group selected from:
  • Figure US20170217923A1-20170803-C00019
  • In some embodiments, R2 is aryl.
  • In some embodiments, each R1 is independently C1-C8 alkyl (e.g., each R1 is methyl). In some embodiments, each R1 is independently halo (e.g., each R1 is fluoro or each R1 is chloro). In some embodiments, one R1 is fluoro and the other is chloro. In some embodiments, one R1 is chloro and the other is bromo.
  • In some embodiments, each R1 is independently —ORd. In some embodiments, each Rd is independently C1-C8 alkyl (e.g., each Rd is methyl).
  • In some embodiments, one R1 is halo (e.g., chloro) and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, one R1 is halo (e.g., fluoro) and the other is heterocyclylalkyl (e.g., —CH2-heterocyclyl). In some embodiments, the heterocyclyl is morpholino. In some embodiments, the heterocyclyl is pyrrolidinyl. In some embodiments, the heterocyclyl is piperazinyl. In some embodiments, the piperazinyl is substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is halo (e.g., fluoro or chloro) and the other is haloalkyl (e.g., trifluoromethyl).
  • In some embodiments, one R1 is halo (e.g., chloro) and the other is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).
  • In some embodiments, one R1 is halo (e.g., chloro) and the other is —C(O)ORa. In some embodiments, Ra is hydrogen.
  • In some embodiments, one R1 is halo (e.g., fluoro or chloro) and the other is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is halo (e.g., chloro) and the other is —NRcC(Y)Rc′. In some embodiments, Y is O. In some embodiments, Rc is hydrogen and Rc′ is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is halo (e.g., fluoro or chloro) and the other is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is halo (e.g., fluoro or chloro) and the other is —CN.
  • In some embodiments, one R1 is halo (e.g., chloro) and the other is —NO2. In some embodiments, one R1 is —C(O)ORa and the other is —NO2. In some embodiments, Ra is hydrogen.
  • In some embodiments, one R1 is —C(O)ORa and the other is —ORd. In some embodiments, each Ra and Rd is hydrogen.
  • In some embodiments, one R1 is —C(Y)NRbRb′ and the other is haloalkyl (e.g., trifluoromethyl). In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, one R1 is —C(Y)NRbRb′ and the other is haloalkoxy (e.g., trifluoromethoxy). In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, one R1 is —C(Y)NRbRb′ and the other is —S(O)qRf. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rf is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is —C(Y)NRbRb′ and the other is —CN. In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, one R1 is —ORd and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is —ORd and the other is haloalkyl (e.g., trifluoromethyl). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is —ORd and the other is —C(O)ORa. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, Ra is hydrogen. In some embodiments, Ra is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is —ORd and the other is —NRcC(O)Rc′. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, Rc is hydrogen and Rc is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is haloalkyl (e.g., trifluoromethyl) and the other is —CN.
  • In some embodiments, two R1, together with the atoms to which they are attached, are taken together to form a cyclyl ring (e.g., a substituted cyclyl ring). In some embodiments, two R1, together with the atoms to which they are attached, are taken together to form a heterocyclyl ring (e.g., a substituted heterocyclyl ring). In some embodiments, two R1, together with the atoms to which they are attached, are taken together to form a heteroaryl ring (e.g., a substituted heteroaryl ring).
  • In some embodiments, two R1 and ring B are taken together to form a group selected from:
  • Figure US20170217923A1-20170803-C00020
    Figure US20170217923A1-20170803-C00021
  • In some embodiments, R2 is aryl.
  • In some embodiments, each R1 is independently halo (e.g., all three R1 are fluoro or all three R1 are chloro).
  • In some embodiments, two R1 are independently halo (e.g., both are chloro) and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, two R1 are independently halo (e.g., both are chloro) and the other is heteroaryl (e.g., pyrrolyl). In some embodiments, two R1 are independently halo (e.g., both are fluoro) and the other is —C(Y)NRbRb′ (e.g., —C(O)NH2). In some embodiments, two R1 are independently C1-C8 alkyl (e.g., both are methyl) and the other is halo (e.g., chloro or bromo).
  • In some embodiments, one R1 is C1-C8 alkyl (e.g., methyl), and two R1, together with the atoms to which they are attached, are taken together to form a heterocyclyl ring.
  • In some embodiments, one R1 is —ORd, and two R1, together with the atoms to which they are attached, are taken together to form a heterocyclyl ring. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, three R1 and ring B are taken together to form a group selected from:
  • Figure US20170217923A1-20170803-C00022
  • In some embodiments, B is a 6-membered heteroaryl.
  • In some embodiments, B is pyridyl. In some embodiments, B is 3-pyridyl. In some embodiments, m is 2. In some embodiments, two R1, together with the atoms to which they are attached, are taken together to form an aryl ring (e.g., a phenyl ring). In some embodiments, m is 3. In some embodiments, one R1 is —ORd, and two R1, together with the atoms to which they are attached, are taken together to form an aryl ring (e.g., a phenyl ring). In some embodiments, Rd is hydrogen.
  • In some embodiments, B is pyrazolyl. In some embodiments, m is 2. In some embodiments, two R1, together with the atoms to which they are attached, are taken together to form a cyclyl ring (e.g., a cyclohexyl ring).
  • In some embodiments, B is selected from:
  • Figure US20170217923A1-20170803-C00023
  • In some embodiments, B is a 5-membered heteroaryl (e.g., pyrazolyl).
  • In some embodiments, m is 1.
  • In some embodiments, R1 is aryl (e.g., phenyl).
  • In some embodiments, R1 is phenyl substituted with 1 R6.
  • In some embodiments, R6 is halo (e.g., chloro). In some embodiments, R1 is selected from:
  • Figure US20170217923A1-20170803-C00024
  • In some embodiments, m is 2.
  • In some embodiments, one R1 is C1-C8 alkyl (e.g., methyl) and the other is aryl (e.g., phenyl). In some embodiments, the aryl is phenyl substituted with 1 R6. In some embodiments, R6 is halo (e.g., chloro). In some embodiments, R1 is:
  • Figure US20170217923A1-20170803-C00025
  • In some embodiments, B is thienyl. In some embodiments, B is selected from:
  • Figure US20170217923A1-20170803-C00026
  • In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments m is 2 and two R1, together with the atoms to which they are attached, form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring
  • In some embodiments, R1 is —C(O)ORa. In some embodiments, Ra is C1-C8 alkyl (e.g., ethyl).
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, m is 2.
  • In some embodiments, one R1 is C1-C8 alkyl (e.g., methyl) and the other is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, B is thiazolyl.
  • In some embodiments, m is 1.
  • In some embodiments, R1 is aryl (e.g., phenyl).
  • In some embodiments, m is 2.
  • In some embodiments, two R1, together with the atoms to which they are attached, form an aryl ring. In some embodiments, the aryl ring is substituted with —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, B is:
  • Figure US20170217923A1-20170803-C00027
  • In some embodiments, B is:
  • Figure US20170217923A1-20170803-C00028
  • In some embodiments, E is aryl (e.g., phenyl).
  • In some embodiments, n is 1.
  • In some embodiments, R2 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is C1-C8 alkyl substituted with 1-3 R6. In some embodiments, R2 is C1 alkyl substituted with 1 R6.
  • In some embodiments, R6 is —NRbRb′. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl, or Rb and Rb′ are both ethyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is haloalkyl (e.g., trifluoroethyl).
  • In some embodiments, R6 is —ORd. In some embodiments, Rd is cyclyl (e.g., cyclopentyl). In some embodiments, Rd is heterocyclylalkyl (e.g., —CH2— tetrahydropyranyl).
  • In some embodiments, R2 is C2 alkyl substituted with 1 R6.
  • In some embodiments, R6 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rb and Rb′, are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R6 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is heterocyclyl (e.g., morpholino or thiomorpholino). In some embodiments, Re is thiomorpholino substituted with 2 R7. In some embodiments, each R7 is oxo. In some embodiments, Re is:
  • Figure US20170217923A1-20170803-C00029
  • In some embodiments, R2 is C3 alkyl substituted with 1 R6.
  • In some embodiments, R6 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rb and Rb′, are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R6 is —NRcC(Y)Rc′. In some embodiments, Y is O. In some embodiments, Rc and Rc′ are each independently C1-C8 alkyl (e.g., Rc and Rc′ are both methyl).
  • In some embodiments, R6 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R6 is silyloxy (e.g., tert-butyldimethylsilyloxy).
  • In some embodiments, R6 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is heterocyclyl (e.g., morpholino).
  • In some embodiments, R2 is C2-C8 alkynyl. In some embodiments, R2 is C2-C8 alkynyl substituted with 1 R6 (e.g., C3 alkynyl substituted with 1 R6). In some embodiments, R2 is —C≡C—CH2—R6. In some embodiments, R6 is —NRbRb′. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, R6 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, R6 is silyloxy (e.g., tert-butyldimethylsilyloxy). In some embodiments, R6 is heterocyclyl (e.g., morpholino or thiomorpholino). In some embodiments, R6 is thiomorpholino substituted with 2 R7. In some embodiments, each R7 is oxo. In some embodiments, R6 is:
  • Figure US20170217923A1-20170803-C00030
  • In some embodiments, R2 is aryl (e.g., phenyl). In some embodiments, R2 is unsubstituted phenyl.
  • In some embodiments, R2 is phenyl substituted with 1 R6.
  • In some embodiments, R6 is heterocyclylalkyl (e.g., —CH2-morpholino). In some embodiments, R6 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R6 is —CN. In some embodiments, R6 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R6 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is heterocyclyl (e.g., morpholino).
  • In some embodiments, R2 is phenyl substituted with 2 R6.
  • In some embodiments, each R6 is independently —ORd. In some embodiments, each Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, one R6 is halo (e.g., fluoro) and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, one R6 is —C(O)ORa and the other is —ORd. In some embodiments, Ra and Rd are each independently C1-C8 alkyl (e.g., Ra and Rd are both methyl).
  • In some embodiments, R2 is heteroaryl.
  • In some embodiments, R2 is isoxazolyl. In some embodiments, R2 is isoxazolyl substituted with 2 R6. In some embodiments, each R6 is independently C1-C8 alkyl (e.g., R6 is methyl).
  • In some embodiments, R2 is pyrazolyl. In some embodiments, R2 is pyrazolyl substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is pyridyl. In some embodiments, R2 is unsubstituted pyridyl. In some embodiments, R2 is pyridyl substituted with 1 R6. In some embodiments, R6 is halo (e.g., fluoro). In some embodiments, R6 is —NRbRb′. In some embodiments, Rb and Rb′ are each hydrogen. In some embodiments, R6 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R6 is heterocyclyl (e.g., morpholino or piperazinyl). In some embodiments, R6 is piperazinyl substituted with 1 R7. In some embodiments, R7 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is pyrimidinyl.
  • In some embodiments, R2 is pyridazinyl.
  • In some embodiments, R2 is cyclyl (e.g., cyclopropyl).
  • In some embodiments, R2 is heterocyclyl (e.g., morpholino or pyrrolidinyl).
  • In some embodiments, R2 is aralkyl (e.g., benzyl).
  • In some embodiments, R2 is heterocyclylalkyl. In some embodiments, the alkyl is C1 alkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the heterocyclyl is piperidinyl. In some embodiments, the heterocyclyl is piperazinyl. In some embodiments, the heterocyclyl is piperazinyl substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl). In some embodiments, the heterocyclyl is pyrrolidinyl. In some embodiments, the heterocyclyl is morpholino. In some embodiments, the heterocyclyl is thiomorpholino. In some embodiments, the heterocyclyl is thiomorpholino substituted with 2 R6. In some embodiments, each R6 is oxo. In some embodiments, the heterocyclyl is:
  • Figure US20170217923A1-20170803-C00031
  • In some embodiments, R2 is halo (e.g., fluoro, chloro, bromo or iodo).
  • In some embodiments, R2 is haloalkyl (e.g., trifluoromethyl).
  • In some embodiments, R2 is haloalkoxy (e.g., trifluoromethoxy).
  • In some embodiments, R2 is —CN.
  • In some embodiments, R2 is —NO2.
  • In some embodiments, R2 is —C(O)ORa. In some embodiments, Ra is hydrogen. In some embodiments, Ra is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are each hydrogen. In some embodiments, Rb and Rb′, are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl or ethyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is heterocyclylalkyl (e.g., —CH2—CH2-morpholino). In some embodiments, one of Rb and Rb′ is hydrogen and the other is haloalkyl (e.g., trifluoroethyl).
  • In some embodiments, R2 is —NRbRb′. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is heterocyclyl (e.g., tetrahydropyranyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is heterocyclylalkyl. In some embodiments, the alkyl is C1 alkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the heterocyclyl is morpholino. In some embodiments, the heterocyclyl is pyrrolidinyl. In some embodiments, the heterocyclyl is tetrahydrofuranyl. In some embodiments, the heterocyclyl is tetrahydropyranyl. In some embodiments, one of Rb and Rb′ is hydrogen and the other is hydroxyalkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, one of Rb and Rb′ is hydrogen and the other is alkoxyalkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the alkoxy is methoxy. In some embodiments, one of Rb and Rb′ is hydrogen and the other is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is C1-C8 alkyl (e.g., methyl). In some embodiments, Re is heterocyclyl. In some embodiments, Re is tetrahydropyranyl.
  • In some embodiments, R2 is —ORd.
  • In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, Rd is ethyl. In some embodiments, Rd is C3 alkyl (e.g., isopropyl or n-propyl). In some embodiments, Rd is optionally substituted heteroaralkyl. In some embodiments, Rd is optionally substituted pyrindinalkyl.
  • In some embodiments, Rd is n-propyl. In some embodiments, Rd is cyclyl (e.g., cyclopentyl).
  • In some embodiments, Rd is heteroaralkyl (e.g., —CH2-pyridyl).
  • In some embodiments, Rd is heterocyclylalkyl. In some embodiments, the alkyl is C1 alkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the alkyl is C4 alkyl. In some embodiments, the heterocyclyl is morpholino. In some embodiments, the heterocyclyl is piperidyl. In some embodiments, the heterocyclyl is tetrahydrofuranyl. In some embodiments, Rd is cyclylalkyl (e.g., —CH2-cyclobutyl).
  • In some embodiments, Rd is alkoxyalkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the alkoxy is methoxy.
  • In some embodiments, Rd is dialkylaminoalkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the dialkylamino is dimethylamino.
  • In some embodiments, R2 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is heterocyclyl. In some embodiments, Re is piperidyl. In some embodiments, Re is pyrrolidinyl. In some embodiments, Re is piperazinyl. In some embodiments, Re is morpholino. In some embodiments, Re is thiomorpholino.
  • In some embodiments, n is 2.
  • In some embodiments, each R2 is independently halo (e.g., each R2 is chloro).
  • In some embodiments, each R2 is independently —ORd.
  • In some embodiments, each Rd is C1-C8 alkyl.
  • In some embodiments, each R2 is methoxy. In some embodiments, one R2 is methoxy and the other is ethoxy. In some embodiments, one R2 is methoxy and the other is propoxy. In some embodiments, one R2 is methoxy and the other is isopropoxy.
  • In some embodiments, one R2 is methoxy and the other is ethoxy substituted with 1 R6. In some embodiments, R6 is —NRbRb′. In some embodiments, Rb and Rb′, are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, R6 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is methoxy and the other is propoxy substituted with 1 R6. In some embodiments, R6 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is —ORd and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl or ethyl).
  • In some embodiments, one R2 is —ORd and the other is halo (e.g., chloro). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is —ORd and the other is —CN. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is —ORd and the other is —C(O)ORa. In some embodiments, Rd and Ra are both hydrogen.
  • In some embodiments, one R2 is —ORd and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is —ORd and the other is —C(Y)Re. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, Y is O. In some embodiments, Re is heterocyclyl (e.g., morpholino).
  • In some embodiments, one R2 is halo (e.g., chloro or bromo) and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is C1-C8 alkyl (e.g., methyl) and the other is —CN.
  • In some embodiments, one R2 is C1-C8 alkyl (e.g., methyl) and the other is heteroaryl (e.g., pyridyl). In some embodiments, the pyridyl is substituted with 1 R6.
  • In some embodiments, R6 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is C1-C8 alkyl (e.g., methyl) and the other is heterocyclylalkyl (e.g., —CH2-morpholino).
  • In some embodiments, p is 0.
  • In some embodiments, p is 1.
  • In some embodiments, R3 is C1-C8 alkyl (e.g., methyl). In some embodiments, R3 is halo (e.g., chloro). In some embodiments, R3 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R3 is oxo.
  • In some embodiments, R3 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R3 is —NRbRb′. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R3 is heterocyclyl (e.g., piperazinyl). In some embodiments, R3 is piperazinyl substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, E is a 5-membered heteroaryl ring.
  • In some embodiments, E is a thiophene ring.
  • In some embodiments, E is a pyrrole ring.
  • In some embodiments, n is 1. In some embodiments, R2 is C1-C8 alkyl (e.g., methyl). In some embodiments, E is an N-methylpyrrole ring.
  • In some embodiments, L is NR5. In some embodiments, R5 is hydrogen.
  • In some embodiments, L is O.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00032
  • In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, R1 is —C(Y)NRbRb′.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00033
  • In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, R1 is —C(Y)NRbRb′.
  • In some embodiments, is
  • Figure US20170217923A1-20170803-C00034
  • In some embodiments, is
  • Figure US20170217923A1-20170803-C00035
  • In some embodiments, L is NH, and
  • Figure US20170217923A1-20170803-C00036
  • is selected from
  • Figure US20170217923A1-20170803-C00037
    Figure US20170217923A1-20170803-C00038
  • In some embodiments R6 is halo.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00039
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, R1 is halo. In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, m is 2 and two R1 are 3,4-dichloro; 3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro, 4-fluoro; or 3-chloro, 5-fluoro. In some embodiments, R2 is —C(O)NRbRb′ and R3 is H. In some embodiments, Rb and Rb′ are H. In some embodiments, Rb and Rb′ are independently C1-C4 alkyl or halo-substituted C1-C4 alkyl. In some embodiments, Rb is methyl and Rb′ is trifluoroethyl. In some embodiments, R1 is C1-C4 alkoxy or halo-substituted C1-C4 alkoxy. In some embodiments, n and p are zero.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00040
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, R1 is halo. In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, m is 2 and two R1 are 3,4-dichloro; 3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro, 4-fluoro; or 3-chloro, 5-fluoro. In some embodiments, R2 is —C(O)NRbRb′ and R3 is H. In some embodiments, Rb and Rb′ are H. In some embodiments, Rb and Rb′ are independently C1-C4 alkyl or halo-substituted C1-C4 alkyl. In some embodiments, Rb is methyl and Rb′ is trifluoroethyl. In some embodiments, R1 is C1-C4 alkoxy or halo-substituted C1-C4 alkoxy. In some embodiments, n and p are zero.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00041
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, R1 is halo. In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, m is 2 and two R1 are 3,4-dichloro; 3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro, 4-fluoro; or 3-chloro, 5-fluoro. In some embodiments, R2 is —C(O)NRbRb′ and R3 is H. In some embodiments, Rb and Rb′ are H. In some embodiments, Rb and Rb′ are independently C1-C4 alkyl or halo-substituted C1-C4 alkyl. In some embodiments, Rb is methyl and Rb′ is trifluoroethyl. In some embodiments, R1 is C1-C4 alkoxy or halo-substituted C1-C4 alkoxy. In some embodiments, n and p are zero.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00042
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, R1 is halo. In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, m is 2 and two R1 are 3,4-dichloro; 3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro, 4-fluoro; or 3-chloro, 5-fluoro. In some embodiments, R2 is —C(O)NRbRb′ and R3 is H. In some embodiments, Rb and Rb′ are H. In some embodiments, Rb and Rb′ are independently C1-C4 alkyl or halo-substituted C1-C4 alkyl. In some embodiments, Rb is methyl and Rb′ is trifluoroethyl. In some embodiments, R1 is C1-C4 alkoxy or halo-substituted C1-C4 alkoxy. In some embodiments, n and p are zero.
    • Compounds of Formula (II)
  • The following aspects and embodiments relate to compounds of formula (II).
    • Item 9. The compound according to item 1 represented by general formula (II) or a salt thereof,
      • wherein:
      • L is CR4R5, O, C(O), NR6C(O) or NR7;
      • A is N;
      • each X1, X2, X3, X4 and X5 is independently CH or N, provided that at least two of X1, X2, X3, X4 and X5 are N;
      • n is 0, 1, 2, 3 or 4;
      • p is 0, 1, 2 or 3;
      • R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl or heterocyclylalkyl, each of which is optionally substituted with 1-5 R9; wherein R1 or R9 is optionally taken together with one of R4, R5, R6 or R7, and the atoms to which they are attached to form a cyclyl, heterocyclyl, aryl or heteroaryl ring that is optionally substituted with 1-3 R10;
      • each R2 and R3 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRc(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R11;
      • each R4, R5, R6 and R7 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRc(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each R9, R10 and R11 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; wherein two R8, two R9, two R10 or two R11 is optionally taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R12 is —ORd;
      • Y is O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, arylalkyl, or heteroarylalkyl.
    • Item 10. The compound according to item 9 represented by general formula (II) or a salt thereof,
      • L is NR7;
      • n is 0, 1 or 2;
      • p is 0;
      • R1 is C1-C8 alkyl, aryl or heteroaryl;
      • each R2 and R3 is independently hydrogen, C1-C8 alkyl, aryl, halo, heterocyclylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R11;
      • R7 is hydrogen; and
      • each R9, R10 and R11 is independently C1-C8 alkyl, heterocyclyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)ORa, —C(Y)NRbRb′, —ORd or —C(Y)Re;
      • Y is O;
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, cyclyl, heterocyclyl, aryl or heteroaryl.
    • Item 11. The compound according to item 10 represented by general formula (II) or a salt thereof,
      • wherein:
      • R1 is C1-C8 alkyl, phenyl or benzodioxolyl;
      • each R2 and R3 is independently hydrogen, C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd;
      • R9 is independently C1-C8 alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)ORa, —C(Y)NRbRb′, —ORd or —C(Y)Re; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, tetrahydropyranyl, phenyl or pyridyl.
    • Item 12. The compound according to item 10 represented by general formula (II) or a salt thereof,
      • wherein:
      • R1 is C1-C8 alkyl, phenyl or benzodioxolyl;
      • each R2 and R3 is independently hydrogen, C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R11;
      • each R9, R10 and R11 is independently C1-C8 alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)ORa, —C(Y)NRbRb′, —ORd or —C(Y)Re; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, tetrahydropyranyl, phenyl, or pyridyl.
    • Item 13. The compound according to item 12 represented by general formula (II) or a salt thereof, wherein:
      • R2 is C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc′, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R11;
      • R3 is hydrogen;
      • R9 is halo, haloalkoxy, —CN, —C(O)ORa or —C(Y)NRbRb′; and
      • R11 is C1-C8 alkyl, morpholinyl, tetrahydropyranyl, halo, —CN, —ORd or —C(Y)Re;
    • Item 14. The compound according to item 11 or 13 represented by general formula (II) or a salt thereof, wherein:
      • R2 is C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc′, —NRbRb′ or —ORd;
      • R3 is hydrogen; and
      • R9 is halo, haloalkoxy, —CN, —C(O)ORa or —C(Y)NRbRb′
  • In some embodiments, A is CH. In some embodiments, A is N.
  • In some embodiments, L is NR7. In some embodiments, R7 is H.
  • In some embodiments, R1 is aryl (e.g., phenyl).
  • In some embodiments, R1 is phenyl substituted with 1 R9. In some embodiments, R1 is phenyl substituted with 1 R9 in the ortho position. In some embodiments, R1 is phenyl substituted with 1 R9 in the meta position. In some embodiments, R9 is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy). In some embodiments, R9 is —CN. In some embodiments, R9 is —C(O)ORa. In some embodiments, Ra is hydrogen. In some embodiments, R9 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, R1 is:
  • Figure US20170217923A1-20170803-C00043
  • In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R1 is phenyl substituted with 2 R9. In some embodiments, each R9 is independently halo (e.g., each R9 is fluoro or each R9 is chloro). In some embodiments, one R9 is fluoro and the other is chloro. In some embodiments, one R9 is halo (e.g., chloro) and the other is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).
  • In some embodiments, 2 R9 are taken together with the atoms to which they are attached to form a heterocyclyl ring, e.g., a 5-membered heterocyclyl ring (e.g., a dioxole ring). In some embodiments, the dioxole ring is unsubstituted. In some embodiments, the dioxole ring is substituted. In some embodiments, the dioxole ring is substituted with two fluoro substituents. In some embodiments, R1 is selected from:
  • Figure US20170217923A1-20170803-C00044
  • In some embodiments, R1 is aralkyl (e.g., benzyl). In some embodiments, R1 is aralkyl substituted with 2 R9 (e.g., benzyl substituted with 2 R9). In some embodiments, 2 R9 substituents are on the phenyl ring. In some embodiments, each R9 is independently halo (e.g., each R9 is chloro).
  • In some embodiments, R1 is alkyl (e.g., methyl).
  • In some embodiments, n is 0.
  • In some embodiments, n is 1.
  • In some embodiments, R2 is C1-C8 alkyl (e.g., methyl). In some embodiments, R2 is C1-C8 alkyl substituted with 1 R11 (e.g., methyl substituted with 1 R11). In some embodiments, R11 is heterocyclyl (e.g., morpholino).
  • In some embodiments, R2 is aryl (e.g., phenyl). In some embodiments, R2 is phenyl substituted with 1 R11. In some embodiments, R11 is —CN. In some embodiments, R11 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R11 is halo.
  • In some embodiments, R2 is halo (e.g., fluoro, chloro, bromo or iodo). In some embodiments, R2 is —NRcC(Y)Rc′. In some embodiments, Rc is hydrogen. In some embodiments, Y is O. In some embodiments, Rc′ is alkyl (e.g., methyl). In some embodiments, Rc′ is aryl (e.g., phenyl). In some embodiments, Rc′ is phenyl substituted with 1 R8. In some embodiments, R8 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, Rc′ is heteroaryl. In some embodiments, Rc′ is furanyl. In some embodiments, Rc′ is pyridyl. In some embodiments, Rc′ is pyridyl substituted with 1 R8. In some embodiments, R8 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, Rc′ is cyclyl (e.g., cyclohexyl). In some embodiments, Rc′ is cyclohexyl substituted with 1 R8. In some embodiments, R8 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, Rc′ is heterocyclyl (e.g., tetrahydropyranyl).
  • In some embodiments, R2 is —NRbRb′. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl).
  • In some embodiments, R2 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl or ethyl). In some embodiments, Rd is ethyl substituted with 1 R8. In some embodiments, R8 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R2 is —OCH2CH2OCH3. In some embodiments, R2 is —OCH2CH2OCH2CH2CH3. In some embodiments, R2 is —OCH2CH2OCH2CH2OCH3.
  • In some embodiments, n is 2.
  • In some embodiments, one R2 is C1-C8 alkyl (e.g., methyl) and the other is halo (e.g., chloro).
  • In some embodiments, one R2 is —ORd and the other is halo (e.g., chloro). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, X1 and X4 are N and X2, X3 and X5 are CH.
  • In some embodiments, X1 and X3 are N and X2, X4 and X5 are CH.
  • In some embodiments, X2 and X3 are N and X1, X4 and X5 are CH.
  • In some embodiments, X2 and X4 are N and X1, X3 and X5 are CH.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00045
  • wherein s is 0, 1, 2, 3 or 4.
  • In some embodiments, R9 is —C(O)NH2, C1-C4 alkoxy, or substituted C1-C4 alkoxy. In some embodiments, R9 is halo.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00046
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R1 is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, LR1 is NH(CH3).
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00047
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R1 is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, LR1 is NH(CH3).
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00048
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R1 is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, LR1 is NH(CH3).
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00049
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R1 is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, LR1 is NH(CH3).
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00050
  • wherein t is 1-3.
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R1 is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, LR1 is NH(CH3). In some embodiments, R11 is independently halo, nitrile, C1-C4 alkoxy, —C(O)NH2, hydroxy, or C1-C4 hydroxyalkyl. In some embodiments, R11 is fluoro. In some embodiments, R11 is methoxy, ethoxy, or methoxyethoxy ether. In some embodiments, R11 is —OCH2CH2OCH3. In some embodiments, R1 is —OCH2CH2OCH2CH2CH3. In some embodiments, R11 is —OCH2CH2OCH2CH2OCH3.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00051
  • wherein t is 1-3.
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, LR1 is NH(CH3). In some embodiments, R11 is independently halo, nitrile, C1-C4 alkoxy, —C(O)NH2, hydroxy, or C1-C4 hydroxyalkyl. In some embodiments, R11 is fluoro. In some embodiments, R11 is methoxy, ethoxy, or methoxyethoxy ether. In some embodiments, R11 is —OCH2CH2OCH3. In some embodiments, R11 is —OCH2CH2OCH2CH2CH3. In some embodiments, R11 is —OCH2CH2OCH2CH2OCH3.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00052
  • wherein t is 1-3.
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, LR1 is NH(CH3). In some embodiments, R11 is independently halo, nitrile, C1-C4 alkoxy, —C(O)NH2, hydroxy, or C1-C4 hydroxyalkyl. In some embodiments, R11 is fluoro. In some embodiments, R11 is methoxy, ethoxy, or methoxyethoxy ether. In some embodiments, R11 is —OCH2CH2OCH3. In some embodiments, R11 is —OCH2CH2OCH2CH2CH3. In some embodiments, R11 is —OCH2CH2OCH2CH2OCH3.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00053
  • wherein t is 1-3.
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, LR1 is NH(CH3). In some embodiments, R11 is independently halo, nitrile, C1-C4 alkoxy, —C(O)NH2, hydroxy, or C1-C4 hydroxyalkyl. In some embodiments, R11 is fluoro. In some embodiments, R11 is methoxy, ethoxy, or methoxyethoxy ether. In some embodiments, R11 is —OCH2CH2OCH3. In some embodiments, R11 is —OCH2CH2OCH2CH2CH3. In some embodiments, R11 is —OCH2CH2OCH2CH2OCH3.
    • Compounds of Formula (III)
  • The following aspects and embodiments relate to compounds of formula (III).
    • Item 15. The compound according to item 1 represented by general formula (III) or a salt thereof,
      • wherein:
      • A is CH or N;
      • L is O, a direct bond or NH;
      • one of X1, X2, X3, X4 and X5 is N and the others are CH;
      • m is 1, 2 or 3;
      • n is 1, 2, 3 or 4;
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl, hydroxyalkyl, heteroaryl, heteroarylalkyl, arylalkyl, —C(Y)Re, cyclyl, cyclylalkyl or heterocyclyl, each of which is optionally substituted with 1-3 R7;
      • R2 is aryl or heteroaryl, each of which is optionally substituted with 1-5 R9;
      • each R3 or R4 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R10;
      • each R7, R9 and R10 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; wherein two R7 or two R9 are optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R12 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R13;
      • R13 is independently C1-C8 alkyl, haloalkyl, halo, heterocyclyl, cyclyl, oxo or —C(Y)NRbRb′;
      • Y is O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryl, cyclylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl.
    • Item 16. The compound according to item 15 represented by general formula (III) or a salt thereof,
      • wherein:
      • m is 1;
      • n is 1;
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, heteroaryl, heterocyclyl, arylalkyl, cyclylalkyl, heteroarylalkyl, alkoxyalkyl, hydroxyalkyl or —C(O)Re, each of which is optionally substituted with 1-3 R7;
      • R2 is aryl, heteroaryl or benzofuryl, each of which is optionally substituted with 1-5 R9;
      • each R3 or R4 is independently hydrogen, C1-C8 alkyl, halo, haloalkyl or —ORd;
      • R6 is hydrogen or C1-C8 alkyl;
      • each R7 and R9 is independently C1-C8 alkyl, aryl, heteroaryl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —C(O)NRbRb′, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12;
      • R12 is independently C1-C8 alkyl, oxo, halo, haloalkyl, —CN, —C(O)NRbRb′ or —C(O)Re each of which is optionally substituted with 1-3 R13;
      • R13 is independently C1-C8 alkyl, halo or heterocyclyl; and
        • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, cyclyl, heterocyclyl, arylalkyl, alkoxyalkyl, heterocyclylalkyl, heteroarylalkyl, alkylaminoalkyl, dialkylaminoalkyl or phenyl.
    • Item 17. The compound according to Item 16 represented by general formula (III) or a salt thereof,
      • wherein:
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl, hydroxyalkyl, imidazolyl, pyridylalkyl, phenylalkyl, oxazolylalkyl, thienylalkyl, thiazolidinyl isoindolyl, —C(O)Re, dihydroindenyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-3 R7;
      • R2 is phenyl, naphthyl, benzofuryl, indazolyl, benzothienyl, pyridyl, pyrimidinyl, dihydrobenzodioxinyl, benzodioxolyl, benzoimidazolyl, isoxazolyl, pyrazolyl, indolinyl or benzoisoxazolyl, each of which is optionally substituted with 1-5 R9;
      • each R3 or R4 is independently hydrogen, C1-C8 alkyl, halo, haloalkyl or —ORd;
      • R6 is hydrogen or C1-C8 alkyl;
        each R7 and R9 is independently C1-C8 alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —C(O)NRbRb′, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl, alkoxyalkyl, morholinylalkyl, oxazolidinylalkyl, imidazolylalkyl, tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl, thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl, dihydrobenzoxazinylalkyl, tetrahydrofurylalkyl, tetrahydrofuryl, alkylaminoalkyl, dialkylaminoalkyl or phenyl.
    • Item 18. The compound according to item 16 represented by general formula (III) or a salt thereof,
      • wherein:
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl, hydroxyalkyl, imidazolyl, furylalkyl, pyridylalkyl, phenylalkyl, oxazolylalkyl, thienylalkyl, thiazolidinyl, isoindolyl, —C(O)Re, dihydroindenyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-3 R7;
      • R2 is phenyl, naphthyl, benzofuryl, indazolyl, benzothienyl, pyridyl, pyrimidinyl, dihydrobenzodioxinyl, benzodioxolyl, benzoimidazolyl, isoxazolyl, pyrazolyl, indolinyl or benzisoxazolyl, each of which is optionally substituted with 1-5 R9;
      • each R3 or R4 is independently hydrogen, C1-C8 alkyl, halo, haloalkyl or —ORd;
      • R6 is hydrogen or C1-C8 alkyl;
      • each R7 and R9 is independently C1-C8 alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO2, —C(O)ORa, —C(O)NRbRb′, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12;
      • R12 is independently C1-C8 alkyl, oxo, halo, haloalkyl, —CN, —C(O)NRbRb′ or —C(O)Re, each of which is optionally substituted with 1-3 R13;
      • R13 is independently C1-C8 alkyl, halo or pyrrolidinyl; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl, alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl, tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl, thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl, dihydrobenzoxazinylalkyl, tetrahydrofurylalkyl, tetrahydrofuryl, alkylaminoalkyl, dialkylaminoalkyl or phenyl.
    • Item 19. The compound according to item 18 represented by general formula (III) or a salt thereof,
      • wherein:
      • A is N;
      • R3 is hydrogen, C1-C8 alkyl, halo, haloalkyl, or —ORd;
      • R4 is hydrogen, C1-C8 alkyl, halo, or —ORd;
      • R7 is C1-C8 alkyl, phenyl, halo, haloalkyl, oxo, —C(O)ORa, —C(O)NRbRb′ or —ORd each of which is optionally substituted with 1-3 R12;
      • R9 is C1-C8 alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, —CN, —NO2, —C(O)NRbRb′, —C(O)ORa, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl, alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl, tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl, thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl, tetrahydrofurylalkyl, dihydrobenzoxazinylalkyl, tetrahydrofuryl, alkylaminoalkyl, dialkylaminoalkyl or phenyl.
    • Item 20. The compound according to item 17 or 19 represented by general formula (III) or a salt thereof,
      • wherein:
      • A is N;
      • R3 is hydrogen, C1-C8 alkyl, halo, haloalkyl, or —ORd;
      • R4 is hydrogen, C1-C8 alkyl, halo, or —ORd;
      • R7 is C1-C8 alkyl, phenyl, halo, haloalkyl, oxo, —C(O)ORa, —C(O)NRbRb′ or —ORd;
      • R9 is C1-C8 alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, —CN, —NO2, —C(O)NRbRb′, —C(O)ORa, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydropyranyl, phenylalkyl, alkoxyalkyl, morpholinylalkyl, oxazolidinylalkyl, imidazolylalkyl, tetrahydropyranylalkyl, pyridylalkyl, pyrazolylalkyl, tetrazolylalkyl, thiazolylalkyl, pyrrolylalkyl, benzoxazolylalkyl, indazolylalkyl, tetrahydrofurylalkyl, tetrahydrofuryl, dihydrobenzoxazinylalkyl, alkylaminoalkyl, dialkylaminoalkyl or phenyl.
    • Item 21. The compound according to item 20 represented by general formula (III) or a salt thereof,
      • wherein:
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl, hydroxyalkyl, imidazolyl, furylalkyl, pyridylalkyl, phenylalkyl, oxazolylalkyl, thienylalkyl, isoindolyl, —C(O)Re, dihydroindenyl, C3-C8 cycloalkyl, C3-C8 cycloalkylalkyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-3 R7;
      • R2 is phenyl, which is optionally substituted with 1-5 R9; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re and Rf is independently hydrogen, C1-C8 alkyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, alkoxyalkyl, morpholinylalkyl, tetrahydropyranylalkyl, pyridylalkyl, thiazolylalkyl, pyrrolylalkyl, tetrahydrofuryl, alkylaminoalkyl or phenyl.
  • In some embodiments, R1 is C1-C8 alkyl, which is optionally substituted with 1-3 R7; or when L is NR6, R1 and R6 may be taken together with the atoms to which they are attached to form a heterocyclyl or heteroaryl ring that is optionally substituted with 1-3 R8.
  • In some embodiments, A is CH. In some embodiments, A is N.
  • In some embodiments, L is NR6. In some embodiments, R6 is hydrogen.
  • In some embodiments, R1 is C1-C8 alkyl, e.g., methyl, ethyl, C3 alkyl (e.g., n-propyl or isopropyl), C4 alkyl (e.g., n-butyl, isobutyl or tert-butyl), or C5 alkyl (e.g., pentan-3-yl).
  • In some embodiments, R1 is C1-C8 alkyl substituted with 1-3 R7 (e.g., C1-C8 alkyl substituted with 1 R7). In some embodiments, R1 is methyl substituted with 1 R7. In some embodiments, R7 is cyclyl (e.g., cyclopropyl). In some embodiments, R7 is aryl (e.g., phenyl).
  • In some embodiments, R1 is ethyl substituted with 1 R7. In some embodiments, R7 is aryl (e.g., phenyl). In some embodiments, R7 is —ORd. In some embodiments, Rd is aryl (e.g., phenyl).
  • In some embodiments, R1 is n-propyl substituted with 1 R7. In some embodiments, R7 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., C3 alkyl, e.g., n-propyl).
  • In some embodiments, R1 is C1-C8 alkyl substituted with 3 R7. In some embodiments, R1 is ethyl substituted with 3 R7. In some embodiments, each R7 is independently halo (e.g., each R7 is fluoro). In some embodiments, R1 is 2,2,2-trifluoroethyl.
  • In some embodiments, R1 is C2-C8 alkenyl, e.g., C3 alkenyl (e.g., —CH2—CH═CH2).
  • In some embodiments, R1 is C2-C8 alkynyl, e.g., C3 alkynyl (e.g. —CH2—C≡CH).
  • In some embodiments, R1 is cyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl). In some embodiments, the cyclyl group is a bicyclic group (e.g., indanyl).
  • In some embodiments, R1 is heterocyclyl (e.g., piperidyl). In some embodiments, R1 is piperidyl substituted with 1 R7. In some embodiments, R7 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is C1-C8 alkyl (e.g., methyl). In some embodiments, R7 is —ORd.
  • In some embodiments, R6 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R1 and R6 are taken together with the atoms to which they are attached to form a heterocyclyl ring (e.g. a pyrrolidine ring).
  • In some embodiments, R1 and R6 are taken together with the atoms to which they are attached to form a heteroaryl ring (e.g., an imidazole ring).
  • In some embodiments, L is O.
  • In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is aryl (e.g., phenyl). In some embodiments, R2 is unsubstituted phenyl. In some embodiments, R2 is phenyl substituted with 1-3 R9. In some embodiments, R2 is phenyl substituted with 1 R9.
  • In some embodiments, R2 is:
  • Figure US20170217923A1-20170803-C00054
  • In some embodiments, R9 is halo (e.g., fluoro or chloro). In some embodiments, R9 is —CN. In some embodiments, R9 is —NO2. In some embodiments, R9 is haloalkoxy (e.g., trifluoroethoxy). In some embodiments, R9 is —NRbRb′. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl).
  • In some embodiments, R9 is —ORd. In some embodiments, R9 is —OCH2CH2OCH3. In some embodiments, R9 is —OCH2CH2OCH2CH2CH3. In some embodiments, R9 is —OCH2CH2OCH2CH2OCH3. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, Rd is ethyl.
  • In some embodiments, R9 is hydroxyalkyl (e.g., —CH2OH). In some embodiments, R9 is alkoxyalkyl (e.g., —CH2—O—CH3). In some embodiments, R9 is —C(O)Re. In some embodiments, Re is heterocyclyl (e.g., morpholino). In some embodiments, R9 is —S(O)qRf. In some embodiments, q is 1. In some embodiments, Rf is C1-C8 alkyl (e.g., methyl.).
  • In some embodiments, R2 is phenyl substituted with 2 R9. In some embodiments, each R9 is independently halo (e.g., each R9 is fluoro). In some embodiments, each R9 is independently —ORd. In some embodiments, each Rd is independently C1-C8 alkyl (e.g., each Rd is methyl).
  • In some embodiments, R2 is heteroaryl. In some embodiments, R2 is a 6-membered heteroaryl. In some embodiments, R2 is a 6-membered nitrogen-containing heteroaryl, e.g., pyridyl. In some embodiments, R2 is unsubstituted pyridyl.
  • In some embodiments, R2 is pyridyl substituted with 1 R9. In some embodiments, R9 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is a 5-membered heteroaryl. In some embodiments, R2 is a 5-membered nitrogen-containing heteroaryl (e.g., pyrrolyl or oxazolyl).
  • In some embodiments, m is 0.
  • In some embodiments, m is 1.
  • In some embodiments, R4 is C1-C8 alkyl (e.g., methyl). In some embodiments, R4 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R4 is halo. In some embodiments, R4 is methoxy. In some embodiments, Rd is C1-C8 alkyl.
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00055
  • wherein one of X1 and X2 is N and the other is CH.
  • In some embodiments, X1 is CH and X2 is N. In some embodiments, X1 is N and X2 is CH. In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00056
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00057
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00058
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00059
  • wherein R1 is C1-C8 alkyl, which is optionally substituted with 1-3 R7.
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00060
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is
  • Figure US20170217923A1-20170803-C00061
    Figure US20170217923A1-20170803-C00062
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00063
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments R1 is C1-C8 alkyl (e.g., methyl). In some embodiments, R2 is
  • Figure US20170217923A1-20170803-C00064
    Figure US20170217923A1-20170803-C00065
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00066
  • wherein p is 1, 2, 3, 4 or 5.
  • In some embodiments, L is NR6. In some embodiments, L is O. In some embodiments, R1 is hydrogen or C1-C8 alkyl. In some embodiments, R1 is cyclyl or heterocyclyl. In some embodiments, R1 is aralkyl or heteroaralkyl. In some embodiments, R1 is methyl, cyclohexyl, t-butyl, or
  • Figure US20170217923A1-20170803-C00067
  • In some embodiments, R6 is hydrogen or C1-C8 alkyl.
    In some embodiments, R9 is C1-C8 alkyl, halo, —CN, or —ORd. In some embodiments, R3 is hydrogen.
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00068
  • wherein p is 1, 2, 3, 4 or 5.
  • In some embodiments, L is NR6. In some embodiments, L is O. In some embodiments, R1 is hydrogen or C1-C8 alkyl. In some embodiments, R1 is cyclyl or heterocyclyl. In some embodiments, R1 is aralkyl or heteroaralkyl. In some embodiments, R1 is methyl, cyclohexyl, t-butyl, or
  • Figure US20170217923A1-20170803-C00069
  • In some embodiments, R6 is hydrogen or C1-C8 alkyl. In some embodiments, R9 is C1-C8 alkyl, halo, —CN, or —ORd. In some embodiments, R3 is hydrogen.
    • Compounds of Formula (IV)
  • The following aspects and embodiments relate to compounds of formula (IV), corresponding to formula (I) of U.S. Provisional Patent Application No. 61/291,544, entitled “Therapeutic Compounds and Related Methods of Use” filed on Dec. 31, 2009, and incorporated herein by reference in its entirety.
    • Item 38. A compound of formula (IV):
  • Figure US20170217923A1-20170803-C00070
      • wherein:
      • A is CH, CR4 or N;
      • B is aryl or a 5- or 6-membered heteroaryl;
      • m is 0, 1, 2, 3, 4 or 5;
      • E is aryl or a 5-membered heteroaryl;
      • when E is aryl, n is 1, 2, 3 or 4; and when E is a 5-membered heteroaryl, n is 0, 1, 2 or 3;
      • L is NR5 or O;
      • one of X and Z is N and the other is CH;
      • p is 0, 1, 2, 3 or 4;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRc(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6;
      • R5 is hydrogen; or when m is not 0, R5 and 1 R1 may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;
      • each R6 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R7;
      • each R7 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each Y is independently O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy and silylalkoxyalkyl, each of which may be optionally substituted with 1-3 R6, wherein Rb and Rb′, together with the atoms to which they are attached, may form an optionally substituted cyclyl or heterocyclyl ring;
      • or a pharmaceutically acceptable derivative or prodrug thereof,
      • wherein when B is phenyl, two R1 are not taken together to form a pyrazole ring;
      • when B is phenyl, R2 is not
  • Figure US20170217923A1-20170803-C00071
      • and where in the compound is not:
  • Figure US20170217923A1-20170803-C00072
  • In some embodiments, when B is phenyl, R2 is not a substituted pyridyl. In some embodiments, when B is phenyl and n=1, R2 is not a substituted pyridyl.
  • In some embodiments, when X is N, B is not 4-pyridyl.
  • In some embodiments, each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy and silylalkoxyalkyl, each of which may be optionally substituted with 1-3 R6.
  • In some embodiments, B is aryl.
    • Item 39. A compound of formula (IV):
  • Figure US20170217923A1-20170803-C00073
      • wherein:
      • A is CH, CR4 or N;
      • B is aryl or a 5-membered heteroaryl;
      • m is 0, 1, 2, 3, 4 or 5;
      • E is aryl or a 5-membered heteroaryl;
      • when E is aryl, n is 1, 2, 3 or 4; and when E is a 5-membered heteroaryl, n is 0, 1, 2 or 3;
      • L is NR5 or O;
      • one of X and Z is N and the other is CH;
      • p is 0, 1, 2, 3 or 4;
      • each R1, R2 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6;
      • R5 is hydrogen; or when m is not 0, R5 and 1 R1 may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;
      • each R6 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R7;
      • each R7 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each Y is independently O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy and silylalkoxyalkyl, each of which may be optionally substituted with 1-3 R6 wherein Rb and Rb′, together with the atoms to which they are attached, may form an optionally substituted cyclyl or heterocyclyl ring;
      • or a pharmaceutically acceptable derivative or prodrug thereof,
      • wherein when B is phenyl, two R1 are not taken together to form a pyrazole ring; and
      • when B is phenyl, R2 is not
  • Figure US20170217923A1-20170803-C00074
  • In some embodiments, each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy and silylalkoxyalkyl, each of which may be optionally substituted with 1-3 R6.
  • In some embodiments, when B is phenyl, R2 is not a substituted pyridyl. In some embodiments, when B is phenyl and n=1, R2 is not a substituted pyridyl.
  • In one aspect, the invention features a compound of formula (IV):
  • Figure US20170217923A1-20170803-C00075
      • wherein:
      • A is CH, CR4 or N;
      • B is aryl or a 5-membered heteroaryl;
      • E is aryl or a 5-membered heteroaryl;
      • L is NR5 or O;
      • one of X and Z is N and the other is CH;
      • m is 0, 1, 2, 3, 4 or 5;
      • n is 1, 2, 3 or 4;
      • p is 0, 1, 2, 3 or 4;
      • each R1 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • each R2 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6; wherein two R1, together with the carbons to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRc(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6;
      • R5 is hydrogen; or when m is not 0, R5 and 1 R1 may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;
      • each R6 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R7;
      • each R7 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRc(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • Y is O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of which may be optionally further substituted with 1-3 R6 wherein Rb and Rb′, together with the atoms to which they are attached, may form an optionally substituted cyclyl or heterocyclyl ring;
      • or a pharmaceutically acceptable derivative or prodrug thereof,
      • wherein when B is phenyl, two R1 are not taken together to form a pyrazole ring.
  • In some embodiments, each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy and silylalkoxyalkyl, each of which may be optionally substituted with 1-3 R6.
  • In one aspect, the invention features a compound of formula (IV):
  • Figure US20170217923A1-20170803-C00076
      • wherein:
      • A is CH, CR4 or N;
      • B is aryl or a 5-membered heteroaryl;
      • E is aryl or a 5-membered heteroaryl;
      • L is NR5 or O;
      • one of X and Z is N and the other is CH;
      • m is 0, 1, 2, 3, 4 or 5;
      • n is 1, 2, 3 or 4;
      • p is 0, 1, 2, 3 or 4;
      • each R1 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6; wherein two R1, together with the atoms to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, or aryl ring;
      • each R2 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6; wherein two R1, together with the carbons to which they are attached, may form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • R4 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R6;
      • R5 is hydrogen; or when m is not 0, R5 and 1 R1 may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;
      • each R6 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally substituted with 1-3 R7;
      • each R7 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • Y is O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of which may be optionally further substituted with 1-3 R6, wherein Rb and Rb′, together with the atoms to which they are attached, may form an optionally substituted cyclyl or heterocyclyl ring;
  • In some embodiments, A is N. In some embodiments, A is CH. In some embodiments, A is CR4.
  • In some embodiments, B is aryl (e.g., phenyl).
  • In some embodiments, m is 0.
  • In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.
  • In some embodiments, R1 is in the ortho position. In some embodiments, R1 is in the meta position. In some embodiments, R1 is in the para position.
  • In some embodiments, R1 is C1-C8 alkyl (e.g., methyl or tert-butyl). In some embodiments, R1 is heteroaryl (e.g., oxazolyl, oxadiazolyl or quinazolinyl).
  • In some embodiments, R1 is heteroaryl substituted with 1-3 R6 (e.g., 1 R6).
  • In some embodiments, R1 is oxadiazolyl substituted with 1 R6. some embodiments, R6 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R1 is heteroaryl substituted with 2 R6. In some embodiments, R1 is quinazolinyl substituted with 2 R6. In some embodiments, one R6 is halo (e.g., bromo) and the other is heteroaryl (e.g., pyridyl).
  • In some embodiments, m is 1 and R1 is halo (e.g., fluoro, chloro or bromo). In some embodiments, m is 2 and each R1 is halo (e.g., fluoro, chloro or bromo). In some embodiments, m is 3 and each R1 is halo (e.g., fluoro, chloro or bromo). In some embodiments, R1 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R1 is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).
  • In some embodiments, R1 is haloalkoxy substituted with 1 R6. In some embodiments, R1 is —O—CF2—R6. In some embodiments, R6 is —C(Y)NRbRb′. In some embodiments, Y is O, Rb is hydrogen and Rb′ is C1-C8 alkyl (e.g., methyl). In some embodiments, R1 is —O—CF2—CH2—R6. In some embodiments, R6 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R6 is —NRbRb′. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, R6 is heterocyclyl (e.g., morpholino).
  • In some embodiments, R1 is aminoalkyl. In some embodiments, R1 is —CH2NH2. In some embodiments, R1 is alkylaminoalkyl. In some embodiments, R1 is —CH2NHCH2CH2CH3. In some embodiments, R1 is dialkylaminoalkyl. In some embodiments, R1 is —CH2N(CH(CH3)2)2.
  • In some embodiments, R1 is hydroxyalkyl. In some embodiments, R1 is —CH2OH.
  • In some embodiments, R1 is —CN.
  • In some embodiments, R1 is —NO2.
  • In some embodiments, R1 is —C(O)ORa. In some embodiments, Ra is hydrogen. In some embodiments, Ra is C1-C8 alkyl (e.g., methyl or ethyl).
  • In some embodiments, R1 is —NRcC(Y)Rc′. In some embodiments, one of Rc and Rc′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R1 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl or ethyl).
  • In some embodiments, R1 is —SO2NRbRb′. In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, R1 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is C1-C8 alkyl (e.g., methyl). In some embodiments, Re is heterocyclyl (e.g., pyrrolidinyl, piperidinyl or morpholino).
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, Y is S. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rb is hydrogen. In some embodiments, Rb is hydrogen and Rb′ is aralkyl. In some embodiments, Rb is hydrogen and Rb′ is optionally substituted benzyl. In some embodiments, Rb′ is C1-C8 alkyl, e.g., methyl, ethyl, C3 alkyl (e.g., n-propyl or isopropyl), C4 alkyl (e.g., n-butyl, sec-butyl or tert-butyl), C5 alkyl (e.g., n-pentyl, isopentyl or pentan-3-yl), C6 alkyl (e.g., n-hexyl or 3,3-dimethylbutan-2-yl), or C7 alkyl (e.g., n-heptyl or 2-heptyl).
  • In some embodiments, Rb′ is C1-C8 alkyl substituted with 1 R6. In some embodiments, R6 is —ORd. In some embodiments, Rd is aryl (e.g., phenyl). In some embodiments, Rb′ is C2-C8 alkenyl, e.g., C3 alkenyl (e.g., —CH2—CH═CH2). In some embodiments, Rb′ is C2-C8 alkynyl, e.g., C3 alkenyl (e.g., —CH2—C≡CH).
  • In some embodiments, Rb′ is aryl (e.g., phenyl). In some embodiments, Rb′ is aryl substituted with 1 R6 (e.g., phenyl substituted with 1 R6). In some embodiments, R6 is haloalkyl (e.g., trifluoromethyl). In some embodiments, Rb′ is cyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl). In some embodiments, Rb′ is cyclyl substituted with 1 R6 (e.g., cyclopropyl substituted with 1 R6 or cyclopentyl substituted with 1 R6). In some embodiments, R6 is C1-C8 alkyl (e.g., methyl). In some embodiments, R6 is —ORd. In some embodiments, Rd is aralkyl (e.g., benzyl).
  • In some embodiments, Rb′ is cyclohexyl substituted with 1 R6. In some embodiments, R6 is —C(O)ORa. In some embodiments, Ra is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, Rb′ is bicyclyl (e.g., indanyl). In some embodiments, Rb′ is heterocyclyl, e.g., a 6-membered heterocyclyl. In some embodiments, Rb′ is a 6-membered oxygen-containing heterocyclyl (e.g., tetrahydropyranyl). In some embodiments, Rb′ is a 6-membered nitrogen-containing heterocyclyl (e.g., piperidinyl).
  • In some embodiments, Rb′ is heterocyclyl substituted with 1 R6 (e.g., piperidinyl substituted with 1 R6). In some embodiments, R6 is —C(O)ORa. In some embodiments, Ra is C1-C8 alkyl (e.g., ethyl). In some embodiments, R6 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is C1-C8 alkyl (e.g., methyl or ethyl).
  • In some embodiments, Rb′ is aralkyl. In some embodiments, the alkyl is a C1-C8 alkyl (e.g., C1, C2, C3 or C4 alkyl). In some embodiments, the alkyl is a straight-chain alkyl. In some embodiments, the alkyl is a branched alkyl. In some embodiments, the aryl is phenyl. In some embodiments, Rb′ is benzyl. In some embodiments, Rb′ is phenylethyl. In some embodiments, the aryl is substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl). In some embodiments, R6 is halo (e.g., fluoro or chloro). In some embodiments, R6 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R6 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, the aryl is substituted with 2 R6. In some embodiments, each R6 is independently —ORd. In some embodiments, each Rd is independently C1-C8 alkyl (e.g., each Rd is methyl). In some embodiments, each R6 is independently halo (e.g., each R6 is fluoro).
  • In some embodiments, Rb′ is heteroaralkyl. In some embodiments, the alkyl is a C1-C8 alkyl (e.g., C1, C2 or C3 alkyl). In some embodiments, the alkyl is a straight-chain alkyl. In some embodiments, the alkyl is a branched alkyl. In some embodiments, the heteroaryl is pyridyl. In some embodiments, the heteroaryl is furanyl. In some embodiments, the heteroaryl is thiazolyl. In some embodiments, the heteroaryl is thienyl. In some embodiments, the heteroaryl is substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl). In some embodiments, R6 is haloalkyl (e.g., trifluoromethyl).
  • In some embodiments, Rb′ is cyclylalkyl. In some embodiments, the alkyl is a C1-C8 alkyl (e.g., C1 alkyl). In some embodiments, the cyclyl group is cyclopropyl. In some embodiments, the cyclyl group is cyclopentyl. In some embodiments, the cyclyl group is a bicyclic group. In some embodiments, the bicyclic group is indanyl. In some embodiments, Rb′ is cyclylalkyl substituted with 1 R6. In some embodiments, R6 is aryl (e.g., phenyl).
  • In some embodiments, Rb′ is heterocyclylalkyl. In some embodiments, the alkyl is a C1-C8 alkyl (e.g., C1 alkyl). In some embodiments, the heterocyclyl group is tetrahydropyranyl.
  • In some embodiments, Rb′ is haloalkyl (e.g., fluoroethyl, difluoroethyl, trifluoroethyl or trifluoropropyl).
  • In some embodiments, Rb′ is alkoxyalkyl. In some embodiments, the alkyl is a C1-C8 alkyl (e.g., C1, C2, C3 or C4 alkyl). In some embodiments, the alkyl is a straight-chain alkyl. In some embodiments, the alkyl is a branched alkyl. In some embodiments, the alkoxy is methoxy.
  • In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl, both ethyl or both isopropyl).
  • In some embodiments, R1 and R5, together with the atoms to which they are attached, form a heteroaryl ring (e.g., a substituted heteroaryl ring). In some embodiments, R1 and R5, together with the atoms to which they are attached, form a heterocyclyl ring (e.g., a substituted heterocyclyl ring).
  • In some embodiments, R1, R5, B and L are taken together to form a bicyclic heteroaryl or heterocyclic ring.
  • In some embodiments, R1, R5, B and L are taken together to form
  • Figure US20170217923A1-20170803-C00077
  • In some embodiments, R6 is halo. In some embodiments, R6 is at the 6, 7, or 8 position.
  • In some embodiments, R1, R5, B and L are taken together to form a group selected from:
  • Figure US20170217923A1-20170803-C00078
  • In some embodiments, R2 is aryl.
  • In some embodiments, each R1 is independently C1-C8 alkyl (e.g., each R1 is methyl). In some embodiments, each R1 is independently halo (e.g., each R1 is fluoro or each R1 is chloro). In some embodiments, one R1 is fluoro and the other is chloro. In some embodiments, one R1 is chloro and the other is bromo.
  • In some embodiments, each R1 is independently —ORd. In some embodiments, each Rd is independently C1-C8 alkyl (e.g., each Rd is methyl).
  • In some embodiments, one R1 is halo (e.g., chloro) and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, one R1 is halo (e.g., fluoro) and the other is heterocyclylalkyl (e.g., —CH2-heterocyclyl). In some embodiments, the heterocyclyl is morpholino. In some embodiments, the heterocyclyl is pyrrolidinyl. In some embodiments, the heterocyclyl is piperazinyl. In some embodiments, the piperazinyl is substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is halo (e.g., fluoro or chloro) and the other is haloalkyl (e.g., trifluoromethyl).
  • In some embodiments, one R1 is halo (e.g., chloro) and the other is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).
  • In some embodiments, one R1 is halo (e.g., chloro) and the other is —C(O)ORa. In some embodiments, Ra is hydrogen.
  • In some embodiments, one R1 is halo (e.g., fluoro or chloro) and the other is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is halo (e.g., chloro) and the other is —NRcC(Y)Rc′. In some embodiments, Y is O. In some embodiments, Rc is hydrogen and Rc′ is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is halo (e.g., fluoro or chloro) and the other is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is halo (e.g., fluoro or chloro) and the other is —CN.
  • In some embodiments, one R1 is halo (e.g., chloro) and the other is —NO2.
  • In some embodiments, one R1 is —C(O)ORa and the other is —NO2. In some embodiments, Ra is hydrogen.
  • In some embodiments, one R1 is —C(O)ORa and the other is —ORd. In some embodiments, each Ra and Rd is hydrogen.
  • In some embodiments, one R1 is —C(Y)NRbRb′ and the other is haloalkyl (e.g., trifluoromethyl). In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, one R1 is —C(Y)NRbRb′ and the other is haloalkoxy (e.g., trifluoromethoxy). In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, one R1 is —C(Y)NRbRb′ and the other is —S(O)qRf. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rf is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is —C(Y)NRbRb′ and the other is —CN. In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, one R1 is —ORd and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is —ORd and the other is haloalkyl (e.g., trifluoromethyl). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is —ORd and the other is —C(O)ORa. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, Ra is hydrogen. In some embodiments, Ra is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is —ORd and the other is —NRcC(O)Rc′. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, Rc is hydrogen and Rc′ is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R1 is haloalkyl (e.g., trifluoromethyl) and the other is —CN.
  • In some embodiments, two R1, together with the atoms to which they are attached, are taken together to form a cyclyl ring (e.g., a substituted cyclyl ring). In some embodiments, two R1, together with the atoms to which they are attached, are taken together to form a heterocyclyl ring (e.g., a substituted heterocyclyl ring). In some embodiments, two R1, together with the atoms to which they are attached, are taken together to form a heteroaryl ring (e.g., a substituted heteroaryl ring).
  • In some embodiments, two R1 and ring B are taken together to form a group selected from:
  • Figure US20170217923A1-20170803-C00079
    Figure US20170217923A1-20170803-C00080
  • In some embodiments, R2 is aryl.
  • In some embodiments, each R1 is independently halo (e.g., all three R1 are fluoro or all three R1 are chloro).
  • In some embodiments, two R1 are independently halo (e.g., both are chloro) and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, two R1 are independently halo (e.g., both are chloro) and the other is heteroaryl (e.g., pyrrolyl). In some embodiments, two R1 are independently halo (e.g., both are fluoro) and the other is —C(Y)NRbRb′ (e.g., —C(O)NH2). In some embodiments, two R1 are independently C1-C8 alkyl (e.g., both are methyl) and the other is halo (e.g., chloro or bromo).
  • In some embodiments, one R1 is C1-C8 alkyl (e.g., methyl), and two R1 together with the atoms to which they are attached, are taken together to form a heterocyclyl ring.
  • In some embodiments, one R1 is —ORd, and two R1, together with the atoms to which they are attached, are taken together to form a heterocyclyl ring. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, three R1 and ring B are taken together to form a group selected from:
  • Figure US20170217923A1-20170803-C00081
  • In some embodiments, B is a 6-membered heteroaryl.
  • In some embodiments, B is pyridyl. In some embodiments, B is 3-pyridyl. In some embodiments, m is 2. In some embodiments, two R1, together with the atoms to which they are attached, are taken together to form an aryl ring (e.g., a phenyl ring). In some embodiments, m is 3. In some embodiments, one R1 is —ORd, and two R1, together with the atoms to which they are attached, are taken together to form an aryl ring (e.g., a phenyl ring). In some embodiments, Rd is hydrogen.
  • In some embodiments, B is pyrazolyl. In some embodiments, m is 2. In some embodiments, two R1, together with the atoms to which they are attached, are taken together to form a cyclyl ring (e.g., a cyclohexyl ring).
  • In some embodiments, B is selected from:
  • Figure US20170217923A1-20170803-C00082
  • In some embodiments, B is a 5-membered heteroaryl (e.g., pyrazolyl).
  • In some embodiments, m is 1.
  • In some embodiments, R1 is aryl (e.g., phenyl).
  • In some embodiments, R1 is phenyl substituted with 1 R6.
  • In some embodiments, R6 is halo (e.g., chloro). In some embodiments, R1 is selected from:
  • Figure US20170217923A1-20170803-C00083
  • In some embodiments, m is 2.
  • In some embodiments, one R1 is C1-C8 alkyl (e.g., methyl) and the other is aryl (e.g., phenyl). In some embodiments, the aryl is phenyl substituted with 1 R6. In some embodiments, R6 is halo (e.g., chloro). In some embodiments, R1 is:
  • Figure US20170217923A1-20170803-C00084
  • In some embodiments, B is thienyl. In some embodiments, B is selected from:
  • Figure US20170217923A1-20170803-C00085
  • In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments m is 2 and two R1, together with the atoms to which they are attached, form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring
  • In some embodiments, R1 is —C(O)ORa. In some embodiments, Ra is C1-C8 alkyl (e.g., ethyl).
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, m is 2.
  • In some embodiments, one R1 is C1-C8 alkyl (e.g., methyl) and the other is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen.
  • In some embodiments, B is thiazolyl.
  • In some embodiments, m is 1.
  • In some embodiments, R1 is aryl (e.g., phenyl).
  • In some embodiments, m is 2.
  • In some embodiments, two R1, together with the atoms to which they are attached, form an aryl ring. In some embodiments, the aryl ring is substituted with —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, B is:
  • Figure US20170217923A1-20170803-C00086
  • In some embodiments, B is:
  • Figure US20170217923A1-20170803-C00087
  • In some embodiments, E is aryl (e.g., phenyl).
  • In some embodiments, n is 1.
  • In some embodiments, R2 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is C1-C8 alkyl substituted with 1-3 R6. In some embodiments, R2 is C1 alkyl substituted with 1 R6.
  • In some embodiments, R6 is —NRbRb′. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl, or Rb and Rb′ are both ethyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is haloalkyl (e.g., trifluoroethyl).
  • In some embodiments, R6 is —ORd. In some embodiments, Rd is cyclyl (e.g., cyclopentyl). In some embodiments, Rd is heterocyclylalkyl (e.g., —CH2— tetrahydropyranyl).
  • In some embodiments, R2 is C2 alkyl substituted with 1 R6.
  • In some embodiments, R6 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rb and Rb′, are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R6 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is heterocyclyl (e.g., morpholino or thiomorpholino). In some embodiments, Re is thiomorpholino substituted with 2 R6. In some embodiments, each R6 is oxo. In some embodiments, Re is:
  • Figure US20170217923A1-20170803-C00088
  • In some embodiments, R2 is C3 alkyl substituted with 1 R6.
  • In some embodiments, R6 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rb and Rb′, are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R6 is —NRcC(Y)Rc′. In some embodiments, Y is O. In some embodiments, Rc and Rc′ are each independently C1-C8 alkyl (e.g., Rc and Rc′ are both methyl).
  • In some embodiments, R6 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R6 is silyloxy (e.g., tert-butyldimethylsilyloxy).
  • In some embodiments, R6 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is heterocyclyl (e.g., morpholino).
  • In some embodiments, R2 is C2-C8 alkynyl. In some embodiments, R2 is C2-C5 alkynyl substituted with 1 R6 (e.g., C3 alkynyl substituted with 1 R6). In some embodiments, R2 is —C═C—CH2—R6. In some embodiments, R6 is —NRbRb′. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, R6 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, R6 is silyloxy (e.g., tert-butyldimethylsilyloxy). In some embodiments, R6 is heterocyclyl (e.g., morpholino or thiomorpholino). In some embodiments, R6 is thiomorpholino substituted with 2 R7. In some embodiments, each R7 is oxo. In some embodiments, R6 is:
  • Figure US20170217923A1-20170803-C00089
  • In some embodiments, R2 is aryl (e.g., phenyl). In some embodiments, R2 is unsubstituted phenyl.
  • In some embodiments, R2 is phenyl substituted with 1 R6.
  • In some embodiments, R6 is heterocyclylalkyl (e.g., —CH2-morpholino). In some embodiments, R6 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R6 is —CN. In some embodiments, R6 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R6 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is heterocyclyl (e.g., morpholino).
  • In some embodiments, R2 is phenyl substituted with 2 R6.
  • In some embodiments, each R6 is independently —ORd. In some embodiments, each Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, one R6 is halo (e.g., fluoro) and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, one R6 is —C(O)ORa and the other is —ORd. In some embodiments, Ra and Rd are each independently C1-C8 alkyl (e.g., Ra and Rd are both methyl).
  • In some embodiments, R2 is heteroaryl.
  • In some embodiments, R2 is isoxazolyl. In some embodiments, R2 is isoxazolyl substituted with 2 R6. In some embodiments, each R6 is independently C1-C8 alkyl (e.g., R6 is methyl).
  • In some embodiments, R2 is pyrazolyl. In some embodiments, R2 is pyrazolyl substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is pyridyl. In some embodiments, R2 is unsubstituted pyridyl. In some embodiments, R2 is pyridyl substituted with 1 R6. In some embodiments, R6 is halo (e.g., fluoro). In some embodiments, R6 is —NRbRb′. In some embodiments, Rb and Rb′ are each hydrogen. In some embodiments, R6 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R6 is heterocyclyl (e.g., morpholino or piperazinyl). In some embodiments, R6 is piperazinyl substituted with 1 R7. In some embodiments, R7 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is pyrimidinyl.
  • In some embodiments, R2 is pyridazinyl.
  • In some embodiments, R2 is cyclyl (e.g., cyclopropyl).
  • In some embodiments, R2 is heterocyclyl (e.g., morpholino or pyrrolidinyl).
  • In some embodiments, R2 is aralkyl (e.g., benzyl).
  • In some embodiments, R2 is heterocyclylalkyl. In some embodiments, the alkyl is C1 alkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the heterocyclyl is piperidinyl. In some embodiments, the heterocyclyl is piperazinyl. In some embodiments, the heterocyclyl is piperazinyl substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl). In some embodiments, the heterocyclyl is pyrrolidinyl. In some embodiments, the heterocyclyl is morpholino. In some embodiments, the heterocyclyl is thiomorpholino. In some embodiments, the heterocyclyl is thiomorpholino substituted with 2 R6. In some embodiments, each R6 is oxo. In some embodiments, the heterocyclyl is:
  • Figure US20170217923A1-20170803-C00090
  • In some embodiments, R2 is halo (e.g., fluoro, chloro, bromo or iodo).
  • In some embodiments, R2 is haloalkyl (e.g., trifluoromethyl).
  • In some embodiments, R2 is haloalkoxy (e.g., trifluoromethoxy).
  • In some embodiments, R2 is —CN.
  • In some embodiments, R2 is —NO2.
  • In some embodiments, R2 is —C(O)ORa. In some embodiments, Ra is hydrogen. In some embodiments, Ra is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are each hydrogen. In some embodiments, Rb and Rb′, are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl or ethyl). In some embodiments, the C1-C8 alkyl is ethyl substituted with 2 R6. In some embodiments, each R6 is independently —ORd. In some embodiments, each Rd is C1-C8 alkyl (e.g., each Rd is methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is heterocyclylalkyl (e.g., —CH2—CH2-morpholino). In some embodiments, one of Rb and Rb′ is hydrogen and the other is haloalkyl (e.g., trifluoroethyl).
  • In some embodiments, R2 is —NRbRb′. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is heterocyclyl (e.g., tetrahydropyranyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is heterocyclylalkyl. In some embodiments, the alkyl is C1 alkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the heterocyclyl is morpholino. In some embodiments, the heterocyclyl is pyrrolidinyl. In some embodiments, the heterocyclyl is tetrahydrofuranyl. In some embodiments, the heterocyclyl is tetrahydropyranyl. In some embodiments, one of Rb and Rb′ is hydrogen and the other is hydroxyalkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, one of Rb and Rb′ is hydrogen and the other is alkoxyalkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the alkoxy is methoxy. In some embodiments, one of Rb and Rb′ is hydrogen and the other is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is C1-C8 alkyl (e.g., methyl). In some embodiments, Re is heterocyclyl. In some embodiments, Re is tetrahydropyranyl.
  • In some embodiments, R2 is —ORd.
  • In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, Rd is methyl substituted with 1 R6. In some embodiments, R6 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is heterocyclyl (e.g., morpholino). In some embodiments, R6 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl or Rb and Rb′ are both ethyl). In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl or ethyl).
  • In some embodiments, Rd is ethyl. In some embodiments, Rd is C3 alkyl (e.g., isopropyl or n-propyl). In some embodiments, Rd is optionally substituted heteroaralkyl. In some embodiments, Rd is optionally substituted pyrindinalkyl.
  • In some embodiments, Rd is n-propyl substituted with 1 R6. In some embodiments, R6 is —NRcC(Y)Rc′. In some embodiments, Y is O. In some embodiments, Rc and Rc′ are each independently C1-C8 alkyl (e.g., Rc and Rc′ are both methyl). In some embodiments, Rd is cyclyl (e.g., cyclopentyl).
  • In some embodiments, Rd is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, the pyridyl is substituted with 1 R6. In some embodiments, R6 is alkyl (e.g., methyl) or haloalkyl (e.g., CF3). In some embodiments, R6 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, Rd is heterocyclylalkyl. In some embodiments, the alkyl is C1 alkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the alkyl is C4 alkyl. In some embodiments, the heterocyclyl is morpholino. In some embodiments, the heterocyclyl is piperidinyl. In some embodiments, the heterocyclyl is tetrahydrofuranyl. In some embodiments, Rd is cyclylalkyl (e.g., —CH2-cyclobutyl).
  • In some embodiments, Rd is alkoxyalkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the alkoxy is methoxy.
  • In some embodiments, Rd is dialkylaminoalkyl. In some embodiments, the alkyl is C2 alkyl. In some embodiments, the alkyl is C3 alkyl. In some embodiments, the dialkylamino is dimethylamino.
  • In some embodiments, R2 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is heterocyclyl. In some embodiments, Re is piperidinyl. In some embodiments, Re is pyrrolidinyl. In some embodiments, Re is piperazinyl. In some embodiments, Re is piperazinyl substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl). In some embodiments, Re is morpholino. In some embodiments, Re is thiomorpholino. In some embodiments, Re is thiomorpholino substituted with 2 R6. In some embodiments, each R6 is oxo. In some embodiments, Re is:
  • Figure US20170217923A1-20170803-C00091
  • In some embodiments, n is 2.
  • In some embodiments, each R2 is independently halo (e.g., each R2 is chloro).
  • In some embodiments, each R2 is independently —ORd.
  • In some embodiments, each Rd is C1-C8 alkyl.
  • In some embodiments, each R2 is methoxy. In some embodiments, one R2 is methoxy and the other is ethoxy. In some embodiments, one R2 is methoxy and the other is propoxy. In some embodiments, one R2 is methoxy and the other is isopropoxy.
  • In some embodiments, one R2 is methoxy and the other is ethoxy substituted with 1 R6. In some embodiments, R6 is —NRbRb′. In some embodiments, Rb and Rb′, are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, R6 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is methoxy and the other is propoxy substituted with 1 R6. In some embodiments, R6 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is —ORd and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl or ethyl).
  • In some embodiments, one R2 is —ORd and the other is halo (e.g., chloro). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is —ORd and the other is —CN. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is —ORd and the other is —C(O)ORa. In some embodiments, Rd and Ra are both hydrogen.
  • In some embodiments, one R2 is —ORd and the other is C1-C8 alkyl (e.g., methyl). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is —ORd and the other is —C(Y)Re. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, Y is O. In some embodiments, Re is heterocyclyl (e.g., morpholino).
  • In some embodiments, one R2 is halo (e.g., chloro or bromo) and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is C1-C8 alkyl (e.g., methyl) and the other is —CN.
  • In some embodiments, one R2 is C1-C8 alkyl (e.g., methyl) and the other is heteroaryl (e.g., pyridyl). In some embodiments, the pyridyl is substituted with 1 R6. In some embodiments, R6 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, one R2 is C1-C8 alkyl (e.g., methyl) and the other is heterocyclylalkyl (e.g., —CH2-morpholino).
  • In some embodiments, p is 0.
  • In some embodiments, p is 1.
  • In some embodiments, R3 is C1-C8 alkyl (e.g., methyl). In some embodiments, R3 is halo (e.g., chloro). In some embodiments, R3 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R3 is oxo.
  • In some embodiments, R3 is —ORd. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R3 is —NRbRb′. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R3 is heterocyclyl (e.g., piperazinyl). In some embodiments, R3 is piperazinyl substituted with 1 R6. In some embodiments, R6 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, E is a 5-membered heteroaryl ring.
  • In some embodiments, E is a thiophene ring.
  • In some embodiments, E is a pyrrole ring.
  • In some embodiments, n is 1. In some embodiments, R2 is C1-C8 alkyl (e.g., methyl). In some embodiments, E is an N-methylpyrrole ring.
  • In some embodiments, L is NR5. In some embodiments, R5 is hydrogen.
  • In some embodiments, L is O.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00092
  • In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, R1 is —C(Y)NRbRb′.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00093
  • In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, R1 is —C(Y)NRbRb′.
  • In some embodiments, L and
  • Figure US20170217923A1-20170803-C00094
  • In some embodiments, L and
  • Figure US20170217923A1-20170803-C00095
  • In some embodiments, L is NH, and
  • Figure US20170217923A1-20170803-C00096
  • is selected from
  • Figure US20170217923A1-20170803-C00097
    Figure US20170217923A1-20170803-C00098
  • In some embodiments R6 is halo. In some embodiments, Rb or Rb′ are disubstituted with R6 (e.g., dichloro, 4-fluoro, 3-chloro, or difluoro).
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00099
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, R1 is halo. In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, m is 2 and two R1 are 3,4-dichloro; 3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro, 4-fluoro; or 3-chloro, 5-fluoro. In some embodiments, R2 is —C(O)NRbRb′ and R3 is H. In some embodiments, Rb and Rb′ are H. In some embodiments, Rb and Rb′ are independently C1-C4 alkyl or halo-substituted C1-C4 alkyl. In some embodiments, Rb is methyl and Rb′ is trifluoroethyl. In some embodiments, R1 is C1-C4 alkoxy or halo-substituted C1-C4 alkoxy. In some embodiments, n and p are zero.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00100
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, R1 is halo. In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, m is 2 and two R1 are 3,4-dichloro; 3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro, 4-fluoro; or 3-chloro, 5-fluoro. In some embodiments, R2 is —C(O)NRbRb′ and R3 is H. In some embodiments, Rb and Rb′ are H. In some embodiments, Rb and Rb′ are independently C1-C4 alkyl or halo-substituted C1-C4 alkyl. In some embodiments, Rb is methyl and Rb′ is trifluoroethyl. In some embodiments, R1 is C1-C4 alkoxy or halo-substituted C1-C4 alkoxy. In some embodiments, n and p are zero.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00101
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, R1 is halo. In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, m is 2 and two R1 are 3,4-dichloro; 3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro, 4-fluoro; or 3-chloro, 5-fluoro. In some embodiments, R2 is —C(O)NRbRb′ and R3 is H. In some embodiments, Rb and Rb′ are H. In some embodiments, Rb and Rb′ are independently C1-C4 alkyl or halo-substituted C1-C4 alkyl. In some embodiments, Rb is methyl and Rb′ is trifluoroethyl. In some embodiments, R1 is C1-C4 alkoxy or halo-substituted C1-C4 alkoxy. In some embodiments, n and p are zero.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00102
  • In some embodiments, R1 is —C(Y)NRbRb′. In some embodiments, R1 is halo. In some embodiments, R2 is C1-C4 alkoxy. In some embodiments, R2 is halo. In some embodiments, m is 2 and two R1 are 3,4-dichloro; 3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro, 4-fluoro; or 3-chloro, 5-fluoro. In some embodiments, R2 is —C(O)NRbRb′ and R3 is H. In some embodiments, Rb and Rb′ are H. In some embodiments, Rb and Rb′ are independently C1-C4 alkyl or halo-substituted C1-C4 alkyl. In some embodiments, Rb is methyl and Rb′ is trifluoroethyl. In some embodiments, R1 is C1-C4 alkoxy or halo-substituted C1-C4 alkoxy. In some embodiments, n and p are zero.
    • Compounds of Formula (V)
  • The following aspects and embodiments relate to compounds of formula (V), corresponding to formula (I) of U.S. Provisional Patent Application No. 61/291,550, entitled “Therapeutic Compounds and Related Methods of Use” filed on Dec. 31, 2009, and incorporated herein by reference in its entirety.
    • Item 40. A compound of formula (V): t,?
      • wherein:
      • L is CR4R5, O, C(O), NR6C(O), or NR7;
      • A is CR8, CH or N;
      • each X1, X2, X3, X4 and X5 is independently CH or N, provided that at least two of X1, X2, X3, X4 and X5 are N;
      • n is 0, 1, 2, 3 or 4;
      • p is 0, 1, 2 or 3;
      • R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl or heterocyclylalkyl, each of which may be optionally substituted with 1-5 R9; wherein R1 or R9 may optionally be taken together with one of R4, R5, R6 or R7, and the atoms to which they are attached, to form a cyclyl, heterocyclyl, aryl or heteroaryl ring that is optionally substituted with 1-3 R10;
      • each R2 and R3 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf; each of which is optionally substituted with 1-3 R11;
      • each R4, R5, R6 and R7 is independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each R8, R9, R10 and R11 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which may be optionally further substituted; wherein two R8, two R9, two R10 or two R11 may optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • each Y is independently O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of which may be optionally substituted with 1-3 R8,
      • or a pharmaceutically acceptable derivative or prodrug thereof.
  • In some embodiments, A is CH. In some embodiments, A is N.
  • In some embodiments, L is NR7. In some embodiments, R7 is H.
  • In some embodiments, R1 is aryl (e.g., phenyl).
  • In some embodiments, R1 is phenyl substituted with 1 R9. In some embodiments, R1 is phenyl substituted with 1 R9 in the ortho position. In some embodiments, R1 is phenyl substituted with 1 R9 in the meta position. In some embodiments, R9 is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy). In some embodiments, R9 is —CN. In some embodiments, R9 is —C(O)ORa. In some embodiments, Ra is hydrogen. In some embodiments, R9 is —C(Y)NRbRb′. In some embodiments, Y is O. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, R1 is:
  • Figure US20170217923A1-20170803-C00103
  • In some embodiments, one of Rb and Rb′ is hydrogen and the other is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R1 is phenyl substituted with 2 R9. In some embodiments, each R9 is independently halo (e.g., each R9 is fluoro or each R9 is chloro). In some embodiments, one R9 is fluoro and the other is chloro. In some embodiments, one R9 is halo (e.g., chloro) and the other is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).
  • In some embodiments, 2 R9 are taken together with the atoms to which they are attached to form a heterocyclyl ring, e.g., a 5-membered heterocyclyl ring (e.g., a dioxole ring). In some embodiments, the dioxole ring is unsubstituted. In some embodiments, the dioxole ring is substituted. In some embodiments, the dioxole ring is substituted with two fluoro substituents. In some embodiments, R1 is selected from:
  • Figure US20170217923A1-20170803-C00104
  • In some embodiments, R1 is aralkyl (e.g., benzyl). In some embodiments, R1 is aralkyl substituted with 2 R9 (e.g., benzyl substituted with 2 R9). In some embodiments, 2 R9 substituents are on the phenyl ring. In some embodiments, each R9 is independently halo (e.g., each R9 is chloro).
  • In some embodiments, R1 is alkyl (e.g., methyl).
  • In some embodiments, n is 0.
  • In some embodiments, n is 1.
  • In some embodiments, R2 is C1-C8 alkyl (e.g., methyl). In some embodiments, R2 is C1-C8 alkyl substituted with 1 R11 (e.g., methyl substituted with 1 R11). In some embodiments, R11 is heterocyclyl (e.g., morpholino).
  • In some embodiments, R2 is aryl (e.g., phenyl). In some embodiments, R2 is phenyl substituted with 1 R11. In some embodiments, R11 is —CN. In some embodiments, R11 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R11 is halo.
  • In some embodiments, R2 is halo (e.g., fluoro, chloro, bromo or iodo).
  • In some embodiments, R2 is —NRcC(Y)Rc′. In some embodiments, Rc is hydrogen. In some embodiments, Y is O. In some embodiments, Rc′ is alkyl (e.g., methyl). In some embodiments, Rc′ is aryl (e.g., phenyl). In some embodiments, Rc′ is phenyl substituted with 1 R8. In some embodiments, R8 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, Rc′ is heteroaryl. In some embodiments, Rc′ is furanyl. In some embodiments, Rc′ is pyridyl. In some embodiments, Rc′ is pyridyl substituted with 1 R8. In some embodiments, R8 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, Rc′ is cyclyl (e.g., cyclohexyl). In some embodiments, Rc′ is cyclohexyl substituted with 1 R8. In some embodiments, R8 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, Rc′ is heterocyclyl (e.g., tetrahydropyranyl). In some embodiments, R2 is —NRbRb′. In some embodiments, Rb and Rb′ are both hydrogen. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl).
  • In some embodiments, R2 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl or ethyl). In some embodiments, Rd is ethyl substituted with 1 R8. In some embodiments, R8 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R2 is —OCH2CH2OCH3. In some embodiments, R2 is —OCH2CH2OCH2CH2CH3. In some embodiments, R2 is —OCH2CH2OCH2CH2OCH3.
  • In some embodiments, n is 2.
  • In some embodiments, one R2 is C1-C8 alkyl (e.g., methyl) and the other is halo (e.g., chloro).
  • In some embodiments, one R2 is —ORd and the other is halo (e.g., chloro). In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, X1 and X4 are N and X2, X3 and X5 are CH.
  • In some embodiments, X1 and X3 are N and X2, X4 and X5 are CH.
  • In some embodiments, X2 and X3 are N and X1, X4 and X5 are CH.
  • In some embodiments, X2 and X4 are N and X1, X3 and X5 are CH.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00105
  • wherein s is 0, 1, 2, 3 or 4.
  • In some embodiments, R9 is —C(O)NH2, C1-C4 alkoxy, or substituted C1-C4 alkoxy. In some embodiments, R9 is halo.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00106
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R1 is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, LR1 is NH(CH3).
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00107
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R1 is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, LR1 is NH(CH3).
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00108
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R1 is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, LR1 is NH(CH3).
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00109
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R1 is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, LR1 is NH(CH3).
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00110
  • wherein t is 1-3.
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R1 is heteroaralkyl (e.g., —CH2-pyridyl). In some embodiments, LR1 is NH(CH3). In some embodiments, R11 is independently halo, nitrile, C1-C4 alkoxy, —C(O)NH2, hydroxy, or C1-C4 hydroxyalkyl. In some embodiments, R11 is fluoro. In some embodiments, R11 is methoxy, ethoxy, or methoxyethoxy ether. In some embodiments, R11 is —OCH2CH2OCH3. In some embodiments, R1 is —OCH2CH2OCH2CH2CH3. In some embodiments, R11 is —OCH2CH2OCH2CH2OCH3.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00111
  • wherein t is 1-3.
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, LR1 is NH(CH3). In some embodiments, R11 is independently halo, nitrile, C1-C4 alkoxy, —C(O)NH2, hydroxy, or C1-C4 hydroxyalkyl. In some embodiments, R11 is fluoro. In some embodiments, R11 is methoxy, ethoxy, or methoxyethoxy ether. In some embodiments, R11 is —OCH2CH2OCH3. In some embodiments, R11 is —OCH2CH2OCH2CH2CH3. In some embodiments, R11 is —OCH2CH2OCH2CH2OCH3.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00112
  • wherein t is 1-3.
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, LR1 is NH(CH3). In some embodiments, R11 is independently halo, nitrile, C1-C4 alkoxy, —C(O)NH2, hydroxy, or C1-C4 hydroxyalkyl. In some embodiments, R11 is fluoro. In some embodiments, R11 is methoxy, ethoxy, or methoxyethoxy ether. In some embodiments, R11 is —OCH2CH2OCH3. In some embodiments, R1 is —OCH2CH2OCH2CH2CH3. In some embodiments, R11 is —OCH2CH2OCH2CH2OCH3.
  • In some embodiments, the compound is:
  • Figure US20170217923A1-20170803-C00113
  • wherein t is 1-3.
  • In some embodiments, R1 is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, LR1 is NH(CH3). In some embodiments, R11 is independently halo, nitrile, C1-C4 alkoxy, —C(O)NH2, hydroxy, or C1-C4 hydroxyalkyl. In some embodiments, R11 is fluoro. In some embodiments, R11 is methoxy, ethoxy, or methoxyethoxy ether. In some embodiments, R11 is —OCH2CH2OCH3. In some embodiments, R11 is —OCH2CH2OCH2CH2CH3. In some embodiments, R11 is —OCH2CH2OCH2CH2OCH3.
    • Compounds of Formula (VI)
  • The following aspects and embodiments relate to compounds of formula (VI) corresponding to formula (I) of U.S. Provisional Patent Application No. 61/291,554, entitled “Therapeutic Compounds and Related Methods of Use” filed on Dec. 31, 2009, and incorporated herein by reference in its entirety.
    • Item 41. A compound of formula (VI):
  • Figure US20170217923A1-20170803-C00114
      • wherein:
      • A is CR5, CH or N;
      • L is O or NR6;
      • 1, 2 or 3 of X1, X2, X3, X4 and X5 are N and the others are CH;
      • m is 0, 1, 2 or 3;
      • n is 0, 1, 2, 3 or 4;
      • R1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R7; or when L is NR6, R1 or R7 may be taken together with R6 and the atoms to which they are attached to form a heterocyclyl or heteroaryl ring that is optionally substituted with 1-3 Rs;
      • R2 is aryl or heteroaryl, each of which is optionally substituted with 1-5 R9;
      • each R3, R4 and R5 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R10;
      • R6 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11;
      • each R7, R8, R9 and R10 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; wherein two R7, two R8, two R9 or two R10 may optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
      • each R11 and R12 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thiono, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
      • each Y is independently O or S;
      • q is 1 or 2; and
      • each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of which may be optionally substituted with 1-3 R7;
      • or a pharmaceutically acceptable derivative or prodrug thereof,
      • wherein when R1 is cyclopropyl, R9 is not:
  • Figure US20170217923A1-20170803-C00115
  • In some embodiments, R9 is not:
  • Figure US20170217923A1-20170803-C00116
  • In some embodiments, R1 is C1-C8 alkyl, which is optionally substituted with 1-3 R7; or when L is NR6, R1 and R6 may be taken together with the atoms to which they are attached to form a heterocyclyl or heteroaryl ring that is optionally substituted with 1-3 R8.
  • In some embodiments, A is CH. In some embodiments, A is N.
  • In some embodiments, L is NR6. In some embodiments, R6 is hydrogen.
  • In some embodiments, R1 is C1-C8 alkyl, e.g., methyl, ethyl, C3 alkyl (e.g., n-propyl or isopropyl), C4 alkyl (e.g., n-butyl, isobutyl or tert-butyl), or C5 alkyl (e.g., pentan-3-yl).
  • In some embodiments, R1 is C1-C8 alkyl substituted with 1-3 R7 (e.g., C1-C8 alkyl substituted with 1 R7). In some embodiments, R1 is methyl substituted with 1 R7. In some embodiments, R7 is cyclyl (e.g., cyclopropyl). In some embodiments, R7 is aryl (e.g., phenyl).
  • In some embodiments, R1 is ethyl substituted with 1 R7. In some embodiments, R7 is aryl (e.g., phenyl). In some embodiments, R7 is —ORd. In some embodiments, Rd is aryl (e.g., phenyl).
  • In some embodiments, R1 is n-propyl substituted with 1 R7. In some embodiments, R7 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., C3 alkyl, e.g., n-propyl).
  • In some embodiments, R1 is C1-C8 alkyl substituted with 3 R7. In some embodiments, R1 is ethyl substituted with 3 R7. In some embodiments, each R7 is independently halo (e.g., each R7 is fluoro). In some embodiments, R1 is 2,2,2-trifluoroethyl.
  • In some embodiments, R1 is C2-C8 alkenyl, e.g., C3 alkenyl (e.g., —CH2—CH═CH2).
  • In some embodiments, R1 is C2-C8 alkynyl, e.g., C3 alkynyl (e.g. —CH2—C≡CH).
  • In some embodiments, R1 is cyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl). In some embodiments, the cyclyl group is a bicyclic group (e.g., indanyl).
  • In some embodiments, R1 is heterocyclyl (e.g., piperidyl). In some embodiments, R1 is piperidyl substituted with 1 R7. In some embodiments, R7 is —C(Y)Re. In some embodiments, Y is O. In some embodiments, Re is C1-C8 alkyl (e.g., methyl). In some embodiments, R7 is —ORd.
  • In some embodiments, R6 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R1 and R6 are taken together with the atoms to which they are attached to form a heterocyclyl ring (e.g., a pyrrolidine ring).
  • In some embodiments, R1 and R6 are taken together with the atoms to which they are attached to form a heteroaryl ring (e.g., an imidazole ring).
  • In some embodiments, L is O.
  • In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is aryl (e.g., phenyl). In some embodiments, R2 is unsubstituted phenyl. In some embodiments, R2 is phenyl substituted with 1-3 R9. In some embodiments, R2 is phenyl substituted with 1 R9.
  • In some embodiments, R2 is:
  • Figure US20170217923A1-20170803-C00117
  • In some embodiments, R9 is halo (e.g., fluoro or chloro). In some embodiments, R9 is —CN. In some embodiments, R9 is —NO2. In some embodiments, R9 is haloalkoxy (e.g., trifluoroethoxy). In some embodiments, R9 is —NRbRb′. In some embodiments, Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl).
  • In some embodiments, R9 is —ORd. In some embodiments, R9 is —OCH2CH2OCH3. In some embodiments, R9 is —OCH2CH2OCH2CH2CH3. In some embodiments, R9 is —OCH2CH2OCH2CH2OCH3. In some embodiments, Rd is hydrogen. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, Rd is methyl substituted with 1 R7. In some embodiments, R7 is —CYNRbRb′. In some embodiments, Y is O and Rb and Rb′ are each independently C1-C8 alkyl (e.g., Rb and Rb′ are both methyl). In some embodiments, Rd is ethyl. In some embodiments, Rd is ethyl substituted with 1 R7. In some embodiments, R7 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R7 is heterocyclyl (e.g., morpholino).
  • In some embodiments, R9 is hydroxyalkyl (e.g., —CH2OH). In some embodiments, R9 is alkoxyalkyl (e.g., —CH2—O—CH3). In some embodiments, R9 is —C(O)Re. In some embodiments, Re is heterocyclyl (e.g., morpholino). In some embodiments, R9 is —S(O)qRf. In some embodiments, q is 1. In some embodiments, Rf is C1-C8 alkyl (e.g., methyl.).
  • In some embodiments, R2 is phenyl substituted with 2 R9. In some embodiments, each R9 is independently halo (e.g., each R9 is fluoro). In some embodiments, each R9 is independently —ORd. In some embodiments, each Rd is independently C1-C8 alkyl (e.g., each Rd is methyl).
  • In some embodiments, R2 is heteroaryl. In some embodiments, R2 is a 6-membered heteroaryl. In some embodiments, R2 is a 6-membered nitrogen-containing heteroaryl, e.g., pyridyl. In some embodiments, R2 is unsubstituted pyridyl.
  • In some embodiments, R2 is pyridyl substituted with 1 R9. In some embodiments, R9 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is a 5-membered heteroaryl. In some embodiments, R2 is a 5-membered nitrogen-containing heteroaryl (e.g., pyrrolyl or oxazolyl).
  • In some embodiments, m is 0.
  • In some embodiments, m is 1.
  • In some embodiments, R4 is C1-C8 alkyl (e.g., methyl). In some embodiments, R4 is —ORd. In some embodiments, Rd is C1-C8 alkyl (e.g., methyl). In some embodiments, R4 is halo. In some embodiments, R4 is methoxy. In some embodiments, Rd is C1-C8 alkyl.
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00118
  • wherein one of X1 and X2 is N and the other is CH.
  • In some embodiments, X1 is CH and X2 is N. In some embodiments, X1 is N and X2 is CH. In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00119
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00120
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00121
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00122
  • wherein R1 is C1-C8 alkyl, which is optionally substituted with 1-3 R7.
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00123
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments, R1 is C1-C8 alkyl (e.g., methyl).
  • In some embodiments, R2 is
  • Figure US20170217923A1-20170803-C00124
    Figure US20170217923A1-20170803-C00125
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00126
  • In some embodiments, R2 is aryl. In some embodiments, R2 is heteroaryl. In some embodiments R1 is C1-C8 alkyl (e.g., methyl). In some embodiments, R2 is
  • Figure US20170217923A1-20170803-C00127
    Figure US20170217923A1-20170803-C00128
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00129
  • wherein p is 1, 2, 3, 4 or 5.
  • In some embodiments, L is NR6. In some embodiments, L is O. In some embodiments, R1 is hydrogen or C1-C8 alkyl. In some embodiments, R1 is cyclyl or heterocyclyl. In some embodiments, R1 is aralkyl or heteroaralkyl. In some embodiments, R1 is methyl, cyclohexyl, t-butyl, or
  • Figure US20170217923A1-20170803-C00130
  • In some embodiments, R6 is hydrogen or C1-C8 alkyl.
    In some embodiments, R9 is C1-C8 alkyl, halo, —CN, or —ORd. In some embodiments, R3 is hydrogen.
  • In some embodiments, the compound has the following structure:
  • Figure US20170217923A1-20170803-C00131
  • wherein p is 1, 2, 3, 4 or 5.
  • In some embodiments, L is NR6. In some embodiments, L is O. In some embodiments, R1 is hydrogen or C1-C8 alkyl. In some embodiments, R1 is cyclyl or heterocyclyl. In some embodiments, R1 is aralkyl or heteroaralkyl. In some embodiments, R1 is methyl, cyclohexyl, t-butyl, or
  • Figure US20170217923A1-20170803-C00132
  • In some embodiments, R6 is hydrogen or C1-C8 alkyl. In some embodiments, R9 is C1-C8 alkyl, halo, —CN, or —ORd. In some embodiments, R3 is hydrogen.
    • Aspects and Embodiments of Compounds of Formulas (I), (II), (III), (IV), (V), and (VI)
  • In one aspect, the invention features a composition comprising a compound of formula (I), (II), (III), (IV), (V), or (VI) and an acceptable carrier.
  • In one aspect, the invention features a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), or (VI) and a pharmaceutically acceptable carrier.
  • In one aspect, the invention features a kit comprising a composition comprising a compound of formula (I), (II), (III), (IV), (V), or (VI) and an acceptable carrier.
  • In one aspect, the invention features a kit comprising a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), or (VI) and a pharmaceutically acceptable carrier.
  • In one aspect, the invention features a dosage form comprising a composition comprising a compound of formula (I), (II), (III), (IV), (V), or (VI) and an acceptable carrier.
  • In one aspect, the invention features a dosage form comprising a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), or (VI) and a pharmaceutically acceptable carrier.
  • In one aspect, the invention features a method of treating a disorder that would benefit by the modulation of STEP (e.g., by activation or inhibition of STEP) in a subject, the method comprising administering to a subject in need thereof a compound of formula (I), (II), (III), (IV), (V), or (VI). In one aspect, the invention features a method of treating a disorder that would benefit by the inhibition of STEP, the method comprising administering to a subject in need thereof a compound of formula (I), (II), (III), (IV), (V), or (VI). In some embodiments, the disorder is selected from schizophrenia, schizoaffective disorder, bipolar disorder, manic-depressive disorder, psychosis, mood and anxiety disorders, mania, drug or substance addiction, cognition disorders, learning disabilities, learning and memory disorders, aging and neurologic disorders associated with or linked with cognitive impairments; mild cognitive impairments (MCI), Alzheimer's disease, Alzheimer-related cognition disorders, Huntington's disease, Parkinson's disease, CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), amnesia, Wernicke-Korsakoff syndrome, Korsakoff syndrome, mild traumatic head injury (MBTI), traumatic head injury (TBI), fragile X syndrome, stroke, attention-deficit and hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), loss of concentration, autism, cerebral palsy, encephalopathy, and narcolepsy. In some embodiments, the disorder affects learning and memory, neurogenesis, neuronal plasticity, pain perception, mood and anxiety, or neuroendocrine regulation. In some embodiments, the disorder is a cognitive deficit disorder. In some embodiments, the disorder involves pain perception or neuroendocrine regulation. In some embodiments, the disorder affects the central nervous system. In some embodiments the disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type disorder; depression; endogenous depression; major depression; melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorder; adjustment disorder; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism; anhedonia; iatrogenic anhedonia; anhedonia of a psychic or mental cause; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease; Parkinson's disease and associated neurodegenerative diseases; cognitive impairment of schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain (ache); mental retardation; autism disorder (autism); Tourette's disorder; tic disorder; attention-deficit/hyperactivity disorder; conduct disorder; and Down's syndrome.
  • In one aspect, the invention features a method of treating a condition that would benefit by the modulation of STEP (e.g., by activation or inhibition of STEP) in a subject, the method comprising administering to a subject in need thereof a compound of formula (I), (II), (III), (IV), (V), or (VI). In some embodiments, the condition is selected from decreased neurogenesis, cell resilience, or neuronal plasticity due to normal aging, neurodegenerative disorders of the CNS; Alzheimer's disease, Huntington's disease, fragile X syndrome, amyotrophic lateral sclerosis/Lou Gehrig's disease, stroke, Parkinson's disease, parkinsonism, dementia, Pick disease, Corticobasal degeneration, Multiple system atrophy, Progressive supranuclear palsy, traumatic brain injury, head trauma, mild traumatic head injury (MBTI), traumatic head injury (TBI), encephalopathy, intoxication related to ethanol, alcoholism, fetal alcohol syndrome, drug addiction or drug abuse.
  • In some embodiments, a compound of formula (I), (II), (III), (IV), (V), or (VI) is administered in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an atypical antipsychotic. In some embodiments, the additional therapeutic agent is selected from the group consisting of aripiprazole, clozapine, ziprasidone, risperidone, quetiapine, olanzapine, amisulpride, asenapine, iloperidone, melperone, paliperidone, perospirone, sertindole and sulpiride. In some embodiments, the additional therapeutic agent is a typical antipsychotic. In some embodiments, the additional therapeutic agent is selected from the group consisting of haloperidol, molindone, loxapine, thioridazine, molindone, thiothixene, pimozide, fluphenazine, trifluoperazine, mesoridazine, chlorprothixene, chlorpromazine, perphenazine, triflupromazine and zuclopenthixol.
    • DETAILED DESCRIPTION
  • A compound or composition described herein can be used, e.g., in a method of treating schizophrenia or cognitive deficit. Many of the compounds described herein modulate STEP activity and can be used, e.g., to reduce or inhibit STEP activity, e.g., in a subject.
    • Definitions
  • The term “acyl” refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted (e.g., by one or more substituents).
  • The term “alkenyl” refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms (unless otherwise noted) and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent.
  • The term “alkenylene” refers to a divalent alkenyl, e.g. —CH═CH—, —CH2—CH═CH—, and —CH═CH—CH2—.
  • The term “alkynyl” refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms (unless otherwise noted) and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.
  • The term “alkynylene” refers to a divalent alkynyl, e.g. —CH═CH—, —CH2—CH═CH—, and —CH═CH—CH2—.
  • The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group, as defined below, having an oxygen radical attached thereto. Representative alkoxy groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “alkoxyalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by an alkoxy group.
  • An “ether” is two hydrocarbons covalently linked by an oxygen.
  • The term “alkyl” refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, and branched-chain alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 12 or fewer carbon atoms in its backbone (unless otherwise noted) e.g., from 1-12, 1-8, 1-6, or 1-4. Exemplary alkyl moieties include methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, isobutyl or t-butyl), pentyl (e.g., n-pentyl, isopentyl or pentan-3-yl), hexyl and hepty.
  • The term “alkylene” refers to a divalent alkyl, e.g., —CH2—, —CH2CH2—, and —CH2CH2CH2—.
  • The term “alkoxylene” refers to an alkylene wherein a CH2 is substituted with an oxygen. For example, an aryl alkoxylene refers to a group with an alkylene attached to an aryl group through an oxygen, an optionally substituted heteroaryl alkoxylene refers to a group with an alkylene attached to an heteroaryl group through an oxygen.
  • The term “amino” refers to —NH2.
  • The term “aminoalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by an amino group.
  • The terms “alkylamino” and “dialkylamino” refer to —NH(alkyl) and —N(alkyl)2 radicals respectively.
  • The term “aralkylamino” or “arylalkylamino” refers to a —NH(aralkyl) radical. The term “alkylaminoalkyl” refers to a (alkyl)NH-alkyl-radical; the term “dialkylaminoalkyl” refers to an (alkyl)2N-alkyl-radical.
  • The term “amido” refers to a —NHC(O)— or C(O)NH2 substituent.
  • The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl and the like. The term “arylalkyl” or “aralkyl” refers to alkyl substituted with an aryl. Exemplary aralkyls include but are not limited to benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, phenethyl, and trityl groups. The term “arylalkenyl” refers to an alkenyl substituted with an aryl. The term “arylalkynyl” refers to an alkynyl substituted with an aryl. Terms such as “arylC2-C6alkyl” are to be read as a further limitation on the size of the alkyl group. The term “arylalkoxy” refers to an alkoxy substituted with aryl. The term “arylenyl” refers to a divalent aryl (i.e., —Ar—).
  • The terms “cycloalkyl” or “cyclyl” as employed herein include saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group may be optionally substituted. Exemplary cyclyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cyclyl moieties also include both bridged and fused ring systems. Cyclyl groups also include those that are fused to additional ring systems, which may be saturated or unsaturated. A cyclyl group may thus be a bicyclic group in which one ring is saturated or partially unsaturated and the other is fully unsaturated (e.g., indanyl).
  • The term “cyclylalkyl” as used herein, refers to an alkyl group substituted with a cyclyl group. Cyclylalkyl includes groups in which more than one hydrogen atom of an alkyl group has been replaced by a cyclyl group.
  • The term “cycloalkylalkyl” as used herein, refers to an alkyl group substituted with a cycloalkyl group.
  • The term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or iodine.
  • The term “haloalkyl” refers to an alkyl group that may have any number of hydrogens available on the group replaced with a halogen atom. Representative haloalkyl groups include but are not limited to: —CH2Cl, —CH2ClCF3, —CHBr2, —CF3, —CH2F, —CHF2, and —CH2CF3. The term “fluoroalkyl” refers to an alkyl group that may have any number of hydrogens available on the group replaced with a fluorine atom. Representative fluoroalkyl groups include but are not limited to: —CH2F, —CH2FCF3, —CHF2 and —CF3. The term “haloalkoxy” refers to an alkoxy group that may have any number of hydrogen atoms available on the alkyl group replaced with a halogen atom. Representative haloalkoxy groups include but are not limited to: —OCH2Cl, —OCH2ClCF3, —OCHBr2, —OCHF2 or —OCF3. The term “fluoroalkoxy” refers to an alkoxy group that may have any number of hydrogens available on the group replaced with a fluorine atom. Representative fluoroalkoxy groups include but are not limited to: —OCH2F, —OCH2FCF3, —OCHF2 or —OCF3.
  • The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, phosphorus and silicon. A heteroatom may be present in any oxidation state (e.g., any oxidized form of nitrogen, sulfur, phosphorus or silicon) and any charged state (e.g., the quaternized form of any basic nitrogen), and includes a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl).
  • The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, oxazolyl and the like. The term “heteroarylalkyl” or the term “heteroaralkyl” refers to an alkyl substituted with a heteroaryl. The term “heteroarylalkenyl” refers to an alkenyl substituted with a heteroaryl. The term “heteroarylalkynyl” refers to an alkynyl substituted with a heteroaryl. The term “heteroarylalkoxy” refers to an alkoxy substituted with heteroaryl.
  • The term “heteroaryl” refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 it electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. When a heteroaryl is substituted by a hydroxy group, it also includes its corresponding tautomer. The term “heteroaryl,” as used herein, also includes groups in which a heteroaromatic ring is fused to one or more aryl rings. Nonlimiting examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3 (4H)-one. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. A ring nitrogen atom of a heteroaryl may be oxidized to form the corresponding N-oxide compound. A nonlimiting example of such a heteroaryl having an oxidized ring nitrogen atom is N-oxopyridyl.
  • The term “heteroarylalkyl” or “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl. Heteroaralkyl includes groups in which more than one hydrogen atom has been replaced by a heteroaryl group.
  • As used herein, the terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2/y-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiomorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. Additionally, a heterocyclic ring also includes groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or cyclyl rings. A ring nitrogen atom of a heterocyclic ring also may be oxidized to form the corresponding N-hydroxy compound.
  • The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl. Heterocyclylalkyl includes groups in which more than one hydrogen atom has been replaced by a heterocyclyl group.
  • The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a heteroaryl group. Examplary heteroaralkyl groups include but are not limited to methylpyridyl or methylpyrimidyl.
  • The term “heterocyclyl” or “heterocyclylalkyl” refers to a nonaromatic 5-8 membered monocyclic, 5-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and include both bridged and fused ring systems. The term “heterocyclylalkyl” refers to an alkyl substituted with a heterocyclyl.
  • The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.
  • The term “heteroalkyl,” as used herein, refers to a saturate or unsaturated, straight or branched chain aliphatic group, wherein one or more of the carbon atoms in the chain are independently replaced by a heteroatom. Exemplary hetero atoms include O, S, and N.
  • In the case of aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl etc., groups described as optionally substituted, it is intended that either or both aryl, heteroaryl, cyclyl, heterocyclyl and alkyl moieties may be independently optionally substituted or unsubstituted.
  • The term “hydroxyalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a hydroxy group.
  • The term “oxo” refers to an oxygen atom (═O), which forms a carbonyl when attached to carbon, an N-oxide when attached to nitrogen, and a sulfoxide or sulfone when attached to sulfur.
    The term “thioalkyl” as used herein refers to an —S(alkyl) group, where the point of attachment is through the sulfur atom and the alkyl group is as defined above.
    The term “thiono” or “thioxo” refers to a sulfur atom (═S), which forms a thioketone when attached to carbon.
  • The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • The term “substituent” refers to a group “substituted” on a moiety described herein. Any atom on any substituent can be substituted. Substituents can include any substituents described herein. Examplary substituents include, without limitation, alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12 straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as CF3), aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (e.g., perfluoroalkoxy such as OCF3), halo, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkylamino, SO3H, sulfate, phosphate, methylenedioxy (—O—CH2—O— wherein oxygens are attached to vicinal atoms), ethylenedioxy, oxo, thioxo (e.g., C═S), imino (alkyl, aryl, aralkyl), S(O)nalkyl (where n is 0-2), S(O)n aryl (where n is 0-2), S(O), heteroaryl (where n is 0-2), S(O)n heterocyclyl (where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), ester (alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl), amide (mono-, di-, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), sulfonamide (mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof). In one aspect, the substituents on a group are independently any one single, or any subset of the aforementioned substituents. In another aspect, a substituent may itself be substituted with any one of the above substituents.
  • As used herein, the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, means that a hydrogen radical of the designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. The term “substitutable”, when used in reference to a designated atom, means that attached to the atom is a hydrogen radical, which hydrogen atom can be replaced with the radical of a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • As used herein, the term “optionally substituted” means substituted or unsubstituted.
  • As used herein, the term “partially unsaturated” refers to a moiety that includes at least one double or triple bond between atoms. The term “partially unsaturated” encompasses rings, e.g., having one or more sites of unsaturation, but that are not completely unsaturated so as to be aryl or heteroaryl.
  • The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. With respect to the nomenclature of a chiral center, terms “R” and “S” configuration are as defined by the IUPAC Recommendations. The term “enantiomers” refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a “racemic mixture” or a “racemate.” The term “isomers” or “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. For example, isomers include cis- and trans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. The term “diastereomers” refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.
  • The term “administration” or “administering” includes routes of introducing the compounds, or a composition thereof, of the invention to a subject to perform their intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), oral, inhalation, rectal and transdermal. The pharmaceutical compositions may be given by forms suitable for each administration route. For example, these compositions are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred. The injection can be bolus or can be continuous infusion. Depending on the route of administration, a compound described herein can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally affect its ability to perform its intended function. A compound or composition described herein can be administered alone, or in conjunction with either another agent as described above or with a pharmaceutically-acceptable carrier, or both. A compound or composition described herein can be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent. Furthermore, a compound described herein can also be administered in a pro-drug form which is converted into its active metabolite, or more active metabolite in vivo.
  • The language “biological activities” of a compound described herein includes all activities elicited by a compound described herein in a responsive subject or cell. It includes genomic and non-genomic activities elicited by these compounds.
  • The terms “inhibit” and “inhibitor” as used herein means an agent that measurably slows or stops the production of STriatal-Enriched tyrosine Phosphatase (STEP), or decreases or inactivates STEP, or interferes with STEP-mediated biological pathways. Inhibitors of STEP include compounds of the invention, e.g., compounds of Formulas (I), (II), or (III). A compound can be evaluated to determine if it is an inhibitor by measuring either directly or indirectly the activity of STEP in the presence of the compound suspected to inhibit STEP. Exemplary methods of measure STEP inhibition are described in the EXAMPLES herein.
  • An “effective amount” or “an amount effective” refers to an amount of the compound or composition which is effective, upon single or multiple dose administrations to a subject and for periods of time necessary, in treating a cell, or curing, alleviating, relieving or improving a symptom of a disorder, e.g., a disorder described herein. An effective amount of a compound described herein may vary according to factors such as the disease state, age, and weight of the subject, and the ability of a compound described herein to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of a compound described herein are outweighed by the therapeutically beneficial effects. The term “effective amount” includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., modulate or regulate protein tyrosine phosphatases, e.g., STEP, in a subject and/or treat a disorder described herein such as a protein tyrosine phosphatase related disorder. Exemplary disorders include those related to cognition, learning and memory, neurogenesis. An effective amount may also affect neuronal plasticity, pain perception, mood and anxiety, and neuroendocrine regulation.
  • An effective amount of a compound described herein may vary according to factors such as the disease state, age, and weight of the subject, and the ability of a compound described herein to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of a compound described herein are outweighed by the therapeutically beneficial effects.
  • A therapeutically effective amount of a compound described herein (i.e., an effective dosage) may range from about 0.001 to 50 mg/kg body weight, preferably about 0.01 to 40 mg/kg body weight, more preferably about 0.1 to 35 mg/kg body weight, still more preferably about 1 to 30 mg/kg, and even more preferably about 10 to 30 mg/kg. The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a compound described herein can include a single treatment or, preferably, can include a series of treatments. In one example, a subject is treated with a compound described herein in the range of between about 0.1 to 20 mg/kg body weight, one time per week for between about 1 to 10 weeks, preferably between 2 to 8 weeks, more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks. It will also be appreciated that the effective dosage of a compound described herein used for treatment may increase or decrease over the course of a particular treatment.
  • As used herein, an amount of a compound effective to prevent a disorder, or “a prophylactically effective amount” of the compound refers to an amount effective, upon single- or multiple-dose administration to the subject, in preventing or delaying the occurrence of the onset or recurrence of a disorder or a symptom of the disorder.
  • The language “improved biological properties” refers to any activity inherent in a compound described herein that enhances its effectiveness in vivo. In a preferred embodiment, this term refers to any qualitative or quantitative improved therapeutic property of a compound described herein, such as reduced off-target effects.
  • The term “modulate” refers to an increase or decrease, e.g., in the activity of an enzyme in response to exposure to a compound or composition described herein, e.g., the activation or inhibition of STEP, in at least a sub-population of cells in a subject such that a desired end result is achieved (e.g., a therapeutic result). In some embodiments, a compound as described herein inhibits a target described herein, e.g., STEP. In some embodiments, a compound as described herein is activates a target described herein, e.g., STEP.
  • As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein, or a normal subject. The term “non-human animals” includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.
  • As used herein, the term “treat” or “treating” is defined as applying or administering a compound or composition, alone or in combination with a second compound or composition, to a subject, e.g., a patient, or applying or administering the compound or composition to an isolated tissue or cell, e.g., cell line, from a subject, e.g., a patient, who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e.g., to prevent at least one symptom of the disorder or to delay onset of at least one symptom of the disorder).
  • The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • The term “prodrug” or “pro-drug” includes compounds with moieties that can be metabolized in vivo. Generally, the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). The prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferred prodrug moieties are propionoic acid esters and acyl esters. Prodrugs which are converted to active forms through other mechanisms in vivo are also included.
  • The language “a prophylactically effective amount” of a compound refers to an amount of a compound described herein any formula herein or otherwise described herein which is effective, upon single or multiple dose administration to the patient, in preventing or treating a disease or condition.
  • The language “reduced off-target effects” is intended to include a reduction in any undesired side effect elicited by a compound described herein when administered in vivo. In some embodiments, a compound described herein has little to no cardio and/or pulmonary toxicity (e.g., when administered to a subject). In some embodiments, a compound described herein has little to no hallucinogenic activity (e.g., when administered to a subject).
  • The term “selective” means a greater activity against a first target. In some embodiments a compound has a selectivity of at least 1.25-fold, at least 1.5 fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold or at least 100-fold greater towards a first target relative to a second target. In some embodiments, a compound described herein, e.g., a compound of Formulas (I), (II), or (III) is selective toward STEP relative to one or more other protein tyrosine phosphatases.
  • The term “subject” includes organisms which are capable of suffering from a serotonin-receptor-related disorder or who could otherwise benefit from the administration of a compound described herein of the invention, such as human and non-human animals. Preferred humans include human patients suffering from or prone to suffering from a serotonin-related disorder or associated state, as described herein. The term “non-human animals” of the invention includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, e.g., sheep, dog, cow, chickens, amphibians, reptiles, etc.
  • The phrases “systemic administration,” “administered systemically”, “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound described herein(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
    • Compounds
  • The compounds described herein can be used for a variety of purposes, e.g., therapeutic purposes. Many of the compounds modulate STEP activity and can be used, for example to inhibit STEP, e.g., in a subject.
  • Exemplary compounds include a compound of formula (I):
  • Figure US20170217923A1-20170803-C00133
  • wherein A, B, E, L, X, Z, R1, R2, R3, m, n and p are as defined above in the section relating to compound of Formula (I). In preferred embodiments, L is NH, B is aryl (e.g., phenyl) that may be optionally substituted, E is aryl (e.g., phenyl), A is N, X is CH and Z is N.
  • Exemplary compounds include a compound of formula (II):
  • Figure US20170217923A1-20170803-C00134
  • wherein A, L, X1, X2, X3, X4, X5, R1, R2, R3, n and p are as defined above in the section relating to compound of Formula (II).
  • Exemplary compounds include a compound of formula (III):
  • Figure US20170217923A1-20170803-C00135
  • wherein A, L, X1, X2, X3, X4, X5, R1, R2, R3, R4, m, and n are as defined above in the section relating to compound of Formula (III).
  • Exemplary compounds include a compound of formula (IV):
  • Figure US20170217923A1-20170803-C00136
  • wherein A, B, E, L, X, Z, R1, R2, R3, m, n and p are as defined above in the section relating to compound of Formula (IV). In preferred embodiments, L is NH, B is aryl (e.g., phenyl) that may be optionally substituted, E is aryl (e.g., phenyl), A is N, X is CH and Z is N.
  • Exemplary compounds include a compound of formula (V):
  • Figure US20170217923A1-20170803-C00137
  • wherein A, L, X1, X2, X3, X4, X5, R1, R2, R3, n and p are as defined above in the section relating to compound of Formula (V).
  • Exemplary compounds include a compound of formula (VI):
  • Figure US20170217923A1-20170803-C00138
  • wherein A, L, X1, X2, X3, X4, X5, R1, R2, R3, R4, m, and n are as defined above in the section relating to compound of Formula (VI).
  • The present invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, the replacement of a carbon by a 13C- or 14C-enriched carbon, or the replacement of a fluorine by a 19F-enriched fluorine are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as bioactive agents.
  • In the compounds of the present invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom unless otherwise stated (e.g., hydrogen, 2H or deuterium and 3H or tritium). The formulas described herein may or may not indicate whether atoms at certain positions are isotopically enriched. When a structural formula is silent with respect to whether a particular position is isotopically enriched, it is to be understood that the isotopes at that particular position are present in natural abundance or, that the particular position is isotopically enriched with one or more naturally occurring stable isotopes. For example, the formula —CH2— represents the following possible structures: —CH2—, —CHD- or —CD2-.
  • The variable “D” is defined as deuterium.
  • The terms “compound” or “compounds,” when referring to a compound of this invention or a compound described herein, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated hydrogen atoms will contain lesser amounts of isotopologues having deuterium atoms at one or more of the designated hydrogen positions in that structure. Alternatively, a compound represented by a particular chemical structure containing indicated deuterium atoms will contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will depend on a number of factors including isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthetic steps used to prepare the compound. The relative amount of such isotopologues in total will be less than 55% of the compound. In other embodiments, the relative amount of such isotopologues in total will be less than 50%, less than 45%, less than 40%, less than 35%, less than 35%, less than 15%, less than 10%, less than 5%, less than 1% or less than 0.5% of the compound.
  • The term “isotopologue” refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof. Isotopologues can differ in the level of isotopic enrichment at one or more positions and/or in the position(s) of isotopic enrichment.
  • The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. Described herein are enantiomerically enriched compounds (e.g., a compound resolved to an enantiomeric excess of 60%, 70%, 80%, 85%, 90%, 95%, 99% or greater). All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also contain linkages (e.g., carbon-carbon bonds) or substituents that can restrict bond rotation, e.g. restriction resulting from the presence of a ring or double bond. Accordingly, all cis/trans and E/Z isomers are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
  • Naturally occurring or synthetic isomers can be separated in several ways known in the art. Methods for separating a racemic mixture of two enantiomers include chromatography using a chiral stationary phase (see, e.g., “Chiral Liquid Chromatography,” W. J. Lough, Ed. Chapman and Hall, New York (1989)). Enantiomers can also be separated by classical resolution techniques. For example, formation of diastereomeric salts and fractional crystallization can be used to separate enantiomers. For the separation of enantiomers of carboxylic acids, the diastereomeric salts can be formed by addition of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and the like. Alternatively, diastereomeric esters can be formed with enantiomerically pure chiral alcohols such as menthol, followed by separation of the diastereomeric esters and hydrolysis to yield the free, enantiomerically enriched carboxylic acid. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. For example a compound can be resolved to an enantiomeric excess (e.g., 60%, 70%, 80%, 85%, 90%, 95%, 99% or greater) via formation of diasteromeric salts, e.g. with a chiral base, e.g., (+) or (−) α-methylbenzylamine, or via high performance liquid chromatography using a chiral column. In some embodiments a product is purified directly on a chiral column to provide enantiomerically enriched compound.
  • Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic administration to a subject).
  • Compounds of formulas (I), (II), (III), (IV), (V), and (VI) are described herein, for example as provided in the summary above. Exemplary compounds are shown in Tables 1-30 in the Examples section.
  • Synthetic Methods
  • A compound described herein may be prepared via a variety of synthetic methods. Representative syntheses are shown in the Examples section.
  • As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.
  • Additionally, the compounds disclosed herein can be prepared on a solid support. The term “solid support” refers a material to which a compound is attached to facilitate identification, isolation, purification, or chemical reaction selectivity of the compound. Such materials are known in the art and include, for example, beads, pellets, disks, fibers, gels, or particles such as cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally cross-linked with divinylbenzene and optionally grafted with polyethylene glycol, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N,N′-bis-acryloyl ethylene diamine, glass particles coated with hydrophobic polymer, and material having a rigid or semi-rigid surface. The solid supports optionally have functional groups such as amino, hydroxy, carboxy, or halo groups, (see, Obrecht, D. and Villalgrodo, J. M., Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Pergamon-Elsevier Science Limited (1998)), and include those useful in techniques such as the “split and pool” or “parallel” synthesis techniques, solid-phase and solution-phase techniques, and encoding techniques (see, for example, Czarnik, A. W., Curr. Opin. Chem. Bio., (1997) 1, 60).
  • A compound described herein may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., brain, blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • Included herein are pharmaceutically acceptable derivatives or prodrugs of the compounds described herein. A “pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention (for example an imidate ester of an amide), which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound described herein. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. In an exemplary embodiment, the prodrug is a derivative including a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. In another exemplary embodiment, the prodrug is suitable for treatment or prevention of those diseases and conditions that require the drug molecule to cross the blood brain barrier. In a preferred embodiment, the prodrug enters the brain, where it is converted into the active form of the drug molecule.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate and undecanoate. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)4 + salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • Evaluating Compounds
  • A variety of methods can be used to evaluate a compound for ability to modulate STEP activity. Evaluation methods include in vitro assays (e.g., enzyme-based assays), in vitro cell-based signaling assays, and in vivo methods (e.g., testing in animal models). The evaluation methods can evaluate binding activity, phosphatase activity, or an activity downstream of STEP, such as the activity of ERK.
  • For example, a compound described herein may be evaluated using a fluorescence-based phosphatase assay. A phosphate-containing reagent may be used in the assay which, upon dephosphorylation by a phosphatase, generates a fluorescent product that may be detected using a fluorometer or fluorescence plate reader. Data may be expressed as percentage (%) inhibition of enzyme activity. For compounds showing enzymatic activation, data may be represented as percentage of inhibition but with negative values.
    • Compositions and Routes of Administration
  • The invention also provides a pharmaceutical composition, comprising an effective amount of a compound described herein (e.g., a compound capable of treating or preventing a condition as described herein, e.g., a compound of any formula herein or otherwise described herein) and a pharmaceutically acceptable carrier.
  • The compositions delineated herein include the compounds delineated herein (e.g., a compound described herein), as well as additional therapeutic agents if present, in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.
  • The term “pharmaceutically acceptable carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
  • The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
  • The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. 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. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.
  • Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens 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 status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
  • Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
    • Methods of Treatment
  • The compounds and compositions described herein can be administered to cells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and/or diagnose a variety of disorders, including those described herein below.
  • The compounds and compositions described herein can be administered to a subject, for example using a method described herein, who is suffering from a disorder described herein, e.g., a disorder that would benefit from the modulation of STEP (e.g., activating or inhibiting STEP). The compounds and compositions described herein can be administered to a subject, for example using a method described herein, who is at risk for a disorder described herein, e.g., a disorder that would benefit from the modulation of STEP (e.g., activating or inhibiting STEP).
  • Inhibitors of STEP may increase phosphorylation of an NMDA-R. Thus, in some embodiments, a compound described herein, e.g., a compound that inhibits STEP, may be useful for treating a disorder in which increasing phosphorylation of an NMDA-R would be beneficial.
  • Inhibitors of STEP may activate an ERK1 or ERK2 kinase, for example, in the CNS. Thus, in some embodiments, a compound described herein, e.g., a compound that inhibits STEP, may be useful for treating a disorder in which activate an ERK1 or ERK2 kinase would be beneficial.
  • Compounds described herein may be useful in treating a variety of disorders, including disorders of the CNS. Exemplary disorders include schizophrenia, schizo-affective disorders, major depression, bipolar disorder, cognitive deficit, mild cognitive impairment (MCI), Alzheimer's disease (AD), attention-deficit/hyperactivity disorder (ADHD), dementia, generalized anxiety disorders, panic disorders, obsessive-compulsive disorders, phobias, post-traumatic stress syndrome, anorexia nervosa, drug addiction, ischemic stroke, head trauma or brain injury, Huntington's disease, Parkinson's disease, spinocerebellar degeneration, motor neuron diseases, epilepsy, neuropathic pain, chronic pain, neuropathies, autism and autistic disorders.
  • Compounds described herein may be useful for treating or preventing central nervous system disorders selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type disorder; depression; endogenous depression; major depression; melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorder; adjustment disorder; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism; anhedonia; iatrogenic anhedonia; anhedonia of a psychic or mental cause; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease; Parkinson's disease and associated neurodegenerative diseases; cognitive impairment of schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain (ache); mental retardation; autism disorder (autism); Tourette's disorder; tic disorder; attention-deficit/hyperactivity disorder; conduct disorder; and Down's syndrome.
  • Compounds described herein may be useful for treating or preventing disorders selected from schizophrenia, schizoaffective disorder, bipolar disorder, manic-depressive disorder, psychosis, mood and anxiety disorders, mania, drug or substance addiction, cognition disorders, learning disabilities, learning and memory disorders, aging and neurologic disorders associated with or linked with cognitive impairments; mild cognitive impairments (MCI), Alzheimer's disease, Alzheimer-related cognition disorders, Huntington's disease, Parkinson's disease, CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), amnesia, Wernicke-Korsakoff syndrome, Korsakoff syndrome, mild traumatic head injury (MBTI), traumatic head injury (TBI), fragile X syndrome, stroke, attention-deficit and hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), loss of concentration, autism, cerebral palsy, encephalopathy, and narcolepsy. The disorder may affect learning and memory, neurogenesis, neuronal plasticity, pain perception, mood and anxiety, or neuroendocrine regulation. The disorder may be a cognitive deficit disorder. The disorder may involve pain perception or neuroendocrine regulation.
  • Schizophrenia
  • In some embodiments, a compound or composition described herein can be used in the treatment of schizophrenia. Schizophrenia is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality. Distortions in perception may affect all five senses, including sight, hearing, taste, smell and touch, but most commonly manifests as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking with significant social or occupational dysfunction. Onset of symptoms typically occurs in young adulthood, with approximately 0.4-0.6% of the population affected. Diagnosis is based on the patient's self-reported experiences and observed behavior.
  • The disorder is thought to mainly affect cognition, but it also usually contributes to chronic problems with behavior and emotion. People with schizophrenia are likely to have additional (comorbid) conditions, including major depression and anxiety disorders. Social problems, such as long-term unemployment, poverty and homelessness, are common. Furthermore, the average life expectancy of people with the disorder is 10 to 12 years less than those without, due to increased physical health problems and a higher suicide rate.
  • The Diagnostic and Statistical Manual of Mental Disorders (DSM) contains five sub-classifications of schizophrenia. These include Paranoid type (where delusions and hallucinations are present but thought disorder, disorganized behavior, and affective flattening are absent); Disorganized type (also known as hebephrenic schizophrenia, where thought disorder and flat affect are present together); Catatonic type (the subject may be almost immobile or exhibit agitated, purposeless movement; symptoms can include catatonic stupor and waxy flexibility); Undifferentiated type (psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met); and Residual type (where positive symptoms are present at a low intensity only).
  • The International Statistical Classification of Diseases and Related Health Problems (10th Revision) defines two additional subtypes. These include Post-schizophrenic depression (a depressive episode arising in the aftermath of a schizophrenic illness where some low-level schizophrenic symptoms may still be present); and Simple schizophrenia (insidious and progressive development of prominent negative symptoms with no history of psychotic episodes.)
  • An agent for the treatment of schizophrenia may improve so-called positive symptoms in the acute period of schizophrenia such as hallucinations, delusions, excitations and the like. An agent for treating schizophrenia may also improve so-called negative symptoms that are observed in the chronic period of schizophrenia such as apathy, emotional depression, hyposychosis and the like.
  • Schizoaffective Disorder
  • Schizoaffective disorder is a psychiatric diagnosis that describes a mental disorder characterized by recurring episodes of elevated or depressed mood, or simultaneously elevated and depressed mood that alternate or occur together with distortions in perception. The perceptual distortion component of the disorder, called psychosis, may affect all five senses, including sight, hearing, taste, smell and touch, but most commonly manifest as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking with significant social and occupational dysfunction. The elevated, depressed or simultaneously elevated and depressed mood episode components of the disorder, called mood disorder, are broadly recognized as depressive and bipolar types of the illness; the division is based on whether the individual has ever had a manic, hypomanic or mixed episode. Onset of symptoms usually begins in early adulthood and is rarely diagnosed in childhood (prior to age 13). The lifetime prevalence of the disorder is uncertain (due to studies using varying diagnostic criteria), although it is generally agreed to be less than 1 percent, and possibly in the range of 0.5 to 0.8 percent. Diagnosis is based on the patient's self-reported experiences and observed behavior. No laboratory test for schizoaffective disorder currently exists. As a group, people with schizoaffective disorder have a more favorable prognosis than people with schizophrenia, but a worse prognosis than those with mood disorders.
  • The disorder is thought to mainly affect cognition and emotion, but it also usually contributes to ongoing problems with behavior and motivation. People with schizoaffective disorder are likely to have additional (comorbid) conditions, including anxiety disorders and substance abuse. Social problems, such as long-term unemployment, poverty and homelessness, are common. Furthermore, the average life expectancy of people with the disorder is shorter than those without the disorder, due to increased physical health problems and a higher suicide rate.
  • Cognitive Deficit
  • Treatment using a compound or composition described herein may improve a cognitive deficit associated with a cognition-related disorder. Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to cognitive performance. The term may describe deficits in global intellectual performance, such as mental retardation, it may describe specific deficits in cognitive abilities (learning disorders, dyslexia), or it may describe drug-induced cognitive/memory impairment, such as that seen with alcohol and the benzodiazepines. Cognitive deficits may be congenital or caused by environmental factors such as brain injuries, neurological disorders, or mental illness.
  • Exemplary cognition-related disorders (e.g., cognitive dysfunction) include, without limitation, mild cognitive impairment (MCI), dementia, delirium, amnestic disorder, Alzheimer's disease, Parkinson's disease and Huntington's disease; memory disorders including memory deficits associated with depression, senile dementia, dementia of Alzheimer's disease; cognitive deficits or cognitive dysfunction associated with neurological conditions including, for example, Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, depression, schizophrenia and other psychotic disorders such as paranoia and manic-depressive illness; cognitive dysfunction in schizophrenia; disorders of attention and learning such as attention deficit disorders (e.g., attention deficit hyperactivity disorder (ADHD)) and dyslexia; cognitive dysfunction associated with developmental disorders such as Down's syndrome and Fragile X syndrome; loss of executive function; loss of learned information; vascular dementia; schizophrenia; cognitive decline; a neurodegenerative disorder; and other dementias, for example, dementia due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple etiologies. Cognition-related disorders also include, without limitation, cognitive dysfunction associated with MCI and dementias such as Lewy Body, vascular, and post stroke dementias. Cognitive dysfunction associated with surgical procedures, traumatic brain injury or stroke may also be treated in accordance with the embodiments described herein.
  • Major Depression
  • Major depression (also known as clinical depression, major depressive disorder, unipolar depression, or unipolar disorder) is a mental disorder characterized by a pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Types of Major depressive disorder include, e.g., Atypical depression, Melancholic depression, Psychotic depression, Catatonic depression, Postpartum depression, and Seasonal affective disorder.
  • Bipolar Disorder
  • Bipolar disorder, also known as manic depressive disorder, manic depressive psychosis, manic depression or bipolar affective disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated mood clinically referred to as mania or, if milder, hypomania. Individuals who experience manic episodes also commonly experience depressive episodes or symptoms, or mixed episodes in which features of both mania and depression are present at the same time. These episodes are usually separated by periods of “normal” mood, but in some individuals, depression and mania may rapidly alternate, known as rapid cycling. Extreme manic episodes can sometimes lead to psychotic symptoms such as delusions and hallucinations. The disorder has been subdivided into bipolar I, bipolar II, cyclothymia, and other types, based on the nature and severity of mood episodes experienced; the range is often described as the bipolar spectrum.
  • Anxiety Disorders
  • Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders. Recent surveys have found that as many as 18% of Americans may be affected by one or more of them.
  • Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.
  • In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).
  • Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.
  • The single largest category of anxiety disorders is that of Phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.
  • Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.
  • Combination Therapies
  • In some embodiments, the subject is being treated with an additional therapeutic agent. Such additional agents include atypical antipsychotics such as aripiprazole, clozapine, ziprasidone, risperidone, quetiapine, olanzapine, amisulpride, asenapine, iloperidone, melperone, paliperidone, perospirone, sertindole and sulpiride; and typical antipsychotics such as haloperidol, molindone, loxapine, thioridazine, molindone, thiothixene, pimozide, fluphenazine, trifluoperazine, mesoridazine, chlorprothixene, chlorpromazine, perphenazine, triflupromazine and zuclopenthixol.
  • Clinical Outcomes
  • In some embodiments, treatment with a compound or composition described herein, for example, using a method described herein, improves one or more clinical outcomes. For example, in some embodiments, treatment with a compound or composition described herein may improve cognitive function. Elements of cognitive function include memory, orientation, attention, reasoning, language and praxis.
  • In some embodiments, clinical outcomes may be assessed using known methods. One such method is the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients.
  • In some embodiments, clinical outcomes may be assessed using the 7-point Clinical Global Impression (CGI) rating scale, a commonly used measure of symptom severity, treatment response and the efficacy of treatments. The CGI reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.
  • In some embodiments, clinical outcomes may be assessed using the 30-item Positive and Negative Symptoms Scale (PANSS). The name refers to the two types of symptoms in schizophrenia, as defined by the American Psychiatric Association: positive symptoms, which refer to an excess or distortion of normal functions (e.g. hallucinations and delusions), and negative symptoms, which represent a dimunition or loss of normal functions.
  • In some embodiments, clinical outcomes may be assessed using the Scale for Assessing Negative Symptoms (SANS). SANS assesses five symptom complexes to obtain clinical ratings of negative symptoms in patients with schizophrenia. They are: affective blunting; alogia (impoverished thinking); avolition/apathy; anhedonia/asociality; and disturbance of attention. Assessments are conducted on a six-point scale.
  • The invention is further illustrated by the following examples which are intended to illustrate but not limit the scope of the invention.
    • EXAMPLES Abbreviations: DCM: Dichloromethane
  • EA, EtOAc or AcOEt: Ethyl acetate
    PE: Petroleum ether
    • DIPEA: Diisopropylethylamine TEA: Triethylamine
  • rt: Room temperature
    SOCl2: Thionyl chloride
    POCl3: Phosphorous oxychloride
    • THF: Tetrahydrofuran
  • NaOAc: Sodium acetate
    • MeOH: Methanol
  • i-AmOH: Isoamyl alcohol
    NaH: Sodium hydride
    NaBH3CN: Sodium cyanoborohydride
    n-BuLi: n-Butyl lithium
    LHMDS: Lithium bis(trimethylsilyl)amide
    LDA: Lithium diisopropylamide
    i-PrOH: Isopropyl alcohol
    Na2SO4: Sodium sulfate
    Mg2SO4: Magnesium sulfate
    • MeCN: Acetonitrile
  • NaOH: Sodium hydroxide
    • EtOH: Ethanol
  • CuI: Copper(I) iodide
    Pd(PPh3)2Cl2: trans-Dichlorobis(triphenylphosphine)palladium(II)
    MsCl: Methanesulfonyl chloride
    BINAM: [1,1′-Binaphthalene]-2,2′-diamine
    Xphos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl
    Sphos: 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl
    • DavePhos: 2-(Dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl
  • Cs2CO3: Cesium carbonate
    K2CO3: Potassium carbonate
    • Mwave or μW or mW: Microwave
  • t-BuOH: tert-Butanol
    K3PO4: Potassium phosphate
    Pd(APhos)2Cl2:Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloro palladium(II)
    Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium (0)
    Pd(dppf)2Cl2: Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)
    PdOAc: Palladium(II) acetate
    Pd2dba3: Tris(dibenzylideneacetone)dipalladium (0)
    Pd-118: Dichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium(II)
    • Xantphos: 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene
  • BINAP: (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene
    EDCI: 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide
    • HOBt: Hydroxybenzotriazole
  • NH4OH: Ammonium hydroxide
    • H2O: Water
  • Pd/C: Palladium on carbon
    • DMF: N,N-Dimethylformamide
  • KOCN: Potassium cyanate
    WSC-HCl or WSCDI: Water Soluble Carbodiimide hydrochloride
    HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
    HBTU: O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
    Py-Brop: Bromotripyrrolidinophosphonium hexafluorophosphate
    BOP: Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluoro phosphate
    DBU: diaza(1,3)bicyclo[5.4.0]undecene
    DMSO: Dimethyl sulfoxide
    LCMS: Liquid chromatography mass spectrometry
    HPLC: High performance liquid chromatography
    • DMA: N,N-dimethylacetamide
  • h: hour
    TLC: Thin layer chromatography
    TFA: Trifluoroacetic acid
    • Et3N: Triethylamine DIPEA: N,N-Diisopropylethylamine O.N: Overnight
  • TBSO: tert-Butyldimethylsilyloxy
    DME: Dimethyl ether
    NMP: 1-methyl-2-pyrrolidinone
    PS-BEMP: 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine supported on Polystyrene
    PBr3: Phosphorus tribromide
    NaOtBu: Sodium tert-butoxide
    KI: Potassium iodide
    • PPh3: Triphenylphosphine NMM: N-Methylmorpholine HCHO: Formaldehyde
  • PG: Protecting group
    ISCO: Teledyne ISCO purification systems
    BINAM: 1,1′-binaphthyl-2,2′-diamine.
    • General Experimental:
  • All exemplified target compounds are fully analyzed and characterized (TLC, LCMS, 1H-NMR) prior to submission for biological evaluation. Thin-layer chromatography was carried out on native silica 254F plates. Visualization was accomplished with ultraviolet or phosphomolybdic acid. 1H-NMR spectra were recorded on multiple NMR spectrometers, either on 400 MHz on a Avance III 400 Ultra shield-plus TM digital Spectrometer or on 300 MHz using a Varian Mercury 300Plus Spectrometer, designated by 400 MHz or 300 MHz, respectively. 1H-NMR spectra were also recorded on a Bruker Spectrospin 300 MHz Spectrometer at 300.13 MHz in DMSO-d6 with TMS as an internal standard and will be designated as Bruker 300 Hz. NMR assignments are based on a combination of the 1H, 13C, 1HCOSY, HMBC and HMQC spectra. Coupling constants are given in hertz (Hz). Anhydrous methylene chloride, tetrahydrofuran, and dimethylformamide were obtained by distillation, and other materials are reagent grade.
  • LC-MS Methods are listed here:
    • Method A
  • Mobile phase: A=0.1% TFA/H2O, B=0.01% TFA/MeCN; Gradient: B=5%-95% in 1.5 min; Flow rate: 2.0 mL/min; Column: sunfire-C18, 50×4.6 mm, 3.5 um;
    • Method B
  • Mobile phase: A=10 mM NH4HCO3/H2O, B=MeCN; Gradient: B=5%-95% in 1.5 min; Flow rate: 2.0 mL/min; Column: Xbridge-Cis, 50×4.6 mm, 3.5 um;
    • Method C
  • Mobile phase: A=10 mM ammonium formate/H2O/4.9% MeCN, B=MeCN; Gradient: B=5%-100% in 2.0 min; Flow rate: 2.5 mL/min; Column: Atlantis T3 3 uM 4.6×30 mm
    • Method D
  • Mobile phase: A=0.1% formic acid/H2O/4.9% MeCN, B=MeCN; Gradient: B=5%-100% in 2.0 min; Flow rate: 2.5 mL/min; Column: Atlantis T3 3 uM 4.6×30 mm
    • Method E
  • Mobile phase: A=0.05% TFA/H2O, B=0.05% TFA/MeCN; Gradient: B=5%-100% in 3.0 min; Flow rate: 0.8 mL/min; Column: CAPCELL PAK C18 (Shiseido, UG120, 3 mM, 2.0 mm I.D.×50 mm).
  • Representative Conditions of PREP-HPLC are listed here:
    • PREP-HPLC Condition A (Basic Mobile Phase):
  • Instrument: Gilson 281
  • Mobile Phase: A=0.01% NH4HCO3/H2O, B=MeCN
  • Flow Rate: 40.0 mL/min
  • Column: AGT Venusil XBP C18, 10.0 um, 30 mm×100 mm
    • PREP-HPLC Condition B (Basic Mobile Phase):
  • Instrument: Gilson 281
  • Mobile Phase: A=NH3—H2O, 10 mmol/L, B=MeCN
  • Flow Rate: 40.0 mL/min
  • Column: Waters X-Bridge, 5.0 um, 30 mm×150 mm
    • PREP-HPLC Condition C (Basic Mobile Phase):
  • Instrument: Gilson 281
  • Mobile Phase: A=0.01% NH4HCO3/H2O, B=MeCN
  • Flow Rate: 30.0 mL/min
  • Column: Shimadzu PRC-ODS, 10.0 um, 20 mm×250 mm
  • Gradient: B=xx %-yy % 0.0 to 8.0 min
      • yy %-95% 8.0 to 8.2 min
      • 95%-95% 8.2 to 11.0 min
        The following table shows the relationship of representative value (xx %-yy %) of gradient and retention time on LC-MS of corresponding compound.
  • 25%-30% 0.5-1.0 min
  • 30%-50% 1.0-1.5 min
  • 50%-70% 1.5-1.75 min
  • 70%-90% 1.7-2.0 min
    • PREP-HPLC Condition D:
  • Instrument: Waters 600 pump, Waters 2996, Photodiode Array Detector, Waters Micromass ZQ, Gilson 215 Liquid Handler.
  • Mobile Phase: A=0.05% TFA/H2O, B=MeCN
  • Flow Rate: 36.0 mL/min
  • Column: Shiseido CAPCELL PAK C18, UG120, 5 uM, 20 mm I.D.×50 mm
  • Gradient: B=5%-100% 0.0 to 4.0 min
  • Figure US20170217923A1-20170803-C00139
  • Figure US20170217923A1-20170803-C00140
    • Method A: 2-Nitro-5-propoxy-benzamide (i-a)
  • A mixture of 2-nitro-5-propoxy-benzoic acid (1.97 g, 8.75 mmol) and DMF (0.1 mL) in SOCl2 (20 mL) was stirred at 65° C. for 2 h. After the reaction was completed, the mixture was cooled to room temperature. SOCl2 was removed in vacuo and the residue was dissolved in anhydrous CH2Cl2 (10 mL), which was added to NH3—H2O (28%) dropwise. After 1 h, the precipitate was collected and dried in vacuo to give 1.68 g of i-a as a yellow solid (85.2%). LCMS m/z=208.1 (M−16), 225.1 (M+1) (Method B) (retention time=1.88 min).
    • Method B: 2-Amino-5-propoxy-benzamide (ii-a)
  • To a mixture of 2-nitro-5-propoxy-benzamide (1.20 g, 5.36 mmol) in MeOH—H2O (v/v, 3:1, 60 mL) was added NH4Cl (2.84 g, 53.6 mmol) and Fe (2.99 g, 53.6 mmol). The resulting mixture was stirred at 60° C. for 3 h. After the reaction was completed, the mixture was cooled to room temperature and the iron was filtered off. The filtrate was concentrated to 15 mL and the formed precipitate was collected and dried in vacuo to give 1.02 g of ii-a as a pale yellow solid (98%). LCMS m/z=178.1 (M−16), 195.1 (M+1) (Method B) (retention time=1.46 min).
  • Figure US20170217923A1-20170803-C00141
    • Method I: 2-Amino-4-chlorobenzamide (ii-b)
  • To a mixture of 2-amino-4-chlorobenzoic acid (3.42 g, 20 mmol) in DMF (45 mL) was added HOBt (2.70 g, 20 mmol). After stirring for 10 min, EDC hydrogen chloride (3.82 g, 20 mmol) was added to the mixture. The resulted mixture was stirred at room temperature for 2 h. NH4OH (28%, 5 mL) was added at 0° C. with vigorous stirring. After addition, the mixture was stirred at room temperature for another 2 h. The reaction mixture was added to water (200 mL) dropwise with stirring, then a precipitate formed. The precipitate was collected and dried in vacuo to give 2.98 g of ii-b as a grey solid (87.6% yield). LCMS m/z=171.0 (M+1), 173.0 (M+3) (Method B) (retention time=1.39 min). 1H NMR (400 MHz, DMSO-d6): δ 7.27 (d, J=9.6 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.60 (dd, J=8.4, 2.0 Hz, 1H), 5.50-5.82 (m, 4H).
  • Figure US20170217923A1-20170803-C00142
    • Method F for Chlorinating Conditions F1: POCl3/N,N-dimethylbenzeneamine F2: SOCl2/DMF/80° C.
  • F3: SOCl2 (4-8 equiv.)/DMF/DCM/rt−40° C.
    F4: Phenylphosphinic dichloride/80-120° C.
    • F5: POCl3/Δ F6: POCl3/Toluene/100° C.
  • F7: PBr3/CH2Cl2/DMF/60° C.
    • Method G for Coupling Conditions
  • G1: i-PrOH/85-100° C.
    • G2: THF/reflux
  • G3: i-AmOH/100-130° C.
    • G4: MeOH/microwave/150° C.
  • G5: i-AmOH/microwave/150° C.
    • G6: THF/Et3N/reflux G7: THF-H2O/NaOAc/rt-60° C. G8: NaH/THF
  • G9: n-BuLi/THF
    • G10: LHMDS/THF G11: LDA/THF
  • G12: K2CO3/DMF/60° C.
    G13: Cs2CO3/DMA/80° C.
    • G14: NaOtBu/DMF/Microwave/100° C. Method J for Coupling Conditions
  • J1: Pd(PPh3)4/t-BuOK/Dioxane
    J2: Pd2(dba)3/Xantphos/Cs2CO3/Dioxane
  • Figure US20170217923A1-20170803-C00143
    Figure US20170217923A1-20170803-C00144
    • Method C: N-(2-Carbamoyl-4-propoxy-phenyl)-nicotinamide (iii-a)
  • To a solution of 2-amino-5-propoxy-benzamide (760 mg, 3.91 mmol) in THF (15 mL) and Et3N (1 mL) was added nicotinoyl chloride (607 mg, 4.30 mmol) in anhydrous THF (15 mL) dropwise. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the volatiles were removed. The residue was washed with H2O (10 mL). The pH was adjusted to approximately 5 by adding dilute HCl (2N in water). The resulting solid was collected and dried in vacuo to give 1.00 g of iii-a as a pale yellow solid (89.0%). LCMS m/z=300.1 (M+1) (Method B) (retention time=1.60 min).
    • Method D: 2-benzamido-5-methoxy-3-methylbenzamide (iii-b)
  • A 50 mL round-bottom flask was charged with nicotinic acid (41 mg, 0.33 mmol, 1.0 eq.), 2-amino-5-methoxy-3-methylbenzamide (60 mg, 0.33 mmol, 1.0 eq.) and HBTU (190 mg, 0.50 mmol, 1.5 eq), which were suspended in 4 mL of DMF. DIPEA (86 mg, 0.66 mmol, 2.0 eq.) was added dropwise at room temperature and the reaction mixture was stirred overnight. The reaction mixture was added to water (10 mL) dropwise with stirring. The mixture was extracted with ethyl acetate. The ethyl acetate was evaporated and 55 mg of the orange solid (58.5% yield) was obtained. LCMS m/z=286.1 (M+1) (Method B) (retention time=1.24 min).
    • Method E: 6-Propoxy-2-pyridin-3-yl-1H-quinazolin-4-one (iv-a)
  • A mixture of N-(2-carbamoyl-4-propoxy-phenyl)-nicotinamide (980 mg, 3.27 mmol) in EtOH (20 mL) was treated with NaOH (654 mg, 16.37 mmol). The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the volatiles were removed in vacuo. The residue was partitioned between H2O (50 mL) and ethyl acetate (50 mL). The aqueous layer was neutralized to pH 7 by slowly adding aq. citric acid and then a precipitate formed. The precipitate was collected and dried to give 1.00 g of iv-a as a grey solid (quantitative yield). LCMS m/z=282.1 (M+1) (Method B) (retention time=1.60 min).
    • Method F1: 4-Chloro-6-propoxy-2-pyridin-3-yl-quinazoline (v-a)
  • (This method is representative of method F1, F2, F3 and F4. These three methods can be implemented in a similar way except for substitution of the appropriate chlorinating reagent, solvent and temperature) To a mixture of 6-propoxy-2-pyridin-3-yl-1H-quinazolin-4-one (1.00 g, 3.56 mmol) in POCl3 (10 mL) was added N,N-dimethylaniline (0.1 mL). The resulting mixture was stirred at 120° C. for 2 h. After the reaction was completed, POCl3 was removed in vacuo, and the residue was added to ice-water slowly. The pH was adjusted to around 7 by slowly adding NaHCO3 (sat.) at 0° C. The resultant solid was collected and purified by chromatography on silica gel eluted with petroleum ether/ethyl acetate (v/v=4:1 to 1:1) to give 580 mg of v-a as a pale yellow solid (54.7%).
    • Method F5: 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (v-c)
  • In a sealed tube, phosphorus oxychloride (11 mL, 120 mmol) was added to 6-methoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (2.70 g, 10.66 mmol). The mixture was refluxed at 120° C. for 12 h. After cooling, the remaining phosphorus oxychloride was removed in vacuo to leave a tan solid. This residue was added to an ice-water mixture (100 mL) with cooling and allowed to stir. The pH of the suspension was adjusted to about pH 9 via dropwise addition of 28% ammonium hydroxide, and stirring was continued for 30 mins. The resulting solid was filtered to give the desired product as a tan solid (2.55 g, 9.39 mmol, 88%). LC-MS m/z=272.0 (M+1) (retention time=2.05)1H NMR (300 MHz, DMSO) δ 9.55 (s, 1H), 8.81-8.64 (m, 2H), 8.09 (d, J=9.2 Hz, 1H), 7.78 (dd, J=9.2, 2.8 Hz, 1H), 7.61 (dd, J=7.9, 4.8 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 4.00 (s, 3H).
    • Method F6: 6-Bromo-4-chloro-8-fluoro-2-(pyridin-3-yl)quinazoline (v-d)
  • To a suspension of 6-bromo-8-fluoro-2-(pyridin-3-yl)quinazolin-4-ol (6.16 g, 0.0192 mol) in toluene (60 mL) was added phosphorus oxychloride (5.30 ml, 0.0579 mol) at room temperature. The mixture was refluxed for 3 h. The solvent was evaporated and water was added to the residue under cooling conditions. The suspension was stirred at room temperature for 30 min, the resulting precipitate was filtered and dried to give the title compound (6.5 g, quantitative). 1H NMR (400 MHz, DMSO) δ 9.58 (d, J=1.6 Hz, 1H), 8.82 (dd, J=4.7, 1.5 Hz, 1H), 8.80-8.75 (m, 1H), 8.37 (dd, J=9.7, 1.9 Hz, 1H), 8.34-8.29 (m, 1H), 7.67 (dd, J=7.8, 4.6 Hz, 1H).
    • Method F7: 4-Bromo-6-methoxy-2-(pyridin-3-yl)quinazoline (v-e)
  • To a sealed tube containing 6-methoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one (1.30 g, 5.13 mmol) in dichloromethane (20 mL) was added 1 M phosphorus tribromide in dichloromethane (10.3 mL, 10.3 mmol) and DMF (2 mL). The reaction mixture was heated at 60° C. for 4 h. After cooling, excess dichloromethane was evaporated leaving a tan residue. This solid was added to an ice-water mixture (100 mL) with cooling and allowed to stir. The pH of the suspension was adjusted to about pH 9 via dropwise addition of 28% ammonium hydroxide, and stirring was continued for 30 mins. The resulting solid was filtered to give the desired product as a tan solid (1.49 g, 4.71 mmol, 92%). LC-MS m/z=318.3 (M+2) (retention time=2.19).
    • Method G1: 2-(6-Propoxy-2-pyridin-3-yl-quinazolin-4-ylamino)-benzamide (vi-a)
  • (This method is representative of method G1, G2, and G3. These three methods can be implemented in a similar way except for substitution of the appropriate solvent and temperature) A mixture of 4-chloro-6-propoxy-2-(pyridin-3-yl)quinazoline (90 mg, 0.3 mmol) and 2-aminobenzamide (52 mg, 0.4 mmol) in i-PrOH (5 mL) was stirred at 85° C. for 18 h. The yellow precipitate was collected and washed with i-PrOH (10 mL). The solid was suspended in water (10 mL) and NH3—H2O (1 mL) was added. After filtration the solid was dried in vacuo to afford 31.0 mg of vi-a as a white solid (30.8%). LCMS m/z=400.1 (M+1) (Method B) (retention time=1.96 min). 1H-NMR (400 MHz, DMSO-d6): δ 9.59 (d, J=2.0 Hz, 1H), 9.58 (d, J=7.6 Hz, 1H), 8.69-8.74 (m, 2H), 8.48 (s, 1H), 7.97 (d, J=6.8 Hz, 2H), 7.90 (d, J=8.8 Hz 1H), 7.74 (t, J=7.6 Hz, 1H), 7.56-7.61 (m, 3H), 7.20 (t, J=7.2 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 1.86 (dd, J=14.0, 6.8 Hz, 2H), 1.07 (t, J=7.2 Hz, 3H).
    • Method G8: 2-(6-ethoxy-2-(pyridin-3-yl)quinazolin-4-yloxy)benzamide (vii-a)
  • (The method G8 is representative of method G6, G7, G9, G10 and G11. These six methods can be implemented in a similar way except for substitution of the appropriate base, solvent and temperature) To a 2.5 dram reaction vial was first added sodium hydride 60% (0.028 g, 0.700 mmol) and salicylamide (0.072 g, 0.525 mmol) in DMF (2 mL). The mixture was allowed to stir at room temperature for 1 h. Then, 4-chloro-6-ethoxy-2-(pyridin-3-yl)quinazoline (0.100 g, 0.350 mmol) was added to the mixture, and the reaction was allowed to proceed at room temperature overnight. LC-MS analysis of the crude mixture showed about 85% of product formed and 10% remaining starting material. Water (30 mL) was added to the mixture, and the product was extracted with chloroform (3×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified via ISCO (silica gel, 97.5:2.5 CH2Cl2/MeOH; 12 g column) to afford 13.9 mg of the desired product as a white solid (10.3%) LCMS m/z=387 (M+1) (Method C) (retention time=2.05 min). 1H NMR (300 MHz, DMSO) δ 11.47 (s, 2H), 9.39 (s, 1H), 8.66 (d, J=2.8 Hz, 1H), 8.56-8.47 (m, 1H), 8.01-7.90 (m, 2H), 7.69-7.55 (m, 2H), 7.55-7.40 (m, 2H), 7.05 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 4.23 (q, J=6.9 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H).
    • Method G13: 4-(4-chlorophenyl)-N-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-yl)thiazol-2-amine (vi-c)
  • (The method G13 is representative of method G12 also. This method can be implemented in a similar way except for substitution of the appropriate base, solvent and temperature) To a suspension of 4-chloro-6-methoxy-2-(pyridine-3-yl)quinazoline (645.2 mg, 2.375 mmol) and 2-amino-4-(4-chlorophenyl)thiazole (1050 mg, 4.98 mmol) in DMA (40 mL) was added Cs2CO3 (2430 mg, 7.46 mmol) at room temperature. The mixture was stirred at 80° C. for 9.5 h. Water was added and a precipitate formed which was collected by filtration and washed with H2O. Recrystallization from acetone/DMF/methanol gave 383.6 mg of the product in a 36% yield as yellow solid, >98% purity by 1H NMR). 1H NMR (400 MHz DMSO-d6) δ 12.52 (s, 1H), 9.78 (d, J=1.56 Hz, 1H), 8.91-8.88 (m, 1H), 8.74 (dd, J=4.74, 1.60 Hz, 1H), 8.33 (brs, 1H), 8.06 (d, J=8.56 Hz, 2H), 7.93 (d, J=9.08 hz, 1H), 7.89 (s, 1H), 7.66-7.59 (m, 2H), 7.55 (d, J=8.56 Hz, 2H), 4.01 (s, 3H).
    • Method G14: 4-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-1H-pyrazole-5-carboxamide, 2 HCl (vi-d)
  • (The method G14 is representative of method G4 and G5 also. This method can be implemented in a similar way except for substitution of the appropriate solvent and adjustment of the temperature) To a microwave vial containing 4-bromo-6-methoxy-2-(pyridin-3-yl)quinazoline (150.0 mg, 0.47 mmol) in DMF (2 mL) was added 4-amino-1H-pyrazole-5-carboxamide (66.0 mg, 0.52 mmol) and sodium tert-butoxide (50 mg, 0.52 mmol). The reaction mixture was heated at 100° C. for 15 mins by microwave irradiation. Water (50 mL) was added to the reaction mixture, and extracted with ethyl acetate (5×50 mL). The crude material was purified via ISCO (silica, 12 g column, 93% CH2Cl2—7% MeOH—0.1% NH4OH) giving the product as a yellow solid. The free base was then converted to the HCl salt to yield the final product as an orange solid (59.8 mg, 0.14 mmol, 22%). LC-MS m/z=362.4 (M+1) (retention time=1.57)1H NMR (300 MHz, DMSO) δ 11.28 (s, 1H), 9.62 (d, J=1.7 Hz, 1H), 9.17 (d, J=7.8 Hz, 1H), 8.93 (dd, J=5.2, 1.3 Hz, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 8.03-7.94 (m, 2H), 7.77 (s, 1H), 7.64 (dd, J=9.2, 2.5 Hz 1H), 7.40 (d, J=2.6 Hz, 1H), 3.97 (s, 3H).
    • Method J1: 1-(6-Methoxy-2-(pyridin-3-yl)quinazolin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (vi-b)
  • To a 50-mL two-neck round bottom flask equipped with a reflux condenser was added a mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (50 mg, 0.18 mmol, 1 eq.) and 1H-benzo[d]imidazol-2(3H)-one (27 mg, 0.21 mmol, 1.1 eq.) in 5 mL of dry 1,4-dioxane. Pd(PPh3)4 (10.6 mg, 0.009 mmol, 0.05 eq) and t-BuOK (41 mg, 0.36 mmol, 2 eq.) were added. The resulting mixture was stirred at 100° C. under N2 atmosphere overnight. After cooling, 20 mL of methanol was added. The mixture was filtered, the filtrate was concentrated in vacuo and then was purified with chromatography on silica gel (ethyl acetate/petroleum ether from 1:4 to 1:2) to give the crude product, which was further purified with reverse phase HPLC to afford 4.8 mg of vi-e as a pale yellow solid (7%). MS m/z=370.1 (M+1) (Method B) (retention time=1.680 min). 1H NMR (400 MHz, DMSO-d6): δ 11.51 (s, 1H), 8.78 (d, J=8.0 Hz, 2H), 8.17 (d, J=9.2 Hz, 1H), 7.80 (dd, J=9.2, 2.8 Hz, 1H), 7.70-7.64 (m, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.20 (d, J=4.0 Hz, 2H), 7.16-7.08 (m, 1H), 3.89 (s, 3H).
    • Method J2: 6-methoxy-N-(pyridin-2-yl)-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride (vi-e)
  • To a suspension of 4-chloro-6-methoxy-2-(pyridine-3-yl)quinazoline (600 mg, 2.208 mmol) in dioxane (40 mL) under N2, was added tris(dibenzylideneacetone)dipalladium(0) (103.1 mg, 0.113 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (132.2 mg, 0.228 mmol) and cesium carbonate (1.1289 g, 3.46 mmol) at room temperature. 2-Aminopyridine (229 mg, 2.43 mmol) was added and the mixture was stirred at 100° C. for 2 h 30 min. Water was added and then a precipitate formed. The solid was collected and washed with water. The solid was dissolved in CH2Cl2. Purification was carried out using NH-silica gel to give the free base (649.3 mg). The free base was converted to the HCl salt by dissolving the compound in CH2Cl2/MeOH and 1.5 ml of 4N HCl in ethyl acetate was added and then a precipitate formed. The solid was collected and dried in vacuo (at 40 degrees on and 60 degrees for ca. 3 h) and then washed with methanol. The resulting solid was dried in vacuo at 60 degrees to give 682 mg of the desired product as the HCl salt in a 77% yield as a pale yellow solid. 1H NMR (DMSO-d6) δ 11.14 (brs, 1H), 9.58 (s, 1H), 9.13 (dd, J=7.96 Hz, 1H), 8.93 (d, J=5.24 Hz, 1H), 8.54 (d, J=4.72 Hz, 1H), 8.48 (d, J=8.32 Hz, 1H), 8.28 (brs, 1H), 8.09 (brt, J=7.16 Hz, 1H), 8.02-7.96 (m, 2H), 7.65 (dd, J=8.80, 2.48 Hz, 1H), 7.34 (brt, J=6.52 Hz, 1H), 4.01 (s, 3H). The 1H of 2 HCl was not observed.
    • Method J3: N-(Biphenyl-4-yl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine hydrochloride (vi-f)
  • To a suspension of N-(4-bromophenyl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine (548.7 mg, 1.347 mmol) and phenylboronic acid (270 mg, 2.21 mmol) in dioxane/H2O (2/1) (30 mL) under N2 was added Na2CO3 (485 mg, 4.58 mmol) and tetrakis(triphenylphosphine) palladium(0) (78 mg, 0.067 mmol) at room temperature. The mixture was stirred at 100° C. for 1 h. Water was added and then a precipitate formed. The solid was dissolved in methanol/acetone at 60° C. The solution was filtrated through Celite to remove any extra palladium. The filtrate was concentrated down to give 493.4 mg of a solid residue in. The solid was added to CH2Cl2 followed by addition of 4N HCl in ethyl acetate (0.4 mL) at room temperature to form the HCl salt. The mixture was stirred at room temperature and the resulting solid was filtered and dried in vacuo to give 435.2 mg and a yield of 73% as the HCl salt. 1H NMR (DMSO-d6) δ 10.24 (br, 1H), 9.54 (s, 1H), 8.92 (d, J=7.52 Hz, 1H), 8.82 (d, J=3.96 Hz, 1H), 8.10 (d, J=2.44 Hz, 1H), 8.03 (d, J=8.68 Hz, 2H), 7.92 (d, J=9.08 Hz, 1H), 7.84 (d, J=8.68 Hz, 2H), 7.81 (m, 1H), 7.77-7.75 (m, 2H), 7.62 (dd, J=9.08, 2.44 Hz, 1H), 7.50 (m, 2H), 7.38 (m, 1H), 4.01 (s, 3H). The 1H of HCl was not observed.
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 1 and 5 (prepared according to method procedure A-J as designated).
  • TABLE 1
    Method
    Salt Molecular 1H-NMR LCMS Purity for
    Number Product type Mass 1H-NMR Solvent LCMS Protocol percent Coupling
    1
    Figure US20170217923A1-20170803-C00145
         		399.45 1H-NMR (400 MHz, DMSO-d6): δ 9.59 (d, J = 2.0 Hz, 1H), 9.58 (d, J = 7.6 Hz, 1H), 8.69-8.74 (m, 2H), 8.48 (s, 1H), 7.97 (d, J = 6.8 Hz, 2H), 7.90 (d, J = 8.8 Hz 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.56- 7.61 (m, 3H), 7.20 (t, J = 7.2 Hz, 1H), 4.16 (t, J = 6.4 Hz, 2H), 1.86 (dd, J = 7.2, 6.8 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H). DMSO 400.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    2
    Figure US20170217923A1-20170803-C00146
         		HCl 398.46 1H-NMR (400 MHz, DMSO-d6): δ 13.20 (s, 1H), 9.79 (s, 1H), 9.02-9.08 (m, 2H), 8.87 (d, J = 3.2 Hz, 1H), 8.53 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 6.8 Hz, 1H), 7.74-7.99 (m, 5H), 7.28 (t, J = 7.6 Hz, 1H), 4.92 (d, J = 4.0 Hz, 2H), 2.87 (d, J = 3.2 Hz, 6H). DMSO 399.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    3
    Figure US20170217923A1-20170803-C00147
         		HCl 424.50 1H-NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H), 9.64 (d, J = 1.6 Hz, 1H), 9.15 (d, J = 8.0 Hz, 1H), 8.78 (ddd, J = 8.0, 4.0, 2.4 Hz, 1H), 8.73 (dd, J = 4.4, 1.2 Hz, 1H), 8.49 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.92-7.69 (m, 3H), 7.67-7.74 (m, 2H), 7.62 (dd, J = 8.0, 4.8 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 4.29 (s, 2H), 2.61 (brs, 4H), 1.70 (brs, 4H). DMSO 425.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    4
    Figure US20170217923A1-20170803-C00148
         		422.43 1H-NMR (400 MHz, DMSO-d6): δ 9.87 (s, 1H), 9.52 (s, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.94 (s, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.50-7.58 (m, 3H), 7.30 (t, J = 34.0 Hz, 1H), 7.00 (dd, J = 8.4, 2.0 Hz, 1H), 4.16 (t, J = 6.4 Hz, 2H), 1.86 (dd, J = 7.2, 6.4 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H). DMSO 423.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    5
    Figure US20170217923A1-20170803-C00149
         		HCl 408.86 1H-NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.48 (s, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.85 (d, J = 4.4 Hz, 1H), 8.18 (dd, J = 7.6, 2.4 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.85-7.93 (m, 3H), 7.62 (dd, J = 8.8, 6.4 Hz, 1H), 7.55 (t, J = 8.8 Hz, 1H), 4.17 (t, J = 6.4 Hz, 3H), 1.86 (dd, J = 7.6, 6.4 Hz, 2H), 1.06 (t, J = 7.6 Hz, 3H). DMSO 409.1, 411.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    6
    Figure US20170217923A1-20170803-C00150
         		425.31 1H-NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 9.51 (s, 1H), 8.68-8.71 (m, 2H), 8.16 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.56- 7.60 (m, 2H), 7.37 (s, 1H), 4.14 (t, J = 6.4 Hz, 2H), 1.84 (dd, J = 10.4 Hz, 7.2 Hz, 2H), 1.07 (t, J = 7.6 Hz, 3H). DMSO 425.0, 427.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    7
    Figure US20170217923A1-20170803-C00151
         		392.4 1H-NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.49 (s, 1H), 8.77-8.81 (m, 2H), 8.09 (ddd, J = 10.0, 7.6, 2.4 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.69-7.74 (m, 2H), 7.54-7.61 (m, 2H), 4.15 (t, J = 6.4 Hz, 2H), 1.86 (dd, J = 14.0, 7.6 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H). DMSO 393.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    8
    Figure US20170217923A1-20170803-C00152
         		425.31 1H-NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 9.51 (s, 1H), 8.75-8.80 (m, 2H), 8.34 (d, J = 2.4 Hz, 1H), 7.96-8.00 (m, 2H), 7.88 (d, J = 9.2 Hz, 1H), 7.68-7.75 (m, 2H), 7.59 (dd, J = 9.2, 2.8 Hz, 1H), 4.15 (t, J = 6.4 Hz, 2H), 1.86 (dd, J = 7.2, 6.8 Hz, 2H), 1.06 (t, J = 7.6 Hz, 3H). DMSO 425.0, 427.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    9
    Figure US20170217923A1-20170803-C00153
         		415.44 1H-NMR (400 MHz, DMSO-d6): δ 13.03 (s, 1H), 9.59 (d, J = 1.2 Hz, 1H), 9.15 (d, J = 8.4 Hz, 1H), 8.69-8.74 (m, 2H), 8.49 (s, 1H), 7.96-8.06 (m, 2H), 7.90 (d, J = 9.2 Hz, 1H), 7.56-7.63 (m, 3H), 7.20 (t, J = 8.0 Hz, 1H), 4.31 (t, J = 4.0 Hz, 2H), 3.79 (t, J = 4.8 Hz, 2H), 3.31 (s, 3H). DMSO 416.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    10
    Figure US20170217923A1-20170803-C00154
         		438.43 1H-NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 9.53 (s, 1H), 8.66-8.68 (m, 2H), 8.02 (d, J = 2.8 Hz, 1H), 7.95 (t, J = 2.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.48-7.60 (m, 3H), 7.30 (t, J = 74.4 Hz, 1H), 7.00 (dd, J = 8.0, 2.0 Hz, 1H), 4.33 (t, J = 4.8 Hz, 2H), 3.79 (t, J = 4.4 Hz, 2H), 3.37 (s, 3H). DMSO 439.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    11
    Figure US20170217923A1-20170803-C00155
         		HCl 424.86 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.48 (s, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.19 (dd, J = 6.8, 2.4 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.85-7.93 (m, 3H), 7.64 (dd, J = 9.2, 6.8 Hz, 1H), 7.55 (t, J = 8.8 Hz, 1H), 4.34 (t, J = 4.4 Hz, 2H), 3.78 (t, J = 4.4 Hz, 2H), 3.31 (s, 3H). DMSO 425.1, 427.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    12
    Figure US20170217923A1-20170803-C00156
         		397.43 1H-NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 9.50 (s, 1H), 8.78 (dd, J = 17.6, 7.6 Hz, 1H), 8.39 (s, 1H), 8.26 (dd, J = 8.0, 2.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.61-7.73 (m, 4H), 4.34 (t, J = 4.8 Hz, 2H), 3.79 (t, J = 4.4 Hz, 2H), 3.35 (s, 3H). DMSO 398.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    13
    Figure US20170217923A1-20170803-C00157
         		408.4 1H-NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.67 (dd, J = 4.8, 1.6 Hz, 1H), 8.64 (dt, J = 8.0, 1.6 Hz, 1H), 8.12 (ddd, J = 13.2, 7.2, 2.4 Hz, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 9.2, 1H), 7.69-7.72 (m, 1H), 7.52-7.60 (m, 3H), 4.31 (t, J = 4.0 Hz, 2H), 3.76-3.80 (m, 2H), 3.37 (s, 3H). DMSO 409.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    14
    Figure US20170217923A1-20170803-C00158
         		441.31 1H-NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 9.52 (d, J = 1.2 Hz, 1H), 8.64-8.68 (m, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 10.6, 2.4 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.55 (dd, J = 8.0, 4.8 Hz, 1H), 4.31 (t, J = 4.08 Hz, 2H), 3.78 (t, J = 4.4 Hz, 2H), 3.37 (s, 3H). DMSO 441.0, 443.0 (M + 1), 221.9 (M/2 + 1) Method A (TFA) 95 Method C, G1
    15
    Figure US20170217923A1-20170803-C00159
         		441.31 1H-NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 9.53 (d, J = 1.6 Hz, 1H), 8.66-8.70 (m, 2H), 8.18 (s, 1H), 8.17 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.8, 2.4 Hz, 1H), 7.56 (dd, J = 7.6, 4.8 Hz, 1H), 7.39 (t, J = 2.0 Hz, 1H), 4.33 (t, J = 4.8 Hz, 2H), 3.79 (t, J = 4.4 Hz, 2H), 3.37 (s, 3H). DMSO 441.1, 443.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    16
    Figure US20170217923A1-20170803-C00160
         		HCl 375.79 1H-NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.53 (d, J = 1.2 Hz, 1H), 9.16 (d, J = 1.2 Hz, 1H), 8.74 (dd, J = 4.0, 1.6 Hz, 1H), 8.66-8.69 (m, 2H), 8.20-8.28 (m, 2H), 8.00 (d, J = 8.4 Hz, 1H), 7.89-7.93 (m, 1H), 7.55-7.61 (m, 2H). DMSO 376.0, 378.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    17
    Figure US20170217923A1-20170803-C00161
         		393.8 1H-NMR (400 MHz, DMSO-d6): δ 10.37 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H), 9.09 (s, 1H), 8.69 (d, J = 10.0 Hz, 1H), 8.68 (d, J = 8.0 Hz, 1H), 8.23-8.27 (m, 2H), 8.11 (s, 1H), 8.78 (s, 2H), 7.50-7.58 (m, 3H). DMSO 394.1, 396.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    18
    Figure US20170217923A1-20170803-C00162
         		HCl 394.79 1H-NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.48 (d, J = 0.8 Hz, 1H), 9.28 (d, J = 0.8 Hz, 1H), 8.69 (d, J = 10.0 Hz, 1H), 8.68 (d, J = 8.0 Hz, 1H), 8.23-8.27 (m, 2H), 8.11 (s, 1H), 8.78 (s, 2H), 7.50- 7.58 (m, 3H). DMSO 395.0, 397.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    19
    Figure US20170217923A1-20170803-C00163
         		422.38 1H-NMR (400 MHz, DMSO-d6): δ 10.11 (brs, 1H), 9.48 (s, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.88-7.90 (m, 1H), 1.77 (d, J = 8.0 Hz, 1H), 7.52-7.62 (m, 3H), 4.27 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). DMSO 423.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    20
    Figure US20170217923A1-20170803-C00164
         		HCl 408.81 1H-NMR (400 MHz, DMSO-d6): δ 10.73 (s, 1H), 9.52 (d, J = 1.6 Hz, 1H), 9.32 (d, J = 1.6 Hz, 1H), 9.01 (d, J = 4.8 Hz, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.39 (dd, J = 8.4, 1.6 Hz, 1H), 8.17 (dd, J = 6.8, 2.0 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.90- 7.95 (m, 2H), 7.55 (t, J = 9.2 Hz, 1H), 3.98 (s, 3H). DMSO 409.1, 411.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    21
    Figure US20170217923A1-20170803-C00165
         		399.45 1H-NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.56 (s, 1H), 9.14 (d, J = 8.0 Hz, 1H), 8.83-8.66 (m, 2H), 8.48 (s, 1H), 8.06-7.91 (m, 2H), 7.76-7.58 (m, 2H), 7.35 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 4.15 (q, J = 6.8 Hz, 2H), 2.64 (s, 3H), 1.43 (t, J = 6.8 Hz, 1H). DMSO 400.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    22
    Figure US20170217923A1-20170803-C00166
         		440.42 1H-NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.55 (d, J = 1.2 Hz, 1H), 8.73-8.60 (m, 2H), 8.14 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.53 (dd, J = 7.6, 4.8 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.23 (q, J = 6.8 Hz, 2H), 2.70 (s, 3H), 1.44 (t, J = 6.8 Hz, 3H) DMSO 440.9 (M + 1) Method A (TFA) 95 Method D, G1
    23
    Figure US20170217923A1-20170803-C00167
         		405.81 1H-NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.42 (s, 1H), 8.68 (d, J = 3.6 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H), 8.15 (dd, J = 6.8, 2.4 Hz, 1H), 8.04 (s, 1H), 7.93-7.78 (m, 1H), 7.54 (td, J = 8.3, 6.9 Hz, 2H), 4.08 (s, 3H) DMSO 406.1, 408.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    24
    Figure US20170217923A1-20170803-C00168
         		493.92 1H-NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.49-9.51 (m, 1H), 8.62-8.70 (m, 2H), 8.21 (dd, J = 6.8, 2.8 Hz, 1H), 8.03 (s, 1H), 7.87-7.91 (m, 1H), 7.75 (s, 1H), 7.53-7.59 (m, 2H), 4.02 (s, 3H), 3.64-3.73 (m, 4H), 3.49-3.58 (m, 2H), 3.14-3.22 (m, 2H). DMSO 494.1, 496.1 (M + 1) Method B (NH4HCO4) 95 Method C, G1
    25
    Figure US20170217923A1-20170803-C00169
         		TFA 369.38 1H-NMR (400 MHz, DMSO-d6): δ 11.51 (s, 1H), 8.78 (d, J = 8.0 Hz, 2H), 8.17 (d, J = 9.2 Hz, 1H), 7.80 (dd, J = 9.2, 2.8 Hz, 1H), 7.70-7.64 (m, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 4.0 Hz, 2H), 7.16-7.08 (m, 1H), 3.89 (s, 3H). DMSO 370.1 (M + 1) Method B (NH4HCO3) 95 Method C, J1
    26
    Figure US20170217923A1-20170803-C00170
         		408.4 1H-NMR (400 MHz, DMSO-d6): δ 9.87 (s, 1H), 8.53 (dd, J = 4.7, 1.5 Hz, 1H), 8.23 (d, J = 6.8 Hz, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.8 (t, J = 2.1 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.73 (dd, J = 8.2, 1.2 Hz, 1H), 7.58 (dd, J = 9.1, 2.6 Hz, 1H), 7.41- 7.25 (m, 3H), 7.24 (t, J = 74.0 Hz, 1H), 6.96 (dd, J = 8.0, 2.2 Hz, 1H), 3.99 (s, 3H), 2.75 (s, 3H). DMSO 409.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    27
    Figure US20170217923A1-20170803-C00171
         		385.42 1H-NMR (400 MHz, DMSO-d6): δ 13.09 (s, 1H), 9.08 (d, J = 7.8 Hz, 1H), 8.55 (dd, J = 4.8, 1.6 Hz, 1H), 8.49 (s, 1H), 8.22 (dd, J = 7.8, 1.7 Hz, 1H), 8.01 (s, 1H), 7.95 (dd, J = 7.9, 1.2 Hz, 1H), 7.87 (d, J = 9.6 Hz, 1H), 7.66-7.58 (m, 3H), 7.40 (dd, J = 7.7, 4.8 Hz, 1H), 7.15 (dd, J = 11.5, 4.4 Hz, 1H), 3.99 (s, 3H), 2.77 (s, 3H). DMSO 386.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    28
    Figure US20170217923A1-20170803-C00172
         		394.83 1H-NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 8.63 (d, J = 4.1 Hz, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.15 (dd, J = 6.8, 2.5 Hz, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.88-7.78 (m, 2H), 7.58 (ddd, J = 12.5, 8.3, 4.1 Hz, 2H), 7.49 (t, J = 9.1 Hz, 1H), 3.99 (s, 3H), 2.80 (s, 3H). DMSO 395.1, 397.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    29
    Figure US20170217923A1-20170803-C00173
         		HCl 440.5 1H-NMR (400 MHz, DMSO-d6): δ 13.19 (s, 1H), 11.12-10.93 (m, 1H), 9.83 (d, J = 1.5 Hz, 1H), 9.21 (d, J = 7.8 Hz, 1H), 9.01 (d, J = 7.8 Hz, 1H), 8.93-8.89 (m, 1H), 8.53 (s, 1H), 8.36 (dd, J = 11.8, 7.9 Hz, 2H), 8.02-7.73 (m, 6H), 7.29 (d, J = 8.02 Hz, 1H), 5.01 (s, 2H), 3.95-3.81 (m, 4H), , 3.37 (s, 4H). DMSO 441.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    30
    Figure US20170217923A1-20170803-C00174
         		HCl 449.91 1H-NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 9.56 (s, 1H), 8.73-8.66 (m, 2H), 8.47 (d, J = 8.1 Hz, 1H), 8.28 (dd, J = 6.8, 2.5 Hz, 1H), 7.99-7.90 (m, 2H), 7.67-7.50 (m, 3H), 4.16 (s, 2H), 3.62 (s, 4H), 2.53 (s, 4H). DMSO 450.1, 452.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    31
    Figure US20170217923A1-20170803-C00175
         		400.33 1H-NMR (400 MHz, DMSO-d6): δ 9.47 (d, J = 2.0 Hz, 2H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.65-8.59 (m, 1H), 8.06 (s, 1H), 7.91 (dt, J = 8.1, 6.0 Hz, 1H), 7.82 (dd, J = 8.2, 1.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 8.2 Hz, 1H), 7.51 (ddd, J = 20.0, 10.0, 6.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H). DMSO 401.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    32
    Figure US20170217923A1-20170803-C00176
         		HCl 368.77 1H-NMR (400 MHz, DMSO-d6): δ 9.53 (d, J = 11.3 Hz, 1H), 9.44 (d, J = 1.2 Hz, 1H), 8.84-8.79 (m, 2H), 8.09 (dd, J = 6.8, 2.6 Hz, 1H), 7.97-7.89 (m, 1H), 7.85-7.75 (m, 3H), 7.57-7.47 (m, 2H). DMSO 369.1, 371.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    33
    Figure US20170217923A1-20170803-C00177
         		HCl 359.36 1H-NMR (400 MHz, DMSO-d6): δ 12.21 (d, J = 12.1 Hz, 1H), 9.53 (d, J = 1.2 Hz, 1H), 8.99 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 4.2 Hz, 1H), 8.71 (d, J = 7.9 Hz, 1H), 8.35 (s, 1H), 7.97-7.76 (m, 5H), 7.72- 7.65 (m, 1H), 7.50 (dd, J = 12.1, 7.5 Hz, 1H), 7.29 (t, J = 7.1 Hz, 1H). DMSO 360.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    34
    Figure US20170217923A1-20170803-C00178
         		382.34 1H-NMR (400 MHz, DMSO-d6): δ 9.49 (d, J = 1.8 Hz, 1H), 9.42 (s, 1H), 8.71 (dd, J = 4.6, 1.3 Hz, 1H), 8.65 (d, J = 7.8 1H), 7.90 (dd, J = 15.8, 9.7 Hz, 2H), 7.73 (dd, J = 19.0, 8.26 Hz, 2H), 7.56- 7.12 (m, 4H), 7.04 (dd, J = 8.2, 1.8 Hz, 1H). DMSO 383.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    35
    Figure US20170217923A1-20170803-C00179
         		HCl 400.33 1H-NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.52 (s, 1H), 8.89 (d, J = 8.2 Hz, 1H), 8.85 (d, J = 4.2 Hz, 1H), 8.78 (dd, J = 9.2, 5.9 Hz, 1H), 8.09 (s, 1H), 7.95 (dd, J = 8.2, 1.2 Hz, 1H), 7.80 (dd, J = 7.9, 5.2 Hz, 1H), 7.72-7.58 (m, 3H), 7.21 (d, J = 8.4 Hz, 1H). DMSO 401.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    36
    Figure US20170217923A1-20170803-C00180
         		HCl 405.84 1H-NMR (400 MHz, DMSO-d6): δ 10.74- 10.48 (m, 1H), 9.36 (d, J = 1.6 Hz, 1H), 8.95 (d, J = 8.2 Hz, 1H), 8.89-8.85 (m, 1H), 8.06 (d, J = 1.7 Hz, 1H), 8.02 (d, J = 9.15 Hz, 1H), 7.93-7.86 (m, 2H), 7.73- 7.63 (m, 3H), 7.60-7.52 (m, 2H), 3.98 (s, 3H). DMSO 406.1, 408.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    37
    Figure US20170217923A1-20170803-C00181
         		HCl 359.36 1H-NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 9.00 (dd, J = 15.4, 8.2 Hz, 2H), 8.86 (d, J = 4.13 Hz, 1H), 8.52 (s, 1H), 8.04-7.94 (m, 3H), 7.86-7.70 (m, 4H), 7.26 (dd, J = 11.2, 4.2 Hz, 1H). DMSO 360.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    38
    Figure US20170217923A1-20170803-C00182
         		HCl 368.77 1H-NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 9.52 (s, 1H), 8.73 (d, J = 3.6 Hz, 1H), 8.69 (td, J = 8.0, 1.8 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.25 (dd, J = 6.8, 2.6 Hz, 1H), 7.91 (ddd, J = 9.0, 4.2, 2.6 Hz, 1H), 7.79 (dd, J = 9.8, 7.9 Hz, 1H), 7.67 (dd, J = 8.2, 5.2 Hz, 1H), 7.61-7.53 (m, 2H). DMSO 369.0, 371.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    39
    Figure US20170217923A1-20170803-C00183
         		HCl 400.33 1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.52 (d, J = 1.4 Hz, 1H), 9.04 (d, J = 8.0 Hz, 1H), 8.92 (dd, J = 5.2, 1.2 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.97 (d, J = 1.2 Hz, 2H), 7.86-7.80 (m, 1H), 7.74-7.68 (m, 1H), 7.62 (t, J = 8.2 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H). DMSO 401.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    40
    Figure US20170217923A1-20170803-C00184
         		360.34 1H-NMR (400 MHz, DMSO-d6): δ 9.68 (d, J = 1.6 Hz, 1H), 8.82 (td, J = 7.9, 1.8 Hz, 1H), 8.71 (dd, J = 4.6, 1.6 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.87 (dd, J = 7.8, 1.9 Hz, 1H), 7.73 (dd, J = 9.2, 7.8 Hz, 1H), 7.59 (dt, J = 8.1, 5.0 Hz, 2H), 7.21-7.15 (m, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.54 (t, J = 7.4 Hz, 1H). DMSO 360.9 (M + 1), 382.9 (M + 23) Method B (NH4HCO3) 95 Method C, G9
    41
    Figure US20170217923A1-20170803-C00185
         		380.08 1H-NMR (400 MHz, DMSO-d6): δ 10.56 (brs, 1H), 9.62 (d, J = 1.2 Hz, 1H), 9.05 (d, J = 8.4 Hz, 1H), 9.00 (dd, J = 1.6, 4.8 Hz, 1H), 8.71 (d, J = 9.2 Hz, 1H), 8.31 (dd, J = 2.0, 7.2 Hz, 1H), 8.02-7.99 (m, 2H), 7.66 (t, J = 9.2 Hz, 1H), 7.54 (s, 1H), 7.50 (dd, J = 2.4, 9.2 Hz, 1H), 4.11 (s, 3H). DMSO 381.1, 383.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    42
    Figure US20170217923A1-20170803-C00186
         		476.67 1H-NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.51 (s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 1.6 Hz, 1H), 8.20 (dd, J = 4.4, 6.8 Hz, 1H), 8.04 (dd, J = 7.2, 8.8 Hz, 1H), 7.93-7.86 (m, 2H), 7.35 (t, J = 9.2 Hz, 1H). DMSO 477.0, 499.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    43
    Figure US20170217923A1-20170803-C00187
         		429.67 1H-NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 9.49 (s, 1H), 8.95 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 4.97 Hz, 1H), 8.60 (d, J = 8.9 Hz, 1H), 8.19 (dd, J = 6.8, 2.6 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.96-7.83 (m, 3H), 7.53 (t, J = 9.0 Hz, 1H). DMSO 429.0, 430.9, 433.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    44
    Figure US20170217923A1-20170803-C00188
         		HCl 385.42 1H-NMR (400 MHz, DMSO-d6): δ 13.05 (s, 1H), 9.44 (d, J = 1.7 Hz, 1H), 9.16- 8.91 (m, 2H), 8.03-7.89 (m, 3H), 7.88- 7.82 (m, 1H), 7.75-7.68 (m, 1H), 7.67- 7.60 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 4.00 (s, 3H), 2.74 (s, 3H). DMSO 386.0 (M + 1) 193.4 (M/2 + 1) Method A (TFA) 95 Method C, G1
    45
    Figure US20170217923A1-20170803-C00189
         		HCl 408.4 1H-NMR (400 MHz, DMSO-d6): δ 10.37- 10.12 (m, 1H), 9.35 (d, J = 1.8 Hz, 1H), 8.95 (dd, J = 4.6, 3.4 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.87 (s, 1H), 7.84-7.74 (m, 2H), 7.62 (dd, J = 9.1, 2.6 Hz, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.32 (t, J = 74.0 Hz, 1H), 7.05 (dd, J = 8.3, 1.9 Hz, 1H), 4.00 (s, 3H), 2.72 (s, 3H). DMSO 409.0 (M + 1) 205.0 (M/2 + 1) Method A (TFA) 95 Method C, G1
    46
    Figure US20170217923A1-20170803-C00190
         		HCl 394.83 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (brs, 1H), 9.32 (d, J = 1.7 Hz, 1H), 8.93 (d, J = 7.5 Hz, 1H), 8.19 (dd, J = 6.8, 2.5 Hz, 1H), 8.07 (d, J = 2.3 Hz, 1H), 7.88- 7.92 (m, 2H), 7.84 (d, J = 8.1 Hz, 1H), 7.62 (dd, J = 9.2, 2.5 Hz, 1H), 7.54 (t, J = 9.1 Hz, 1H), 4.00 (s, 3H), 2.72 (s, 3H). DMSO 395.0, 397.0 (M + 1) 197.8, 198.8 (M/2 + 1) Method A (TFA) 95 Method C, G1
    47
    Figure US20170217923A1-20170803-C00191
         		HCl 378.37 1H-NMR (400 MHz, DMSO-d6): δ 10.58- 10.30 (m, 1H), 9.32 (d, J = 1.9 Hz, 1H), 9.04 (d, J = 7.9 Hz, 1H), 8.17-8.04 (m, 2H), 7.95 (d, J = 9.0 Hz, 2H), 7.73-7.66 (m, 1H), 7.63 (dd, J = 9.2, 2.6 Hz, 1H), 7.60-7.50 (m, 1H), 4.01 (s, 3H), 2.76 (s, 3H). DMSO 379.0 (M + 1) 190.0 (M/2 + 1) Method A (TFA) 95 Method C, G1
    48
    Figure US20170217923A1-20170803-C00192
         		HCl 411.28 1H-NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 9.33 (d, J = 1.7 Hz, 1H), 9.04- 8.89 (m, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.8, 2.5 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.62 (dd, J = 9.1, 2.5 Hz, 1H), 4.00 (s, 3H), 2.73 (s, 3H). DMSO 411.0, 413.0 (M + 1) 205.0, 206.9 (M/2 + 1) Method A (TFA) 95 Method C, G1
    49
    Figure US20170217923A1-20170803-C00193
         		411.28 1H-NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 9.31 (d, J = 1.5 Hz, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.13 (d, J = 1.7 Hz, 2H), 8.07 (d, J = 2.3 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 9.1, 2.6 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 4.00 (s, 3H), 2.72 (s, 3H). DMSO 411.0, 413.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    50
    Figure US20170217923A1-20170803-C00194
         		HCl 389.84 1H-NMR (400 MHz, DMSO-d6): δ 13.09 (s, 1H), 9.38 (s, 1H), 9.16 (d, J = 8.4 Hz, 1H), 8.83 (d, J = 8.3 Hz, 1H), 8.50 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.05-7.99 (m, 2H), 7.97 (d, J = 7.9 Hz, 1H), 7.92 (s, 1H), 7.81 (dd, J = 8.8, 2.0 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 2.82 (s, 3H). DMSO 390.1, 392.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    51
    Figure US20170217923A1-20170803-C00195
         		HCl 412.82 1H-NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 9.35 (d, J = 1.7 Hz, 1H), 9.08 (dd, J = 8.3, 1.5 Hz, 1H), 8.75 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.87 (s, 1H), 7.80 (dd, J = 9.0, 2.0 Hz, 2H), 7.53 (t, J = 8.2 Hz, 1H), 7.31 (t, J = 74.0 Hz, 1H), 7.06 (dd, J = 8.1, 2.0 Hz, 1H), 2.79 (s, 3H). DMSO 413.0, 415.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    52
    Figure US20170217923A1-20170803-C00196
         		399.25 1H-NMR (400 MHz, DMSO-d6): δ 10.49 (s, 1H), 9.32 (d, J = 1.7 Hz, 1H), 9.00 (d, J = 8.4 Hz, 1H), 8.69 (d, J = 8.9 Hz, 1H), 8.20 (dd, J = 6.8, 2.6 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.96-7.86 (m, 2H), 7.80 (dd, J = 8.9, 2.1 Hz, 1H), 7.53 (t, J = 9.1 Hz, 1H), 2.76 (s, 3H). DMSO 399.0, 401.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    53
    Figure US20170217923A1-20170803-C00197
         		HCl 382.79 1H-NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H), 9.32 (d, J = 1.7 Hz, 1H), 9.07 (dd, J = 8.2, 1.2 Hz, 1H), 8.73 (d, J = 8.9 Hz, 1H), 8.08 (ddd, J = 13.0, 7.5, 2.6 Hz, 1H), 8.00 (dd, J = 8.9, 5.2 Hz, 2H), 7.80 (dd, J = 8.9, 2.1 Hz, 1H), 7.71 (dd, J = 6.1, 2.9 Hz, 1H), 7.54 (dd, J = 19.7, 9.2 Hz, 1H), 2.78 (s, 3H) DMSO 383.0, 385.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    54
    Figure US20170217923A1-20170803-C00198
         		HCl 415.7 1H-NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 9.30 (d, J = 1.7 Hz, 1H), 9.07 (dd, J = 8.3, 1.8 Hz, 1H), 8.75 (d, J = 9.0 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.96 (dd, J = 8.9, 2.5 Hz, 1H), 7.77 (dd, J = 8.9, 2.1 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 2.81 (s, 3H). DMSO 415.0, 417.0, 419.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    55
    Figure US20170217923A1-20170803-C00199
         		HCl 415.7 1H-NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 9.32 (s, 1H), 9.01 (dd, J = 8.0, 1.8 Hz, 1H), 8.72 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 1.8 Hz, 2H), 8.01 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.80 (dd, J = 8.9, 2.0 Hz, 1H), 2.78 (s, 3H). DMSO 415.0, 417.0, 419.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    56
    Figure US20170217923A1-20170803-C00200
         		379.36 1H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.47 (s, 1H), 8.79 (dd, J = 8.9, 7.1 Hz, 2H), 7.91 (s, 1H), 7.84-7.77 (m, 2H), 7.76-7.68 (m, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H), 7.39 (dd, J = 8.9, 2.2 Hz, 1H), 7.29 (t, J = 74.0 Hz, 1H), 7.00 (dd, J = 8.1, 2.1 Hz, 1H), 4.23 (brs, 2H). DMSO 380.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    57
    Figure US20170217923A1-20170803-C00201
         		HCl 463.48 1H-NMR (400 MHz, DMSO-d6): δ 10.43- 10.20 (m, 2H), 9.72 (s, 1H), 8.89-8.67 (m, 3H), 8.29-8.21 (m, 1H), 7.97 (s, 1H), 7.87-7.80 (m, 1H), 7.81-7.73 (m, 1H), 7.63-7.46 (m, 2H), 7.30 (t, J = 74.0 Hz, 1H), 7.08-6.98 (m, 1H), 5.00 (s, 2H), 4.05-3.65 (m, 4H), 3.39-3.36 (m, 4H). DMSO 464.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    58
    Figure US20170217923A1-20170803-C00202
         		HCl 399.45 1H-NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 9.30 (d, J = 1.6 Hz, 1H), 9.03- 8.96 (m, 1H), 8.94-8.88 (m, 1H), 8.71 (d, J = 8.4 Hz, 1H), 7.91-7.83 (m, 3H), 7.67-7.55 (m, 3H), 7.25 (t, J = 7.2 Hz, 1H), 3.98 (s, 3H), 2.80-2.74 (m, 6H). DMSO 400.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    59
    Figure US20170217923A1-20170803-C00203
         		HCl 389.38 1H-NMR (400 MHz, DMSO-d6): δ 13.27 (s, 1H), 9.23 (s, 1H), 8.98 (d, J = 5.2 Hz, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.54 (dd, J = 12.0, 2.6 Hz, 1H), 8.48 (s, 1H), 8.07 (dd, J = 8.0, 5.6 Hz, 1H), 7.97-7.93 (m, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.37 (dd, J = 9.0, 2.4 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 6.91 (dt, J = 8.4, 2.6 Hz, 1H), 3.80 (s, 3H). DMSO 390.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    60
    Figure US20170217923A1-20170803-C00204
         		415.70 1H-NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 9.48 (s, 1H), 8.87 (dd, J = 14.0, 6.2 Hz, 2H), 8.54 (d, J = 1.7 Hz, 1H), 8.10 (d, J = 1.8 Hz, 2H), 7.89-7.78 (m, 2H), 7.37 (t, J = 1.8 Hz, 1H), 2.70 (s, 3H). DMSO 414.9, 416.9, 419.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    61
    Figure US20170217923A1-20170803-C00205
         		415.70 1H-NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.44 (s, 1H), 8.86 (d, J = 7.8 Hz, 1H), 8.79 (d, J = 4.5 Hz, 1H), 8.50 (d, J = 1.7 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 8.8, 2.4 Hz, 1H), 7.83- 7.71 (m, 2H), 7.62 (d, J = 8.8 Hz, 1H), 2.62 (s, 3H) DMSO 414.9, 416.9, 418.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    62
    Figure US20170217923A1-20170803-C00206
         		412.82 1H-NMR (400 MHz, DMSO-d6): δ:10.02 (s, 1H), 9.58 (d, J = 1.8 Hz, 1H), 8.76- 8.67 (m, 2H), 8.59 (d, J = 1.8 Hz, 1H), 7.96 (s, 1H), 7.82 (d, J = 6.6 Hz, 2H), 7.54 (ddd, J = 16.4, 10.0, 6.4 Hz, 2H), 7.30 (t, J = 74.0 Hz, 1H), 7.01 (dd, J = 8.0, 2.0 Hz, 1H), 2.74 (s, 3H). DMSO 413.0, 415.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    63
    Figure US20170217923A1-20170803-C00207
         		389.84 1H-NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 9.58 (s, 1H), 9.03 (d, J = 0.8 Hz, 1H), 8.78-8.84 (m, 2H), 8.50 (s, 1H), 7.95-8.03 (m, 3H), 7.80 (s, 1H), 7.70- 7.74 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 2.70 (s, 3H). DMSO 391.0, 392.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    64
    Figure US20170217923A1-20170803-C00208
         		371.82 1H-NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 9.48 (d, J = 1.2 Hz, 1H), 9.01 (d, J = 8.4 Hz, 1H), 8.90 (d, J = 4.0 Hz, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 8.27 (dd, J = 6.0, 2.0 Hz, 1H), 7.95- 7.63 (m, 3H), 2.70 (s, 3H). DMSO 372.0 373.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    65
    Figure US20170217923A1-20170803-C00209
         		476.67 1H-NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.46 (d, J = 1.2 Hz, 1H), 9.01 (d, J = 1.2 Hz, 1H), 8.83 (dd, J = 8.4, 1.6 Hz, 2H), 8.19-8.14 (m, 2H), 7.89-7.49 (m, 2H). DMSO 476.9, 478.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    66
    Figure US20170217923A1-20170803-C00210
         		399.25 1H-NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 8.54 (s, 1H), 8.71-8.67 (m, 2H), 8.53 (s, 1H), 8.26 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 7.83 (s, 1H), 7.58-7.52 (m, 2H), 2.72 (s, 3H). DMSO 399.0, 401.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    67
    Figure US20170217923A1-20170803-C00211
         		382.79 1H-NMR (400 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.51 (d, J = 1.2 Hz, 1H), 8.72- 8.69 (m, 2H), 8.53 (d, J = 2.0 Hz, 1H), 8.08 (ddd, J = 9.2, 7.6, 2.4 Hz, 1H), 7.79- 7.48 (m, 4H), 2.69 (s, 3H). DMSO 383.0, 385.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    68
    Figure US20170217923A1-20170803-C00212
         		HCl 399.45 1H-NMR (400 MHz, DMSO-d6): δ 13.02 (s, 1H), 9.59 (s, 1H), 9.09 (d, J = 8.0 Hz, 1H), 8.96 (d, J = 8.4 Hz, 1H), 8.91 (d, J = 4.61 Hz, 1H), 8.48 (s, 1H), 7.97 (dd, J = 8.0, 2.8 Hz, 4H), 7.72 (t, J = 7.6 Hz, 1H), 7.64-7.61 (m, 2H), 7.26 (t, J = 7.6 Hz, 1H), 4.88-4.82 (m, 1H), 1.43 (d, J = 6.0 Hz, 6H). DMSO 400.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    69
    Figure US20170217923A1-20170803-C00213
         		HCl 422.43 1H-NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 9.51 (s, 1H), 9.09 (d, J = 7.6 Hz, 1H), 8.91 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H), 8.03-7.97 (m, 1H), 7.83-7.80 (m, 2H), 7.64 (dd, J = 9.2, 2.4 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.32 (t, J = 74.0 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 5.02-4.97 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H). DMSO 423.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    70
    Figure US20170217923A1-20170803-C00214
         		HCl 408.86 1H-NMR (400 MHz, DMSO-d6): δ 10.61 (s, 1H), 9.48 (s, 1H), 9.05 (d, J = 7.2 Hz, 1H), 8.93 (d, J = 5.2 Hz, 1H), 8.19- 8.15 (m, 2H), 8.01-7.92 (m, 3H), 7.63- 7.53 (m, 2H), 5.01-4.94 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H). DMSO 409.1, 411.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    71
    Figure US20170217923A1-20170803-C00215
         		HCl 425.31 1H NMR (400 MHz, DMSO-d6): δ 9.92 (s, 1H), 9.52 (d, J = 1.2 Hz, 1H), 8.70-8.66 (m, 2H), 8.17 (d, J = 1.6 Hz, 2H), 7.98 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.60-7.56 (m, 2H), 7.39 (t, J = 1.8 Hz, 1H), 4.94-4.88 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H). DMSO 424.9, 426.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    72
    Figure US20170217923A1-20170803-C00216
         		HCl 392.4 1H -NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.49 (d, J = 1.2 Hz, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.86-8.84 (m, 1H), 8.10-8.05 (m, 2H), 7.93-7.85 (m, 2H), 7.71-7.69 (m, 2H), 7.61-7.52 (m, 1H), 4.97-4.91 (m, 1H), 1.39 (d, J = 6.0 Hz, 6H). DMSO 393.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    73
    Figure US20170217923A1-20170803-C00217
         		HCl 385.42 1H-NMR (400 MHz, DMSO-d6): δ 13.03 (s, 1H), 9.53 (d, J = 1.2 Hz, 1H), 9.10 (d, J = 8.4 Hz, 1H), 8.93-8.90 (m, 2H), 8.49 (s, 1H), 8.01-7.91 (m, 4H), 7.69 (t, J = 7.6 Hz, 1H), 7.59-7.54 (m, 2H), 7.24 (t, J = 7.6 Hz, 1H), 4.21 (q, J = 6.8 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H). DMSO 386.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    74
    Figure US20170217923A1-20170803-C00218
         		HCl 367.4 1H-NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.49 (s, 1H), 8.95 (d, J = 7.6 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.37 (s, 1H), 8.28 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.94-7.85 (m, 2H), 7.73-7.60 (m, 3H), 4.28 (q, J = 6.8 Hz, 2H), 1.46 (t, J = 6.8 Hz, 3H). DMSO 368.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    75
    Figure US20170217923A1-20170803-C00219
         		HCl 394.83 1H-NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 9.44 (s, 1H), 8.99 (d, J = 8.4 Hz, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.17 (d, J = 3.2 Hz, 2H), 7.59-7.50 (m, 2H), 4.26 (q, J = 6.8 Hz, 2H), 1.44 (t, J = 6.8 Hz, 3H). DMSO 395.1 397.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    76
    Figure US20170217923A1-20170803-C00220
         		HCl 411.28 1H-NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 9.47 (s, 1H), 9.02 (d, J = 7.6 Hz, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.13 (s, 1H), 8.01-7.91 (m, 3H), 7.72 (d, J = 8.8 Hz, 1H), 7.59-7.57 (m, 1H), 4.26 (q, J = 6.8 Hz, 2H), 1.44 (t, J = 6.8 Hz, 3H). DMSO 411.0 413.0 415.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    77
    Figure US20170217923A1-20170803-C00221
         		HCl 411.28 1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 9.48 (s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.14 (s, 2H), 8.05 (d, J = 1.6 Hz, 1H), 7.92-7.85 (m, 2H), 7.61 (dd, J = 9.1, 1.8 Hz, 1H), 7.41 (s, 1H), 4.26 (q, J = 6.8 Hz, 2H), 1.45 (t, J = 6.8 Hz, 3H). DMSO 411.0 413.1 415.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    78
    Figure US20170217923A1-20170803-C00222
         		HCl 378.37 1H-NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 9.49 (s, 1H), 8.98 (d, J = 8.0 Hz, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.11-8.05 (m, 2H), 7.95-7.91 (m, 2H), 7.72-7.52 (m, 3H), 4.28 (q, J = 6.8 Hz, 2H), 1.45 (t, J = 6.8 Hz, 3H). DMSO 379.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    79
    Figure US20170217923A1-20170803-C00223
         		HCl 429.47 1H-NMR (400 MHz, DMSO-d6): δ 12.99 (s, 1H), 9.59 (d, J = 1.6 Hz, 1H), 9.14 (d, J = 7.6 Hz, 1H), 8.75-8.69 (m, 2H), 8.48 (s, 1H), 7.99-7.96 (m, 2H), 7.90 (d, J = 8.8 Hz,, 1H), 7.76-7.72 (m, 1H), 7.61-7.56 (m, 3H), 7.22-7.19 (m, 1H), 4.24 (t, J = 6.0 Hz, 2H), 3.56 (t, J = 6.0 Hz, 2H), 3.28 (s, 3H), 2.11-2.04 (m, 2H). DMSO 430.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    80
    Figure US20170217923A1-20170803-C00224
         		HCl 380.80 1H-NMR (400 MHz, DMSO-d6): δ 11.67 (s, 1H), 9.18 (d, J = 2.0 Hz, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.66 (dd, J = 8.8, 2.4 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.14-8.08 (m, 2H), 7.90-7.81 (m, 2H), 7.62 (t, J = 9.2 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H). DMSO 380.9, 382.9 (M + 1) Method A (TFA) 95 Method C, G1
    81
    Figure US20170217923A1-20170803-C00225
         		HCl 394.79 1H-NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.49 (d, J = 1.2 Hz, 1H), 9.28 (d, J = 0.8 Hz, 1H), 9.15 (d, J = 8.0 Hz, 1H), 9.02 (d, J = 5.2 Hz, 1H), 8.37-8.34 (m, 1H), 8.12-8.09 (m, 2H), 8.01 (d, J = 8.4 Hz, 1H), 7.95-7.91 (m, 1H), 7.53 (t, J = 9.0 Hz, 1H). DMSO 395.0, 397.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    82
    Figure US20170217923A1-20170803-C00226
         		385.39 1H-NMR (400 MHz, DMSO-d6): δ 9.63 (d, J = 1.6 Hz, 1H), 9.13 (s, 1H), 8.80-8.75 (m, 2H), 8.21 (d, J = 9.2 Hz, 1H), 7.97- 7.94 (m, 1H), 7.82 (dd, J = 9.2, 2.8 Hz, 1H), 7.73 (dd, J = 9.2, 2.4 Hz, 1H), 7.64- 7.61 (m, 1H), 7.38-7.32 (m, 2H), 4.18 (q, J = 6.8 Hz, 2H), 3.19 (t, J = 7.0 Hz, 3H). DMSO 386.1 (M + 1) Method B (NH4HCO3) 95 Method C, G10
    83
    Figure US20170217923A1-20170803-C00227
         		HCl 426.39 1H-NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.49 (d, J = 1.6 Hz, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.89 (dd, J = 9.2, 1.6 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.05 (s. 1H), 7.97-7.89 (m, 3H), 7.65-7.61 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 4.29 (q, J = 6.8 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). DMSO 427.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    84
    Figure US20170217923A1-20170803-C00228
         		426.47 1H-NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 9.55 (s, 1H), 9.12 (d, J = 8.0 Hz, 1H), 8.94 (d, J = 4.8 Hz, 1H), 8.84 (d, J = 8.4 Hz, 1H), 8.11-8.09 (m, 1H), 8.02- 7.99 (m, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.82-7.11 (m, 1H), 7.65 (s, 1H), 7.62- 7.59 (m, 1H), 7.30 (t, J = 7.2, Hz, 1H), 5.06-5.03 (m, 1H), 2.15-2.09 (m, 2H), 1.86-1.74 (m, 4H), 1.68-1.65 (m, 2H). DMSO 427.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    85
    Figure US20170217923A1-20170803-C00229
         		375.81 1H-NMR (400 MHz, DMSO-d6): δ 13.09 (s, 1H), 9.58 (s, 1H), 9.12 (d, J = 8.4 Hz, 1H), 8.94 (d, J = 4.4 Hz, 1H), 8.88 (d, J = 8.4 Hz, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 8.01-7.96 (m, 5H), 7.71 (t, J = 8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H). DMSO 376.0, 378.0 (M + 1) 397.9 (M + 23) 188.4 (M/2 + 1) Method A (TFA) 95 Method C, G1
    86
    Figure US20170217923A1-20170803-C00230
         		398.79 1H-NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.54 (s, 1H), 8.78 (s, 1H), 8.71- 8.67 (m, 2H), 7.96 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.56-7.51 (m, 2H), 7.30 (t, J = 74.0 Hz, 1H), 7.01 (dd, J = 2.0, 8.0 Hz, 1H). DMSO 399.0, 401.0 (M + 1) 199.9, 200.8 (M/2 + 1) Method A (TFA) 95 Method C, G1
    87
    Figure US20170217923A1-20170803-C00231
         		443.7 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.39 (s, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.90 (d, J = 5.6 Hz, 1H), 8.62 (d, J = 1.6 Hz, 1H), 8.11 (dd, J = 6.8, 2.4 Hz, 1H), 7.95-7.91 (m, 1H), 7.89-7.85 (m, 1H), 7.80 (s, 1H), 7.45 (t, J = 8.8 Hz, 1H), 2.66 (s, 3H). DMSO 443.0, 445.0, 447.0 (M + 1) Method B (NH4HCO3) 98 Method C, G1
    88
    Figure US20170217923A1-20170803-C00232
         		401.42 1H-NMR (400 MHz, DMSO-d6): δ 13.19 (s, 1H), 9.43 (d, J = 8.0 Hz, 1H), 8.53 (s, 1H), 8.31 (dd, J = 4.8, 1.6 Hz, 1H), 8.26 (dd, J = 1.6, 7.2 Hz, 1H), 8.03 (s, 1H), 7.96-7.89 (m, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.65-7.54 (m, 3H), 7.18-7.12 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H). DMSO 402.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    89
    Figure US20170217923A1-20170803-C00233
         		410.83 1H-NMR (400 MHz, DMSO-d6): δ 9.79 (s, 1H), 8.52 (dd, J = 2.4, 7.2 Hz, 1H), 8.28 (dd, J = 5.6, 2.4 Hz, 1H), 8.12 (dd, J = 2.4, 5.2 Hz, 1H), 7.98-7.94 (m, 2H), 7.82 (d, J = 9.2 Hz, 1H), 7.56 (dd, J = 9.2, 2.8 Hz, 1H), 7.47 (t, J = 9.2 Hz, 1H), 7.14-7.11 (m, 1H), 4.00 (s, 3H), 3.99 (s, 3H). DMSO 411.1, 413.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    90
    Figure US20170217923A1-20170803-C00234
         		415.44 1H-NMR (400 MHz, DMSO-d6): δ 13.03 (s, 1H), 9.21 (d, J = 2.2 Hz, 1H), 9.16 (d, J = 7.9 Hz, 1H), 8.67 (dd, J = 8.7, 2.4 Hz, 1H), 8.50 (s, 1H), 8.02 (s, 1H), 7.99- 7.93 (m, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.78-7.72 (m, 1H), 7.56 (dd, J = 11.2, 2.1 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.24 (q, J = 6.9 Hz, 2H), 3.96 (s, 3H), 1.46 (t, J = 6.9 Hz, 3H). DMSO 416.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    91
    Figure US20170217923A1-20170803-C00235
         		HCl 405.84 1H-NMR (400 MHz, DMSO-d6): δ 13.28 (s, 1H), 9.55 (d, J = 1.7 Hz, 1H), 9.31 (d, J = 2.1 Hz, 1H), 8.90 (d, J = 8.3 Hz, 1H), 8.83 (dd, J = 5.0, 1.4 Hz, 1H), 8.58 (s, 1H), 8.12 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.82 (dd, J = 7.9, 5.0 Hz, 1H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.30 (dd, J = 8.5, 2.2 Hz, 1H), 3.98 (s, 3H). DMSO 406.0, 408.0 (M + 1) Method A (TFA) 95 Method C, G2
    92
    Figure US20170217923A1-20170803-C00236
         		429.47 1H-NMR (400 MHz, DMSO-d6): δ 12.99 (s, 1H), 9.21 (d, J = 2.0 Hz, 1H), 9.14 (d, J = 8.4 Hz, 1H), 8.67 (dd, J = 8.7, 2.3 Hz, 1H), 8.49 (s, 1H), 8.05-7.90 (m, 2H), 7.85 (d, J = 9.0 Hz, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.67-7.47 (m, 2H), 7.20 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.15 (t, J = 6.3 Hz, 2H), 3.96 (s, 3H), 1.07 (t, J = 7.4 Hz, 3H), 1.86 (dd, J = 14.0, 6.7 Hz, 2H). DMSO 430.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    93
    Figure US20170217923A1-20170803-C00237
         		HCl 389.38 1H-NMR (400 MHz, DMSO-d6): δ 11.34 (s, 1H), 9.52 (d, J = 1.7 Hz, 1H), 8.99 (d, J = 7.8 Hz, 1H), 8.85 (dd, J = 5.2, 1.3 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.11-8.00 (m, 2H), 7.95 (d, J = 9.1 Hz, 1H), 7.87 (dd, J = 7.9, 5.3 Hz, 1H), 7.77-7.59 (m, 3H), 7.27-7.16 (m, 1H), 3.99 (s, 3H). DMSO 390.1 (M + 1) Method B (NH4HCO3) 95 Method C, G3
    94
    Figure US20170217923A1-20170803-C00238
         		436.29 1H-NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 9.17 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.76 (d, J = 4.0 Hz, 1H), 8.26-8.07 (m, 3H), 7.83 (dd, J = 9.1, 2.5 Hz, 1H), 7.63 (dd, J = 7.5, 5.0 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 4.18 (q, J = 6.8 Hz, 2H), 1.39 (t, J = 6.9 Hz, 3H). DMSO 436.1, 438.0 (M + 1) Method B (NH4HCO3) 95 Method C, G10
    95
    Figure US20170217923A1-20170803-C00239
         		405.84 1H-NMR (400 MHz, DMSO-d6): δ 12.93 (s, 1H), 9.58 (s, 1H), 9.16 (d, J = 9.0 Hz, 1H), 8.70-8.74 (m, 2H), 8.59 (s, 1H), 8.13 (s, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.82 (dd, J = 8.9, 2.1 Hz, 1H), 7.65-7.49 (m, 3H), 3.98 (s, 3H). DMSO 406.1, 408.0 (M + 1) Method B (NH4HCO3) 95 Method C, G3
    96
    Figure US20170217923A1-20170803-C00240
         		429.67 1H-NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 9.47 (s, 1H), 9.02-8.92 (m, 3H), 8.18-8.16 (m, 1H), 8.06-8.04 (m, 1H), 7.96-7.84 (m, 3H), 7.54-7.50 (m, 1H). DMSO 429.9, 431.0, 433.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    97
    Figure US20170217923A1-20170803-C00241
         		398.79 1H-NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 9.58 (s, 1H), 8.85-8.76 (m, 2H), 8.60 (d, J = 7.2 Hz, 1H), 8.12-8.10 (m, 1H), 7.92 (s, 1H), 7.83-7.80 (m, 1H), 7.71-7.64 (m, 2H), 7.56-7.52 (m, 1H), 7.30 (t, J = 74.0 Hz, 1H), 7.05-7.03 (m, 1H). DMSO 399.0, 401.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    98
    Figure US20170217923A1-20170803-C00242
         		385.22 1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.50 (s, 1H), 9.04 (d, J = 8.0 Hz, 1H), 8.93 (d, J = 5.2 Hz, 2H), 8.64 (d, J = 8.8 Hz, 1H), 8.20-8.18 (m, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.97-7.92 (m, 2H), 7.68-7.64 (m, 1H), 7.53 (t, J = 9.2 Hz, 1H). DMSO 385.0, 386.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    99
    Figure US20170217923A1-20170803-C00243
         		401.68 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.55 (d, J = 1.6 Hz, 1H), 8.96 (d, J = 4.0 Hz, 1H), 8.88-8.87 (m, 1H), 8.61 (d, J = 7.6 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.14-8.12 (m, 1H), 7.99-7.95 (m, 1H), 7.88 (dd, J = 8.0, 5.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70-7.67 (m, 1H). DMSO 400.9, 402.9, 404.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    100
    Figure US20170217923A1-20170803-C00244
         		368.77 1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.51 (d, J = 1.2 Hz, 1H), 9.04 (d, J = 8.0 Hz, 1H), 8.92 (d, J = 5.6 Hz, 1H), 8.65 (d, J = 8.0 Hz, 1H), 8.11-8.05 (m, 2H), 7.97 (dd, J = 8.0, 4.0 Hz, 1H), 7.75- 7.73 (m, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.58-7.51 (m, 1H). DMSO 369.0, 371.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    101
    Figure US20170217923A1-20170803-C00245
         		375.09 1H-NMR (400 MHz, DMSO-d6): δ 13.18 (s, 1H), 9.61 (s, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.52 (s, 1H), 8.16-8.08 (m, 2H), 7.98-7.94 (m, 2H), 7.80-7.67 (m, 3H), 7.26 (t, J = 7.6 Hz, 1H). DMSO 376.0, 378.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    102
    Figure US20170217923A1-20170803-C00246
         		401.68 1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.49 (d, J = 2.0 Hz, 1H), 9.00- 8.98 (m, 1H), 8.91 (dd, J = 5.2, 1.6 Hz, 1H), 8.64-8.62 (m, 1H), 8.12-8.09 (m, 3H), 7.94 (dd, J = 8.0, 5.2 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.41 (t, J = 2.0 Hz, 1H). DMSO 400.9, 402.9, 404.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    103
    Figure US20170217923A1-20170803-C00247
         		434.77 1H-NMR (400 MHz, DMSO-d6): δ 10.17 (d, J = 1.2 Hz, 1H), 9.51 (s, 1H), 8.71- 8.62 (m, 3H), 8.25-8.22 (m, 1H), 8.04- 8.00 (m, 1H), 7.92-7.87 (m, 2H), 7.58- 7.53 (m, 2H). DMSO 435.1, 437.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    104
    Figure US20170217923A1-20170803-C00248
         		448.35 1H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.55 (d, J = 1.2 Hz, 1H), 8.72- 8.68 (m, 3H), 8.05 (d, J = 9.2 Hz, 1H), 7.92-7.95 (m, 2H), 7.80 (dd, J = 8.0, 1.2 Hz, 1H), 7.57-7.53 (m, 2H), 7.31 (t, J = 74.4 Hz, 1H), 7.03 (dd, J = 8.0, 1.2 Hz, 1H). DMSO 449.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    105
    Figure US20170217923A1-20170803-C00249
         		425.36 1H-NMR (400 MHz, DMSO-d6): δ 13.24 (s, 1H), 9.59 (s, 1H), 9.06 (d, J = 8.0 Hz, 1H), 8.74-8.73 (m, 2H), 8.54 (s, 1H), 8.10-7.91 (m, 5H), 7.77-7.73 (m, 1H), 7.61-7.58 (m, 1H), 7.26 (t, J = 7.6 Hz, 1H). DMSO 426.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    106
    Figure US20170217923A1-20170803-C00250
         		448.35 1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 9.55 (d, J = 1.6 Hz, 1H), 8.76 (d, J = 9.1 Hz, 1H), 8.74- 8.67 (m, 2H), 7.94 (t, J = 2.0 Hz, 1H), 7.82-7.78 (m, J = 10.3 Hz, 2H), 7.68 (dd, J = 9.0, 1.8 Hz, 1H), 7.59-7.50 (m, 2H), 7.30 (t, J = 74.0 Hz, 1H), 7.03 (dd, J = 8.2, 2.2 Hz, 1H). DMSO 449.0 (M + 1) 225.0 (M/2 + 1) Method A (TFA) 95 Method C, G1
    107
    Figure US20170217923A1-20170803-C00251
         		425.36 1H-NMR (400 MHz, DMSO-d6): δ 13.17 (s, 1H), 9.59 (s, 1H), 9.04 (d, J = 8.0 Hz, 1H), 8.74-8.70 (m, 2H), 8.51 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H), 8.02-7.90 (m, 2H), 7.86-7.69 (m, 3H), 7.65-7.56 (m, 1H), 7.25 (t, J = 9.8 Hz, 1H). DMSO 426.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    108
    Figure US20170217923A1-20170803-C00252
         		434.77 1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.52 (s, 1H), 8.81-8.59 (m, 3H), 8.24 (dd, J = 6.9, 2.5 Hz, 1H), 7.89- 7.52 (m, 1H), 7.79 (s, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.65-7.50 (m, 2H). DMSO 435.0, 437.0 (M + 1) 218.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    109
    Figure US20170217923A1-20170803-C00253
         		455.39 1H-NMR (400 MHz, DMSO-d6): δ 13.35 (s, 1H), 9.58 (s, 1H), 9.27 (s, 1H), 8.83- 8.70 (m, 2H), 8.62 (s, 1H), 8.18 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.68-7.58 (m, 2H), 7.54 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 8.4, 2.17 Hz, 1H), 3.98 (s, 3H). DMSO 456.0 (M + 1) 228.5 (M/2 + 1) Method A (TFA) 95 Method C, J1
    110
    Figure US20170217923A1-20170803-C00254
         		425.48 1H-NMR (400 MHz, DMSO-d6): δ 13.08 (s, 1H), 9.59 (s, 1H), 9.07 (d, J = 7.6 Hz, 1H), 9.02 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 4.0 Hz, 1H), 8.50 (s, 1H), 7.92-7.99 (m, 4H), 7.73 (t, J = 7.6 Hz, 1H), 7.59-7.60 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 2.12- 2.15 (m, 2H), 5.02-5.03 (m, 1H), 1.67- 1.86 (m, 6H). DMSO 426.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    111
    Figure US20170217923A1-20170803-C00255
         		448.46 1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 4.4 Hz, 1H), 8.08 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 9.6 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.60-7.63 (m, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 74.0 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 5.14 (s, 1H), 2.03-2.09 (m, 2H), 1.61-1.81 (m, 6H). DMSO 449.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    112
    Figure US20170217923A1-20170803-C00256
         		434.89 1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.47 (s, 1H), 8.97 (d, J = 7.6 Hz, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.16-8.19 (m, 1H), 7.53-7.61 (m, 2H), 8.10 (s, 1H), 7.90-7.96 (m, 3H), 5.15 (s, 1H), 2.09-2.10 (m, 2H), 1.67-1.78 (m, 6H). DMSO 435.0, 437.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    113
    Figure US20170217923A1-20170803-C00257
         		451.35 1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 9.49 (s, 1H), 8.85 (d, J = 7.6 Hz, 1H), 8.80 (d, J = 4.0 Hz, 1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.97-7.99 (m, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.77-7.79 (m, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.55-7.58 (m, 1H), 5.13 (s, 1H), 2.08 (d, J = 8.4 Hz, 2H), 1.79 (d, J = 9.6 Hz, 4H). DMSO 451.0, 453.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    114
    Figure US20170217923A1-20170803-C00258
         		418.44 1H-NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.49 (s, 1H), 8.92 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 6.4 Hz, 1H), 8.04-8.11 (m, 2H), 7.92 (d, J = 9.2 Hz, 1H), 7.84- 7.91 (m, 1H), 7.69-7.71 (m, 1H), 7.52- 7.61 (m, 2H), 5.13 (s, 1H), 2.06-2.11 (m, 2H), 1.65-1.81 (m, 6H). DMSO 419.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    115
    Figure US20170217923A1-20170803-C00259
         		407.47 1H-NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 9.45 (s, 1H), 8.98 (d, J = 6.8 Hz, 1H), 8.89 (d, J = 6.0 Hz, 1H), 8.37 (s, 1H), 8.32 (d, J = 6.8 Hz, 1H), 8.18 (s, 1H), 7.93 (t, J = 9.2 Hz, 2H), 7.70 (t, J = 7.2 Hz, 2H), 7.56 (d, J = 8.8 Hz, 1H), 5.18 (s, 1H), 2.09 (s, 2H), 1.77 (m, 4H), 1.66 (m, 2H). DMSO 408.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    116
    Figure US20170217923A1-20170803-C00260
         		401.68 1H-NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 9.47 (s, 1H), 8.71 (d, J = 6.4 Hz, 1H), 8.62 (d, J = 7.6 Hz, 1H), 8.26 (s, 1H), 7.88 (t, J = 7.2 Hz, 3H), 7.75-7.73 (m, 2H), 7.57-7.56 (m, 1H). DMSO 401.0, 403.0 405.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    117
    Figure US20170217923A1-20170803-C00261
         		368.77 1H-NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H), 9.45 (d, J = 1.2 Hz, 1H), 8.70 (dd, J = 4.4, 1.6 Hz, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.04-8.00 (m, 1H), 7.88-7.85 (m, 2H), 7.74 (dd, J = 8.4, 1.6 Hz, 1H), 7.65- 7.63 (m, 1H), 7.57-7.56 (m, 2H). DMSO 369.1, 371.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    118
    Figure US20170217923A1-20170803-C00262
         		436.34 1H-NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H), 8.87-8.20 (m, 2H), 8.27 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.90-7.72 (m, 3H), 7.39-7.36 (m, 2H), 3.44 (brs, 4H), 2.05 (brs, 4H). DMSO 435.9, 437.9, 439.8 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    119
    Figure US20170217923A1-20170803-C00263
         		403.43 1H-NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 9.43 (d, J = 1.2 Hz, 1H), 8.85- 8.80 (m, 2H), 8.07-8.05 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 6.8 Hz, 1H), 7.69-7.67 (m, 1H), 7.58-7.83 (m, 1H), 7.43-7.41 (m, 2H), 3.45 (brs, 4H), 2.06 (brs, 4H). DMSO 403.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    120
    Figure US20170217923A1-20170803-C00264
         		368.77 1H-NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.49 (s, 1H), 8.77-8.87 (m, 3H), 8.06-8.12 (m, 1H), 7.90-7.95 (m, 2H), 7.78-7.81 (m, 1H), 7.57-7.73 (m, 1H), 7.53 (dd, J = 19.6 Hz, 9.2 Hz, 1H). DMSO 369.0, 371.1 (M + 1) Method A (TFA) 95 Method C, G1
    121
    Figure US20170217923A1-20170803-C00265
         		401.68 1H-NMR (400 MHz, DMSO-d6): δ 10.37 (s, 1H), 9.52 (s, 1H), 8.95 (d, J = 3.2 Hz, 1H), 8.87 (m, 1H), 8.81 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.95-7.99 (m, 3H), 7.87- 7.89 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H). DMSO 401.0, 403.0, 405.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    122
    Figure US20170217923A1-20170803-C00266
         		385.22 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.50 (s, 1H), 8.69 (s, 2H), 8.64 (d, J = 8.0 Hz, 1H), 8.26 (dd, J = 10.6 Hz, 1.8 Hz, 1H), 7.89-7.90 (m, 3H), 7.51- 7.57 (m, 2H). DMSO 385.0, 387.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    123
    Figure US20170217923A1-20170803-C00267
         		357.8 1H-NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 9.52 (s, 1H), 8.67-8.76 (m, 3H), 8.44 (s, 1H), 8.27 (m, 1H), 7.96 (s, 2H), 7.66-7.69 (m, 2H), 7.57-7.59 (m, 1H). DMSO 358.0 (M + 1) Method A (TFA) 95 Method C, G1
    124
    Figure US20170217923A1-20170803-C00268
         		411.86 1H-NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 9.54 (s, 1H), 9.08 (d, J = 8.4 Hz, 1H), 8.94-8.90 (m, 2H), 8.15 (d, J = 8.4 Hz, 2H), 8.00-7.93 (m, 5H), 7.39 (s, 2H). DMSO 412.0, 414.0 (M + 1) Method A (TFA) 95 Method C, G1
    125
    Figure US20170217923A1-20170803-C00269
         		411.86 1H-NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 9.54 (s, 1H), 9.22 (s, 1H), 8.92- 8.98 (m, 2H), 8.70 (s, 1H), 8.10 (s, 1H), 8.03-8.05 (m, 1H), 7.95 (s, 2H), 7.69 (s, 2H), 7.53 (s, 2H). DMSO 412.0, 414.0 (M + 1) Method A (TFA) 95 Method C, G1
    126
    Figure US20170217923A1-20170803-C00270
         		364.35 1H-NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 9.47 (s, 1H), 9.02 (d, J = 7.6 Hz, 1H), 8.92 (s, 1H), 8.21 (s, 1H), 8.08- 8.10 (m, 1H), 7.95-7.97 (m, 2H), 7.74- 7.75 (m, 1H), 7.54-7.62 (m, 2H), 4.00 (s, 3H). DMSO 365.1 (M + 1), 183.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    127
    Figure US20170217923A1-20170803-C00271
         		397.26 1H-NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 9.48 (s, 1H), 9.02 (d, J = 8.0 Hz, 1H), 8.91-8.92 (m, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.16-8.17 (m, 1H), 7.92-8.03 (m, 3H), 7.72 (d, J = 8.8 Hz, 1H), 7.58- 7.61 (m, 1H), 4.00 (s, 3H). DMSO 397.0, 399.0 (M + 1), 200.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    128
    Figure US20170217923A1-20170803-C00272
         		407.45 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.55 (s, 1H), 8.92-8.84 (m, 2H), 8.16-8.09 (m, 3H), 7.95-7.89 (m, 3H), 7.83-7.79 (m, 1H), 7.62-7.58 (m, 1H), 7.36 (s, 2H), 3.40 (s, 3H). DMSO 408.1 (M + 1) Method A (TFA) 95 Method C, G1
    129
    Figure US20170217923A1-20170803-C00273
         		362.81 1H-NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.51 (s, 1H), 8.82-8.85 (m, 2H), 8.10-8.11 (m, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.98-7.93 (m, 2H), 7.75-7.77 (m, 1H), 7.59-7.61 (m, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.27-7.28 (m, 1H), 3.99 (s, 3H). DMSO 363.0, 365.0 (M + 1), 182.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    130
    Figure US20170217923A1-20170803-C00274
         		380.8 1H-NMR (300 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.50 (s, 1H), 7.78-8.79 (m, 2H), 8.19-8.24 (m, 1H), 7.86-8.00 (m, 3H), 7.52-7.70 (m, 3H), 3.98 (s, 3H). DMSO 381.1, 383.1 (M + 1), 191.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    131
    Figure US20170217923A1-20170803-C00275
         		371.39 1H-NMR (300 MHz, DMSO-d6): δ 13.08 (s, 1H), 9.59 (s, 1H), 9.07 (d, J = 8.1 Hz, 1H), 8.96 (d, J = 8.1 Hz, 1H), 8.83 (d, J = 3.9 Hz, 1H), 8.49 (s, 1H), 7.89-7.99 (m, 3H), 7.80-7.84 (m, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.60-7.63 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H), 3.98 (s, 3H). DMSO 371.9 (M + 1) Method A (TFA) 95 Method C, G1
    132
    Figure US20170217923A1-20170803-C00276
         		362.81 1H-NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.28 (s, 1H), 8.69 (d, J = 4.0 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.68-7.70 (m, 2H), 7.57-7.63 (m, 2H), 7.48-7.53 (m, 1H), 7.40-7.44 (m, 1H), 3.86 (s, 3H). DMSO 363.0, 365.1 (M + 1), 182.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    133
    Figure US20170217923A1-20170803-C00277
         		348.35 1H-NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 9.11 (s, 1H), 8.79-8.76 (m, 2H), 8.00-7.94 (m, 1H), 7.83-7.73 (m, 3H), 7.62-7.48 (m, 3H), 3.00 (s, 3H). DMSO 349.1 (M + 1), 175.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    134
    Figure US20170217923A1-20170803-C00278
         		381.26 1H-NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 9.13 (s, 1H), 8.75-8.77 (m, 2H), 8.18 (s, 1H), 7.72-7.85 (m, 5H), 7.49- 7.50 (m, 1H), 3.00 (s, 3H). DMSO 381.0, 383.0, 385.0 (M + 1) Method A (TFA) 95 Method C, G1
    135
    Figure US20170217923A1-20170803-C00279
         		364.8 1H-NMR (400 MHz, DMSO-d6): δ 9.43 (m, 2H), 8.94-8.89 (m, 2H), 8.08-8.06 (m, 1H), 7.92-7.81 (m, 4H), 7.57-7.53 (m, 2H), 3.03 (s, 3H). DMSO 365.0, 367.0 (M + 1), 183.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    136
    Figure US20170217923A1-20170803-C00280
         		337.38 1H-NMR (400 MHz, DMSO-d6): δ 9.52- 9.44 (m, 2H), 8.98 (d, J = 8.0 Hz, 1H), 8.92 (d, J = 4.4 Hz, 1H), 8.36-8.19 (m, 2H), 8.02-7.84 (m, 3H), 7.73-7.69 (m, 2H), 7.55 (d, J = 6.8 Hz, 1H), 3.04 (s, 3H). DMSO 338.1 (M + 1), 169.6 (M/2 + 1) Method A (TFA) 95 Method C, G1
    137
    Figure US20170217923A1-20170803-C00281
         		364.35 1H-NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 9.51 (s, 1H), 8.69-8.66 (m, 2H), 8.16-8.08 (m, 2H), 7.75-7.73 (m, 1H), 7.61-7.53 (m, 3H), 7.40 (d, J = 7.6 Hz, 1H), 4.01 (s, 3H). DMSO 183.1 (M/2 + 1) 365.1 (M + 1) Method A (TFA) 95 Method C, G1
    138
    Figure US20170217923A1-20170803-C00282
         		397.26 1H-NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.53 (s, 1H), 8.67-8.70 (m, 2H), 8.41 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.95-7.99 (m, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.56-7.63 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H). DMSO 397.0, 399.0 (M + 1) Method A (TFA) 95 Method C, G1
    139
    Figure US20170217923A1-20170803-C00283
         		380.8 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.48 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 4.8 Hz, 1H), 8.15-8.22 (m, 2H), 7.92-7.95 (m, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 8.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 4.02 (s, 3H). DMSO 191.1 (M/2 + 1) 381.1, 383.1 (M + 1) Method A (TFA) 95 Method C, G1
    140
    Figure US20170217923A1-20170803-C00284
         		401.68 1H-NMR (400 MHz, DMSO-d6): δ 10.11 (s, 1H), 8.50 (m, 1H), 8.63-8.70 (m, 3H), 8.14 (d, J = 2.0 Hz, 2H), 7.92 (m, 2H), 7.57 (m, 1H), 7.38 (t, J = 1.6 Hz, 1H). DMSO 401.0, 403.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    141
    Figure US20170217923A1-20170803-C00285
         		348.35 1H-NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 9.11 (s, 1H), 8.76-8.70 (m, 2H), 7.95-7.99 (m, 1H), 7.78-7.60 (m, 3H), 7.54-7.44 (m, 3H), 3.00 (s, 3H). DMSO 175.1 (M/2 + 1) 349.1 (M + 1) Method A (TFA) 95 Method C, G1
    142
    Figure US20170217923A1-20170803-C00286
         		397.26 1H-NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 8.39 (s, 1H), 8.83 (s, 2H), 8.03- 8.12 (m, 3H), 7.79-7.81 (m, 2H), 7.50- 7.51 (m, 1H), 7.32 (s, 1H), 3.96 (s, 3H). DMSO 397.0, 399.0, 401.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    143
    Figure US20170217923A1-20170803-C00287
         		452.34 1H-NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 9.51 (s, 1H), 8.65-8.66 (m, 2H), 8.34-8.35 (m, 1H), 7.95-7.96 (m, 1H), 7.72-7.80 (m, 4H), 7.54 (m, 1H), 3.84 (m, 4H), 3.56 (m, 4H). DMSO 452.1, 454.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    144
    Figure US20170217923A1-20170803-C00288
         		435.88 1H-NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 9.49 (s, 1H), 8.62-8.65 (m, 2H), 8.21-8.23 (m, 1H), 7.89-7.91 (m, 1H), 7.78-7.81 (m, 1H), 7.72-7.73 (m, 2H), 7.51-7.54 (m, 2H), 3.84 (t, J = 4.0 Hz, 4H), 3.36 (m, 4H). DMSO 436.1, 438.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    145
    Figure US20170217923A1-20170803-C00289
         		419.43 1H-NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 9.45 (s, 1H), 8.83-8.90 (m, 2H), 8.06-8.08 (m, 1H), 7.70-7.93 (m, 5H), 7.56 (dd, J = 19.6, 9.6 Hz, 1H), 3.82- 3.83 (m, 4H), 3.39-3.41 (m, 4H). DMSO 420.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    146
    Figure US20170217923A1-20170803-C00290
         		408.46 1H-NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 9.44 (s, 1H), 8.90 (d, J = 8.0 Hz, 1H), 8.84 (d, J = 4.4 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 7.67-7.92 (m, 6H), 3.82-3.83 (m, 4H), 3.39-3.40 (m, 4H). DMSO 409.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    147
    Figure US20170217923A1-20170803-C00291
         		452.34 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.42 (s, 1H), 8.85-8.87 (m, 2H), 8.11 (s, 2H), 7.73-7.88 (m, 4H), 7.38 (s, 1H), 3.82-3.83 (m, 4H), 3.39-3.40 (m, 4H). DMSO 452.1, 454.1, 456.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    148
    Figure US20170217923A1-20170803-C00292
         		426.47 1H-NMR (400 MHz, DMSO-d6): δ 12.93 (s, 1H), 9.57 (m, 1H), 9.12 (d, J = 8.4 Hz, 1H), 8.68-8.72 (m, 2H), 8.56 (s, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.96 (s, 1H), 7.72-7.84 (m, 3H), 7.56-7.57 (m, 1H), 7.40 (m, 1H), 7.19 (t, J = 8.0 Hz, 1H), 3.84 (t, J = 4.4 Hz, 4H), 3.35 (t, J = 4.4 Hz, 4H). DMSO 427.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    149
    Figure US20170217923A1-20170803-C00293
         		393.84 1H-NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 9.48 (s, 1H), 8.62-8.63 (m, 2H), 8.23 (m, 1H), 7.92 (m, 1H), 7.77 (d, J = 9.6 Hz, 1H), 7.51-7.56 (m, 3H), 7.42 (m, 1H), 3.12 (s, 6H). DMSO 394.1, 396.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    150
    Figure US20170217923A1-20170803-C00294
         		377.39 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 9.48 (m, 1H), 8.60-8.63 (m, 2H), 8.08-8.14 (m, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.69-7.71 (m, 1H), 7.50-7.57 (m, 3H), 7.42-7.43 (m, 1H), 3.12 (s, 6H). DMSO 378.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    151
    Figure US20170217923A1-20170803-C00295
         		410.3 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 9.49 (s, 1H), 8.60-8.64 (m, 2H), 8.17 (s, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.51-7.53 (m, 2H), 7.37 (s, 1H), 7.32 (s, 1H), 3.11 (s, 6H). DMSO 410.1, 412.0, 414.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    152
    Figure US20170217923A1-20170803-C00296
         		410.3 1H-NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 9.45 (s, 1H), 8.83-8.91 (m, 2H), 8.26-8.27 (m, 1H), 7.72-7.99 (m, 4H), 7.57-7.61 (m, 2H), 3.14 (s, 6H). DMSO 410.1, 412.1, 414.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    153
    Figure US20170217923A1-20170803-C00297
         		366.42 1H-NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 9.48 (s, 1H), 8.55-8.64 (m, 2H), 8.41 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.50-7.61 (m, 3H), 7.43 (m, 1H), 3.12 (s, 6H). DMSO 367.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    154
    Figure US20170217923A1-20170803-C00298
         		435.23 1H-NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H), 9.53 (s, 1H), 8.86-8.94 (m, 3H), 8.32-8.33 (m, 1H), 8.21 (s, 1H), 7.97- 8.01 (m, 2H), 7.84-7.88 (m, 1H), 7.73 (d, J = 8.8 Hz, 1H). DMSO 435.1, 437.1, 439.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    155
    Figure US20170217923A1-20170803-C00299
         		402.32 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.51-9.52 (m, 1H), 8.65-8.78 (m, 3H), 8.19 (s, 1H), 8.11 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.71 (m, 1H), 7.55- 7.59 (m, 2H). DMSO 403.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    156
    Figure US20170217923A1-20170803-C00300
         		435.23 1H-NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 9.46 (s, 1H), 8.88-8.97 (m, 3H), 8.17 (s, 1H), 8.10-8.11 (m, 2H), 7.97 (s, 1H), 7.95 (s, 1H), 7.39 (s, 1H). DMSO 435.1, 437.0, 439.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    157
    Figure US20170217923A1-20170803-C00301
         		418.77 1H-NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.52 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.88-8.90 (m, 2H), 8.20-8.23 (m, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.92-7.95 (m, 2H), 7.54 (t, J = 9.2 Hz, 1H). DMSO 419.1, 421.1 (M + 1) Method B (NH4HCO3) 95 Method C, G
    158
    Figure US20170217923A1-20170803-C00302
         		409.36 1H-NMR (400 MHz, DMSO-d6): δ 13.24 (s, 1H), 9.56 (s, 1H), 9.10 (d, J = 8.4 Hz, 1H), 8.96 (s, 1H), 8.87 (d, J = 8.0 Hz, 1H), 8.54 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H), 7.95-8.01 (m, 4H), 7.70 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H). DMSO 410.1 (M + 1) Method B (NH4HCO3) 95 Method C, G
    159
    Figure US20170217923A1-20170803-C00303
         		391.35 1H-NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.50 (s, 1H), 9.04 (d, J = 8.0 Hz, 1H), 8.96 (d, J = 8.8 Hz, 2H), 8.37 (s, 1H), 8.30-8.28 (m, 1H), 8.21 (s, 1H), 7.98 (d, J = 7.6 Hz, 2H), 7.68-7.69 (m, 2H). DMSO 392.2 (M + 1) Method B (NH4HCO3) 95 Method C, G
    160
    Figure US20170217923A1-20170803-C00304
         		450.34 1H-NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.54-9.55 (m, 1H), 8.82-8.84 (m, 1H), 8.67-8.73 (m, 2H), 8.16-8.21 (m, 2H), 7.93-8.00 (m, 2H), 7.54-7.64 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H). DMSO 451.1 (M + 1) Method B (NH4HCO3) 95 Method C, G
    161
    Figure US20170217923A1-20170803-C00305
         		416.78 1H-NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.49 (s, 1H), 8.62-8.72 (m, 3H), 8.13 (s, 1H), 7.88-7.92 (m, 3H), 7.51- 7.60 (m, 2H), 7.14-7.16 (m, 1H). DMSO 417.1, 419.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    162
    Figure US20170217923A1-20170803-C00306
         		375.81 1H-NMR (400 MHz, DMSO-d6): δ 13.13 (s, 1H), 9.53 (s, 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.68-8.72 (m, 2H), 8.50 (s, 1H), 8.10 (d, J = 8.8, 1H), 7.88-7.97 (m, 3H), 7.70-7.72 (m, 2H), 7.57-7.59 (m, 1H), 7.22 (t, J = 7.6, 1H). DMSO 376.0, 378.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    163
    Figure US20170217923A1-20170803-C00307
         		376.8 1H-NMR (400 MHz, DMSO-d6): δ 12.07 (s, 1H), 9.56 (s, 1H), 8.84 (d, J = 8.4 Hz, 1H), 8.71-8.73 (m, 2H), 8.34 (s, 1H), 7.96-8.09 (m, 3H), 7.59-7.80 (m, 2H), 7.29 (t, J = 7.2 Hz, 1H). DMSO 377.0, 379.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    164
    Figure US20170217923A1-20170803-C00308
         		394.37 1H-NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 9.53 (s, 1H), 8.67 (d, J = 5.2 Hz, 2H), 7.99 (d, J = 2.4 Hz, 1H), 7.94 (m, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.49-7.59 (m, 3H), 7.31 (t, J = 74.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 3.99 (s, 3H). DMSO 395.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    165
    Figure US20170217923A1-20170803-C00309
         		HCl 458.51 1H-NMR (400 MHz, DMSO-d6): δ 9.42 (s, 1H), 8.98 (d, J = 8.4 Hz, 1H), 8.68- 8.71 (m, 2H), 7.94 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.57 (t, J = 5.6 Hz, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.19 (t, J = 7.2 Hz, 1H), 4.52 (s, 2H), 4.00 (s, 3H), 3.63 (s, 2H), 2.89 (s, 6H). DMSO 459.1 (M + 1) 230.2 (M/2 + 1) Method A (TFA) 95 Method C, G1
    166
    Figure US20170217923A1-20170803-C00310
         		467.92 1H-NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.62- 8.67 (m, 2H), 8.20 (dd, J = 6.8, 2.4 Hz, 1H), 7.86-7.89 (m, 2H), 7.51-7.55 (m, 2H), 7.31 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 3.98 (s, 3H), 2.77 (t, J = 5.6 Hz, 2H), 2.29 (s, 6H). DMSO 468.1 (M + 1) 234.6 (M/2 + 1) Method B (NH4HCO3) 95 Method C, G1
    167
    Figure US20170217923A1-20170803-C00311
         		HCl 428.82 1H-NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.98 (d, J = 8.4 Hz, 1H), 8.88 (dd, J = 5.2, 1.6 Hz, 1H), 8.13 (d, J = 2.8 Hz, 1H), 8.00 (t, J = 2.0 Hz, 1H), 7.89-7.95 (m, 3H), 7.62 (dd, J = 9.2, 3.2 Hz, 1H), 7.36 (t, J = 73.6 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 4.01 (s, 3H). DMSO 429.1, 431.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    168
    Figure US20170217923A1-20170803-C00312
         		385.42 1H-NMR (400 MHz, DMSO-d6): δ 13.03 (s, 1H), 9.62 (d, J = 1.6 Hz, 1H), 9.20 (d, J = 8.4 Hz, 1H), 8.74-8.77 (m, 1H), 8.70 (dd, J = 4.4, 1.6 Hz, 1H), 8.48 (s, 1H), 7.96-7.99 (m, 2H), 7.72-7.76 (m, 1H), 7.57-7.60 (m, 1H), 7.47 (m, 1H), 7.41 (m, 1H), 7.17-7.21 (m, 1H), 3.95 (s, 3H), 2.72 (s, 3H). DMSO 386.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    169
    Figure US20170217923A1-20170803-C00313
         		HCl 368.77 1H-NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 9.47 (s, 1H), 8.86-8.93 (m, 2H), 8.54 (dd, J = 10.0, 2.8 Hz, 1H), 8.21 (dd, J = 6.8, 2.4 Hz, 1H), 7.82-8.00 (m, 4H), 7.52 (t, J = 9.2 Hz, 1H). DMSO 369.0, 371.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    170
    Figure US20170217923A1-20170803-C00314
         		HCl 400.33 1H-NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.53 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 4.0 Hz, 1H), 8.60 (dd, J = 10.4, 3.2 Hz, 1H), 7.97-8.09 (m, 3H), 7.88-7.92 (m, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H). DMSO 401.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    171
    Figure US20170217923A1-20170803-C00315
         		359.36 1H-NMR (400 MHz, DMSO-d6): δ 13.06 (s, 1H), 9.58 (s, 1H), 9.07 (d, J = 8.4 Hz, 1H), 8.72 (d, J = 5.6 Hz, 2H), 8.52 (s, 1H), 7.96-8.02 (m, 3H), 7.83-7.87 (m, 2H), 7.74 (t, J = 8.0 Hz, 1H), 7.59 (t, J = 6.0 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H). DMSO 360.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    172
    Figure US20170217923A1-20170803-C00316
         		HCl 382.34 1H-NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 9.53 (d, J = 1.2 Hz, 1H), 8.98 (d, J = 8.0 Hz, 1H), 8.88 (d, J = 4.4 Hz, 1H), 8.62 (dd, J = 10.0, 2.8 Hz, 1H), 8.01- 8.05 (m, 1H), 7.84-7.92 (m, 4H), 7.50- 7.56 (m, 1H), 7.32 (t, J = 74.0 Hz, 1H), 7.03 (dd, J = 8.0, 2.0 Hz, 1H). DMSO 383.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    173
    Figure US20170217923A1-20170803-C00317
         		348.35 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.51 (s, 1H), 8.79-8.76 (m, 2H), 8.38 (s, 1H), 8.16-8.11 (m, 1H), 7.86- 7.66 (m, 4H), 7.59-7.50 (m, 1H), 2.57 (s, 3H). DMSO 349.1 (M + 1), 175.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    174
    Figure US20170217923A1-20170803-C00318
         		364.8 1H-NMR (300 Hz, CD3OD): δ 9.50 (d, J = 1.2 Hz, 1H), 9.14 (d, J = 8.4 Hz, 1H), 8.94 (d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 8.09-7.99 (m, 2H), 7.93 (s, 2H), 7.78- 7.73 (m, 1H), 7.39 (t, J = 9.0 Hz, 1H), 2.64 (s, 3H). CD3OD 365.1, 367.1 (M + 1) Method A (TFA) 95 Method C, G1
    175
    Figure US20170217923A1-20170803-C00319
         		381.26 1H-NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 9.51 (s, 1H), 8.84-8.79 (m, 2H), 8.36-8.34 (m, 2H), 7.96 (dd, J = 8.8, 2.5 Hz, 1H), 7.85-7.70 (m, 4H), 2.55 (s, 3H). DMSO 381.0, 383.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    176
    Figure US20170217923A1-20170803-C00320
         		346.81 1H-NMR (300 Hz, CD3OD): δ 9.48 (d, J = 1.2 Hz, 1H), 8.99-8.95 (m, 1H), 8.82- 8.80 (m, 1H), 8.30-8.29 (m, 1H), 7.90- 7.81 (m, 5H), 7.52-7.46 (m, 2H), 2.62 (s, 3H). CD3OD 347.0, 349.1 (M + 1) Method A (TFA) 95 Method C, G1
    177
    Figure US20170217923A1-20170803-C00321
         		346.81 1H-NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.52 (s, 1H), 8.84-8.78 (m, 2H), 8.42 (s, 1H), 8.16-8.15 (m, 1H), 7.94- 7.91 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.75-7.71 (m, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.27-7.23 (m, 1H), 2.56 (s, 3H). DMSO 347.1, 349.1 (M + 1) Method A (TFA) 95 Method C, G1
    178
    Figure US20170217923A1-20170803-C00322
         		380.37 1H-NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H), 9.50 (d, J = 2.1 Hz, 1H), 9.00 (d, J = 8.1 Hz, 1H), 8.90 (dd, J = 5.1, 1.2 Hz, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.96-7.90 (m, 2H), 7.84 (d, J = 8.1 Hz, 1H), 7.27 (t, J = 8.2 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 2.62 (s, 3H). DMSO 381.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    179
    Figure US20170217923A1-20170803-C00323
         		414.81 1H-NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 9.50 (s, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.92 (d, J = 5.2 Hz, 1H), 8.59 (d, J = 2.8 Hz, 1H), 8.54 (s, 1H), 8.34 (dd, J = 8.6, 2.6 Hz, 1H), 7.96-7.90 (m, 2H), 7.81 (d, J = 8.8 Hz, 2H), 2.56 (s, 3H). DMSO 415.1, 417.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    180
    Figure US20170217923A1-20170803-C00324
         		401.37 1H-NMR (400 MHz, DMSO-d6): δ 13.91 (s, 1H), 10.38 (s, 1H), 9.59 (s, 1H), 8.79- 8.76 (m, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.44 (s, 1H), 8.33 (dd, J = 9.0, 2.6 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.81 (dd, J = 8.4, 1.2 Hz, 1H), 7.60- 7.57 (m, 1H), 2.58 (s, 3H). DMSO 402.0 (M + 1) Method A (TFA) 95 Method C, G1
    181
    Figure US20170217923A1-20170803-C00325
         		381.26 1H-NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.47 (s, 1H), 8.98 (d, J = 7.5 Hz, 1H), 8.91 (d, J = 4.5 Hz, 1H), 8.48 (s, 1H), 8.12 (d, J = 2.1 Hz, 2H), 7.97-7.93 (m, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.40 (s, 1H), 2.55 (s, 3H). DMSO 381.0, 383.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    182
    Figure US20170217923A1-20170803-C00326
         		390.82 1H-NMR (400 MHz, DMSO-d6): δ 12.25 (s, 1H), 9.54 (s, 1H), 9.25 (s, 1H), 8.84- 8.80 (m, 2H), 8.09 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.77-7.75 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H), 2.56 (s, 3H). DMSO 391.1, 393.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    183
    Figure US20170217923A1-20170803-C00327
         		366.34 1H-NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 8.66-8.63 (m, 1H), 8.30 (s, 1H), 7.99-7.95 (m, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.6, 1.4 Hz, 1H), 7.58-7.55 (m, 1H), 2.55 (s, 3H). DMSO 367.1 (M + 1), 184.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    184
    Figure US20170217923A1-20170803-C00328
         		415.7 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.51 (s, 1H), 8.75-8.72 (m, 2H), 8.38 (s, 2H), 8.32 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.66- 7.64 (m, 1H), 2.55 (s, 3H). DMSO 414.8, 416.8 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    185
    Figure US20170217923A1-20170803-C00329
         		354.4 1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.56 (s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.81 (d, J = 4.0 Hz, 1H), 8.65 (s, 1H), 8.48 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.88-7.88 (m, 3H), 7.65 (t, J = 7.6 Hz, 1H), 2.65 (s, 3H), 2.58 (s, 3H). DMSO 355.1 (M + 1), 178.1 (M/2 + 1) Method A (TFA) 95 Method C, G1
    186
    Figure US20170217923A1-20170803-C00330
         		356.38 1H-NMR (400 MHz, DMSO-d6): δ 12.18 (s, 1H), 9.57 (s, 1H), 9.07 (d, J = 8.4 Hz, 1H), 8.71 (d, J = 5.6 Hz, 2H), 8.10 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.86-7.76 (m, 3H), 7.58 (t, J = 6.2 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 2.55 (s, 3H). DMSO 357.1 (M + 1) Method A (TFA) 95 Method C, G1
    187
    Figure US20170217923A1-20170803-C00331
         		337.38 1H-NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.51 (s, 1H), 8.65-8.70 (m, 2H), 8.45 (s, 1H), 8.38 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.54-7.57 (m, 1H), 2.56 (s, 3H). DMSO 338.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    188
    Figure US20170217923A1-20170803-C00332
         		355.39 1H-NMR (400 MHz, DMSO-d6): δ 13.11 (s, 1H), 9.61 (s, 1H), 9.09 (d, J = 8.8 Hz, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.81 (s, 1H), 8.50 (s, 1H), 8.01-7.98 (m, 2H), 7.96 (dd, J = 7.8, 1.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.78-7.72 (m, 3H), 7.23 (t, J = 7.4 Hz, 1H), 2.56 (s, 3H), DMSO 356.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    189
    Figure US20170217923A1-20170803-C00333
         		385.42 1H-NMR (400 MHz, DMSO-d6): δ 12.62 (s, 1H), 9.58 (s, 1H), 9.03 (d, J = 8.4 Hz, 1H), 8.92 (d, J = 4.0 Hz, 1H), 8.74-8.69 (m, 2H), 7.92-7.87 (m, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.66-7.56 (m, 3H), 7.23 (t, J = 7.6 Hz, 1H), 4.00 (s, 3H), 2.84 (d, J = 4.4 Hz, 3H). DMSO 386.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    190
    Figure US20170217923A1-20170803-C00334
         		461.51 1H-NMR (400 MHz, DMSO-d6): δ 12.40 (s, 1H), 9.57 (d, J = 1.2 Hz, 1H), 9.48 (t, J = 6.0 Hz, 1H), 8.89 (d, J = 8.8 Hz, 1H), 8.73-8.68 (m, 2H), 7.96 (dd, J = 8.0, 1.2 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.76-7.72 (m, 1H), 7.61-7.55 (m, 3H), 7.34-7.20 (m, 6H), 4.52 (d, J = 5.6 Hz, 2H), 3.93 (s, 3H). DMSO 462.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    191
    Figure US20170217923A1-20170803-C00335
         		368.77 1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.55-9.45 (m, 1H), 8.93-8.76 (m, 2H), 8.63 (d, J = 8.9 Hz, 1H), 8.10 (ddd, J = 13.2, 7.5, 2.6 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.80-7.67 (m, 3H), 7.62-7.49 (m, 1H). DMSO 369.0, 371.0 (M + 1) Method B (NH4HCO3) 97 Method C, G1
    192
    Figure US20170217923A1-20170803-C00336
         		401.68 1H NMR (300 MHz, DMSO-d6): δ 10.38 (s, 1H), 9.58-9.43 (m, 1H), 8.90-8.79 (m, 2H), 8.65 (d, J = 9.0 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.01-7.90 (m, 2H), 7.82-7.68 (m, 3H). DMSO 401.0, 403.0, 405.0 (M + 1) Method B (NH4HCO3) 97 Method C, G1
    193
    Figure US20170217923A1-20170803-C00337
         		367.23 1H NMR (300 MHz, DMSO-d6): δ 10.19 (s, 1H), 9.53 (d, J = 2.1 Hz, 1H), 8.78- 8.56 (m, 3H), 8.17 (t, J = 2.0 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.93-7.85 (m, 1H), 7.75 (dd, J = 8.9, 2.2 Hz, 1H), 7.58 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.26 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H). DMSO 367.0, 369.0 (M + 1) Method B (NH4HCO3) 98 Method C, G1
    194
    Figure US20170217923A1-20170803-C00338
         		376.80 1H NMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), 10.27 (s, 1H), 9.58 (d, J = 2.1 Hz, 1H), 8.87-8.62 (m, 4H), 8.21-8.10 (m, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.82- 7.68 (m, 2H), 7.64-7.53 (m, 2H). DMSO 377.0, 379.0 (M + 1) Method A (TFA) 95 Method C, G1
    195
    Figure US20170217923A1-20170803-C00339
         		401.68 1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.52-9.49 (m, 1H), 8.85-8.73 (m, 2H), 8.61 (d, J = 9.0 Hz, 1H), 8.18- 8.08 (m, 2H), 7.99-7.95 (m, 1H), 7.77 (dd, J = 8.9, 2.2 Hz, 1H), 7.71 (dd, J = 7.8, 5.0 Hz, 1H), 7.42-7.39 (m, 1H). DMSO 401.0, 403.0, 405.0 (M + 1) Method B (NH4HCO3) 97 Method C, G1
    196
    Figure US20170217923A1-20170803-C00340
         		386.76 1H-NMR (300 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.49 (d, J = 1.9 Hz, 1H), 8.95- 8.82 (m, 2H), 8.64 (d, J = 9.0 Hz, 1H), 8.01-7.82 (m, 4H), 7.78 (dd, J = 8.9, 2.2 Hz, 1H). DMSO 387.0, 389.1 (M + 1) Method B (NH4HCO3) 97 Method C, G1
    197
    Figure US20170217923A1-20170803-C00341
         		411.86 1H NMR (400 MHz, DMSO-d6): δ 10.50 (brs, 1H), 9.56 (s, 1H), 9.08-8.93 (m, 1H), 8.92-8.82 (m, 1H), 8.73 (d, J = 8.9 Hz, 1H), 8.21-8.11 (m, 2H), 8.02 (d, J = 1.9 Hz, 1H), 7.98-7.77 (m, 4H), 7.38 (s, 2H). DMSO 412.1, 414.1 (M + 1) Method B (NH4HCO3) 97 Method C, G1
    198
    Figure US20170217923A1-20170803-C00342
         		385.22 1H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 9.51 (d, J = 1.4 Hz, 1H), 8.77- 8.69 (m, 2H), 8.60 (d, J = 9.0 Hz, 1H), 8.27-8.20 (m, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.90 (ddd, J = 9.0, 4.3, 2.6 Hz, 1H), 7.76 (dd, J = 8.9, 2.1 Hz, 1H), 7.64 (dd, J = 8.0, 4.9 Hz, 1H), 7.55 (t, J = 9.1 Hz, 1H). DMSO 385.0, 387.0 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    199
    Figure US20170217923A1-20170803-C00343
         		357.80 1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.53-9.49 (m, 1H), 8.81-8.70 (m, 2H), 8.64 (d, J = 8.9 Hz, 1H), 8.45- 8.36 (m, 1H), 8.29-8.21 (m, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.9, 2.1 Hz, 1H), 7.74-7.61 (m, 3H). DMSO 357.9, 359.9 (M + 1) Method B (NH4HCO3) 99 Method C, G1
    200
    Figure US20170217923A1-20170803-C00344
         		435.23 1H-NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 9.53 (s, 1H), 8.84-8.74 (m, 2H), 8.69-8.61 (m, 2H), 8.26 (dd, J = 8.8, 2.6 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.9, 2.1 Hz, 1H), 7.70 (dd, J = 7.7, 5.3 Hz, 1H). DMSO 435.0, 437.0 (M + 1) Method B (NH4HCO3) 99 Method C, G1
    201
    Figure US20170217923A1-20170803-C00345
         		400.78 1H-NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 9.53 (d, J = 1.5 Hz, 1H), 8.85 (d, J = 8.1 Hz, 1H), 8.82 (dd, J = 5.0, 1.4 Hz, 1H), 8.69 (d, J = 9.0 Hz, 1H), 8.49 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.83-7.67 (m, 3H), 7.56 (d, J = 7.8 Hz, 1H). DMSO 401.1, 403.0 (M + 1) Method B (NH4HCO3) 99 Method C, G1
    202
    Figure US20170217923A1-20170803-C00346
         		375.79 1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.49 (s, 1H), 8.87-8.77 (m, 2H), 8.63 (d, J = 8.9 Hz, 1H), 8.42 (dd, J = 5.8, 2.7 Hz, 1H), 8.26 (ddd, J = 9.1, 4.9, 2.8 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.83-7.72 (m, 2H), 7.66 (t, J = 9.1 Hz, 1H). DMSO 375.9, 377.9 (M + 1) Method B (NH4HCO3) 99 Method C, G1
    203
    Figure US20170217923A1-20170803-C00347
         		348.35 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.51 (s, 1H), 8.91 (d, J = 6.8 Hz, 1H), 8.86 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.11 (ddd, J = 13.0, 7.5, 2.5 Hz, 1H), 7.90-7.68 (m, 3H), 7.65-7.46 (m, 2H), 2.56 (s, 3H). DMSO 349.1 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    204
    Figure US20170217923A1-20170803-C00348
         		381.26 1H-NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 9.54 (s, 1H), 8.75-8.65 (m, 2H), 8.46 (d, J = 8.5 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 8.8, 2.4 Hz, 1H), 7.72 (d, J = 9.1 Hz, 2H), 7.57 (dd, J = 7.9, 4.9 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 2.55 (s, 3H). DMSO 381.0, 383.0 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    205
    Figure US20170217923A1-20170803-C00349
         		364.35 1H-NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 9.53 (s, 1H), 8.79-8.58 (m, 2H), 8.49 (d, J = 9.0 Hz, 1H), 8.13 (ddd, J = 9.2, 7.1, 1.7 Hz, 1H), 7.84-7.65 (m, 1H), 7.67-7.46 (m, 2H), 7.41-7.23 (m, 2H), 3.97 (s, 3H). DMSO 365.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    206
    Figure US20170217923A1-20170803-C00350
         		364.80 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.50 (d, J = 1.4 Hz, 1H), 8.92- 8.77 (m, 2H), 8.53 (d, J = 8.5 Hz, 1H), 8.24 (dd, J = 6.8, 2.5 Hz, 1H), 7.98- 7.87 (m, 1H), 7.83-7.70 (m, 2H), 7.60- 7.50 (m, 2H), 2.56 (s, 3H). DMSO 365.1, 367.1 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    207
    Figure US20170217923A1-20170803-C00351
         		381.26 1H-NMR (400 MHz, DMSO d6) δ 10.21 (s, 1H), 9.53 (s, 1H), 8.87-8.73 (m, 2H), 8.50 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 1.7 Hz, 2H), 7.77 (s, 1H), 7.72 (dd, J = 7.8, 5.1 Hz, 1H), 7.57 (dd, J = 8.4, 0.9 Hz, 1H), 7.39 (t, J = 1.6 Hz, 1H), 2.56 (s, 3H). DMSO 381.1, 383.0 (M + 1) Method B (NH4HCO3) 99 Method C, G1
    208
    Figure US20170217923A1-20170803-C00352
         		337.38 1H-NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.53 (d, J = 1.6 Hz, 1H), 8.77- 8.63 (m, 2H), 8.53-8.42 (m, 2H), 8.28 (d, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.60-7.51 (m, 2H), 2.55 (s, 3H). DMSO 338.2 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    209
    Figure US20170217923A1-20170803-C00353
         		355.39 1H-NMR (400 MHz, DMSO-d6): δ 13.09 (s, 1H), 9.60 (s, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.96 (d, J = 8.4 Hz, 1H), 8.85 (d, J = 4.0 Hz, 1H), 8.49 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 7.83 (dd, J = 8.0, 5.2 Hz, 1H), 7.80 (s, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 2.56 (s, 3H). DMSO 356.1 (M + 1) Method B (NH4HCO3) 99 Method C, G1
    210
    Figure US20170217923A1-20170803-C00354
         		375.81 1H-NMR (400 MHz, DMSO-d6): 13.13 (s, 1H), 9.59 (s, 1H), 9.03-8.89 (m, 3H), 8.50 (s, 1H), 8.21-8.19 (d, J = 8.6 Hz, 1H), 7.99-7.87 (m, 4H), 7.82-7.79 (dd, J = 8.8, 2.3 Hz, 1H), 7.74-7.70 (m, 1H), 7.28-7.24 (m, 1H). DMSO 376.1, 378.1 (M + 1) Method B (NH4HCO3) 98 Method C, G1
    211
    Figure US20170217923A1-20170803-C00355
         		444.79 1H-NMR (400 MHz, DMSO-d6): δ 13.68 (brs, 1H), 11.98 (s, 1H), 9.49 (s, 1H), 8.83-8.64 (m, 2H), 8.11-7.90 (m, 3H), 7.81 (d, J = 2.0 Hz, 1H), 7.75-7.62 (m, 2H), 7.22 (t, J = 7.6 Hz, 1H). DMSO 444.9, 446.9 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    212
    Figure US20170217923A1-20170803-C00356
         		HCl 466.79 1H-NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.62 (s, 1H), 8.90 (dd, J = 8.2, 1.3 Hz, 1H), 8.69 (d, J = 9.0 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.92-7.86 (m, 1H), 7.86-7.79 (m, 1H), 7.77 (dd, J = 8.9, 2.1 Hz, 1H), 7.53 (t, J = 8.2 Hz, 1H), 7.30 (t, J = 73.3 Hz, 1H), 7.04 (dd, J = 8.1, 2.1 Hz, 1H). DMSO 466.9, 468.9 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    213
    Figure US20170217923A1-20170803-C00357
         		469.67 1H-NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 9.57 (s, 1H), 8.85 (dd, J = 8.1, 1.3 Hz, 1H), 8.60 (d, J = 9.0 Hz, 1H), 8.35-8.23 (m, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.00-7.90 (m, 2H), 7.80-7.65 (m, 2H). DMSO 468.9, 470.8 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    214
    Figure US20170217923A1-20170803-C00358
         		436.77 1H-NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.56 (s, 1H), 8.84 (d, J = 8.3 Hz, 1H), 8.64 (d, J = 9.0 Hz, 1H), 8.14-7.99 (m, 2H), 7.95 (d, J = 2.1 Hz, 1H), 7.81- 7.65 (m, 2H), 7.59-7.48 (m, 1H). DMSO 436.9, 438.9 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    215
    Figure US20170217923A1-20170803-C00359
         		440.37 1H-NMR (400 MHz, DMSO-d6): δ 13.81 (brs, 1H), 11.97 (s, 1H), 9.57 (s, 1H), 9.01-8.91 (m, 1H), 8.84 (d, J = 8.3 Hz, 1H), 8.06 (dd, J = 7.9, 1.4 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.79-7.70 (m, 1H), 7.52 (dd, J = 9.1, 2.6 Hz, 1H), 7.49-7.44 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 3.94 (s, 3H). DMSO 441.1 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    216
    Figure US20170217923A1-20170803-C00360
         		396.80 1H-NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 9.80 (s, 1H), 8.34 (dd, J = 9.6, 2.6 Hz, 1H), 8.22 (s, 1H), 8.11 (dd, J = 6.9, 2.6 Hz, 1H), 7.88 (d, J = 2.7 Hz, 1H), 7.84-7.77 (m, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.56-7.43 (m, 2H), 6.44 (d, J = 9.6 Hz, 1H), 3.95 (s, 3H). DMSO 397.1, 399.1 (M + 1) Method B (NH4HCO3) 100 Method D, G1
    217
    Figure US20170217923A1-20170803-C00361
         		410.37 1H-NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 9.80 (s, 1H), 8.36 (dd, J = 9.6, 2.6 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.80-7.67 (m, 3H), 7.53-7.46 (m, 2H), 7.27 (t, J = 74.0 Hz, 1H), 6.98 (dd, J = 8.2, 2.0 Hz, 1H), 6.43 (d, J = 9.6 Hz, 1H), 3.96 (s, 3H). DMSO 411.1 (M + 1) Method B (NH4HCO3) 100 Method D, G1
    218
    Figure US20170217923A1-20170803-C00362
         		387.39 1H-NMR (400 MHz, DMSO-d6): δ 12.98 (s, 1H), 12.58-12.05 (m, 1H), 8.55 (s, 2H), 8.41 (s, 1H), 8.33 (dd, J = 9.7, 2.5 Hz, 1H), 8.11-7.98 (m, 1H), 7.97-7.86 (m, 2H), 7.79-7.64 (m, 3H), 7.44-7.29 (m, 1H), 6.52 (d, J = 9.7 Hz, 1H), 3.98 (s, 3H). DMSO 388.2 (M + 1) Method B (NH4HCO3) 100 Method D, G1
    219
    Figure US20170217923A1-20170803-C00363
         		389.38 1H-NMR (400 MHz, DMSO-d6): δ 12.73 (s, 1H), 9.56 (s, 1H), 9.10 (dd, J = 8.9, 5.4 Hz, 1H), 8.79-8.63 (m, 2H), 8.50 (s, 1H), 8.08 (s, 1H), 7.95-7.76 (m, 2H), 7.68-7.45 (m, 4H), 3.97 (s, 3H). DMSO 390.1 (M + 1) Method B (NH4HCO3) 98 Method C, G1
    220
    Figure US20170217923A1-20170803-C00364
         		369.80 1H-NMR (400 MHz, DMSO-d6): δ 14.87 (brs, 1H), 10.08 (brs, 1H), 8.85-7.66 (m, 6H), 7.69-6.63 (m, 3H), 3.96 (s, 3H). DMSO 397.1, 399.1 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    221
    Figure US20170217923A1-20170803-C00365
         		387.39 1H-NMR (400 MHz, DMSO-d6): δ 14.80 (brs, 1H), 13.19 (s, 1H), 8.68 (d, J = 7.3 Hz, 1H), 8.44 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 8.10-8.03 (m, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.78-7.65 (m, 2H), 7.43 (t, J = 7.5 Hz, 1H), 6.78 (t, J = 6.8 Hz, 1H), 3.99 (s, 3H). DMSO 388.1 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    222
    Figure US20170217923A1-20170803-C00366
         		410.37 1H-NMR (400 MHz, DMSO-d6): δ 15.33 (brs, 1H), 13.47 (brs, 1H), 11.69 (s, 1H), 8.62 (dd, J = 7.5, 2.1 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.07 (dd, J = 6.2, 2.1 Hz, 1H), 7.81- 7.68 (m, 3H), 7.61 (t, J = 8.1 Hz, 1H), 7.32 (t, J = 74.0 Hz, 1H), 7.26-7.18 (m, 1H), 6.80-6.69 (m, 1H), 4.03 (s, 3H). DMSO 411.1 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    223
    Figure US20170217923A1-20170803-C00367
         		401.22 1H-NMR (400 MHz, DMSO-d6): δ 11.22 (brs, 1H), 8.47 (d, J = 8.8 Hz, 1H), 8.30 (dd, J = 9.6, 2.3 Hz, 1H), 8.27-8.18 (m, 1H), 8.11 (dd, J = 6.8, 2.4 Hz, 1H), 7.90- 7.73 (m, 2H), 7.60 (dd, J = 8.8, 1.8 Hz, 1H), 7.47 (t, J = 9.1 Hz, 1H), 6.44 (d, J = 9.6 Hz, 1H). DMSO 401.0, 403.0 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    224
    Figure US20170217923A1-20170803-C00368
         		414.79 1H-NMR (400 MHz, DMSO-d6): δ 12.00 (s, 1H), 10.07 (s, 1H), 8.54 (d, J = 8.9 Hz, 1H), 8.34 (dd, J = 9.6, 2.6 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.87-7.69 (m, 3H), 7.62 (dd, J = 8.9, 2.1 Hz, 1H), 7.48 (t, J = 8.2 Hz, 1H), 7.26 (t, J = 74.0 Hz, 1H), 7.00 (dd, J = 8.1, 2.0 Hz, 1H), 6.44 (d, J = 9.6 Hz, 1H). DMSO 415.1, 417.1 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    225
    Figure US20170217923A1-20170803-C00369
         		432.78 1H-NMR (400 MHz, DMSO-d6): δ 12.06 (s, 1H), 10.15 (s, 1H), 8.55 (d, J = 9.0 Hz, 1H), 8.34 (dd, J = 9.6, 2.5 Hz, 1H), 8.29 (s, 1H), 7.97 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 8.8, 2.1 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 6.44 (d, J = 9.6 Hz, 1H). DMSO 433.0, 435.0 (M + 1) Method B (NH4HCO3) 100 Method C, G1
    226
    Figure US20170217923A1-20170803-C00370
         		428.36 1H-NMR (400 MHz, DMSO-d6): δ 12.28 (brs, 1H), 8.47-8.06 (m, 3H), 8.06- 7.76 (m, 3H), 7.67-7.59 (m, 2H), 7.28 (s, 1H), 6.47 (d, J = 9.7 Hz, 1H), 3.98 (s, 3H). DMSO 429.1 (M + 1) Method B (NH4HCO3) 94 Method D, G1
    227
    Figure US20170217923A1-20170803-C00371
         		401.42 1H-NMR (400 MHz, DMSO-d6): δ 12.97 (s, 1H), 12.27 (s, 1H), 8.73-8.56 (m, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 8.33 (dd, J = 9.7, 2.6 Hz, 1H), 8.04-7.86 (m, 3H), 7.74-7.59 (m, 3H), 7.34 (t, J = 8.7 Hz, 1H), 6.52 (d, J = 9.7 Hz, 1H), 4.23 (q, J = 6.9 Hz, 2H), 1.45 (t, J = 6.9 Hz, 3H). DMSO 402.2 (M + 1) Method B (NH4HCO3) 100 Method D, G1
    228
    Figure US20170217923A1-20170803-C00372
         		465.91 1H-NMR (400 MHz, DMSO-d6): δ 8.43- 8.31 (m, 2H), 8.27 (s, 1H), 8.14 (dd, J = 6.7, 2.3 Hz, 1H), 7.89-7.70 (m, 3H), 7.47 (t, J = 9.1 Hz, 1H), 6.44 (d, J = 9.6 Hz, 1H), 3.62 (d, J = 9.3 Hz, 6H), 2.42 (s, 4H). DMSO 466.1, 468.1 (M + 1) Method B (NH4HCO3) 97 Method D, G1
    229
    Figure US20170217923A1-20170803-C00373
         		436.41 1H-NMR (400 MHz, DMSO-d6): δ 10.28 (brs, 1H), 9.47 (s, 1H), 8.91 (d, J = 7.2 Hz, 1H), 8.84 (d, J = 5.2 Hz, 1H), 8.08- 8.06 (m, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 8 Hz, 1H), 7.65-7.60 (m, 2H), 7.54-7.52 (m, 1H), 4.17 (t, J = 7.6 Hz, 2H), 1.86 (q, J = 6.8 Hz, 2H), 1.08- 1.03 (m, 3H). DMSO 423.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    230
    Figure US20170217923A1-20170803-C00374
         		403.41 1H-NMR (400 MHz, DMSO-d6): δ 13.42 (s, 1H), 9.53 (s, 1H), 9.10 (d, J = 12.8 Hz, 1H), 8.70-8.65 (m, 2H), 8.50 (s, 1H), 8.07-8.04 (m, 2H), 7.86 (d, J = 8.8 Hz, 1H), 7.60-7.55 (m, 2H), 7.48 (s, 1H), 7.06-7.01 (m, 1H), 4.21 (q, J = 6.8 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). DMSO 403.9 (M + 1) Method A (TFA) 95 Method C, G1
    231
    Figure US20170217923A1-20170803-C00375
         		440.42 1H-NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H), 9.48 (s, 1H), 9.01 (d, J = 7.6 Hz, 1H), 8.90 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.93 (t, J = 5.6 Hz, 1H), 7.64-7.60 (m, 2H), 7.22 (d, J = 8.4 Hz, 1H), 4.19 (t, J = 6.4 Hz, 1H), 1.87-1.81 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H). DMSO 440.9 (M + 1) Method A (TFA) 95 Method C, G1
    232
    Figure US20170217923A1-20170803-C00376
         		359.12 1H-NMR (400 MHz, DMSO-d6): δ 13.10 (s, 1H), 9.54 (s, 1H), 8.96 (d, J = 8.4 Hz, 1H), 8.82-8.80 (m, 2H), 8.52 (s, 1H), 8.22-8.17 (m, 1H), 7.97-7.93 (m, 2H), 7.70-7.59 (m, 4H), 7.21 (t, J = 8.0 Hz, 1H). DMSO 360.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    233
    Figure US20170217923A1-20170803-C00377
         		381.26 1H-NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 9.08 (s, 1H), 8.67-8.70 (m, 1H), 8.64 (d, J = 8.0 Hz, 1H), 7.98 (s, 2H), 7.76-7.78 (m, 2H), 7.55-7.57 (m, 1H), 7.43-7.46 (m, 1H), 7.36 (s, 1H), 2.99 (s, 3H). DMSO 381.0, 383.0, 385.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    234
    Figure US20170217923A1-20170803-C00378
         		HCl 408.4 1H-NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 9.51 (s, 1H), 9.00 (d, J = 7.2 Hz, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.13 (s, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.88- 7.91 (m, 2H), 7.86 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 9.2, 2.0 Hz, 1H), 7.55 (t, J = 8.4 Hz, 1H), 7.31 (t, J = 74.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 4.28 (q, J = 6.8 Hz, 2H), 1.46 (t, J = 6.8 Hz, 3H). DMSO 409.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    235
    Figure US20170217923A1-20170803-C00379
         		412.36 1H-NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.49 (s, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.91 (dd, J = 5.2, 1.2 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.06 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.94-7.91 (m, 1H), 7.64-7.60 (m, 2H), 7.22 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H). DMSO 412.9 (M + 1) Method A (TFA) 95 Method C, G1
    236
    Figure US20170217923A1-20170803-C00380
         		395.46 1H-NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.90 (s, 1H), 8.77 (dd, J = 13.5, 6.2 Hz, 2H), 8.19 (d, J = 9.2 Hz, 1H), 7.81 (dd, J = 9.2, 2.4 Hz, 1H), 7.72- 7.56 (m, 3H), 7.33 (d, J = 2.0 Hz, 1H), 4.15 (q, J = 6.8 Hz, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 1.38 (t, J = 6.8 Hz, 3H). DMSO 396.2 (M + 1) Method B (NH4HCO3) 98 Method C, J1
    237
    Figure US20170217923A1-20170803-C00381
         		376.8 1H-NMR (400 MHz, DMSO-d6): δ 11.64 (brs, 1H), 11.31 (brs, 1H), 9.45 (s, 1H), 8.82-8.69 (m, 1H), 8.61 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.04-7.91 (m, 1H), 7.81 (dd, J = 8.9, 2.1 Hz, 1H), 7.70- 7.55 (m, 1H), 7.47 (s, 1H), 7.06 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H). DMSO 376.9, 378.9 (M + 1) Method B (NH4HCO3) 95 Method C, G8
    238
    Figure US20170217923A1-20170803-C00382
         		412.23 1H-NMR (400 MHz, DMSO-d6): δ 10.70 (s, 1H), 9.62 (d, J = 2.4 Hz, 1H), 9.51 (d, J = 1.6 Hz, 1H), 8.76-8.79 (m, 2H), 8.57 (dd, J = 6.8, 2.0 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.94 (dd, J = 6.8, 2.0 Hz, 1H), 7.71 (m, 2H). DMSO 412.0, 414.0, 416.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    239
    Figure US20170217923A1-20170803-C00383
         		381.26 1H-NMR (400 MHz, DMSO-d6): 10.04 (s, 1H), 9.59 (d, J = 1.2 Hz, 1H), 8.74-8.70 (m, 2H), 8.42-8.39 (m, 2H), 7.98 (dd, J = 2.4 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.59-7.55 (m, 2H), 2.75 (s, 3H). DMSO 381, 383 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    240
    Figure US20170217923A1-20170803-C00384
         		348.35 1H-NMR (400 MHz, DMSO-d6): 10.00 (s, 1H), 9.57 (d, J = 1.2 Hz, 1H), 8.72-8.70 (m, 2H), 8.38 (d, J = 8.4 Hz, 1H), 8.17- 8.12 (m, 1H), 7.79-7.74 (m, 2H), 7.59- 7.50 (m, 3H), 2.74 (s, 3H). DMSO 349.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    241
    Figure US20170217923A1-20170803-C00385
         		355.39 1H-NMR (400 MHz, DMSO-d6): 11.10 (s, 1H), 9.60 (d, J = 1.6 Hz, 1H), 9.16 (d, J = 8.4 Hz, 1H), 8.82-8.72 (m, 2H), 8.50 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.97- 7.92 (m, 2H), 7.77-7.72 (m, 2H), 7.63- 7.60 (m, 2H), 7.24-7.19 (m, 1H), 2.76 (s, 3H). DMSO 356.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    242
    Figure US20170217923A1-20170803-C00386
         		337.4 1H-NMR (400 MHz, DMSO-d6): 10.12 (s, 1H), 9.57 (s, 1H), 8.73-8.70 (m, 2H), 8.46 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.72-7.56 (m, 4H), 2.76 (s, 3H). DMSO 338.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    243
    Figure US20170217923A1-20170803-C00387
         		396.37 1H-NMR (400 MHz, DMSO-d6): 10.07 (s, 1H), 9.59 (s, 1H), 8.75-8.69 (m, 2H), 8.44 (d, J = 8.0 Hz, 1H), 8.20 (s, 1H), 7.97-7.94 (m, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.62-7.54 (m, 3H), 7.16 (d, J = 8.4 Hz, 1H), 2.76 (s, 3H). DMSO 397.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    244
    Figure US20170217923A1-20170803-C00388
         		378.37 1H-NMR (400 MHz, DMSO-d6): 9.98 (s, 1H), 9.60 (s, 1H), 8.75-8.69 (m, 2H), 8.44 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.58-7.00 (m, 4H), 6.98 (d, J = 2.0 Hz, 1H), 2.76 (s, 3H). DMSO 379.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    245
    Figure US20170217923A1-20170803-C00389
         		360.34 1H-NMR (400 MHz, DMSO-d6): δ 11.95- 11.11 (m, 2H), 9.43 (d, J = 1.6 Hz, 1H), 8.71 (dd, J = 4.7, 1.5 Hz, 1H), 8.56 (td, J = 8.0, 1.9 Hz, 1H), 8.15 (dd, J = 9.2, 5.3 Hz, 1H), 8.08 (dd, J = 9.4, 2.7 Hz, 1H), 8.02-7.88 (m, 2H), 7.54 (dd, J = 7.90, 4.81 Hz, 1H), 7.50-7.40 (m, 1H), 7.04 (t, J = 7.1 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H). DMSO 360.8 (M + 1) Method B (NH4HCO3) 95 Method C, G8
    246
    Figure US20170217923A1-20170803-C00390
         		393.8 1H-NMR (400 MHz, DMSO-d6): δ 13.29 (s, 1H), 9.54 (s, 1H), 9.29 (s, 1H), 8.06 (d, J = 0.9 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.82 (dd, J = 26.4, 8.4 Hz, 2H), 7.58 (dd, J = 7.9, 4.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 8.72 (d, J = 3.6 Hz, 1H), 8.67 (d, J = 7.8 Hz, 1H), 8.64-8.53 (m, 1H). DMSO 394.0, 396.0 (M + 1) Method B (NH4HCO3) 95 Method C, J1
    247
    Figure US20170217923A1-20170803-C00391
         		1H-NMR (400 MHz, DMSO-d6): δ 13.36 (brs, 1H), 9.54 (s, 1H), 9.36-9.08 (m, 1H), 8.12 (d, J = 8.8 Hz, 2H), 8.08-7.96 (m, 1H), 7.94-7.78 (m, 2H), 7.57 (dd, J = 7.8, 4.8 Hz, 1H), 7.29-7.16 (m, 1H), 8.94-8.49 (m, 3H). DMSO 444.1 (M + 1) Method B (NH4HCO3) 95 Method C, J1
    248
    Figure US20170217923A1-20170803-C00392
         		376.8 1H-NMR (400 MHz, DMSO-d6): δ 9.57 (s, 1H), 8.71 (d, J = 5.6 Hz, 2H), 8.40 (d, J = 1.8 Hz, 1H), 8.01-7.97 (m, 2H), 7.89 (dd, J = 7.8, 1.5 Hz, 1H), 7.63- 7.51 (m, 1H), 7.29 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.76-6.74 (m, 1H). DMSO 377.0, 379.0 (M + 1) Method B (NH4HCO3) 95 Method C, G8
    249
    Figure US20170217923A1-20170803-C00393
         		426.35 1H-NMR (400 MHz, DMSO-d6): δ 9.70 (d, J = 1.5 Hz, 1H), 8.74 (td, J = 8.0, 1.9 Hz, 1H), 8.71 (dd, J = 4.7, 1.7 Hz, 1H), 8.50 (d, J = 9.0 Hz, 1H), 7.88 (dd, J = 7.8, 1.9 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.20-7.11 (m, 1H), 7.64-7.56 (m, 2H)., 6.70-6.60 (m, 1H), 6.52 (dd, J = 10.8, 3.9 Hz, 1H). DMSO 427.1 (M + 1) Method B (NH4HCO3) 95 Method C, G8
    250
    Figure US20170217923A1-20170803-C00394
         		360.34 1H-NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.83 (d, J = 7.4 Hz, 1H), 8.71 (d, J = 3.9 Hz, 1H), 8.49 (t, J = 7.2 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.63-7.51 (m, 3H), 7.14 (t, J = 7.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.46 (t, J = 7.2 Hz, 1H). DMSO 360.8 (M + 1) Method B (NH4HCO3) 95 Method C, G8
    251
    Figure US20170217923A1-20170803-C00395
         		400.43 1H-NMR (400 MHz, DMSO-d6): δ 12.92 (s, 1H), 9.04 (d, J = 8.3 Hz, 1H), 8.66 (dd, J = 7.7, 1.7 Hz, 1H), 8.48 (s, 1H), 8.10 (dd, J = 4.6, 1.7 Hz, 1H), 8.01- 7.94 (m, 2H), 7.89 (d, J = 8.9 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.55 (m, 2H), 7.20 (t, J = 7.5 Hz, 1H), 6.74 (dd, J = 7.7, 4.7 Hz, 1H), 4.24 (q, J = 6.9 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H). DMSO 401.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    252
    Figure US20170217923A1-20170803-C00396
         		483.44 1H-NMR (400 MHz, DMSO-d6): δ 13.28 (s, 1H), 9.54 (s, 1H), 9.28 (s, 1H), 8.70- 8.66 (m, 2H), 8.59 (s, 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.9 Hz, 1H), 7.64-7.49 (m, 3H), 7.18 (d, J = 8.2 Hz, 1H), 4.14 (t, J = 6.2 Hz, 2H), 1.86 (q, J = 6.8 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H). DMSO 484.0 (M + 1) Method B (NH4HCO3) 95 Method C, J1
    253
    Figure US20170217923A1-20170803-C00397
         		1H-NMR (400 MHz, DMSO-d6): δ 13.24 (s, 1H), 9.56 (s, 1H), 9.39 (d, J = 2.1 Hz, 1H), 8.77-8.73 (m, 2H), 8.55 (s, 1H), 8.09 (s, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.65 (dd, J = 7.9, 4.9 Hz, 1H), 7.59 (dd, J = 9.1, 2.5 Hz, 1H), 4.24 (q, J = 6.9 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H). DMSO 420.0, 422.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    254
    Figure US20170217923A1-20170803-C00398
         		469.42 1H-NMR (400 MHz, DMSO-d6): δ 13.34 (s, 1H), 9.60 (s, 1H), 9.35 (s, 1H), 8.77 (d, J = 3.5 Hz, 1H), 8.72 (d, J = 7.9 Hz, 1H), 8.67 (s, 1H), 8.22 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.69-7.58 (m, 2H), 7.55 (s, 1H), 7.24 (d, J = 8.5 Hz, 1H), 4.29 (q, J = 7.0 Hz, 2H), 1.53 (t, J = 6.9 Hz, 3H). DMSO 470.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    255
    Figure US20170217923A1-20170803-C00399
         		403.41 1H-NMR (400 MHz, DMSO-d6): δ 11.43 (s, 1H), 9.53 (s, 1H), 8.68-8.66 (m, 2H), 8.56 (d, J = 8.3 Hz, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.72-7.64 (m, 1H), 7.61-7.47 (m, 3H), 7.17-7.08 (m, 1H), 4.23 (q, J = 6.9 Hz, 2H), 1.46 (t, J = 6.9 Hz, 3H). DMSO 404.2 (M + 1) Method B (NH4HCO3) 95 Method C, G1
  • Salt Molecular 1H NMR Retention LCMS Purity Method of
    Number Product Type Mass 1H NMR Solvent LCMS Time (min) Protocol percent Coupling
    256
    Figure US20170217923A1-20170803-C00400
         		HCl 456.723 1H NMR (300 MHz, DMSO) δ 9.55 (s, 1H), 9.09 (d, J = 8.0 Hz, 1H), 9.01-8.76 (m, 2H), 8.50 (s, 1H), 8.37 (s, 1H), 8.13-7.91 (m, 4H), 7.85 (d, J = 8.9 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H). DMSO 420 (M + 1) 1.89 Method D 100 Method G1
    257
    Figure US20170217923A1-20170803-C00401
         		HCl 524.39 1H NMR (300 MHz, DMSO) δ 10.68 (s, 1H), 9.50 (s, 1H), 9.08 (d, J = 8.1 Hz, 1H), 8.92 (d, J = 5.2 Hz, 1H), 8.28 (s, 1H), 8.11 (s, 1H) 8.06-7.93 (m, 2H) 7.87 (d, J = 7.6 Hz, 1H), 7.70-7.51 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 4.28 (t, J = 9.1 Hz, 2H), 4 DMSO 452 (M + 1) 1.34 Method D 100 Method G1
    258
    Figure US20170217923A1-20170803-C00402
         		HCl 474.89 1H NMR (300 MHz, DMSO) δ 10.36 (s, 1H), 9.52 (s, 1H), 9.00 (d, J = 8.2 Hz, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.12 (s, 1H), 8.02- 7.78 (m, 4H), 7.64 (d, J = 9.2 Hz, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 4.08-3.87 (m, 5H), 3.46 (s, 3H). DMSO 439 (M + 1) 2.21 Method C 98 Method G1
    259
    Figure US20170217923A1-20170803-C00403
         		HCl 460.86 1H NMR (300 MHz, DMSO) δ 10.61 (s, 1H), 9.51 (s, 1H), 9.10 (d, J = 8.2 Hz, 1H), 8.94 (d, J = 4.9 Hz, 1H), 8.22 (s, 1H), 8.08- 7.94 (m, 2H), 7.93-7.78 (m, 2H), 7.65 (d, J = 9.1 Hz, 1H), 7.53 (t, J = 8.2 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 4.01 (s, 3H), 3 DMSO 425 (M + 1) 1.64 Method C 98 Method G1
    260
    Figure US20170217923A1-20170803-C00404
         		HCl 429.67 No Data 428.9 (M + 1) 2.35 Method C 100 Method G1
    261
    Figure US20170217923A1-20170803-C00405
         		HCl 443.24 1H NMR (300 MHz, DMSO) δ 10.35 (s, 1H), 9.52 (d, J = 1.5 Hz, 1H), 8.97 (dd, J = 6.6, 1.8 Hz, 2H), 8.91-8.83 (m, 1H), 8.07 (dd, J = 8.9, 2.0 Hz, 1H), 7.85 (dd, J = 14.6, 8.2 Hz, 4H), 7.54 (dd, J = 11.7, 4.6 Hz, 1H), 7.31 (s, 1H), 7.10-6.99 (m, 1H). DMSO 442.96 (M + 1) 2.36 Method C 100 Method G1
    262
    Figure US20170217923A1-20170803-C00406
         		HCl 426.39 1H NMR (300 MHz, DMSO) δ 10.71 (s, 1H), 9.47 (s, 1H), 9.01 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 4.0 Hz, 1H), 8.23 (s, 1H), 8.08- 7.86 (m, 4H), 7.61 (t, J = 8.2 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 4.28 (d, J = 7.0 Hz, 2H), 1.44 (t, J = 6.9 Hz, 3H). DMSO 427.1 (M + 1) 2.47 Method C 93 Method G1
    263
    Figure US20170217923A1-20170803-C00407
         		HCl 446.13 1H NMR (300 MHz, DMSO) δ 10.35 (s, 1H), 9.47 (s, 1H), 8.90 (s, 3H), 8.27 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 8.8 Hz, 1H). DMSO 494.0 (M + 1) 2.29 Method C 91 Method G1
    264
    Figure US20170217923A1-20170803-C00408
         		395.46 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 8.88 (s, 1H), 8.83- 8.71 (m, 2H), 8.18 (d, J = 9.2 Hz, 1H), 7.80 (dd, J = 9.2, 2.3 Hz, 1H), 7.69-7.57 (m, 3H), 7.32 (d, J = 2.1 Hz, 1H), 4.14 (q, J = 6.6 Hz, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 1.37 (t, J = 6.9 Hz, 3 DMSO 396.10 (M + 1) 2.3 Method C 100 Method G12
    265
    Figure US20170217923A1-20170803-C00409
         		HCl 469.53 1H NMR (300 MHz, DMSO) δ 12.13 (s, 1H), 9.54 (s, 1H), 8.99 (d, J = 7.4 Hz, 1H), 8.85 (s, 2H), 8.61 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.86 (d, J = 7.3 Hz, 2H), 7.68 (dd, J = 15.1, 7.8 Hz, 3H), 7.32 (d, J = 6.8 Hz, 1H), 4.00 (s, 3H), 3.71 (d, J DMSO 470.1 (M + 1) 2.15 Method C 100 Method G1
    266
    Figure US20170217923A1-20170803-C00410
         		HCl 455.51 1H NMR (300 MHz, DMSO) δ 12.07 (s, 1H), 9.52 (s, 1H), 8.82- 8.65 (m, 4H), 7.88 (dd, J = 8.1, 5.0 Hz, 2H), 7.73-7.55 (m, 4H), 7.27 (t, J = 7.2 Hz, 1H), 3.98 (m, 1H), 3.82 (d, J = 10.4 Hz, 2H), 3.35 (t, J = 11.7 Hz, 2H), 1.68 (d, J = 10.3 Hz, 2H), 1.55- DMSO 456.1 (M + 1) 2.09 Method C 100 Method G1
    267
    Figure US20170217923A1-20170803-C00411
         		HCl 408.36 1H NMR (300 MHz, DMSO) δ 10.57 (s, 1H), 9.45 (d, J = 1.5 Hz, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 3.9 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 7.4 Hz, 2H), 7.63 (ddd, J = 9.3, 6.9, 2.3 Hz, 2H), 7.52 (d, J = 8.7 Hz, DMSO 409.1 (M + 1) 2.3 Method C 100 Method G1
    268
    Figure US20170217923A1-20170803-C00412
         		HCl 367.4 1H NMR (300 MHz, DMSO) δ 11.12 (s, 1H), 9.81 (s, 1H), 9.43- 9.37 (m, 1H), 8.58 (ddd, J = 8.0, 4.8, 1.4 Hz, 2H), 8.09 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.53-7.41 (m, 3H), 7.17 (t, J = 7.5 Hz, 1H), 7.0 DMSO 368.1 (M + 1) 1.98 Method C 100 Method G1
    269
    Figure US20170217923A1-20170803-C00413
         		386.4 1H NMR (300 MHz, DMSO) δ 11.47 (s, 2H), 9.39 (s, 1H), 8.66 (d, J = 2.8 Hz, 1H), 8.56-8.47 (m, 1H), 8.01-7.90 (m, 2H), 7.69- 7.55 (m, 2H), 7.55-7.40 (m, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.23 (q, J = 6.9 Hz, 2H), 1.44 (t, J = DMSO 387.0 (M + 1) 2.05 Method C 100 Method G8
    270
    Figure US20170217923A1-20170803-C00414
         		407.45 1H NMR (300 MHz, DMSO) δ 10.52 (s, 1H), 9.44 (s, 1H), 8.92 (d, J = 7.4 Hz, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.46 (d, J = 6.4 Hz, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.92- 7.74 (m, 6H), 7.68 (dd, J = 9.2, 2.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 3.98 (s, 4H). DMSO 408.0 (M + 1) 1.92 Method C 100 Method G1, with two drops of conc. HCl
    271
    Figure US20170217923A1-20170803-C00415
         		HCl 385.42 1H NMR (300 MHz, DMSO) δ 9.75 (s, 1H), 9.66 (s, 1H), 9.39 (s, 1H), 8.61 (d, J = 3.1 Hz, 1H), 8.54 (d, J = 8.2 Hz, 1H), 7.85 (s, 1H), 7.82 (s, 2H), 7.71 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 9.1 Hz, 1H), 7.46 (dd, J = 7.5, 5.2 Hz, 1H), 7.35-7.23 (m, 2H), 3.9 DMSO 386.1 (M + 1) 1.79 Method C 96 Method G2
    272
    Figure US20170217923A1-20170803-C00416
         		HCl 413.47 1H NMR (300 MHz, DMSO) δ 12.30 (s, 1H), 9.57 (d, J = 2.1 Hz, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.77- 8.67 (m, 2H), 8.63 (d, J = 7.7 Hz, 1H), 7.94-7.83 (m, 2H), 7.71 (t, J = 7.1 Hz, 1H), 7.66-7.52 (m, 3H), 7.25 (t, J = 7.4 Hz, 1H), 4.24- 4.06 (m, 1H), 3 DMSO 414.2 (M + 1) 2.36 Method C 100 Method G1
    273
    Figure US20170217923A1-20170803-C00417
         		HCl 387.46 1H NMR (300 MHz, DMSO) δ 10.96 (s, 1H), 10.29 (s, 1H), 9.85 (s, 1H), 9.51 (d, J = 2.0 Hz, 1H), 8.71-8.62 (m, 2H), 8.47 (dd, J = 8.2, 0.9 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.67-7.62 (m, 2H), 7.60 (d, J = 2.5 Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.55-7 DMSO 388.1 (M + 1) 2.01 Method C 95 Method G1
    274
    Figure US20170217923A1-20170803-C00418
         		HCl 399.45 1H NMR (300 MHz, DMSO) δ 12.45 (s, 1H), 9.57 (d, J = 1.3 Hz, 1H), 8.96 (dd, J = 8.4, 0.9 Hz, 1H), 8.89 (t, J = 5.2 Hz, 1H), 8.75- 8.66 (m, 2H), 7.94-7.84 (m, 2H), 7.72 (t, J = 7.9 Hz, 1H), 7.65- 7.52 (m, 3H), 7.24 (t, J = 7.6 Hz, 1H), 4.00 (s, 3H), 3. DMSO 400.3 (M + 1) 2.21 Method C 100 Method G1
    275
    Figure US20170217923A1-20170803-C00419
         		HCl 453.42 1H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.54 (d, J = 2.0 Hz, 1H), 9.40 (t, J = 6.1 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.73-8.63 (m, 2H), 7.89 (d, J = 9.8 Hz, 2H), 7.76 (t, J = 7.1 Hz, 1H), 7.64- 7.50 (m, 3H), 7.30 (t, J = 7.1 Hz, 1H), 4.16-4.01 (m, 2 DMSO 454.0 (M + 1) 2.28 Method C 100 Method G1
    276
    Figure US20170217923A1-20170803-C00420
         		421.25 1H NMR (300 MHz, DMSO) δ 9.26 (d, J = 2.2 Hz, 1H), 8.71-8.62 (m, 2H), 8.46 (dt, J = 8.0, 1.9 Hz, 1H), 8.21 (dd, J = 8.9, 2.3 Hz, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.89 (s, 1H), 7.78 (dd, J = 7.6, 1.6 Hz, 1H), 7.72-7.62 (m, 1H), 7.56- 7.45 (m, 3H), 7.32 DMSO 423.0 (M + 1) 1.85 Method C 94 Method G1
    277
    Figure US20170217923A1-20170803-C00421
         		HCl 447.49 1H NMR (300 MHz, DMSO) δ 11.25 (s, 1H), 10.46 (s, 1H), 9.45 (s, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.82 (d, J = 3.9 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.97-7.79 (m, 4H), 7.73 (t, J = 7.1 Hz, 1H), 7.62 (dd, J = 9.1, 2.5 Hz, 1H), 7.53- 7.39 (m, 3H), 7.19 (t, DMSO 448.1 (M + 1) 2.67 Method C 100 Method G1
    278
    Figure US20170217923A1-20170803-C00422
         		HCl 399.45 1H NMR (300 MHz, DMSO) δ 12.59 (s, 1H), 9.57 (d, J = 1.4 Hz, 1H), 9.03 (dd, J = 8.4, 0.9 Hz, 1H), 8.91 (d, J = 4.6 Hz, 1H), 8.76- 8.64 (m, 2H), 7.88 (t, J = 7.8 Hz, 2H), 7.72 (t, J = 7.9 Hz, 1H), 7.63- 7.53 (m, 3H), 7.22 (td, J = 7.9, 1.1 Hz, 1H), 4.28 DMSO 400.1 (M + 1) 2.5 Method C 100 Method G1
    279
    Figure US20170217923A1-20170803-C00423
         		HCl 399.45 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.37 (d, J = 1.4 Hz, 1H), 8.61 (dd, J = 4.7, 1.7 Hz, 1H), 8.58-8.51 (m, 1H), 7.84 (dd, J = 9.0, 5.3 Hz, 3H), 7.65-7.42 (m, 4H), 7.38 (t, J = 7.5 Hz, 1H), 3.95 (s, 3H), 2.74 (s, 6H). DMSO 400.1 (M + 1) 2.2 Method C 100 Method G1
    280
    Figure US20170217923A1-20170803-C00424
         		HCl 439.51 1H NMR (300 MHz, DMSO) δ 12.05 (s, 1H), 9.51 (d, J = 1.6 Hz, 1H), 9.04 (d, J = 8.1 Hz, 1H), 8.88 (dd, J = 5.2, 1.3 Hz, 1H), 8.60 (d, J = 7.0 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.00-7.87 (m, 2H), 7.83 (dd, J = 7.8, 1.4 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), DMSO 440.1 (M + 1) 2.52 Method C 100 Method G1
    281
    Figure US20170217923A1-20170803-C00425
         		HCl 403.41 1H NMR (300 MHz, DMSO) δ 10.98 (s, 1H), 9.50 (s, 1H), 8.72- 8.55 (m, 3H), 8.38 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.72- 7.45 (m, 4H), 7.19-7.07 (m, 1H), 3.96 (s, J = 5.2 Hz, 3H), 2.73 (d, J = 4.5 Hz, 3H). DMSO 404.1 (M + 1) 2.18 Method C 100 Method G1
    282
    Figure US20170217923A1-20170803-C00426
         		HCl 417.44 1H NMR (300 MHz, DMSO) δ 10.96 (s, 1H), 9.50 (d, J = 1.9 Hz, 1H), 8.71-8.55 (m, 3H), 8.38 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.66 (dd, J = 14.8, 8.3 Hz, 1H), 7.60-7.47 (m, 3H), 7.21- 7.05 (m, 1H), 4.24 (q, J = 6.9 Hz, 2H), 2.73 (d, J = 4. DMSO 419.1 (M + 1) 2.38 Method C 100 Method G1
    283
    Figure US20170217923A1-20170803-C00427
         		HCl 439.39 1H NMR (300 MHz, DMSO) δ 13.10 (s, 1H), 9.68 (d, J = 1.1 Hz, 1H), 9.52 (d, J = 1.4 Hz, 1H), 8.75- 8.58 (m, 3H), 8.26 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.59-7.47 (m, 3H), 7.45 (d, J = 2.5 Hz, 1H), 3.95 (s, 3H). DMSO 440.1 (M + 1) 2.25 Method C 100 Method G1
    284
    Figure US20170217923A1-20170803-C00428
         		HCl 453.42 1H NMR (300 MHz, DMSO) δ 13.08 (s, 1H), 9.70 (s, 1H), 9.55 (d, J = 1.3 Hz, 1H), 8.77-8.60 (m, 3H), 8.26 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.62-7.39 (m, 4H), 4.21 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 6.9 Hz, 3H). DMSO 454.1 (M + 1) 2.43 Method C 95 Method G1
    285
    Figure US20170217923A1-20170803-C00429
         		HCl 410.43 1H NMR (300 MHz, DMSO) δ 12.87 (s, 1H), 9.50 (d, J = 1.5 Hz, 2H), 8.73-8.59 (m, 3H), 8.26 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.64 (dd, J = 8.1, 1.5 Hz, 1H), 7.59-7.49 (m, 2H), 7.42 (d, J = 2.4 Hz, 1H), 4.19 (q, J = 6.9 Hz, 2H DMSO 411.1 (M + 1) 2.16 Method C 95 Method G1
    286
    Figure US20170217923A1-20170803-C00430
         		HCl 397.43 1H NMR (300 MHz, DMSO) δ 13.63 (s, 1H), 9.55 (s, 1H), 9.13 (d, J = 8.3 Hz, 1H), 8.75-8.58 (m, 3H), 7.84 (d, J = 9.8 Hz, 1H), 7.69- 7.48 (m, 4H), 7.01 (d, J = 7.4 Hz, 1H), 3.94 (s, 3H), 3.46-3.36 (m, 2H), 2.96 (t, J = 5.7 Hz, 2H). DMSO 398.3 (M + 1) 2.12 Method C 100 Method G1
    287
    Figure US20170217923A1-20170803-C00431
         		HCl 411.46 1H NMR (300 MHz, DMSO) δ 13.61 (s, 1H), 9.56 (s, 1H), 9.14 (d, J = 8.1 Hz, 1H), 8.75-8.60 (m, 3H), 7.84 (d, J = 9.8 Hz, 1H), 7.70- 7.46 (m, 4H), 7.02 (d, J = 7.2 Hz, 1H), 4.19 (q, J = 6.9 Hz, 3H), 3.48- 3.37 (m, 2H), 2.96 (t, J = 6.1 Hz, 2H), 1.44 (t, DMSO 412.4 (M + 1) 2.4 Method C 100 Method G1
    288
    Figure US20170217923A1-20170803-C00432
         		HCl 383.4 1H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 9.60 (d, J = 1.5 Hz, 1H), 9.02 (s, 1H), 8.88 (d, J = 8.0 Hz, 1H), 8.80-8.65 (m, 2H), 7.90 (d, J = 9.0 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.66-7.51 (m, 3H), 7.27 (d, J = 7.6 Hz, 1H), 4.47 (s, 2H), 3.97 (s, 3H). DMSO 384.1 (M + 1) 2.01 Method C 95 Method G1
    289
    Figure US20170217923A1-20170803-C00433
         		HCl 421.4 1H NMR (300 MHz, DMSO) δ 12.07 (s, 1H), 9.48 (d, J = 1.6 Hz, 1H), 8.76-8.55 (m, 3H), 8.34 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.62-7.49 (m, 2H), 7.38 (d, J = 2.5 Hz, 1H), 7.14 (ddd, J = 11.5, 9.0, 2.6 Hz, 1H), 4.19 (q, J = 6.9 Hz, 2H), 1. DMSO 422.2 (M + 1) 2.35 Method C 100 Method G1
    290
    Figure US20170217923A1-20170803-C00434
         		HCl 412.44 1H NMR (300 MHz, DMSO) δ 9.82 (s, 1H), 9.50 (d, J = 2.0 Hz, 1H), 8.68-8.58 (m, 2H), 7.98 (d, J = 2.5 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.80 (d, J = 9.1 Hz, 1H), 7.55- 7.43 (m, 3H), 7.23 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.37 (d, J = 4.2 Hz, 6H). DMSO 413.0 (M + 1) 1.79 Method C Method G1
    291
    Figure US20170217923A1-20170803-C00435
         		HCl 426.47 1H NMR (300 MHz, DMSO) δ 9.78 (s, 1H), 9.50 (d, J = 2.0 Hz, 1H), 8.68-8.57 (m, 2H), 7.97 (d, J = 2.5 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.55- 7.43 (m, 3H), 7.22 (d, J = 8.4 Hz, 1H), 4.22 (q, J = 6.9 Hz, 2H), 3.37 (d, J = 4.3 H DMSO 427.1 (M + 1) 1.92 Method C Method G1
    292
    Figure US20170217923A1-20170803-C00436
         		404.39 1H NMR (300 MHz, DMSO) δ 9.36 (d, J = 1.4 Hz, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 8.9 Hz, 2H), 7.64 (d, J = 13.5 Hz, 2H), 7.50 (dd, J = 7.7, 4.2 Hz, 1H), 6.86 (t, J = 6.8 Hz, 1H), 6.70 (dd, J = 11.8, 1.7 Hz, 1H), 4.22 (q, DMSO 405.1 (M + 1) 1.98 Method C 95 Method G8
    293
    Figure US20170217923A1-20170803-C00437
         		406.82 1H NMR (300 MHz, DMSO) δ 9.23 (d, J = 1.4 Hz, 1H), 8.63 (d, J = 3.6 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.92 (s, 1H), 7.81-7.65 (m, 4H), 7.55 (dd, J = 8.4, 2.1 Hz, 1H), 7.48 (dd, J = 6.7, 3.8 Hz, 1H), 7.37 (s, 1H), 3.97 (s, 3H). DMSO 407.1 (M + 1) 1.88 Method C 100 Method G8
    294
    Figure US20170217923A1-20170803-C00438
         		HCl 406.46 1H NMR (300 MHz, DMSO) δ 10.11 (s, 1H), 9.39 (d, J = 1.4 Hz, 1H), 8.63 (dd, J = 4.7, 1.7 Hz, 1H), 8.59-8.53 (m, 1H), 8.50 (dd, J = 8.2, 0.8 Hz, 1H), 8.03 (dd, J = 8.0, 1.4 Hz, 1H), 7.96-7.84 (m, 2H), 7.65-7.46 (m, 4H), 3.94 (s, 3H), 3.25 (s, 3H). DMSO 407.1 (M + 1) 2.13 Method C 95 Method G1
  • 1H Method
    Starting Starting Salt NMR Purity of
    Number Material 1 Material 2 Product Type 1H NMR Solvent percent Coupling
    295
    Figure US20170217923A1-20170803-C00439
    Figure US20170217923A1-20170803-C00440
    Figure US20170217923A1-20170803-C00441
         		1H NMR (400 MHz, DMSO) δ 13.12 (s, 1H), 9.90 (s, 1H), 9.47 (d, J = 1.4 Hz, 1H), 8.70-8.54 (m, 2H), 8.20- 8.15 (m, 1H), 8.14 (s, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.88-7.75 (m, 2H), 7.65 (d, J = 8.9 Hz, 1H), 7.59-7.44 (m, 2H), 3.98 (s, 3H). DMSO >98 G1
    296
    Figure US20170217923A1-20170803-C00442
    Figure US20170217923A1-20170803-C00443
    Figure US20170217923A1-20170803-C00444
         		1H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 9.54-9.47 (m, 1H), 9.36 (s, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.69- 8.59 (m, 2H), 8.19 (d, J = 8.8 Hz, 1H), 8.08-7.97 (m, 2H), 7.86 (d, J = 9.1 Hz, 1H), 7.61-7.47 (m, 2H), 3.99 (s, 3H). DMSO >98 G1
    297
    Figure US20170217923A1-20170803-C00445
    Figure US20170217923A1-20170803-C00446
    Figure US20170217923A1-20170803-C00447
         		1H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 9.55-9.45 (m, 1H), 8.72-8.60 (m, 2H), 7.95 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.58-7.48 (m, 3H), 7.34 (dd, J = 8.7, 2.5 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.39-4.23 (m, 4H), 3.97 (s, 3H). DMSO >98 G1
    298
    Figure US20170217923A1-20170803-C00448
    Figure US20170217923A1-20170803-C00449
    Figure US20170217923A1-20170803-C00450
         		1H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 9.79 (s, 1H), 9.53 (d, J = 1.4 Hz, 1H), 8.75-8.58 (m, 2H), 8.07 (s, 1H), 8.03 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.56-7.47 (m, 2H), 7.43 (dd, J = 8.5, 1.8 Hz, 1H), 7.39-7.34 (m, 1H), 6.50-6.41 (m, 1H), 3.99 (s, 3H). DMSO >98 G1
    299
    Figure US20170217923A1-20170803-C00451
    Figure US20170217923A1-20170803-C00452
    Figure US20170217923A1-20170803-C00453
         		1H NMR (400 MHz, DMSO) δ 9.54 (s, 1H), 9.42-9.34 (m, 1H), 8.61 (dd, J = 4.7, 1.7 Hz, 1H), 8.57-8.47 (m, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.56-7.44 (m, 2H), 7.19 (dd, J = 7.9, 1.5 Hz, 1H), 7.00-6.91 (m, 1H), 6.86 (dd, J = 8.2, 1.6 Hz, 1H), 4.34-4.17 (m, 4H), 3.95 (s, 3H). DMSO >98 G1
    300
    Figure US20170217923A1-20170803-C00454
    Figure US20170217923A1-20170803-C00455
    Figure US20170217923A1-20170803-C00456
         		1H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 10.01 (s, 1H), 9.17-9.06 (m, 1H), 8.53 (dd, J = 4.7, 1.7 Hz, 1H), 8.36-8.27 (m, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.60- 7.48 (m, 2H), 7.36 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.32-7.28 (m, 1H), 7.25 (d, J = 6.8 Hz, 1H), 7.16-7.04 (m, 1H), 6.54 (dd, J = 3.0, 1.9 Hz, 1H), 3.98 (s, 3H). DMSO >98 G1
    301
    Figure US20170217923A1-20170803-C00457
    Figure US20170217923A1-20170803-C00458
    Figure US20170217923A1-20170803-C00459
         		1H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 9.48 (d, J = 1.5 Hz, 1H), 9.33 (d, J = 1.0 Hz, 1H), 8.69-8.59 (m, 2H), 8.37 (d, J = 1.7 Hz, 1H), 8.10 (dd, J = 9.0, 2.1 Hz, 1H), 8.00 (d, J = 2.7 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.57 (dd, J = 9.1, 2.7 Hz, 1H), 7.54-7.47 (m, 1H), 3.99 (s, 3H). DMSO >98 G1
    302
    Figure US20170217923A1-20170803-C00460
    Figure US20170217923A1-20170803-C00461
    Figure US20170217923A1-20170803-C00462
         		1H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 9.18 (dd, J = 2.2, 0.8 Hz, 1H), 8.60 (dd, J = 4.7, 1.7 Hz, 1H), 8.45- 8.36 (m, 1H), 8.03 (d, J = 2.7 Hz, 1H), 7.97-7.90 (m, 2H), 7.88 (d, J = 7.0 Hz, 1H), 7.77 (dd, J = 9.0, 7.1 Hz, 1H), 7.61 (dd, J = 9.1, 2.7 Hz, 1H), 7.44 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 4.01 (s, 3H). DMSO >98 G1
    303
    Figure US20170217923A1-20170803-C00463
    Figure US20170217923A1-20170803-C00464
    Figure US20170217923A1-20170803-C00465
         		1H NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 9.60-9.56 (m, 1H), 8.72-8.67 (m, 1H), 8.65 (dd, J = 4.8, 1.7 Hz, 1H), 8.26-8.21 (m, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.56-7.50 (m, 2H), 7.46 (dd, J = 8.5, 1.8 Hz, 1H), 7.35 (d, J = 3.1 Hz, 1H), 6.46 (dd, J = 3.1, 0.8 Hz, 1H), 3.99 (s, 3H), 3.86 (s, 3H). DMSO >98 G1
    304
    Figure US20170217923A1-20170803-C00466
    Figure US20170217923A1-20170803-C00467
    Figure US20170217923A1-20170803-C00468
         		1H NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 9.51-9.45 (m, 1H), 8.68-8.59 (m, 2H), 8.57-8.52 (m, 1H), 8.02- 7.88 (m, 3H), 7.87-7.80 (m, 1H), 7.58-7.46 (m, 2H), 3.98 (s, 3H), 2.83 (s, 3H). DMSO >98 G1
    305
    Figure US20170217923A1-20170803-C00469
    Figure US20170217923A1-20170803-C00470
    Figure US20170217923A1-20170803-C00471
         		1H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 9.51-9.43 (m, 1H), 8.68-8.58 (m, 2H), 8.39 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 2.7 Hz, 1H), 7.87-7.80 (m, 2H), 7.78 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 9.1, 2.7 Hz, 1H), 7.51 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 4.19 (s, 3H), 3.98 (s, 3H). DMSO >98 G1
    306
    Figure US20170217923A1-20170803-C00472
    Figure US20170217923A1-20170803-C00473
    Figure US20170217923A1-20170803-C00474
         		1H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 9.52-9.47 (m, 1H), 8.67-8.60 (m, 2H), 7.98 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.78-7.74 (m, 1H), 7.68-7.62 (m, 1H), 7.55-7.48 (m, 2H), 7.32 (d, J = 8.1 Hz, 1H), 3.97 (s, 3H), 2.99-2.88 (m, 4H), 2.15- 2.04 (m, 2H). DMSO >98 G1
    307
    Figure US20170217923A1-20170803-C00475
    Figure US20170217923A1-20170803-C00476
    Figure US20170217923A1-20170803-C00477
         		1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 9.37-9.31 (m, 1H), 8.60 (dd, J = 4.7, 1.7 Hz, 1H), 8.53-8.46 (m, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.52 (dd, J = 9.1, 2.7 Hz, 1H), 7.47 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.34 (d, J = 7.0 Hz, 1H), 7.31- 7.24 (m, 1H), 7.22 (d, J = 7.1 Hz, 1H), 3.96 (s, 3H), 2.99 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.06-1.96 (m, 2H). DMSO >98 G1
    308
    Figure US20170217923A1-20170803-C00478
    Figure US20170217923A1-20170803-C00479
    Figure US20170217923A1-20170803-C00480
         		HCl 1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 9.50-9.44 (m, 1H), 8.94- 8.87 (m, 1H), 8.83 (dd, J = 5.1, 1.5 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.97-7.89 (m, 2H), 7.83 (dd, J = 8.0, 5.2 Hz, 1H), 7.63 (dd, J = 9.1, 2.7 Hz, 1H), 4.01 (s, 3H), 2.83 (s, 3H). DMSO >98 G1
    309
    Figure US20170217923A1-20170803-C00481
    Figure US20170217923A1-20170803-C00482
    Figure US20170217923A1-20170803-C00483
         		HCl 1H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 9.47 (d, J = 1.5 Hz, 1H), 8.94 (d, J = 8.1 Hz, 1H), 8.86 (dd, J = 5.2, 1.5 Hz, 1H), 8.54-8.48 (m, 1H), 8.23- 8.16 (m, 1H), 8.04-7.94 (m, 2H), 7.92-7.83 (m, 2H), 7.78 (d, J = 5.4 Hz, 1H), 7.65 (dd, J = 9.1, 2.6 Hz, 1H), 7.51 (dd, J = 5.4, 0.7 Hz, 1H), 4.02 (s, 3H). DMSO >98 G1
    310
    Figure US20170217923A1-20170803-C00484
    Figure US20170217923A1-20170803-C00485
    Figure US20170217923A1-20170803-C00486
         		HCl 1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 9.43 (d, J = 1.6 Hz, 1H), 8.94 (d, J = 7.5 Hz, 1H), 8.89 (dd, J = 5.2, 1.5 Hz, 1H), 8.30-8.20 (m, 1H), 8.13- 7.99 (m, 3H), 7.94-7.84 (m, 1H), 7.74 (d, J = 1.3 Hz, 2H), 7.67 (dd, J = 9.1, 2.5 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 4.02 (s, 3H). DMSO >98 G1
    311
    Figure US20170217923A1-20170803-C00487
    Figure US20170217923A1-20170803-C00488
    Figure US20170217923A1-20170803-C00489
         		HCl 1H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 9.48 (d, J = 1.5 Hz, 1H), 8.93 (d, J = 7.7 Hz, 1H), 8.85 (dd, J = 5.2, 1.5 Hz, 1H), 8.44 (d, J = 1.9 Hz, 1H), 8.20-8.15 (m, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 9.1 Hz, 1H), 7.92 (dd, J = 8.7, 2.0 Hz, 1H), 7.86 (dd, J = 7.8, 5.1 Hz, 1H), 7.64 (dd, J = 9.1, 2.6 Hz, 1H), 4.02 (s, 3H), 2.85 (s, 3H). DMSO >98 G1
    312
    Figure US20170217923A1-20170803-C00490
    Figure US20170217923A1-20170803-C00491
    Figure US20170217923A1-20170803-C00492
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 9.47 (s, 1H), 9.32 (s, 1H), 9.03 (d, J = 8.0 Hz, 1H), 8.93-8.87 (m, 1H), 8.86- 8.78 (m, 2H), 8.44 (dd, J = 8.8, 1.9 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.99-7.89 (m, 2H), 7.78-7.71 (m, 1H), 7.55 (d, J = 8.7 Hz, 1H). DMSO >98 G1
    313
    Figure US20170217923A1-20170803-C00493
    Figure US20170217923A1-20170803-C00494
    Figure US20170217923A1-20170803-C00495
         		2 HCl 1H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H), 9.51 (d, J = 2.0 Hz, 1H), 9.46-9.39 (m, 1H), 9.10-9.01 (m, 1H), 8.97-8.88 (m, 2H), 8.86 (dd, J = 5.3, 1.3 Hz, 1H), 8.63-8.55 (m, 1H), 8.48 (dd, J = 8.8, 1.9 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.04-7.90 (m, 4H), 7.79 (d, J = 5.4 Hz, 1H), 7.52 (dd, J = 5.4, 0.7 Hz, 1H). DMSO >98 G1
    314
    Figure US20170217923A1-20170803-C00496
    Figure US20170217923A1-20170803-C00497
    Figure US20170217923A1-20170803-C00498
         		HCl 1H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 9.48 (d, J = 1.5 Hz, 1H), 8.93 (d, J = 7.9 Hz, 1H), 8.85 (dd, J = 5.2, 1.5 Hz, 1H), 8.24 (s, 1H), 8.16 (d, J = 2.5 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 9.1 Hz, 1H), 7.87 (dd, J = 8.1, 5.3 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 8.4, 1.8 Hz, 1H), 7.64 (dd, J = 9.1, 2.6 Hz, 1H), 7.03 (dd, J = 2.2, 1.0 Hz, 1H), 4.02 (s, 3H). DMSO >98 G1
    315
    Figure US20170217923A1-20170803-C00499
    Figure US20170217923A1-20170803-C00500
    Figure US20170217923A1-20170803-C00501
         		HCl 1H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 9.46 (d, J = 1.5 Hz, 1H), 8.96 (d, J = 8.2 Hz, 1H), 8.87 (dd, J = 5.2, 1.5 Hz, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.06-7.96 (m, 2H), 7.93-7.84 (m, 2H), 7.78 (d, J = 5.4 Hz, 1H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H), 7.51 (dd, J = 5.4, 0.7 Hz, 1H), 4.29 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H). DMSO >98 G1
    316
    Figure US20170217923A1-20170803-C00502
    Figure US20170217923A1-20170803-C00503
    Figure US20170217923A1-20170803-C00504
         		1H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 9.60-9.52 (m, 1H), 8.75- 8.63 (m, 2H), 8.16 (d, J = 2.0 Hz, 1H), 8.04-7.95 (m, 2H), 7.93-7.83 (m, 2H), 7.63-7.53 (m, 2H), 6.32 (d, J = 1.2 Hz, 1H), 4.01 (s, 3H), 2.47 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    317
    Figure US20170217923A1-20170803-C00505
    Figure US20170217923A1-20170803-C00506
    Figure US20170217923A1-20170803-C00507
         		1H NMR (400 MHz, DMSO) δ 11.82 (s, 1H), 10.06 (s, 1H), 9.53-9.46 (m, 1H), 8.81-8.70 (m, 2H), 8.04 (d, J = 2.6 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.67 (dd, J = 7.9, 5.0 Hz, 1H), 7.57 (dd, J = 9.1, 2.7 Hz, 1H), 7.53 (dd, J = 8.7, 2.1 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 4.00 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    318
    Figure US20170217923A1-20170803-C00508
    Figure US20170217923A1-20170803-C00509
    Figure US20170217923A1-20170803-C00510
         		1H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 9.57-9.48 (m, 1H), 8.72-8.58 (m, 2H), 8.01 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.59-7.49 (m, 3H), 7.43 (d, J = 8.6 Hz, 1H), 3.98 (s, 3H), 3.41 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    319
    Figure US20170217923A1-20170803-C00511
    Figure US20170217923A1-20170803-C00512
    Figure US20170217923A1-20170803-C00513
         		1H NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 9.52-9.44 (m, 1H), 8.71-8.59 (m, 2H), 8.02-7.91 (m, 2H), 7.83 (d, J = 9.1 Hz, 1H), 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.58-7.48 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.40 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    320
    Figure US20170217923A1-20170803-C00514
    Figure US20170217923A1-20170803-C00515
    Figure US20170217923A1-20170803-C00516
         		1H NMR (400 MHz, DMSO) δ 10.01 (s, 1H), 9.58-9.51 (m, 1H), 9.45 (s, 1H), 8.75 (d, J = 1.9 Hz, 1H), 8.71- 8.63 (m, 2H), 8.25 (d, J = 8.7 Hz, 1H), 8.08-8.00 (m, 2H), 7.86 (d, J = 9.1 Hz, 1H), 7.61-7.50 (m, 2H), 4.00 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    321
    Figure US20170217923A1-20170803-C00517
    Figure US20170217923A1-20170803-C00518
    Figure US20170217923A1-20170803-C00519
         		1H NMR (400 MHz, DMSO) δ 10.43 (s, 1H), 9.72 (s, 1H), 9.51-9.45 (m, 1H), 8.67-8.57 (m, 2H), 7.96 (d, J = 2.7 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.73-7.68 (m, 1H), 7.64 (dd, J = 8.3, 2.1 Hz, 1H), 7.56-7.48 (m, 2H), 6.93 (d, J = 8.3 Hz, 1H), 3.97 (s, 3H), 3.58 (s, 2H). DMSO >98 G1 (0.1 N HCl added)
    322
    Figure US20170217923A1-20170803-C00520
    Figure US20170217923A1-20170803-C00521
    Figure US20170217923A1-20170803-C00522
         		1H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 9.54-9.45 (m, 1H), 8.67 (dd, J = 4.7, 1.7 Hz, 1H), 8.66-8.60 (m, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.89-7.83 (m, 2H), 7.63- 7.52 (m, 3H), 3.98 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    323
    Figure US20170217923A1-20170803-C00523
    Figure US20170217923A1-20170803-C00524
    Figure US20170217923A1-20170803-C00525
         		1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.75 (s, 1H), 9.55-9.49 (m, 1H), 8.69-8.62 (m, 2H), 7.96 (d, J = 2.7 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.58-7.49 (m, 3H), 7.35 (dd, J = 8.7, 2.5 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 4.62 (s, 2H), 3.97 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    324
    Figure US20170217923A1-20170803-C00526
    Figure US20170217923A1-20170803-C00527
    Figure US20170217923A1-20170803-C00528
         		HCl 1H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 9.58-9.51 (m, 1H), 8.92- 8.84 (m, 1H), 8.80 (dd, J = 5.0, 1.5 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.98 (dd, J = 8.8, 2.1 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.83-7.72 (m, 2H), 7.61 (dd, J = 9.1, 2.6 Hz, 1H), 6.37 (s, 1H), 4.75 (d, J = 1.2 Hz, 2H), 4.01 (s, 3H), 3.47 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    325
    Figure US20170217923A1-20170803-C00529
    Figure US20170217923A1-20170803-C00530
    Figure US20170217923A1-20170803-C00531
         		HCl 1H NMR (400 MHz, DMSO) δ 12.01 (s, 1H), 10.15 (s, 1H), 9.58 (d, J = 1.5 Hz, 1H), 8.94-8.86 (m, 1H), 8.78 (dd, J = 5.0, 1.5 Hz, 1H), 8.07 (d, J = 2.6 Hz, 1H), 8.04-7.98 (m, 1H), 7.91 (dd, J = 9.3, 2.2 Hz, 2H), 7.78-7.69 (m, 2H), 7.66 (dd, J = 8.5, 2.0 Hz, 1H), 7.61 (dd, J = 9.1, 2.7 Hz, 1H), 6.44 (d, J = 9.5 Hz, 1H), 4.01 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    326
    Figure US20170217923A1-20170803-C00532
    Figure US20170217923A1-20170803-C00533
    Figure US20170217923A1-20170803-C00534
         		HCl 1H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 10.21 (s, 1H), 9.58-9.51 (m, 1H), 8.94-8.86 (m, 1H), 8.81 (dd, J = 5.1, 1.6 Hz, 1H), 8.10 (d, J = 2.6 Hz, 1H), 7.96-7.88 (m, 2H), 7.79 (dd, J = 7.9, 5.1 Hz, 1H), 7.68-7.56 (m, 3H), 4.00 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    327
    Figure US20170217923A1-20170803-C00535
    Figure US20170217923A1-20170803-C00536
    Figure US20170217923A1-20170803-C00537
         		HCl 1H NMR (400 MHz, DMSO) δ 10.43 (s, 1H), 9.57-9.50 (m, 1H), 9.07- 8.98 (m, 1H), 8.88 (dd, J = 5.2, 1.4 Hz, 1H), 8.16 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 1.9 Hz, 1H), 8.00-7.89 (m, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 8.5, 2.0 Hz, 1H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H), 4.02 (s, 3H), 3.47 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    328
    Figure US20170217923A1-20170803-C00538
    Figure US20170217923A1-20170803-C00539
    Figure US20170217923A1-20170803-C00540
         		HCl 1H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 10.24 (s, 1H), 9.45 (d, J = 1.6 Hz, 1H), 9.05-8.95 (m, 1H), 8.92 (dd, J = 5.2, 1.5 Hz, 1H), 8.25-8.16 (m, 1H), 8.09-7.99 (m, 1H), 7.98- 7.89 (m, 1H), 7.71-7.60 (m, 3H), 6.98 (d, J = 8.3 Hz, 1H), 4.00 (s, 3H), 2.99 (t, J = 7.5 Hz, 2H), 2.57-2.52 (m, 2H). DMSO >98 G1 (0.1 N HCl added)
    329
    Figure US20170217923A1-20170803-C00541
    Figure US20170217923A1-20170803-C00542
    Figure US20170217923A1-20170803-C00543
         		2 HCl 1H NMR (400 MHz, DMSO) δ 12.05 (s, 1H), 10.98 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 9.32 (s, 1H), 9.03 (d, J = 8.2 Hz, 1H), 8.98 (d, J = 1.7 Hz, 1H), 8.92 (dd, J = 5.3, 1.4 Hz, 1H), 8.53 (d, J = 2.6 Hz, 1H), 8.46 (dd, J = 8.8, 1.8 Hz, 1H), 8.30 (s, 1H), 8.13 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.95 (dd, J = 7.7, 5.3 Hz, 1H), 7.82 (dd, J = 8.6, 2.1 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 4.06 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    330
    Figure US20170217923A1-20170803-C00544
    Figure US20170217923A1-20170803-C00545
    Figure US20170217923A1-20170803-C00546
         		HCl 1H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 9.05- 8.97 (m, 1H), 8.87 (dd, J = 5.2, 1.5 Hz, 1H), 8.15-8.06 (m, 3H), 8.00- 7.87 (m, 3H), 7.81 (d, J = 8.5 Hz, 1H), 7.64 (dd, J = 9.1, 2.7 Hz, 1H), 6.43 (d, J = 9.4 Hz, 1H), 4.02 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    331
    Figure US20170217923A1-20170803-C00547
    Figure US20170217923A1-20170803-C00548
    Figure US20170217923A1-20170803-C00549
         		2 HCl 1H NMR (400 MHz, DMSO) δ 12.05 (s, 1H), 10.77 (s, 1H), 9.51 (d, J = 1.5 Hz, 1H), 9.43-9.35 (m, 1H), 9.31- 9.21 (m, 1H), 9.04-8.93 (m, 1H), 8.88 (dd, J = 5.2, 1.5 Hz, 1H), 8.81 (dd, J = 5.1, 1.4 Hz, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.42 (dd, J = 8.8, 1.8 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.94-7.83 (m, 2H), 7.80 (dd, J = 8.6, 2.2 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H). DMSO >98 G1 (0.1 N HCl added)
    332
    Figure US20170217923A1-20170803-C00550
    Figure US20170217923A1-20170803-C00551
    Figure US20170217923A1-20170803-C00552
         		HCl 1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 9.55 (d, J = 1.6 Hz, 1H), 9.09- 9.01 (m, 1H), 8.90 (dd, J = 5.3, 1.5 Hz, 1H), 8.65-8.59 (m, 1H), 8.24- 8.16 (m, 2H), 8.14 (dd, J = 9.6, 0.8 Hz, 1H), 8.03-7.92 (m, 2H), 7.65 (dd, J = 9.1, 2.7 Hz, 1H), 4.03 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    333
    Figure US20170217923A1-20170803-C00553
    Figure US20170217923A1-20170803-C00554
    Figure US20170217923A1-20170803-C00555
         		HCl 1H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 10.31 (s, 1H), 9.58 (d, J = 1.5 Hz, 1H), 9.08 (d, J = 7.9 Hz, 1H), 8.87 (dd, J = 5.2, 1.5 Hz, 1H), 8.13 (d, J = 2.6 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.98-7.88 (m, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 8.8, 2.1 Hz, 1H), 7.63 (dd, J = 9.1, 2.7 Hz, 1H), 6.36 (s, 1H), 4.02 (s, 3H), 2.46 (d, J = 1.1 Hz, 3H). DMSO >98 G1 (0.1 N HCl added)
    334
    Figure US20170217923A1-20170803-C00556
    Figure US20170217923A1-20170803-C00557
    Figure US20170217923A1-20170803-C00558
         		HCl 1H NMR (400 MHz, DMSO) δ 10.51 (s, 1H), 9.53 (d, J = 1.6 Hz, 1H), 9.08- 9.02 (m, 1H), 8.90 (dd, J = 5.3, 1.5 Hz, 1H), 8.63-8.59 (m, 1H), 8.22- 8.10 (m, 3H), 8.00-7.92 (m, 2H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H), 4.30 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H). DMSO >98 G1 (0.1 N HCl added)
    335
    Figure US20170217923A1-20170803-C00559
    Figure US20170217923A1-20170803-C00560
    Figure US20170217923A1-20170803-C00561
         		HCl 1H NMR (400 MHz, DMSO) δ 11.99 (s, 1H), 10.34 (s, 1H), 9.62-9.52 (m, 1H), 9.11 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 4.4 Hz, 1H), 8.13 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 1.8 Hz, 1H), 8.00- 7.88 (m, 3H), 7.75 (d, J = 8.6 Hz, 1H), 7.68-7.60 (m, 2H), 6.46 (d, J = 9.5 Hz, 1H), 4.29 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H). DMSO >98 G1 (0.1 N HCl added)
    336
    Figure US20170217923A1-20170803-C00562
    Figure US20170217923A1-20170803-C00563
    Figure US20170217923A1-20170803-C00564
         		HCl 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 10.49 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 9.02 (d, J = 8.1 Hz, 1H), 8.90 (dd, J = 5.2, 1.5 Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 8.00 (d, J = 9.1 Hz, 1H), 7.93 (dd, J = 7.8, 5.4 Hz, 1H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.7, 2.5 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 4.64 (s, 2H), 4.28 (q, J = 6.9 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H). DMSO >98 G1 (0.1 N HCl added)
    337
    Figure US20170217923A1-20170803-C00565
    Figure US20170217923A1-20170803-C00566
    Figure US20170217923A1-20170803-C00567
         		HCl 1H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 10.25 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.98 (d, J = 8.1 Hz, 1H), 8.86 (dd, J = 5.2, 1.5 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.87 (dd, J = 7.7, 5.2 Hz, 1H), 7.61 (dd, J = 9.1, 2.6 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.1, 2.1 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 4.27 (q, J = 7.0 Hz, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.56-2.52 (m, 2H), 1.45 (t, J = 7.0 Hz, 3H). DMSO >98 G1 (0.1 N HCl added)
    338
    Figure US20170217923A1-20170803-C00568
    Figure US20170217923A1-20170803-C00569
    Figure US20170217923A1-20170803-C00570
         		1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.50-9.39 (m, 1H), 9.03 (dd, J = 2.1, 0.7 Hz, 1H), 8.52 (dd, J = 4.7, 1.7 Hz, 1H), 8.48 (d, J = 6.0 Hz, 1H), 8.31-8.24 (m, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.91-7.78 (m, 3H), 7.58 (dd, J = 9.1, 2.7 Hz, 1H), 7.35 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 4.01 (s, 3H). DMSO >98 J2
    339
    Figure US20170217923A1-20170803-C00571
    Figure US20170217923A1-20170803-C00572
    Figure US20170217923A1-20170803-C00573
         		1H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 9.37 (dd, J = 2.1, 0.7 Hz, 1H), 8.62 (dd, J = 4.7, 1.7 Hz, 1H), 8.57- 8.49 (m, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.58 (dd, J = 9.1, 2.7 Hz, 1H), 7.47 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.40-7.30 (m, 3H), 3.98 (s, 3H). DMSO >98 J2
    340
    Figure US20170217923A1-20170803-C00574
    Figure US20170217923A1-20170803-C00575
    Figure US20170217923A1-20170803-C00576
         		1H NMR (400 MHz, DMSO) δ 11.31 (s, 1H), 9.56 (s, 1H), 9.54 (dd, J = 2.1, 0.7 Hz, 1H), 8.80-8.66 (m, 2H), 8.14 (d, J = 9.2 Hz, 1H), 7.77 (dd, J = 9.2, 2.8 Hz, 1H), 7.58 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H), 7.03-6.94 (m, 1H), 6.68 (dd, J = 7.8, 0.8 Hz, 1H), 6.56 (dd, J = 8.2, 0.8 Hz, 1H), 3.86 (s, 3H). DMSO >98 J2
    341
    Figure US20170217923A1-20170803-C00577
    Figure US20170217923A1-20170803-C00578
    Figure US20170217923A1-20170803-C00579
         		1H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 9.54-9.49 (m, 1H), 8.75 (s, 1H), 8.69-8.62 (m, 2H), 8.50 (d, J = 1.7 Hz, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.91-7.85 (m, 2H), 7.83 (dd, J = 8.6, 1.9 Hz, 1H), 7.60-7.51 (m, 2H), 4.00 (s, 3H). DMSO >98 J2
    342
    Figure US20170217923A1-20170803-C00580
    Figure US20170217923A1-20170803-C00581
    Figure US20170217923A1-20170803-C00582
         		1H NMR (400 MHz, DMSO) δ 10.08 (s, 1H), 9.34-9.27 (m, 1H), 8.60 (dd, J = 4.7, 1.7 Hz, 1H), 8.51-8.44 (m, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.58 (dd, J = 9.1, 2.7 Hz, 1H), 7.56-7.51 (m, 1H), 7.51- 7.47 (m, 2H), 7.45 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 3.98 (s, 3H). DMSO >98 J2
    343
    Figure US20170217923A1-20170803-C00583
    Figure US20170217923A1-20170803-C00584
    Figure US20170217923A1-20170803-C00585
         		1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.93 (s, 1H), 9.26 (d, J = 1.4 Hz, 1H), 8.59 (dd, J = 4.8, 1.7 Hz, 1H), 8.50-8.43 (m, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.98 (d, J = 9.5 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 9.1, 2.7 Hz, 1H), 7.49-7.42 (m, 1H), 7.36 (d, J = 8.3 Hz, 1H), 6.55 (dd, J = 9.5, 1.7 Hz, 1H), 3.98 (s, 3H), 2.33 (s, 3H). DMSO >98 J2
    344
    Figure US20170217923A1-20170803-C00586
    Figure US20170217923A1-20170803-C00587
    Figure US20170217923A1-20170803-C00588
         		HCl 1H NMR (400 MHz, DMSO) δ 9.34- 9.28 (m, 1H), 8.81-8.75 (m, 1H), 8.74-8.65 (m, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.80-7.72 (m, 2H), 7.69 (d, J = 2.8 Hz, 1H), 7.59 (dd, J = 8.8, 2.7 Hz, 1H), 4.00 (s, 3H). DMSO >98 G8 using DMF instead of THF
    345
    Figure US20170217923A1-20170803-C00589
    Figure US20170217923A1-20170803-C00590
    Figure US20170217923A1-20170803-C00591
         		HCl 1H NMR (400 MHz, DMSO) δ 9.35- 9.29 (m, 1H), 8.87-8.78 (m, 2H), 8.19 (d, J = 9.4 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.86 (dd, J = 8.0, 5.3 Hz, 1H), 7.77 (dd, J = 9.1, 2.9 Hz, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 8.5, 2.3 Hz, 1H), 6.56 (d, J = 9.6 Hz, 1H), 4.02 (s, 3H). DMSO >98 G12 at room temper- ature
    346
    Figure US20170217923A1-20170803-C00592
    Figure US20170217923A1-20170803-C00593
    Figure US20170217923A1-20170803-C00594
         		HCl 1H NMR (400 MHz, DMSO) δ 11.98 (s, 1H), 9.29 (d, J = 1.7 Hz, 1H), 8.88- 8.78 (m, 2H), 8.08 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 9.6 Hz, 1H), 7.88 (dd, J = 8.1, 5.4 Hz, 1H), 7.81 (d, J = 2.6 Hz, 1H), 7.78-7.72 (m, 2H), 7.67 (dd, J = 8.9, 2.6 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 6.60 (d, J = 9.5 Hz, 1H), 4.02 (s, 3H). DMSO >98 G12 at room temper- ature
    347
    Figure US20170217923A1-20170803-C00595
    Figure US20170217923A1-20170803-C00596
    Figure US20170217923A1-20170803-C00597
         		HCl 1H NMR (400 MHz, DMSO) δ 9.33- 9.28 (m, 1H), 8.87-8.67 (m, 2H), 8.06 (d, J = 9.1 Hz, 1H), 7.91-7.79 (m, 1H), 7.75 (dd, J = 9.1, 2.9 Hz, 1H), 7.71 (d, J = 2.8 Hz, 1H), 7.67- 7.61 (m, 2H), 7.58-7.51 (m, 2H), 4.01 (s, 3H). DMSO >98 G12 at room temper- ature
    348
    Figure US20170217923A1-20170803-C00598
    Figure US20170217923A1-20170803-C00599
    Figure US20170217923A1-20170803-C00600
         		HCl 1H NMR (400 MHz, DMSO) δ 9.28 (d, J = 2.0 Hz, 1H), 8.85-8.67 (m, 2H), 8.06 (d, J = 9.0 Hz, 1H), 7.88-7.77 (m, 1H), 7.77-7.69 (m, 2H), 7.62- 7.54 (m, 2H), 7.51-7.45 (m, 2H), 7.44-7.37 (m, 1H), 4.02 (d, J = 3.9 Hz, 3H). DMSO >98 G12 at room temper- ature
    349
    Figure US20170217923A1-20170803-C00601
    Figure US20170217923A1-20170803-C00602
    Figure US20170217923A1-20170803-C00603
         		HCl 1H NMR (400 MHz, DMSO) δ 9.23 (dd, J = 2.1, 0.7 Hz, 1H), 8.80 (dd, J = 5.2, 1.6 Hz, 1H), 8.72-8.64 (m, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.84-7.71 (m, 4H), 7.66 (dd, J = 8.1, 1.6 Hz, 1H), 7.61-7.54 (m, 1H), 7.52-7.45 (m, 1H), 4.02 (s, 3H). DMSO >98 G12 at room temper- ature
    350
    Figure US20170217923A1-20170803-C00604
    Figure US20170217923A1-20170803-C00605
    Figure US20170217923A1-20170803-C00606
         		HCl 1H NMR (400 MHz, DMSO) δ 9.22 (d, J = 1.7 Hz, 1H), 8.87-8.79 (m, 1H), 8.77-8.67 (m, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.92-7.79 (m, 1H), 7.74 (dd, J = 9.1, 2.9 Hz, 1H), 7.70 (d, J = 2.8 Hz, 1H), 7.45-7.37 (m, 2H), 7.33- 7.27 (m, 1H), 7.17-7.09 (m, 1H), 4.01 (s, 3H), 3.71 (s, 3H). DMSO >98 G12 at room temper- ature
    351
    Figure US20170217923A1-20170803-C00607
    Figure US20170217923A1-20170803-C00608
    Figure US20170217923A1-20170803-C00609
         		2 HCl 1H NMR (400 MHz, DMSO) δ 12.03 (s, 1H), 10.69 (s, 1H), 9.65 (d, J = 1.8 Hz, 1H), 9.26-9.21 (m, 1H), 9.20- 9.12 (m, 1H), 8.99-8.88 (m, 2H), 8.52 (d, J = 2.6 Hz, 1H), 8.49-8.42 (m, 1H), 8.25-8.17 (m, 1H), 8.15- 8.08 (m, 2H), 8.02-7.96 (m, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 8.5, 1.9 Hz, 1H), 6.47 (d, J = 9.6 Hz, 1H), 4.04 (s, 3H). DMSO >98 G1
    352
    Figure US20170217923A1-20170803-C00610
    Figure US20170217923A1-20170803-C00611
    Figure US20170217923A1-20170803-C00612
         		2 HCl 1H NMR (400 MHz, DMSO) δ 12.04 (s, 1H), 10.92 (s, 1H), 9.65 (d, J = 1.7 Hz, 1H), 9.58-9.50 (m, 1H), 9.46- 9.39 (m, 1H), 9.27-9.18 (m, 1H), 9.01-8.92 (m, 2H), 8.88 (dd, J = 5.3, 1.2 Hz, 1H), 8.48 (dd, J = 8.8, 1.9 Hz, 1H), 8.20-8.10 (m, 2H), 8.09-8.01 (m, 2H), 7.93 (d, J = 9.5 Hz, 1H), 7.81- 7.72 (m, 2H), 6.47 (d, J = 9.5 Hz, 1H). DMSO >98 G1
    353
    Figure US20170217923A1-20170803-C00613
    Figure US20170217923A1-20170803-C00614
    Figure US20170217923A1-20170803-C00615
         		HCl 1H NMR (300 MHz, DMSO) δ 10.90 (s, 1H), 9.63 (s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.76 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.78- 7.65 (m, 2H), 7.63-7.49 (m, 2H), 7.47-7.33 (m, 2H), 3.98 (s, 3H). DMSO >98 G1
    354
    Figure US20170217923A1-20170803-C00616
    Figure US20170217923A1-20170803-C00617
    Figure US20170217923A1-20170803-C00618
         		HCl 1H NMR (300 MHz, DMSO) δ 11.44 (s, 1H), 9.58 (d, J = 1.8 Hz, 1H), 9.16 (d, J = 8.2 Hz, 1H), 8.96 (dd, J = 5.3, 1.3 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.99 (dd, J = 8.0, 5.4 Hz, 1H), 7.72-7.49 (m, 2H), 7.44-7.27 (m, 3H), 7.12 (s, 1H), 3.99 (s, 3H), 2.52 (s, 3H). DMSO >98 G1
    355
    Figure US20170217923A1-20170803-C00619
    Figure US20170217923A1-20170803-C00620
    Figure US20170217923A1-20170803-C00621
         		HCl 1H NMR (300 MHz, DMSO) δ 11.38 (s, 1H), 9.53 (s, 1H), 9.18 (d, J = 8.1 Hz, 1H), 8.97 (d, J = 5.3 Hz, 1H), 8.21 (s, 1H), 8.14-8.02 (m, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 9.1 Hz, 1H), 6.90 (s, 1H), 3.99 (s, 3H). DMSO >98 G1
    356
    Figure US20170217923A1-20170803-C00622
    Figure US20170217923A1-20170803-C00623
    Figure US20170217923A1-20170803-C00624
         		HCl 1H NMR (300 MHz, DMSO) δ 11.30 (s, 1H), 9.59 (d, J = 1.8 Hz, 1H), 9.19 (d, J = 8.2 Hz, 1H), 8.97 (dd, J = 5.3, 1.2 Hz, 1H), 8.24 (d, J = 2.5 Hz, 1H), 8.11-7.93 (m, 2H), 7.76-7.54 (m, 4H), 7.40 (t, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.21 (d, J = 7.4 Hz, 1H), 3.98 (s, 3H), 2.41 (s, 3H). DMSO >98 G1
    357
    Figure US20170217923A1-20170803-C00625
    Figure US20170217923A1-20170803-C00626
    Figure US20170217923A1-20170803-C00627
         		HCl 1H NMR (300 MHz, DMSO) δ 11.21 (s, 1H), 9.59 (d, J = 1.7 Hz, 1H), 9.22 (d, J = 8.1 Hz, 1H), 9.02-8.95 (m, 1H), 8.23 (d, J = 2.5 Hz, 1H), 8.13- 7.96 (m, 3H), 7.85 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.60 (dd, J = 9.1, 2.6 Hz, 1H), 7.31 (s, 1H), 3.98 (s, 3H). DMSO >98 G1
    358
    Figure US20170217923A1-20170803-C00628
    Figure US20170217923A1-20170803-C00629
    Figure US20170217923A1-20170803-C00630
         		HCl 1H NMR (300 MHz, DMSO) δ 10.87 (s, 1H), 9.65-9.55 (m, 1H), 8.93 (dt, J = 8.0, 1.8 Hz, 1H), 8.81 (dd, J = 5.0, 1.6 Hz, 1H), 8.18 (d, J = 2.6 Hz, 1H), 7.94-7.82 (m, 4H), 7.78 (dd, J = 8.0, 5.0 Hz, 1H), 7.60-7.46 (m, 4H), 7.44- 7.35 (m, 1H), 7.32 (s, 1H), 3.98 (s, 3H). DMSO >98 G1
    359
    Figure US20170217923A1-20170803-C00631
    Figure US20170217923A1-20170803-C00632
    Figure US20170217923A1-20170803-C00633
         		HCl H NMR (300 MHz, DMSO) δ 11.29 (s, 1H), 9.59 (s, 1H), 9.20 (d, J = 8.1 Hz, 1H), 9.01-8.94 (m, 1H), 8.25 (s, 1H), 8.12-7.98 (m, 2H), 7.90-7.75 (m, 2H), 7.62 (d, J = 9.1 Hz, 1H), 7.21 (s, 1H), 7.08 (d, J = 8.6 Hz, 2H), 3.99 (s, 3H), 3.84 (s, 3H). DMSO >98 G1
    360
    Figure US20170217923A1-20170803-C00634
    Figure US20170217923A1-20170803-C00635
    Figure US20170217923A1-20170803-C00636
         		HCl 1H NMR (300 MHz, DMSO) δ 11.29 (s, 1H), 9.60 (s, 1H), 9.21 (d, J = 8.0 Hz, 1H), 8.99 (d, J = 5.3 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.11-7.99 (m, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.62 (dd, J = 9.1, 2.4 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.26 (s, 1H), 3.99 (s, 3H), 2.37 (s, 3H). DMSO >98 G1
    361
    Figure US20170217923A1-20170803-C00637
    Figure US20170217923A1-20170803-C00638
    Figure US20170217923A1-20170803-C00639
         		HCl 1H NMR (300 MHz, DMSO) δ 11.00 (s, 1H), 9.55 (d, J = 1.7 Hz, 1H), 8.96 (dt, J = 8.1, 1.7 Hz, 1H), 8.86 (dd, J = 5.1, 1.5 Hz, 1H), 8.19 (d, J = 2.6 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.83 (dt, J = 9.5, 4.8 Hz, 1H), 7.55 (dd, J = 9.1, 2.6 Hz, 1H), 6.72 (s, 1H), 3.95 (d, J = 7.0 Hz, 3H), 2.35 (d, J = 3.5 Hz, 3H). DMSO >98 G1
    362
    Figure US20170217923A1-20170803-C00640
    Figure US20170217923A1-20170803-C00641
    Figure US20170217923A1-20170803-C00642
         		HCl H NMR (300 MHz, DMSO) δ 11.21 (s, 1H), 9.58 (d, J = 1.5 Hz, 1H), 9.21- 9.06 (m, 1H), 8.95 (d, J = 4.3 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.09-7.92 (m, 2H), 7.70-7.51 (m, 3H), 7.24- 7.17 (m, 1H), 7.13 (s, 1H), 3.99 (s, 3H). DMSO >98 G1
    363
    Figure US20170217923A1-20170803-C00643
    Figure US20170217923A1-20170803-C00644
    Figure US20170217923A1-20170803-C00645
         		HCl 1H NMR (300 MHz, DMSO) δ 11.07 (s, 1H), 9.60 (s, 1H), 9.13 (d, J = 6.5 Hz, 1H), 8.93 (d, J = 5.1 Hz, 1H), 8.23 (s, 1H), 8.05-7.85 (m, 4H), 7.67- 7.54 (m, 1H), 7.43-7.23 (m, 3H), 3.99 (s, 3H). DMSO >98 G1
    364
    Figure US20170217923A1-20170803-C00646
    Figure US20170217923A1-20170803-C00647
    Figure US20170217923A1-20170803-C00648
         		2 HCl 1H NMR (300 MHz, DMSO) δ 11.16 (s, 1H), 9.57 (d, J = 1.5 Hz, 1H), 9.14 (d, J = 8.1 Hz, 1H), 8.93 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.03- 7.89 (m, 4H), 7.61 -7.54 (m, 2H), 7.32 (s, 1H), 3.97 (s, 3H). DMSO >98 G1
    365
    Figure US20170217923A1-20170803-C00649
    Figure US20170217923A1-20170803-C00650
    Figure US20170217923A1-20170803-C00651
         		2 HCl 1H NMR (300 MHz, DMSO) δ 11.29 (s, 1H), 9.58 (d, J = 1.6 Hz, 1H), 9.27 (d, J = 8.2 Hz, 1H), 9.06-8.99 (m, 1H), 8.18 (d, J = 2.5 Hz, 1H), 8.10 (dd, J = 8.1, 5.5 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.91 (dd, J = 10.7, 1.8 Hz, 1H), 7.80-7.65 (m, 2H), 7.57 (dd, J = 9.1, 2.6 Hz, 1H), 7.29 (s, 1H), 3.96 (s, 3H). DMSO >98 G1
    366
    Figure US20170217923A1-20170803-C00652
    Figure US20170217923A1-20170803-C00653
    Figure US20170217923A1-20170803-C00654
         		2 HCl 1H NMR (300 MHz, DMSO) δ 11.17 (s, 1H), 9.60 (s, 1H), 9.24 (d, J = 8.2 Hz, 1H), 8.98 (d, J = 5.1 Hz, 1H), 8.22 (d, J = 2.5 Hz, 1H), 8.11 -8.04 (m, 1H), 8.02-7.91 (m, 2H), 7.82-7.68 (m, 2H), 7.62 (dd, J = 9.1, 2.5 Hz, 1H), 7.36 (s, 1H), 4.01 (d, J = 11.0 Hz, 3H). DMSO >98 G1
    367
    Figure US20170217923A1-20170803-C00655
    Figure US20170217923A1-20170803-C00656
    Figure US20170217923A1-20170803-C00657
         		2 HCl 1H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 9.58 (d, J = 1.8 Hz, 1H), 9.20 (d, J = 8.2 Hz, 1H), 8.98 (dd, J = 5.3, 1.3 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 8.04-7.95 (m, 1H), 7.80-7.68 (m, 2H), 7.63- 7.57 (m, 1H), 7.56-7.48 (m, 1H), 7.31 (s, 1H), 3.99 (d, J = 6.7 Hz, 3H). DMSO >98 G1
    368
    Figure US20170217923A1-20170803-C00658
    Figure US20170217923A1-20170803-C00659
    Figure US20170217923A1-20170803-C00660
         		2 HCl 1H NMR (300 MHz, DMSO) δ 11.24 (s, 1H), 9.59 (d, J = 1.7 Hz, 1H), 9.26 (d, J = 8.3 Hz, 1H), 9.00 (d, J = 4.2 Hz, 1H), 8.23 (d, J = 2.6 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 8.1, 5.4 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.91 (dd, J = 8.4, 2.1 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 9.1, 2.5 Hz, 1H), 7.37 (s, 1H), 3.98 (s, 3H). DMSO >98 G1
    369
    Figure US20170217923A1-20170803-C00661
    Figure US20170217923A1-20170803-C00662
    Figure US20170217923A1-20170803-C00663
         		HCl 1H NMR (300 MHz, DMSO) δ 11.33 (s, 1H), 9.62 (s, 1H), 9.27 (d, J = 8.4 Hz, 1H), 9.01 (d, J = 5.2 Hz, 1H), 8.29- 8.19 (m, 3H), 8.13-8.01 (m, 2H), 7.79-7.73 (m, 2H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H), 7.42 (s, 1H), 3.99 (s, 3H). DMSO >98 G1
    370
    Figure US20170217923A1-20170803-C00664
    Figure US20170217923A1-20170803-C00665
    Figure US20170217923A1-20170803-C00666
         		HCl 1H NMR (300 MHz, DMSO) δ 11.31 (s, 1H), 9.55 (d, J = 1.7 Hz, 1H), 9.07 (d, J = 7.9 Hz, 1H), 8.92 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.98-7.68 (m, 5H), 7.63 (dd, J = 9.2, 2.5 Hz, 1H), 7.13 (s, 1H), 4.00 (s, 3H). DMSO >98 G1
    371
    Figure US20170217923A1-20170803-C00667
    Figure US20170217923A1-20170803-C00668
    Figure US20170217923A1-20170803-C00669
         		2 HCl 1H NMR (300 MHz, CDCl3) δ 11.29 (s, 1H), 9.57 (d, J = 1.8 Hz, 1H), 9.07 (d, J = 8.1 Hz, 1H), 8.93 (dd, J = 5.2, 1.3 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.07-7.97 (m, 2H), 7.92 (dd, J = 8.0, 5.3 Hz, 1H), 7.67-7.51 (m, 4H), 7.28 (s, 1H), 3.99 (s, 3H). DMSO >98 G1
    372
    Figure US20170217923A1-20170803-C00670
    Figure US20170217923A1-20170803-C00671
    Figure US20170217923A1-20170803-C00672
         		2 HCl 1H NMR (300 MHz, DMSO) δ 11.32 (s, 1H), 9.60 (d, J = 1.7 Hz, 1H), 9.27 (d, J = 8.1 Hz, 1H), 9.03 (d, J = 5.4 Hz, 1H), 8.22 (d, J = 2.5 Hz, 1H), 8.12 (dd, J = 8.1, 5.7 Hz, 1H), 8.03 (d, J = 8.8 Hz, 3H), 7.59 (dd, J = 9.1, 2.5 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.32 (s, 1H), 3.98 (d, J = 6.7 Hz, 3H). DMSO >98 G1
    373
    Figure US20170217923A1-20170803-C00673
    Figure US20170217923A1-20170803-C00674
    Figure US20170217923A1-20170803-C00675
         		2 HCl 1H NMR (300 MHz, DMSO) δ 11.38 (s, 1H), 9.61 (d, J = 1.6 Hz, 1H), 9.26 (d, J = 8.2 Hz, 1H), 9.02 (d, J = 5.3 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.12- 8.01 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.71-7.56 (m, 2H), 7.45-7.33 (m, 2H), 4.10-3.90 (m, 3H). DMSO >98 G1
    374
    Figure US20170217923A1-20170803-C00676
    Figure US20170217923A1-20170803-C00677
    Figure US20170217923A1-20170803-C00678
         		2 HCl 1H NMR (300 MHz, DMSO) δ 11.29 (s, 1H), 9.56 (s, 1H), 9.12 (d, J = 7.7 Hz, 1H), 8.94 (d, J = 4.9 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 8.07-7.90 (m, 2H), 7.71-7.57 (m, 2H), 7.51 (s, 1H), 7.47-7.37 (m, 1H), 7.17 (s, 1H), 3.99 (s, 3H), 2.53 (s, 3H). DMSO >98 G1
    375
    Figure US20170217923A1-20170803-C00679
    Figure US20170217923A1-20170803-C00680
    Figure US20170217923A1-20170803-C00681
         		2 HCl 1H NMR (300 MHz, DMSO) δ 13.13- 11.88 (m, 1H), 9.66 (d, J = 1.4 Hz, 1H), 9.36 (d, J = 8.2 Hz, 1H), 9.00 (d, J = 5.4 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.14 (dd, J = 8.1, 5.6 Hz, 1H), 8.01 (d, J = 7.5 Hz, 2H), 7.89 (d, J = 9.1 Hz, 1H), 7.78 (s, 1H), 7.64-7.35 (m, 9H), 5.23 (s, 2H). DMSO >98 J NaOtBu, Pd(OAc)2, Tri-t- butylphos- phonium tetrafluoro- borate, Toluene
    376
    Figure US20170217923A1-20170803-C00682
    Figure US20170217923A1-20170803-C00683
    Figure US20170217923A1-20170803-C00684
         		2 HCl 1H NMR (300 MHz, DMSO) δ 12.49 (s, 1H), 9.63 (s, 1H), 9.27 (d, J = 8.1 Hz, 1H), 8.96 (d, J = 5.4 Hz, 1H), 8.34 (s, 1H), 8.07 (dd, J = 8.1, 5.6 Hz, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 9.1 Hz, 1H), 7.80 (s, 1H), 7.64-7.35 (m, 9H), 5.21 (s, 2H). DMSO >98 J NaOtBu, Pd(OAc)2, Tri-t- butylphos- phonium tetrafluoro- borate, Toluene
    377
    Figure US20170217923A1-20170803-C00685
    Figure US20170217923A1-20170803-C00686
    Figure US20170217923A1-20170803-C00687
         		2 HCl 1H NMR (300 MHz, DMSO) 6 9.56 (d, J = 1.8 Hz, 1H), 9.30-9.21 (m, 1H), 9.01 (dd, J = 5.5, 1.2 Hz, 1H), 8.18- 8.03 (m, 2H), 7.76-7.64 (m, 2H), 7.55-7.45 (m, 2H), 7.33 (dd, J = 8.6, 2.3 Hz, 1H), 4.69 (t, J = 7.9 Hz, 2H), 3.92 (s, 3H), 3.26 (t, J = 7.8 Hz, 2H). DMSO >98 G8
    378
    Figure US20170217923A1-20170803-C00688
    Figure US20170217923A1-20170803-C00689
    Figure US20170217923A1-20170803-C00690
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.54 (d, J = 1.9 Hz, 1H), 8.70-8.65 (m, 2H), 7.95 (d, J = 9.2 Hz, 1H), 7.66-7.50 (m, 2H), 7.45-7.36 (m, 2H), 7.27 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 4.61 (t, J = 8.1 Hz, 2H), 3.87 (s, 3H), 3.38-3.17 (m, 5H). DMSO >98 G8 at 50° C.
    379
    Figure US20170217923A1-20170803-C00691
    Figure US20170217923A1-20170803-C00692
    Figure US20170217923A1-20170803-C00693
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.54 (d, J = 1.9 Hz, 1H), 9.28-9.18 (m, 1H), 8.99 (dd, J = 5.5, 1.3 Hz, 1H), 8.18- 8.02 (m, 2H), 7.69 (dd, J = 9.2, 2.7 Hz, 1H), 7.58-7.46 (m, 2H), 7.39 (dd, J = 8.2, 5.9 Hz, 1H), 6.96-6.85 (m, 1H), 4.71 (t, J = 8.0 Hz, 2H), 3.92 (s, 3H), 3.22 (t, J = 7.8 Hz, 2H). DMSO >98 G8 at 50° C.
    380
    Figure US20170217923A1-20170803-C00694
    Figure US20170217923A1-20170803-C00695
    Figure US20170217923A1-20170803-C00696
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.55 (d, J = 1.8 Hz, 1H), 9.11 (d, J = 8.1 Hz, 1H), 8.93 (dd, J = 5.3, 1.4 Hz, 1H), 8.10-7.93 (m, 2H), 7.76 (dd, J = 8.7, 4.7 Hz, 1H), 7.67 (dd, J = 9.2, 2.6 Hz, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.28 (dd, J = 8.4, 2.6 Hz, 1H), 7.12 (td, J = 9.0, 2.7 Hz, 1H), 4.70 (t, J = 7.9 Hz, 2H), 3.92 (s, 3H), 3.26 (t, J = 7.5 Hz, 2H). DMSO >98 G8 at 50° C.
    381
    Figure US20170217923A1-20170803-C00697
    Figure US20170217923A1-20170803-C00698
    Figure US20170217923A1-20170803-C00699
         		HCl 1H NMR (300 MHz, DMSO) δ 9.66 (d, J = 2.0 Hz, 1H), 9.15-9.06 (m, 1H), 8.91 (dd, J = 5.2, 1.5 Hz, 1H), 8.27- 8.17 (m, 2H), 8.01 (d, J = 8.9 Hz, 1H), 7.94 (dd, J = 8.2, 5.2 Hz, 1H), 7.88- 7.78 (m, 2H), 7.42 (d, J = 2.7 Hz, 1H), 7.35 (dd, J = 8.8, 2.2 Hz, 1H), 6.96 (d, J = 3.5 Hz, 1H), 3.91 (s, 3H). DMSO >98 G8 at 50° C.
    382
    Figure US20170217923A1-20170803-C00700
    Figure US20170217923A1-20170803-C00701
    Figure US20170217923A1-20170803-C00702
         		HCl 1H NMR (300 MHz, DMSO) δ 9.56 (d, J = 1.6 Hz, 1H), 9.26 (d, J = 8.2 Hz, 1H), 9.05-8.98 (m, 1H), 8.20-8.02 (m, 2H), 7.69 (dd, J = 9.2, 2.7 Hz, 1H), 7.53-7.40 (m, 2H), 7.32 (dd, J = 14.0, 8.0 Hz, 1H), 6.92 (t, J = 8.5 Hz, 1H), 4.71 (t, J = 7.9 Hz, 2H), 3.91 (s, 3H), 3.28 (t, J = 7.8 Hz, 2H). DMSO >98 G8 at 50° C.
    383
    Figure US20170217923A1-20170803-C00703
    Figure US20170217923A1-20170803-C00704
    Figure US20170217923A1-20170803-C00705
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.66 (d, J = 1.5 Hz, 1H), 9.23-9.09 (m, 1H), 8.93 (dd, J = 5.3, 1.5 Hz, 1H), 8.31- 8.16 (m, 2H), 8.08-7.93 (m, 2H), 7.82 (dd, J = 9.2, 2.8 Hz, 1H), 7.56 (dd, J = 9.4, 2.5 Hz, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.19 (td, J = 9.2, 2.7 Hz, 1H), 7.02-6.89 (m, 1H), 3.91 (s, 3H). DMSO >98 G8 at 50° C.
    384
    Figure US20170217923A1-20170803-C00706
    Figure US20170217923A1-20170803-C00707
    Figure US20170217923A1-20170803-C00708
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.66 (d, J = 1.6 Hz, 1H), 9.23-9.09 (m, 1H), 8.94 (dd, J = 5.3, 1.5 Hz, 1H), 8.26- 8.14 (m, 2H), 8.00 (dd, J = 8.1, 5.3 Hz, 1H), 7.90-7.73 (m, 3H), 7.45 (d, J = 2.7 Hz, 1H), 7.25-7.10 (m, 1H), 6.98 (d, J = 3.5 Hz, 1H), 3.92 (s, 3H). DMSO >98 G8 at 50° C.
    385
    Figure US20170217923A1-20170803-C00709
    Figure US20170217923A1-20170803-C00710
    Figure US20170217923A1-20170803-C00711
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.54 (d, J = 1.8 Hz, 1H), 9.21 (dt, J = 8.2, 1.6 Hz, 1H), 8.98 (dd, J = 5.5, 1.3 Hz, 1H), 8.20-8.00 (m, 2H), 7.68 (dd, J = 9.2, 2.7 Hz, 1H), 7.55-7.31 (m, 3H), 7.00-6.78 (m, 1H), 4.69 (t, J = 7.9 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.22 (t, J = 7.9 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H). DMSO >98 G8 at 50° C.
    386
    Figure US20170217923A1-20170803-C00712
    Figure US20170217923A1-20170803-C00713
    Figure US20170217923A1-20170803-C00714
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.42 (d, J = 1.5 Hz, 1H), 9.06 (d, J = 8.1 Hz, 1H), 8.93 (d, J = 5.4 Hz, 1H), 8.09- 7.99 (m, 2H), 7.68 (dd, J = 9.1, 2.7 Hz, 1H), 7.53 (d, J = 2.6 Hz, 1H), 7.30- 7.16 (m, 3H), 4.66 (t, J = 7.9 Hz, 2H), 3.98 (s, 3H), 3.29 (t, J = 7.7 Hz, 2H). DMSO >98 G8 at 50° C.
    387
    Figure US20170217923A1-20170803-C00715
    Figure US20170217923A1-20170803-C00716
    Figure US20170217923A1-20170803-C00717
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.37 (d, J = 1.4 Hz, 1H), 9.11 (d, J = 8.2 Hz, 1H), 8.99 (d, J = 4.9 Hz, 1H), 8.14 (dd, J = 8.2, 5.6 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.70 (dd, J = 9.2, 2.6 Hz, 1H), 7.51 (d, J = 2.7 Hz, 1H), 7.45- 7.36 (m, 2H), 7.26-7.15 (m, 1H), 4.83 (d, J = 9.5 Hz, 1H), 4.49-4.38 (m, 2H), 4.00 (s, 3H), 3.48-3.28 (m, 1H), 3.27-3.05 (m, 1H). DMSO >98 G8 at 50° C.
    388
    Figure US20170217923A1-20170803-C00718
    Figure US20170217923A1-20170803-C00719
    Figure US20170217923A1-20170803-C00720
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.56 (d, J = 1.9 Hz, 1H), 9.31-9.19 (m, 1H), 9.00 (dd, J = 5.5, 1.3 Hz, 1H), 8.21- 8.02 (m, 2H), 7.73-7.64 (m, 2H), 7.47 (dd, J = 5.4, 2.4 Hz, 2H), 7.32 (dd, J = 8.6, 2.3 Hz, 1H), 4.67 (t, J = 8.0 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H), 3.26 (t, J = 7.8 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H). DMSO >98 G8 at 50° C.
    389
    Figure US20170217923A1-20170803-C00721
    Figure US20170217923A1-20170803-C00722
    Figure US20170217923A1-20170803-C00723
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.54 (d, J = 1.8 Hz, 1H), 9.25 (dt, J = 8.2, 1.6 Hz, 1H), 9.04 (dd, J = 5.5, 1.1 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.16 (dd, J = 8.0, 5.6 Hz, 1H), 8.11-7.96 (m, 2H), 7.91 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.6, 2.3 Hz, 1H), 4.68 (t, J = 7.9 Hz, 2H), 3.25 (t, J = 7.8 Hz, 2H). DMSO >98 G8 at 50° C.
    390
    Figure US20170217923A1-20170803-C00724
    Figure US20170217923A1-20170803-C00725
    Figure US20170217923A1-20170803-C00726
         		HCl 1H NMR (400 MHz, DMSO) δ 9.37 (d, J = 1.4 Hz, 1H), 8.82 (dd, J = 5.1, 1.5 Hz, 1H), 8.76 (dd, J = 8.1 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.46 (dd, J = 8.8, 2.1 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.91 (dd, J = 6.3, 2.6 Hz, 1H), 7.80 (dd, J = 8.0, 5.1 Hz, 1H), 7.71- 7.59 (m, 2H), 7.52-7.38 (m, 3H), 7.10-7.01 (m, 1H), 3.89 (s, 3H). DMSO >98 G8 with DMF instead of THF
    391
    Figure US20170217923A1-20170803-C00727
    Figure US20170217923A1-20170803-C00728
    Figure US20170217923A1-20170803-C00729
         		HCl 1H NMR (400 MHz, DMSO) δ 9.38 (d, J = 1.4 Hz, 1H), 8.82 (d, J = 5.1 Hz, 1H), 8.76 (d, J = 7.9 Hz, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.46 (dd, J = 8.8, 2.2 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 2.7 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.84-7.76 (m, 1H), 7.64 (dd, J = 8.8, 2.7 Hz, 1H), 7.52-7.39 (m, 3H), 7.10-7.02 (m, 1H), 3.88 (s, 3H). DMSO >98 G8 with DMF instead of THF
    392
    Figure US20170217923A1-20170803-C00730
    Figure US20170217923A1-20170803-C00731
    Figure US20170217923A1-20170803-C00732
         		HCl 1H NMR (400 MHz, DMSO) δ 9.39 (t, J = 3.2 Hz, 1H), 8.93-8.82 (m, 2H), 8.62 (d, J = 1.8 Hz, 1H), 8.47 (dd, J = 8.8, 2.2 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.91 (dd, J = 8.1, 5.3 Hz, 1H), 7.84-7.77 (m, 1H), 7.73-7.63 (m, 1H), 7.53-7.40 (m, 4H), 7.09-7.03 (m, 1H), 3.87 (d, J = 6.5 Hz, 3H). DMSO >98 G8 with DMF instead of THF
    393
    Figure US20170217923A1-20170803-C00733
    Figure US20170217923A1-20170803-C00734
    Figure US20170217923A1-20170803-C00735
         		HCl 1H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 11.10 (s, 1H), 9.42 (d, J = 1.9 Hz, 1H), 8.90-8.69 (m, 2H), 8.62 (d, J = 1.7 Hz, 1H), 8.40 (dd, J = 8.8, 1.9 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.84-7.69 (m, 1H), 7.57-7.40 (m, 3H), 7.11-7.02 (m, 2H), 6.96 (d, J = 8.3 Hz, 1H), 3.89 (s, 3H). DMSO >98 G8 with DMF instead of THF
    394
    Figure US20170217923A1-20170803-C00736
    Figure US20170217923A1-20170803-C00737
    Figure US20170217923A1-20170803-C00738
         		HCl 1H NMR (400 MHz, DMSO) δ 9.43- 9.29 (m, 1H), 8.75-8.64 (m, 2H), 8.60-8.48 (m, 1H), 8.47-8.32 (m, 1H), 8.21-8.01 (m, 2H), 7.86-7.74 (m, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.59- 7.34 (m, 4H), 7.13-7.01 (m, 1H), 6.87 (d, J = 8.7 Hz, 1H), 3.90 (t, J = 5.3 Hz, 3H). DMSO >98 G8 with DMF instead of THF
    395
    Figure US20170217923A1-20170803-C00739
    Figure US20170217923A1-20170803-C00740
    Figure US20170217923A1-20170803-C00741
         		HCl 1H NMR (400 MHz, DMSO) δ 9.24 (dd, J = 2.2, 0.8 Hz, 1H), 8.76 (dd, J = 5.0, 1.7 Hz, 1H), 8.61-8.54 (m, 1H), 8.49 (dd, J = 1.8, 1.1 Hz, 1H), 8.21- 8.12 (m, 2H), 7.75 (dd, J = 8.0, 1.5 Hz, 1H), 7.70-7.62 (m, 2H), 7.62- 7.53 (m, 1H), 7.53-7.44 (m, 1H). DMSO >98 G8 with DMF instead of THF
    396
    Figure US20170217923A1-20170803-C00742
    Figure US20170217923A1-20170803-C00743
    Figure US20170217923A1-20170803-C00744
         		HCl 1H NMR (400 MHz, DMSO) δ 11.71 (s, 1H), 11.10 (s, 1H), 9.42 (d, J = 1.9 Hz, 1H), 8.90-8.69 (m, 2H), 8.62 (d, J = 1.7 Hz, 1H), 8.40 (dd, J = 8.8, 1.9 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.84-7.69 (m, 1H), 7.57-7.40 (m, 3H), 7.11-7.02 (m, 2H), 6.96 (d, J = 8.3 Hz, 1H), 3.89 (s, 3H). DMSO >98 G12
    397
    Figure US20170217923A1-20170803-C00745
    Figure US20170217923A1-20170803-C00746
    Figure US20170217923A1-20170803-C00747
         		HCl 1H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.99 (d, J = 8.2 Hz, 1H), 8.88 (dd, J = 5.3, 1.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.14-8.06 (m, 1H), 7.99-7.88 (m, 2H), 7.78-7.66 (m, 2H), 7.61-7.51 (m, 3H), 7.50-7.34 (m, 3H), 5.34 (s, 2H). DMSO >98 Method G1
    398
    Figure US20170217923A1-20170803-C00748
    Figure US20170217923A1-20170803-C00749
    Figure US20170217923A1-20170803-C00750
         		1H NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 9.52 (d, J = 1.4 Hz, 1H), 8.68 (dd, J = 9.9 Hz, 1H), 8.65 (d, J = 9.9 Hz, 1H), 8.16 (dd, J = 2.5, 5.4 Hz, 2H), 7.68-7.41 (m, 2H), 7.78-7.66 (m, 8H), 7.39-7.19 (m, 1H), 5.30 (s, 2H). DMSO >98 Method G1
    399
    Figure US20170217923A1-20170803-C00751
    Figure US20170217923A1-20170803-C00752
    Figure US20170217923A1-20170803-C00753
         		1H NMR (DMSO-d6) ppm 12.52 (s, 1H), 9.78 (d, J = 1.56 Hz, 1H), 8.91- 8.88 (m, 1H), 8.74 (dd, J = 4.74, 1.60 Hz, 1H), 8.33 (brs, 1H), 8.06 (d, J = 8.56 Hz, 2H), 7.93 (d, J = 9.08 hz, 1H), 7.89 (s, 1H), 7.66-7.59 (m, 2H), 7.55 (d, J = 8.56 Hz, 2H), 4.01 (s, 3H). DMSO >98 G13
    400
    Figure US20170217923A1-20170803-C00754
    Figure US20170217923A1-20170803-C00755
    Figure US20170217923A1-20170803-C00756
         		2 HCl 1H NMR (DMSO-d6) ppm 12.80- 12.40 (br, 1H), 9.77 (d, J = 1.84 Hz, 1H), 9.32 (d, J = 8.04 Hz, 1H), 8.97 (dd, J = 5.36, 1.40 Hz, 1H), 8.34 (d, J = 2.68 Hz, 1H), 8.09-8.06 (m, 3H), 7.97 (d, J = 9.12 Hz, 1H), 7.91 (s, 1H), 7.64 (dd, J = 9.12, 2.68 Hz, 1H), 7.55 (d, J = 8.60 Hz, 2H), 4.01 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13
    401
    Figure US20170217923A1-20170803-C00757
    Figure US20170217923A1-20170803-C00758
    Figure US20170217923A1-20170803-C00759
         		2 HCl 1H NMR (DMSO-d6) ppm 11.14 (brs, 1H), 9.58 (s, 1H), 9.13 (dd, J = 7.96 Hz, 1H), 8.93 (d, J = 5.24 Hz, 1H), 8.54 (d, J = 4.72 Hz, 1H), 8.48 (d, J = 8.32 Hz, 1H), 8.28 (brs, 1H), 8.09 (brt, J = 7.16 Hz, 1H), 8.02-7.96 (m, 2H), 7.65 (dd, J = 8.80, 2.48 Hz, 1H), 7.34 (brt, J = 6.52 Hz, 1H), 4.01 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 J2
    402
    Figure US20170217923A1-20170803-C00760
    Figure US20170217923A1-20170803-C00761
    Figure US20170217923A1-20170803-C00762
         		2 HCl 1H NMR (DMSO-d6) ppm 10.89 (s, 1H), 9.57 (d, J = 1.60 Hz, 1H), 9.04 (d, J = 8.04 Hz, 1H), 8.88 (dd, J = 5.16, 1.40 Hz, 1H), 8.55 (dd, J = 2.64, 0.52 Hz, 1H), 8.50 (d, J = 8.92 Hz, 1H), 8.22 (d, J = 2.68 Hz, 1H), 8.08 (d, J = 8.92, 2.68 Hz, 1H), 7.94-7.90 (m, 2H), 7.61 (dd, J = 9.08, 2.68 Hz, 1H), 3.99 (s, 3H). The 1H of 2HCl was not observed. DMSO DMSO J2
    403
    Figure US20170217923A1-20170803-C00763
    Figure US20170217923A1-20170803-C00764
    Figure US20170217923A1-20170803-C00765
         		2 HCl 1H NMR (DMSO-d6) ppm 10.53 (s, 1H), 9.38 (s, 1H), 8.99 (d, J = 8.08 Hz, 1H), 8.88 (d, J = 4.60 Hz, 1H), 8.11 (brs, 1H), 8.01-7.95 (m, 2H), 7.90 (d, J = 8.60 Hz, 2H), 7.66 (dd, J = 9.12, 2.68 Hz, 1H), 7.50 (d, J = 8.60 Hz, 2H), 6.93 (s, 1H), 4.00 (s, 3H), 3.80 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 J2
    404
    Figure US20170217923A1-20170803-C00766
    Figure US20170217923A1-20170803-C00767
    Figure US20170217923A1-20170803-C00768
         		HCl 1H NMR (DMSO-d6) ppm 11.81 (brs, 1H), 9.64 (s, 1H), 9.00 (d, J = 7.48 Hz, 1H), 8.85 (brs, 1H), 8.14 (d, J = 2.56 Hz, 1H), 8.00 (d, J = 8.60 Hz, 2H), 7.96 (d, J = 9.08 Hz, 1H), 7.86 (br, 1H), 7.66-7.63 (m, 3H), 7.25 (s, 1H), 4.00 (s, 3H). The 1H of HCl was not observed. DMSO >98 J2
    405
    Figure US20170217923A1-20170803-C00769
    Figure US20170217923A1-20170803-C00770
    Figure US20170217923A1-20170803-C00771
         		HCl 1H NMR (DMSO-d6) ppm 11.80 (brs, 1H), 9.65 (brs, 1H), 9.04 (d, J = 7.92 Hz, 1H), 8.88 (brs, 1H), 8.14 (d, J = 2.60 Hz, 1H), 8.05-8.02 (m, 2H), 7.96 (d, J = 9.12 Hz, 1H), 7.89 (m, 1H), 7.64 (dd, J = 9.12, 2.60 Hz, 1H), 7.42 (t, J = 8.84 Hz, 2H), 7.23 (s, 1H), 3.99 (s, 3H). The 1H of HCl was not observed. DMSO >98 J2
    406
    Figure US20170217923A1-20170803-C00772
    Figure US20170217923A1-20170803-C00773
    Figure US20170217923A1-20170803-C00774
         		HCl 1H NMR (DMSO-d6) ppm 10.31 (s, 1H), 9.37 (s, 1H), 8.88 (m, 2H), 8.04 (d, J = 2.60 Hz, 1H), 7.94 (d, J = 9.12 Hz, 1H), 7.91 (m, 1H), 7.64 (dd, J = 9.12, 2.68 Hz, 1H), 7.56 (d, J = 1.88 Hz, 1H), 6.40 (d, J = 1.88 Hz, 1H), 3.98 (s, 3H), 3.74 (s, 3H). The 1H of HCl was not observed. DMSO >98 J2
    407
    Figure US20170217923A1-20170803-C00775
    Figure US20170217923A1-20170803-C00776
    Figure US20170217923A1-20170803-C00777
         		2 HCl 1H NMR (DMSO-d6) ppm 12.89 (brs, 1H), 9.56 (s, 1H), 8.92 (d, J = 4.92 Hz, 2H), 8.04 (d, J = 8.84 Hz, 1H), 7.98 (d, J = 2.88 Hz, 1H), 7.84 (br, 1H), 7.71-7.66 (m, 3H), 7.45-7.39 (m, 2H), 4.00 (s, 3H), 3.94 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 J2
    408
    Figure US20170217923A1-20170803-C00778
    Figure US20170217923A1-20170803-C00779
    Figure US20170217923A1-20170803-C00780
         		HCl 1H NMR (DMSO-d6) ppm 10.39 (s, 1H), 9.38 (s, 1H), 8.90 (d, J = 8.00 Hz, 1H), 8.84 (d, J = 4.76 hz, 1H), 8.06 (d, J = 2.68 Hz, 1H), 7.95 (d, J = 9.16 Hz, 1H), 7.90-7.88 (m, 3H), 7.65 (dd, J = 9.16, 2.68 Hz, 1H), 7.44 (brt, J = 7.40 Hz, 2H), 7.35-7.31 (m, 1H), 6.88 (s, 1H), 3.99 (s, 3H), 3.80 (s, 3H). The 1H of HCl was not observed. DMSO >98 J2 Temper- ature at 100° C.
    409
    Figure US20170217923A1-20170803-C00781
    Figure US20170217923A1-20170803-C00782
    Figure US20170217923A1-20170803-C00783
         		HCl 1H NMR (DMSO-d6) ppm 10.44 (brs, 1H), 9.01 (s, 1H), 8.68 (brs, 1H), 8.39 (brs, 1H), 8.23 (s, 1H), 8.07 (brs, 1H), 7.84 (d, J = 9.04 Hz, 1H), 7.70-7.54 (m, 2H), 7.44 (brd, J = 7.32 Hz, 2H), 7.15 (brt, J = 7.56 Hz, 2H), 7.00 (brt, 7.40 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H). The 1H of HCl was not observed. DMSO >98 J2 Temper- ature at 100° C.
    410
    Figure US20170217923A1-20170803-C00784
    Figure US20170217923A1-20170803-C00785
    Figure US20170217923A1-20170803-C00786
         		HCl 1H NMR (DMSO-d6) ppm 11.13 (s, 1H), 9.59 (d, J = 1.64 Hz, 1H), 9.03 (brs, 1H), 8.88 (brs, 1H), 8.63 (d, J = 2.52 Hz, 1H), 8.23 (d, J = 2.32 Hz, 1H), 7.93-7.82 (brm, 4H), 7.61-7.53 (m, 3H), 7.35-7.31 (brm, 2H), 4.00 (s, 3H). The 1H of HCl was not observed. DMSO >98 J2 Temper- ature at 100° C.
    411
    Figure US20170217923A1-20170803-C00787
    Figure US20170217923A1-20170803-C00788
    Figure US20170217923A1-20170803-C00789
         		1H NMR (DMSO-d6) ppm 9.54 (s, 1H), 8.79 (s, 1H), 8.69 (d, J = 7.60 Hz, 1H), 7.89 (brd, J = 8.96 Hz, 2H), 7.68-7.58 (m, 4H), 7.38-7.30 (m, 2H), 3.98 (s, 3H). The 1H of NH— was not observed. DMSO >98 J2 Temper- ature at 100° C.
    412
    Figure US20170217923A1-20170803-C00790
    Figure US20170217923A1-20170803-C00791
    Figure US20170217923A1-20170803-C00792
         		HCl 1H NMR (DMSO-d6) ppm 9.70 (s, 1H), 9.05 (d, J = 7.88 Hz, 1H), 8.85 (brd, J = 4.44 Hz, 1H), 8.24 (brs, 1H), 8.04 (d, J = 8.44 Hz, 2H), 7.94 (d, J = 9.00 Hz, 1H), 7.84 (m, 1H), 7.66 (d, J = 8.44 Hz, 2H), 7.62 (dd, J = 9.00, 2.64 Hz, 1H), 3.99 (s, 3H). The 1H of HCl and NH— were not observed. DMSO >98 G12 Temper- ature at 100° C.
    413
    Figure US20170217923A1-20170803-C00793
    Figure US20170217923A1-20170803-C00794
    Figure US20170217923A1-20170803-C00795
         		1H NMR (CDCl3) ppm 15.18 (brs, 1H), 9.57 (d, J = 2.32 Hz, 1H), 8.86 (dd, J = 4.80, 1.56 Hz, 1H), 8.59-8.56 (m, 1H), 7.78-7.73 (m, 4H), 7.55-7.52 (m, 1H), 7.43 (d, J = 8.56 Hz, 2H), 7.38 (dd, J = 8.88, 2.96 Hz, 1H), 7.34 (s, 1H), 3.97 (s, 3H), 3.30 (s, 3H), 3.11 (s, 3H). CDCl3 >98 J2 Temper- ature at 100° C.
  • 1H Method Reten-
    Num- Starting Starting Salt NMR Purity of tion LCMS
    ber Material 1 Material 2 Product type 1H NMR Solvent percent Coupling LCMS Time Method
    414
    Figure US20170217923A1-20170803-C00796
    Figure US20170217923A1-20170803-C00797
    Figure US20170217923A1-20170803-C00798
         		2 HCl 1H NMR (DMSO-d6) ppm 9.72 (s, 1H), 9.16 (brs, 1H), 8.93 (d, J = 4.36 Hz, 1H), 8.14 (br, 1H), 7.96 (brm, 2H), 7.63 (dd, J = 9.08, 2.56 Hz, 1H), 7.00 (s, 1H), 3.98 (s, 3H), 2.37 (s, 3H). The 1H of 2HCl and NH— were not observed. DMSO >98 G12 Temper- ature at 100° C.
    415
    Figure US20170217923A1-20170803-C00799
    Figure US20170217923A1-20170803-C00800
    Figure US20170217923A1-20170803-C00801
         		2 HCl 1H NMR (DMSO-d6) ppm 12.60 (brs, 1H), 9.78 (s, 1H), 9.12 (d, J = 8.00 Hz, 1H), 8.86 (brs, 1H), 8.35 (brd, J = 2.60 Hz, 1H), 8.01 (d, J = 8.56 Hz, 2H), 7.96 (d, J = 9.08 Hz, 1H), 7.92 (s, 1H), 7.86 (m, 1H), 7.69 (d, J = 8.56 Hz, 2H), 7.63 (dd, J = 9.08, 2.60 Hz, 1H), 4.02 (s, 3H). The 1H of HCl was not observed. DMSO >98 G12 Temper- ature at 100° C.
    416
    Figure US20170217923A1-20170803-C00802
    Figure US20170217923A1-20170803-C00803
    Figure US20170217923A1-20170803-C00804
         		HCl 1H NMR (DMSO-d6) ppm 12.80-12.40 (br, 1H), 9.79 (d, J = 1.64 Hz, 1H), 9.16 (d, J = 7.88 Hz, 1H), 8.88 (d, J = 3.88 Hz, 1H), 8.36 (brd, J = 2.64 Hz, 1H), 8.06-8.04 (m, 2H), 7.96 (d, J = 9.08 Hz, 1H), 7.90 (m, 1H), 7.85 (s, 1H), 7.63 (dd, J = 9.08, 2.64 Hz, 1H), 7.49 (m, 2H), 7.38 (m, 1H), 4.02 (s, 3H). The 1H of HCl was not observed. DMSO >98 G12 Temper- ature at 100° C.
    417
    Figure US20170217923A1-20170803-C00805
    Figure US20170217923A1-20170803-C00806
    Figure US20170217923A1-20170803-C00807
         		HCl 1H NMR (DMSO-d6) ppm 12.80 (s, 1H), 9.74 (d, J = 1.60 Hz, 1H), 9.01 (brs, 1H), 8.83 (brs, 1H), 8.31 (d, J = 2.64 Hz, 1H), 8.15 (d, J = 1.00 Hz, 1H), 7.96 (d, J = 9.12 Hz, 1H), 7.78 (br, 1H), 7.64 (dd, J = 9.12, 2.64 Hz, 1H), 3.99 (s, 3H). The 1H of HCl was not observed. DMSO >98 G12 Temper- ature at 100° C.
    418
    Figure US20170217923A1-20170803-C00808
    Figure US20170217923A1-20170803-C00809
    Figure US20170217923A1-20170803-C00810
         		HCl 1H NMR (DMSO-d6) ppm 12.60 (br, 1H), 9.79 (d, J = 1.72 Hz, 1H), 9.19 (d, J = 8.00 Hz, 1H), 8.93 (dd, J = 5.16, 1.44 Hz, 1H), 8.23 (brs, 1H), 8.10 (s, 1H), 7.99 (m, 1H), 7.95 (d, J = 9.08 Hz, 1H), 7.77-7.75 (br, 2H), 7.62 (dd, J = 9.08, 2.72 Hz, 1H), 7.50 DMSO >98 G12 Temper- ature at 100° C.
    (m, 2H), 7.37 (m, 1H), 3.99
    (s, 3H). The 1H of HCl was
    not observed.
    419
    Figure US20170217923A1-20170803-C00811
    Figure US20170217923A1-20170803-C00812
    Figure US20170217923A1-20170803-C00813
         		HCl 1H NMR (DMSO-d6) ppm 12.56 (s, 1H), 9.78 (s, 1H), 9.09 (d, J = 8.20 Hz, 1H), 8.84 (d, J = 3.96 Hz, 1H), 8.35 (d, J = 2.60 Hz, 1H), 8.10-8.07 (m, 2H), 7.95 (d, J = 9.12 Hz, 1H), 7.83 (brt, J = 6.60 Hz, 2H), 7.63 (dd, J = 9.12, 2.60 Hz, 1H), 7.32 (m, 2H), 4.02 (s, 3H). The 1H of HCl was not observed. DMSO >98 G12 Temper- ature at 100° C.
    420
    Figure US20170217923A1-20170803-C00814
    Figure US20170217923A1-20170803-C00815
    Figure US20170217923A1-20170803-C00816
         		HCl 1H NMR (DMSO-d6) ppm 9.74 (s, 1H), 9.04 (d, J = 6.68 Hz, 1H), 8.86 (brs, 1H), 8.29 (brs, 1H), 8.05 (brs, J = 7.44 Hz, 2H), 7.97 (d, J = 9.08 Hz, 1H), 7.89 (br, 1H), 7.67-7.58 (m, 4H), 4.00 (s, 3H). The 1H of HCl and NH— were not observed. DMSO >98 G12 Temper- ature at 100° C.
    421
    Figure US20170217923A1-20170803-C00817
    Figure US20170217923A1-20170803-C00818
    Figure US20170217923A1-20170803-C00819
         		1H NMR (DMSO-d6) ppm 9.88 (s, 1H), 9.51 (dd, J = 2.16, 0.8 Hz, 1H), 8.68-8.64 (m, 2H), 7.98 (d, J = 2.40 Hz, 1H), 7.91 (d, J = 8.84 Hz, 2H), 7.86 (d, J = 9.12 Hz, 1H), 7.68 (d, J = 8.84 Hz, 2H), 7.58-7.53 (m, 2H), 3.98 (s, 3H). DMSO >98 G1
    422
    Figure US20170217923A1-20170803-C00820
    Figure US20170217923A1-20170803-C00821
    Figure US20170217923A1-20170803-C00822
         		HCl 1H NMR (DMSO-d6) ppm 10.24 (br, 1H), 9.54 (s, 1H), 8.92 (d, J = 7.52 Hz, 1H), 8.82 (d, J = 3.96 Hz, 1H), 8.10 (d, J = 2.44 Hz, 1H), 8.03 (d, J = 8.68 Hz, 2H), 7.92 (d, J = 9.08 Hz, 1H), 7.84 (d, J = 8.68 Hz, 2H), 7.81 (m, 1H), 7.77-7.75 (m, 2H), 7.62 (dd, J = 9.08, 2.44 Hz, 1H), 7.50 (m, 2H), 7.38 DMSO >98 J3 using Na2CO3 instead of K2CO3
    (m, 1H), 4.01 (s, 3H). The
    1H of HCl was not observed.
    423
    Figure US20170217923A1-20170803-C00823
    Figure US20170217923A1-20170803-C00824
    Figure US20170217923A1-20170803-C00825
         		HCl 1H NMR (DMSO-d6) ppm 9.72 (s, 1H), 9.09 (d, J = 8.00 Hz, 1H), 8.89 (d, J = 4.24 Hz, 1H), 8.26 (brs, 1H), 8.12-8.09 (m, 2H), 7.96 (d, J = 9.12 Hz, 1H), 7.91 (m, 1H), 7.64 (dd, J = 9.12, 2.64 Hz, 1H), 7.45 (t, J = 8.80 Hz, 2H), 3.99 (s, 3H). The 1H of HCl and NH— were not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3
    424
    Figure US20170217923A1-20170803-C00826
    Figure US20170217923A1-20170803-C00827
    Figure US20170217923A1-20170803-C00828
         		HCl 1H NMR (DMSO-d6) ppm 10.30-10.15 (br, 1H), 9.54 (s, 1H), 8.91 (brs, 1H), 8.82 (brs, 1H), 8.10 (brs, 1H), 8.04 (d, J = 8.56 Hz, 2H), 7.92 (d, J = 9.6 Hz, 1H), 7.85 (d, J = 8.56 Hz, 2H), 7.80 (m, 1H), 7.79 (d, J = 8.56 Hz, 2H), 7.65-7.59 (brm, 1H), 7.55 (d, J = 8.56 Hz, 2H), 4.01 (s, 3H). The 1H of HCl was not DMSO >98 J3
    observed.
    425
    Figure US20170217923A1-20170803-C00829
    Figure US20170217923A1-20170803-C00830
    Figure US20170217923A1-20170803-C00831
         		HCl 1H NMR (DMSO-d6) ppm 9.91 (s, 1H), 9.53 (d, J = 1.84 Hz, 1H), 8.69 (d, J = 5.56 Hz, 2H), 8.31 (t, J = 1.88 Hz, 1H), 7.99 (d, J = 2.68 Hz, 1H), 7.98-7.94 (m, 1H), 7.87 (d, J = 9.08 Hz, 1H), 7.60- 7.54 (m, 2H), 7.46 (t, J = 8.04 Hz, 1H), 7.39-7.35 (m, 1H), 3.99 (s, 3H). The 1H of HCl was not observed. DMSO >98 G1
    426
    Figure US20170217923A1-20170803-C00832
    Figure US20170217923A1-20170803-C00833
    Figure US20170217923A1-20170803-C00834
         		HCl 1H NMR (DMSO-d6) ppm 10.25 (br, 1H), 9.52 (s, 1H), 8.89 (brs, 1H), 8.88 (brs, 1H), 8.22 (brs, 1H), 8.11 (brs, 1H), 7.98-7.92 (brm, 2H), 7.80- 7.70 (brm, 3H), 7.63-7,.69 (brm, 2H), 7.55-7.50 (brm, 3H), 7.41 (m, 1H), 4.00 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3 at 120° C.
    427
    Figure US20170217923A1-20170803-C00835
    Figure US20170217923A1-20170803-C00836
    Figure US20170217923A1-20170803-C00837
         		HCl 1H NMR (DMSO-d6) ppm 10.31 (br, 1H), 9.51 (brs, 1H), 8.92 (brd, J = 7.44 Hz, 1H), 8.84 (brs, 1H), 8.22 (brs, 1H), 8.12 (brd, J = 2.28 Hz, 1H), 8.00-7.93 (brm, 2H), 7.83- 7.77 (brm, 3H), 7.64-7.54 (brm, 5H), 4.01 (s, 3H). The 1H of HCl was not observed. DMSO >98 J3 using Na2CO3 instead of K2CO3
    428
    Figure US20170217923A1-20170803-C00838
    Figure US20170217923A1-20170803-C00839
    Figure US20170217923A1-20170803-C00840
         		4 HCl 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.72 Hz, 1H), 9.06 (d, J = 8.08 Hz, 1H), 8.88 (d, J = 3.72 Hz, 1H), 8.28 (brs, 1H), 8.01-7.96 (m, 3H), 7.88 (m, 1H), 7.81 (d, J = 8.60 Hz, 2H), 7.65 (dd, J = 9.08, 2.64 Hz, 1H), 4.00 (s, 3H). The 1H of 4HCl and NH— were not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3
    429
    Figure US20170217923A1-20170803-C00841
    Figure US20170217923A1-20170803-C00842
    Figure US20170217923A1-20170803-C00843
         		HCl 1H NMR (DMSO-d6) ppm 12.60 (br, 1H), 9.78 (d, J = 1.76 Hz, 1H), 9.28 (d, J = 8.04 Hz, 1H), 8.95 (dd, J = 5.20, 1.20 Hz, 1H), 8.36 (d, J = 2.28 Hz, 1H), 8.04- 7.93 (m, 4H), 7.77 (s, 1H), 7.64 (dd, J = 9.12, 2.68 Hz, 1H), 7.30 (d, J = 8.04 Hz, 2H), 4.02 (s, 3H), 2.36 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3
    430
    Figure US20170217923A1-20170803-C00844
    Figure US20170217923A1-20170803-C00845
    Figure US20170217923A1-20170803-C00846
         		2 HCl 1H NMR (DMSO-d6) ppm 12.70-12.40 (br, 1H), 9.71 (s, 1H), 9.27 (d, J = 8.20 Hz, 1H), 8.94 (d, J = 4.24 Hz, 1H), 8.34 (d, J = 2.64 Hz, 1H), 8.13 (t, J = 1.80 Hz, 1H), 8.04-7.95 (m, 4H), 7.63 (dd, J = 9.08, 2.68 Hz, 1H), 7.52 (t, J = 7.88 Hz, 1H), 7.44-7.42 (m, 1H), 4.02 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3
    431
    Figure US20170217923A1-20170803-C00847
    Figure US20170217923A1-20170803-C00848
    Figure US20170217923A1-20170803-C00849
         		HCl 1H NMR (DMSO-d6) ppm 12.57 (br, 1H), 9.80 (brs, 1H), 9.04 (d, J = 7.36 Hz, 1H), 8.82 (brs, 1H), 8.34 (brs, 1H), 7.99 (brd, J = 7.28 Hz, 1H), 7.95 (d, J = 9.08 Hz, 1H), 7.82 (brs, 1H), 7.76 (brm, 1H), 7.62 (m, 2H), 7.50-7.41 (m, 2H), 4.00 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3
    432
    Figure US20170217923A1-20170803-C00850
    Figure US20170217923A1-20170803-C00851
    Figure US20170217923A1-20170803-C00852
         		HCl 1H NMR (DMSO-d6) ppm 10.40 (br, 1H), 9.23 (s, 1H), 8.80 (d, J = 4.68 Hz, 1H), 8.66 (brd, J = 8.20 Hz, 1H), 7.92 (brs, 1H), 7.87 (brd, J = 9.28 Hz, 1H), 7.78 (brm, 1H), 7.63-7.52 (m, 5H), 7.47-7.44 (m, 2H), 7.21- 7.12 (m, 3H), 3.91 (s, 3H). . The 1H of HCl was not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3
    433
    Figure US20170217923A1-20170803-C00853
    Figure US20170217923A1-20170803-C00854
    Figure US20170217923A1-20170803-C00855
         		HCl 1H NMR (DMSO-d6) ppm 12.34 (br, 1H), 9.75 (s, 1H), 9.01 (d, J = 7.52 Hz, 1H), 8.81 (brs, 1H), 8.40- 8.20 (br, 1H), 7.92 (d, J = 9.08 Hz, 1H), 7.77 (m, 1H), 7.60 (dd, J = 9.08, 2.72 Hz, 1H), 6.95 (br, 1H), 3.98 (s, 3H), 2.67 (m, 1H), 2.05 (m, 2H), 1.83-1.70 (m, 3H), 1.54- 1.23 (m, 5H). The 1H of HCl was not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3
    434
    Figure US20170217923A1-20170803-C00856
    Figure US20170217923A1-20170803-C00857
    Figure US20170217923A1-20170803-C00858
         		2 HCl 1H NMR (DMSO-d6) ppm 12.58 (br, 1H), 9.79 (s, 1H), 9.19 (d, J = 7.32 Hz, 1H), 8.90 (d, J = 5.6 Hz, 1H), 8.36 (s, 1H), 7.96 (d, J = 9.08 Hz, 1H), 7.94 (m, 1H), 7.88 (s, 1H), 7.65-7.62 (m, 3H), 7.40 (t, J = 8.16 Hz, 1H), 6.96- 6.93 (m, 1H), 4.02 (s, 3H), 3.84 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3
    435
    Figure US20170217923A1-20170803-C00859
    Figure US20170217923A1-20170803-C00860
    Figure US20170217923A1-20170803-C00861
         		2 HCl 1H NMR (DMSO-d6) ppm 12.80-12.40 (br, 1H), 9.79 (d, J = 1.44 Hz, 1H), 9.26 (d, J = 8.24 Hz, 1H), 8.93 (d, J = 4.08 Hz, 1H), 8.36 (d, J = 2.28 Hz, 1H), 8.02-7.96 (m, 4H), 7.68 (s, 1H), 7.64 (dd, J = 9.12, 2.68 Hz, 1H), 7.05 (d, J = 8.92 Hz, 2H), 4.02 (s, 3H), 3.82 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3
    436
    Figure US20170217923A1-20170803-C00862
    Figure US20170217923A1-20170803-C00863
    Figure US20170217923A1-20170803-C00864
         		HCl 1H NMR (DMSO-d6) ppm 12.52 (br, 1H), 9.79 (s, 1H), 9.23 (d, J = 8.00 Hz, 1H), 8.91 (d, J = 4.12 Hz, 1H), 8.35 (brs, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 9.08 Hz, 1H), 7.93 (m, 1H), 7.85 (s, 1H), 7.64 (dd, J = 9.08, 2.68 Hz, 1H), 7.39- 7.35 (m, 1H), 7.18 (d, J = 7.72 Hz, 1H), 7.11-7.07 (m, 1H), 4.02 (s, 3H), 3.96 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13 using K2CO3 instead of Cs2CO3
    437
    Figure US20170217923A1-20170803-C00865
    Figure US20170217923A1-20170803-C00866
    Figure US20170217923A1-20170803-C00867
         		1H NMR (DMSO-d6) ppm 9.94 (s, 1H), 9.27 (d, J = 1.92 Hz, 1H), 8.59 (dd, J = 4.72, 1.68 Hz, 1H), 8.45 (dt, J = 8.04, 1.8 Hz, 1H), 7.96 (d, J = 2.72 Hz, 1H), 7.84 (d, J = 8.28 Hz, 2H), 7.67 (d, J = 8.00 Hz, 1H), 7.55 (m, 2H), 7.46-7.43 (m, 1H), 7.33 (m, 1H), 3.96 (s, 3H). DMSO >98 G13 using K2CO3 instead of Cs2CO3 at 120° C.
    438
    Figure US20170217923A1-20170803-C00868
    Figure US20170217923A1-20170803-C00869
    Figure US20170217923A1-20170803-C00870
         		HCl 1H NMR (DMSO-d6) ppm 10.48 (br, 1H), 9.23 (s, 1H), 8.83 (brd, J = 3.68 Hz, 1H), 8.70 (brd, J = 7.36 Hz, 1H), 7.95 (brs, 1H), 7.91 (d, J = 9.12 Hz, 1H), 7.82 (m, 1H), 7.63-7.51 (m, 5H), 7.48 (d, J = 8.52 Hz, 2H), 7.26 (d, J = 8.52 Hz, 2H), 3.93 (s, 3H). The 1H of HCl was not observed. DMSO >98 J3 using Na2CO3 instead of K2CO3
    439
    Figure US20170217923A1-20170803-C00871
    Figure US20170217923A1-20170803-C00872
    Figure US20170217923A1-20170803-C00873
         		HCl 1H NMR (DMSO-d6) ppm 12.60 (br, 1H), 9.78 (s, 1H), 9.17 (d, J = 7.96 Hz, 1H), 8.88 (d, J = 4.20 Hz, 1H), 8.35 (d, J = 2.60 Hz, 1H), 8.24-8.21 (m, 1H), 7.96 (d, J = 9.08 Hz, 1H), 7.91-7.88 (brm, 1H), 7.74 (d, J = 2.48 Hz, 1H), 7.63 (dd, J = 9.08, 2.60 Hz, 1H), 7.47-7.41 (m, 1H), 7.36 8m, 2H), 4.02 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13 at 100° C.
    440
    Figure US20170217923A1-20170803-C00874
    Figure US20170217923A1-20170803-C00875
    Figure US20170217923A1-20170803-C00876
         		HCl 1H NMR (DMSO-d6) ppm 12.60-12.45 (br, 1H), 9.79 (d, J = 1.52 Hz, 1H), 9.15 (d, J = 8.36 Hz, 1H), 8.88 (d, J = 5.04 Hz, 1H), 8.35 (d, J = 2.44 Hz, 1H), 7.96 (d, J = 9.12 Hz, 1H), 7.89 (brt, J = 7.08 Hz, 2H), 7.82 (brm, 1H), 7.81 (s, 1H), 7.63 (dd, J = 9.12, 2.44 Hz, 1H), 7.37 (t, J = 7.64 Hz, 1H), 7.19 (d, J = 7.48 Hz, 1H), 4.02 (s, 3H), 2.40 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13 at 100° C.
    441
    Figure US20170217923A1-20170803-C00877
    Figure US20170217923A1-20170803-C00878
    Figure US20170217923A1-20170803-C00879
         		HCl 1H NMR (DMSO-d6) ppm 12.60 (br, 1H), 9.77 (s, 1H), 9.25 (d, J = 8.08 Hz, 1H), 8.93 (d, J = 4.28 Hz,1H), 8.34 (d, J = 2.60 Hz, 1H), 8.01-7.84 (m, 5H), 7.63 (dd, J = 9.12, 2.60 Hz, 1H), 7.56-7.51 (m, 1H), 7.21 (m, 1H). The 1H of HCl was not observed. DMSO >98 G13 at 100° C.
    442
    Figure US20170217923A1-20170803-C00880
    Figure US20170217923A1-20170803-C00881
    Figure US20170217923A1-20170803-C00882
         		2 HCl 1H NMR (DMSO-d6) ppm 12.66 (brs, 1H), 9.78 (d, J = 1.68 Hz, 1H), 9.27 (d, J = 8.08 Hz, 1H), 8.94 (dd, J = 5.20, 1.40 Hz, 1H), 8.36 (d, J = 2.56 Hz, 1H), 8.17 (d, J = 8.84 Hz, 2H), 8.01 (m, 1H), 7.97 (d, J = 9.08 Hz, 1H), 7.93 (s, 1H), 7.64 (dd, J = 9.08, 2.56 Hz, 1H), 7.49 (brd, J = 8.84 Hz, 2H), 4.02 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 at 100° C.
    443
    Figure US20170217923A1-20170803-C00883
    Figure US20170217923A1-20170803-C00884
    Figure US20170217923A1-20170803-C00885
         		2 HCl 1H NMR (DMSO-d6) ppm 12.64 (br, 1H), 9.79 (s, 1H), 9.13 (d, J = 7.56 Hz, 1H), 8.87 (d, J = 5.08 Hz, 1H), 8.36 (d, J = 2.60 Hz, 1H), 8.27 (d, J = 8.00 Hz, 2H), 8.08 (s, 1H), 7.96 (d, J = 9.12 Hz, 1H), 7.87 (m, 1H), 7.86 (d, J = 8.00 Hz, 2H), 7.64 (dd, J = 9.12, 2.60 Hz, 1H), 4.02 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 at 100° C.
    444
    Figure US20170217923A1-20170803-C00886
    Figure US20170217923A1-20170803-C00887
    Figure US20170217923A1-20170803-C00888
         		2 HCl 1H NMR (MeOD-d4) ppm 9.79 (s, 1H), 9.37 (br, 1H), 8.49 (dd, J = 5.28, 1.32 Hz, 1H), 8.12 (m, 1H), 8.09 (d, J = 2.72 Hz, 1H), 7.98 (d, J = 9.16 Hz, 1H), 7.68 (dd, J =9.16, 2.72 Hz, 1H), 7.58 (d, J = 7.12 Hz, 1H), 7.42- 7.30 (m, 3H), 7.30 (s, 1H), 4.05 (s, 3H), 2.50 (s, 3H). The 1H of 2HCl was not observed. MeOD >98 G13
    445
    Figure US20170217923A1-20170803-C00889
    Figure US20170217923A1-20170803-C00890
    Figure US20170217923A1-20170803-C00891
         		2 HCl 1H NMR (DMSO-d6) ppm 12.59 (br, 1H), 9.78 (d, J = 1.48 Hz, 1H), 9.19 (d, J = 8.00 Hz, 1H), 8.90 (dd, J = 5.16, 1.48 Hz, 1H), 8.34 (d, J = 2.60 Hz, 1H), 8.10- 8.04 (m, 1H), 7.97-7.88 (m, 4H), 7.64 (dd, J = 2.60 Hz, 1H), 7.59-7.52 (m, 1H), 4.02 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13
    446
    Figure US20170217923A1-20170803-C00892
    Figure US20170217923A1-20170803-C00893
    Figure US20170217923A1-20170803-C00894
         		HCl 1H NMR (DMSO-d6) ppm 12.61 (br, 1H), 9.78 (d, J = 1.72 Hz, 1H), 9.20 (d, J = 7.92 Hz, 1H), 8.90 (d, J = 4.00 Hz, 1H), 8.35 (d, J = 2.60 Hz, 1H), 8.27-8.21 (m, 1H), 7.96 (d, J = 9.12 Hz, 1H), 7.93 (m, 1H), 7.71 (d, J = 2.56 Hz, 1H), 7.64 (dd, J = 9.12, 2.60 Hz, 1H), 7.43 (m, 1H), 7.27 (m, 1H), 4.02 (s, 1H). The 1H of HCl was not observed. DMSO >98 G13
    447
    Figure US20170217923A1-20170803-C00895
    Figure US20170217923A1-20170803-C00896
    Figure US20170217923A1-20170803-C00897
         		2 HCl 1H NMR (DMSO-d6) ppm 12.57 (br, 1H), 9.77 (d, J = 1.76 Hz, 1H), 9.25 (d, J = 8.08 Hz, 1H), 8.93 (dd, J = 5.16, 1.2 Hz, 1H), 8.34 (d, J = 2.60 Hz, 1H), 8.29 (t, J = 1.76 Hz, 1H), 8.05 (dd, J = 7.84, 1.12 Hz, 1H), 8.02- 7.98 (m, 1H), 7.99 (s, 1H), 7.96 (d, J = 9.08 Hz, 1H), 7.64 (dd, J = 9.08, 2.60 Hz, 1H), 7.58-7.56 (m, 1H), 7.45 (t, J = 7.84 Hz, 1H), 4.02 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13
    448
    Figure US20170217923A1-20170803-C00898
    Figure US20170217923A1-20170803-C00899
    Figure US20170217923A1-20170803-C00900
         		HCl 1H NMR (DMSO-d6) ppm 12.62 (br, 1H), 9.77 (d, J = 1.52 Hz, 1H), 9.10 (d, J = 8.16 Hz, 1H), 8.85 (dd, J = 5.00, 1.56 Hz, 1h), 8.34 (d, J = 2.60 Hz, 1H), 8.24 (d, J = 8.60 Hz, 2H), 8.13 (s, 1H), 7.96 (d, J = 8.60 Hz, 2H), 7.96 (d, J = 9.08 Hz, 1H), 7.86-7.83 (brm, 1H), 7.63 (dd, J = 9.08, 2.60 Hz, 1H), 4.02 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13
    449
    Figure US20170217923A1-20170803-C00901
    Figure US20170217923A1-20170803-C00902
    Figure US20170217923A1-20170803-C00903
         		2 HCl 1H NMR (DMSO-d6) ppm 12.56 (brs, 1H), 9.79 (brs, 1H), 9.11 (d, J = 8.04 Hz, 1H), 8.87 (brs, 1H), 8.43 (brs, 1H), 8.34 (brs, 2H), 8.09 (s, 1H), 7.96 (d, J = 9.08 Hz, 1H), 7.87 (brs, 1H), 7.74 (brd, J = 5.00 Hz, 2H), 7.64 (dd, J = 9.08, 2.48 Hz, 1H), 4.03 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 at 100° C.
    450
    Figure US20170217923A1-20170803-C00904
    Figure US20170217923A1-20170803-C00905
    Figure US20170217923A1-20170803-C00906
         		2 HCl 1H NMR (DMSO-d6) ppm 12.63 (br, 1H), 9.80 (d, J = 1.72 Hz, 1H), 9.27 (d, J = 8.16 Hz, 1H), 8.93 (dd, J = 5.20, 1.36 Hz, 1H), 8.33 (d, J = 2.24 Hz, 1H), 7.99 (m, 1H), 7.98 (d, J = 9.08 Hz, 1H), 7.88 (brd, J = 7.72 Hz, 1H), 7.71-7.75 (m, 2H), 7.70-7.63 (m, 2H), 7.45 (s, 1H), 3.98 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13 at 100° C.
    451
    Figure US20170217923A1-20170803-C00907
    Figure US20170217923A1-20170803-C00908
    Figure US20170217923A1-20170803-C00909
         		HCl 1H NMR (DMSO-d6) ppm 12.70 (br, 1H), 9.79 (d, J = 1.60 Hz, 1H), 9.30 (d, J = 7.56 Hz, 1H), 8.95 (d, J = 4.96 Hz, 1H), 8.34 (d, J = 2.20 Hz, 1H), 8.02 (m, 1H), 7.98 (d, J = 9.12 Hz, 1H), 7.85-7.77 (m, 2H), 7.73 (s, 1H), 7.64 (dd, J = 9.12, 2.68 Hz, 1H), 7.52 (m, 1H), 7.36 (m, 1H), 4.00 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13
    452
    Figure US20170217923A1-20170803-C00910
    Figure US20170217923A1-20170803-C00911
    Figure US20170217923A1-20170803-C00912
         		HCl 1H NMR (DMSO-d6) ppm 12.64 (br, 1H), 9.78 (d, J = 1.72 Hz, 1H), 9.19 (d, J = 7.92 Hz, 1H), 8.90 (d, J = 3.88 Hz, 1H), 8.36 (d, J = 2.64 Hz, 1H), 8.02-7.91 (m, 3H), 7.83 (d, J = 2.40 hz, 1H), 7.64 (dd, J = 9.08, 2.64 Hz, 1H), 7.46 (m, 1H), 7.36 (m, 1H), 4.02 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13
    453
    Figure US20170217923A1-20170803-C00913
    Figure US20170217923A1-20170803-C00914
    Figure US20170217923A1-20170803-C00915
         		2 HCl 1H NMR (DMSO-d6) ppm 12.62 (br, 1H), 9.77 (d, J = 1.84 Hz, 1H), 9.30 (d, J = 8.00 Hz, 1H), 8.46 (dd, J = 5.36, 1.48 Hz, 1H), 8.48 (br, 1H), 8.39-8.33 (m, 2H), 8.08 (s, 1H), 8.05 (m, 1H), 7.97(d, J = 9.12 Hz, 1H), 7.85-7.83 (m, 1H), 7.71 (t, J = 7.84 Hz, 1H), 7.64 (dd, J = 9.12, 2.60 Hz, 1H), 4.02 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13
    454
    Figure US20170217923A1-20170803-C00916
    Figure US20170217923A1-20170803-C00917
    Figure US20170217923A1-20170803-C00918
         		2 HCl 1H NMR (DMSO-d6) ppm 12.65 (br, 1H), 9.79 (d, J = 1.72 Hz, 1H), 9.25 (d, J = 8.04 Hz, 1H), 8.92 (d, J = 5.36 Hz, 1H), 8.36 (d, J = 2.60 Hz, 1H), 8.24-8.22 (,m, 1H), 7.97 (d, J = 9.08 Hz, 1H), 7.96 (m, 1H), 7.69 (s, 1H), 7.65 (dd, J = 9.08, 2.60 Hz, 1H), 7.55 (m, 3H), 4.02 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13
    455
    Figure US20170217923A1-20170803-C00919
    Figure US20170217923A1-20170803-C00920
    Figure US20170217923A1-20170803-C00921
         		HCl 1H NMR (DMSO-d6) ppm 12.52 (br, 1H), 9.78 (d, J = 1.48 Hz, 1H), 9.03 (d, J = 6.6 Hz, 1H), 8.81 (d, J = 4.72 Hz, 1H), 8.34 (d, J = 2.56 Hz, 1H), 8.09 (d, J = 7.88 Hz, 1H), 8.03 (brs, 2H), 7.96 (d, J =9.12 Hz, 1H), 7.78 (br, 1H), 7.65 (m, 2H), 7.38 (m, 1H), 4.02 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13
    456
    Figure US20170217923A1-20170803-C00922
    Figure US20170217923A1-20170803-C00923
    Figure US20170217923A1-20170803-C00924
         		2 HCl 1H NMR (DMSO-d6) ppm 12.45 (br, 1H), 9.78 (d, J = 1.64 Hz, 1H), 9.15 (br, 1H), 8.89 (d, J = 4.52 Hz, 1H), 8.30 (brs, 1H), 7.94 (d, J = 9.08 Hz, 1H), 7.90 (brm, 1H), 7.76 (m, 2H), 7.62 (dd, J = 9.08, 2.64 Hz, 1H), 7.51 (m, 2H), 7.40 (m, 1H), 3.99 (s, 3H), 2.61 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 G13
    457
    Figure US20170217923A1-20170803-C00925
    Figure US20170217923A1-20170803-C00926
    Figure US20170217923A1-20170803-C00927
         		HCl 1H NMR (DMSO-d6) ppm 12.55 (br, 1H), 9.78 (d, J = 1.48 Hz, 1H), 9.08 (d, J = 8.48 Hz, 1H), 8.84 (dd, J = 5.04, 1.56 Hz, 1H), 8.34 (d, J = 2.72 Hz, 1H), 8.09 (s, 1H), 7.96 (d, J = 9.12 Hz, 1H), 7.84 (m, 1H), 7.77 (m, 2H), 7.64 (dd, J = 9.12, 2.72 Hz, 1H), 7.25 (m, 1H), 4.02 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13
    458
    Figure US20170217923A1-20170803-C00928
    Figure US20170217923A1-20170803-C00929
    Figure US20170217923A1-20170803-C00930
         		HCl 1H NMR (DMSO-d6) ppm 12.55 (br, 1H), 9.77 (d, J = 1.56 Hz, 1H), 9.14 (d, J = 8.00 Hz, 1H), 8.87 (dd, J = 5.08, 1.48 Hz, 1H), 8.34 (d, J = 2.60 Hz, 1H), 7.98 (m, 1H), 7.96 (d, J = 9.08 Hz, 1H), 7.89-7.86 (brm, 1H), 7.83 (d, J = 2.44 Hz, 1H), 7.64 (dd, J = 9.08, 2.60 Hz, 1H), 7.47-7.41 (m, 1H), 7.29 (m, 1H), 4.02 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13
    459
    Figure US20170217923A1-20170803-C00931
    Figure US20170217923A1-20170803-C00932
    Figure US20170217923A1-20170803-C00933
         		HCl 1H NMR (DMSO-d6) ppm 12.66 (br, 1H), 9.79 (d, J = 1.60 Hz, 1H), 9.25 (d, J = 7.16 Hz, 1H), 8.92 (d, J = 5.20 Hz, 1H), 8.35 (d, J = 2.56 Hz, 1H), 7.98 (d, J = 9.12 Hz, 1H), 7.97 (m, 1H), 7.68 (s, 1H), 7.64 (dd, J = 9.12, 2.56 Hz, 1H), 7.55 (m, 1H), 7.27 (m, 2H), 3.99 (s, 3H). The 1H of HCl was not observed. DMSO >98 G13
    460
    Figure US20170217923A1-20170803-C00934
    Figure US20170217923A1-20170803-C00935
    Figure US20170217923A1-20170803-C00936
         		2 HCl 1H NMR (DMSO-d6) ppm 9.73 (s, 1H), 9.17 (brs, 1H), 8.92 (dd, J = 5.16, 1.4 Hz, 1H), 8.30-8.10 (br, 1H), 7.97 (d, J = 9.04 Hz, 1H), 7.96 (m, 1H), 7.63 (dd, J = 9.04, 2.72 Hz, 1H), 7.02 (s, 1H), 3.98 (s, 3H), 2.57 (d, J = 7.16 Hz, 2H), 2.08 (m, 1H), 0.94 (d, J = 6.60 Hz, 6H). The 1H of HCl and NH— were not observed. DMSO >98 G13
    461
    Figure US20170217923A1-20170803-C00937
    Figure US20170217923A1-20170803-C00938
    Figure US20170217923A1-20170803-C00939
         		2 HCl 1H NMR (DMSO-d6) ppm 12.80-12.20 (br, 1H), 9.78 (d, J = 1.76 Hz, 1H), 9.28 (d, J = 8.04 Hz, 1H), 8.96 (dd, J = 5.28, 1.32 Hz, 1H), 8.29 (brs, 1H), 8.07-8.03 (brm, 1H), 7.95 (d, J = 9.12 Hz, 1H), 7.79 (d, J = 8.60 Hz, 2H), 7.62 (dd, J = 9.12, 2.64 Hz, 1H), 7.57 (d, J = 8.60 Hz, 2H), 3.99 (s, 3H), 2.61 (brs, 3H). The 1H of 2HCl was not observed. DMSO >98 G13
    462
    Figure US20170217923A1-20170803-C00940
    Figure US20170217923A1-20170803-C00941
    Figure US20170217923A1-20170803-C00942
         		2 HCl 1H NMR (DMSO-d6) ppm 12.80-12.20 (br, 1H),. 9.74 (s, 1H), 9.19 (d, J = 4.96 Hz, 1H), 8.91 (dd, J = 5.2, 1.4 Hz, 1H), 8.22 (brs, 1H), 7.96 (br, 1H), 7.95 (d, J = 9.08 Hz, 1H), 7.61 (dd, J = 9.08, 2.68 Hz, 1H), 7.35-7.31 (m, 4H), 7.23 (m, 1H), 7.09 (brs, 1H), 4.07 (brs, 2H), 3.96 (brs, 3H). The 1H of 2HCl was not observed. DMSO >98 G13
    463
    Figure US20170217923A1-20170803-C00943
    Figure US20170217923A1-20170803-C00944
    Figure US20170217923A1-20170803-C00945
         		2 HCl 1H NMR (DMSO-d6) ppm 12.50 (br, 1H), 9.78 (d, J = 1.76 Hz, 1H), 9.25 (brs, 1H), 8.96 (brd, J = 4.68 Hz, 1H), 8.29 (brs, 1H), 8.04 (brs, 1H), 7.96 (d, J = 9.20 Hz, 1H), 7.70 (brm, 2H), 7.63 (dd, J = 9.20, 2.68 Hz, 1H), 7.51 (brm, 2H), 7.41 (brm, 1H), 3.99 (s, 3H), 3.02 (q, J = 7.40 Hz, 2H), 1.49 (t, J = 7.40 Hz, 3H). The 1H of 2HCl was not observed. DMSO >98 G13
    464
    Figure US20170217923A1-20170803-C00946
    Figure US20170217923A1-20170803-C00947
    Figure US20170217923A1-20170803-C00948
         		2 HCl 1H NMR (DMSO-d6) ppm 12.53 (br, 1H), 9.78 (d, J = 1.76 Hz, 1H), 9.20 (d, J = 8.36 Hz, 1H), 8.94 (dd, J = 5.2, 1.4 Hz., 1H), 8.29 (brs, 1H), 8.00 (brm, 1H), 7.96 (d, J = 9.12 Hz, 1H), 7.66- 7.61 (m, 3H), 7.52 (brm, 2H), 7.43 (t, J 7.40 Hz, 1H), 3.98 (s, 3H), 1.43 (d, J = 6.8 Hz, 6H). The 1H of 2HCl was not observed.The CH proton of iPr group was not observed because of overlapping the DMSO >98 G13
    H2O peak.
    465
    Figure US20170217923A1-20170803-C00949
    Figure US20170217923A1-20170803-C00950
    Figure US20170217923A1-20170803-C00951
         		2 HCl 1H NMR (DMSO-d6) ppm 12.59 (brs, 1H), 9.77 (d, J - 1.72 Hz, 1H), 9.25 (d, J = 7.76 Hz, 1H), 8.96 (d, J = 4.04 Hz, 1H), 8.29 (br, 1H), 8.04 (m, 1H), 7.96 (d, J = 9.12 Hz, 1H), 7.69 (brd, J = 7.12 Hz, 2H), 7.63 (dd, J = 9.12, 2.68 Hz, 1H), 7.51 (t, J = 7.36 Hz, 2H), 7.42 (t, J = 7.36 Hz, 1H), 3.99 (s, 3H), 2.96 (t, J = 7.52 Hz, 2H), DMSO >98 G13
    1.78 (m, 2H), 1.01 (t, J = 7.24
    Hz, 3H). The 1H of 2HCl was
    not observed.
    466
    Figure US20170217923A1-20170803-C00952
    Figure US20170217923A1-20170803-C00953
    Figure US20170217923A1-20170803-C00954
         		2 HCl 1H NMR (DMSO-d6) ppm 12.96 (brs, 1H), 9.74 (d, J = 2.04 Hz, 1H), 9.11 (d, J = 7.96 Hz, 1H), 8.90 (d, J = 4.96 Hz, 1H), 8.31 (brd, J = 2.64 Hz, 1H), 7.97 (d, J = 9.12 Hz, 1H), 7.87 (brm, 1H), 7.83-7.80 (m, 2H), 7.64 (dd, J = 9.12, 2.62 Hz, 1H), 7.48 (m, 3H), 4.25 (q, J = 7.04 Ha, 2H), 3.98 (s, 3H), 1.29 (t, J = 7.04 Hz, 3H). DMSO >98 G13
    The 1H of 2HCl was not
    observed.
    467
    Figure US20170217923A1-20170803-C00955
    Figure US20170217923A1-20170803-C00956
    Figure US20170217923A1-20170803-C00957
         		HCl 1H NMR (DMSO-d6) ppm 12.63 (br, 1H), 9.76 (d, J = 1.76 Hz, 1H), 9.29 (d, J = 8.16 Hz, 1H), 8.95 (dd, J = 5.28, 1.36 Hz, 1H), 8.32 (brd, J = 2.60 Hz, 1H), 8.07 (d, J = 8.52 Hz, 2H), 8.08-8.00 (m, 1H), 7.95 (d, J = 9.12 Hz, 1H), 7.90 (s, 1H), 7.61 (dd, J = 9.12, 2.60 Hz, 1H), 7.55 (d, J = 8.52 Hz, 2H), 4.24 (q, J = 6.88 Hz, 2H), 1.47 (t, J = 6.88 Hz, 3H). The 1H of HCl was not observed. DMSO >98 G13
    468
    Figure US20170217923A1-20170803-C00958
    Figure US20170217923A1-20170803-C00959
    Figure US20170217923A1-20170803-C00960
         		2 HCl 1H NMR (DMSO-d6) ppm 12.58 (brs, 1H), 9.76 (d, J = 1.80 Hz, 1H), 9.27 (d, J = 8.16 Hz, 1H), 8.94 (dd, J = 5.20, 1.32 Hz, 1H), 8.32 (d, J = 2.48 Hz, 1H), 8.09- 8.01 (m, 2H), 7.96-7.89 (m, 3H), 7.62-7.52 (m, 2H), 4.29 (q, J = 6.88 Hz, 2H), 1.47 (t, J = 6.88 Hz, 3H). The 1H of 2HCl was not observed. DMSO >98 G13
    469
    Figure US20170217923A1-20170803-C00961
    Figure US20170217923A1-20170803-C00962
    Figure US20170217923A1-20170803-C00963
         		2 HCl 1H NMR (DMSO-d6) ppm 9.72 (s, 1H), 9.13 (brd, J = 5.52 Hz, 1H), 8.92 (d, J = 3.52 Hz, 1H), 8.16 (brs, 1H), 7.95 (brd, J = 9.08 Hz, 2H), 7.62 (dd, J = 2.4 Hz, 1H), 7.39 (brs, 1H), 3.97 (s, 3H), 2.47 (s, 3H). The 1H of 2HCl and NH— were not observed. DMSO >98 G13
    470
    Figure US20170217923A1-20170803-C00964
    Figure US20170217923A1-20170803-C00965
    Figure US20170217923A1-20170803-C00966
         		HCl 1H NMR (DMSO-d6) ppm 12.58 (brs, 1H), 9.76 (d, J = 1.68 Hz, 1H), 9.17 (d, J = 8.12 Hz, 1H), 8.89 (dd, J = 5.12, 1.48 Hz, 1H), 8.32 (d, J = 2.56 Hz, 1H), 8.01- 8.00 (m, 1H), 7.94 (d, J = 9.08 Hz, 1H), 7.930-7.90 (m, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 9.08, 2.40 Hz, 1H), 7.50-7.43 (m, 1H), 7.38-7.33 (m, 1H), 4.28 (q, J = 7.00 Hz, DMSO >98 G13
    2H), 1.47 (t, J = 7.00 Hz, 3H).
    The 1H of HCl was not
    observed.
    471
    Figure US20170217923A1-20170803-C00967
    Figure US20170217923A1-20170803-C00968
    Figure US20170217923A1-20170803-C00969
         		2 HCl 1H NMR (DMSO-d6) ppm 12.53 (brs, 1H), 9.73 (d, J = 1.76 Hz, 1H), 9.29 (d, J = 8.16 Hz, 1H), 8.95 (dd, J = 5.32, 1.36 Hz, 1H), 8.29 (d, J = 2.56 Hz, 1H), 8.05- 8.02 (brm, 1H), 7.97-7.92 (m, 1H), 7.93 (d, J = 9.08 Hz, 1H), 7.78 (d, J = 2.36 Hz, 1H), 7.60 (dd, J = 9.08, 2.6 Hz, 1H), 7.46-7.40 (m, 1H), 7.31-7.25 (m, 1H), 4.27 (q, DMSO >98 G13
    J = 6.92 Hz, 2H), 1.47 (t, J =
    6.92 Hz, 3H). The 1H of
    2HCl was not observed.
    472
    Figure US20170217923A1-20170803-C00970
    Figure US20170217923A1-20170803-C00971
    Figure US20170217923A1-20170803-C00972
         		3 HCl 1H NMR (DMSO-d6) ppm 12.61 (brs, 1H), 9.76 (d, J = 1.8 Hz, 1H), 9.29 (d, J = 8.16 Hz, 1H), 8.95 (dd, J = 5.24, 1.2 Hz, 1H), 8.32 (d, J = 2.52 Hz, 1H), 8.24-8.20 (m, 1H), 8.05-8.01 (brm, 1H), 7.95 (d, J = 9.08 Hz, 1H), 7.68 (d, J = 2.52 HZ, 1H), 7.61 (dd, J = 9.08, 2.52 Hz, 1H), 7.46-7.40 (m, 1H), 7.28-7.24 (m, 1H), 4.28 (q, J = 6.92 Hz, 2H), DMSO >98 G13
    1.47 (t, J = 6.92 Hz, 3H).
    The 1H of 3HCl was not
    observed.
    473
    Figure US20170217923A1-20170803-C00973
    Figure US20170217923A1-20170803-C00974
    Figure US20170217923A1-20170803-C00975
         		2 HCl 1H NMR (DMSO-d6) ppm 12.63 (brs, 1H), 9.78 (d, J = 1.68 Hz, 1H), 9.32 (d, J = 8.12 Hz, 1H), 8.97 (d, J = 5.24 Hz, 1H), 8.35 (d, J = 2.16 Hz, 1H), 8.08-8.04 (m, 3H), 7.96 (d, J = 9.08 Hz, 1H), 7.85 (s, 1H), 7.62 (dd, J = 9.08, 2.52 Hz, 1H), 7.49 (t, J = 7.44 Hz, 2H), 7.38 (t, J = 7.28 Hz, 1H), 4.30 (q, J = 6.96 Hz, 2H), 1.47 (t, J = J = 6.96 Hz, 3H). The 1H of 2HCl was not DMSO >98 G13
    observed.
    474
    Figure US20170217923A1-20170803-C00976
    Figure US20170217923A1-20170803-C00977
    Figure US20170217923A1-20170803-C00978
         		1H NMR (DMSO-d6) ppm 12.68 (s, 1H), 9.73 (d, J = 1.64 Hz, 1H), 8.87-8.84 (m, 1H), 8.75-8.73 (m, 1H), 8.33 (brs, 1H), 8.24 (brs, 1H), 7.93 (d, J - 9.16 Hz, 1H), 7.64-7.59 (m, 2H), 4.34 (q, J = 7.08 Hz, 2H), 3.98 (s, 3H), 1.34 (t, J = 7.08 Hz, 3H). DMSO >98 G13
    475
    Figure US20170217923A1-20170803-C00979
    Figure US20170217923A1-20170803-C00980
    Figure US20170217923A1-20170803-C00981
         		HCl 1H NMR (300 MHz, DMSO) δ 10.35 (s, 1H), 9.42 (s, 1H), 8.99-8.76 (m, 2H), 8.11 (d, J = 6.7 Hz, 1H), 7.99-7.75 (m, 3H), 7.67-7.43 (m, 2H), 7.23 (d, J = 8.2 Hz, 1H), 4.14 (s, 3H). DMSO 98 G1 381 (M + 1) 2.07 Method A (Formic acid)
    476
    Figure US20170217923A1-20170803-C00982
    Figure US20170217923A1-20170803-C00983
         		HCl 1H NMR (300 MHz, DMSO) δ 13.78 (s, 1H), 9.62 (d, J = 1.7 Hz, 1H), 9.21 (d, J = 8.1 Hz, 1H), 8.98 (d, J = 4.2 Hz, 1H), 8.07 (dd, J = 7.9, 5.3 Hz, 1H), 7.83 (d, J = 9.1 Hz, 2H), 7.63-7.50 (m, 4H), 7.41 (d, J = 6.5 Hz, 2H), 7.14 (d, J = 2.5 Hz, 1H), 5.30 (s, 1H), 3.91 (s, 3H), 2.15 (s, 3H). DMSO 95 Method G1 468.1 (M + 1) Method C
    477
    Figure US20170217923A1-20170803-C00984
    Figure US20170217923A1-20170803-C00985
         		HCl 1H NMR (300 MHz, DMSO) δ 13.78 (s, 1H), 9.64 (d, J = 1.5 Hz, 1H), 9.11 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 3.8 Hz, 1H), 7.95 (dd, J = 10.6, 2.6 Hz, 1H), 7.84 (d, J = 9.1 Hz, 2H), 7.60-7.48 (m, 4H), 7.38 (d, J = 6.5 Hz, 2H), 7.17 (d, J = 2.4 Hz, 1H), 5.28 (s, 1H), 4.14 (q, J = 6.9 Hz, 2H), 2.15 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H). DMSO 95 Method G1 482.1 (M + 1) Method C
    478
    Figure US20170217923A1-20170803-C00986
    Figure US20170217923A1-20170803-C00987
         		HCl 1H NMR (300 MHz, DMSO) δ 12.59 (s, 1H), 9.56 (s, 1H), 8.70 (d, J = 5.8 Hz, 2H), 8.58 (d, J = 5.2 Hz, 1H), 7.95 (d, J = 5.2 Hz, 2H), 7.87 (d, J = 9.1 Hz, 2H), 7.64-7.49 (m, 2H), 7.40 (d, J = 2.4 Hz, 1H), 4.21 (q, J = 6.8 Hz, 2H), 1.44 (t, J = 6.9 Hz, 3H). DMSO 99 Method G1 392.1 (M + 1) Method C
    479
    Figure US20170217923A1-20170803-C00988
    Figure US20170217923A1-20170803-C00989
         		HCl 1H NMR (300 MHz, DMSO) δ 13.75 (s, 1H), 9.60 (s, 1H), 8.98 (s, 1H), 8.82 (d, J = 3.6 Hz, 1H), 7.82 (d, J = 9.0 Hz, 3H), 7.52 (d, J = 9.3 Hz, 1H), 7.15 (s, 1H), 6.94-6.62 (s, 1H), 4.13 (d, J = 6.9 Hz, 2H), 2.90 (d, J = 21.9 Hz, 4H), 2.41 (s, 2H), 1.43 (t, J = 6.9 Hz, 3H). DMSO 95 Method G1 432.1 (M + 1) Method C
    480
    Figure US20170217923A1-20170803-C00990
    Figure US20170217923A1-20170803-C00991
         		HCl 1H NMR (300 MHz, DMSO) δ 12.50 (s, 1H), 9.56 (s, 1H), 8.89 (s, 1H), 8.68 (d, J = 5.3 Hz, 2H), 8.00-7.79 (m, 3H), 7.73 (d, J = 7.2 Hz, 4H), 7.62- 7.38 (m, 9H), 7.34 (d, J = 2.2 Hz, 2H), 4.18 (dd, J = 13.5, 6.5 Hz, 2H), 1.43 (t, J = 6.9 Hz, 3H). DMSO 99 Method G1 468.1 (M + 1) Method C
    481
    Figure US20170217923A1-20170803-C00992
    Figure US20170217923A1-20170803-C00993
         		HCl 1H NMR (300 MHz, DMSO) δ 12.51 (s, 1H), 9.54 (s, 1H), 8.86 (s, 1H), 8.74-8.61 (m, 2H), 7.90 (s, J = 15.7 Hz, 2H), 7.83 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 7.1 Hz, 2H), 7.63- 7.40 (m, 6H), 7.33 (d, J = 2.3 Hz, 1H), 3.92 (s, 3H). DMSO 99 Method G1 454.1 (M + 1) Method C
    482
    Figure US20170217923A1-20170803-C00994
    Figure US20170217923A1-20170803-C00995
         		HCl 1H NMR (300 MHz, DMSO) δ 13.70 (s, 1H), 9.70 (d, J = 2.1 Hz, 1H), 8.81 (d, J = 8.0 Hz, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.66-7.53 (m, 2H), 7.29 (d, J = 2.2 Hz, 1H), 3.95 (s, 3H), 2.78 (d, J = 12.9 Hz, 4H), 1.78 (s, 4H). DMSO 99 Method G1 432.1 (M + 1) Method C
    483
    Figure US20170217923A1-20170803-C00996
    Figure US20170217923A1-20170803-C00997
         		HCl 1H NMR (300 MHz, DMSO) δ 13.64 (s, 1H), 9.68 (s, 1H), 8.79 (d, J = 7.9 Hz, 1H), 8.69 (d, J = 4.7 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.63-7.50 (m, 2H), 7.24 (s, 1H), 4.18 (q, J = 6.7 Hz, 2H), 2.76 (d, J = 10.4 Hz, 4H), 1.78 (s, 4H), 1.43 (t, J = 6.9 Hz, 3H). DMSO 99 Method G1 446.1 (M + 1) Method C
    484
    Figure US20170217923A1-20170803-C00998
    Figure US20170217923A1-20170803-C00999
         		HCl 1H NMR (300 MHz, DMSO) δ 12.82 (s, 1H), 9.67 (d, J = 2.1 Hz, 1H), 8.77 (dt, J = 8.1, 2.0 Hz, 1H), 8.71 (dd, J = 4.8, 1.7 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.83 (s, 1H), 7.60- 7.53 (m, 3H), 7.48 (s, 1H), 7.20 (d, J = 2.6 Hz, 1H), 4.20 (q, J = 6.9 Hz, 2H), 2.90 (d, J = 4.7 Hz, 3H), 1.44 (t, J = 6.9 Hz, 3H). DMSO 95 Method G1 422.1 (M + 1) Method C
    485
    Figure US20170217923A1-20170803-C01000
    Figure US20170217923A1-20170803-C01001
         		HCl 1H NMR (300 MHz, DMSO) δ 9.66 (s, 1H), 9.44 (d, J = 1.4 Hz, 1H), 8.64-8.55 (m, 2H), 7.90 (s, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.69 (s, 2H), 7.54-7.45 (m, 2H), 4.19 (q, J = 7.0 Hz, 2H), 4.04 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H). DMSO 99 Method G1 390.1 (M + 1) Method C
    486
    Figure US20170217923A1-20170803-C01002
    Figure US20170217923A1-20170803-C01003
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.57 (d, J = 1.5 Hz, 1H), 9.07 (d, J = 4.6 Hz, 1H), 8.94 (dd, J = 5.2, 1.4 Hz, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.97 (dd, J = 6.7, 6.0 Hz, 1H), 7.67 (dd, J = 9.1, 2.8 Hz, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.36 (dd, J = 6.4, 2.3 Hz, 2H), 7.14-7.03 (m, 2H), 3.74 (s, 3H), 3.69 (s, 3H). DMSO 99 Method G1 382.5 (M + 1) Method C
    487
    Figure US20170217923A1-20170803-C01004
    Figure US20170217923A1-20170803-C01005
         		2 HCl 1H NMR (300 MHz, DMSO) δ 12.59 (s, 1H), 9.58 (d, J = 2.0 Hz, 1H), 8.94 (d, J = 8.2 Hz, 1H), 8.84 (d, J = 5.2 Hz, 1H), 8.73 (s, 1H), 8.09 (s, 1H), 7.95 (s, 3H), 7.82 (dd, J = 8.4, 5.4 Hz, 2H), 7.75 (d, J = 7.4 Hz, 2H), 7.59-7.42 (m, 3H). DMSO 99 Method G1 458.4 (M + 1) Method C
    488
    Figure US20170217923A1-20170803-C01006
    Figure US20170217923A1-20170803-C01007
         		2 HCl 1H NMR (300 MHz, DMSO) δ 13.79 (s, 1H), 9.49 (d, J = 1.5 Hz, 1H), 8.96 (d, J = 8.0 Hz, 1H), 8.86 (d, J = 3.7 Hz, 1H), 7.95-7.71 (m, 4H), 7.65 (d, J = 1.6 Hz, 1H), 6.76 (s, 1H), 2.85 (d, J = 22.5 Hz, 4H), 2.44-2.29 (m, 2H). DMSO 93 Method G1 422.4 (M + 1) Method C
    489
    Figure US20170217923A1-20170803-C01008
    Figure US20170217923A1-20170803-C01009
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.53 (d, J = 1.8 Hz, 1H), 9.04 (d, J = 7.9 Hz, 1H), 8.93 (d, J = 3.9 Hz, 1H), 7.95 (dd, J = 8.0, 5.2 Hz, 1H), 7.90- 7.78 (m, 2H), 7.70 (d, J = 1.7 Hz, 1H), 2.29 (s, 3H), 2.24 (s, 3H). DMSO 94 Method G1 410.3 (M + 1) Method C
    490
    Figure US20170217923A1-20170803-C01010
    Figure US20170217923A1-20170803-C01011
         		1H NMR (300 MHz, DMSO) δ 13.07 (s, 1H), 9.93 (d, J = 1.8 Hz, 1H), 9.64 (d, J = 1.6 Hz, 1H), 8.90-8.78 (m, 1H), 8.76-8.62 (m, 2H), 8.29 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.71 (dd, J = 8.3, 1.9 Hz, 1H), 7.65 (s, 1H), 7.57 (dd, J = 9.1, 2.5 Hz, 1H), 7.53-7.44 (m, 2H), 7.01 (s, 1H), 4.21 (q, J = 6.9 DMSO 99 Method G1 464.2 (M + 1) Method C
    Hz, 2H), 3.34 (s, 3H), 1.44 (t,
    J = 6.9 Hz, 3H).
    491
    Figure US20170217923A1-20170803-C01012
    Figure US20170217923A1-20170803-C01013
         		1H NMR (300 MHz, DMSO) δ 9.78 (s, 1H), 9.50 (d, J = 2.0 Hz, 1H), 8.68-8.57 (m, 2H), 7.97 (d, J = 2.5 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.55-7.43 (m, 3H), 7.22 (d, J = 8.4 Hz, 1H), 4.22 (q, J = 6.9 Hz, 2H), 3.37 (d, J = 4.3 Hz, 6H), 1.43 (t, J = 6.9 Hz, 3H). DMSO 99 Method G1 427.5 (M + 1) Method C
    492
    Figure US20170217923A1-20170803-C01014
         		1H NMR (300 MHz, DMSO) δ 11.48 (s, 1H), 10.97 (s, 1H), 9.28 (d, J = 1.5 Hz, 1H), 8.64 (dd, J = 4.6, 1.7 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 7.94-7.80 (m, 3H), 7.53-7.35 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 4.04 (s, H). DMSO 99 Method F5, G13 391.1 (M + 1) Method C
    493
    Figure US20170217923A1-20170803-C01015
         		2 HCl 1H NMR (300 MHz, DMSO) δ 11.28 (s, 1H), 9.62 (d, J = 1.7 Hz, 1H), 9.17 (d, J = 7.8 Hz, 1H), 8.93 (dd, J = 5.2, 1.3 Hz, 1H), 8.60 (s, 1H), 8.05 (s, 1H), 8.03-7.94 (m, 2H), 7.77 (s, 1H), 7.64 (dd, J = 9.2, 2.5 Hz 1H), 7.40 (d, J = 2.6 Hz, 1H), 3.97 (s, 3H). DMSO 99 Method G14 362.4 (M + 1) Method C
    494
    Figure US20170217923A1-20170803-C01016
         		1H-NMR (400 MHz, DMSO- d6): δ 10.14 (s, 1H), 9.54 (s, 1H), 8.70-8.67 (m, 2H), 8.48 (s, 1H), 8.16 (s, 1H), 7.96- 7.89 (m, 3H), 7.60 (t, J = 8.0 Hz, 1H), 7.55-7.52 (m, 1H), 7.17 (d, J = 8.8 Hz, 1H), 3.71 (s, 2H), 2.72-2.65 (m, 8H). DMSO 95 Method G1 498.1 (M + 1) t = 2.128 min Method B (NH4HCO3)
    495
    Figure US20170217923A1-20170803-C01017
         		1H-NMR (400 MHz, DMSO- d6): δ 10.71 (s, 1H), 9.37 (s, 1H), 8.93 (s, 1H), 8.67 (d, J = 3.2 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.65 (m, 2H), 7.04 (d, J = 8.0 Hz, 1H), 2.95 (t, J = 8.0 Hz, 2H), 2.64 (t, J = 8.0 Hz, 2H). DMSO 95 Method G1 402.0 (M + 1) t = 1.746 min Method B (NH4HCO3)
    496
    Figure US20170217923A1-20170803-C01018
         		1H-NMR (400 MHz, DMSO- d6): δ 11.38 (s, 1H), 9.51 (s, 1H), 8.67-8.60 (m, 3H), 8.24- 8.10 (m, 2H), 7.88-7.83 (m, 2H), 7.58-7.55 (m, 3H), 7.33 (dd, J = 7.2, 4.8 Hz, 1H), 3.97 (s, 3H). DMSO 95 Method J1 373.0 (M + 1) t = 1.523 min Method B (NH4HCO3)
    497
    Figure US20170217923A1-20170803-C01019
         		2HCl 1H-NMR (400 MHz, DMSO- d6): δ 9.92 (s, 1H), 9.30 (s, 1H), 8.60 (d, J = 3.4 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 4.4 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.59-7.40 (m, 5H), 4.24 (q, J = 6.9 Hz, 2H), 2.55 (d, J = 4.5 Hz, 3H), 1.45 (t, J = 6.9 Hz, 3H). DMSO 95 Method G1 418.2 (M + 1) 1.782 min Method B (NH4HCO3)
    498
    Figure US20170217923A1-20170803-C01020
         		1H-NMR (400 MHz, DMSO- d6): δ 10.14 (s, 1H), 9.54 (d, J = 2.0 Hz, 1H), 8.70-8.67 (m, 2H), 8.50 (s, 1H), 8.15 (s, 1H), 7.94-7.92 (m, 3H), 7.61 (t, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.0, 4.8 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 3.90 (s, 2H), 3.17 (s, 4H), 2.98 (s, 4H). DMSO 95 Method G1 530.0 (M + 1) 1.856 min Method B (NH4HCO3)
    499
    Figure US20170217923A1-20170803-C01021
         		2HCl 1H-NMR (400 MHz, DMSO- d6): δ 13.19 (s, 1H), 9.65 (s, 1H), 9.17 (d, J = 8.2 Hz, 1H), 8.97 (d, J = 4.5 Hz, 1H), 8.93 (s, 1H), 8.81 (d, J = 8.2 Hz, 1H), 8.45 (s, 1H), 8.40 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 16.0, 10.4 Hz, 3H), 7.74 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 3.38 (s, 3H). DMSO 95 Method G1 420.1 (M + 1) t = 1.478 min Method B (NH4HCO3)
    501
    Figure US20170217923A1-20170803-C01022
         		HCl 1H-NMR (400 MHz, DMSO- d6): δ 13.46 (s, 1H), 9.46 (s, 1H), 8.97 (d, J = 7.9 Hz, 1H), 8.93 (d, J = 4.4 Hz, 1H), 8.77 (d, J = 12.1 Hz, 1H), 8.55 (s, 1H), 8.16-7.91 (m, 4H), 7.83 (t, J = 7.5 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.05 (t, J = 6.9 Hz, 1H). DMSO 95 Method G1 378.1 (M + 1) t = 1.873 min Method B (NH4HCO3)
    502
    Figure US20170217923A1-20170803-C01023
         		1H-NMR (400 MHz, DMSO- d6): δ 13.00 (s, 1H), 9.83 (s, 1H), 9.17 (d, J = 8.0 Hz, 1H), 9.00 (d, J = 8.0 Hz, 1H), 8.73- 8.72 (m, 1H), 8.49 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.76 (t, = 7.2 Hz, 1H), 7.63-7.53 (m, 3H), 7.28 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H). DMSO 95 Method G1 358.0 (M + 1) t = 1.644 min Method B (NH4HCO3)
    503
    Figure US20170217923A1-20170803-C01024
         		1H-NMR (400 MHz, DMSO- d6): δ 11.34 (s, 1H), 9.50 (s, 1H), 8.69 (d, J = 3.6 Hz, 1H), 8.65 (d, J = 7.6 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 8.00-7.97 (m, 1H), 7.91-7.84 (m, 2H), 7.69-7.66 (m, 1H), 7.55- 7.52 (m, 1H), 7.16 (t, J = 9.2 Hz, 1H). DMSO 95 Method G1 378.0 (M + 1) t = 1.780 min Method B (NH4HCO3)
    504
    Figure US20170217923A1-20170803-C01025
         		HCl 1H-NMR (300 MHz, DMSO): δ 10.48 (s, 1H), 9.57 (s, 1H), 9.13 (d, J = 7.6 Hz, 1H), 8.97- 8.80 (m, 2H), 8.31 (s, 1H), 8.19 (s, 1H), 8.10 (d, J = 6.5 Hz, 1H), 7.97 (d, J = 9.1 Hz, 2H), 7.83 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 7.9 Hz, 2H), 7.47 (d, J = 5.4 Hz, 1H), 4.02 (s, 3H). DMSO 95 Method G1 396.1 (M + 1) Method C
    505
    Figure US20170217923A1-20170803-C01026
    Figure US20170217923A1-20170803-C01027
    Figure US20170217923A1-20170803-C01028
         		1H NMR (400 MHz, DMSO) δ 15.71 (s, 1H), 10.01 (s, 1H), 9.59-9.51 (m, 1H), 8.73-8.62 (m, 2H), 8.60-8.54 (m, 1H), 8.13-7.96 (m, 2H), 7.93-7.82 (m, 2H), 7.62-7.49 (m, 2H), 4.01 (s, 3H). DMSO >98 G1
    506
    Figure US20170217923A1-20170803-C01029
    Figure US20170217923A1-20170803-C01030
    Figure US20170217923A1-20170803-C01031
         		1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 9.75 (s, 1H), 9.55-9.46 (m, 1H), 8.73-8.60 (m, 2H), 7.96 (d, J = 2.7 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.58- 7.47 (m, 3H), 6.99 (d, J = 8.5 Hz, 1H), 4.64 (s, 2H), 3.97 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    507
    Figure US20170217923A1-20170803-C01032
    Figure US20170217923A1-20170803-C01033
    Figure US20170217923A1-20170803-C01034
         		1H NMR (400 MHz, DMSO) δ 12.54 (s, 1H), 9.85 (s, 1H), 9.51 (s, 1H), 8.70-8.60 (m, 2H), 8.27-8.16 (m, 2H), 8.03 (d, J = 2.5 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.72-7.59 (m, 2H), 7.56-7.47 (m, 2H), 3.99 (s, 3H). DMSO >98 G1
    508
    Figure US20170217923A1-20170803-C01035
    Figure US20170217923A1-20170803-C01036
    Figure US20170217923A1-20170803-C01037
         		1H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 9.50-9.47 (m, 1H), 8.66-8.61 (m, 2H), 8.21 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.74 (dd, J = 8.7, 1.9 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.56-7.47 (m, 2H), 3.99 (s, 3H), 3.90 (s, 3H). DMSO >98 G1
    509
    Figure US20170217923A1-20170803-C01038
    Figure US20170217923A1-20170803-C01039
    Figure US20170217923A1-20170803-C01040
         		1H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 9.47 (dd, J = 2.1, 0.8 Hz, 1H), 8.67-8.60 (m, 2H), 8.15 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 2.7 Hz, 1H), 7.88-7.81 (m, 2H), 7.57- 7.49 (m, 2H), 7.44 (d, J = 8.7 Hz, 1H), 3.98 (s, 3H), 3.47 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    510
    Figure US20170217923A1-20170803-C01041
    Figure US20170217923A1-20170803-C01042
    Figure US20170217923A1-20170803-C01043
         		1H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 10.62 (s, 1H), 9.71 (s, 1H), 9.53-9.48 (m, 1H), 8.68-8.62 (m, 2H), 7.98 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.55-7.49 (m, 2H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 3.97 (s, 3H). DMSO >98 G1 (0.1 N HCl added)
    511
    Figure US20170217923A1-20170803-C01044
    Figure US20170217923A1-20170803-C01045
    Figure US20170217923A1-20170803-C01046
         		1H NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 9.49 (dd, J = 2.1, 0.8 Hz, 1H), 8.79 (s, 1H), 8.67-8.61 (m, 2H), 8.39-8.36 (m, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.90-7.84 (m, 3H), 7.56 (dd, J = 9.1, 2.7 Hz, 1H), 7.54- 7.50 (m, 1H), 3.99 (s, 3H). DMSO >98 J2
    512
    Figure US20170217923A1-20170803-C01047
    Figure US20170217923A1-20170803-C01048
    Figure US20170217923A1-20170803-C01049
         		1H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 9.48 (dd, J = 2.1, 0.8 Hz, 1H), 8.67-8.61 (m, 2H), 8.10-8.08 (m, 1H), 8.00 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.65- 7.63 (m, 2H), 7.57-7.49 (m, 2H), 4.22 (s, 3H), 3.99 (s, 3H). DMSO >98 G1
    513
    Figure US20170217923A1-20170803-C01050
    Figure US20170217923A1-20170803-C01051
    Figure US20170217923A1-20170803-C01052
         		1H NMR (400 MHz, DMSO) δ 9.92 (s, 1H), 9.49 (dd, J = 2.1, 0.8 Hz, 1H), 8.67-8.60 (m, 2H), 8.22 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.70- 7.64 (m, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.57-7.49 (m, 2H), 4.21 (s, 3H), 3.98 (s, 3H). DMSO >98 J2
    514
    Figure US20170217923A1-20170803-C01053
    Figure US20170217923A1-20170803-C01054
    Figure US20170217923A1-20170803-C01055
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.43 (d, J = 1.6 Hz, 1H), 8.98-8.91 (m, 1H), 8.89 (dd, J = 5.2, 1.3 Hz, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 8.13-8.04 (m, 2H), 7.92-7.85 (m, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.70-7.63 (m, 2H), 4.21 (s, 3H), 4.02 (s, 3H). DMSO >98 G1
    515
    Figure US20170217923A1-20170803-C01056
    Figure US20170217923A1-20170803-C01057
    Figure US20170217923A1-20170803-C01058
         		HCl 1H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 10.45 (s, 1H), 9.46 (d, J = 1.7 Hz, 1H), 8.97-8.89 (m, 1H), 8.85 (dd, J = 5.2, 1.5 Hz, 1H), 8.16- 8.10 (m, 2H), 8.03-7.97 (m, 2H), 7.94 (d, J = 9.1 Hz, 1H), 7.90-7.82 (m, 1H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.58 (d, J = DMSO >98 G1 (0.1 N HCl added)
    9.4 Hz, 1H), 4.00 (s, 3H).
    516
    Figure US20170217923A1-20170803-C01059
    Figure US20170217923A1-20170803-C01060
    Figure US20170217923A1-20170803-C01061
         		1H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 9.53-9.50 (m, 1H), 8.68-8.63 (m, 2H), 8.27 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 9.1 Hz, 1H), 7.81 (dd, J = 8.7, 2.1 Hz, 1H), 7.58-7.50 (m, 2H), 4.20 (s, 3H), 3.99 (s, 3H). DMSO >98 G1
    517
    Figure US20170217923A1-20170803-C01062
    Figure US20170217923A1-20170803-C01063
    Figure US20170217923A1-20170803-C01064
         		HCl 1H NMR (300 MHz, DMSO) δ 11.35 (s, 1H), 9.58 (d, J = 1.6 Hz, 1H), 9.24 (d, J = 8.2 Hz, 1H), 9.05-8.97 (m, 1H), 9.05-8.95 (m, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.11-8.02 (m, 3H), 7.90 (d, J = 7.8 Hz, 1H), 7.58 (dd, J = 8.8, 2.0 Hz, 2H), 7.52-7.46 (m, 1H), 7.28 (s, DMSO >98 G1
    1H), 3.98 (d, J = 9.2 Hz, 3H).
    518
    Figure US20170217923A1-20170803-C01065
    Figure US20170217923A1-20170803-C01066
    Figure US20170217923A1-20170803-C01067
         		2 HCl 1H NMR (300 MHz, DMSO) δ 11.32 (s, 1H), 9.60 (s, 1H), 9.23 (d, J = 8.0 Hz, 1H), 8.98 (d, J = 5.4 Hz, 1H), 8.26 (s, 1H), 8.06 (dd, J = 13.2, 7.3 Hz, 2H), 7.63 (d, J = 9.1 Hz, 1H), 7.50-7.36 (m, 4H), 7.32 (s, 1H), 7.06-6.90 (m, 1H), 3.99 (s, 3H), 3.86 (s, 3H). DMSO >98 G1
    519
    Figure US20170217923A1-20170803-C01068
    Figure US20170217923A1-20170803-C01069
    Figure US20170217923A1-20170803-C01070
         		2HCl 1H NMR (300 MHz, DMSO) δ 13.17 (s, 1H), 11.46 (s, 1H), 9.19 (d, J = 1.7 Hz, 1H), 8.95- 8.78 (m, 2H), 8.31 (d, J = 2.6 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.86 (dd, J = 7.9, 5.4 Hz, 1H), 7.77-7.54 (m, 3H), 7.44 (dd, J = 11.4, 3.9 Hz, 1H), 7.20-7.02 (m, 1H), 4.01 (s, 3H). DMSO >98 G1
    520
    Figure US20170217923A1-20170803-C01071
    Figure US20170217923A1-20170803-C01072
    Figure US20170217923A1-20170803-C01073
         		HCl 1H NMR (300 MHz, DMSO) δ 11.10 (s, 1H), 9.59 (d, J = 1.8 Hz, 1H), 9.15 (d, J = 8.0 Hz, 1H), 8.93 (d, J = 3.9 Hz, 1H), 8.22 (d, J = 2.6 Hz, 1H), 7.99 (t, J = 7.4 Hz, 2H), 7.72 (dd, J = 8.4, 4.7 Hz, 2H), 7.63-7.50 (m, 2H), 7.35 (s, 1H), 7.27-7.18 (m, 1H), 3.99 DMSO >98 G1
    (s, 3H).
    521
    Figure US20170217923A1-20170803-C01074
    Figure US20170217923A1-20170803-C01075
    Figure US20170217923A1-20170803-C01076
         		HCl 1H NMR (300 MHz, DMSO) δ 11.51 (s, 1H), 9.63 (d, J = 1.9 Hz, 1H), 9.18 (d, J = 8.1 Hz, 1H), 8.98 (dd, J = 5.2, 1.2 Hz, 1H), 8.31 (d, J = 2.5 Hz, 1H), 8.17 (d, J = 9.1 Hz, 1H), 8.01 (dd, J = 8.0, 5.3 Hz, 1H), 7.84 (dd, J = 7.7, 1.5 Hz, 1H), 7.66 (dd, J = 9.1, 2.5 Hz, 1H), 7.48-7.35 (m, 2H), 7.21 (d, J = 8.2 Hz, 1H), 7.10 (t, DMSO >98 G1
    J = 7.5 Hz, 1H), 3.99 (d, J =
    6.3 Hz, 6H).
    1758
    Figure US20170217923A1-20170803-C01077
    Figure US20170217923A1-20170803-C01078
    Figure US20170217923A1-20170803-C01079
         		3HCl 1H NMR (DMSO-d6) ppm 13.00-12.40 (br, 1H), 9.79 (d, J = 1.68 Hz, 1H), 9.30 (d, J = 8.20 Hz, 1H), 8.95 (dd, J = 5.32, 1.44 Hz, 1H), 8.71 (d, J = 4.24 Hz, 1H), 8.37 (brd, J = 2.56 Hz, 1H), 8.25- 8.21 (m, 2H), 8.11-8.02 (m, 2H), 7.98 (d, J = 9.12 Hz, 1H), 7.66 (dd, J = 9.12, 2.68 Hz, 1H), 7.53-7.50 (m, 1H), 4.03 (s, 3H). The 1H of 3HCl was not observed. DMSO >98 G13
    1759
    Figure US20170217923A1-20170803-C01080
    Figure US20170217923A1-20170803-C01081
    Figure US20170217923A1-20170803-C01082
         		3HCl 1H NMR (DMSO-d6) ppm 10.35 (br, 1H), 9.37 (d, J = 1.6 Hz, 1H), 8.96 (d, J = 7.28 Hz, 1H), 8.90 (d, J = 4.2 Hz, 1H), 8.04 (s, 1H), 7.98 (m, 1H), 7.95 (d, J = 9.16 Hz, 1H), 7.64 (dd, J = 9.16, 2.56 Hz, 1H), 6.18 (s, 1H), 3.98 (s, 3H), 3.66 (s, 3H), 2.24 (s, 3H). The 1H of 3HCl was not observed. DMSO >98 J2
  • Figure US20170217923A1-20170803-C01083
    Figure US20170217923A1-20170803-C01084
  • Figure US20170217923A1-20170803-C01085
    Figure US20170217923A1-20170803-C01086
    • Method K: 2-Amino-5-methoxybenzoic acid (viii-a)
  • 5-Methoxy-2-nitrobenzoic acid (30.0 g, 152.2 mmol) was hydrogenated over Pd/C (10%, 300 mg) in THF (250 mL) at room temperature under H2 balloon. The mixture was stirred for 18 h. After the reaction was completed, the catalyst was removed by filtration over Celite and the filtrate was concentrated to afford 25.0 g of 2-amino-5-methoxybenzoic acid as a brown solid (98%). LCMS m/z=168.1 (M+1), 150.1 (M−17) (Method B) (retention time=0.53 min) 1H NMR (400 MHz, DMSO-d6): δ 7.31 (d, J=2.8 Hz, 1H), 6.61 (dd, J=8.8, 3.2 Hz, 1H), 6.44 (d, J=8.8 Hz, 1H), 3.60 (s, 3H).
    • Method H: 6-Methoxyquinazoline-2,4(1H, 3H)-dione (ix-a)
  • 2-Amino-5-methoxybenzoic acid (13.0 g, 77.8 mmol, 1.0 eq.) was suspended in water (200 mL) and glacial acetic acid (5.2 mL) at 35° C. A freshly prepared solution of potassium cyanate (8.21 g, 101.4 mmol, 1.3 eq.) in water (86 mL) was added dropwise to the stirred mixture. After 4 h, NaOH (104.0 g, 2600 mL, 33.4 eq.) was added in portions, keeping the reaction temperature below 40° C. A clear solution was obtained momentarily before a precipitate formed. After cooling, the precipitate was filtered off and dissolved in hot water which was acidified to pH 5. The precipitate was collected and washed with water, dried by lyophilization to afford 9.63 g of 6-methoxyquinazoline-2,4 (1H, 3H)-dione as a white solid (65%). LCMS m/z=193.1 (M+1) (Method B) (retention time=1.22 min). 1H-NMR (400 MHz, DMSO-d6): δ 11.26 (s, 1H), 11.01 (s, 1H), 7.31-7.25 (m, 2H), 7.10 (d, 1H, J=8.8 Hz), 3.77 (s, 3H).
    • Method F1: 2,4-Dichloro-6-methoxyquinazoline (x-a)
  • To a mixture of 6-methoxyquinazoline-2,4(1H, 3H)-dione (9.63 g, 50.2 mmol) in POCl3 (150 mL) was added N,N-dimethylaniline (0.5 mL). The resulting mixture was stirred at 120° C. for 2 h. After the reaction was completed, POCl3 was removed in vacuo, and the residue was added to ice-water slowly. The pH was adjusted to ˜7 by slowly adding NaHCO3 (sat.) at 0° C., then a precipitate formed. The solid was collected and dried in vacuo to give 11.2 g of 2,4-dichloro-6-methoxyquinazoline in a 98% yield as a brown solid. LCMS m/z=229.1, 231.0 (M+1) (Method B) (retention time=1.87 min). 1H-NMR (400 MHz, DMSO-d6): δ 7.89 (d, J=9.2 Hz, 1H), 7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.38 (d, J=1.6 Hz, 1H), 3.91 (s, 3H).
    • Method M: 2-Chloro-6-methoxyquinazolin-4-ol (xi-a)
  • A mixture of 2,4-dichloro-6-methoxyquinazoline (4.20 g, 18.5 mmol, 1.0 eq.) in THF (60 mL) and H2O (60 mL) was treated with NaOH (4.00 g, 100 mmol, 5.4 eq.). The resulting mixture was stirred at 40° C. for 2 h. The reaction color turned to dark green and then a precipitate formed. After the reaction was completed, the mixture was cooled to room temperature. The precipitate was filtered off and the filtrate was concentrated down to 60 mL. The pH was then adjusted to 6 by adding 2N HCl in water. The precipitate which formed was collected and dried in vacuo to give 4.00 g of 2-chloro-6-methoxyquinazolin-4-ol as a grey solid (98%). LCMS m/z=211.1, 213.0 (M+1) (Method B) (retention time=1.11 min).
    • Method N: 6-Methoxy-2-(pyridin-3-yl) quinazolin-4-ol (xii-a)
  • To a mixture of 2-chloro-6-methoxyquinazolin-4-ol (1.20 g, 5.7 mmol, 1.0 eq.), pyridin-3-ylboronic acid (1.27 g, 8.6 mmol, 1.5 eq.), K2CO3 (2.37 g, 17.1 mmol, 3.0 eq.) in dioxane (100 mL) and H2O (10 mL) was added Pd(PPh3)2Cl2 (230 mg, 0.29 mmol, 0.05 eq.) under N2 atmosphere. The resulting mixture was stirred at 105° C. under N2 atmosphere overnight. After reaction was completed, the mixture was cooled to room temperature, and the resultant precipitate was removed by filtration. The filtrate was concentrated in vacuo and the residue was partitioned between H2O (30 mL) and ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over MgSO4. After filtration and evaporation, the crude product was obtained, which was combined with the filter cake and dried in vacuo to give 1.35 g of 6-methoxy-2-(pyridin-3-yl) quinazolin-4-ol as a gray solid. LCMS m/z=254.1 (M+1) (Method B) (retention time=1.39 min). The crude product was used for the next step without further purification.
    • Method F1: 4-Chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (xiii-a)
  • To a mixture of 6-methoxy-2-(pyridin-3-yl) quinazolin-4-ol (600 mg, 2.37 mmol) in POCl3 (5 mL) was added N,N-dimethylaniline (1 drop). The resulting mixture was stirred at 120° C. for 30 min. After the reaction was completed, POCl3 was removed in vacuo, and the residue was added to ice-water slowly. The pH was adjusted to ˜7 by slowly adding NaHCO3 (sat.) at 0° C. and then a precipitate formed. The solid was collected and was purified by chromatography on silica gel eluted with petroleum ether/ethyl acetate (v/v=4:1 to 1:1) to give 260 mg of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline as a pale yellow solid (40.4%). LCMS m/z=272.1, 274.0 (M+1) (Method B) (retention time=1.90 min).
    • Method G1: N-(2-Fluorophenyl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine (xiv-a)
  • A mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (80 mg, 0.293 mmol, 1.0 eq.) and 2-fluoroaniline (65 mg, 0.58 mmol, 2 eq.) in i-PrOH (5 mL) was stirred at 85° C. for 18 h. After the reaction was completed, the mixture was filtered, and the filter cake was washed with H2O (10 mL) and diethyl ether (10 mL). After drying, the crude product was purified by PREP-HPLC (Condition C: Gradient: B=5%-50%, Target Peak: at 7.2 min) to give 16.5 mg of N-(2-fluorophenyl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine as a yellow solid, yield 16.4%. LCMS m/z=347.0 (M+1) (Method A) (retention time=1.31 min). 1H-NMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.33 (s, 1H), 8.72 (d, J=4.4 Hz, 1H), 8.66 (d, J=8.0 Hz, 1H), 8.80 (d, J=1.2 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.70-7.65 (m, 2H), 7.58 (dd, J=8.8, 1.2 Hz, 1H), 7.44-7.35 (m, 3H), 3.97 (s, 3H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 6 substituting with appropriate nitro benzoic acid, boronic acid and aniline
  • TABLE 2
    LCMS Method
    Number Product Salt type Molecular mass 1H-NMR 1H-NMR Solvent LCMS Protocol Purity percent for Coupling
    522
    Figure US20170217923A1-20170803-C01087
         		455.34 1H-NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 9.52-9.51 (m, 1H), 8.63-8.66 (m, 2H), 8.32 (d, J = 2.4 Hz, 1H), 7.94- 7.91 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.54 (q, J = 3.2 Hz, 1H), 7.32 (s, 1H), 4.87-4.90 (m, 1H), 3.96 (s, 3H), 1.38 (d, J = 6.0 Hz, 6H). DMSO 454.9, 457.0 (M + 1), 228.8 (M/2 + 1) Method A (TFA) 95 Method N, G1
    523
    Figure US20170217923A1-20170803-C01088
         		438.88 1H-NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 9.49 (d, J = 2.0 Hz, 1H), 8.60-8.66 (m, 2H), 8.18 (dd, J = 6.4, 2.4 Hz, 1H), 7.84-7.88 (m, 2H), 7.50-7.54 (m, 2H), 7.31 (s, 1H), 4.85-4.88 (m, 1H), 3.96 (s, 3H), 1.38 (d, J = 6.4 Hz, 6H). DMSO 439.1, 441.1 (M + 1), 220.1, 220.8 (M/2 + 1) Method A (TFA) 95 Method N, G1
    524
    Figure US20170217923A1-20170803-C01089
         		422.43 1H-NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 9.48 (s, 1H), 8.60- 8.65 (m, 2H), 8.04-8.10 (m, 1H), 7.92 (s, 1H), 7.49-7.66 (m, 3H), 7.30 (s, 1H), 4.86-4.92 (m, 1H), 3.96 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H) DMSO 423.2 (M + 1), 212.2 (M/2 + 1) Method A (TFA) 95 Method N, G1
    525
    Figure US20170217923A1-20170803-C01090
         		HCl 429.47 1H-NMR (400 MHz, DMSO-d6): δ 12.96 (s, 1H), 9.60 (d, J = 8.0 Hz, 1H), 9.14 (d, J = 8.0 Hz, 1H), 8.68-8.74 (m, 2H), 8.46 (s, 1H), 7.95-7.96 (m, 2H), 7.74-7.70 (m, 1H), 7.59-7.54 (m, 2H), 7.36 (s, 1H), 7.19-7.15 (m, 1H), 4.76-4.82 (m, 1H), 3.99 (s, 3H), 1.44 (d, J = 6.0 Hz, 6H). DMSO 430.2 (M + 1) 215.7 (M/2 + 1) Method A (TFA) 95 Method N, G1
    526
    Figure US20170217923A1-20170803-C01091
         		452.45 1H-NMR (400 MHz, DMSO-d6): δ 9.70 (s, 1H), 9.52-9.53 (m, 1H), 8.64-8.67 (m, 2H), 7.89- 7.94 (m, 2H), 7.73- 7.74 (m, 1H), 7.48-7.53 (m, 3H), 7.32 (t, J = 83.6 Hz, 1H), 6.96-6.99 (m, 1H), 4.89-4.92 (m, 1H), 3.98 (s, 3H), 1.38 (d, J = 6.0 Hz, 6H). DMSO 453.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    527
    Figure US20170217923A1-20170803-C01092
         		455.34 1H-NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 9.52 (d, J = 1.6 Hz, 1H), 8.64-8.68 (m, 2H), 8.12-8.13 (m, 2H), 7.90 (s, 1H), 7.54-7.58 (m, 1H), 7.34-7.36 (m, 2H), 4.86-4.92 (m, 1H), 3.98 (s, 3H), 1.40 (d, J = 6.0 Hz, 6H). DMSO 455.0, 457.0 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    528
    Figure US20170217923A1-20170803-C01093
         		455.34 1H-NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 9.52 (d, J = 1.2 Hz, 1H), 8.64-8.67 (m, 2H), 8.32 (d, J = 2.8 Hz, 1H), 7.94 (dd, J = 8.8, 2.4 Hz, 1H), 7.86 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.53- 7.56 (m, 1H), 7.32 (s, 1H), 4.14 (t, J = 6.4 Hz, 2H), 3.99 (s, 3H), 1.85- 1.92 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H). DMSO 455.1, 457.1 (M + 1) 229.1 (M/2 + 1) Method A (TFA) 95 Method N, G1
    529
    Figure US20170217923A1-20170803-C01094
         		438.88 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.62-8.66 (m, 2H), 8.20 (dd, J = 6.4, 2.4 Hz, 1H), 7.85-7.89 (m, 2H), 7.50-7.55 (m, 2H), 7.31 (s, 1H), 4.13 (t, J = 6.4 Hz, 2H), 3.98 (s, 3H), 1.82-1.90 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H). DMSO 439.1, 441.1 (M + 1) 220.1, 220.8 (M/2 + 1) Method A (TFA) 95 Method N, G1
    530
    Figure US20170217923A1-20170803-C01095
         		422.43 1H-NMR (400 MHz, DMSO-d6): δ 9.74-9.76 (m, 1H), 9.52 (d, J = 1.6 Hz, 1H), 8.64-8.69 (m, 2H), 8.08-8.14 (m, 1H), 7.90 (s, 1H), 7.68-7.70 (m, 1H), 7.52-7.60 (m, 2H), 7.34 (s, 1H), 4.16 (t, J = 6.4 Hz, 2H), 4.01 (s, 3H), 1.85-1.94 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H). DMSO 423.0 (M + 1) 445.0 (M + 23) 212.1 (M/2 + 1) Method A (TFA) 95 Method N, G1
    531
    Figure US20170217923A1-20170803-C01096
         		HCl 429.47 1H-NMR (400 MHz, DMSO-d6): δ 12.86 (s, 1H), 9.59 (d, J = 1.6 Hz, 1H), 9.05 (d, J = 8.4 Hz, 1H), 8.85 (d, J = 8.0 Hz, 1H), 8.76-8.78 (m, 1H), 8.44 (s, 1H), 7.96 (dd, J = 8.0, 1.6 Hz, 2H), 7.70- 7.73 (m, 2H), 7.53 (s, 1H), 7.37 (s, 1H), 6.96- 7.22 (m ,1H), 4.16 (t, J = 6.4 Hz, 2H), 4.01 (s, 3H), 1.86-1.90 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H). DMSO 430.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    532
    Figure US20170217923A1-20170803-C01097
         		452.45 1H-NMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 9.50 (d, J = 4.0 Hz, 1H), 8.62-8.65 (m, 2H), 7.89-7.92 (m, 3H), 7.44- 7.54 (m, 1H), 7.29- 7.31 (m, 3H), 7.26 (t, J = 74.0 Hz, 1H), 4.14 (t, J = 6.8 Hz, 2H), 3.98 (s, 3H), 1.84-1.90 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H). DMSO 453.1 (M + 1) 227.2 (M/2 + 1) Method A (TFA) 95 Method N, G1
    533
    Figure US20170217923A1-20170803-C01098
         		HCl 454.88 1H-NMR (400 MHz, DMSO-d6): δ 9.73 (s, 1H), 9.50 (d, J = 2.4 Hz, 1H), 8.62-8.67 (m, 2H), 8.20 (dd, J = 7.2 Hz, 2.8 Hz, 1H), 7.85-7.89 (m, 2H), 7.51-7.57 (m, 2H), 7.33 (s, 1H), 4.31 (t, J = 4.0 Hz, 2H), 3.99 (s, 3H) 3.80 (t, J = 4.8 Hz, 2H), 3.37 (s, 3H). DMSO 455.1, 457.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    534
    Figure US20170217923A1-20170803-C01099
         		445.47 1H-NMR (400 MHz, CD3OD): δ 9.34 (s, 1H), 8.92 (d, J = 6.0 Hz, 1H), 8.73 (m, 2H), 7.84 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.15 (s, 2H), 4.21 (s, 2H), 3.92 (s, 3H), 3.78 (t, J = 4.4 Hz, 2H), 3.40 (s, 3H). CD3OD 446.2, 447.2 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    535
    Figure US20170217923A1-20170803-C01100
         		HCl 468.45 1H-NMR (400 MHz, DMOS-d6): δ 9.72 (s, 1H), 9.53 (s, 1H), 8.66 (d, J = 5.6 Hz, 2H), 7.91 (d, J = 6.4 Hz, 2H), 7.75 (d, J = 7.2 Hz, 1H), 7.51 (dd, J = 7.6 Hz, 2H), 7.34 (s, 1H), 7.30 (t, J = 74.0 Hz, 1H), 6.97 (dd, J = 8.0, 2.0 Hz, 1H), 4.32 (t, J = 4.4 Hz, 2H), 3.99 (s, 3H), 3.80 (t, J = 4.4 Hz, 2H), 3.37 (s, 3H). DMSO 469.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    536
    Figure US20170217923A1-20170803-C01101
         		468.91 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.47 (s, 1H), 8.96 (d, J = 6.4 Hz, 1H), 8.90 (d, J = 5.2 Hz, 1H), 8.11 (dd, J = 6.8 Hz, 2.4 Hz, 1H), 8.05 (s, 2H), 7.85-7.94 (m, 2H), 7.55 (t, J = 9.2 Hz, 1H), 7.47 (s, 1H) 4.26 (t, J = 6.4 Hz, 2H), 4.01 (s, 3H), 3.55 (t, J = 6.0 Hz, 2H), 3.29 (s, 3H), 2.06-2.13 (m, 2H). DMSO 469.0, 471.0 (M + 1) 234.9, 235.6 (M/2 + 1) Method A (TFA) 95 Method N, G1
    537
    Figure US20170217923A1-20170803-C01102
         		397.26 1H-NMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.54 (s, 1H), 8.76 (s, 2H), 8.49 (d, J = 7.0 Hz, 1H), 8.36 (s, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.66- 7.23 (m, 2H), 7.33 (s, 2H), 3.98 (s, 3H). DMSO 397.1, 399.0 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    538
    Figure US20170217923A1-20170803-C01103
         		397.26 1H-NMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 8.54 (d, J = 1.3 Hz, 1H), 8.72-8.56 (m, 2H), 8.47 (d, J = 9.2 Hz, 1H), 8.17 (s, 1H), 8.16 (s, 1H), 7.59-7.56 (m, 1H), 7.35- 7.30 (m, 3H), 3.98 (s, 3H). DMSO 397.0, 399.0 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    539
    Figure US20170217923A1-20170803-C01104
         		364.35 1H-NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.53 (d, J = 1.6 Hz, 1H), 8.70-8.65 (m, 2H), 8.47 (d, J = 8.4 Hz, 1H), 8.12 (ddd, J = 13.2, 7.6, 2.8 Hz, 1H), 7.72-7.70 (m, 1H), 7.58-7.49 (m, 2H), 7.32-7.27 (m, 2H), 3.97 (s, 3H). DMSO 365.2 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    540
    Figure US20170217923A1-20170803-C01105
         		353.38 1H-NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.53 (d, J = 1.6 Hz, 1H), 8.71-8.66 (m, 2H), 8.50-8.43 (m, 2H), 8.26- 8.24 (m, 1H), 7.70- 7.54 (m, 3H), 7.34-7.30 (m, 2H), 3.98 (s, 3H). DMSO 354.2 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    541
    Figure US20170217923A1-20170803-C01106
         		394.37 1H-NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 9.54 (s, 1H), 8.68 (d, J = 5.2 Hz, 2H), 8.51 (d, J = 9.2 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J = 7.67 Hz, 1H), 7.55-7.10 (m, 5H), 6.96 (dd, J = 8.0, 2.0 Hz, 1H), 3.96 (s, 3H). DMSO 395.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    542
    Figure US20170217923A1-20170803-C01107
         		371.39 1H-NMR (400 MHz, DMSO-d6): δ 12.97 (s, 1H), 9.60 (s, 1H), 9.10 (d, J = 8.4 Hz, 1H), 8.75- 8.71 (m, 2H), 8.48 (s, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.95-7.90 (m, 2H), 7.74-7.70 (m, 1H), 7.58 (dd, J = 8.0, 4.8 Hz, 1H), 7.35-7.33 (m, 2H), 7.19 (t, J = 7.2 Hz, 1H), 3.97 (s, 3H). DMSO 372.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    543
    Figure US20170217923A1-20170803-C01108
         		431.7 1H-NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 9.49-9.48 (m, 1H), 8.69-8.67 (m, 1H), 8.63- 8.59 (m, 1H), 8.31 (d, J = 2.4 Hz, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.93- 7.90 (m, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.56-7.53 (m, 1H), 4.07 (s, 3H). DMSO 430.9, 432.9, 434.9 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    544
    Figure US20170217923A1-20170803-C01109
         		431.7 1H-NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.46 (d, J = 3.2 Hz, 1H), 8.68 (dd, J = 4.8, 2.0 Hz, 1H), 8.60-8.57 (m, 1H), 8.09 (s, 1H), 8.08 (s, 1H), 7.97 (s, 2H), 7.54 (dd, J = 8.8, 4.8 Hz, 1H), 7.38 (t, J = 2.0 Hz, 1H), 4.05 (s, 3H). DMSO 430.9, 432.9, 434.9 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    545
    Figure US20170217923A1-20170803-C01110
         		415.25 1H-NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.47 (s, 1H), 8.70- 8.62 (m, 2H), 8.19-8.17 (m, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.84-7.88 (m, 1H), 7.59-7.53 (m, 2H), 4.07 (s, 3H). DMSO 415.1, 417.0, 419.0 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    546
    Figure US20170217923A1-20170803-C01111
         		398.79 1H-NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.47 (d, J = 1.6 Hz, 1H), 8.69-8.67 (m, 1H), 8.62-8.59 (m, 1H), 8.08- 8.04 (m, 2H), 8.00 (s, 1H), 7.65-7.53 (m, 3H), 4.07 (s, 3H). DMSO 399.1, 401.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    547
    Figure US20170217923A1-20170803-C01112
         		428.82 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.45 (d, J = 1.2 Hz, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.85-7.78 (m, 3H), 7.55-7.51 (m, 1H), 7.31 (t, J = 72.8 Hz, 1H), 7.05-7.03 (m, 1H), 4.07 (s, 3H). DMSO 429.1, 431.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    548
    Figure US20170217923A1-20170803-C01113
         		387.82 1H-NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.38 (s, 1H), 8.97- 8.90 (m, 2H), 8.32-8.26 (m, 3H), 7.97-7.94 (m, 2H), 7.69-7.65 (m, 2H), 4.08 (s, 3H). DMSO 387.9, 390.0 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    549
    Figure US20170217923A1-20170803-C01114
         		405.84 1H-NMR (400 MHz, DMSO-d6): δ 12.98 (s, 1H), 9.36 (s, 1H), 8.94- 8.77 (m, 3H), 8.48 (s, 1H), 7.98-7.83 (m, 4H), 7.59-7.14 (m, 2H), 7.17 (s, 1H), 3.96 (s, 3H). DMSO 405.9, 408.0 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    550
    Figure US20170217923A1-20170803-C01115
         		436.12 1H-NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.39 (s, 1H), 8.87 (s, 1H), 8.81 (d, J = 4.4 Hz, 1H), 8.73 (d, J = 8.0 Hz, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.76-7.73 (m, 1H), 7.66 (d, J = 8.8 Hz, 1H). DMSO 434.9, 436.9, 438.8 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    551
    Figure US20170217923A1-20170803-C01116
         		410.26 1H-NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 9.46 (s, 1H), 8.87 (d, J = 8.4 Hz, 1H), 8.74 (d, J = 3.6 Hz, 1H), 8.68 (d, J = 7.2 Hz, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.02 (s, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.69-7.61 (m, 2H), 7.23- 7.20 (m, 1H). DMSO 410.0, 412.0, 413.9 (M + 1) 432.0 (M + 22) Method A (TFA) 95 Method N, G1
    552
    Figure US20170217923A1-20170803-C01117
         		433.24 1H-NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 9.53 (s, 1H), 9.02 (s, 1H), 8.83-8.80 (m, 2H), 8.20 (s, 1H), 7.91 (s, 1H), 7.81-7.79 (m, 1H), 7.74- 7.71 (m, 1H), 7.56- 7.52 (m, 1H), 7.30 (t, J = 73.6 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H). DMSO 432.9, 434.9 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    553
    Figure US20170217923A1-20170803-C01118
         		419.67 1H-NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.40 (s, 1H), 8.97 (s, 1H), 8.89-8.85 (m, 2H), 8.15-8.14 (m, 1H), 8.05 (s, 1H), 7.89-7.87 (m, 2H), 7.51-7.47 (m, 1H). DMSO 419.0, 421.0, 423.0 (M + 1 ) Method B (NH4HCO3) 95 Method N, G1
    554
    Figure US20170217923A1-20170803-C01119
         		403.21 1H-NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 9.40 (s, 1H), 8.96 (s, 1H), 8.84-8.89 (m, 2H), 8.04-8.00 (m, 2H), 7.88 (s, 1H), 7.69-7.67 (m, 1H), 7.54-7.47 (m, 1H). DMSO 402.9, 404.9 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    555
    Figure US20170217923A1-20170803-C01120
         		436.12 1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 8.28 (s, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.85 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.96 (s, 1H), 7.90-7.86 (m, 2H), 7.29 (s, 1H). DMSO 434.9, 436.9, 438.9 (M + 1) Method A (TFA) 95 Method N, G1
    556
    Figure US20170217923A1-20170803-C01121
         		441.31 1H-NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H), 9.50 (s, 1H), 8.66- 8.64 (m, 2H), 8.31 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.52 (dd, J = 7.4, 5.0 Hz, 1H), 7.29 (s, 1H), 4.22 (q, J = 6.8 Hz, 2H), 3.97 (s, 3H), 1.45 (t, J = 6.8 Hz, 3H). DMSO 441.0, 443.0 (M + 1) Method B NH4HCO3) 95 Method N, G1
    557
    Figure US20170217923A1-20170803-C01122
         		424.86 1H-NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.48 (s, 1H), 8.74- 8.73 (m, 2H), 8.18-8.16 (m, 1H), 7.90-7.85 (m, 2H), 7.67-7.65 (m, 1H), 7.53 (t, J = 9 Hz, 1H), 7.33 (s, 1H), 4.24 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). DMSO 425.0, 427.0 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    558
    Figure US20170217923A1-20170803-C01123
         		408.4 1H-NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 9.49 (s, 1H), 8.66- 8.61 (m, 2H), 8.10-8.04 (m, 1H), 7.84 (s, 1H), 7.66-7.64 (m, 1H), 7.56- 7.49 (m, 2H), 7.30 (s, 1H), 4.23 (q, J = 6.8 Hz, 2H), 3.98 (s, 3H), 1.46 (t, J = 6.8 Hz, 3H). DMSO 409.0 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    559
    Figure US20170217923A1-20170803-C01124
         		397.43 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.43 (s, 1H), 8.82- 8.78 (m, 2H), 8.32 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.98 (s, 1h), 7.77- 7.73 (m, 1H), 7.68-7.60 (m, 2H), 7.35 (s, 1H), 4.23 (q, J = 6.8 Hz, 2H), 3.96 (s, 3H), 1.44 (t, J = 6.8 Hz, 3H). DMSO 398.1 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    560
    Figure US20170217923A1-20170803-C01125
         		410.83 1H-NMR (400 MHz, DMSO-d6): δ 9.89 (s, 1H), 9.48 (s, 1H), 8.74 (d, J = 6.0 Hz, 2H), 8.16 (dd, J = 6.8, 2.4 Hz, 1H), 7.85- 7.88 (m, 2H), 7.67 (t, J = 6.4 Hz, 1H), 7.53 (t, J = 8.7 Hz, 1H), 7.32 (s, 1H), 3.98 (s, 6H). DMSO 411.1, 413.1 (M + 1) Method A (TFA) 95 Method N, G1
    561
    Figure US20170217923A1-20170803-C01126
         		394.37 1H-NMR (400 MHz, DMSO-d6): δ 9.92 (s, 1H), 9.49 (s, 1H), 8.77 (d, J = 6.4 Hz, 2H), 8.02- 8.08 (m, 1H), 7.90 (s, 1H), 7.70-7.74 (m, 1H), 7.64-7.66 (m, 1H), 7.52- 7.59 (m, 1H), 7.33 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H). DMSO 395.0 (M + 1), 198.1 (M/2 + 1) Method A (TFA) 95 Method N, G1
    562
    Figure US20170217923A1-20170803-C01127
         		383.4 1H-NMR (400 MHz, DMSO-d6): δ 9.87 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.63-8.68 (m, 2H), 8.38 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.52-7.56 (m, 1H), 7.33 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H). DMSO 384.2 (M + 1) Method B (NH4HCO3) 95 Method N, G1
    563
    Figure US20170217923A1-20170803-C01128
         		427.28 1H-NMR (400 MHz, DMSO-d6): δ 9.70 (s, H), 9.50 (d, J = 1.6 Hz, 1H), 8.66 (d, J = 4.8 Hz, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 1.2 Hz, 2H), 7.79 (s, 1H), 7.53 (dd, J = 7.6, 4.8 Hz, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 3.97 (s, 6H). DMSO 427.1, 429.1, 431.0 (M + 1 ) Method B (NH4HCO3) 95 Method N, G1
    564
    Figure US20170217923A1-20170803-C01129
         		2HCl 389.3824 1H-NMR (400 MHz, DMSO-d6): δ 13.08 (s, 1H), 9.40 (s, 1H), 8.86 (d, J = 8.1 Hz, 1H), 8.78 (s, 1H), 8.53 (d, J = 10.0 Hz, 1H), 8.46 (s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 8.00- 7.88 (m, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 10.3 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 3.99 (s, 3H). DMSO 390.0 (M + 1) Method B (NH4CO3) 95 Method N, G1
    565
    Figure US20170217923A1-20170803-C01130
         		2HCl 401.4180 1H-NMR (400 MHz, CD3OD): δ 9.20 (s, 1H), 8.85 (s, 1H), 8.78 (s, 1H), 8.72 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.77-7.67 (m, 3H), 7.39 (t, J = 7.6 Hz, 1H), 4.18 (s, 3H), 4.08 (s, 3H). MeOD 402.1 (M + 1 ) Method B (NH4CO3) 95 Method N, G1
  • Figure US20170217923A1-20170803-C01131
  • Figure US20170217923A1-20170803-C01132
    Figure US20170217923A1-20170803-C01133
  • Method O1: CuI/Pd(PPh3)2Cl2/Et3N/DMF/rt
      • O2: Propargyl bromide/CuI/Pd(PPh3)2Cl2/Nucleophile/DMF/rt
      • O3: Pd(OAc)2/PPh3/TBAB/piperdine/THF-H2O/rt
    Method O1: 6-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (xv-a)
  • A suspension of N-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 5-iodo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (1.00 g, 2.10 mmol), tert-butyldimethyl(2-propynyloxy)silane (0.85 ml, 4.20 mmol), copper(I) iodide (4.0 mg, 0.021 mmol), dichlorobis(triphenylphosphine) palladium (II) (Pd(PPh3)2Cl2) (29 mg, 0.042 mmol), and triethylamine (1.17 ml, 8.39 mmol) in DMF (15 mL) was stirred overnight at room temperature under argon atmosphere. Water (30 mL) and ethyl acetate (30 mL) were added to the mixture. The resultant precipitate was removed by filtration. The filtrate was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (1×100 mL) and brine (1×100 mL) and was dried over Na2SO4. After filtration and evaporation, the crude product was obtained, which was purified by column chromatography on silica gel (eluted with hexane/ethyl acetate 6:1 to 1:3) to give 0.73 g of 6-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine as light brown solid (67%). LCMS m/z=519 (M+1) (Method D) (retention time=3.22 min). 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.35 (s, 1H), 8.62-8.44 (m, 3H), 8.11 (dd, J=6.8, 2.6 Hz, 1H), 7.76-7.66 (m, 3H), 7.45-7.30 (m, 2H), 4.48 (s, 2H), 0.75 (s, 9H), 0.16 (s, 6H).
    • Method P: 6-(3-(tert-butyldimethylsilyloxy)propyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (xvi-a)
  • A suspension of 6-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (0.20 g, 0.39 mmol) and 5% Pd—S—C (40 mg) in EtOAc (5 mL) and MeOH (5 mL) was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with hexane/ethyl acetate 6:1 to 2:3) to give 0.15 g of 6-(3-(tert-butyldimethylsilyloxy)propyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine as yellow solid (74%). LCMS m/z=523 (M+1) (Method D) (retention time=3.35 min). 1H NMR (300 MHz, CDCl3) δ 9.69 (dd, J=2.2, 0.8 Hz, 1H), 8.79-8.65 (m, 2H), 8.07 (dd, J=6.5, 2.7 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.76-7.61 (m, 3H), 7.47-7.37 (m, 2H), 7.31-7.18 (m, 1H), 3.68 (t, J=6.1 Hz, 2H), 3.01-2.83 (m, 2H), 2.03-1.86 (m, 2H), 0.94 (s, 9H), 0.08 (s, 6H).
    • Method Q: 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propan-1-ol (xvii-a)
  • To a suspension of 6-(3-(tert-butyldimethylsilyloxy)propyl)-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (0.35 g, 0.67 mmol) in MeOH (10 mL) was added 1-chloroethyl chloroformate (7.2 al, 0.067 mmol). The mixture was stirred overnight at room temperature. Methanol was removed in vacuo. Sat. NaHCO3 aqueous (10 mL) and CH2Cl2 (10 mL) were added to the residue and stirred for a while. The resultant solid was collected by filtration and dried to give 0.25 g of 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propan-1-ol as light yellow solid (91%). MS m/z=409 (M+1) (Method D) (retention time=1.71 min). 1H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 9.51 (s, 1H), 8.66 (m, 2H), 8.37 (s, 1H), 8.29-8.20 (m, 1H), 7.94-7.67 (m, 3H), 7.63-7.43 (m, 2H), 4.60 (t, J=5.0 Hz, 1H), 3.56-3.35 (m, 2H), 2.94-2.69 (m, 2H), 2.15-1.56 (m, 2H).
    • Method R: 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propyl methanesulfonate (xviii-a)
  • To a suspension of 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propan-1-ol (0.25 g, 0.61 mmol) and triethylamine (0.17 ml, 1.22 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (0.057 ml, 0.73 mmol). The mixture was stirred at room temperature for 1 h. Water (10 mL) was added to the mixture and stirred for a while. The resultant precipitate was collected by filtration and washed with CH2Cl2 and dried to give 0.27 g of 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propyl methanesulfonate as pale yellow solid (91%), which was used without further purification.
    • Method G4: N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride (xviv-a)
  • (This method is representative of method G4 and G5. These two methods can be implemented in a similar way except for substitution of the appropriate solvent and temperature)
  • A solution of 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propyl methanesulfonate (40 mg, 82 mmol) and 40% Me2NH aqueous (1 mL) in methanol (2 mL) was placed in a microwave reaction vial. The mixture was heated under microwave irradiation conditions at 150° C. for 30 minutes after which the solvent was removed in vacuo. The crude product was obtained, which was purified by column chromatography on basic silica gel (eluted with ethyl acetate/methanol 1:0-*5:1). The HCl salt generated by 4 M HCl in dioxane was crystallized from 2-propanol to give 10 mg of N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride as pale brown powder (24%). LCMS m/z=436 (M+1) (Method C) (retention time=1.68 min). 1H NMR (300 MHz, DMSO) δ 10.59 (s, 1H), 10.18 (s, 1H), 9.51 (s, 1H), 8.98-8.76 (m, 2H), 8.65 (s, 1H), 8.26 (dd, J=6.8, 2.6 Hz, 1H), 8.05-7.74 (m, 4H), 7.54 (t, J=9.1 Hz, 1H), 3.19-3.03 (m, 2H), 2.97-2.83 (m, 2H), 2.78 (s, 3H), 2.77 (s, 3H), 2.16 (s, 2H).
  • Figure US20170217923A1-20170803-C01134
    • N-(3-chloro-4-fluorophenyl)-6-(3-morpholinoprop-1-ynyl)-2-(pyridin-3-yl) quinazolin-4-amine (xx-a)
  • To a solution of N-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 5-iodo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (2.19 g, 4.6 mmol, 1 eq.), Pd(PPh3)2Cl2 (161 mg, 0.23 mmol, 0.05 eq.), CuI (87 mg, 0.46 mmol, 0.1 eq.) in morpholine (15 mL) was added 3-bromoprop-1-yne (814 mg, 6.9 mmol, 1.5 eq.) at 0° C. under Ar atmosphere, following a procedure from Tetrahedron, 2007, 63, 10671-10683. The mixture was stirred at 40° C. overnight. After cooling, the mixture was filtered and methanol (60 mL) was added to the filtrate to form a precipitate. The precipitate was collected and re-crystallized from ethyl acetate twice to afford 1.60 g of xx-a as yellow solid (yield 74%). LCMS m/z=474.1 (M+1), 476.1 (M+3) (Method C) (retention time=1.97 min).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 8 substituting with appropriate nucleophile.
  • TABLE 3
    Meth-
    Reten- od
    Molecu- 1H-NMR tion for
    Num- Salt lar Sol- Time LCMS Purity Coup
    ber Product type Mass 1H-NMR vent LCMS (Min) Protocol percent ling
    566
    Figure US20170217923A1-20170803-C01135
         		519.085 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.35 (s, 1H), 8.62-8.44 (m, 3H), 8.11 (dd, J = 6.8, 2.6 Hz, 1H), 7.76-7.66 (m, 3H), 7.45- 7.30 (m, 2H), 4.48 (s, 2H), 0.75 (s, 9H), 0.00 (s, 6H). DMSO 519 (M + 1) 3.22 Method D 96 Meth- od D1
    567
    Figure US20170217923A1-20170803-C01136
         		523.117 1H NMR (300 MHz, CDCl3) δ 9.69 (dd, J = 2.2, 0.8 Hz, 1H), 8.79-8.65 (m, 2H), 8.07 (dd, J = 6.5, 2.7 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.76-7.61 (m, 3H), 7.47-7.37 (m, 2H), 7.31-7.18 (m, 1H), 3.68 (t, J = 6.1 Hz, 2H), 3.01-2.83 (m, 2H), 2.03-1. CDCl3 523 (M + 1) 3.35 Method D 100 Meth- od O1, P
    568
    Figure US20170217923A1-20170803-C01137
         		408.856 1H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 9.51 (s, 1H), 8.66 (m, 2H), 8.37 (s, 1H), 8.29- 8.20 (m, 1H), 7.94-7.67 (m, 3H), 7.63-7.43 (m, 2H), 4.60 (t, J = 5.0 Hz, 1H), 3.56-3.35 (m, 2H), 2.94-2.69 (m, 2H), 2.15-1.56 (m, 2H). DMSO 409 (M + 1) 1.71 Method D 100 Meth- od O1, P, Q
    569
    Figure US20170217923A1-20170803-C01138
         		2 HCl 508.846 1H NMR (300 MHz, DMSO) δ 10.59 (s, 1H), 10.18 (s, 1H), 9.51 (s, 1H), 8.98-8.76 (m, 2H), 8.65 (s, 1H), 8.26 (dd, J = 6.8, 2.6 Hz, 1H), 8.05-7.74 (m, 4H), 7.54 (t, J = 9.1 Hz, 1H), 3.19-3.03 (m, 2H), 2.97-2.83 (m, 2H), 2.78 (s, 3H), 2.77 (s, 3H), 2. DMOS 436 (M + 1) 1.68 Method C 100 Meth- od G4
    570
    Figure US20170217923A1-20170803-C01139
         		409.841 1H NMR (300 MHz, CDCl3) δ 9.49 (d, J = 1.4 Hz, 1H), 8.73-8.51 (m, 2H), 8.14 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.81 (dd, J = 8.6, 1.9 Hz, 1H), 7.51-7.13 (m, 4H), 3.77 (dd, J = 11.5, 6.2 Hz, 2H), 3.11-2.86 (m, 2H), 2.16- 1.93 (m, 2H), 1.44 (t, J = 5 CDCl3 410 (M + 1) 1.95 Method D 100 Meth- ods O1, P, Q
    571
    Figure US20170217923A1-20170803-C01140
         		2 HCl 550.882 1H NMR (300 MHz, DMSO) δ 10.83-10.37 (m, 2H), 9.51 (s, 1H), 8.97-8.74 (m, 2H), 8.62 (s, 1H), 8.27 (d, J = 4.2 Hz, 1H), 8.05- 7.72 (m, 4H), 7.54 (t, J = 9.0 Hz, 1H), 3.96 (d, J = 12.7 Hz, 2H), 3.76 (t, J = 12.1 Hz, 2H), 3.47 (d, J = 12.0 Hz, 2H), 3.24 DMSO 478 (M + 1) 2.01 Method C 100 Meth- od G4
    572
    Figure US20170217923A1-20170803-C01141
         		422.882 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.51 (s, 1H), 8.75-8.60 (m, 2H), 8.37 (s, 1H), 8.26 (dd, J = 6.9, 2.6 Hz, 1H), 7.99-7.88 (m, 1H), 7.88-7.73 (m, 2H), 7.60-7.46 (m, 2H), 3.39 (dd, J = 8.4, 4.1 Hz, 2H), 3.27 (s, 3H), 2.92-2.78 (m, 2H), 2.05 DMSO 423 (M + 1) 2.09 Method D 100 Meth- od G4
    573
    Figure US20170217923A1-20170803-C01142
         		HCl 548.909 1H NMR (300 MHz, DMSO) δ 10.69 (s, 1H), 10.12 (s, 1H), 9.51 (s, 1H), 9.02-8.80 (m, 2H), 8.69 (s, 1H), 8.27 (dd, J = 6.9, 2.7 Hz, 1H), 8.06-7.78 (m, 4H), 7.54 (t, J = 9.1 Hz, 1H), 3.46 (d, J = 10.2 Hz, 2H), 3.17-3.00 (m, 2H), 2.99-2.75 (m, 4H), 2.3 DMSO 476 (M + 1) 1.79 Method C 100 Meth- od G4
    574
    Figure US20170217923A1-20170803-C01143
         		HCl 500.395 1H NMR (300 MHz, DMSO) δ 10.68 (s, 1H), 9.49 (s, 1H), 9.12-8.99 (m, 1H), 8.94 (d, J = 3.9 Hz, 1H), 8.58 (d, J = 11.5 Hz, 1H), 8.17 (dd, J = 6.7, 2.6 Hz, 1H), 8.07-7.82 (m, 5H), 7.55 (t, J = 9.1 Hz, 1H), 3.43-3.29 (m, 2H), 3.08-2.65 (m, 5H), 2.09- DMSO 464 (M + 1) 1.78 Method D 95 Meth- od G4 fol- lowed by acyla- tion with acetyl chlor- ide/ TEA/ DCM, rt
    575
    Figure US20170217923A1-20170803-C01144
         		HCl 600.39 1H NMR (300 MHz, DMSO) δ 11.79 (s, 1H), 10.81 (s, 1H), 9.50 (s, 1H), 8.98 (d, J = 8.2 Hz, 1H), 8.89 (d, J = 5.0 Hz, 1H), 8.75 (s, 1H), 8.27 (d, J = 4.8 Hz, 1H), 8.10-7.79 (m, 4H), 7.53 (t, J = 9.1 Hz, 1H), 5.18-3.09 (m, 10H), 3.01-2.69 (m, 5H), 2.37 DMSO 491 (M + 1) 1.76 Method C 100 Meth- od G4
    576
    Figure US20170217923A1-20170803-C01145
         		473.93 1H NMR (300 MHz, DMSO) δ 10.17 (s, 1H), 9.52 (s, 1H), 8.70 (s, 1H), 8.66 (d, J = 8.1 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.27 (dd, J = 6.9, 2.6 Hz, 1H), 7.93 (s, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.61-7.51 (m, 2H), 3.67-3.61 (m, 6H), 2.61-2.55 (m, 4H). DMSO 473.9 (M + 1) 2.2 Method C 100 Meth- od O1
    577
    Figure US20170217923A1-20170803-C01146
         		435.92 1H NMR (300 MHz, DMSO) δ 10.06 (s, 1H), 9.54 (s, 1H), 8.77-8.63 (m, 2H), 8.52 (d, J = 8.4 Hz, 1H), 8.29 (d, J = 6.8 Hz, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.64-7.51 (m, 3H), 3.00 (t, J = 8.2 Hz, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.72 (s, 6H), 2.14-1.99 ( DMSO 436.0 (M + 1) 1.68 Method C 100 Meth- ods O1, P
    578
    Figure US20170217923A1-20170803-C01147
         		519.09 1H NMR (300 MHz, DMSO) δ 10.17 (s, 1H), 9.67-9.43 (m, 1H), 6.68 (s, 2H), 8.55 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 7.89 (s, 2H), 7.68 (s, 1H), 7.56 (d, J = 9.1 Hz, 2H), 4.64 (s, 2H), 0.92 (s, 9H), 0.18 (s, 6H). DMSO 518.8 (M + 1) 3.18 Method C 100 Meth- od O1
    579
    Figure US20170217923A1-20170803-C01148
         		404.62 1H NMR (300 MHz, DMSO) δ 10.19 (s, 1H), 9.51 (s, 1H), 8.65 (d, J = 8.1 Hz, 2H), 8.54 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 7.85 (s, 2H), 7.67-7.60 (m, 1H), 7.52 (d, J = 7.0 Hz, 2H), 5.48 (s, 1H), 4.39 (d, J = 5.8 Hz, 2H). DMSO 404.9 (M + 1) 2.05 Method C 100 Meth- ods O1, Q
    580
    Figure US20170217923A1-20170803-C01149
         		477.96 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.51 (s, 1H), 8.73-8.61 (m, 2H), 8.45 (d, J = 8.6 Hz, 1H), 8.28 (dd, J = 6.8, 2.5 Hz, 1H), 7.97-7.86 (m, 1H), 7.71 (s, 1H), 7.60-7.47 (m, 3H), 3.63-3.51 (m, 4H), 2.82 (t, J = 7.5 Hz, 2H), 2.42-2.25 (m, 6H). DMSO 477.9 (M + 1) 1.99 Method C 100 Meth- ods O1, P
    581
    Figure US20170217923A1-20170803-C01150
         		523.12 1H NMR (300 MHz, CDCl3) δ 9.67 (d, J = 1.3 Hz, 1H), 8.76-8.66 (m, 2H), 8.03 (dd, J = 6.5, 2.7 Hz, 1H), 7.82-7.74 (m, 2H), 7.64 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 7.46 (s, 1H), 7.44-7.37 (m, 2H), 7.20 (t, J = 8.7 Hz, 1H), 3.67 (t, J = 6.1 Hz, 2H), 2.95 CDCl3 523.1 (M + 1) 3.35 Method C 100 Meth- ods O1, P
    582
    Figure US20170217923A1-20170803-C01151
         		408.86 1H NMR (300 MHz, CD3OD) δ 9.50 (d, J = 1.3 Hz, 1H), 8.77 (d, J = .0 Hz, 1H), 8.62 (dd, J = 4.9, 1.6 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.18 (dd, J = 6.7, 2.6 Hz, 1H), 7.83-7.71 (m, 2H), 7.61-7.47 (m, 2H), 7.30 (t, J = 9.0 Hz, 1H), 3.65 (t, J = 6.4 Hz CD3OD 409.0 (M + 1) 1.99 Method C 100 Meth- ods O1, P, Q
    583
    Figure US20170217923A1-20170803-C01152
         		494.03 1H NMR (300 MHz, CD3OD) δ 9.50-9.46 (m, 1H), 8.77-8.70 (m, 1H), 8.61 (dd, J = 4.9, 1.6 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.17 (dd, J = 6.8, 2.6 Hz, 1H), 7.75 (ddd, J = 9.0, 4.2, 2.7 Hz, 1H), 7.70 (s, 1H), 7.54 (ddd, J = 8.0, 4.9, 0.8 Hz, 1H), 7.46 (d CD3OD 494.0 (M + 1) 2.29 Method C 91 Meth- od G4
    584
    Figure US20170217923A1-20170803-C01153
         		522 1H NMR (300 MHz, DMSO) δ 10.15 (s, 1H), 8.74-8.61 (m, 2H), 8.25 (d, J = 3.5 Hz, 1H), 7.96-7.80 (m, 4H), 7.59-7.46 (m, 2H), 3.79 (s, 2H), 3.18 (s, 4H), 3.06 (s, 4H). DMSO 522.0 (M + 1) 2.18 Method C 100 Meth- od O2
    585
    Figure US20170217923A1-20170803-C01154
         		526.06 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.52 (d, J = 2.0 Hz, 1H), 8.72-8.62 (m, 2H), 8.37 (s, 1H), 8.27 (dd, J = 6.9, 2.6 Hz, 1H), 7.96-7.88 (m, 1H), 7.83 (d, J = 2.6 Hz, 2H), 7.61-7.50 (m, 2H), 3.10 (s, J = 17.4 Hz, 6H), 2.95-2.80 (m, 8H), 2.58- DMSO 526.1 (M + 1) 2.11 Method C 91 Meth- ods O2, P
    586
    Figure US20170217923A1-20170803-C01155
         		HCl 494.82 1H NMR (300 MHz, DMSO) δ 10.49 (s, 1H), 9.50 (s, 1H), 8.96-8.53 (m, 5H), 8.25 (dd, J = 6.9, 2.5 Hz, 1H), 8.05-7.73 (m ,4H), 7.54 (t, J = 9.1 Hz, 1H), 3.02-2.78 (m, 4H), 2.64- 2.37 (m, 3H), 2.15-1.99 (m, 2H). DMSO 422 (M + 1) 1.64 Method B (Ammonium formate) 100 Meth- od O2
    587
    Figure US20170217923A1-20170803-C01156
         		HCl 480.79 1H NMR (300 MHz, DMSO) δ 10.61 (s, 1H), 9.50 (s, 1H), 9.00-8.78 (m, 2H), 8.66 (s, 1H), 8.25 (dd, J = 6.8, 2.6 Hz, 1H), 8.13-7.75 (m, 7H), 7.54 (t, J = 9.1 Hz, 1H), 3.02-2.73 (m, 4H), 2.14-1.94 (m, 2H). DMSO 408 (M + 1) 1.60 Method B (Ammonium formate) 100 Meth- od O2
    588
    Figure US20170217923A1-20170803-C01157
         		431.89 1H NMR (300 MHz, DMSO) δ 10.18 (s, 1H), 8.65 (d, J = 6.6 Hz, 1H), 8.56 (d, J = 8.7 Hz, 1H), 8.23 (dd, J = 6.9, 2.4 Hz, 1H), 8.01 (s, 1H), 7.91 (dd, J = 7.0, 3.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.68-7.39 (m, 3H), 4.07 (s, 2H), 2.67 (s, 6H). DMSO 431.9 (M + 1) Method C 99 Meth- od O1
    589
    Figure US20170217923A1-20170803-C01158
         		435.92 1H NMR (300 MHz, DMSO) δ 10.06 (s, 1H), 9.53 (s, 1H), 8.76-8.62 (m, 2H), 8.51 (d, J = 8.4 Hz, 1H), 8.28 (dd, J = 6.9, 2.5 Hz, 1H), 7.92 (dd, J = 4.5, 1.8 Hz, 1H), 7.79 (s, 1H), 7.65-7.49 (m, 3H), 3.08-2.95 (m, 2H), 2.86 (t, J = 7.6 Hz, 2H), 2.71 (s, J = 7.2 Hz, 6H), 2.05 (dt, J = 13.8, 7.1 Hz, 2H). DMSO 436.0 (M + 1) Method C 99 Meth- od O1, P
    590
    Figure US20170217923A1-20170803-C01159
         		409.44 1H-NMR (300 MHz, DMSO): δ 13.19 (s, 1H), 9.11 (s, 1H), 8.88 (s, 1H), 8.53 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.94 (d, J = 10.6 Hz, 4H), 7.78 (s, 1H), 7.25 (s, 1H), 4.44 (s, 2H), 3.37 (s, 3H). DMOS 410.5 (M + 1) Method C 95 Meth- od O1
    591
    Figure US20170217923A1-20170803-C01160
         		413.47 DMSO 414.5 (M + 1) Method C 95 Meth- od O1, P
  • Figure US20170217923A1-20170803-C01161
    • Method N1: Pd(APhos)2Cl2/K3PO4 or Cs2CO3/Boronic acid or ester/Dioxane—H2O, Heat Method N2: Pd(PPh3)2Cl2/K2CO3/Boronic acid or ester/DME-EtOH-H2O/Microwave, 120° C. Method N3: Pd(OAc)2/Xphos/Cs2CO3/THF—H2O, 80° C. Method N4: Pd(OAc)2/Sphos/K2CO3/MeCN—H2O, Microwave, 120° C. Method N5: Pd(PPh3)4/K3PO4/Dioxane—H2O, Heat Method N6: Pd(dppf)Cl2—CH2Cl2/K3PO4/Dioxane—H2O, Heat
  • Figure US20170217923A1-20170803-C01162
    • N-(3-chloro-4-fluorophenyl)-6-(6-methoxypyridin-3-yl)-2-(pyridin-3-yl)quinazolin-4-amine (xxi-a)
  • A 2.0 dram reaction vial was charged with 6-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 5-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol, 1.0 equiv), 6-methoxypyridin-3-ylboronic acid (44.5 mg, 0.291 mmol, 1.25 equiv), Pd(APhos)2Cl2 (6.6 mg, 0.0093 mmol, 4 mol %) and potassium phosphate monohydrate (69 mg, 0.70 mmol, 3.0 equiv). The mixture was suspended in dioxane/water (9:1, 4 mL), and the reaction was heated at 90° C. for 14 h. The reaction mixture was cooled to room temperature, diluted with water (15 mL) and the resultant precipitate was collected by filtration. The crude product was purified by stirring in methanol for 30 min at 60° C. to give the desired product as a pale yellow solid (58 mg, 54%) LCMS m/z=458.1 (M+1) (Method C) (retention time=2.56 min). 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.53 (s, 1H), 8.82 (s, 1H), 8.70 (dd, J=16.9, 5.4 Hz, 3H), 8.25 (d, J=8.6 Hz, 3H), 8.01-7.87 (m, 2H), 7.57 (dd, J=11.2, 6.0 Hz, 2H), 7.03 (d, J=8.6 Hz, 1H), 3.94 (s, 3H).
  • Figure US20170217923A1-20170803-C01163
    • N-(3-chloro-4-fluorophenyl)-7-(6-methoxypyridin-3-yl)-2-(pyridin-3-yl)quinazolin-4-amine (xxi-b)
  • A microwave vial was charged with 7-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 4-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol), 6-methoxypyridin-3-ylboronic acid (44.5 mg, 0.291 mmol, 1.25 equiv), Pd(PPh3)2Cl2 (8.1 mg, 5 mol %) and potassium carbonate (160.1 mg, 1.16 mmol, 5.0 equiv). The mixture was suspended in DME/water/ethanol (7:3:2, 4 mL), and the reaction was heated under microwave irradiation conditions at 120° C. for 10 minutes. The crude reaction mixture was diluted with water (10 mL) and then filtered. The solid residue was dissolved in methanol/THF (1:1, 5 mL) with heating and then filtered through Celite to remove the catalyst. The resulting filtrate was concentrated to afford the desired product as a tan solid (7.0 mg, 6.5%). LCMS m/z=458.1 (M+1) (Method C) (retention time=2.51 min). 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.55 (s, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.72-8.65 (m, 2H), 8.62 (d, J=8.6 Hz, 1H), 8.34-8.26 (m, 2H), 8.15 (d, J=1.6 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.97-7.88 (m, 1H), 7.61-7.49 (m, 2H), 6.99 (d, J=8.7 Hz, 1H), 3.94 (s, 3H).
  • Figure US20170217923A1-20170803-C01164
    • N-(3-chloro-4-fluorophenyl)-7-(piperidin-1-ylmethyl)-2-(pyridin-3-yl)quinazolin-4-amine (xxi-c)
  • A dry 15 mL sealed tube was charged with 7-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 4-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol), potassium 1-trifluoroboratomethylpiperidine (52.5 mg, 0.256 mmol), cesium carbonate (227.5 mg, 0.698 mmol), Pd(OAc)2 (1.6 mg, 3 mol %) and XPhos (6.7 mmol, 6 mol %) in THF/water (10:1, 3.3 mL). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was filtered through a pad of Celite and solvent was removed in vacuo. The crude product was purified by ISCO (silica, 12 g column, 97% dichloromethane—3% methanol—0.1% NH4OH) to yield the desired compound as a yellow solid (23.3 mg, 22%). LCMS m/z=448.0 (M+1) (Method C) (retention time=1.95 min). 1H NMR (300 MHz, CD3OD) δ 9.40 (d, J=1.4 Hz, 1H), 8.70-8.62 (m, 1H), 8.56 (dd, J=4.9, 1.6 Hz, 1H), 8.18-8.09 (m, 2H), 7.69 (ddd, J=6.8, 4.1, 2.1 Hz, 2H), 7.54-7.45 (m, 2H), 7.23 (t, J=9.0 Hz, 1H), 3.61 (s, 2H), 2.47 (s, 4H), 1.64 (dd, J=13.9, 8.9 Hz, 5H), 1.49 (d, J=4.1 Hz, 2H).
  • Figure US20170217923A1-20170803-C01165
    • N-(3-chloro-4-fluorophenyl)-6-(3-chlorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (xxi-d)
  • A mixture of N-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine (1.0 g, 2.10 mmol), 3-chlorophenylboronic acid (0.49 g, 3.13 mmol), Pd(PPh3)4 (0.24 g, 0.210 mmol), K3PO4 (1.34 g, 6.31 mmol) in dioxane (20 mL) and water (2.0 mL) was stirred under reflux for 2 h. Ethyl acetate (20 mL) was added to the cooled mixture and filtered. The filtered solid was recrystallized from DMF and water to give the title compound (0.50 g, 51.6%). 1H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.54 (s, 1H), 8.87 (s, 1H), 8.74-8.65 (m, 2H), 8.31-8.23 (m, 2H), 8.04-7.85 (m, 4H), 7.64-7.49 (m, 4H).
  • Figure US20170217923A1-20170803-C01166
    • 2-(7-(3-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide dihydrochloride (xxi-e)
  • A mixture of 2-(7-bromo-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (0.40 g, 0.952 mmol), 3-fluorophenylboronic acid (0.20 g 1.43 mmol), Pd(dppf)2Cl2 (77 mg, 0.094 mmol), K3PO4 (606 mg, 2.85 mmol) in dioxane (8 mL) and water (2 mL) was refluxed under argon atmosphere for 4 h and cooled. Ethyl acetate (10 mL) was added to the mixture and a precipitate formed and was filtered. The filtered solid was recrystallized from DMF and water to give the title compound as free form. The solid as free form was suspended in ethyl acetate (10 mL) and 4N HCl in ethyl acetate (0.71 mL) was added to the suspension. A precipitate formed and was subjected to sonication for 20 min, filtered and dried to give the title compound (0.24 g, 49.6%). 1H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.64 (s, 1H), 9.21-9.08 (m, 1H), 9.07-8.89 (m, 2H), 8.51 (s, 1H), 8.38-8.26 (m, 2H), 8.16 (d, J=8.5 Hz, 1H), 8.07-7.87 (m, 3H), 7.83-7.70 (m, 3H), 7.62 (dd, J=14.2, 7.7 Hz, 1H), 7.40-7.22 (m, 2H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 11 substituting with appropriate boronic acid/ester or boronate salt, catalyst and solvent Table 4:
  • TABLE 4
    Re- Meth-
    Mo- ten- Puri- od
    lecu- 1H- tion LCMS ty for
    Num- Salt lar NMR (min) Proto- per- Coup-
    ber PRODUCT type Mass 1H-NMR Solvent LCMS Time col cent ling
    592
    Figure US20170217923A1-20170803-C01167
         		2 HCl 536.401 1H NMR (300 MHz, DMSO) δ 11.34 (s, 1H), 10.53 (s, 1H), 9.56 (s, 1H), 9.17- 8.95 (m, 2H), 8.89 (d, J = 4.5 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.08-7.81 (m, 4H), 7.62-6.98 (m, 3H), 4.53 (s, 2H), 4.05-3.74 (m, 4H), 3.48-3.07 (m, 4H). DMSO 464 (M + 1) 2.01 Meth- od C 100 Meth- od N3
    593
    Figure US20170217923A1-20170803-C01168
         		HCl 515.406 1H NMR (300 MHz, DMSO) δ 10.40 (s, 1H), 9.51 (s, 1H), 9.00-8.78 (m, 2H), 8.55 (s, 1H), 8.20 (d, J = 4.4 Hz, 1H), 8.03- 7.75 (m ,4H), 7.54 (t, J = 9.1 Hz, 1H), 4.68 (s, 1H), 3.83 (d, J = 11.2 Hz, 2H), 3.44-3.18 (m, 4H), 1.98-1.78 (m, 1H), 1.62 (d, J DMSO 479 (M + 1) 2.08 Meth- od D 97 Meth- od N3
    594
    Figure US20170217923A1-20170803-C01169
         		448.920 1H NMR (300 MHz, DMSO) δ 10.10 (s, 1H), 9.51 (s, 1H), 8.75-8.60 (m ,2H), 8.47 (s, 1H), 8.32-8.19 (m, 1H), 7.97- 7.77 (m, 3H), 7.63-7.44 (m, 2H), 4.62 (s, 2H), 4.16-3.97 (m, 1H), 1.88-1.42 (m, 8H). DMSO 449 (M + 1) 2.62 Meth- od D 92 Meth- od N3
    595
    Figure US20170217923A1-20170803-C01170
         		457.89 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.53 (s, 1H), 8.82 (s, 1H), 8.70 (dd, J = 16.9, 5.4 Hz, 3H), 8.25 (d, J = 8.6 Hz, 3H), 8.01-7.87 (m, 2H), 7.57 (dd, J = 11.2, 6.0 Hz, 2H), 7.03 (d, J = 8.6 Hz, 1H), 3.94 (s, 3H). DMSO 458.2 (M + 1) 2.56 Meth- od C 100 Meth- od N1
    596
    Figure US20170217923A1-20170803-C01171
         		449.91 1H NMR (300 MHz, DMSO) δ 10.13 (s, 1H), 9.52 (s, 1H), 8.67 (d, J = 9.8 Hz, 2H), 8.47 (s, 1H), 8.34-8.20 (m, 1H), 8.02- 7.84 (m, 3H), 7.54 (t, J = 9.2 Hz, 2H), 3.64 (d, J = 17.6 Hz, 6H), 2.43 (s, 4H). DMSO 449.9 (M + 1) 2.13 Meth - od C 100 Meth- od N3
    597
    Figure US20170217923A1-20170803-C01172
         		456.9 DMSO 456.0 (M + 1) 2.64 Meth- od C 100 Meth- od N1
    598
    Figure US20170217923A1-20170803-C01173
         		445.88 1H NMR (300 MHz, DMSO) δ 10.04 (s, 1H), 9.52 (s, 1H), 8.68 (t, J = 6.5 Hz, 2H), 8.51 (s, 1H), 8.22 (dd, J = 6.7, 2.4 Hz, 1H), 8.03-7.83 (m, 3H), 7.54 (dd, J = 11.9, 6.6 Hz, 2H), 2.50 (s, 3H), 2.33 (s, 3H). DMSO 446 (M + 1) 2.35 Meth- od C 100 Meth- od N1
    599
    Figure US20170217923A1-20170803-C01174
         		427.86 1H NMR (300 MHz, DMSO) δ 10.10 (s, 1H), 9.51 (s, 1H), 9.13 (s, 1H), 8.86 (s, 1H), 8.66 (s, 3H), 8.24 (s, 3H), 7.94 (d, J = 8.7 Hz, 2H), 7.55 (dd, J = 16.7, 9.9 Hz, 3H). DMSO 427.95 (M + 1) 2.25 Meth- od C 100 Meth- od N1
    600
    Figure US20170217923A1-20170803-C01175
         		430.86 1H NMR (300 MHz, DMSO) δ 9.98 (s, 1H), 9.51 (d, J = 1.6 Hz, 1H), 8.66 (dd, J = 11.7, 2.2 Hz, 3H), 8.38-8.20 (m, 2H), 8.20-8.02 (m, 2H), 8.02-7.80 (m, 2H), 7.71-7.42 (m, 2H), 3.93 (s, 3H). DMSO 430.9 (M + 1) 2.17 Meth- od C 100 Meth- od N1
    601
    Figure US20170217923A1-20170803-C01176
         		449.91 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.52 (d, J = 1.3 Hz, 1H), 8.77-8.55 (m, 2H), 8.41 (s, 1H), 8.28 (dd, J = 6.9, 2.6 Hz, 1H), 8.03-7.77 (m, 3H), 7.65-7.44 (m, 2H), 3.34 (s, 8H), 3.15-2.90 (m, 5H), 2.90-2.64 (m, 5H). DMSO 449.9 (M + 1) 2.04 Meth- od C 100 Meth- od N1
    602
    Figure US20170217923A1-20170803-C01177
         		445.85 1H NMR (300 MHz, DMSO) δ 10.09 (s, 1H), 9.50 (s, 1H), 8.88-8.74 (m, 2H), 8.66 (dd, J = 14.1, 5.5 Hz, 2H), 8.56- 8.42 (m, 1H), 8.23 (dd, J = 10.0, 5.7 Hz, 2H), 7.98-7.85 (m, 2H), 7.62-7.46 (m, 2H), 7.45-7.36 (m, 1H). DMSO 445.9 (M + 1) 2.43 Meth- od C 99 Meth- od N1
    603
    Figure US20170217923A1-20170803-C01178
         		512.97 1H NMR (300 MHz, DMSO) δ 10.05 (s, 1H), 9.51 (s, 1H), 8.70 (dd, J = 24.1, 7.0 Hz, 4H), 8.22 (dd, J = 14.3, 7.3 Hz, 2H), 8.10 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.4 Hz, 2H), 7.00 (d, J = 8.8 Hz, 1H), 3.74 (s, 4H), 3.55 (d, J = 4.7 DMSO 512.9 (M + 1) 2.5 Meth- od C 100 Meth- od N1
    604
    Figure US20170217923A1-20170803-C01179
         		456.9 1H NMR (300 MHz, DMSO) δ 10.16 (s, 1H), 9.53 (s, 1H), 8.81 (s, 1H), 8.78-8.60 (m, 2H), 8.30-8.20 (m, 2H), 7.99-7.89 (m, 2H), 7.55 (dd, J = 8.2, 4.7 Hz, 2H), 7.46 (t, J = 7.,6 Hz, 3H), 7.10-6.96 (m, 1H), 3.88 (s, 3H). DMSO 458.9 (M + 2) 2.65 Meth- od C 100 Meth- od N1
    605
    Figure US20170217923A1-20170803-C01180
         		486.92 1H NMR (300 MHz, DMSO) δ 10.16 (s, 1H), 9.54 (s, 1H), 8.79 (d, J = 9.7 Hz, 1H), 8.71 (s, 2H), 8.26 (d, J = 8.7 Hz, 1H), 7.95 (dd, J = 8.7, 3.7 Hz, 2H), 7.56 (dd, J = 11.7, 6.4 Hz, 1H), 7.43 (d, J = 15.2 Hz, 2H), 7.22-7.06 (m, 2H), 3.92 (s, 3H), 3.84 (s, DMSO 486.9 (M + 1) 2.48 Meth- od C 100 Meth- od N1
    606
    Figure US20170217923A1-20170803-C01181
         		486.92 DMSO 487.1 (M + 1) 2.58 Meth- od C 100 Meth- od N1
    607
    Figure US20170217923A1-20170803-C01182
         		390.84 DMSO 390.9 (M + 1) 2.48 Meth- od C 100 Meth- od N1
    608
    Figure US20170217923A1-20170803-C01183
         		539.99 1H NMR (300 MHz, DMSO) δ 10.15 (s, 1H), 9.51 (s, 1H), 8.84 (s, 1H), 8.66 (dd, J = 9.7, 6.5 Hz, 2H), 8.29-8.19 (m, 2H), 7.92 (ddd, J = 8.9, 7.5, 4.6 Hz, 4H), 7.65- 7.48 (m, 4H), 3.64 (s, 6H), 3.35 (s, 2H). DMSO 539.9 (M + 1) 2.23 Meth- od C 100 Meth- od N1
    609
    Figure US20170217923A1-20170803-C01184
         		526 526.16 (M + 1) 2.55 Meth- od C 94 Meth- od N1
    610
    Figure US20170217923A1-20170803-C01185
         		471.91 1H NMR (300 MHz, DMSO) δ 10.03 (s, 1H), 9.56 (d, J = 2.1 Hz, 1H), 8.77-8.66 (m, 3H), 8.64 (s, 1H), 8.24 (ddd, J = 8.7, 6.6, 2.6 Hz, 2H), 8.13 (s, 1H), 7.96-7.90 (m, 1H), 7.62-7.52 (m, 2H), 7.01 (d, J = 8.7 Hz, 1H), 3.94 (s, 3H), 2.78 (s, 3H). CDCl3 471.9 (M + 1) 2.93 Meth- od C 100 Meth- od N1
    611
    Figure US20170217923A1-20170803-C01186
         		474.34 1H NMR (300 MHz, DMSO) δ 10.09 (s, 1H), 9.53 (s, 1H), 8.77 (s, 1H), 8.67 (dd, J = 12.3, 4.1 Hz, 3H), 8.35 (d, J = 2.3 Hz, 1H), 8.27-8.13 (m, 2H), 8.02-7.88 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 7.7, 4.6 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 3. DMSO 474.02 (M + 1) 2.72 Meth- od C 100 Meth- od N1
    612
    Figure US20170217923A1-20170803-C01187
         		442.88 DMSO 443.1 (M + 1) 2.37 Meth- od C 100 Meth- od N1
    613
    Figure US20170217923A1-20170803-C01188
         		465.91 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.54 (s, 1H), 8.75-8.63 (m, 3H), 8.20 (dd, J = 8.2, 5.6 Hz, 2H), 8.09 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.88 (s, 1H), 7.55 (d, J = 9.1 Hz, 2H), 2.76 (s, 3H). DMSO 466.1 (M + 1) 2.78 Meth- od C 100 Meth- od N1
    614
    Figure US20170217923A1-20170803-C01189
         		457.89 1H NMR (300 MHz, DMSO) d 10.18 (s, 1H), 9.51 (s, 1H), 8.92 (s, 1H), 8.67 (dd, J = 12.7, 5.8 Hz, 2H), 8.39-8.16 (m, 3H), 7.91 (dd, J = 14.8, 5.7 Hz, 2H), 7.65-7.45 (m, 3H), 7.35 (s, 1H), 3.94 (s, 3H). DMSO 458.1 (M + 1) 2.62 Meth- od C 100 Meth- od N1
    615
    Figure US20170217923A1-20170803-C01190
         		514.93 1H NMR (300 MHz, DMSO) d 10.19 (s, 1H), 9.52 (s, 1H), 8.86 (s, 1H), 8.67 (dd, J = 10.1, 3.4 Hz, 2H), 8.28 (ddd, J = 9.4, 7.7, 2.1 Hz, 2H), 8.06-7.75 (m, 2H), 7.54 (dd, J = 9.0, 4.1 Hz, 4H), 3.99 (s, 3H), 3.82 (s, 3H) DMSO 515.1 (M + 1) 2.54 Meth- od C 100 Meth- od N1
    616
    Figure US20170217923A1-20170803-C01191
         		451.88 1H NMR (300 MHz, DMSO) d 10.16 (s, 1H), 9.50 (s, 1H), 8.86 (s, 1H), 8.66 (dd, J = 15.2, 6.9 Hz, 2H), 8.35-8.16 (m, 2H), 8.15-7.82 (m, 6H), 7.55 (dd, J = 11.1, 6.0 Hz, 2H). DMSO 452.0 (M + 1) 2.61 Meth- od C 96 Meth- od N1
    617
    Figure US20170217923A1-20170803-C01192
         		436.47 437.2 (M + 1) 2.08 Meth- od C 95 Meth- od N1
    618
    Figure US20170217923A1-20170803-C01193
         		421.45 422.2 (M + 1) 1.8 Meth- od C 100 Meth- od N1
    619
    Figure US20170217923A1-20170803-C01194
         		449.91 1H NMR (300 MHz, DMSO) δ 10.06 (s, 1H), 9.52 (d, J = 1.3 Hz, 1H), 8.73-8.64 (m, 2H), 8.51 (d, J = 8.5 Hz, 1H), 8.27 (dd, J = 6.9, 2.6 Hz, 1H), 7.96-7.86 (m, 1H), 7.82 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 3.9 Hz, 1H), 7.52 (t, J = 9.1 Hz, 1H), 3.69 (s, 2H), 3.62 (s, 4H), 2.44 (s, 4H). DMSO 449.9 (M + 1) 2.13 Meth- od C 100 Meth- od N3
    620
    Figure US20170217923A1-20170803-C01195
         		457.89 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.55 (s, 1H), 8.76 (d, J = 2.5 Hz, 1H), 8.72-8.65 (m, 2H), 8.62 (d, J = 8.6 Hz, 1H), 8.34-8.26 (m, 2H), 8.15 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.97- 7.88 (m, 1H), 7.61-7.49 (m, 2H), 6.99 (d, J = 8.7 Hz, 1H), 3.94 (s, 3H). DMSO 458.1 (M + 1) 2.51 Meth- od C 100 Meth- od N2
    621
    Figure US20170217923A1-20170803-C01196
         		462.95 1H NMR (300 MHz, CD3OD) δ 9.40 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.56 (s, 1H), 8.19-8.09 (m, 2H), 7.74 (s, 1H), 7.72-7.65 (m, 1H), 7.54-7.45 (m, 2H), 7.24 (t, J = 9.0 Hz, 1H), 3.68 (d, J = 8.0 Hz, 2H), 2.75-2.41 (m, 8H), 2.30 (s, 3H). CD3OD 463.0 (M + 1) 1.71 Meth- od C 100 Meth- od N3
    622
    Figure US20170217923A1-20170803-C01197
         		433.91 434.0 (M + 1) 1.73 Meth- od C 100 Meth- od N3
    623
    Figure US20170217923A1-20170803-C01198
         		435.92 436.0 (M + 1) 1.84 Meth- od C 100 Meth- od N3
    624
    Figure US20170217923A1-20170803-C01199
         		430.865 1H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 9.52 (d, J = 1.3 Hz, 1H), 8.72-8.60 (m, 2H), 8.49 (d, J = 8.6 Hz, 1H), 8.44 (s, 1H), 8.28 (dd, J = 6.9, 2.6 Hz, 1H), 8.15 (s, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.95-7.83 (m, 2H), 7.60-7.45 (m, 2H), 3.91 (s, 3H). DMSO 431.0 (M + 1) 2.12 Meth- od C 100 Meth- od N2
    625
    Figure US20170217923A1-20170803-C01200
         		465.97 1H NMR (300 MHz, CD3OD) δ 9.56-9.50 (m, 1H), 8.79 (dt, J = 8.1, 1.6 Hz, 1H), 8.63 (dd, J = 4.9, 1.7 Hz, 1H), 8.30 (s, 1H), 8.19 (dd, J = 6.7, 2.6 Hz, 1H), 7.91 (d, J = 1.1 Hz, 2H), 7.80 (ddd, J = 9.0, 4.2, 2.7 Hz, 1H), 7.58 (dd, J = 8.0, 4.9 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 3.75 (s, 2H), 2.84- 2.66 (m, 8H). CD3OD 466.0 (M + 1) 2.46 Meth- od C 94 Meth- od N3
    626
    Figure US20170217923A1-20170803-C01201
         		491.94 1H NMR (300 MHz, DMSO) δ 10.00 (s, 1H), 9.52 (s, 1H), 8.73-8.63 (m, 2H), 8.42 (s, 1H), 8.28 (dd, J = 6.8, 2.6 Hz, 1H), 7.92 (ddd, J = 6.8, 4.2, 2.0 Hz, 1H), 7.85 (s, 2H), 7.60-7.50 (m, 2H), 3.56- 3.43 (m, 9H), 3.07 (t, J = 7.6 Hz, 2H), 2.79 (t, J = 7.7 Hz, 2H). DMSO 491.9 (M + 1) 2 Meth- od C 93 Meth- od N1
    627
    Figure US20170217923A1-20170803-C01202
         		463.93 1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.54 (s, 1H), 8.67 (d, J = 5.3 Hz, 2H), 8.30- 8.22 (m, 2H), 7.96-7.87 (m, 1H), 7.73 (s, 1H), 7.60-7.46 (m, 2H), 3.60 (s, 6H), 2.71 (s, 3H), 2.41 (s, 4H). DMSO 464.0 (M + 1) 2.52 Meth- od C 100 Meth- od N3
    628
    Figure US20170217923A1-20170803-C01203
         		419.43 1H NMR (300 MHz, DMSO) δ 9.41 (d, J = 1.4 Hz, 1H), 9.15 (d, J = 1.7 Hz, 1H), 8.74-8.64 (m, 3H), 8.55 (dt, J = 7.9, 1.8 Hz, 1H), 8.42 (dd, J = 8.7, 2.0 Hz, 1H), 8.36- 8.29 (m, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.90 (dd, J = 7.8, 1.7 Hz, 1H), 7.61 (dd, J = 8.0, 4.8 Hz, 1H), 7.53 (dd, J = 7.9, 4.8 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H). DMSO 420.1 (M + 1) 2.12 Meth- od C 99 Meth- od N4
    Num- Starting Starting Salt
    ber Material 1 Material 2 Product type
    629
    Figure US20170217923A1-20170803-C01204
    Figure US20170217923A1-20170803-C01205
    Figure US20170217923A1-20170803-C01206
    630
    Figure US20170217923A1-20170803-C01207
    Figure US20170217923A1-20170803-C01208
    Figure US20170217923A1-20170803-C01209
    631
    Figure US20170217923A1-20170803-C01210
    Figure US20170217923A1-20170803-C01211
    Figure US20170217923A1-20170803-C01212
    632
    Figure US20170217923A1-20170803-C01213
    Figure US20170217923A1-20170803-C01214
    Figure US20170217923A1-20170803-C01215
    633
    Figure US20170217923A1-20170803-C01216
    Figure US20170217923A1-20170803-C01217
    Figure US20170217923A1-20170803-C01218
    634
    Figure US20170217923A1-20170803-C01219
    Figure US20170217923A1-20170803-C01220
    Figure US20170217923A1-20170803-C01221
    635
    Figure US20170217923A1-20170803-C01222
    Figure US20170217923A1-20170803-C01223
    Figure US20170217923A1-20170803-C01224
    636
    Figure US20170217923A1-20170803-C01225
    Figure US20170217923A1-20170803-C01226
    Figure US20170217923A1-20170803-C01227
    637
    Figure US20170217923A1-20170803-C01228
    Figure US20170217923A1-20170803-C01229
    Figure US20170217923A1-20170803-C01230
    638
    Figure US20170217923A1-20170803-C01231
    Figure US20170217923A1-20170803-C01232
    Figure US20170217923A1-20170803-C01233
    639
    Figure US20170217923A1-20170803-C01234
    Figure US20170217923A1-20170803-C01235
    Figure US20170217923A1-20170803-C01236
    640
    Figure US20170217923A1-20170803-C01237
    Figure US20170217923A1-20170803-C01238
    Figure US20170217923A1-20170803-C01239
    641
    Figure US20170217923A1-20170803-C01240
    Figure US20170217923A1-20170803-C01241
    Figure US20170217923A1-20170803-C01242
    642
    Figure US20170217923A1-20170803-C01243
    Figure US20170217923A1-20170803-C01244
    Figure US20170217923A1-20170803-C01245
    643
    Figure US20170217923A1-20170803-C01246
    Figure US20170217923A1-20170803-C01247
    Figure US20170217923A1-20170803-C01248
    644
    Figure US20170217923A1-20170803-C01249
    Figure US20170217923A1-20170803-C01250
    Figure US20170217923A1-20170803-C01251
    645
    Figure US20170217923A1-20170803-C01252
    Figure US20170217923A1-20170803-C01253
    Figure US20170217923A1-20170803-C01254
    646
    Figure US20170217923A1-20170803-C01255
    Figure US20170217923A1-20170803-C01256
    Figure US20170217923A1-20170803-C01257
    647
    Figure US20170217923A1-20170803-C01258
    Figure US20170217923A1-20170803-C01259
    Figure US20170217923A1-20170803-C01260
    648
    Figure US20170217923A1-20170803-C01261
    Figure US20170217923A1-20170803-C01262
    Figure US20170217923A1-20170803-C01263
    649
    Figure US20170217923A1-20170803-C01264
    Figure US20170217923A1-20170803-C01265
    Figure US20170217923A1-20170803-C01266
    650
    Figure US20170217923A1-20170803-C01267
    Figure US20170217923A1-20170803-C01268
    Figure US20170217923A1-20170803-C01269
    651
    Figure US20170217923A1-20170803-C01270
    Figure US20170217923A1-20170803-C01271
    Figure US20170217923A1-20170803-C01272
    652
    Figure US20170217923A1-20170803-C01273
    Figure US20170217923A1-20170803-C01274
    Figure US20170217923A1-20170803-C01275
    653
    Figure US20170217923A1-20170803-C01276
    Figure US20170217923A1-20170803-C01277
    Figure US20170217923A1-20170803-C01278
    654
    Figure US20170217923A1-20170803-C01279
    Figure US20170217923A1-20170803-C01280
    Figure US20170217923A1-20170803-C01281
    655
    Figure US20170217923A1-20170803-C01282
    Figure US20170217923A1-20170803-C01283
    Figure US20170217923A1-20170803-C01284
    656
    Figure US20170217923A1-20170803-C01285
    Figure US20170217923A1-20170803-C01286
    Figure US20170217923A1-20170803-C01287
    657
    Figure US20170217923A1-20170803-C01288
    Figure US20170217923A1-20170803-C01289
    Figure US20170217923A1-20170803-C01290
    658
    Figure US20170217923A1-20170803-C01291
    Figure US20170217923A1-20170803-C01292
    Figure US20170217923A1-20170803-C01293
    659
    Figure US20170217923A1-20170803-C01294
    Figure US20170217923A1-20170803-C01295
    Figure US20170217923A1-20170803-C01296
    660
    Figure US20170217923A1-20170803-C01297
    Figure US20170217923A1-20170803-C01298
    Figure US20170217923A1-20170803-C01299
    661
    Figure US20170217923A1-20170803-C01300
    Figure US20170217923A1-20170803-C01301
    Figure US20170217923A1-20170803-C01302
    662
    Figure US20170217923A1-20170803-C01303
    Figure US20170217923A1-20170803-C01304
    Figure US20170217923A1-20170803-C01305
    663
    Figure US20170217923A1-20170803-C01306
    Figure US20170217923A1-20170803-C01307
    Figure US20170217923A1-20170803-C01308
    664
    Figure US20170217923A1-20170803-C01309
    Figure US20170217923A1-20170803-C01310
    Figure US20170217923A1-20170803-C01311
    665
    Figure US20170217923A1-20170803-C01312
    Figure US20170217923A1-20170803-C01313
    Figure US20170217923A1-20170803-C01314
    666
    Figure US20170217923A1-20170803-C01315
    Figure US20170217923A1-20170803-C01316
    Figure US20170217923A1-20170803-C01317
         		2 HCl
    667
    Figure US20170217923A1-20170803-C01318
    Figure US20170217923A1-20170803-C01319
    Figure US20170217923A1-20170803-C01320
         		HCl
    668
    Figure US20170217923A1-20170803-C01321
    Figure US20170217923A1-20170803-C01322
    Figure US20170217923A1-20170803-C01323
         		2 HCl
    669
    Figure US20170217923A1-20170803-C01324
    Figure US20170217923A1-20170803-C01325
    Figure US20170217923A1-20170803-C01326
         		HCl
    670
    Figure US20170217923A1-20170803-C01327
    Figure US20170217923A1-20170803-C01328
    Figure US20170217923A1-20170803-C01329
         		HCl
    671
    Figure US20170217923A1-20170803-C01330
    Figure US20170217923A1-20170803-C01331
    Figure US20170217923A1-20170803-C01332
         		HCl
    672
    Figure US20170217923A1-20170803-C01333
    Figure US20170217923A1-20170803-C01334
    Figure US20170217923A1-20170803-C01335
         		HCl
    673
    Figure US20170217923A1-20170803-C01336
    Figure US20170217923A1-20170803-C01337
    Figure US20170217923A1-20170803-C01338
         		HCl
    674
    Figure US20170217923A1-20170803-C01339
    Figure US20170217923A1-20170803-C01340
    Figure US20170217923A1-20170803-C01341
         		HCl
    675
    Figure US20170217923A1-20170803-C01342
    Figure US20170217923A1-20170803-C01343
    Figure US20170217923A1-20170803-C01344
         		HCl
    676
    Figure US20170217923A1-20170803-C01345
    Figure US20170217923A1-20170803-C01346
    Figure US20170217923A1-20170803-C01347
         		HCl
    677
    Figure US20170217923A1-20170803-C01348
    Figure US20170217923A1-20170803-C01349
    Figure US20170217923A1-20170803-C01350
         		2 HCl
    678
    Figure US20170217923A1-20170803-C01351
    Figure US20170217923A1-20170803-C01352
    Figure US20170217923A1-20170803-C01353
         		HCl
    679
    Figure US20170217923A1-20170803-C01354
    Figure US20170217923A1-20170803-C01355
    Figure US20170217923A1-20170803-C01356
         		2 HCl
    680
    Figure US20170217923A1-20170803-C01357
    Figure US20170217923A1-20170803-C01358
    Figure US20170217923A1-20170803-C01359
    681
    Figure US20170217923A1-20170803-C01360
    Figure US20170217923A1-20170803-C01361
    Figure US20170217923A1-20170803-C01362
    682
    Figure US20170217923A1-20170803-C01363
    Figure US20170217923A1-20170803-C01364
    Figure US20170217923A1-20170803-C01365
    683
    Figure US20170217923A1-20170803-C01366
    Figure US20170217923A1-20170803-C01367
    Figure US20170217923A1-20170803-C01368
    684
    Figure US20170217923A1-20170803-C01369
    Figure US20170217923A1-20170803-C01370
    Figure US20170217923A1-20170803-C01371
    685
    Figure US20170217923A1-20170803-C01372
    Figure US20170217923A1-20170803-C01373
    Figure US20170217923A1-20170803-C01374
    686
    Figure US20170217923A1-20170803-C01375
    Figure US20170217923A1-20170803-C01376
    Figure US20170217923A1-20170803-C01377
    687
    Figure US20170217923A1-20170803-C01378
    Figure US20170217923A1-20170803-C01379
    Figure US20170217923A1-20170803-C01380
    688
    Figure US20170217923A1-20170803-C01381
    Figure US20170217923A1-20170803-C01382
    Figure US20170217923A1-20170803-C01383
    689
    Figure US20170217923A1-20170803-C01384
    Figure US20170217923A1-20170803-C01385
    Figure US20170217923A1-20170803-C01386
    690
    Figure US20170217923A1-20170803-C01387
    Figure US20170217923A1-20170803-C01388
    Figure US20170217923A1-20170803-C01389
    691
    Figure US20170217923A1-20170803-C01390
    Figure US20170217923A1-20170803-C01391
    Figure US20170217923A1-20170803-C01392
         		HCl
    692
    Figure US20170217923A1-20170803-C01393
    Figure US20170217923A1-20170803-C01394
    Figure US20170217923A1-20170803-C01395
         		HCl
    693
    Figure US20170217923A1-20170803-C01396
    Figure US20170217923A1-20170803-C01397
    Figure US20170217923A1-20170803-C01398
         		3 HCl
    694
    Figure US20170217923A1-20170803-C01399
    Figure US20170217923A1-20170803-C01400
    Figure US20170217923A1-20170803-C01401
         		3 HCl
    695
    Figure US20170217923A1-20170803-C01402
    Figure US20170217923A1-20170803-C01403
    Figure US20170217923A1-20170803-C01404
         		HCl
    696
    Figure US20170217923A1-20170803-C01405
    Figure US20170217923A1-20170803-C01406
    Figure US20170217923A1-20170803-C01407
         		HCl
    697
    Figure US20170217923A1-20170803-C01408
    Figure US20170217923A1-20170803-C01409
    Figure US20170217923A1-20170803-C01410
         		HCl
    698
    Figure US20170217923A1-20170803-C01411
    Figure US20170217923A1-20170803-C01412
    Figure US20170217923A1-20170803-C01413
         		HCl
    699
    Figure US20170217923A1-20170803-C01414
    Figure US20170217923A1-20170803-C01415
    Figure US20170217923A1-20170803-C01416
         		2 HCl
    700
    Figure US20170217923A1-20170803-C01417
    Figure US20170217923A1-20170803-C01418
    Figure US20170217923A1-20170803-C01419
         		2 HCl
    701
    Figure US20170217923A1-20170803-C01420
    Figure US20170217923A1-20170803-C01421
    Figure US20170217923A1-20170803-C01422
         		2 HCl
    702
    Figure US20170217923A1-20170803-C01423
    Figure US20170217923A1-20170803-C01424
    Figure US20170217923A1-20170803-C01425
         		2 HCl
    703
    Figure US20170217923A1-20170803-C01426
    Figure US20170217923A1-20170803-C01427
    Figure US20170217923A1-20170803-C01428
         		2 HCl
    704
    Figure US20170217923A1-20170803-C01429
    Figure US20170217923A1-20170803-C01430
    Figure US20170217923A1-20170803-C01431
         		2 HCl
    705
    Figure US20170217923A1-20170803-C01432
    Figure US20170217923A1-20170803-C01433
    Figure US20170217923A1-20170803-C01434
         		2 HCl
    706
    Figure US20170217923A1-20170803-C01435
    Figure US20170217923A1-20170803-C01436
    Figure US20170217923A1-20170803-C01437
         		2 HCl
    707
    Figure US20170217923A1-20170803-C01438
    Figure US20170217923A1-20170803-C01439
    Figure US20170217923A1-20170803-C01440
         		2 HCl
    708
    Figure US20170217923A1-20170803-C01441
    Figure US20170217923A1-20170803-C01442
    Figure US20170217923A1-20170803-C01443
         		HCl
    709
    Figure US20170217923A1-20170803-C01444
    Figure US20170217923A1-20170803-C01445
    Figure US20170217923A1-20170803-C01446
         		HCl
    710
    Figure US20170217923A1-20170803-C01447
    Figure US20170217923A1-20170803-C01448
    Figure US20170217923A1-20170803-C01449
    711
    Figure US20170217923A1-20170803-C01450
    Figure US20170217923A1-20170803-C01451
    Figure US20170217923A1-20170803-C01452
    712
    Figure US20170217923A1-20170803-C01453
    Figure US20170217923A1-20170803-C01454
    Figure US20170217923A1-20170803-C01455
    713
    Figure US20170217923A1-20170803-C01456
    Figure US20170217923A1-20170803-C01457
    Figure US20170217923A1-20170803-C01458
    714
    Figure US20170217923A1-20170803-C01459
    Figure US20170217923A1-20170803-C01460
    Figure US20170217923A1-20170803-C01461
    715
    Figure US20170217923A1-20170803-C01462
    Figure US20170217923A1-20170803-C01463
    Figure US20170217923A1-20170803-C01464
    716
    Figure US20170217923A1-20170803-C01465
    Figure US20170217923A1-20170803-C01466
    Figure US20170217923A1-20170803-C01467
    717
    Figure US20170217923A1-20170803-C01468
    Figure US20170217923A1-20170803-C01469
    Figure US20170217923A1-20170803-C01470
    718
    Figure US20170217923A1-20170803-C01471
    Figure US20170217923A1-20170803-C01472
    Figure US20170217923A1-20170803-C01473
    719
    Figure US20170217923A1-20170803-C01474
    Figure US20170217923A1-20170803-C01475
    Figure US20170217923A1-20170803-C01476
    720
    Figure US20170217923A1-20170803-C01477
    Figure US20170217923A1-20170803-C01478
    Figure US20170217923A1-20170803-C01479
    721
    Figure US20170217923A1-20170803-C01480
    Figure US20170217923A1-20170803-C01481
    Figure US20170217923A1-20170803-C01482
    722
    Figure US20170217923A1-20170803-C01483
    Figure US20170217923A1-20170803-C01484
    Figure US20170217923A1-20170803-C01485
    723
    Figure US20170217923A1-20170803-C01486
    Figure US20170217923A1-20170803-C01487
    Figure US20170217923A1-20170803-C01488
    724
    Figure US20170217923A1-20170803-C01489
    Figure US20170217923A1-20170803-C01490
    Figure US20170217923A1-20170803-C01491
    725
    Figure US20170217923A1-20170803-C01492
    Figure US20170217923A1-20170803-C01493
    Figure US20170217923A1-20170803-C01494
    726
    Figure US20170217923A1-20170803-C01495
    Figure US20170217923A1-20170803-C01496
    Figure US20170217923A1-20170803-C01497
    727
    Figure US20170217923A1-20170803-C01498
    Figure US20170217923A1-20170803-C01499
    Figure US20170217923A1-20170803-C01500
    728
    Figure US20170217923A1-20170803-C01501
    Figure US20170217923A1-20170803-C01502
    Figure US20170217923A1-20170803-C01503
    729
    Figure US20170217923A1-20170803-C01504
    Figure US20170217923A1-20170803-C01505
    Figure US20170217923A1-20170803-C01506
    730
    Figure US20170217923A1-20170803-C01507
    Figure US20170217923A1-20170803-C01508
    Figure US20170217923A1-20170803-C01509
    731
    Figure US20170217923A1-20170803-C01510
    Figure US20170217923A1-20170803-C01511
    Figure US20170217923A1-20170803-C01512
    732
    Figure US20170217923A1-20170803-C01513
    Figure US20170217923A1-20170803-C01514
    Figure US20170217923A1-20170803-C01515
    733
    Figure US20170217923A1-20170803-C01516
    Figure US20170217923A1-20170803-C01517
    Figure US20170217923A1-20170803-C01518
    734
    Figure US20170217923A1-20170803-C01519
    Figure US20170217923A1-20170803-C01520
    Figure US20170217923A1-20170803-C01521
    735
    Figure US20170217923A1-20170803-C01522
    Figure US20170217923A1-20170803-C01523
    Figure US20170217923A1-20170803-C01524
    736
    Figure US20170217923A1-20170803-C01525
    Figure US20170217923A1-20170803-C01526
    Figure US20170217923A1-20170803-C01527
    737
    Figure US20170217923A1-20170803-C01528
    Figure US20170217923A1-20170803-C01529
    Figure US20170217923A1-20170803-C01530
         		HCl
    738
    Figure US20170217923A1-20170803-C01531
    Figure US20170217923A1-20170803-C01532
    Figure US20170217923A1-20170803-C01533
    739
    Figure US20170217923A1-20170803-C01534
    Figure US20170217923A1-20170803-C01535
    Figure US20170217923A1-20170803-C01536
    740
    Figure US20170217923A1-20170803-C01537
    Figure US20170217923A1-20170803-C01538
    Figure US20170217923A1-20170803-C01539
    741
    Figure US20170217923A1-20170803-C01540
    Figure US20170217923A1-20170803-C01541
    Figure US20170217923A1-20170803-C01542
    742
    Figure US20170217923A1-20170803-C01543
    Figure US20170217923A1-20170803-C01544
    Figure US20170217923A1-20170803-C01545
    743
    Figure US20170217923A1-20170803-C01546
    Figure US20170217923A1-20170803-C01547
    Figure US20170217923A1-20170803-C01548
    744
    Figure US20170217923A1-20170803-C01549
    Figure US20170217923A1-20170803-C01550
    Figure US20170217923A1-20170803-C01551
    745
    Figure US20170217923A1-20170803-C01552
    Figure US20170217923A1-20170803-C01553
    Figure US20170217923A1-20170803-C01554
    746
    Figure US20170217923A1-20170803-C01555
    Figure US20170217923A1-20170803-C01556
    Figure US20170217923A1-20170803-C01557
         		2 HCl
    747
    Figure US20170217923A1-20170803-C01558
    Figure US20170217923A1-20170803-C01559
    Figure US20170217923A1-20170803-C01560
    1H NMR Purity Method of
    Number 1H NMR Solvent Percent Coupling
    629 1H NMR (400 MHz, DMSO) δ 10.20 (s, DMSO >98 N5
    1H), 9.54 (s, 1H), 8.87 (s, 1H), 8.74-
    8.65 (m, 2H), 8.31-8.23 (m, 2H),
    8.04-7.85 (m, 4H), 7.64-7.49 (m,
    4H).
    630 1H NMR (400 MHz, DMSO) δ 10.20 (s, DMSO >98 N5
    1H), 9.54 (d, J = 1.4 Hz, 1H), 8.86 (s,
    1H), 8.76-8.64 (m, 2H), 8.26 (dd, J =
    6.8, 2.3 Hz, 2H), 8.03-7.89 (m, 4H),
    7.70-7.52 (m, 4H).
    631 1H NMR (400 MHz, DMSO) δ 10.20 (s, DMSO >98 N5
    1H), 9.54 (d, J = 1.4 Hz, 1H), 8.86 (s,
    1H), 8.76-8.64 (m, 2H), 8.26 (dd, J =
    6.8, 2.3 Hz, 2H), 8.03-7.89 (m, 4H),
    7.70-7.52 (m, 4H).
    632 1H NMR (400 MHz, DMSO) δ 10.22- DMSO >98 N5
    10.11 (m, 1H), 9.54 (s, 1H), 8.86-
    8.77 (m, 1H), 8.74-8.65 (m, 2H),
    8.30-8.17 (m, 2H), 8.01-7.90 (m,
    2H), 7.74-7.66 (m, 2H), 7.60-7.51
    (m, 2H), 7.51-7.42 (m, 1H), 7.28 (d,
    J = 7.5 Hz, 1H), 2.45 (s, 3H).
    633 1H NMR (400 MHz, DMSO) δ 10.20 (s, DMSO >98 N5
    1H), 9.61-9.53 (m, 1H), 8.92 (s, 1H),
    8.78 -8.67 (m, 2H), 8.43-8.24 (m,
    3H), 8.14-7.89 (m, 3H), 7.84-7.76
    (m, 1H), 7.66-7.53 (m, 2H).
    634 1H NMR (400 MHz, DMSO) δ 10.20 (s, DMSO >98 N5
    1H), 9.55 (d, J = 1.2 Hz, 1H), 8.89 (s,
    1H), 8.75-8.67 (m, 2H), 8.35-8.22
    (m, 2H), 8.00 (d, J = 8.7 Hz, 1H), 7.96-
    7.90 (m, 1H), 7.84-7.75 (m, 2H),
    7.66-7.52 (m, 3H), 7.34-7.27 (m,
    1H).
    635 1H NMR (400 MHz, DMSO) δ 10.27 (s, DMSO >98 N5
    1H), 9.54 (d, J = 1.2 Hz, 1H), 8.94 (s,
    1H), 8.77-8.66 (m, 3H), 8.40-8.21
    (m, 4H), 7.99 (d, J = 8.9 Hz, 1H), 7.88
    (t, J = 8.0 Hz, 2H), 7.61-7.50 (m,
    2H).
    636 1H NMR (400 MHz, DMSO) δ 10.13 (s, DMSO >98 N5
    1H), 9.56 (s, 1H), 8.77-8.68 (m, 2H),
    8.65 (s, 1H), 8.27 (dd, J = 6.9, 2.6 Hz,
    1H), 8.04-7.97 (m, 2H), 7.96-7.88
    (m, 1H), 7.70-7.43 (m, 6H).
    637 1H NMR (400 MHz, DMSO) δ 10.10 (s, DMSO >98 N5
    1H), 9.56 (s, 1H), 8.76-8.68 (m, 2H),
    8.63 (s, 1H), 8.28 (dd, J = 6.7, 2.7 Hz,
    1H), 8.05 (dd, J = 8.7, 1.8 Hz, 1H),
    8.00-7.90 (m, 2H), 7.70-7.43 (m,
    4H), 7.21 (d, J = 8.1 Hz, 1H), 7.14 (t, J =
    7.4 Hz, 1H), 3.82 (s, 3H).
    638 1H NMR (400 MHz, DMSO) δ 10.16 (s, DMSO >98 N5
    1H), 9.54 (s, 1H), 8.81 (s, 1H), 8.74-
    8.64 (m, 2H), 8.30-8.17 (m, 2H),
    8.01-7.87 (m, 4H), 7.61-7.51 (m,
    2H), 7.42 (t, J = 8.8 Hz, 2H).
    639 1H NMR (400 MHz, DMSO) δ 10.21 (s, DMSO >98 N5
    1H), 9.57 (s, 1H), 8.80 (d, J = 1.8 Hz,
    1H), 8.76-8.59 (m, 2H), 8.27 (dd, J =
    6.9, 2.6 Hz, 1H), 8.14 (dd, J = 8.6, 1.8
    Hz, 1H), 8.10-8.02 (m, 2H), 7.97-
    7.88 (m, 2H), 7.83 (d, J = 6.8 Hz, 1H),
    7.70 (td, J = 7.6, 1.2 Hz, 1H), 7.63-
    7.52 (m, 2H).
    640 1H NMR (400 MHz, DMSO) δ 10.12 (s, DMSO >98 N5
    1H), 9.55 (s, 1H), 8.77-8.66 (m, 2H),
    8.62 (s, 1H), 8.25 (dd, J = 6.8, 2.3 Hz,
    1H), 8.16 (d, J = 8.3 Hz, 1H), 7.99-
    7.80 (m, 4H), 7.80-7.71 (m, 2H),
    7.61-7.49 (m, 2H).
    641 1H NMR (400 MHz, DMSO) δ 9.57 (s, DMSO >98 N5
    1H), 8.85-8.55 (m, 3H), 8.20-7.95 (m,
    3H), 7.85-7.20 (m, 7H)
    642 1H NMR (400 MHz, DMSO) δ 10.19 (s, DMSO >98 N5
    1H), 9.55 (d, J = 1.2 Hz, 1H), 8.83 (s,
    1H), 8.74-8.66 (m, 2H), 8.32-8.23
    (m, 2H), 8.02-7.89 (m, 2H), 7.61-
    7.53 (m, 2H), 7.05 (d, J = 2.2 Hz, 2H),
    6.62 (t, J = 2.1 Hz, 1H), 3.88 (s, 6H).
    643 1H NMR (400 MHz, DMSO) δ 10.18 (s, DMSO >98 N5
    1H), 9.55 (d, J = 2.0 Hz, 1H), 8.81 (d,
    J = 1.7 Hz, 1H), 8.74-8.65 (m, 2H),
    8.31-8.20 (m, 2H), 8.04-7.88 (m,
    2H), 7.65-7.53 (m, 2H), 7.42-7.34
    (m, 1H), 7.23-7.09 (m, 2H), 6.83 (dd,
    J = 8.3, 1.9 Hz, 1H), 3.02 (s, 6H).
    644 1H NMR (400 MHz, DMSO) δ 10.14 (s, DMSO >98 N5
    1H), 9.55 (s, 1H), 8.77-8.68 (m, 2H),
    8.65 (d, J = 1.5 Hz, 1H), 8.28 (dd, J =
    6.9, 2.6 Hz, 1H), 8.05 (dd, J = 8.6, 1.7
    Hz, 1H), 8.01-7.90 (m, 2H), 7.60-
    7.51 (m, 2H), 7.29-7.21 (m, 1H),
    7.18 (dd, J = 8.3, 1.6 Hz, 1H), 7.12
    (dd, J = 7.6, 1.6 Hz, 1H), 3.89 (s, 3H),
    3.58 (s, 3H).
    645 1H NMR (400 MHz, DMSO) δ 10.09 (s, DMSO >98 N5
    1H), 9.56 (s, 1H), 8.74-8.67 (m, 2H),
    8.64 (s, 1H), 8.28 (dd, J = 6.9, 2.6 Hz,
    1H), 8.06 (dd, J = 8.6, 1.7 Hz, 1H),
    7.98-7.89 (m, 2H), 7.62-7.51 (m,
    2H), 7.14 (d, J = 9.0 Hz, 1H), 7.09 (d,
    J = 3.1 Hz, 1H), 7.02 (dd, J = 8.9, 3.1
    Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H).
    646 1H NMR (400 MHz, DMSO) δ 9.99 (s, DMSO >98 N5
    1H), 9.56 (d, J = 0.9 Hz, 1H), 8.71 (dd,
    J = 7.1, 1.6 Hz, 2H), 8.46 (d, J = 1.5
    Hz, 1H), 8.29 (dd, J = 6.9, 2.6 Hz, 1H),
    8.00-7.87 (m, 2H), 7.73 (dd, J = 8.5,
    1.7 Hz, 1H), 7.63-7.47 (m, 2H), 7.41
    (t, J = 8.4 Hz, 1H), 6.84 (d, J = 8.5 Hz,
    2H), 3.77-3.66 (m, 6H).
    647 1H NMR (400 MHz, DMSO) δ 10.06- DMSO >98 N5
    9.96 (m, 1H), 9.52 (s, 1H), 8.75-8.62
    (m, 3H), 8.40-8.33 (m, 1H), 8.28-
    8.22 (m, 1H), 8.22-8.14 (m, 1H),
    7.97-7.85 (m, 3H), 7.64-7.49 (m,
    2H), 7.16 (s, 1H).
    648 1H NMR (400 MHz, DMSO) δ 10.10 (s, DMSO >98 N5
    1H), 9.54 (s, 1H), 8.85 (s, 1H), 8.77-
    8.65 (m, 2H), 8.32 (d, J = 8.7 Hz, 1H),
    8.26 (dd, J = 6.8, 2.6 Hz, 1H), 8.12 (s,
    1H), 7.94 (d, J = 8.7 Hz, 2H), 7.86-
    7.76 (m, 2H), 7.64-7.54 (m, 2H).
    649 1H NMR (400 MHz, DMSO) δ 10.20 (s, DMSO >98 N5
    1H), 9.53 (s, 1H), 8.78 (s, 1H), 8.71-
    8.64 (m, 2H), 8.26-8.19 (m, 2H),
    7.95-7.90 (m, 2H), 7.77-7.69 (m,
    2H), 7.60-7.53 (m, 2H), 7.26 (t, J =
    3.7 Hz, 1H).
    650 1H NMR (400 MHz, DMSO) δ 10.12 (s, DMSO >98 N5
    1H), 9.55 (d, J = 2.2 Hz, 1H), 8.75-
    8.67 (m, 3H), 8.33-8.23 (m, 2H),
    8.13 (dd, J = 8.7, 1.8 Hz, 1H), 8.00-
    7.90 (m, 3H), 7.63-7.51 (m, 2H),
    7.22 (dd, J = 7.3, 5.0 Hz, 1H), 3.95 (s,
    3H).
    651 1H NMR (400 MHz, DMSO) δ 10.22 (s, DMSO >98 N5
    1H), 9.53 (s, 1H), 8.97 (s, 1H), 8.75
    (d, J = 5.5 Hz, 2H), 8.73-8.64 (m,
    2H), 8.38-8.30 (m, 1H), 8.24 (d, J =
    6.8 Hz, 1H), 8.05-7.97 (m, 1H), 7.97-
    7.88 (m, 3H), 7.63-7.51 (m, 2H).
    652 1H NMR (400 MHz, DMSO) δ 10.05 (s, DMSO >98 N5
    1H), 9.50 (s, 1H), 9.33 (s, 2H), 9.26 (s,
    1H), 8.90 (s, 1H), 8.69 (d, J = 3.6 Hz,
    1H), 8.64 (d, J = 8.0 Hz, 1H), 8.33 (d,
    J = 8.6 Hz, 1H), 8.22 (dd, J = 6.7, 2.0
    Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.93-
    7.86 (m, 1H), 7.61-7.48 (m, 2H). DMSO >98 N5
    653 1H NMR (400 MHz, DMSO) δ 10.10 (s,
    1H), 9.55 (d, J = 1.2 Hz, 1H), 8.77-
    8.67 (m, 2H), 8.61 (s, 1H), 8.26 (dd, J =
    6.9, 2.6 Hz, 1H), 8.12 (dd, J = 8.7,
    1.8 Hz, 1H), 8.01-7.89 (m, 3H), 7.62-
    7.51 (m ,2H), 4.02 (s, 3H), 4.00 (s,
    3H).
    654 1H NMR (400 MHz, DMSO) δ 10.09 (s, DMSO >98 N5
    1H), 9.56 (s, 1H), 8.77-8.68 (m, 2H),
    8.65 (d, J = 1.6 Hz, 1H), 8.30 (dd, J =
    6.9, 2.6 Hz, 1H), 8.17 (dd, J = 8.7, 1.7
    Hz, 1H), 7.99-7.88 (m, 2H), 7.61-
    7.50 (m, 2H), 7.42-7.33 (m, 2H),
    7.21-7.08 (m, 2H), 2.53 (s, 6H). DMSO >98 N5
    655 1H NMR (400 MHz, DMSO) δ 10.08 (s,
    1H), 9.55 (s, 1H), 8.74-8.66 (m, 2H),
    8.63 (s, 1H), 8.26 (dd, J = 6.8, 2.5 Hz,
    1H), 8.12 (d, J = 8.7 Hz, 1H), 7.97-
    7.88 (m, 3H), 7.62-7.51 (m, 2H),
    6.61 (d, J = 8.1 Hz, 1H), 3.97 (s, 3H),
    3.96 (s, 3H).
    656 1H NMR (400 MHz, DMSO) δ 10.21 (s, DMSO >98 N5
    1H), 9.54 (d, J = 2.0 Hz, 1H), 8.91 (s,
    1H), 8.76-8.65 (m, 2H), 8.31 (d, J =
    8.8 Hz, 1H), 8.26 (dd, J = 6.8, 2.6 Hz,
    1H), 8.15-7.89 (m, 7H), 7.61-7.52
    (m, 2H), 7.46 (s, 1H).
    657 1H NMR (400 MHz, DMSO) δ 10.21 (s, DMSO >98 N5
    1H), 9.54 (d, J = 2.0 Hz, 1H), 8.91 (s,
    1H), 8.76-8.65 (m, 2H), 8.31 (d, J =
    8.8 Hz, 1H), 8.26 (dd, J = 6.8, 2.6 Hz,
    1H), 8.15-7.89 (m, 7H), 7.61-7.52
    (m, 2H), 7.46 (s, 1H).
    658 1H NMR (400 MHz, DMSO) δ 10.20 (s, DMSO >98 N5
    1H), 9.54 (s, 1H), 8.88 (s, 1H), 8.79-
    8.61 (m, 2H), 8.34-8.22 (m, 2H),
    8.05-7.84 (m, 4H), 7.72 (t, J = 8.0
    Hz, 1H), 7.65-7.53 (m, 2H), 7.47 (d,
    J = 8.4 Hz, 1H).
    659 1H NMR (400 MHz, DMSO) δ 10.06 (s, DMSO >98 N5
    1H), 9.53 (s, 1H), 8.75 (s, 1H), 8.75-
    8.66 (m, 3H), 8.28-8.21 (m, 1H),
    8.20 (dd, J = 7.7, 1.8 Hz, 1H), 8.06
    (dd, J = 8.9, 2.5 Hz, 1H), 7.96-7.90
    (m, 2H), 7.58-7.54 (m, 2H), 6.81 (d,
    J = 8.9 Hz, 1H), 3.11 (s, 6H).
    660 1H NMR (400 MHz, DMSO) δ 10.15 (s, DMSO >98 N5
    1H), 9.54 (s, 1H), 8.91 (s, 1H), 8.76 (s,
    1H), 8.74-8.66 (m, 2H), 8.39 (d, J =
    2.7 Hz, 1H), 8.37-8.30 (m, 1H), 8.26
    (dd, J = 6.8, 2.6 Hz, 1H), 8.03-7.97
    (m, 1H), 7.97-7.90 (m, 1H), 7.85 (d,
    J = 1.9 Hz, 1H), 7.62-7.52 (m, 2H),
    3.98 (s, 3H).
    661 1H NMR (400 MHz, DMSO) δ 10.06 (s, DMSO >98 N5
    1H), 9.52 (d, J = 1.3 Hz, 1H), 8.76 (d,
    J = 19.6 Hz, 1H), 8.73-8.61 (m, 3H),
    8.29-8.16 (m, 3H), 7.99-7.87 (m,
    2H), 7.61-7.51 (m, 2H), 6.98 (d, J =
    8.6 Hz, 1H), 4.39 (q, J = 7.0 Hz, 2H),
    1.37 (t, J = 7.0 Hz, 3H).
    662 1H NMR (400 MHz, DMSO) δ 10.11 (s, DMSO >98 N5
    1H), 9.53 (dd, J = 2.1, 0.7 Hz, 1H),
    8.75 (d, J = 1.9 Hz, 1H), 8.73-8.64
    (m, 2H), 8.25 (dd, J = 6.9, 2.6 Hz,
    1H), 8.19 (dd, J = 8.7, 1.9 Hz, 1H),
    7.97-7.89 (m, 2H), 7.61-7.50 (m,
    3H), 7.41 (dd, J = 8.1, 1.9 Hz, 1H),
    7.11 (d, J = 8.1 Hz, 1H), 6.13 (s, 2H).
    663 1H NMR (400 MHz, DMSO) δ 10.19 (s, DMSO >98 N5
    1H), 9.54 (s, 1H), 8.85 (s, 1H), 8.76-
    8.66 (m, 2H), 8.33-8.22 (m, 2H),
    8.00-7.89 (m, 2H), 7.62-7.52 (m,
    3H), 7.43 (s, 1H), 7.14 (s, 1H), 3.91 (s,
    3H).
    664 1H NMR (400 MHz, DMSO) δ 10.16 (s, DMSO >98 N5
    1H), 9.52 (d, J = 1.3 Hz, 1H), 8.89-
    8.81 (m, 1H), 8.73-7.64 (m, 2H),
    8.37-8.28 (m, 1H), 8.28-8.21 (m,
    1H), 8.01-7.86 (m, 2H), 7.81-7.69
    (m, 2H), 7.60-7.51 (m, 2H), 7.33 (s,
    1H), 3.97 (s, 3H).
    665 1H NMR (400 MHz, DMSO) δ 10.19 (s, DMSO >98 N5
    1H), 9.53 (d, J = 1.9 Hz, 1H), 8.89 (s,
    1H), 8.73-8.61 (m, 2H), 8.57 (d, J =
    4.5 Hz, 1H), 8.34-8.18 (m, 2H), 8.09-
    7.86 (m, 5H), 7.62-7.49 (m, 2H),
    2.88-2.80 (m, 4H).
    666 1H NMR (400 MHz, DMSO) δ 10.57 (s, DMSO >98 N5
    1H), 9.52 (d, J = 1.6 Hz, 1H), 9.21 (s,
    2H), 9.08-9.02 (m, 1H), 9.02-8.96
    (m, 1H), 8.89 (dd, J = 5.2, 1.5 Hz,
    1H), 8.39-8.30 (m, 1H), 8.25-8.18
    (m, 1H), 8.07-7.87 (m, 3H), 7.56 (t, J =
    9.1 Hz, 1H).
    667 1H NMR (400 MHz, DMSO) δ 10.78 (s, DMSO >98 N5
    1H), 9.53 (s, 1H), 9.16-9.02 (m, 2H),
    8.99-8.88 (m, 1H), 8.66-8.55 (m,
    1H), 8.38 (d, J = 8.2 Hz, 1H), 8.20 (d,
    J = 5.0 Hz, 1H), 8.04 (dt, J = 27.3,
    13.6 Hz, 7H), 7.57 (t, J = 8.8 Hz, 1H),
    2.84 (d, J = 3.8 Hz, 3H).
    668 1H NMR (400 MHz, DMSO) δ 10.49 (s, DMSO >98 N5
    1H), 9.53 (d, J = 1.5 Hz, 1H), 8.99-
    8.83 (m, 3H), 8.34-8.25 (m, 1H),
    8.21 (dd, J = 6.8, 2.6 Hz, 1H), 8.03 (d,
    J = 8.7 Hz, 1H), 7.98-7.91 (m, 1H),
    7.86 (dd, J = 7.8, 5.2 Hz, 1H), 7.78-
    7.70 (m, 2H), 7.57 (t, J = 9.1 Hz, 1H),
    7.47 (t, J = 7.6 Hz, 1H), 7.29 (d, J =
    7.5 Hz, 1H), 2.45 (s, 6H).
    669 1H NMR (400 MHz, DMSO) δ 10.22 (s, DMSO >98 N5
    1H), 9.55 (d, J = 1.4 Hz, 1H), 8.81-
    8.70 (m, 3H), 8.25 (dd, J = 6.8, 2.6
    Hz, 1H), 8.13-8.05 (m, 1H), 7.99 (d,
    J = 8.7 Hz, 1H), 7.97-7.89 (m, 1H),
    7.64 (dd, J = 7.9, 4.9 Hz, 1H), 7.61-
    7.49 (m, 2H), 7.37-7.26 (m, 2H),
    2.41 (s, 3H).
    670 1H NMR (400 MHz, DMSO) δ 10.77 (s, DMSO >98 N5
    1H), 9.52 (d, J = 1.6 Hz, 1H), 9.09-
    8.95 (m, 2H), 8.90 (dd, J = 5.2, 1.5
    Hz, 1H), 8.41-8.29 (m, 1H), 8.23 (dd,
    J = 6.8, 2.6 Hz, 1H), 8.05 (d, J = 8.7
    Hz, 1H), 8.01-7.88 (m, 2H), 7.56 (t, J =
    9.1 Hz, 1H), 7.50-7.38 (m, 2H),
    7.32 (d, J = 8.2 Hz, 1H), 3.97 (s, 3H),
    2.23 (s, 3H).
    671 1H NMR (400 MHz, DMSO) δ 10.77 (s, DMSO >98 N5
    1H), 9.52 (d, J = 1.6 Hz, 1H), 9.09-
    8.95 (m, 2H), 8.90 (dd, J = 5.2, 1.5
    Hz, 1H), 8.41-8.29 (m, 1H), 8.23 (dd,
    J = 6.8, 2.6 Hz, 1H), 8.05 (d, J = 8.7
    Hz, 1H), 8.01-7.88 (m, 2H), 7.56 (t, J =
    9.1 Hz, 1H), 7.50-7.38 (m, 2H),
    7.32 (d, J = 8.2 Hz, 1H), 3.97 (s, 3H),
    2.23 (s, 3H).
    672 1H NMR (400 MHz, DMSO) δ 10.67 (s, DMSO >98 N5
    1H), 9.47 (d, J = 1.6 Hz, 1H), 9.04-
    8.94 (m, 2H), 8.89 (dd, J = 5.3, 1.5
    Hz, 1H), 8.26 (dd, J = 8.8, 1.9 Hz, 1H),
    8.18 (dd, J = 6.8, 2.6 Hz, 1H), 8.09-
    8.00 (m, 1H), 8.00-7.87 (m, 3H),
    7.86-7.77 (m, 1H), 7.68-7.57 (m,
    1H), 7.53 (t, J = 9.1 Hz, 1H).
    673 1H NMR (400 MHz, DMSO) δ 10.82 (s, DMSO >98 N5
    1H), 9.53 (s, 1H), 9.17-9.04 (m, 1H),
    9.04-8.93 (m, 2H), 8.34 (dd, J = 8.7,
    1.7 Hz, 1H), 8.18 (dd, J = 6.8, 2.6 Hz,
    1H), 8.08 (d, J = 8.6 Hz, 1H), 8.05-
    7.89 (m, 2H), 7.57 (t, J = 9.0 Hz, 1H),
    7.53-7.44 (m, 3H), 7.09-6.98 (m,
    1H), 4.82 (dt, J = 11.7, 5.9 Hz, 1H),
    1.33 (d, J = 6.0 Hz, 6H).
    674 1H NMR (400 MHz, DMSO) δ 10.60 (s, DMSO >98 N5
    1H), 9.50 (d, J = 1.7 Hz, 1H), 9.11-
    9.02 (m, 1H), 8.99-8.91 (m, 1H),
    8.76 (d, J = 8.8 Hz, 1H), 8.25 (d, J =
    1.4 Hz, 1H), 8.19 (dd, J = 6.8, 2.6 Hz,
    1H), 8.10-7.92 (m, 4H), 7.82-7.72
    (m, 1H), 7.65-7.56 (m, 1H), 7.52 (t, J =
    9.1 Hz, 1H).
    675 1H NMR (400 MHz, DMSO) δ 10.51 (s, DMSO >98 N5
    1H), 9.51 (d, J = 1.7 Hz, 1H), 9.07-
    9.00 (m, 1H), 8.93 (dd, J = 5.3, 1.4
    Hz, 1H), 8.75 (d, J = 8.8 Hz, 1H), 8.28
    (d, J = 1.7 Hz, 1H), 8.21 (dd, J = 6.8,
    2.6 Hz, 1H), 8.10 (dd, J = 8.7, 1.9 Hz,
    1H), 8.02-7.93 (m, 2H), 7.74-7.65
    (m, 2H), 7.52 (t, J = 9.1 Hz, 1H), 7.40-
    7.31 (m, 1H).
    676 1H NMR (400 MHz, DMSO) δ 10.63 (s, DMSO >98 N5
    1H), 9.54 (d, J = 1.7 Hz, 1H), 9.10 (d,
    J = 8.1 Hz, 1H), 8.95 (dd, J = 5.3, 1.4
    Hz, 1H), 8.81 (d, J = 8.7 Hz, 1H), 8.26-
    8.14 (m, 2H), 8.08-7.91 (m, 3H),
    7.75-7.64 (m, 1H), 7.51 (ddd, J =
    14.7, 14.2, 6.9 Hz, 2H), 7.44-7.34
    (m, 1H),
    677 1H NMR (400 MHz, DMSO) δ 10.52 (s, DMSO >98 N5
    1H), 9.60-9.49 (m, 1H), 9.37-9.31
    (m, 1H), 8.99 (d, J = 8.3 Hz, 1H), 8.95-
    8.81 (m, 3H), 8.75 (d, J = 8.3 Hz,
    1H), 8.40 (d, J = 1.7 Hz, 1H), 8.30-
    8.18 (m, 2H), 8.04-7.87 (m, 3H),
    7.56 (t, J = 9.1 Hz, 1H).
    678 1H NMR (400 MHz, DMSO) δ 10.42 (s, DMSO >98 N5
    1H), 9.50 (d, J = 1.6 Hz, 1H), 9.38 (s,
    2H), 9.30 (s, 1H), 9.00-8.92 (m, 1H),
    8.92-8.86 (m, 1H), 8.65 (d, J = 8.7
    Hz, 1H), 8.34 (d, J = 1.7 Hz, 1H), 8.23
    (dd, J = 6.8, 2.6 Hz, 1H), 8.15 (dd, J =
    8.6, 1.8 Hz, 1H), 7.99-7.85 (m, 2H),
    7.52 (t, J = 9.1 Hz, 1H).
    679 1H NMR (400 MHz, DMSO) δ 10.47 (s, DMSO >98 N5
    1H), 9.58-9.49 (m, 1H), 9.21 (s, 2H),
    9.09-8.98 (m, 1H), 8.92 (d, J = 3.8
    Hz, 1H), 8.77 (d, J = 8.8 Hz, 1H), 8.32
    (d, J = 1.8 Hz, 1H), 8.27-8.20 (m,
    1H), 8.15 (dd, J = 8.7, 1.8 Hz, 1H),
    8.03-7.89 (m, 2H), 7.55 (t, J = 9.1
    Hz, 1H), 4.02 (s, 3H).
    680 1H NMR (400 MHz, DMSO) δ 10.09 (s, DMSO >98 N5
    1H), 9.56 (d, J = 1.3 Hz, 1H), 8.75-
    8.67 (m, 2H), 8.60 (d, J = 8.7 Hz, 1H),
    8.32 (dd, J = 6.9, 2.6 Hz, 1H), 8.10 (d,
    J = 1.6 Hz, 1H), 8.03-7.87 (m, 4H),
    7.60-7.50 (m, 2H), 7.12 (d, J = 8.8
    Hz, 2H), 3.85 (s, 3H).
    681 1H NMR (400 MHz, DMSO) δ 10.05 (s, DMSO >98 N5
    1H), 9.55-9.46 (m, 1H), 8.69-8.60
    (m, 2H), 8.56 (d, J = 8.7 Hz, 1H), 8.25
    (dd, J = 6.9, 2.6 Hz, 1H), 8.10 (d, J =
    1.8 Hz, 1H), 7.96 (dd, J = 8.7, 1.9 Hz,
    1H), 7.91-7.85 (m ,1H), 7.55-7.35
    (m, 5H), 7.03-6.95 (m, 1H), 3.83 (s,
    3H).
    682 1H NMR (400 MHz, DMSO) δ 10.09 (s, DMSO >98 N5
    1H), 9.55 (d, J = 1.9 Hz, 1H), 8.74-
    8.67 (m, 2H), 8.57 (d, J = 8.7 Hz, 1H),
    8.32 (dd, J = 6.9, 2.6 Hz, 1H), 8.00-
    7.91 (m, 2H), 7.80 (dd, J = 8.6, 1.7
    Hz, 1H), 7.60-7.41 (m, 4H), 7.21 (d,
    J = 7.8 Hz, 1H), 7.12 (td, J = 7.4, 0.9
    Hz, 1H), 3.84 (s, 3H).
    683 1H NMR (400 MHz, DMSO) δ 10.10 (s, DMSO >98 N5
    1H), 9.55 (s, 1H), 8.74-8.65 (m, 2H),
    8.56 (d, J = 8.6 Hz, 1H), 8.35-8.26
    (m, 1H), 7.99-7.89 (m, 2H), 7.81 (s,
    1H), 7.70 (dd, J = 8.6, 1.6 Hz, 1H),
    7.63-7.47 (m, 6H), 7.40 (s, 1H).
    684 1H NMR (400 MHz, DMSO) δ 10.16 (s, DMSO >98 N5
    1H), 9.61-9.53 (m, 1H), 8.76-8.62
    (m, 3H), 8.35-8.28 (m, 1H), 8.24 (d,
    J = 1.8 Hz, 1H), 8.16-7.99 (m, 6H),
    7.99-7.92 (m, 1H), 7.63-7.51 (m,
    2H), 7.45 (s, 1H).
    685 1H NMR (400 MHz, DMSO) δ 10.21 (s, DMSO >98 N5
    1H), 9.55 (d, J = 1.5 Hz, 1H), 8.78-
    8.62 (m, 3H), 8.31 (dd, J = 6.9, 2.6
    Hz, 1H), 8.15-8.00 (m, 2H), 8.00-
    7.80 (m, 5H), 7.74-7.65 (m, 1H),
    7.64-7.51 (m, 2H).
    686 1H NMR (400 MHz, DMSO) δ 10.18 (s, DMSO >98 N5
    1H), 9.60-9.55 (m, 1H), 8.77-8.65
    (m, 2H), 8.46 (s, 1H), 8.37-8.28 (m,
    2H), 8.17-8.10 (m, 1H), 7.99-7.93
    (m, 2H), 7.81-7.72 (m, 2H), 7.62-
    7.50 (m, 3H).
    687 1H NMR (400 MHz, DMSO) δ 10.18 (s, DMSO >98 N5
    1H), 9.56 (d, J = 2.2 Hz, 1H), 8.75-
    8.61 (m, 3H), 8.32 (dd, J = 6.8, 2.6
    Hz, 1H), 8.07 (s, 1H), 7.99-7.91 (m,
    1H), 7.91-7.85 (m, 1H), 7.82-7.75
    (m, 1H), 7.61-7.50 (m, 3H), 7.47-
    7.36 (m, 2H).
    688 1H NMR (400 MHz, DMSO) δ 10.14 (s, DMSO >98 N5
    1H), 9.60-9.53 (m, 1H), 8.74-8.61
    (m, 3H), 8.31 (dd, J = 6.9, 2.6 Hz,
    1H), 8.20 (d, J = 1.8 Hz, 1H), 8.06 (dd,
    J = 8.7, 1.9 Hz, 1H), 7.99-7.90 (m,
    1H), 7.86-7.77 (m, 2H, 7.65-7.48
    (m, 3H), 7.37-7.26 (m, 1H).
    689 1H NMR (400 MHz, DMSO) δ 10.13 (s, DMSO >98 N5
    1H), 9.56 (d, J = 1.5 Hz, 1H), 8.75-
    8.60 (m, 3H), 8.31 (dd, J = 6.9, 2.6
    Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.07-
    7.88 (m, 4H), 7.65-7.49 (m, 2H),
    7.39 (t, J = 8.8 Hz, 2H).
    690 1H NMR (400 MHz, DMSO) δ 10.14 (s, DMSO >98 N5
    1H), 9.54 (d, J = 1.6 Hz, 1H), 8.76-
    8.60 (m, 3H), 8.34-8.25 (m, 1H)
    8.21 (d, J = 1.7 Hz, 1H), 8.13 (d, J =
    8.4 Hz, 2H), 8.10-7.97 (m, 3H), 7.97-
    7.87 (m, 1H), 7.62-7.45 (m, 2H).
    691 1H NMR (400 MHz, DMSO) δ 10.45 (s, DMSO >98 N5
    1H), 9.54 (d, J = 1.6 Hz, 1H), 8.99-
    8.91 (m, 1H), 8.91-8.83 (m, 1H),
    8.75 (d, J = 8.8 Hz, 1H), 8.42 (s, 1H),
    8.31 (t, J = 3.2 Hz, 1H), 8.29-8.22
    (m, 2H), 8.13 (dd, J = 8.7, 1.8 Hz,
    1H), 8.08 (d, J = 7.8 Hz, 1H), 8.03-
    7.92 (m, 2H), 7.86 (dd, J = 8.0, 5.2
    Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.59-
    7.46 (m, 2H).
    692 1H NMR (400 MHz, DMSO) δ 10.38 (s, DMSO >98 N5
    1H), 9.56 (d, J = 1.5 Hz, 1H), 8.93 (d,
    J = 8.2 Hz, 1H), 8.85 (dd, J = 5.1, 1.5
    Hz, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.27
    (dd, J = 6.8, 2.6 Hz, 1H), 8.21 (d, J =
    1.7 Hz, 1H), 8.10 (dd, J = 8.7, 1.8 Hz,
    1H), 8.01-7.90 (m, 3H), 7.83 (dd, J =
    7.8, 5.0 Hz, 1H), 7.64-7.46 (m, 4H).
    693 1H NMR (400 MHz, DMSO) δ 10.91 (s, DMSO >98 N5
    1H), 9.52 (d, J = 1.5 Hz, 1H), 9.14 (d,
    J = 8.1 Hz, 1H), 9.00 (dd, J = 5.4, 1.2
    Hz, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.34
    (d, J = 5.1 Hz, 1H), 8.20 (dd, J = 6.8,
    2.6 Hz, 1H), 8.14-8.04 (m, 2H), 8.04-
    7.89 (m, 2H), 7.75-7.48 (m, 4H),
    3.18 (s, 6H).
    694 1H NMR (400 MHz, DMSO) δ 10.99 (s, DMSO >98 N5
    1H), 9.52 (d, J = 1.7 Hz, 1H), 9.08 (d,
    J = 8.0 Hz, 1H), 8.97 (dd, J = 5.3, 1.4
    Hz, 1H), 8.80 (d, J = 8.8 Hz, 1H), 8.33
    (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 6.8,
    2.6 Hz, 1H), 8.10 (dd, J = 8.8, 1.8 Hz,
    1H), 8.04-7.91 (m, 2H), 7.85 (d, J =
    8.7 Hz, 2H), 7.56 (t, J = 9.1 Hz, 1H),
    709 (s, 2H), 3.05 (s, 6H).
    695 1H NMR (400 MHz, DMSO) δ 10.67 (s, DMSO >98 N5
    1H), 9.53 (d, J = 1.7 Hz, 1H), 9.07 (d,
    J = 8.2 Hz, 1H), 8.95 (dd, J = 5.3, 1.4
    Hz, 1H), 8.78 (d, J = 8.7 Hz, 1H), 8.26
    (s, 1H), 8.21 (dd, J = 6.8, 2.6 Hz, 1H),
    8.09 (dd, J = 8.7, 1.8 Hz, 1H), 8.04-
    7.92 (m, 2H), 7.79-7.67 (m, 2H),
    7.55 (t, J = 9.1 Hz, 1H), 7.46 (t, J =
    7.6 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H),
    2.45 (s, 3H).
    696 1H NMR (400 MHz, DMSO) δ 10.48 (s, DMSO >98 N5
    1H), 9.54 (d, J = 1.5 Hz, 1H), 8.97 (d,
    J = 8.1 Hz, 1H), 8.93-8.84 (m, 1H),
    8.71 (d, J = 8.8 Hz, 1H), 8.30-8.16
    (m, 2H), 8.08 (dd, J = 8.7, 1.8 Hz,
    1H), 8.01-7.78 (m, 4H), 7.55 (t, J =
    9.1 Hz, 1H), 7.39 (d, J = 7.9 Hz, 2H),
    2.40 (s, 3H).
    697 1H NMR (400 MHz, DMSO) δ 10.68 (s, DMSO >98 N5
    1H), 9.52 (s, 1H), 9.08 (d, J = 8.1 Hz,
    1H), 8.95 (d, J = 4.7 Hz, 1H), 8.82 (d,
    J = 8.7 Hz, 1H), 8.25-8.12 (m, 2H),
    8.06-7.88 (m, 3H), 7.63-7.48 (m,
    3H), 7.47-7.35 (m, 1H).
    698 1H NMR (400 MHz, DMSO) δ 10.47 (s, DMSO >98 N5
    1H), 9.53 (d, J = 1.6 Hz, 1H), 9.01-
    8.92 (m, 1H), 8.87 (dd, J = 5.1, 1.4
    Hz, 1H), 8.73 (d, J = 8.7 Hz, 1H), 8.24
    (dd, J = 6.8, 2.6 Hz, 1H), 8.09 (s, 1H),
    7.99-7.78 (m, 4H), 7.59-7.42 (m,
    2H), 7.37-7.25 (m, 1H).
    699 1H NMR (400 MHz, DMSO) δ 13.12 (s, DMSO >98 Scheme 4
    1H), 9.59 (s, 1H), 9.10 (d, J = 8.1 Hz, synthesis
    1H), 9.00-8.86 (m, 2H), 8.50 (s, 1H), using
    8.22-8.07 (m, 2H), 8.03-7.86 (m, method N6
    4H), 7.72 (t, J = 7.9 Hz, 1H), 7.28 (t, J = coupling
    7.1 Hz, 1H).
    700 1H NMR (400 MHz, DMSO) δ 13.19 (s, DMSO >98 N6
    1H), 9.64 (s, 1H), 9.21-9.08 (m, 1H),
    9.07-8.89 (m, 2H), 8.51 (s, 1H), 8.38-
    8.26 (m, 2H), 8.16 (d, J = 8.5 Hz,
    1H), 8.07-7.87 (m, 3H), 7.83-7.70
    (m, 3H), 7.62 (dd, J = 14.2, 7.7 Hz,
    1H), 7.40-7.22 (m, 2H).
    701 1H NMR (400 MHz, DMSO) δ 13.17 (s, DMSO >98 N6
    1H), 9.65 (s, 1H), 9.13-8.99 (m, 2H),
    8.89 (d, J = 5.1 Hz, 1H), 8.50 (s, 1H),
    8.31 (d, J = 8.7 Hz, 1H), 8.21 (d, J =
    1.8 Hz, 1H), 8.11 (dd, J = 8.6, 1.9 Hz,
    1H), 8.05-7.84 (m, 5H), 7.81-7.67
    (m, 1H), 7.46-7.34 (m, 2H), 7.27 (dd,
    J = 11.8, 4.5 Hz, 1H).
    702 1H NMR (400 MHz, DMSO) δ 13.19 (s, DMSO >98 N6
    1H), 9.66 (d, J = 1.8 Hz, 1H), 9.20 (d,
    J = 7.5 Hz, 1H), 9.04-8.89 (m, 2H),
    8.50 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H),
    8.17 (s, 1H), 8.11-7.86 (m, 4H), 7.86-
    7.68 (m, 2H), 7.65-7.52 (m, 1H),
    7.52-7.39 (m, 2H), 7.39-7.23 (m,
    1H).
    703 1H NMR (400 MHz, DMSO) δ 13.17 (s, DMSO >98 N6
    1H), 9.62 (d, J = 1.6 Hz, 1H), 9.18 (d,
    J = 8.2 Hz, 1H), 9.03-8.91 (m, 2H),
    8.51 (s, 1H), 8.34-8.20 (m, 2H), 8.16-
    7.86 (m, 5H), 7.84-7.68 (m, 2H),
    7.68-7.54 (m, 1H), 7.35-7.19 (m,
    1H).
    704 1H NMR (400 MHz, DMSO) δ 13.19 (s, DMSO >98 N6
    1H), 9.61 (d, J = 1.8 Hz, 1H), 9.32-
    9.22 (m, 1H), 9.02 (dd, J = 5.5, 1.2
    Hz, 1H), 8.88 (d, J = 7.8 Hz, 1H), 8.75
    (s, 1H), 8.53 (s, 1H), 8.28 (d, J = 8.7
    Hz, 1H), 8.16-8.07 (m, 2H), 8.01-
    7.88 (m, 3H), 7.85-7.76 (m, 1H),
    7.76-7.65 (m, 1H), 7.54-7.42 (m,
    1H), 7.37-7.19 (m, 2H).
    705 1H NMR (400 MHz, DMSO) δ 13.20 (s, DMSO >98 N6
    1H), 9.63 (s, 1H), 9.26 (d, J = 8.1 Hz,
    1H), 9.01 (d, J = 5.0 Hz, 1H), 8.91 (d,
    J = 8.3 Hz, 1H), 8.52 (s, 1H), 8.33 (d,
    J = 8.7 Hz, 1H), 8.21-8.06 (m, 2H),
    8.06-7.87 (m, 3H), 7.72 (t, J = 7.7
    Hz, 1H), 7.66-7.52 (m, 2H), 7.49-
    7.35 (m, 1H), 7.29 (t, J = 7.5 Hz, 1H).
    706 1H NMR (400 MHz, DMSO) δ 9.64 (d, J = DMSO >98 N6
    1.7 Hz, 1H), 9.25 (d, J = 8.2 Hz,
    1H), 9.05-8.89 (m, 2H), 8.67-8.45
    (m, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.19
    (s, 1H), 8.09 (dd, J = 8.0, 5.5 Hz, 1H),
    8.04-7.88 (m, 3H), 7.79-7.62 (m,
    2H), 7.56-7.35 (m, 2H), 7.35-7.23
    (m, 1H).
    707 1H NMR (400 MHz, DMSO) δ 13.18 (s, DMSO >98 N6
    1H), 9.62 (d, J = 1.5 Hz, 1H), 9.16 (d,
    J = 8.1 Hz, 1H), 9.08-8.88 (m, 2H),
    8.51 (s, 1H), 8.37-8.23 (m, 2H), 8.19-
    8.09 (m, 1H), 8.09-7.88 (m, 3H),
    7.83-7.63 (m, 3H), 7.43-7.32 (m,
    1H), 7.32-7.21 (m ,1H).
    708 1H NMR (400 MHz, DMSO) δ 10.52 (s, DMSO >98 N6/F5
    1H), 9.56 (d, J = 1.6 Hz, 1H), 9.04 (d, followed by
    J = 7.8 Hz, 1H), 8.92 (d, J = 4.8 Hz, G1
    1H), 8.78 (d, J = 8.8 Hz, 1H), 8.24 (d,
    J = 1.7 Hz, 1H), 8.13-8.08 (m, 2H),
    8.08-7.98 (m, 3H), 7.98-7.88 (m,
    1H), 7.63 (t, J = 8.2 Hz, 1H), 7.42 (d, J =
    8.8 Hz, 2H), 7.28-7.15 (m, 1H).
    709 1H NMR (400 MHz, DMSO) δ 10.60 (s, DMSO >98 N6/F5
    1H), 9.56 (s, 1H), 9.07 (d, J = 7.9 Hz, followed by
    1H), 8.93 (d, J = 4.3 Hz, 1H), 8.77 (d, G1
    J = 8.7 Hz, 1H), 8.41 (s, 1H), 8.37-
    8.27 (m, 1H), 8.24 (d, J = 1.7 Hz, 1H),
    8.11 (dd, J = 8.7, 1.8 Hz, 1H), 8.08-
    7.94 (m, 3H), 7.79-7.65 (m, 2H),
    7.41 (t, J = 8.8 Hz, 2H).
    710 1H NMR (DMSO-d6) ppm 3.81 (s, 3H), DMSO >98 N6/F5
    3.88 (s, 3H), 7.11-7.71 (m, 9H), 7.91 followed by
    (d, 1H, J = 8.7 Hz), 8.23 (d, 1H, J = G1
    8.7 Hz), 8.53-8.64 (m, 2H), 8.87 (d,
    1H, J = 1.5 Hz), 9.37 (d, 1H, J = 1.5
    Hz), 9.83 (s, 1H)
    711 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), DMSO >98 N6/F5
    7.04 (d, 1H, J = 4.1 Hz), 7.48-7.57 (m, followed by
    5H), 7.98 (dd, 1H, J = 7.1, 1.7 Hz), G1
    8.26-8.29 (m, 3H), 8.27 (dd, 1H, J =
    7.1, 8.7 Hz), 8.78-9.53 (m, 3H), 9.54
    (s, 1H), 10.37 (s, 1H)
    712 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), DMSO >98 N6/F5
    7.05 (d, 1H, J = 4.1 Hz), 7.48-7.57 (m, followed by
    4H), 7.88 (dd, 1H, J = 7.1, 1.7 Hz), G1
    8.25-8.29 (m, 3H), 8.37 (dd, 1H, J =
    7.1, 8.7 Hz), 8.78-9.53 (m, 3H), 9.54
    (s, 1H), 10.37 (s, 1H)
    713 1H NMR (DMSO-d6) ppm 3.88 (s, 3H), DMSO >98 N6/F5
    7.05-7.51 (m, 9H), 7.95 (d, 1H, J = 8.7 followed by
    Hz), 8.26 (d, 1H, J = 8.7 Hz), 8.54- G1
    8.88 (m, 3H), 9.38 (s, 1H), 10.19 (s,
    1H)
    714 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), DMSO >98 N6/F5
    7.04-7.06 (m, 2H), 7.46-7.76 (m, 8H), followed by
    7.95 (d, 2H, J = 8.6 Hz), 8.24 (d, 1H, J = G1
    1.7 Hz), 8.69-8.87 (m, 3H), 9.56 (s,
    1H), 10.18 (s, 1H)
    715 1H NMR (DMSO-d6) ppm 3.84 (s, 3H), DMSO >98 N6/F5
    3.89 (s, 3H), 6.81-7.56 (m, 2H), 7.40- followed by
    7.70 (m, 7H), 7.95 (d, 1H, J = 8.5 Hz), G1
    8.23 (d, 1H, J = 1.5 Hz), 8.69-8.89
    (m, 3H), 9.58 (s, 1H), 10.06 (s, 1H)
    716 1H NMR (DMSO-d6) ppm 3.88 (s, 3H), DMSO >98 N6/F5
    7.03-7.06 (m, 1H), 7.50-8.39 (m, 10H), followed by
    8.86-8.98 (m, 3H), 9.58 (s, 1H), 10.06 G1
    (s, 1H)
    717 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), DMSO >98 N6/F5
    7.02-7.07 (m, 2H), 7.31 (s, 1H), 7.47- followed by
    7.56 (m, 5H), 7.81-8.26 (m, 4H), 8.26- G1
    8.90 (m, 3H), 9.57 (s, 1H), 10.27 (s,
    1H)
    718 1H NMR (DMSO-d6) ppm 3.87 (s, 3H), DMSO >98 N6/F5
    7.03-7.50 (m, 8H), 7.98 (d, 1H, J = 8.7 followed by
    Hz), 8.30 (d, 1H, J = 8.7 Hz), 8.48- G1
    8.91 (m, 3H), 9.30 (s, 1H), 10.19 (s,
    1H)
    719 1H NMR (DMSO-d6) ppm 3.88 (s, 3H), DMSO >98 N6/F5
    7.03-7.54 (m, 8H), 7.97 (d, 1H, J = 8.7 followed by
    Hz), 8.28 (d, 1H, J = 8.7 Hz), 8.56- G1
    8.86 (m, 3H), 9.40 (s, 1H), 10.23 (s,
    1H)
    720 1H NMR (DMSO-d6) ppm 3.88 (s, 3H), DMSO >98 N6/F5
    7.03-7.52 (m, 8H), 7.95 (d, 1H, J = 8.7 followed by
    Hz), 8.26 (d, 1H, J = 8.7 Hz), 8.52- G1
    8.85 (m, 3H), 9.38 (s, 1H), 10.17 (s,
    1H)
    721 1H NMR (DMSO-d6) ppm 3.87 (s, 3H), DMSO >98 N6/F5
    7.05-7.54 (m, 8H), 8.00 (d, 1H, J = 8.7 followed by
    Hz), 8.27 (d, 1H, J = 8.7 Hz), 8.55- G1
    8.87 (m, 3H), 9.38 (s, 1H), 10.34 (s,
    1H)
    722 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), DMSO >98 N6/F5
    7.05-7.53 (m, 7H), 7.93 (s, 1H), 7.96 followed by
    (d, 1H, J = 8.7 Hz), 8.16 (s, 1H), 8.26 G1
    (d, 1H, J = 8.7 Hz), 8.74-8.89 (m, 3H),
    9.55 (s, 1H), 10.27 (s, 1H)
    723 1H NMR (DMSO-d6) ppm 3.88 (s, 3H), DMSO >98 N6/F5
    7.03-7.54 (m, 8H), 7.92 (s, 1H), 7.97 followed by
    (d, 1H, J = 8.7 Hz), 8.28 (d, 1H, J = G1
    8.7 Hz), 8.546-8.85 (m, 3H), 9.40 (s,
    1H), 10.25 (s, 1H)
    724 1H NMR (DMSO-d6) ppm 3.88 (s, 3H), DMSO >98 N6/F5
    7.03-7.74 (m, 8H), 7.98 (d, 1H, J = 8.7 followed by
    Hz), 8.27 (d, 1H, J = 8.7 Hz), 8.52- G1
    8.87 (m, 3H), 9.32 (s, 1H), 10.22 (s,
    1H)
    725 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), DMSO >98 N6/F5
    7.05-7.71 (m, 8H), 7.99 (d, 1H, J = 8.6 followed by
    Hz), 8.30 (d, 1H, J = 8.7 Hz), 8.67- G1
    8.92 (m, 3H), 9.37 (s, 1H), 10.52 (s,
    1H)
    726 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), DMSO >98 N6/F5
    7.03-7.71 (m, 9H), 7.99 (d, 1H, J = 8.7 followed by
    Hz), 8.29 (d, 1H, J = 8.7 Hz), 8.67- G1
    8.92 (m, 3H), 9.37 (s, 1H), 10.52 (s,
    1H)
    727 1H NMR (DMSO-d6 at 70° C.) ppm 3.89 DMSO >98 N6/F5
    (s, 3H), 7.02-7.52 (m, 8H), 7.90 (d, followed by
    1H, J = 8.5 Hz), 7.93 (s, 1H), 7.99 (d, G1
    1H, J = 8.6 Hz), 8.22 (s, 1H), 8.74-
    8.91 (m, 3H), 9.52 (s, 1H), 10.23 (s,
    1H)
    728 1H NMR (DMSO-d6) ppm 2.50 (s, 3H), DMSO >98 N6/F5
    3.89 (s, 3H), 7.06 (s, 1H), 7.49-7.85 followed by
    (m, 9H), 8.01-8.96 (m, 4H), 9.58 (s, G1
    1H), 10.50 (s, 1H)
    729 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), DMSO >98 N6/F5
    7.04 (br s, 1H), 7.22 (s, 1H), 7.49-8.30 followed by
    (m, 9H), 8.77-8.91 (m, 3H), 9.55 (s, G1
    1H), 10.37 (s, 1H)
    730 1H NMR (DMSO-d6) ppm 3.89 (s, 3H), DMSO >98 N6/F5
    7.04 (s, 1H), 7.49-8.32 (m, 9H), 8.91- followed by
    9.04 (m, 3H), 9.54 (s, 1H), 10.63 (s, G1
    1H)
    731 1H NMR (DMSO-d6) ppm 3.87 (s, 3H), DMSO >98 N6/F5
    7.03 (s, 1H), 7.44-8.25 (m, 9H), 8.71- followed by
    8.84 (m, 3H), 9.52 (s, 1H), 10.23 (s, G1
    1H)
    732 1H NMR (400 MHz, DMSO) δ 12.02 (s, DMSO >98 N6/F5
    1H), 10.53 (s, 1H), 9.49 (s, 1H), 9.02- followed by
    8.72 (m, 3H), 8.30 (dd, J = 8.7, 1.6 G1
    Hz, 1H), 8.05 (dd, J = 32.2, 5.3 Hz,
    2H), 7.81-7.72 (m, 2H), 7.49 (dd, J =
    8.0, 5.4 Hz, 3H), 7.25 (t, J = 9.2 Hz,
    1H), 7.11-6.98 (m, 1H), 3.89 (s, 3H).
    733 1H NMR (400 MHz, DMSO) δ 10.54 (s, DMSO >98 N6/F5
    1H), 9.43 (s, 1H), 8.86 (d, J = 1.8 Hz, followed by
    1H), 8.64 (dd, J = 21.1, 5.9 Hz, 2H), G1
    8.31 (dd, J = 8.7, 1.9 Hz, 1H), 8.01 (d,
    J = 8.7 Hz, 1H), 7.59-7.45 (m, 4H),
    7.42-7.30 (m, 3H), 7.09-6.98 (m,
    1H), 3.89 (s, 3H).
    734 1H NMR (400 MHz, DMSO) δ 13.18 (s, DMSO >98 N6/F5
    1H), 10.57 (s, 1H), 9.48 (s, 1H), 8.98 followed by
    (d, J = 1.3 Hz, 1H), 8.78 (t, J = 7.1 Hz, G1
    2H), 8.30 (dd, J = 8.7, 1.7 Hz, 1H),
    8.18 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.7
    Hz, 1H), 7.83 (dd, J = 8.9, 1.8 Hz, 1H),
    7.74-7.62 (m, 2H), 7.56-7.43 (m,
    2H), 7.09-7.01 (m, 1H), 3.90 (s, 3H).
    735 1H NMR (400 MHz, DMSO) δ 11.16 (s, DMSO >98 N6/F5
    1H), 10.11 (s, 1H), 9.51 (d, J = 1.2 Hz, followed by
    1H), 8.91 (d, J = 1.7 Hz, 1H), 8.71- G1
    8.58 (m, 2H), 8.23 (dd, J = 8.7, 1.9
    Hz, 1H), 7.95 (dd, J = 23.9, 5.2 Hz,
    2H), 7.60-7.34 (m, 5H), 7.06-6.98
    (m, 1H), 6.06 (s, 2H), 3.89 (s, 3H).
    736 1H NMR (400 MHz, DMSO) δ 10.78 (s, DMSO >98 N6/F5
    1H), 10.65 (s, 1H), 10.08 (s, 1H), 9.55 followed by
    (d, J = 2.0 Hz, 1H), 8.88 (d, J = 1.8 G1
    Hz, 1H), 8.76-8.66 (m, 2H), 8.24 (dd,
    J = 8.7, 1.9 Hz, 1H), 7.94 (d, J 8.7 Hz,
    1H), 7.65 (d, J = 1.9 Hz, 1H), 7.58 (dd,
    J = 7.7, 5.1 Hz, 1H), 7.49 (dt, J = 4.7,
    3.1 Hz, 3H), 7.41 (dd, J = 8.4, 2.0 Hz,
    1H), 7.08-6.99 (m, 3H), 3.88 (s, 3H).
    737 1H NMR (400 MHz, DMSO) δ 9.93 (s, DMSO >98 N6/F5
    1H), 9.40 (s, 1H), 8.86 (d, J = 1.7 Hz, followed by
    1H), 8.64 (dd, J = 28.9, 5.8 Hz, 2H), G1
    8.27 (dd, J = 8.7, 1.9 Hz, 1H), 7.96 (d,
    J = 8.7 Hz, 1H), 7.87 (d, J = 2.6 Hz,
    1H), 7.61-7.45 (m, 5H), 7.38 (dd, J =
    8.8, 2.6 Hz, 1H), 7.24 (d, J = 8.9 Hz,
    1H), 7.09-6.98 (m, 1H), 3.89 (d, J =
    2.9 Hz, 1H), 3.83 (s, 3H).
    738 1H NMR (400 MHz, DMSO) δ 10.19 (s, DMSO >98 N6/F5
    1H), 9.56 (s, 1H), 8.88 (d, J = 1.7 Hz, followed by
    1H), 8.75 (t, J = 7.2 Hz, 2H), 8.27 (dd, G1
    J = 8.6, 1.4 Hz, 1H), 8.14 (d, J = 1.6
    Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.84
    (dd, J = 8.2, 2.0 Hz, 1H), 7.63 (dd, J =
    7.7, 4.9 Hz, 1H), 7.48 (dd, J = 11.4,
    4.0 Hz, 4H), 7.10-6.98 (m, 1H), 3.89
    (s, 3H), 3.83 (s, 3H).
    739 1H NMR (400 MHz, DMSO) δ 10.07 (s, DMSO >98 N6/F5
    1H), 9.55 (s, 1H), 8.85 (s, 1H), 8.70 followed by
    (d, J = 5.5 Hz, 2H), 8.24 (dd, J = 8.7, G1
    1.5 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H),
    7.99-7.83 (m, 2H), 7.60-7.40 (m,
    4H), 7.30 (d, J = 9.0 Hz, 1H), 7.04 (dd,
    J = 7.1, 4.4 Hz, 1H), 3.90 (s, 3H), 2.29
    (s, 3H).
    740 1H NMR (400 MHz, DMSO) δ 10.05 (s, DMSO >98 N6/F5
    1H), 9.60 (s, 1H), 8.89 (d, J = 1.8 Hz, followed by
    1H), 8.71 (dd, J = 12.8, 6.3 Hz, 2H), G1
    8.24 (dd, J = 8.7, 1.9 Hz, 1H), 7.95 (d,
    J = 8.7 Hz, 1H), 7.68 (d, J = 1.7 Hz,
    1H), 7.61-7.45 (m, 5H), 7.44-7.37
    (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 3.89
    (s, 3H), 3.65 (s, 3H).
    741 1H NMR (400 MHz, DMSO) δ 10.04 (s, DMSO >98 N6/F5
    1H), 9.60 (s, 1H), 8.89 (d, J = 1.7 Hz, followed by
    1H), 8.71 (dd, J = 12.7, 6.3 Hz, 2H), G1
    8.24 (dd, J = 8.7, 1.9 Hz, 1H), 7.95 (d,
    J = 8.7 Hz, 1H), 7.68 (d, J = 1.7 Hz,
    1H), 7.59-7.45 (m, 4H), 7.44-7.37
    (m, 1H), 7.25 (t, J = 6.7 Hz, 1H), 7.07-
    6.98 (m, 1H), 3.89 (s, 6H), 2.19 (s,
    3H).
    742 1H NMR (400 MHz, DMSO) δ 9.73 (s, DMSO >98 N6/F5
    1H), 9.37 (s, 1H), 8.86 (d, J = 1.6 Hz, followed by
    1H), 8.63 (d, J = 3.4 Hz, 1H), 8.54 (d, G1
    J = 8.0 Hz, 1H), 8.23 (dd, J = 8.7, 1.8
    Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.55-
    7.42 (m, 5H), 7.05-6.98 (m, 1H),
    6.77 (d, J = 2.6 Hz, 1H), 6.68 (dd, J =
    8.6, 2.6 Hz, 1H), 3.89 (s, 3H), 3.85 (s,
    3H), 3.79 (s, 3H).
    743 1H NMR (400 MHz, DMSO) δ 10.25 (s, DMSO >98 N6/F5
    1H), 9.56 (s, 1H), 8.84 (d, J = 1.7 Hz, followed by
    1H), 8.71 (d, J = 9.1 Hz, 1H), 8.27 (dd, G1
    J = 8.7, 1.8 Hz, 1H), 7.99 (d, J = 8.7
    Hz, 1H), 7.86-7.77 (m, 2H), 7.65-
    7.56 (m, 1H), 7.52-7.44 (m, 4H),
    7.09-6.99 (m, 2H), 3.89 (s, 3H).
    744 1H NMR (400 MHz, DMSO) δ 10.42 (s, DMSO >98 N6/F5
    1H), 9.55 (s, 1H), 8.87 (d, J = 26.7 Hz, followed by
    3H), 8.31 (dd, J = 8.7, 1.7 Hz, 2H), G1
    8.17 (d, J = 1.7 Hz, 2H), 8.02 (d, J =
    8.7 Hz, 1H), 7.81 (s, 1H), 7.54-7.39
    (m, 3H), 7.11-6.98 (m, 1H), 3.89 (s,
    3H).
    745 1H NMR (400 MHz, DMSO) δ 14.27 (s, DMSO >98 N6/F5
    1H), 9.79 (s, H), 9.32 (d, J = 8.4 Hz, followed by
    1H), 8.98 (d, J = 5.2 Hz, 1H), 8.34 (dd, G1
    J = 8.7, 1.8 Hz, 1H), 8.29-8.19 (m,
    2H), 8.07 (dd, J = 14.6, 8.3 Hz, 2H),
    7.93 (s, 1H), 7.64 (d, J = 5.9 Hz, 1H),
    7.52 (t, J = 7.9 Hz, 1H), 7.39 (dd, J =
    8.9, 4.9 Hz, 2H), 7.23 (d, J = 5.8 Hz,
    1H), 7.08 (dd, J = 8.2, 1.8 Hz, 1H),
    3.86 (s, 3H).
    746 1H NMR (400 MHz, DMSO) δ 11.10 (s, DMSO N6/F5
    1H), 9.36 (s, 1H), 9.11 (s, 1H), 9.00 followed
    (dd, J = 23.2, 6.7 Hz, 2H), 8.41 (d, J = by
    9.1 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), G1
    8.05 (dd, J = 7.9, 5.5 Hz, 1H), 7.80-
    7.65 (m, 2H), 7.59-7.44 (m, 3H),
    7.41-7.32 (m, 1H), 7.06 (d, J = 8.0
    Hz, 1H), 3.90 (s, 3H).
    747 1H NMR (400 MHz, DMSO) δ 12.92 (d, DMSO >98 N6/F5
    J = 17.9 Hz, 1H), 9.64 (s, 1H), 9.09 (d, followed
    J = 7.9 Hz, 1H), 8.92 (d, J = 4.9 Hz, by
    1H), 8.52 (d, J = 5.4 Hz, 1H), 8.38 (s, G1
    1H), 8.30 (dd, J = 8.7, 1.7 Hz, 1H),
    8.04 (d, J = 8.7 Hz, 1H), 7.98-7.84
    (m, 3H), 7.50 (t, J = 7.9 Hz, 1H), 7.39
    (dd, J = 8.1, 5.0 Hz, 2H), 7.06 (dd, J =
    8.2, 1.8 Hz, 2H), 3.89 (s, 3H).
    Num- Starting Starting Salt
    ber Material 1 Material 2 Product type
    748
    Figure US20170217923A1-20170803-C01561
    Figure US20170217923A1-20170803-C01562
    Figure US20170217923A1-20170803-C01563
         		2 HCl
    749
    Figure US20170217923A1-20170803-C01564
    Figure US20170217923A1-20170803-C01565
    Figure US20170217923A1-20170803-C01566
    750
    Figure US20170217923A1-20170803-C01567
    Figure US20170217923A1-20170803-C01568
    Figure US20170217923A1-20170803-C01569
         		2 HCl
    751
    Figure US20170217923A1-20170803-C01570
    Figure US20170217923A1-20170803-C01571
    Figure US20170217923A1-20170803-C01572
         		HCl
    752
    Figure US20170217923A1-20170803-C01573
    Figure US20170217923A1-20170803-C01574
    Figure US20170217923A1-20170803-C01575
    753
    Figure US20170217923A1-20170803-C01576
    Figure US20170217923A1-20170803-C01577
    Figure US20170217923A1-20170803-C01578
    754
    Figure US20170217923A1-20170803-C01579
    Figure US20170217923A1-20170803-C01580
    Figure US20170217923A1-20170803-C01581
    755
    Figure US20170217923A1-20170803-C01582
    Figure US20170217923A1-20170803-C01583
    Figure US20170217923A1-20170803-C01584
         		2 HCl
    756
    Figure US20170217923A1-20170803-C01585
    Figure US20170217923A1-20170803-C01586
    Figure US20170217923A1-20170803-C01587
    757
    Figure US20170217923A1-20170803-C01588
    Figure US20170217923A1-20170803-C01589
    Figure US20170217923A1-20170803-C01590
         		2 HCl
    758
    Figure US20170217923A1-20170803-C01591
    Figure US20170217923A1-20170803-C01592
    Figure US20170217923A1-20170803-C01593
         		2 HCl
    759
    Figure US20170217923A1-20170803-C01594
    Figure US20170217923A1-20170803-C01595
    Figure US20170217923A1-20170803-C01596
         		HCl
    760
    Figure US20170217923A1-20170803-C01597
    Figure US20170217923A1-20170803-C01598
    Figure US20170217923A1-20170803-C01599
         		2 HCl
    761
    Figure US20170217923A1-20170803-C01600
    Figure US20170217923A1-20170803-C01601
    Figure US20170217923A1-20170803-C01602
         		2 HCl
    762
    Figure US20170217923A1-20170803-C01603
    Figure US20170217923A1-20170803-C01604
    Figure US20170217923A1-20170803-C01605
         		HCl
    763
    Figure US20170217923A1-20170803-C01606
    Figure US20170217923A1-20170803-C01607
    Figure US20170217923A1-20170803-C01608
         		HCl
    764
    Figure US20170217923A1-20170803-C01609
    Figure US20170217923A1-20170803-C01610
    Figure US20170217923A1-20170803-C01611
         		HCl
    765
    Figure US20170217923A1-20170803-C01612
    Figure US20170217923A1-20170803-C01613
    Figure US20170217923A1-20170803-C01614
         		HCl
    766
    Figure US20170217923A1-20170803-C01615
    Figure US20170217923A1-20170803-C01616
    Figure US20170217923A1-20170803-C01617
    767
    Figure US20170217923A1-20170803-C01618
    Figure US20170217923A1-20170803-C01619
    Figure US20170217923A1-20170803-C01620
         		2 HCl
    768
    Figure US20170217923A1-20170803-C01621
    Figure US20170217923A1-20170803-C01622
    Figure US20170217923A1-20170803-C01623
         		HCl
    769
    Figure US20170217923A1-20170803-C01624
    Figure US20170217923A1-20170803-C01625
    Figure US20170217923A1-20170803-C01626
         		3 HCl
    770
    Figure US20170217923A1-20170803-C01627
    Figure US20170217923A1-20170803-C01628
    Figure US20170217923A1-20170803-C01629
         		2 HCl
    771
    Figure US20170217923A1-20170803-C01630
    Figure US20170217923A1-20170803-C01631
    Figure US20170217923A1-20170803-C01632
         		3 HCl
    772
    Figure US20170217923A1-20170803-C01633
    Figure US20170217923A1-20170803-C01634
    Figure US20170217923A1-20170803-C01635
         		3 HCl
    773
    Figure US20170217923A1-20170803-C01636
    Figure US20170217923A1-20170803-C01637
    Figure US20170217923A1-20170803-C01638
         		2 HCl
    774
    Figure US20170217923A1-20170803-C01639
    Figure US20170217923A1-20170803-C01640
    Figure US20170217923A1-20170803-C01641
         		HCl
    775
    Figure US20170217923A1-20170803-C01642
    Figure US20170217923A1-20170803-C01643
    Figure US20170217923A1-20170803-C01644
         		2 HCl
    776
    Figure US20170217923A1-20170803-C01645
    Figure US20170217923A1-20170803-C01646
    Figure US20170217923A1-20170803-C01647
         		2 HCl
    777
    Figure US20170217923A1-20170803-C01648
    Figure US20170217923A1-20170803-C01649
    Figure US20170217923A1-20170803-C01650
         		2 HCl
    778
    Figure US20170217923A1-20170803-C01651
    Figure US20170217923A1-20170803-C01652
    Figure US20170217923A1-20170803-C01653
         		2 HCl
    779
    Figure US20170217923A1-20170803-C01654
    Figure US20170217923A1-20170803-C01655
    Figure US20170217923A1-20170803-C01656
         		HCl
    780
    Figure US20170217923A1-20170803-C01657
    Figure US20170217923A1-20170803-C01658
    Figure US20170217923A1-20170803-C01659
         		2 HCl
    781
    Figure US20170217923A1-20170803-C01660
    Figure US20170217923A1-20170803-C01661
    Figure US20170217923A1-20170803-C01662
         		2 HCl
    782
    Figure US20170217923A1-20170803-C01663
    Figure US20170217923A1-20170803-C01664
    Figure US20170217923A1-20170803-C01665
         		2 HCl
    783
    Figure US20170217923A1-20170803-C01666
    Figure US20170217923A1-20170803-C01667
    Figure US20170217923A1-20170803-C01668
         		2 HCl
    784
    Figure US20170217923A1-20170803-C01669
    Figure US20170217923A1-20170803-C01670
    Figure US20170217923A1-20170803-C01671
         		2 HCl
    785
    Figure US20170217923A1-20170803-C01672
    Figure US20170217923A1-20170803-C01673
    Figure US20170217923A1-20170803-C01674
         		2 HCl
    786
    Figure US20170217923A1-20170803-C01675
    Figure US20170217923A1-20170803-C01676
    Figure US20170217923A1-20170803-C01677
         		2 HCl
    787
    Figure US20170217923A1-20170803-C01678
    Figure US20170217923A1-20170803-C01679
    Figure US20170217923A1-20170803-C01680
    788
    Figure US20170217923A1-20170803-C01681
    789
    Figure US20170217923A1-20170803-C01682
    790
    Figure US20170217923A1-20170803-C01683
    791
    Figure US20170217923A1-20170803-C01684
    792
    Figure US20170217923A1-20170803-C01685
         		HCl
    793
    Figure US20170217923A1-20170803-C01686
         		HCl
    794
    Figure US20170217923A1-20170803-C01687
         		2HCl
    795
    Figure US20170217923A1-20170803-C01688
         		3HCl
    796
    Figure US20170217923A1-20170803-C01689
         		3HCl
    797
    Figure US20170217923A1-20170803-C01690
         		3HCl
    798
    Figure US20170217923A1-20170803-C01691
         		2HCl
    799
    Figure US20170217923A1-20170803-C01692
    800
    Figure US20170217923A1-20170803-C01693
    Figure US20170217923A1-20170803-C01694
    Figure US20170217923A1-20170803-C01695
    801
    Figure US20170217923A1-20170803-C01696
    Figure US20170217923A1-20170803-C01697
    Figure US20170217923A1-20170803-C01698
         		MeOH
    1H
    NMR Purity Method LCMS
    Number 1H NMR Solvent percent of Coupling LCMS Method
    748 1H NMR (400 MHz, DMSO) δ 10.71 DMSO >98 Method N6
    (s, 1H), 9.56 (s, 1H), 9.45 (s, 2H),
    9.29 (s, 1H), 9.22 (s, 1H), 9.13 (d, J =
    7.8 Hz, 1H), 8.96 (d, J = 4.3 Hz,
    1H), 8.47 (d, J = 8.4 Hz, 1H), 8.16-
    8.08 (m, 2H), 8.07-7.99 (m, 1H),
    7.75 (s, 1H), 7.59 (dd, J = 19.3, 9.0
    Hz, 1H).
    749 1H NMR (400 MHz, DMSO) δ 10.12 DMSO >98 Method N6
    (s, 1H), 9.55 (d, J = 1.4 Hz, 1H),
    8.74-8.66 (m, 3H), 8.28 (d, J = 4.9
    Hz, 1H), 8.17-8.08 (m, 2H), 7.98-
    7.91 (m, 2H), 7.73 (d, J = 9.1 Hz,
    1H, 7.61-7.51 (m, 2H), 7.22 (dd,
    J = 7.3, 5.0 Hz, 1H), 3.95 (s, 3H).
    750 1H NMR (400 MHz, DMSO) δ 10.92 DMSO >98 Method N6
    (s, 1H), 9.55 (d, J = 1.5 Hz, 1H),
    9.33 (s, 1H), 9.10-8.99 (m, 2H),
    8.93 (d, J = 5.2 Hz, 1H), 8.54 (d, J =
    2.5 Hz, 1H), 8.46 (dd, J = 8.8, 1.8
    Hz, 1H), 8.33 (s, 1H), 8.18 (ddd, J =
    13.0, 7.4, 2.4 Hz, 1H), 8.08 (d, J =
    8.7 Hz, 1H), 8.01-7.93 (m, 1H),
    7.84 (d, J = 9.0 Hz, 1H), 7.57 (dd, J =
    19.79, 9.1 Hz, 1H), 4.03 (s, 3H).
    751 1H NMR (400 MHz, DMSO) δ 10.57 DMSO >98 Method N6
    (s, 1H), 9.53 (d, J = 1.7 Hz, 1H),
    9.00 (dd, J = 14.9, 4.8 Hz, 2H), 8.90
    (dd, J = 5.1, 1.4 Hz, 1H), 8.78 (d, J =
    2.1 Hz, 1H), 8.31 (dt, J = 8.7, 2.2
    Hz, 2H), 8.11 (ddd, J = 12.9, 7.5,
    2.5 Hz, 1H), 8.03 (d, J = 8.7 Hz,
    1H), 7.93 (dd, J = 8.0, 5.1 Hz, 1H),
    7.75 (dd, J = 6.0, 2.9 Hz, 1H), 7.63-
    7.51 (m, 1H), 7.03 (d, J = 8.6 Hz,
    1H), 3.94 (d, J = 8.4 Hz, 3H).
    752 1H NMR (400 MHz, DMSO) δ 10.05 DMSO >98 Method N6
    (s, 1H), 9.52 (s, 1H), 9.14 (d, J =
    5.6 Hz, 2H), 8.84 (s, 1H), 8.68 (dd,
    J = 14.0, 6.4 Hz, 2H), 8.28 (dd, J =
    8.7, 1.7 Hz, 1H), 8.17-8.06 (m,
    1H), 7.96 (d, J = 8.7 Hz, 1H), 7.70
    (d, J = 9.0 Hz, 1H), 7.62-7.50 (m,
    2H), 4.02 (s, 3H).
    753 1H NMR (400 MHz, DMSO) δ 10.17 DMSO >98 Method N6
    (s, 1H), 9.54 (d, J = 1.5 Hz, 1H),
    9.16 (d, J = 1.9 Hz, 1H), 8.93 (d, J =
    1.7 Hz, 1H), 8.74-8.60 (m, 3H),
    8.35-8.26 (m, 2H), 8.19-8.07 (m,
    1H), 8.01 (d, J = 8.7 Hz, 1H), 7.77-
    7.69 (m, 1H), 7.64-7.51 (m, 3H). DMSO >98 Method N6
    754 1H NMR (400 MHz, DMSO) δ 10.12
    (s, 1H), 9.53 (d, J = 1.4 Hz, 1H),
    8.79-8.62 (m, 3H), 8.24-8.06 (m,
    2H), 7.94 (t, J = 7.7 Hz, 1H), 7.73
    (dd, J = 6.2, 2.9 Hz, 1H), 7.56 (ddd,
    J = 15.3, 10.1, 4.8 Hz, 3H), 7.41
    (dd, J = 8.1, 1.8 Hz, 1H), 7.11 (d, J =
    8.1 Hz, 1H), 6.13 (s, 2H).
    755 1H NMR (400 MHz, DMSO) δ 11.36 DMSO >98 Method N6
    (s, 1H), 9.73 (d, J = 1.7 Hz, 1H),
    9.52 (d, J = 1.8 Hz, 1H), 9.13-9.02
    (m, 3H), 8.96 (dd, J = 5.4, 1.4 Hz,
    1H), 8.79 (d, J = 6.9 Hz, 2H), 8.56
    (dd, J = 8.9, 1.9 Hz, 1H), 8.19 (ddd,
    J = 13.0, 7.5, 2.5 Hz, 1H), 8.09 (d, J =
    8.8 Hz, 1H), 8.02 (dd, J = 8.0, 5.4
    Hz, 1H), 7.90 (dt, J = 9.0, 2.8 Hz,
    1H), 7.62-7.50 (m, 1H).
    756 1H NMR (400 MHz, DMSO) δ 10.19 DMSO >98 Method N6
    (s, 1H), 9.55 (d, J = 1.4 Hz, 1H),
    8.86 (d, J = 1.7 Hz, 1H), 8.69 (dd, J =
    8.8, 2.9 Hz, 2H), 8.25 (dd, J = 8.7,
    1.8 Hz, 1H), 8.18-8.07 (m, 1H),
    7.99 (d, J = 8.7 Hz, 1H), 7.92 (d, J =
    7.2 Hz, 2H), 7.78-7.68 (m, 1H),
    7.62-7.53 (m, 4H), 7.47 (t, J = 7.4
    Hz, 1H).
    757 1H NMR (400 MHz, DMSO) δ 10.84 DMSO >98 Method N6
    (s, 1H), 9.55 (s, 1H), 9.19-9.05
    (m, 2H), 8.95 (d, J = 4.1 Hz, 1H),
    8.53 (s, 1H), 8.41 (dd, J = 8.7, 1.7
    Hz, 1H), 8.28 (s, 1H), 8.16-8.07
    (m, 3H), 8.05-7.92 (m, 2H), 7.79
    (d, J = 9.1 Hz, 1H), 7.70-7.46 (m,
    3H).
    758 1H NMR (400 MHz, DMSO) δ 10.78 DMSO >98 Method N6
    (s, 1H), 9.55 (d, J = 1.8 Hz, 1H),
    9.12 (d, J = 8.6 Hz, 2H), 8.96 (dd, J =
    5.4, 1.4 Hz, 1H), 8.40 (dd, J = 8.8,
    1.8 Hz, 1H), 8.16-7.96 (m, 8H),
    7.79-7.71 (m, 1H), 7.64-7.53 (m,
    1H), 7.47 (s, 1H).
    759 1H NMR (400 MHz, DMSO) δ 10.41 DMSO >98 Method N6
    (s, 1H), 9.56 (s, 1H), 8.98-8.77
    (m, 3H), 8.23-8.02 (m, 4H), 7.99-
    7.65 (m, 5H), 7.56 (dd, J = 19.1, 9.4
    Hz, 1H).
    760 1H NMR (400 MHz, DMSO) δ 10.51 DMSO >98 Method N6
    (s, 1H), 9.55 (d, J = 1.6 Hz, 1H),
    9.04 (d, J = 8.1 Hz, 1H), 8.95-8.84
    (m, 2H), 8.21-8.02 (m, 3H), 7.93
    (dt, J = 10.6, 5.3 Hz), 1H), 7.77-
    7.68 (m, 1H), 7.63-7.51 (m, 3H),
    7.49-7.38 (m, 1H).
    761 1H NMR (400 MHz, DMSO) δ 10.51 DMSO >98 Method N6
    (s, 1H), 9.55 (d, J = 1.5 Hz, 1H),
    9.03 (d, J = 8.2 Hz, 1H), 8.91 (dd, J =
    5.3, 1.5 Hz, 1H), 8.82 (s, 1H),
    8.16-8.00 (m, 3H), 7.94 (dd, J =
    8.0, 5.2 Hz, 1H), 7.87-7.78 (m,
    1H), 7.75-7.66 (m, 1H), 7.61-
    7.44 (m, 2H), 7.39-7.28 (m, 1H).
    762 1H NMR (400 MHz, DMSO) δ 10.75 DMSO >98 Method N6
    (s, 1H), 9.53 (d, J = 1.7 Hz, 1H),
    9.07 (dd, J = 23.2, 4.9 Hz, 2H), 8.95
    (dd, J = 5.3, 1.4 Hz, 1H), 8.36 (dd, J =
    8.8, 1.9 Hz, 1H), 8.15-7.96 (m,
    3H), 7.76 (dd, J = 9.0, 4.1 Hz, 1H),
    7.64-7.50 (m, 1H), 7.41 (dt, J =
    12.9, 1.6 Hz, 2H), 6.99-6.90 (m,
    1H), 3.90 (s, 3H).
    763 1H NMR (400 MHz, DMSO) δ 10.54 DMSO >98 Method N6
    (s, 1H), 9.55 (s, 1H), 9.05 (d, J =
    8.2 Hz, 1H), 8.92 (d, J = 4.6 Hz,
    1H), 8.84 (s, 1H), 8.17-8.02 (m,
    3H), 7.96 (dd, J = 7.9, 5.4 Hz, 1H),
    7.72 (d, J = 9.0 Hz, 1H), 7.56 (dd, J =
    19.6, 9.1 Hz, 1H), 7.39-7.21 (m,
    3H), 3.89 (s, 3H).
    764 1H NMR (400 MHz, DMSO) δ 10.68 DMSO >98 Method N6
    (s, 1H), 9.51 (d, J = 1.3 Hz, 1H),
    9.04 (d, J = 8.1 Hz, 1H), 8.97-8.87
    (m, 2H), 8.51 (s, 1H), 8.32-8.22
    (m, 2H), 8.16-8.05 (m, 2H), 8.00-
    7.90 (m, 2H), 7.80-7.73 (m, 1H),
    7.65 (t, J = 7.8 Hz, 1H), 7.60-7.47
    (m, 2H).
    765 1H NMR (400 MHz, DMSO) δ 10.43 DMSO >98 Method N6
    (s, 1H), 9.46 (d, J = 1.3 Hz, 1H),
    9.01 (d, J = 8.1 Hz, 1H), 8.91 (d,
    1H), 8.63 (s, 1H), 8.13-7.91 (m,
    3H), 7.73-7.66 (m, 1H), 7.59-
    7.49 (m, 2H), 7.44 (dd, J = 8.2, 1.8
    Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H),
    6.12 (s, 2H).
    766 1H NMR (400 MHz, DMSO) δ 10.33 DMSO >98 Method N6
    (s, 1H), 9.52 (s, 1H), 8.83 (s, 1H),
    8.70 (d, J = 6.3 Hz, 2H), 8.32 (d, J =
    8.6 Hz, 2H), 8.13-8.03 (m, 1H),
    7.70 (d, J = 7.3 Hz, 1H), 7.58 (dd, J =
    7.3, 5.7 Hz, 3H), 7.42 (s, 1H),
    3.95 (s, 3H).
    767 1H NMR (400 MHz, DMSO) δ 10.71 DMSO >98 Method N6
    (s, 1H), 9.52-9.41 (m, 3H), 9.26
    (s, 1H), 9.11-9.02 (m, 2H), 8.96
    (d, J = 5.4 Hz, 1H), 8.37 (d, J = 11.6
    Hz, 1H), 8.14-7.99 (m, 2H), 7.80-
    7.71 (m, 1H), 7.55 (d, J = 9.1 Hz,
    1H).
    768 1H NMR (400 MHz, DMSO) δ 10.53 DMSO >98 Method N6
    (s, 1H), 9.51 (d, J = 1.6 Hz, 1H),
    9.07-9.00 (m, 1H), 8.91 (dd, J =
    5.3, 1.5 Hz, 1H), 8.79 (s, 1H), 8.20
    (dd, J = 11.9, 1.6 Hz, 1H), 8.13-
    8.03 (m, 1H), 8.00-7.91 (m, 3H),
    7.76-7.68 (m, 1H), 7.62-7.44 (m,
    4H).
    769 1H NMR (400 MHz, DMSO) δ 11.13 DMSO >98 Method N6
    (s, 1H), 9.64 (d, J = 1.7 Hz, 1H),
    9.47 (d, J = 1.5 Hz, 1H), 9.38 (s,
    1H), 9.09 (t, J = 7.3 Hz, 2H), 9.01-
    8.94 (m, 1H), 8.91-8.83 (m, 1H),
    8.39 (dd, J = 11.6, 1.3 Hz, 1H), 8.22-
    8.13 (m, 1H), 8.11-7.98 (m, 2H),
    7.93-7.84 (m, 1H), 7.53 (dd, J =
    19.7, 9.2 Hz, 1H).
    770 1H NMR (400 MHz, DMSO) δ 10.69 DMSO >98 Method N6
    (s, 1H), 9.55 (d, J = 1.7 Hz, 1H),
    9.12 (d, J = 8.2 Hz, 1H), 8.97 (dd, J =
    5.4, 1.4 Hz, 1H), 8.81 (d, J = 8.7
    Hz, 1H), 8.30 (d, J = 1.3 Hz, 1H),
    8.15-7.99 (m, 3H), 7.96-7.88 (m,
    2H), 7.81-7.72 (m, 1H), 7.63-
    7.47 (m, 4H).
    771 1H NMR (400 MHz, DMSO) δ 10.89 DMSO >98 Method N6
    (s, 1H), 9.54-9.45 (m, 2H), 9.17 (t,
    J = 8.6 Hz, 1H), 9.10-8.93 (m,
    4H), 8.48 (d, J = 1.5 Hz, 1H), 8.25-
    8.06 (m, 4H), 7.89-7.79 (m, 1H),
    7.53 (dd, J = 19.6, 9.2 Hz, 1H).
    772 1H NMR (400 MHz, DMSO) δ 10.67 DMSO >98 Method N6
    (s, 1H), 9.54 (d, J = 1.7 Hz, 1H),
    9.40 (s, 2H), 9.31 (s, 1H), 9.20 (d, J =
    8.2 Hz, 1H), 9.02 (d, J = 4.3 Hz,
    1H), 8.89 (d, J = 8.7 Hz, 1H), 8.43
    (s, 1H), 8.22 (dd, J = 8.7, 1.9 Hz,
    1H), 8.17-8.06 (m, 2H), 7.82-
    7.74 (m, 1H), 7.56 (dd, J = 19.7, 9.2
    Hz, 1H).
    773 1H NMR (400 MHz, DMSO) δ 10.81 DMSO >98 Method N6
    (s, 1H), 9.56 (s, 1H), 9.11 (d, J =
    8.2 Hz, 1H), 8.94 (dd, J = 17.5, 6.7
    Hz, 2H), 8.42 (d, J = 11.9 Hz, 2H),
    8.28 (s, 1H), 8.22-7.94 (m, 5H),
    7.81 (d, J = 8.8 Hz, 1H), 7.71-7.46
    (m, 3H).
    774 1H NMR (400 MHz, DMSO) δ 10.32 DMSO >98 Method N6
    (s, 1H), 9.54 (s, 1H), 8.95-8.78
    (m, 2H), 8.65 (d, J = 8.8 Hz, 1H),
    8.19-8.09 (m, 2H), 8.02 (d, J =
    8.7, 1H), 7.85-7.69 (m, 2H), 7.62-
    7.37 (m, 3H), 7.09 (d, J = 7.0 Hz,
    1H), 6.13 (s, 2H).
    775 1H NMR (400 MHz, DMSO) δ 10.59 DMSO >98 Method N6
    (s, 1H), 9.56 (d, J = 1.7 Hz, 1H),
    9.11 (d, J = 8.1 Hz, 1H), 9.01-8.88
    (m, 1H), 8.79 (d, J = 8.7 Hz, 1H),
    8.18-8.06 (m, 2H), 8.05-7.91 (m,
    2H), 7.82-7.72 (m, 2H), 7.61-
    7.52 (m, 2H), 7.48-7.37 (m, 2H).
    776 1H NMR (400 MHz, DMSO) δ 10.46 DMSO >98 Method N6
    (s, 1H), 9.53 (d, J = 1.6 Hz, 1H),
    9.04 (dt, J = 8.1, 1.6 Hz, 1H), 8.91
    (dd, J = 5.2, 1.4 Hz, 1H), 8.73 (d, J =
    8.7 Hz, 1H), 8.24 (d, J = 1.8 Hz,
    1H), 8.15-8.04 (m, 2H), 7.96 (dd,
    J = 8.0, 5.3 Hz, 1H), 7.84-7.70 (m,
    2H), 7.65-7.48 (m, 2H), 7.39-
    7.25 (m, 1H).
    777 1H NMR (400 MHz, DMSO) δ 10.62 DMSO >98 Method N6
    (s, 1H), 9.55 (d, J = 1.7 Hz, 1H),
    9.12 (d, J = 8.1 Hz, 1H), 8.96 (dd, J =
    5.3, 1.3 Hz, 1H), 8.78 (d, J = 8.7
    Hz, 1H), 8.25 (d, J = 1.7 Hz, 1H),
    8.16-7.91 (m, 6H), 7.81-7.69 (m,
    1H), 7.56 (dd, J = 19.7, 9.1 Hz, 1H),
    7.41 (t, J = 8.8 Hz, 1H).
    778 1H NMR (400 MHz, DMSO) δ 10.65 DMSO >98 Method N6
    (s, 1H), 9.55 (d, J = 1.7 Hz, 1H),
    9.14 (d, J = 8.1 Hz, 1H), 8.97 (dd, J =
    5.4, 1.3 Hz, 1H), 8.81 (d, J = 8.7
    Hz, 1H), 8.20-8.00 (m, 3H), 7.96-
    7.71 (m, 3H), 7.63-7.42 (m, 2H),
    7.38-7.25 (m, 1H).
    779 1H NMR (400 MHz, DMSO) δ 10.40 DMSO >98 Method N6
    (s, 1H), 9.54 (d, J = 1.6 Hz, 1H),
    9.00 (d, J = 8.1 Hz, 1H), 8.90 (dd, J =
    5.2, 1.4 Hz, 1H), 8.71 (d, J = 8.7
    Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H),
    8.17-8.01 (m, 3H), 7.93 (dd, J =
    8.0, 5.2 Hz, 1H), 7.84-7.71 (m,
    2H), 7.69-7.49 (m, 2H). DMSO >98 Method N6
    780 1H NMR (400 MHz, DMSO) δ 10.78
    (s, 1H), 9.54 (d, J = 1.6 Hz, 1H),
    9.19 (d, J = 8.1 Hz, 1H), 9.06-8.96
    (m, 1H), 8.87 (d, J = 8.7 Hz, 1H),
    8.22-8.04 (m, 3H), 7.93 (t, J =
    10.1 Hz, 1H), 7.78 (dd, J = 6.1, 2.9
    Hz, 1H), 7.64-7.49 (m, 3H), 7.47-
    7.35 (m, 1H).
    781 1H NMR (400 MHz, DMSO) δ 10.47 DMSO >98 Method N6
    (s, 1H), 9.53 (d, J = 1.7 Hz, 1H),
    9.08 (d, J = 8.1 Hz, 1H), 8.94 (dd, J =
    5.3, 1.3 Hz, 1H), 8.74 (d, J = 8.8
    Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H),
    8.17-7.95 (m, 3H), 7.80-7.65 (m,
    3H), 7.61-7.48 (m, 1H), 7.42-
    7.30 (m, 1H).
    782 1H NMR (400 MHz, DMSO) δ 13.20 DMSO >98 Method N6
    (s, 1H), 9.63 (s, 1H), 9.20 (d, J =
    8.1 Hz, 1H), 8.97 (dd, J = 5.3, 1.3
    Hz, 1H), 8.89 (d, J = 8.3 Hz, 1H),
    8.56 (d, J = 1.6 Hz, 1H), 8.46 (s,
    1H), 8.31 (dd, J = 8.7, 1.8 Hz, 1H),
    8.13-7.92 (m, 4H), 7.90-7.83 (m,
    2H), 7.77-7.70 (m, 1H), 7.59 (dd,
    J = 10.4, 4.8 Hz, 2H), 7.53-7.46
    (m, 2H), 7.34-7.25 (m, 1H).
    783 1H NMR (400 MHz, DMSO) δ 13.22 DMSO >98 Method N6
    (s, 1H), 9.65 (s, 1H), 9.19 (d, J =
    8.1 Hz, 1H), 9.00-8.91 (m, 2H),
    8.44 (d, J = 12.8 Hz, 2H), 8.18-
    7.89 (m, 5H), 7.84-7.70 (m, 2H),
    7.56-7.45 (m, 1H), 7.38-7.23 (m,
    2H).
    784 1H NMR (400 MHz, DMSO) δ 13.15 DMSO >98 Method N6
    (s, 1H), 9.65 (s, 1H), 9.38-9.27
    (m, 3H), 9.17 (d, J = 9.2 Hz, 1H),
    8.92 (dd, J = 25.3, 6.7 Hz, 2H), 8.68
    (s, 1H), 8.45 (d, J = 8.9 Hz, 2H),
    8.12 (d, J = 9.8 Hz, 1H), 8.04-7.92
    (m, 3H), 7.74 (t, J = 7.6 Hz, 1H),
    7.30 (t, J = 8.1 Hz, 1H).
    785 1H NMR (400 MHz, DMSO) δ 13.10 DMSO >98 Method N6
    (s, 1H), 9.63 (s, 1H), 9.18 (d, J =
    8.0 Hz, 1H), 8.96 (dd, J = 5.3, 1.3
    Hz, 1H), 8.87 (d, J = 8.1 Hz, 1H),
    8.46 (d, J = 21.1 Hz, 2H), 8.27 (dd,
    J = 8.7, 1.8 Hz, 1H), 8.09-7.89 (m,
    4H), 7.74 (t, J = 7.1 Hz, 1H), 7.46
    (d, J = 1.8 Hz, 1H), 7.38 (dd, J =
    8.1, 1.9 Hz, 1H), 7.30 (t, J = 7.2 Hz,
    1H), 7.12 (d, J = 8.1 Hz, 1H), 6.12
    (s, 2H).
    786 1H NMR (DMSO-d6) ppm 9.79 (d, J = DMSO >98 N6 using
    1.56 Hz, 1H), 9.26 (brd, J = 7.2 Na2CO3
    Hz, 1H), 9.00-8.90 (brm, 2H), 8.18 instead of
    (d, J = 8.64 Hz, 1H), 8.11 (d, J = K3PO4
    8.64 Hz, 1H), 8.01 (brt, J = 6.28 Hz,
    1H), 7.86-7.80 (brm, 1H), 7.72 (d, J =
    3.96 Hz, 1H), 7.53-7.46 (m, 2H),
    7.37-7.32 (brm, 1H). The 1H of
    2HCl and NH-were not observed.
    787 1H NMR (DMSO-d6) ppm 12.63 DMSO >98 N6 using
    (brs, 1H), 9.80 (d, J = 1.64 Hz, 1H), Na2CO3
    9.05-8.91 (brm, 2H), 8.76 (brd, J = instead of
    4.6 Hz, 1H), 8.10 (brd, J = 8.64 Hz, K3PO4
    1H), 8.02 (d, J = 8.64 Hz, 1H), 7.86-
    7.80 (brm, 1H), 7.66-7.62 (brm,
    1H), 7.51-7.45 (brm, 1H), 7.34-7.30
    (brm, 1H), 6.94 (brs, 1H), 2.35 (brs,
    3H).
    788 1H NMR (300 MHz, CD3OD) δ 9.40 CD3OD 99 Method N3 463.0 Method C
    (s, 1H), 8.65 (d, J = 8.0 Hz, 1H), (M + 1)
    8.56 (d, J = 3.2 Hz, 1H), 8.18-8.08
    (m, 2H), 7.76-7.65 (m, 2H), 7.54-
    7.44 (m, 2H), 7.23 (t, J = 9.0 Hz,
    1H), 3.66 (s, J = 8.0 Hz, 2H), 2.55
    (s, J = 20.6 Hz, 8H), 2.30 (s, 3H).
    789 99 Method N3 434.0 Method C
    (M + 1)
    790 99 Method N3 436.0 Method C
    (M + 1)
    791 1H-NMR (400 MHz, DMSO-d6): δ DMSO 95 Method N1 422.2 Method B
    12.20 (s, 1H), 9.64 (s, 1H), 9.58 (s, (M + 1) (NH4HCO3)
    1H), 8.73 (d, J = 5.5 Hz, 2H), 8.60
    (s, 1H), 8.53 (dd, J = 7.2, 1.5 Hz,
    1H), 8.28-8.25 (m, 1H), 7.99 (d, J =
    8.7 Hz, 1H), 7.61-7.58 (m, 1H),
    7.50 (t, J = 4.5 Hz, 3H), 7.30 (d, J =
    5.8 Hz, 1H), 7.06 (dd, J = 7.4, 4.1
    Hz, 1H), 6.49 (t, J = 6.9 Hz, 1H),
    3.91 (s, 3H).
    792 1H-NMR (400 MHz, DMSO-d6): δ DMSO 95 Method N1 404.0 Method B
    13.42 (s, 1H), 8.99 (d, J = 8.0 Hz, (M + 1) (NH4HCO3)
    1H), 8.64 (td, J = 7.6, 2.0 Hz, 1H),
    8.51 (s, 1H), 8.44 (d, J = 4.4 Hz,
    1H), 8.01-7.95 (m, 3H), 7.68-
    7.58 (m, 4H), 7.24 (t, J = 7.8 Hz,
    1H), 4.26 (q, J = 2.8 Hz, 2H), 1.47
    (t, J = 2.8 Hz, 3H).
    793 1H-NMR (400 MHz, DMSO-d6): δ DMSO 95 Method N1 445.0 Method B
    10.31 (s, 1H), 9.13 (d, J = 2.0 Hz, (M + 1) (NH4HCO3)
    1H), 8.83 (td, J = 8.4, 2.4 Hz, 1H),
    8.09 (d, J = 1.2 Hz, 2H), 7.93 (d, J =
    8.4 Hz, 2H), 7.66-7.60 (m, 2H),
    7.36 (dd, J = 8.8, 2.4 Hz, 1H), 7.22
    (d, J = 8.0 Hz, 1H), 4.28 (q, J = 6.8
    Hz, 2H), 1.47 (t, J = 6.8 Hz, 3H).
    794 DMSO 95 Method N1 382.5 Method C
    (M + 1)
    795 1H-NMR (300 MHz, DMSO): δ DMSO 95 Method N1 449.4 Method C
    13.10 (s, 1H), 9.61 (s, 1H), 9.12 (d, (M + 1)
    J = 9.8 Hz, 1H), 8.93 (s, 1H), 8.83
    (d, J = 15.2 Hz, 2H), 8.66 (s, 1H),
    8.58-8.36 (m, 3H), 8.08 (d, J =
    11.6 Hz, 2H), 7.96 (d, J = 9.2 Hz,
    3H), 7.73 (s, 1H), 7.29 (t, J = 8.7
    Hz, 1H), 4.02 (s, 3H).
    796 1H-NMR (300 MHz, DMSO): δ DMSO 95 Method N1 419.1 Method C
    12.79 (s, 1H), 9.54 (d, J = 1.6 Hz, (M + 1)
    1H), 9.18 (d, J = 8.2 Hz, 1H), 9.08
    (d, J = 6.7 Hz, 2H), 9.05-8.96 (m,
    2H), 8.63-8.46 (m, 4H), 8.39 (s,
    1H), 8.08 (dd, J = 11.6, 8.5 Hz, 2H),
    7.92 (d, J = 6.7 Hz, 1H), 7.77 (s,
    1H), 7.68 (t, J = 7.1 Hz, 1H), 7.32 (t,
    J = 7.2 Hz, 1H).
    797 1H-NMR (300 MHz, DMSO): δ DMSO 95 Method N1 419.1 Method C
    12.81 (s, 1H), 9.54 (s, 1H), 9.45 (s, (M + 1)
    1H), 9.23 (d, J = 8.2 Hz, 1H), 9.08-
    8.93 (m, 3H), 8.83 (s, 1H), 8.52 (d,
    J = 8.2 Hz, 1H), 8.47-8.34 (m,
    2H), 8.14 (ddd, J = 12.9, 8.1, 4.9
    Hz, 3H), 7.92 (d, J = 6.6 Hz, 1H),
    7.79 (s, 1H), 7.68 (t, J = 7.2 Hz,
    1H), 7.32 (t, J = 7.2 Hz, 1H).
    798 1H-NMR (300 MHz, DMSO): δ DMSO 95 Method N1 448.1 Method C
    13.20 (s, 1H), 9.62 (s, 1H), 9.13 (d, (M + 1)
    J = 8.1 Hz, 1H), 8.94 (d, J = 3.5 Hz,
    2H), 8.55 (s, 1H), 8.48 (s, 1H), 8.31
    (d, J = 8.7 Hz, 1H), 8.06 (d, J = 8.7
    Hz, 1H), 7.96 (s, 3H), 7.74 (s, 1H),
    7.55-7.40 (m, 3H), 7.29 (s, 1H),
    7.06 (d, J = 7.4 Hz, 1H), 3.90 (s,
    3H).
    799 1H-NMR (300 MHz, DMSO): δ DMSO 95 Method N1 422.2 Method C
    13.13 (s, 1H), 9.60 (d, J = 1.4 Hz, (M + 1)
    1H), 9.12 (d, J = 7.8 Hz, 1H), 8.73
    (dd, J = 9.7, 6.4 Hz, 2H), 8.52 (s,
    1H), 8.35 (s, 1H), 8.28 (s, 1H), 8.14
    (d, J = 8.7 Hz, 1H), 8.08-7.88 (m,
    4H), 7.76 (d, J = 7.2 Hz, 1H), 7.59
    (dd, J = 7.4, 4.8 Hz, 1H), 7.23 (t, J =
    7.1 Hz, 1H), 3.94 (s, 3H).
    800 1H NMR (400 MHz, DMSO) δ 10.08 DMSO >98 N5
    (s, 1H), 9.59-9.49 (m, 1H), 8.79-
    8.63 (m, 3H), 8.55 (d, J = 2.1 Hz,
    1H), 8.27 (dd, J = 6.9, 2.6 Hz, 1H),
    8.18 (dd, J = 8.7, 1.9 Hz, 1H), 8.02-
    7.90 (m, 3H), 7.63-7.51 (m, 2H),
    6.62 (d, J = 8.6 Hz, 1H), 6.24 (s,
    2H).
    801 1H NMR (DMSO-d6) ppm 9.78 DMSO >98 N6 using
    (brs, 1H), 9.20-8.80 (br, 3H), 8.14 Na2CO3
    (brd, J = 8.64 Hz, 1H), 8.04 (d, J = instead of
    8.64 Hz, 1H), 7.83 ′brm, 2H), 7.52- K3PO4
    7.47 (m, 1H), 7.35-7.31 (m, 1H), 7.00
    (brs, 1H), 2.36 (brs, 3H), 2.30 (brs,
    3H). The 1H of MsOH and NH
    were not observed.
    Num- Molecular 1H-NMR LCMS Purity Method for
    ber PRODUCT Salt type Mass 1H-NMR Solvent LCMS Protocol percent Coupling
    802
    Figure US20170217923A1-20170803-C01699
         		494.87 1H-NMR (400 MHz, DMSO-d6): δ10.18 (s, 1H), 9.21 (d, J = 1.8 Hz, 1H), 8.65-8.60 (m, 2H), 8.34- 8.24 (m, 2H), 7.96-7.90 (m, 2H), 7.85-7.68 (m, 4H), 7.56 (t, J = 9.0 Hz, 1H), 7.51-7.44 (m, 2H). DMSO 495.0, 497.0 (M + 1) Method B (NH4HCO3) 95 Method N1
    803
    Figure US20170217923A1-20170803-C01700
         		458.89 1H-NMR (400 MHz, DMSO-d6): δ10.14 (s, 1H), 9.44 (s, 1H), 8.73- 8.63 (m, 1H), 8.55 (t, J = 6.6 Hz, 2H), 8.27 (d, J = 4.6 Hz, 1H), 7.96 (d, J = 6.8 Hz, 2H), 7.76-7.64 (m, 3H), 7.58-7.52 (m, 2H), 7.31 (t, J = 9.2 Hz, 1H), 2.37 (s, 3H). DMSO 459.0, 461.0 (M + 1) Method B (NH4HCO4) 95 Method N1
    804
    Figure US20170217923A1-20170803-C01701
         		427.86 1H-NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 9.42 (d, J = 1.5 Hz, 1H), 8.74 (d, J = 5.6 Hz, 2H), 8.69- 8.63 (m, 2H), 8.52 (d, J = 8.0 Hz, 1H), 8.28 (dd, J = 6.8, 2.6 Hz, 1H), 8.05 (d, J= 7.2 Hz, 1H), 7.96- 7.91 (m, 1H), 7.80 (dd, J = 14.6, 6.8 Hz, 3H), 7.59-7.52 (m, 2H). DMSO 428.0, 430.0 (M + 1) 214.6 (M/2 + 1) Method A (TFA) 95 Method N1
    805
    Figure US20170217923A1-20170803-C01702
         		426.87 1H-NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 9.43 (d, J = 1.6 Hz, 1H), 8.66 (dd, J = 4.7, 1.6 Hz, 1H), 8.59-8.56 (m, 1H), 8.52 (td, J = 7.9, 1.8 Hz, 1H), 8.30 (dd, J = 6.84, 2.60 Hz, 1H), 7.99-7.92 (m, 2H), 7.82-7.73 (m, 3H), 7.58- 7.51 (m, 4H), 7.46 (t, J = 7.4 Hz, 1H). DMSO 427.1, 429.1 (M + 1) Method A (TFA) 95 Method N1
    806
    Figure US20170217923A1-20170803-C01703
         		456.9 1H-NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 9.45 (s, 1H), 8.67 (dd, J = 4.7, 1.7 Hz, 1H), 8.62- 8.49 (m, 2H), 8.29 (dd, J = 6.8, 2.6 Hz, 1H), 8.03-7.88 (m, 2H), 7.81- 7.68 (m, 1H), 7.62-7.49 (m, 2H), 7.48-7.30 (m, 3H), 7.04 (dd, J = 7.8, 2.1 Hz, 1H), 3.87-3.81 (m, 3H). DMSO 457.1, 459.1 (M + 1) Method A (TFA) 95 Method N1
    807
    Figure US20170217923A1-20170803-C01704
         		456.9 1H-NMR (400 MHz, DMSO-d6): δ10.10 (s, 1H), 9.31 (d, J = 1.6 Hz, 1H), 8.63 (dd, J = 4.8, 1.7 Hz, 1H), 8.61-8.52 (m, 1H), 8.41 (td, J = 8.0, 1.9 Hz, 1H), 8.30 (dd, J = 6.9, 2.6 Hz, 1H), 7.97-7.92 (m, 1H), 7.83 (dd, J= 7.2, 1.2 Hz, 1H), 7.78- 7.66 (m, 1H), 7.62-7.40 (m, 3H), 7.36 (dd, J = 7.4, 1.7 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 3.66 (s, 3H). DMSO 457.1, 459.1 (M + 2) Method B (NH4HCO3) 95 Method N1
  • Figure US20170217923A1-20170803-C01705
  • Figure US20170217923A1-20170803-C01706
    • Method S: N4-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-N6-(3-(pyrrolidin-1-yl)propyl)quinazoline-4,6-diamine (xxii-a)
  • A 2.0 dram reaction vial was charged with 6-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 5-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol, 1.0 equiv), 3-(pyrrolidin-1-yl)propan-1-amine (40 mg, 0.345 mmol, 1.5 equiv), copper(I) iodide (4.4 mg, 0.023 mmol, 0.1 equiv), L-proline (5.3 mg, 0.046 mmol, 0.2 equiv), and potassium carbonate (96 mg, 0.69 mmol, 3.0 equiv) in DMF (3 mL). The reaction mixture was heated at 100° C. overnight. After cooling, water was added to the reaction mixture, and the resultant precipitate was collected by filtration. The crude product was purified via prep-TLC (silica, 2000 micron plate, 95% dichloromethane—5% methanol—0.1% NH4OH) to yield the desired compound as a brown solid (17.2 mg, 15%). LCMS m/z=477.4 (M+1) (Method C) (retention time=1.68 min). 1H NMR (300 MHz, DMSO) δ 9.68 (s, 1H), 9.46 (s, 1H), 8.59 (d, J=9.4 Hz, 2H), 8.25 (dd, J=6.8, 2.6 Hz, 1H), 7.93 (dd, J=8.3, 3.5 Hz, 1H), 7.69-7.59 (m, 1H), 7.52 (dd, J=11.0, 7.1 Hz, 2H), 7.36-7.19 (m, 2H), 6.41 (s, 1H), 3.34 (m, 2H), 2.69 (m, 6H), 2.02-1.82 (m, 2H), 1.75 (bs, 4H).
  • Figure US20170217923A1-20170803-C01707
    • Method T: N-(3-chloro-4-fluorophenyl)-6-(2-morpholinoethoxy)-2-(pyridin-3-yl)quinazolin-4-amine (xxii-b)
  • A 2.5 dram reaction vial was charged with N-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine (0.250 g, 0.524 mmol), 2-morpholinoethanol (1 ml, 8.17 mmol) as solvent, copper(I) iodide (0.020 g, 0.105 mmol), racemic-2,2′-diamino-1,1′-binaphthyl (0.030 g, 0.105 mmol), and cesium carbonate (0.513 g, 1.573 mmol). The reaction mixture was heated at 110° C. overnight. After cooling, water was added to the reaction mixture, and the resultant precipitate was collected by filtration. The solid residue was purified via ISCO (silica, 12 g column, 95% dichloromethane—5% methanol—0.1% NH4OH) to yield the desired compound as a brown solid. The solid was further washed with a mixture of water and saturated NaHCO3 solution and dried. The product off the column was further purified by prep TLC (silica gel, 1000 micron, 95% dichloromethane—5% methanol—0.1% NH4OH) to afford the desired product as a light brown solid (21.2 mg, 8%). LCMS m/z=480.0 (M+1) (Method C) (retention time=2.09 min). 1H NMR (300 MHz, DMSO) δ 9.81 (s, 1H), 9.47 (d, J=1.8 Hz, 1H), 8.66-8.57 (m, 2H), 8.21 (dd, J=6.8, 2.6 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.87 (ddd, J=8.9, 4.3, 2.7 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H), 7.57-7.47 (m, 3H), 4.25 (t, J=5.8 Hz, 2H), 3.64-3.55 (m, 4H), 2.78 (t, J=5.7 Hz, 2H), 2.55-2.49 (m, 4H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 20 substituting with appropriate amine or alcohol
  • TABLE 5
    Me-
    1H- Reten- Pur- thod
    Mole- NMR tion LCMS ity for
    Num- Salt cular Sol- Time Proto- Per- Coup-
    ber Product type Mass 1H-NMR vent LCMS (min.) col cent ling
    808
    Figure US20170217923A1-20170803-C01708
         		476.98 1H NMR (300 MHz, DMSO) δ 9.68 (s, 1H), 9.46 (s, 1H), 8.59 (d, J = 9.4 Hz, 2H), 8.25 (dd, J = 6.8, 2.6 Hz, 1H), 7.93 (dd, J = 8.3, 3.5 Hz, 1H), 7.69- 7.59 (m, 1H), 7.52 DMSO 477.4 (M + 1) 1.68 Me- thod C 95 Me- thod S
    (dd, J = 11.0, 7.1
    Hz, 2H), 7.36-7.19
    (m, 2H), 6.41 (s,
    1H), 3.34 (m, 2H),
    2.69 (m,
    809
    Figure US20170217923A1-20170803-C01709
         		492.98 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 9.46 (s, 1H), 8.60 (td, J = 4.2, 2.4 Hz, 2H), 8.23 (dd, J = 6.8, 2.6 Hz, 1H), 7.90 (ddd, J = 8.9, 4.2, 2.6 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.57-7.45 (m, DMSO 493 (M + 1) 1.97 Me- thod C 100 Me- thod S
    2H), 7.32 (dd, J = 9.1,
    2.2 Hz, 1H), 7.20 (s,
    1H), 6.38 (s
    810
    Figure US20170217923A1-20170803-C01710
         		423.87 1H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 9.46 (s, 1H), 8.60 (dd, J = 9.1, 3.1 Hz, 2H), 8.22 (dd, J = 6.9, 2.5 Hz, 1H), 7.89 (ddd, J = 9.0, 4.3, 2.7 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.58-7.46 (m, 2H), 7.37 (dd, J = 9.1, DMSO 423.9 (M + 1) 2.16 Me- thod C 100 Me- thod S
    2.2 Hz, 1H), 7.25 (s,
    1H), 6.40 (t
    811
    Figure US20170217923A1-20170803-C01711
         		463.93 1H NMR (300 MHz, DMSO) δ 9.62 (s, 1H), 9.49 (d, J = 1.7 Hz, 1H), 8.70-8.59 (m, 2H), 8.27 (dd, J = 6.9, 2.5 Hz, 1H), 8.19 (dd, J = 9.0, 5.0 Hz, 1H), 7.91- 7.82 (m, 1H), 7.57- 7.43 (m, 2H), 7.01 (dd, J = 9.0, 2.1 Hz, DMSO 464.0 (M + 1) 2.19 Me- thod C 100 Me- thod S
    1H), 6.77 (t, J = 5.3
    Hz, 1H), 6.72
    812
    Figure US20170217923A1-20170803-C01712
         		449.91 1H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.49 (d, J = 2.1 Hz, 1H), 8.69-8.59 (m, 2H), 8.27 (dd, J = 6.9, 2.6 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.87 (ddd, J = 9.0, 4.3, 2.7 Hz, 1H), 7.56-7.43 (m, 2H), 7.00 (dd, J = 9.1, 2.2 Hz, 1H), DMSO 449.9 (M + 1) 2.12 Me- thod C 100 Me- thod S
    6.79 (d, J = 2.1 Hz,
    813
    Figure US20170217923A1-20170803-C01713
         		409.84 1H NMR (300 MHz, DMSO) δ 9.71 (s, 1H), 9.46 (s, 1H), 8.66-8.55 (m, 2H), 8.24 (d, J = 4.3 Hz, 1H), 7.96-7.87 (m, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.58-7.46 (m, 3H), 7.36 (d, J = 9.0 Hz, 1H), 7.28 (s, 1H), 6.38 (s, 1H), 4.96 (s, 1H), 3.69 (s, 2H), DMSO 409.9 (M + 1) 1.86 Me- thod C 100 Me- thod S
    3.42
    814
    Figure US20170217923A1-20170803-C01714
         		463.93 1H NMR (300 MHz, DMSO) δ 9.59 (s, 1H), 9.45 (d, J = 1.2 Hz, 1H), 8.60 (dd, J = 7.4, 5.7 Hz, 2H), 8.23 (dd, J = 6.8, 2.5 Hz, 1H), 7.90 (dd, J = 9.0, 2.7 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.57-7.46 (m, 2H), 7.36 (d, DMSO 464.0 (M + 1) 2.19 Me- thod C 95 Me- thod S
    J = 9.1 Hz, 1H),
    7.19 (s, 1H), 6.38
    (s
    815
    Figure US20170217923A1-20170803-C01715
         		479.93 1H NMR (300 MHz, DMSO) δ 9.81 (s, 1H), 9.47 (d, J = 1.8 Hz, 1H), 8.66-8.57 (m, 2H), 8.21 (dd, J = 6.8, 2.6 Hz, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.87 (ddd, J = 8.9, 4.3, 2.7 Hz, 1H), 7.81 (d, J = 9.1 Hz, DMSO 480.0 (M + 1) 2.09 Me- thod C 91 Me- thod T
    1H), 7.57-7.47 (m,
    3H), 4.25 (t, J = 5.8
    Hz, 2H),
    816
    Figure US20170217923A1-20170803-C01716
         		423.87 1H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 9.47 (s, 1H), 8.67- 8.55 (m, 2H), 8.23 (dd, J = 6.9, 2.5 Hz, 1H), 7.90 (ddd, J = 9.0, 4.3, 2.7 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.58-7.47 (m, 2H), 7.37 (dd, J = 9.1, 2.2 Hz, 1H), 7.25 (d, J = DMSO 423.9 (M + 1) Me- thod C 99 Me- thod S
    1.3 Hz, 1H), 6.41 (t,
    J = 5.6 Hz, 1H), 3.63
    (t, J = 5.7 Hz, 2H),
    3.48-3.35 (m, 5H).
    817
    Figure US20170217923A1-20170803-C01717
         		437.9 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 9.47 (s, 1H), 8.66- 8.55 (m, 2H), 8.23 (dd, J = 6.9, 2.5 Hz, 1H), 7.90 (ddd, J = 8.8, 4.3, 2.5 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.58-7.45 (m, 2H), 7.32 (dd, J = DMSO 438.1 (M + 1) Me- thod C 99 Me- thod S
    9.0, 1.8 Hz, 1H),
    7.21 (s, 1H), 6.34
    (t, J = 5.0 Hz, 1H),
    3.50 (t, J = 6.1 Hz,
    2H), 3.31-3.20 (m,
    5H), 1.92 (p, J =
    6.5 Hz, 2H).
    818
    Figure US20170217923A1-20170803-C01718
         		449.91 1H NMR (300 MHz, DMSO) δ 9.61 (s, 1H), 9.46 (d, J = 2.1 Hz, 1H), 8.65-8.56 (m, 2H), 8.23 (dd, J = 6.9, 2.6 Hz, 1H), 7.90 (ddd, J = 8.9, 4.2, 2.6 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.58- 7.47 (m, 2H), 7.40 (dd, J = 8.9, 2.2 Hz, DMSO 449.9 (M + 1) Me- thod C 94 Me- thod S
    1H), 7.26 (d, J = 1.7
    Hz, 1H), 6.39 (t, J =
    5.7 Hz, 1H), 4.12 (t,
    J = 6.2 Hz, 1H),
    3.85 (dd, J = 14.2,
    7.2 Hz, 1H), 3.70
    (dd, J = 14.2, 7.7 Hz,
    1H), 3.34-3.25 (m,
    5H), 2.15-1.99 (m,
    1H), 1.97-1.80 (m,
    3H), 1.74-1.58 (m,
    2H).
    819
    Figure US20170217923A1-20170803-C01719
         		1H-NMR (300 MHz, DMSO): δ 10.04 (s, 1H), 9.48 (s, 1H), 8.67 (s, 2H), 8.43-8.31 (m, 1H), 8.14-8.01 (m, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.65 (s, 1H), 7.54 (dd, J = 9.7 Hz, 2H), 7.35 (d, J = 9.0 Hz, 1H), 6.77 (s, 1H), DMSO 463.9 (M + 1) Me- thod C 95 Me- thod S
    3.67 (broad doublet,
    4H), 3.41 (bs, 2H),
    3.08 (d, J = 4.7 Hz,
    2H), 2.03 (bs, 2H),
    1.91 (bs, 2H).
  • Figure US20170217923A1-20170803-C01720
  • Figure US20170217923A1-20170803-C01721
    • Method U: 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (xxiii-a)
  • To a suspension of 2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (synthesized as described in Scheme 1 and 4, substituting 5-methoxy-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid) (371 mg, 1.0 mmol) in CH2Cl2 (4.5 mL) was slowly added boron tribromide, 1M solution in dichloromethane (4.5 ml, 4.5 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature after which it was carefully poured into a vigorously stirring mixture of ice and saturated solution of aqueous NaHCO3. The resultant solid was collected by filtration, dried and then stirred in a saturated solution of aqueous NH4Cl for 1 h after which the suspension was filtered to give the desired product as a yellowish tan solid (262 mg, 73%). LCMS m/z=357.9 (M+1) (Method C) (retention time=1.68 min). 1H NMR (300 MHz, DMSO) δ 12.80 (s, 1H), 10.50 (s, 1H), 9.57 (s, 1H), 9.15 (d, J=8.5 Hz, 1H), 8.70 (t, J=7.3 Hz, 2H), 8.50 (s, 1H), 8.08-7.79 (m, 3H), 7.73 (t, J=7.5 Hz, 1H), 7.57 (dd, J=7.6, 4.8 Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H).
    • Method V: 2-(6-(2-chloroethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (xxiv-a)
  • The suspension of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (50 mg, 0.14 mmol), 1-bromo-2-chloroethane (0.015 ml, 0.15 mmol), and potassium carbonate (23 mg, 0.17 mmol) in DMF (5 mL) was stirred for 3 days at room temperature. Water (10 mL) was added to the mixture and extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (1×20 mL) and brine (1×20 mL) and was dried over MgSO4. After filtration and evaporation, the crude product was obtained, which was washed with hexane and dried to give 48 mg of 2-(6-(2-chloroethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide as light brown solid (79%).
    • Method G4: 2-(6-(2-morpholinoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (xxv-a)
  • 2-(6-(2-morpholinoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide was prepared from 2-(6-(3-chloroethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide and morpholine in a manner analogous to that described for N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride in Scheme 9 using Method G4 to give 50 mg of 2-(6-(2-morpholinoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide as light yellow solid. LCMS m/z=485 (M+1) (Method C) (retention time=1.71 min). 1H NMR (300 MHz, DMSO) δ 9.57 (s, 1H), 9.12 (d, J=8.5 Hz, 1H), 8.78-8.63 (m, 2H), 8.48 (s, 1H), 8.02-7.93 (m, 2H), 7.88 (d, J=9.0 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.63-7.49 (m, 3H), 7.20 (t, J=7.6 Hz, 1H), 4.29-4.16 (m, 2H), 3.65-3.51 (m, 4H), 3.44-3.21 (m, 2H), 2.45-2.31 (m, 4H), 2.06-1.91 (m, 2H).
  • Figure US20170217923A1-20170803-C01722
    • Method W: 2-(6-(2-(methylamino)-2-oxoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide
  • The suspension of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (synthesized as described in Scheme 24) (0.20 g, 0.56 mmol), 2-chloro-N-methylacetamide (90 mg, 0.80 mmol), cesium carbonate (0.37 g, 1.12 mmol) and potassium iodide (0.19 g. 1.12 mmol) in DMF (10 mL) was stirred for 4 days at room temperature. Water (20 mL) was added to the mixture. The resultant solid was collected by filtration. The obtained solid was washed with CH2Cl2-THF (1:1) solution and dried to give 0.11 g of 2-(6-(2-(methylamino)-2-oxoethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide as pale brown solid (46%). LCMS m/z=429 (M+1) (Method C) (retention time=1.65 min). 1H NMR (300 MHz, DMSO) δ 9.58 (s, 1H), 9.12 (d, J=8.4 Hz, 1H), 8.82-8.64 (m, 2H), 8.48 (s, 1H), 8.32-8.17 (m, 1H), 8.10-7.87 (m, 3H), 7.81-7.49 (m, 4H), 7.21 (t, J=7.5 Hz, 1H), 4.66 (s, 2H), 2.71 (d, J=4.5 Hz, 3H).
  • Figure US20170217923A1-20170803-C01723
    • Method X: 2-(6-(2-(dimethylamino)ethoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide
  • A suspension of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (synthesized as described in Scheme 24) (25 mg, 0.07 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (20 mg, 0.14 mmol) and cesium carbonate (68.4 mg, 0.21 mmol) in DMF (1 mL) was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and extracted with dichloromethane (3×5 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep-TLC (silica, 2000 micron plate, 95% dichloromethane—5% methanol—0.1% NH4OH) to yield the desired compound as a brown solid (12.6 mg, 40%). LCMS m/z=428.9 (M+1) (Method C) (retention time=1.41 min). 1H NMR (300 MHz, DMSO) δ 12.99 (s, 1H), 9.59 (d, J=1.3 Hz, 1H), 9.12 (d, J=8.4 Hz, 1H), 8.81-8.66 (m, 2H), 8.52 (s, 1H), 8.06-7.88 (m, 3H), 7.80-7.53 (m, 4H), 7.22 (t, J=7.6 Hz, 1H), 4.46 (s, 2H), 3.35 (s, 2H), 2.69 (s, 6H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 23 substituting with appropriate nucleophile.
  • TABLE 6
    Re- Me-
    1H- ten- Pur- thod
    Mole- NMR tion LCMS ity for
    Num- Salt cular Sol- Time Proto- Per- Coup-
    ber Product type Mass 1H-NMR vent LCMS (min.) col cent ling
    820
    Figure US20170217923A1-20170803-C01724
         		484.550 1H NMR (300 MHz, DMSO) δ 9.57 (s, 1H), 9.12 (d, J = 8.5 Hz, 1H), 8.78-8.63 (m, 2H), 8.48 (s, 1H), 8.02-7.93 (m, 2H), 7.88 (d, J = 9.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.63-7.49 (m, 3H), 7.20 (t, DMSO 485 (M + 1) 1.71 Me- thod C 100 Me- thods V, G4
    J = 7.6 Hz, 1H),
    4.29-4.16 (m, 2H),
    3.65-3.51 (m
    821
    Figure US20170217923A1-20170803-C01725
         		470.523 1H NMR (300 MHz, DMSO) δ 9.58 (s, 1H), 9.24-9.08 (m, 1H), 8.82-8.61 (m, 2H), 8.49 (s, 1H), 8.09-7.84 (m, 3H), 7.73 (t, J = 7.8 Hz, 1H), 7.67-7.47 (m, 3H), 7.19 (t, J = 7.5 Hz, 1H), 4.29-4.09 (m, 2H), 3.63-3.42 DMSO 471 (M + 1) 1.75 Me- thod C 100 Me- thods V, G4 fol- lowed by acyl- ation with acetyl chlo- ride/TEA in DCM
    (m, 2H), 3.07-2.77 at rt.
    (m, 3H), 2.2
    822
    Figure US20170217923A1-20170803-C01726
         		442.470 1H NMR (300 MHz, DMSO) δ 9.58 (s, 1H), 9.16 (d, J = 8.4 Hz, 1H), 8.82-8.60 (m, 2H), 8.49 (s, 1H), 8.05-7.80 (m, 3H), 7.79-7.68 (m, 1H), 7.67-7.51 (m, 2H), 7.43 (s, 1H), 7.29-7.12 (m, 1H), 5.03 (s, 2H), 3.10 (s, 3H), 2.89 (s, DMSO 443 (M + 1) 1.63 Me- thod C 100 Me- thod W
    3H).
    823
    Figure US20170217923A1-20170803-C01727
         		HCl 561.94 1H NMR (300 MHz, DMSO) δ 10.51 (s, 1H), 9.49 (s, 1H), 8.95 (d, J = 6.6 Hz, 1H), 8.85 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 8.03-7.80 (m, DMSO 526 (M + 1) 2.02 Me- thod C 100 Me- thod W
    3H), 7.73-7.51 (m,
    2H), 7.19 (d, J =
    7.4 Hz, 1H), 5.12
    (s, 2H), 3.75-3.36
    (m, 8H).
    824
    Figure US20170217923A1-20170803-C01728
         		HCl 598.44 1H NMR (300 MHz, DMSO) δ 10.98 (s, 1H), 10.59 (s, 1H), 9.50 (s, 1H), 8.96 (d, J = 8.1 Hz, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 8.07- DMSO 526 (M + 1) 2.25 Me- thod C 100 Me- thods V, G4
    7.93 (m, 2H), 7.92-
    7.80 (m, 1H), 7.71-
    7.54 (m, 2H), 7.21
    (d, J = 8.0 Hz, 1H),
    4.47-4.23 (m, 2
    825
    Figure US20170217923A1-20170803-C01729
         		469.42 1H NMR (300 MHz, DMSO) δ 9.95 (s, 1H), 9.51 (s, 1H), 8.76-8.56 (m, 2H), 8.26-8.08 (m, 2H), 8.01 (s, 1H), 7.95- 7.81 (m, 2H), 7.70- 7.56 (m, 2H), 7.52 (dd, J = 7.9, 4.9 Hz, DMSO 470 (M + 1) 2.04 Me- thod C 100 Me- thod W
    1H), 7.17 (d, J = 8.3
    Hz, 1H), 4.69 (s,
    2H), 2.71 (d, J = 4.5
    Hz, 3H).
    826
    Figure US20170217923A1-20170803-C01730
         		483.44 1H NMR (300 MHz, DMSO) δ 9.92 (s, 1H), 9.51 (s, 1H), 8.74-8.57 (m, 2H), 8.17 (s, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.96-7.83 (m, 2H), 7.70-7.46 (m, 3H), 7.16 (d, J = 7.0 Hz, DMSO 484 (M + 1) 1.71 Me- thod D 100 Me- thod W
    1H), 5.03 (s, 2H),
    3.06 (s, 3H), 2.88
    (s, 3H).
    827
    Figure US20170217923A1-20170803-C01731
         		HCl 564.91 1H NMR (300 MHz, DMSO) δ 10.59 (s, 1H), 9.99 (s, 1H), 9.49 (s, 1H), 8.97 (d, J = 7.7 Hz, 1H), 8.87 (d, J = 5.3 Hz, 1H), 8.33-8.18 (m, 2H), 8.04-7.83 (m, 3H), 7.68-7.47 (m, DMSO 492 (M + 1) 1.81 Me- thod C 100 Me- thods V, G4
    2H), 4.41-4.27 (m,
    2H), 3.55-3.43 (m,
    2H), 3.34-3.20 (m,
    2H), 3.03-2.
    828
    Figure US20170217923A1-20170803-C01732
         		437.85 1H NMR (300 MHz, DMSO) δ 9.87 (s, 1H), 9.49 (s, 1H), 8.76-8.53 (m, 2H), 8.32-8.08 (m, 2H), 8.01-7.77 (m, 3H), 7.69-7.43 (m, 3H), 4.67 (s, 2H), 2.71 (d, J = 4.6 Hz, 3H). DMSO 438 (M + 1) 1.65 Me- thod D 100 Me- thod W
    829
    Figure US20170217923A1-20170803-C01733
         		493.92 1H NMR (300 MHz, DMSO) δ 9.86 (s, 1H), 9.50 (s, 1H), 8.76-8.57 (m, 2H), 8.27 (d, J = 7.0 Hz, 1H), 8.05-7.80 (m, 3H), 7.69-7.45 (m, 3H), 5.04 (s, 2H), 3.78-3.41 (m, 8H). DMSO 494 (M + 1) 1.98 Me- thod C 98 Me- thod W
    830
    Figure US20170217923A1-20170803-C01734
         		479.93 1H NMR (300 MHz, DMSO) δ 9.85 (s, 1H), 9.50 (s, 1H), 8.76-8.53 (m, 2H), 8.26 (dd, J = 6.9, 2.5 Hz, 1H), 8.08-7.76 (m, 3H), 7.71-7.41 (m, 3H), 4.98 (s, 2H), 3.52-3.09 (m, DMSO 480 (M + 1) 2.20 Me- thod C 100 Me- thod W
    4H), 1.37-0.88 (m,
    6H).
    831
    Figure US20170217923A1-20170803-C01735
         		HCl 580.91 1H NMR (300 MHz, DMSO) δ 10.71 (s, 2H), 9.48 (s, 1H), 9.10-8.95 (m, 1H), 8.94-8.79 (m, 1H), 8.36-8.27 (m, 1H), 8.26-8.16 (m, 1H), 8.07-7.83 (m, 3H), 7.68-7.46 (m, 2H), DMSO 508 (M + 1) 2.14 Me- thod C 100 Me- thods V, G4
    4.39-4.18 (m, 2H),
    4.05-3.89 (m, 2H),
    3.79 (t, J = 11.9 Hz,
    2H), 3.53-
    832
    Figure US20170217923A1-20170803-C01736
         		451.88 1H NMR (300 MHz, DMSO) δ 9.85 (s, 1H), 9.50 (s, 1H), 8.71-8.58 (m, 2H), 8.25 (dd, J = 6.8, 2.5 Hz, 1H), 8.01- 7.80 (m, 3H), 7.66- 7.45 (m, 3H), 5.02 (s, 2H), 3.06 (s, 3H), 2.88 (s, 3H). DMSO 452 (M + 1) 1.99 Me- thod C 100 Me- thod W
    833
    Figure US20170217923A1-20170803-C01737
         		HCl 566.88 1H NMR (300 MHz, DMSO) δ 11.18 (s, 1H), 10.93 (s, 1H), 9.48 (s, 1H), 9.08 (d, J = 8.4 Hz, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.42 (s, 1H), 8.23 (dd, J = 6.8, 2.5 Hz, 1H), 8.12- DMSO 494 (M + 1) 2.10 Me- thod C 100 Me- thods V, G4
    7.89 (m, 3H), 7.63
    (d, J = 9.1 Hz, 1H),
    7.54 (t, J = 9.1 Hz,
    1H), 4.45-4.26 (m,
    834
    Figure US20170217923A1-20170803-C01738
         		366.78 1H NMR (300 MHz, DMSO) δ 9.98-9.59 (m, 1H), 9.53-9.41 (m, 1H), 8.71-8.48 (m, 2H), 8.31 (dd, J = 6.9, 2.5 Hz, 1H), 8.01-7.85 (m, 1H), 7.83-7.66 (m, 2H), 7.59-7.35 (m, 3H). DMSO 367 (M + 1) 1.69 Me- thod D 100 Me- thod U
    835
    Figure US20170217923A1-20170803-C01739
         		428.44 1H NMR (300 MHz, DMSO) δ 9.58 (s, 1H), 9.12 (d, J = 8.4 Hz, 1H), 8.82-8.64 (m, 2H), 8.48 (s, 1H), 8.32-8.17 (m, 1H), 8.10-7.87 (m, 3H), 7.81-7.49 (m, 4H), 7.21 (t, J = 7.5 Hz, 1H), 4.66 (s, 2H), 2.71 (d, J = 4.5 Hz, 3H). DMSO 429 (M + 1) 1.65 Me- thod C 100 Me- thod W
    836
    Figure US20170217923A1-20170803-C01740
         		484.51 1H NMR (300 MHz, DMSO) δ 9.58 (s, 1H), 9.13 (d, J = 8.3 Hz, 1H), 8.78-8.64 (m, 2H), 8.50 (s, 1H), 8.02-7.80 (m, 3H), 7.73 (t, J = 7.9 Hz, 1H), 7.68- 7.53 (m, 2H), 7.49 (s, 1H), 7.20 (t, J = 7.5 Hz, 1H), 5.07 DMSO 485 (M + 1) 1.72 Me- thod C 91 Me- thod W
    (s, 2H), 3.79-3.40
    (m, 8H).
    837
    Figure US20170217923A1-20170803-C01741
         		442.47 1H NMR (300 MHz, DMSO) δ 9.59 (s, 1H), 9.12 (d, J = 8.4 Hz, 1H), 8.78-8.63 (m, 1H), 8.49 (s, 1H), 8.29 (s, 1H), 8.11-7.88 (m, 2H), 7.79-7.47 (m, 4H), 7.26-7.14 (m, 1H), 4.58 (s, 2H), 3.27- 3.08 (m, 2H), 1.18- 0.93 (m, 3H). DMSO 443 (M + 1) 1.69 Me- thod C 100 Me- thod W
    838
    Figure US20170217923A1-20170803-C01742
         		357.37 1H NMR (300 MHz, DMSO) δ 12.80 (s, 1H), 10.50 (s, 1H), 9.57 (s, 1H), 9.15 (d, J = 8.5 Hz, 1H), 8.70 (t, J = 7.3 Hz, 2H), 8.50 (s, 1H), 8.08-7.79 (m, 3H), 7.73 (t, J = 7.5 Hz, 1H), 7.57 (dd, J = 7.6, 4.8 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H). DMSO 357.9 (M + 1) 1.68 Me- thod C 100 Me- thod U
    839
    Figure US20170217923A1-20170803-C01743
         		2HCl 443.86 1H NMR (300 MHz, DMSO) δ 10.57 (s, 1H), 9.49 (s, 1H), 8.97 (d, J = 8.2 Hz, 1H), 8.89 (s, 1H), 8.81 (s, 1H), 8.16 (ddd, J = 12.2, 10.9, 5.2 Hz, 3H), 8.05 (d, J = 2.3 Hz, 1H), 8.00-7.86 (m, 3H), 7.55 (t, J = 9.1 Hz, DMSO 443.9 (M + 1) 1.87 Me- thod C 100 Me- thod U
    1H), 6.55 (d, J =
    9.5 Hz, 1H).
    840
    Figure US20170217923A1-20170803-C01744
         		2HCl 457.89 1H NMR (300 MHz, DMSO) δ 10.27 (s, 1H), 9.47 (s, 1H), 9.09 (d, J = 8.1 Hz, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.56 (s, 1H), 8.18-8.08 (m, 2H), 8.01 (d, J = 6.3 Hz, 3H), 7.96-7.89 (m, 1H), 7.49 (t, J = 9.1 Hz, DMSO 458.0 (M + 1) 2.12 Me- thod D 100 Me- thod U
    1H), 6.52 (d, J =
    9.6 Hz, 1H), 2.71
    (s, 3H).
    841
    Figure US20170217923A1-20170803-C01745
         		448.48 1H NMR (300 MHz, DMSO) δ 13.08 (s, 1H), 9.59 (s, 1H), 9.16 (d, J = 8.4 Hz, 1H), 8.88-8.44 (m, 5H), 8.12-7.85 (m, 4H), 7.73 (q, J = 8.7 Hz, 3H), 7.58 (dd, J = 7.9, 4.8 Hz, 1H), 7.49 (dd, J = 7.8, 4.8 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 5.36 (s, 2H). DMSO 449.2 (M + 1) 1.93 Me- thod C 96 Me- thod X
    842
    Figure US20170217923A1-20170803-C01746
         		448.48 1H NMR (300 MHz, DMSO) δ 13.00 (s, 1H), 9.57 (s, 1H), 9.12 (d, J = 8.4 Hz, 1H), 8.76-8.60 (m, 4H), 8.50 (s, 1H), 8.03-7.89 (m, 3H), 7.68 (dd, J = 15.6, 5.2 Hz, 3H), 7.57 (t, J = 4.6 Hz, 3H), 7.19 (t, J = 7.6 Hz, 1H), 5.37 (s, 2H). DMSO 449.1 (M + 1) 1.89 Me- thod C 100 Me- thod X
    843
    Figure US20170217923A1-20170803-C01747
         		425.48 1H NMR (300 MHz, DMSO) δ 12.95 (s, 1H), 9.56 (s, 1H), 9.10 (d, J = 8.4 Hz, 1H), 8.75-8.64 (m, 2H), 8.46 (s, 1H), 7.98-7.91 (m, 2H), 7.85 (dd, J = 9.0, 0.8 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.61-7.48 (m, 3H), 7.18 (t, J = 7.6 Hz, 1H), 4.12 (d, J = DMSO 426.2 (M + 1) 2.46 Me- thod C 100 Me- thod X
    6.6 Hz, 2H), 2.84
    (dd, J = 14.3, 7.4
    Hz, 1H), 2.18-
    2.05 (m, 2H), 1.97-
    1.84 (m, 5H).
    844
    Figure US20170217923A1-20170803-C01748
         		457.89 1H-NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.78-8.59 (m, 3H), 8.29 (dd, J = 6.8, 2.6 Hz, 1H), 8.16 (d, J = 2.5 Hz, 1H), 8.06-7.86 (m, 3H), 7.69 (dd, J = 9.1, DMSO 458.1, 460.1 (M + 1) 229.6, 230.3 (M/2 + 1) Me- thod A 95 Me- thod X
    2.5 Hz, 1H), 7.64-
    7.47 (m, 3H), 5.37
    (s, 2H).
    845
    Figure US20170217923A1-20170803-C01749
         		487.91 1H-NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H), 9.34 (s, 1H), 8.57-8.41 (m, 2H), 8.22 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 6.8, 2.6 Hz, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.80-7.63 (m, DMSO 488.1, 490.1 (M + 1) 244.6, 245.4 (M/2 + 1) Me- thod A 95 Me- thod X
    3H), 7.53-7.30 (m,
    3H), 6.82-6.68 (m,
    1H), 5.07 (s, 2H),
    3.71 (s, 3H).
  • 1H Pu-
    NMR rity Method
    Num- Starting Starting Salt Sol- per- of
    ber Material R1 Material R3 Product Type 1H NMR vent cent Coupling
    846
    Figure US20170217923A1-20170803-C01750
    Figure US20170217923A1-20170803-C01751
    Figure US20170217923A1-20170803-C01752
         		HCl 1H NMR (400 MHz, DMSO) δ 9.31 (d, J = 1.7 Hz, 1H), 8.83-8.76 (m, 1H), 8.76-8.67 (m, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.86 (dd, J = 6.3, 2.8 Hz, 1H), 7.83-7.73 (m, 2H), 7.70 (d, J = 2.8 Hz, 1H), 7.68-7.61 (m, 1H), 7.60-7.52 (m, 1H), 5.12 (s, 2H), 3.05 (s, 3H), 2.88 (s, 3H). DMSO >98 Method X using K2CO3 instead of Cs2CO3
    847
    Figure US20170217923A1-20170803-C01753
    Figure US20170217923A1-20170803-C01754
    Figure US20170217923A1-20170803-C01755
         		1H NMR (400 MHz, DMSO) δ 9.28 (dd, J = 2.2, 0.8 Hz, 1H), 8.66 (dd, J = 4.8, 1.7 Hz, 1H), 8.50- 8.44 (m, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.75 (dd, J = 9.2, 2.9 Hz, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.56 (dd, J = 8.8, 2.7 Hz, 1H), 7.52 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 5.10 (s, 2H), 3.05 (s, 3H), 2.88 (s, 3H). DMSO >98 Method X using K2CO3 instead of Cs2CO3
    848
    Figure US20170217923A1-20170803-C01756
    Figure US20170217923A1-20170803-C01757
    Figure US20170217923A1-20170803-C01758
         		1H NMR (400 MHz, CDCl3) δ 9.45 (dd, J = 2.1, 0.8 Hz, 1H), 8.61 (dd, J = 4.8, 1.7 Hz, 1H), 8.59- 8.53 (m, 1H), 8.01 (dd, J = 8.7, 0.8 Hz, 1H), 7.72- 7.62 (m, 2H), 7.56-7.47 (m, 2H), 7.39-7.29 (m, 4H), 4.90 (s, 2H), 3.15 (s, 3H), 3.04 (s, 3H). CDCl3 >98 Method X using K2CO3 instead of Cs2CO3
    849
    Figure US20170217923A1-20170803-C01759
    Figure US20170217923A1-20170803-C01760
    Figure US20170217923A1-20170803-C01761
         		2 HCl 1H NMR (300 MHz, DMSO) δ 13.01-11.72 (m, 1H), 9.70 (s, 1H), 9.40-9.30 (m, 1H), 8.99 (d, J = 4.5 Hz, 1H), 8.23 (d, J = 2.6 Hz, 1H), 8.12 (dd, J = 8.1, 5.5 Hz, 1H), 8.06-7.98 (m, 2H), 7.92 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 4.9 Hz, 1H), 7.63 (dd, J = 9.1, 2.6 Hz, 1H), 7.56-7.49 (m, 2H), 5.05 (s, 3H), 3.11 (s, 3H), 2.92 (s, 3H). DMSO >98 W
    850
    Figure US20170217923A1-20170803-C01762
    Figure US20170217923A1-20170803-C01763
    Figure US20170217923A1-20170803-C01764
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.74 (d, J = 1.8 Hz, 1H), 9.47-9.36 (m, 1H), 9.01 (dd, J = 5.5, 1.2 Hz, 1H), 8.28 (d, J = 2.6 Hz, 1H), 8.16 (dd, J = 8.2, 5.5 Hz, 1H), 8.06-7.93 (m, 3H), 7.81 (s, 1H), 7.66 (dd, J = 9.1, 2.6 Hz, 1H), 7.54-7.44 (m, 2H), 7.42-7.33 (m, 1H), 5.07 (s, 2H), 3.11 (s, 3H), 2.91 (s, 3H). DMSO >98 W
    851
    Figure US20170217923A1-20170803-C01765
    Figure US20170217923A1-20170803-C01766
    Figure US20170217923A1-20170803-C01767
         		2 HCl 1H NMR (300 MHz, DMSO) δ 12.67 (s, 1H), 9.31-9.25 (m, 1H), 8.73 (dd, J = 4.8, 1.6 Hz, 1H), 8.52-8.42 (m, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 2.9 Hz, 1H), 7.61-7.47 (m, 4H), 7.45-7.31 (m, 3H), 5.27 (s, 2H), 3.30 (s, 3H). DMSO >98 W
    852
    Figure US20170217923A1-20170803-C01768
    Figure US20170217923A1-20170803-C01769
    Figure US20170217923A1-20170803-C01770
         		3 HCl 1H NMR (300 MHz, DMSO) δ 9.56 (d, J = 1.8 Hz, 1H), 9.25 (d, J = 8.2 Hz, 1H), 9.08-8.98 (m, 1H), 8.81 (d, J = 4.5 Hz, 1H), 8.31 (td, J = 7.8, 1.6 Hz, 1H), 8.20-8.08 (m, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.88-7.63 (m, 4H), 7.47 (d, J = 2.1 Hz, 1H), 7.30 (dd, J = 8.6, 2.2 Hz, 1H), 5.60 (s, 2H), 4.63 (t, J = 7.8 Hz, 2H), 3.25 (t, J = 7.7 Hz, 2H). DMSO >98 W
    853
    Figure US20170217923A1-20170803-C01771
    Figure US20170217923A1-20170803-C01772
    Figure US20170217923A1-20170803-C01773
         		3 HCl 1H NMR (300 MHz, DMSO) δ 9.56 (d, J = 1.8 Hz, 1H), 9.22 (d, J = 8.3 Hz, 1H), 9.00 (dd, J = 5.5, 1.3 Hz, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.29 (td, J = 7.8, 1.6 Hz, 1H), 8.21-8.05 (m, 2H), 8.00-7.66 (m, 5H), 7.29 (dd, J = 8.4, 2.6 Hz, 1H), 7.12 (td, J = 9.0, 2.8 Hz, 1H), 5.59 (s, 2H), 4.66 (t, J = 7.8 Hz, 2H), 3.25 (t, J = 7.6 Hz, 2H). DMSO >98 W
    854
    Figure US20170217923A1-20170803-C01774
    Figure US20170217923A1-20170803-C01775
    Figure US20170217923A1-20170803-C01776
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.55 (d, J = 1.8 Hz, 1H), 9.30-9.18 (m, 1H), 9.00 (dd, J = 5.5, 1.3 Hz, 1H), 8.18-8.02 (m, 2H), 7.87 (dd, J = 8.8, 4.8 Hz, 1H), 7.71 (dd, J = 9.2, 2.7 Hz, 1H), 7.49 (d, J = 2.7 Hz, 1H), 7.29 (dd, J = 8.4, 2.6 Hz, 1H), 7.13 (td, J = 9.1, 2.8 Hz, 1H), 5.05 (s, 2H), 4.63 (d, J = 7.7 Hz, 2H), 3.25 (t, J = 7.5 Hz, 2H), 3.02 (s, 3H), 2.86 (s, 3H). DMSO >98 W
    855
    Figure US20170217923A1-20170803-C01777
    Figure US20170217923A1-20170803-C01778
    Figure US20170217923A1-20170803-C01779
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.55 (d, J = 1.7 Hz, 1H), 9.15 (d, J = 8.2 Hz, 1H), 8.99-8.90 (m, 1H), 8.10-7.98 (m, 2H), 7.77 (dd, J = 8.9, 4.7 Hz, 1H), 7.67 (dd, J = 9.1, 2.7 Hz, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.28 (dd, J = 8.4, 2.7 Hz, 1H), 7.12 (dd, J = 10.3, 7.7 Hz, 1H), 4.70 (t, J = 7.8 Hz, 2H), 4.23-4.14 (m, 2H), 3.26 (t, J = 7.9 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H). DMSO >98 W
    856
    Figure US20170217923A1-20170803-C01780
    Figure US20170217923A1-20170803-C01781
    Figure US20170217923A1-20170803-C01782
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.54 (d, J = 1.7 Hz, 1H), 9.19 (d, J = 8.1 Hz, 1H), 8.98 (d, J = 4.3 Hz, 1H), 8.15-8.02 (m, 2H), 7.90-7.72 (m, 2H), 7.60 (d, J = 2.6 Hz, 1H), 7.53-7.41 (m, 1H), 7.40-7.05 (m, 5H), 5.34 (s, 2H), 4.59 (t, J = 7.8 Hz, 2H), 3.22 (t, J = 7.5 Hz, 2H). DMSO >98 W
    857
    Figure US20170217923A1-20170803-C01783
    Figure US20170217923A1-20170803-C01784
    Figure US20170217923A1-20170803-C01785
         		HCl 1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.49 (d, J = 1.8 Hz, 1H), 9.11 (d, J = 8.0 Hz, 1H), 8.95 (dd, J = 5.4, 1.3 Hz, 1H), 8.26 (dd, J = 24.6, 3.5 Hz, 2H), 8.12-7.95 (m, 3H), 7.71 (dt, J = 9.1, 4.5 Hz, 2H), 7.56 (dd, J = 19.7, 9.1 Hz, 1H), 4.75 (s, 2H), 2.72 (d, J = 5.0 Hz, 3H). DMSO >98 Method W
    858
    Figure US20170217923A1-20170803-C01786
    Figure US20170217923A1-20170803-C01787
    Figure US20170217923A1-20170803-C01788
         		1H NMR (400 MHz, DMSO) δ 9.77 (br s, J = 81.7 Hz, 1H), 9.50 (d, J = 1.5 Hz, 1H), 8.71- 8.57 (m, 2H), 8.22-8.07 (m, 1H), 7.97 (t, J = 5.1 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.81- 7.39 (m, 4H), 5.01 (s, 2H), 3.07 (s, 3H), 2.90 (s, 3H). DMSO >98 Method W
    859
    Figure US20170217923A1-20170803-C01789
    Figure US20170217923A1-20170803-C01790
    Figure US20170217923A1-20170803-C01791
         		HCl 1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.50 (d, J = 1.7 Hz, 1H), 9.01 (d, J = 8.1 Hz, 1H), 8.90 (dd, J = 5.3, 1.5 Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.20-8.09 (m, 1H), 7.95 (dd, J = 8.5, 4.7 Hz, 2H), 7.83-7.74 (m, 1H), 7.67 (dd, J = 9.1, 2.6 Hz, 1H), 7.55 (dd, J = 19.7, 9.1 Hz, 1H), 5.15 (s, 2H), 4.29-3.00 (m, 8H). DMSO >98 Method W
    860
    Figure US20170217923A1-20170803-C01792
    Figure US20170217923A1-20170803-C01793
    Figure US20170217923A1-20170803-C01794
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 9.51 (d, J = 1.6 Hz, 1H), 8.81 (dd, J = 19.3, 6.0 Hz, 2H), 8.29 (s, 1H), 8.16 (dd, J = 10.6, 7.5 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.77 (s, 2H), 7.69-7.51 (m, 2H), 4.67 (s, 2H), 3.99 (s, 2H), 3.81 (br s, 4H), 3.70 (br s, 4H). DMSO >98 Method W
    861
    Figure US20170217923A1-20170803-C01795
    Figure US20170217923A1-20170803-C01796
    Figure US20170217923A1-20170803-C01797
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 9.50 (d, J = 1.3 Hz, 1H), 9.02 (d, J = 8.0 Hz, 1H), 8.90 (d, J = 4.4 Hz, 1H), 8.46 (s, 1H), 8.21-8.10 (m, 1H), 8.03-7.90 (m, 2H), 7.84 (d, J = 8.7 Hz, 1H), 7.68 (dd, J = 9.1, 2.3 Hz, 1H), 7.55 (dd, J = 19.6, 9.3 Hz, 1H), 4.67 (s, 2H), 3.23-3.05 (m, 6H), 2.10-1.78 (m, 4H). DMSO >98 Method W
    862
    Figure US20170217923A1-20170803-C01798
    Figure US20170217923A1-20170803-C01799
    Figure US20170217923A1-20170803-C01800
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 9.49 (d, J = 1.5 Hz, 1H), 9.12 (d, J = 8.1 Hz, 1H), 8.99-8.91 (m, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.12- 7.99 (m, 3H), 7.78-7.71 (m, 1H), 7.66-7.54 (m, 2H), 4.02 (d, J = 6.5 Hz, 2H), 2.24-2.00 (m, 1H), 1.07 (d, J = 6.7 Hz, 6H). DMSO >98 Method W
    863
    Figure US20170217923A1-20170803-C01801
    Figure US20170217923A1-20170803-C01802
    Figure US20170217923A1-20170803-C01803
         		2 HCl 1H NMR (400 MHz, CDCl3) δ10.71 (s, 1H), 9.80 (s, 1H), 9.40 (d, J = 8.2 Hz, 1H), 8.95 (d, J = 5.2 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 9.2 Hz, 1H), 8.08 (dd, J = 8.0, 5.6 Hz, 1H), 7.86-7.76 (m, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.8, 2.2 Hz, 1H), 7.31 (s, 1H), 5.08 (s, 2H), 3.69 (t, J = 6.8 Hz, 2H), 3.55 (t, J = 6.9 Hz, 2H), 2.13- 2.01 (m, 2H), 1.98-1.85 (m, 2H). DMSO >98 Method W
    864
    Figure US20170217923A1-20170803-C01804
    Figure US20170217923A1-20170803-C01805
    Figure US20170217923A1-20170803-C01806
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.50 (d, J = 1.9 Hz, 1H), 9.12 (d, J = 8.2 Hz, 1H), 8.96 (dd, J = 5.5, 1.4 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.15-7.97 (m, 3H), 7.75 (ddd, J = 11.9, 7.4, 3.3 Hz, 2H), 7.56 (dt, J = 10.6, 9.1 Hz, 1H), 4.74 (s, 2H), 4.07- 3.93 (m, 1H), 1.13 (d, J = 6.6 Hz, 6H).. DMSO >98 Method W
    865
    Figure US20170217923A1-20170803-C01807
    Figure US20170217923A1-20170803-C01808
    Figure US20170217923A1-20170803-C01809
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 9.51 (d, J = 1.8 Hz, 1H), 9.15 (d, J = 8.2 Hz, 1H), 8.97 (dd, J = 5.4, 1.3 Hz, 1H), 8.82-8.74 (m, 1H), 8.55 (d, J = 2.6 Hz, 1H), 8.28-8.19 (m, 1H), 8.16-8.01 (m, 3H), 7.94 (d, J = 7.9 Hz, 1H), 7.85-7.75 (m, 2H), 7.70 (dd, J = 7.0, 5.8 Hz, 1H), 7.61-7.49 (m, 1H), 5.63 (s, 2H). DMSO >98 Method W
    866
    Figure US20170217923A1-20170803-C01810
    Figure US20170217923A1-20170803-C01811
    Figure US20170217923A1-20170803-C01812
         		4 HCl 1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.50 (d, J = 1.8 Hz, 1H), 9.11 (d, J = 8.1 Hz, 1H), 8.95 (d, J = 5.4 Hz, 1H), 8.76 (d, J = 5.0 Hz, 1H), 8.42 (s, 1H), 8.18 (t, J = 7.8 Hz, 1H), 8.08-7.96 (m, 4H), 7.89 (d, J = 7.8 Hz, 1H), 7.80 (dd, J = 9.1, 2.6 Hz, 1H), 7.64 (t, J = 8.2 Hz, 2H), 7.24 (d, J = 8.3 Hz, 1H), 5.57 (s, 2H). DMSO >98 Method W
    867
    Figure US20170217923A1-20170803-C01813
    Figure US20170217923A1-20170803-C01814
    Figure US20170217923A1-20170803-C01815
         		HCl 1H NMR (300 MHz, DMSO) δ 9.58 (s, 1H), 9.05 (d, J = 8.2 Hz, 1H), 8.98 (d, J = 8.1 Hz, 1H), 8.88 (d, J = 5.1 Hz, 1H), 8.47 (s, 1H), 8.05-7.85 (m, 4H), 7.71 (m, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.24 (dd, J = 7.6 Hz, 1H). DMSO   94 Method X (K2CO3, DMF-THF (1:1), rt)
    868
    Figure US20170217923A1-20170803-C01816
         		2 HCl 1H NMR (300 MHz, DMSO) δ 13.07 (s, 1H), 9.59 (d, J = 1.4 Hz, 1H), 9.13 (d, J = 8.1 Hz, 1H), 8.97 (d, J = 7.8 Hz, 1H), 8.92 (d, J = 4.1 Hz, 1H), 8.49 (s, 1H), 8.08-7.92 (m, 4H), 7.80- 7.64 (m, 3H), 7.26 (td, J = 7.8, 1.1 Hz, 1H), 7.14 (d, J = 1.5 Hz, 1H), 7.09 (dd, J = 7.9, 1.6 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.03 (s, 2H), 5.19 (s, 2H). DMSO   99 Method W
    869
    Figure US20170217923A1-20170803-C01817
         		3 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 9.40 (d, J = 7.6 Hz, 1H), 9.01 (d, J = 8.4 Hz, 2H), 8.93 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.22 (t, J = 7.2 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.97-7.92 (m, 2H), 7.79-7.71 (m, 3H), 7.33 (t, J = 8.0 Hz, 1H), 5.54 (s, 2H). DMSO   98 Method X
    870
    Figure US20170217923A1-20170803-C01818
         		2 HCl 1H-NMR (400 MHz, CD3OD): δ 9.62 (d, J = 6.9 Hz, 1H), 9.40 (d, J = 8.2 Hz, 1H), 8.99 (d, J = 5.3 Hz, 1H), 8.82 (t, J = 8.2 Hz, 1H), 8.22 (dd, J = 8.1, 5.7 Hz, 1H), 8.02-7.88 (m, 2H), 7.76-7.60 (m, 3H), 7.31 (t, J = 7.6 Hz, 1H), 4.81 (q, J = 8.1 Hz, 2H). MeOD   95 Method W
    871
    Figure US20170217923A1-20170803-C01819
         		4 HCl 1H-NMR (400 MHz, DMSO-d6): δ 12.96 (s, 1H), 9.59 (s, 1H), 9.24 (d, J = 8.1 Hz, 1H), 9.00 (s, 1H), 8.80 (d, J = 5.7 Hz, 2H), 8.50 (s, 1H), 8.22 (t, J = 7.2 Hz, 1H), 8.09 (d, J = 9.2 Hz, 2H), 7.99-7.79 (m, 5H), 7.74-7.54 (m, 6H), 7.30 (t, J = 7.5 Hz, 1H), 5.55 (s, 2H). DMSO- d6   95 Method X
    872
    Figure US20170217923A1-20170803-C01820
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 9.58 (s, 1H), 9.13 (d, J = 6.9 Hz, 1H), 8.93 (s, 1H), 8.82 (d, J = 8.0 Hz, 1H), 8.43 (s, 1H), 8.04- 7.88 (m, 4H), 7.74-7.69 (m, 3H), 7.28 (t, J = 7.6 Hz, 1H), 7.01-6.91 (m, 2H), 6.87-6.85 (m, 2H), 4.74-4.70 (m, 1H), 4.55-4.53 (m, 1H), 4.50-4.47 (m, 1H), 4.29-4.24 (m, 1H). DMSO   95 Method X
    873
    Figure US20170217923A1-20170803-C01821
         		3 HCl 1H-NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H), 9.61 (s, 1H), 9.05-9.00 (m, 2H), 8.88 (d, J = 4 Hz, 1H), 8.51 (s, 1H), 8.25 (s, 1H), 8.11-8.08 (m, 2H), 7.99-7.97 (m, 3H), 7.91-7.88 (m, 2H), 7.76-7.72 (m, 2H), 7.47 (dd, J = 2.0, 8.8 Hz, 1H), 7.27 (t, J = 8.8 Hz, 1H), 5.61 (s, 2H). DMSO   95 Method X
    874
    Figure US20170217923A1-20170803-C01822
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 12.89 (s, 1H), 10.72 (s, 1H), 9.83 (s, 1H), 9.38 (d, J = 8.2 Hz, 1H), 9.22 (d, J = 5.6 Hz, 1H), 9.03 (d, J = 8.3 Hz, 1H), 8.51 (s, 1H), 8.37-8.27 (m, 1H), 8.02-7.86 (m, 3H), 7.71 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.51 (s, 1H), 7.25 (t, J = 7.5 Hz, 1H), 4.71 (d, J = 7.3 Hz, 2H), 1.56 (s, 1H), 0.81-0.64 (m, 4H). DMSO   95 Method X
    875
    Figure US20170217923A1-20170803-C01823
         		3 HCl 1H-NMR (400 MHz, DMSO-d6): δ 12.88 (s, 1H), 9.57 (s, 1H), 9.24 (d, J = 8.1 Hz, 1H), 9.01 (d, J = 5.3 Hz, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.49 (s, 1H), 8.37 (t, J = 7.8 Hz, 1H), 8.10 (dd, J = 11.3, 7.0 Hz, 2H), 7.97 (d, J = 7.8 Hz, 2H), 7.86 (s, 2H), 7.80 (d, J = 7.1 Hz, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 5.65 (s, 2H), 2.78 (s, 3H). DMSO   95 Method X
    876
    Figure US20170217923A1-20170803-C01824
         		CF3 CO OH 1H-NMR (400 MHz, DMSO-d6): δ 12.93 (s, 1H), 10.74 (s, 1H), 9.75 (s, 1H), 9.40 (s, 1H), 9.05 (d, J = 8.0 Hz, 2H), 8.99 (d, J = 6.0 Hz, 1H), 7.99 (s, 1H), 7.98-7.96 (m, 1H), 7.89-7.86 (m, 2H), 7.72-7.51 (m, 2H), 7.24 (t, J = 6.0 Hz, 1H), 5.84 (s, 2H), 3.60-3.56 (m, 2H), 3.43-3.39 (m, 2H), 2.06-2.01 (m, 2H), 1.99-1.84 (m, 2H). DMSO   95 Method W
    1757
    Figure US20170217923A1-20170803-C01825
    Figure US20170217923A1-20170803-C01826
    Figure US20170217923A1-20170803-C01827
         		1H NMR (400 MHz, DMSO) δ 9.32-9.27 (m, 1H), 8.66 (dd, J = 4.8, 1.7 Hz, 1H), 8.64-8.60 (m, 1H), 8.50-8.43 (m, 1H), 8.10-8.03 (m, 1H), 7.93-7.80 (m, 4H), 7.68-7.60 (m, 2H), 7.59-7.49 (m, 2H), 7.39 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 5.43 (s, 2H). DMSO >98 Method W using K2CO3 instead of Cs2CO3
  • Figure US20170217923A1-20170803-C01828
  • Figure US20170217923A1-20170803-C01829
    • Method Y: 2-Amino-N-cyclohexyl-benzamide (ii-b)
  • To a dry reaction vial was added cyclohexylamine (40 uμmol, 1.0 eq) and PS-carbodiimide resin (72 μmol, 1.8 eq). The solution of 2-amino-benzoic acid (44 μmol, 1.1 eq), diisopropyl ethyl amine (10 μL) and HOBt (44 μmol, 1.1 eq) in THF (500 μL) was added to the above vial. The reaction mixture was heated at 40° C. for 6 h on a shaker. The resin was removed by filtration and washed with 10% MeOH/CH2Cl2. The solvent was removed in vacuo and the residue was applied to solid phase extraction cartridge (basic silica, 200 mg) and eluted with 50% EtOAc/CH2Cl2. After removal of the solvents, the crude 2-amino-N-cyclohexyl-benzamide was obtained and used for the following reaction.
    • Method Z: N-Cyclohexyl-2-(6-methoxy-2-pyridin-3-yl-quinazolin-4-ylamino)-benzamide (xiv-f)
  • To the crude amide was added the solution of 4-chloro-6-methoxy-2-pyridin-3-yl-quinazoline (20 μmol) in 2-propanol (200 μL). The mixture was refluxed for 8 h. After evaporation, the residue was dissolved in 5% TFA/MeOH-DMF (1:1) and purified by PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 27, replacing cyclohexylamine with the appropriate amine.
  • TABLE 7
    Method
    Exact LCMS of
    Number Product Mass (M + 1) Coupling
    877
    Figure US20170217923A1-20170803-C01830
         		489 490 Methods Y, Z
    878
    Figure US20170217923A1-20170803-C01831
         		453 454 Methods Y, Z
    879
    Figure US20170217923A1-20170803-C01832
         		495 496 Methods Y, Z
    880
    Figure US20170217923A1-20170803-C01833
         		495 496 Methods Y, Z
    881
    Figure US20170217923A1-20170803-C01834
         		491 492 Methods Y, Z
    882
    Figure US20170217923A1-20170803-C01835
         		491 492 Methods Y, Z
    883
    Figure US20170217923A1-20170803-C01836
         		493 494 Methods Y, Z
    884
    Figure US20170217923A1-20170803-C01837
         		467 468 Methods Y, Z
    885
    Figure US20170217923A1-20170803-C01838
         		441 442 Methods Y, Z
    886
    Figure US20170217923A1-20170803-C01839
         		529 530 Methods Y, Z
    887
    Figure US20170217923A1-20170803-C01840
         		543 544 Methods Y, Z
    888
    Figure US20170217923A1-20170803-C01841
         		543 544 Methods Y, Z
    889
    Figure US20170217923A1-20170803-C01842
         		543 544 Methods Y, Z
    890
    Figure US20170217923A1-20170803-C01843
         		487 488 Methods Y, Z
    891
    Figure US20170217923A1-20170803-C01844
         		493 494 Methods Y, Z
    892
    Figure US20170217923A1-20170803-C01845
         		467 468 Methods Y, Z
    893
    Figure US20170217923A1-20170803-C01846
         		441 442 Methods Y, Z
    894
    Figure US20170217923A1-20170803-C01847
         		529 530 Methods Y, Z
    895
    Figure US20170217923A1-20170803-C01848
         		543 544 Methods Y, Z
    896
    Figure US20170217923A1-20170803-C01849
         		543 544 Methods Y, Z
    897
    Figure US20170217923A1-20170803-C01850
         		543 544 Methods Y, Z
    898
    Figure US20170217923A1-20170803-C01851
         		487 488 Methods Y, Z
    899
    Figure US20170217923A1-20170803-C01852
         		467 468 Methods Y, Z
    900
    Figure US20170217923A1-20170803-C01853
         		501 502 Methods Y, Z
    901
    Figure US20170217923A1-20170803-C01854
         		465 466 Methods Y, Z
    902
    Figure US20170217923A1-20170803-C01855
         		435 436 Methods Y, Z
    903
    Figure US20170217923A1-20170803-C01856
         		519 520 Methods Y, Z
    904
    Figure US20170217923A1-20170803-C01857
         		487 488 Methods Y, Z
    905
    Figure US20170217923A1-20170803-C01858
         		487 488 Methods Y, Z
    906
    Figure US20170217923A1-20170803-C01859
         		467 468 Methods Y, Z
    907
    Figure US20170217923A1-20170803-C01860
         		501 502 Methods Y, Z
    908
    Figure US20170217923A1-20170803-C01861
         		465 466 Methods Y, Z
    909
    Figure US20170217923A1-20170803-C01862
         		435 436 Methods Y, Z
    910
    Figure US20170217923A1-20170803-C01863
         		519 520 Methods Y, Z
  • Figure US20170217923A1-20170803-C01864
  • Figure US20170217923A1-20170803-C01865
    • Method Z: Synthesis of N-(4-chlorophenyl)-6-methoxy-2-(pyridin-3-yl)quinazolin-4-amine (vi-k)
  • To 4-chloroaniline (24 μmol) was added the solution of 4-chloro-6-methoxy-2-pyridin-3-yl-quinazoline (20 μmol) in 2-propanol (200 μL). The mixture was refluxed for 8 h. After evaporation, the residue was dissolved in 5% TFA/MeOH-DMF (1:1) and purified by PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound as the TFA salt whose structure was finally confirmed by LCMS using LCMS Method E.
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 29, replacing 4-chloroaniline with the appropriate aniline.
  • TABLE 8
    Exact LCMS Method of
    Number Product Mass (M + 1) Coupling
    911
    Figure US20170217923A1-20170803-C01866
         		362 363 Method Z
    912
    Figure US20170217923A1-20170803-C01867
         		358 359 Method Z
    913
    Figure US20170217923A1-20170803-C01868
         		396 397 Method Z
    914
    Figure US20170217923A1-20170803-C01869
         		392 393 Method Z
    915
    Figure US20170217923A1-20170803-C01870
         		388 389 Method Z
    916
    Figure US20170217923A1-20170803-C01871
         		372 373 Method Z
    917
    Figure US20170217923A1-20170803-C01872
         		388 389 Method Z
    918
    Figure US20170217923A1-20170803-C01873
         		342 343 Method Z
    919
    Figure US20170217923A1-20170803-C01874
         		353 354 Method Z
    920
    Figure US20170217923A1-20170803-C01875
         		416 417 Method Z
    921
    Figure US20170217923A1-20170803-C01876
         		396 397 Method Z
    922
    Figure US20170217923A1-20170803-C01877
         		396 397 Method Z
    923
    Figure US20170217923A1-20170803-C01878
         		356 357 Method Z
    924
    Figure US20170217923A1-20170803-C01879
         		364 365 Method Z
    925
    Figure US20170217923A1-20170803-C01880
         		372 373 Method Z
    926
    Figure US20170217923A1-20170803-C01881
         		392 393 Method Z
    927
    Figure US20170217923A1-20170803-C01882
         		376 377 Method Z
    928
    Figure US20170217923A1-20170803-C01883
         		426 427 Method Z
    929
    Figure US20170217923A1-20170803-C01884
         		407 408 Method Z
    930
    Figure US20170217923A1-20170803-C01885
         		430 431 Method Z
    931
    Figure US20170217923A1-20170803-C01886
         		440 441 Method Z
    932
    Figure US20170217923A1-20170803-C01887
         		392 393 Method Z
    933
    Figure US20170217923A1-20170803-C01888
         		380 381 Method Z
    934
    Figure US20170217923A1-20170803-C01889
         		380 381 Method Z
    935
    Figure US20170217923A1-20170803-C01890
         		380 381 Method Z
    936
    Figure US20170217923A1-20170803-C01891
         		434 435 Method Z
    937
    Figure US20170217923A1-20170803-C01892
         		421 422 Method Z
    938
    Figure US20170217923A1-20170803-C01893
         		378 379 Method Z
    939
    Figure US20170217923A1-20170803-C01894
         		376 377 Method Z
    940
    Figure US20170217923A1-20170803-C01895
         		387 388 Method Z
    941
    Figure US20170217923A1-20170803-C01896
         		414 415 Method Z
    942
    Figure US20170217923A1-20170803-C01897
         		392 393 Method Z
    943
    Figure US20170217923A1-20170803-C01898
         		380 381 Method Z
    944
    Figure US20170217923A1-20170803-C01899
         		390 391 MethodZ
    945
    Figure US20170217923A1-20170803-C01900
         		428 429 Method Z
    946
    Figure US20170217923A1-20170803-C01901
         		428 429 Method Z
    947
    Figure US20170217923A1-20170803-C01902
         		391 392 Method Z
    948
    Figure US20170217923A1-20170803-C01903
         		356 357 Method Z
    949
    Figure US20170217923A1-20170803-C01904
         		377 378 Method Z
    950
    Figure US20170217923A1-20170803-C01905
         		392 393 Method Z
    951
    Figure US20170217923A1-20170803-C01906
         		368 369 Method Z
    952
    Figure US20170217923A1-20170803-C01907
         		397 398 Method Z
    953
    Figure US20170217923A1-20170803-C01908
         		441 442 Method Z
    954
    Figure US20170217923A1-20170803-C01909
         		379 380 Method Z
    955
    Figure US20170217923A1-20170803-C01910
         		401 402 Method Z
    956
    Figure US20170217923A1-20170803-C01911
         		383 384 Method Z
    957
    Figure US20170217923A1-20170803-C01912
         		382 383 Method Z
    958
    Figure US20170217923A1-20170803-C01913
         		379 380 Method Z
    959
    Figure US20170217923A1-20170803-C01914
         		393 394 Method Z
    960
    Figure US20170217923A1-20170803-C01915
         		411 412 Method Z
    961
    Figure US20170217923A1-20170803-C01916
         		379 380 Method Z
    962
    Figure US20170217923A1-20170803-C01917
         		370 371 Method Z
    963
    Figure US20170217923A1-20170803-C01918
         		385 386 Method Z
    964
    Figure US20170217923A1-20170803-C01919
         		427 428 Method Z
    965
    Figure US20170217923A1-20170803-C01920
         		395 396 Method Z
    966
    Figure US20170217923A1-20170803-C01921
         		379 380 Method Z
    967
    Figure US20170217923A1-20170803-C01922
         		402 403 Method Z
    968
    Figure US20170217923A1-20170803-C01923
         		384 385 Method Z
  • Figure US20170217923A1-20170803-C01924
  • Figure US20170217923A1-20170803-C01925
    • Method Z: Synthesis of 6-chloro-N-(4-chlorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (vi-c)
  • To 4-chloroaniline (24 μmol) was added the solution of 4,6-dichloro-2-(pyridin-3-yl)quinazoline (20 μmol) in 2-propanol (200 μL). The mixture was refluxed for 8 h. After evaporation, the residue was dissolved in 5% TFA/MeOH-DMF(1:1) and purified by PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound as the TFA salt whose structure was finally confirmed by LCMS using LCMS Method E.
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 31, replacing 4-chloroaniline with the appropriate aniline.
  • TABLE 9
    Exact LCMS Method of
    Number Product Mass (M + 1) Coupling
    969
    Figure US20170217923A1-20170803-C01926
         		366 367 Method Z
    970
    Figure US20170217923A1-20170803-C01927
         		362 363 Method Z
    971
    Figure US20170217923A1-20170803-C01928
         		366 367 Method Z
    972
    Figure US20170217923A1-20170803-C01929
         		346 347 Method Z
    973
    Figure US20170217923A1-20170803-C01930
         		392 393 Method Z
    974
    Figure US20170217923A1-20170803-C01931
         		392 393 Method Z
    975
    Figure US20170217923A1-20170803-C01932
         		419 420 Method Z
    976
    Figure US20170217923A1-20170803-C01933
         		392 393 Method Z
    977
    Figure US20170217923A1-20170803-C01934
         		346 347 Method Z
    978
    Figure US20170217923A1-20170803-C01935
         		350 351 Method Z
    979
    Figure US20170217923A1-20170803-C01936
         		350 351 Method Z
    980
    Figure US20170217923A1-20170803-C01937
         		350 351 Method Z
    981
    Figure US20170217923A1-20170803-C01938
         		376 377 Method Z
    982
    Figure US20170217923A1-20170803-C01939
         		420 421 Method Z
    983
    Figure US20170217923A1-20170803-C01940
         		360 361 Method Z
    984
    Figure US20170217923A1-20170803-C01941
         		360 361 Method Z
    985
    Figure US20170217923A1-20170803-C01942
         		360 361 Method Z
    986
    Figure US20170217923A1-20170803-C01943
         		360 361 Method Z
    987
    Figure US20170217923A1-20170803-C01944
         		368 369 Method Z
    988
    Figure US20170217923A1-20170803-C01945
         		368 369 Method Z
    989
    Figure US20170217923A1-20170803-C01946
         		380 381 Method Z
    990
    Figure US20170217923A1-20170803-C01947
         		376 377 Method Z
    991
    Figure US20170217923A1-20170803-C01948
         		396 397 Method Z
    992
    Figure US20170217923A1-20170803-C01949
         		380 381 Method Z
    993
    Figure US20170217923A1-20170803-C01950
         		430 431 Method Z
    994
    Figure US20170217923A1-20170803-C01951
         		392 393 Method Z
    995
    Figure US20170217923A1-20170803-C01952
         		396 397 Method Z
    996
    Figure US20170217923A1-20170803-C01953
         		380 381 Method Z
    997
    Figure US20170217923A1-20170803-C01954
         		382 383 Method Z
    998
    Figure US20170217923A1-20170803-C01955
         		384 385 Method Z
    999
    Figure US20170217923A1-20170803-C01956
         		465 466 Method Z
    1000
    Figure US20170217923A1-20170803-C01957
         		357 358 Method Z
    1001
    Figure US20170217923A1-20170803-C01958
         		396 397 Method Z
    1002
    Figure US20170217923A1-20170803-C01959
         		425 426 Method Z
    1003
    Figure US20170217923A1-20170803-C01960
         		380 381 Method Z
    1004
    Figure US20170217923A1-20170803-C01961
         		434 435 Method Z
    1005
    Figure US20170217923A1-20170803-C01962
         		396 397 Method Z
    1006
    Figure US20170217923A1-20170803-C01963
         		384 385 Method Z
    1007
    Figure US20170217923A1-20170803-C01964
         		446 447 Method Z
    1008
    Figure US20170217923A1-20170803-C01965
         		415 416 Method Z
    1009
    Figure US20170217923A1-20170803-C01966
         		381 382 Method Z
    1010
    Figure US20170217923A1-20170803-C01967
         		381 382 Method Z
    1011
    Figure US20170217923A1-20170803-C01968
         		396 397 Method Z
  • Figure US20170217923A1-20170803-C01969
    • N-(3-Carbamoylthiophen-2-yl)nicotinamide (iii-b)
  • To a solution of 2-aminothiophene-3-carboxamide (800 mg, 5.63 mmol, 1.0 eq.) in THF (15 mL) and Et3N (626 mg, 6.19 mmol, 1.1 eq.) was added nicotinoyl chloride (795 mg, 5.63 mmol, 1.0 eq.) in anhydrous THF (15 mL) dropwise. The resulted mixture was stirred at room temperature overnight. After the reaction was completed, the volatiles were evaporated. The residue was washed with CH2Cl2 (20 mL). The resulting solid was collected and dried in vacuo to give 1.50 g of N-(3-carbamoylthiophen-2-yl)nicotinamide as a brown solid (quantitative yield). LCMS m/z=248.1 (M+1) (Method B) (retention time=1.34 min).
    • 2-(Pyridin-3-yl) thieno [2, 3-d] pyrimidin-4(3H)-one (iv-b)
  • A mixture of N-(3-carbamoylthiophen-2-yl)nicotinamide (1.50 g salt, 6.07 mmol, 1.0 eq.) in EtOH (300 mL) was added NaOH (1.50 g, 37.5 mmol, 6.18 eq.). The resulting mixture was stirred at 80° C. for 7 days. After the reaction was completed, the volatiles were removed in vacuo. Water (20 mL) was added to the residue and the pH was adjusted to around 2 by adding dilute HCl (2N in water). The solution was concentrated in vacuo to give 11.0 g of the HCl salt as a beige solid. LCMS m/z=230.0 (M+1) (Method B) (retention time=1.21 min). The crude product containing salts were used for the next step without further purification.
    • 4-Chloro-2-(pyridin-3-yl) thieno [2, 3-d] pyrimidine (v-c)
  • The suspension of 2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-4(3H)-one (6.0 g, containing salts) in POCl3 (30 mL) was stirred at 120° C. for 10 h. After the reaction was completed, the mixture was added to ice-water slowly. The pH was adjusted to ˜7 by slowly adding NH3.H2O at 0° C., then a precipitate formed. The solid was collected and 540 mg of 4-chloro-2-(pyridin-3-yl) thieno [2, 3-d] pyrimidine was obtained as a brown solid. LCMS m/z=247.9, 250.0 (M+1) (Method B) (retention time=1.85 min).
    • N-(3-Chloro-4-fluorophenyl)-2-(pyridin-3-yl)thieno[2,3-d]pyrimidin-4-amine (vi-I)
  • A mixture of 4-chloro-2-(pyridin-3-yl)thieno[2,3-d]pyrimidine (80 mg, 0.32 mmol, 1.0 eq.) and 3-chloro-4-fluorobenzenamine (93 mg, 0.64 mmol, 2.0 eq.) in i-AmOH (8 mL) was stirred at 130° C. overnight. A yellow precipitate formed and was collected and washed with MeOH (10 mL). The solid was suspended in H2O (10 mL) and NH3—H2O (1 mL) was added. After filtration and drying in vacuo, 23.0 mg of the product was obtained as a yellow solid (20.0%). LCMS m/z=357.0, 359.0 (M+1) (Method B) (retention time=1.96 min). 1H-NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 9.48 (d, J=1.6 Hz, 1H), 8.70-8.67 (m, 1H), 8.63 (d, J=8.0 Hz, 1H), 8.27 (dd, J=6.8, 2.6 Hz, 1H), 7.76-7.93 (m, 3H), 7.54-7.57 (m, 2H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 33, replacing 4-fluoro-3-chloroaniline with the appropriate aniline.
  • TABLE 10
    Molec- 1H- Method
    Num- Salt ular NMR LCMS Purity for
    ber PRODUCT type Mass 1H-NMR Solvent LCMS Protocol percent Coupling
    1012
    Figure US20170217923A1-20170803-C01970
         		347.39 1H-NMR (400 MHz, DMSO-d6): δ 12.69 (s, 1H), 9.55 (d, J = 1.3 Hz, 1H), 9.00 (d, J = 8.0 Hz, 1H), 8.44- (s, 1H), 8.60-8.78 (m, 2H, 7.82- 8.00 (m, 3H), 7.42-7.79 (m, 3H), 7.20 (t, 3 = 7.2 Hz, 1H). DMSO 348.1 (M + 1) Method B (NH4HCO3) 95 Method C, G3
    1013
    Figure US20170217923A1-20170803-C01971
         		370.38 1H-NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 9.51 (d, J = 1.2 Hz, 1H), 8.60-8.77 (m, 2H), 7.98- 7.94 (m, 2H), 7.71-7.86 (m, 2H), 7.56-7.50 (m, 1H), 7.30 (t, J = 74.0 Hz, 1H), 6.96 (dd, J = 8.8, 2.0 Hz, 1H). DMSO 371.0 (M + 1) Method B (NH4HCO3) 95 Method C, G3
    1014
    Figure US20170217923A1-20170803-C01972
         		388.37 1H-NMR (400 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.50 (d, J = 1.6 Hz, 1H), 8.58-8.75 (m, 2H), 8.18 (s, 1H), 7.77-8.00 (m, 3H), 7.50- 7.65 (m, 2H), 7.08-7.18 (m, 1H) DMSO 389.0 (M + 1) Method B (NH4HCO3) 95 Method C, G3
    1015
    Figure US20170217923A1-20170803-C01973
         		356.8 1H-NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 9.48 (d, J = 1.6 Hz, 1H), 8.70-8.67 (m, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.27 (dd, J = 6.8, 2.6 Hz, 1H), 7.76-7.93 (m, 3H), 7.54-7.57 (m, 2H). DMSO 357.0, 359.0 (M + 1) Method B (NH4HCO3) 95 Method C, G3
  • Figure US20170217923A1-20170803-C01974
  • Figure US20170217923A1-20170803-C01975
    • Method AA: 2-Amino-N-(cyclopropylmethyl)benzamide (ii-c)
  • A 100 mL round bottom flask was charged with anthranilic acid (500 mg, 3.65 mmol), added DMF (15 mL) under nitrogen atmosphere and stirring. Then, added N-methylmorpholine (1 mL, 9.12 mmol), aminomethylcyclopropane (311 mg, 4.38 mmol), N-ethyl-N′-dimethylaminopropylcarbodiimide (EDCI) (840 mg, 4.38 mmol) and HOBt (670 mg, 4.38 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with diethyl ether (50 mL×2). The organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated to afford amorphous colorless 2-amino-N-(cyclopropylmethyl)benzamide (500 mg, 72% yield), which was checked by NMR and used for next step without further purification. 1H-NMR (Bruker 300 MHz, DMSO-d6) δ 0.20-1.01 (m, 4H), 1.01-1.04 (m, 1H), 3.06-3.11 (m, 2H), 6.37-8.21 (m, 7H).
    • Method Z: 2-(6-chloro-2-(pyridin-3-yl)quinazolin-4-ylamino)-N-(cyclopropylmethyl) benzamide (xiv-g)
  • A 100 mL round bottom flask was charged with 4,6-dichloro-2-(pyridin-3-yl)quinazoline (synthesized as described in Scheme 1 and 4, substituting 5-chloro-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid) (150 mg, 0.54 mmol) and 2-amino-N-(cyclopropylmethyl)benzamide) (310 mg, 1.63 mmol) and anhydrous i-PrOH (20 mL) was added and refluxed for 3 h. The reaction mixture was cooled to room temperature and Et3N (3 eq) was added. The solvent was removed in vacuo. To the crude product was added a water-methanol mixture (5:1, 50 mL), and then sonicated for 5 min. The solidified compound was collected by filtration, and the solid was recrystallized from hot methanol and washed with water. The product was dried at 50° C. to give 2-(6-chloro-2-(pyridin-3-yl)quinazolin-4-ylamino)-N-(cyclopropylmethyl)benzamide as a colorless cotton (220 mg, 94%). The structure was confirmed by NMR and elemental analysis. 1H NMR (Bruker 300 MHz, DMSO-d6) ppm 0.20-0.98 (m, 5H), 3.07-3.21 (m, 2H), 7.24-8.26 (m, 7H), 8.68-9.55 (m, 5H), 12.22 (s, 1H). CHN Calcd. C: 67.05; H: 4.69; N: 16.29 Found C: 67.15; H: 4.89; N: 16.25.
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 34, replacing aminomethylcyclopropane with the appropriate amine.
  • TABLE 11
    Num- 1H NMR Purity Method of
    ber Product 1H NMR Solvent percent Coupling
    1016
    Figure US20170217923A1-20170803-C01976
         		1H NMR (DMSO-d6) ppm 1.46 (d, 3H, J = 6.7 Hz), 3.90 (s, 3H), 5.17-5.22 (m, 1H), 7.19-7.98 (m, 12H), 8.67-8.71 (m, 2H), 8.90 (d, 1H, J = 8.2 Hz), 9.22 (d, 1H, J = 8.3 Hz), 9.55 (s, 1H), 12.18 (s, 1H). DMSO >98 Method Z
    1017
    Figure US20170217923A1-20170803-C01977
         		1H NMR (DMSO-d6) ppm 1.49- 1.62 (m, 8H), 3.99 (s, 3H), 4.24- 4.26 (m, 1H), 7.24-7.71 (m, 7H), 8.65-9.55 (m, 5H), 12.19 (s, 1H). DMSO >98 Method Z
    1018
    Figure US20170217923A1-20170803-C01978
         		1H NMR (DMSO-d6) ppm 0.88- 1.99 (m, 7H), 3.14-3.16 (m, 2H), 3.02 (s, 3H), 7.57-7.91 (m, 7H), 8.68-9.55 (m, 5H), 12.19 (s, 1H). DMSO >98 Method Z
    1019
    Figure US20170217923A1-20170803-C01979
         		1H NMR (DMSO-d6) ppm 1.07- 1.12 (m, 3H), 3.44-3.52 (m, 2H), 4.01 (s, 3H), 7.24-786 (m, 8H), 8.68-9.55 (m, 5H), 12.19 (s, 1H). DMSO >98 Method Z
    1020
    Figure US20170217923A1-20170803-C01980
         		1H NMR (DMSO-d6) ppm 0.87- 0.92 (m, 3H), 1.53-1.62 (m, 2H, ), 3.30-3.32 (m, 2H), 3.98 (s, 3H), 7.21-7.89 (m, 7H), 8.67-9.55 (m, 5H), 12.38 (s, 1H). DMSO >98 Method Z
    1021
    Figure US20170217923A1-20170803-C01981
         		1H NMR (DMSO-d6) ppm 0.83- 1.51 (m, 7H), 3.30-3.32 (m, 2H), 3.99 (s, 3H), 7.24-7.90 (m, 7H) 8.67-9.55 (m, 5H), 12.38 (s, 1H). DMSO >98 Method Z
    1022
    Figure US20170217923A1-20170803-C01982
         		1H NMR (DMSO-d6) ppm 0.79- 1.52 (m, 9H), 3.25-3.30 (m, 2H), 3.98 (s, 3H), 7.21-7.88 (m, 7H), 8.68-9.55 (m, 5H), 12.30 (s, 1H). DMSO >98 Method Z
    1023
    Figure US20170217923A1-20170803-C01983
         		1H NMR (DMSO-d6) ppm 0.80- 1.49 (m, 11H), 3.26-3.30 (m, 2H), 3.99 (s, 3H), 7.24-7.90 (m, 7H), 8.67-9.56 (m, 5H), 12.30 (s, 1H). DMSO >98 Method Z
    1024
    Figure US20170217923A1-20170803-C01984
         		1H NMR (DMSO-d6) ppm 3.99- 4.10 (m, 5H), 5.07-5.33 (m, 2H), 5.89-5.91 (m, 1H), 7.24-7.90 (m, 7H), 8.68-9.55 (m, 5H), 12.30 (s, 1H). DMSO >98 Method Z
    1025
    Figure US20170217923A1-20170803-C01985
         		1H NMR (DMSO-d6) ppm 3.13 (s, 1H), 3.99-4.12 (m, 5H), 7.21-7.89 (m, 7H), 8.67-9.54 (m, 5H), 12.30 (s, 1H). DMSO >98 Method Z
    1026
    Figure US20170217923A1-20170803-C01986
         		1H NMR (DMSO-d6) ppm 1.68- 2.22 (m, 6H), 3.99 (s, 3H), 4.24- 4.26 (m, 1H), 7.22-7.92 (m, 7H), 8.66-9.55 (m, 5H), 12.30 (s, 1H). DMSO >98 Method Z
    1027
    Figure US20170217923A1-20170803-C01987
         		1H NMR (DMSO-d6) ppm 1.41- 1.86 (m, 12H), 3.90 (br s, 4H), 7.23-7.89 (m, 7H), 8.63-9.55 (m, 5H), 12.30 (s, 1H). DMSO >98 Method Z
    1028
    Figure US20170217923A1-20170803-C01988
         		1H NMR (DMSO-d6) ppm 0.85- 1.60 (m, 9H), 3.27-3.33 (m, 2H), 3.99 (s, 3H), 7.21-7.91 (m, 7H), 8.68-9.55 (m, 5H), 12.19 (s, 1H). DMSO >98 Method Z
    1029
    Figure US20170217923A1-20170803-C01989
         		1H NMR (DMSO-d6) ppm 1.03- 1.34 (m, 6H), 3.17-3.31 (m, 4H), 7.40-7.88 (m, 7H), 8.55-10.03 (m, 5H), 12.32 (s, 1H). DMSO >98 Method Z
    1030
    Figure US20170217923A1-20170803-C01990
         		1H NMR (DMSO-d6) ppm 0.83- 1.52 (m, 5H), 3.20-3.29 (m, 2H), 7.27-8.21 (m, 7H), 8.67-9.53 (m, 5H), 12.33 (s, 1H). DMSO >98 Method Z
    1031
    Figure US20170217923A1-20170803-C01991
         		1H NMR (DMSO-d6) ppm 1.02- 1.07 (m, 3H), 3.24-3.32 (m, 2H), 7.27-8.22 (m, 7H), 8.67-9.53 (m, 5H), 12.34 (s, 1H). DMSO >98 Method Z
    1032
    Figure US20170217923A1-20170803-C01992
         		1H NMR (DMSO-d6) ppm 0.75- 1.37 (m, 7H), 3.18-3.20 (m, 2H), 7.21-8.19 (m, 7H), 8.64-9.48 (m, 5H), 12.15 (s, 1H). DMSO >98 Method Z
    1033
    Figure US20170217923A1-20170803-C01993
         		1H NMR (DMSO-d6) ppm 3.90- 3.92 (m, 2H), 5.02-5.17 (m, 2H), 5.81-5.86 (m, 1H), 7.27-8.23 (m, 7H), 8.68-9.55 (m, 5H), 12.25 (s, 1H). DMSO >98 Method Z
    1034
    Figure US20170217923A1-20170803-C01994
         		1H NMR (DMSO-d6) ppm 0.78- 1.42 (m, 11H), 3.20-3.29 (m, 2H), 7.25-7.91 (m, 7H), 8.23-9.53 (m, 5H), 12.17 (s, 1H). DMSO >98 Method Z
    1035
    Figure US20170217923A1-20170803-C01995
         		1H NMR (DMSO-d6) ppm 3.06 (s, 1H), 4.05-4.08 (m, 2H), 7.28-8.22 (m, 7H), 8.65-9.51 (m, 5H), 12.12 (s, 1H). DMSO >98 Method Z
    1036
    Figure US20170217923A1-20170803-C01996
         		1H NMR (DMSO-d6) ppm 0.88- 1.92 (m, 7H), 3.05-3.16 (m, 2H), 7.23-7.94 (m, 7H), 8.22-9.54 (m, 5H), 12.21 (s, 1H). DMSO >98 Method Z
    1037
    Figure US20170217923A1-20170803-C01997
         		1H NMR (DMSO-d6) ppm 1.37- 1.79 (m, 12H), 3.90-3.96 (m, 1H), 7.25-8.24 (m, 7H), 8.55-9.52 (m, 5H), 12.07 (s, 1H). DMSO >98 Method Z
    1038
    Figure US20170217923A1-20170803-C01998
         		1H NMR (DMSO-d6) ppm 1.49- 1.85 (m, 8H), 4.24-4.26 (m, 1H), 7.23-7.69 (m, 6H), 7.85-9.53 (m, 6H), 12.06 (s, 1H). DMSO >98 Method Z
    1039
    Figure US20170217923A1-20170803-C01999
         		1H NMR (DMSO-d6) ppm 1.12- 1.14 (m, 6H), 4.11-4.18 (m, 1H), 7.23-7.94 (m, 8H), 8.33-9.53 (m, 4H), 12.30 (s, 1H). DMSO >98 Method Z
    1040
    Figure US20170217923A1-20170803-C02000
         		1H NMR (DMSO-d6) ppm 0.84- 1.16 (m, 9H), 3.28-3.34 (m, 2H), 7.23-7.91 (m, 6H), 8.25-9.53 (m, 6H), 12.16 (s, 1H). DMSO >98 Method Z
    1041
    Figure US20170217923A1-20170803-C02001
         		1H NMR (DMSO-d6) ppm 0.79- 1.52 (m, 9H), 3.25-3.32 (m, 2H), 7.24-7.91 (m, 6H), 8.23-9.53 (m, 6H), 12.18 (s, 1H). DMSO >98 Method Z
    1042
    Figure US20170217923A1-20170803-C02002
         		1H NMR (DMSO-d6) ppm 1.04- 1.81 (m, 10H), 3.77-3.82 (m, 1H), 7.21-8.05 (m, 8H), 8.65-9.52 (m, 4H), 11.96 (s, 1H). DMSO >98 Method Z
    1043
    Figure US20170217923A1-20170803-C02003
         		1H NMR (DMSO-d6) ppm 0.47- 0.67 (m, 4H), 2.85-2.88 (m, 1H), 7.26-8.26 (m, 7H), 8.66-9.52 (m, 5H), 12.26 (s, 1H). DMSO >98 Method Z
    1044
    Figure US20170217923A1-20170803-C02004
         		1H NMR (DMSO-d6) ppm 1.14 (s, 9H), 7.30-7.93 (m, 7H), 8.21- 9.50 (m, 5H), 12.22 (s, 1H). DMSO >98 Method Z
    1045
    Figure US20170217923A1-20170803-C02005
         		1H NMR (DMSO-d6) ppm 3.98 (s, 3H), 4.36 (s, 2H), 6.47 (s, 1H), 7.21-7.91 (m, 9H), 8.68-9.56 (m, 5H), 12.22 (s, 1H). DMSO >98 Method Z
    1046
    Figure US20170217923A1-20170803-C02006
         		1H NMR (DMSO-d6) ppm 4.30 (s, 2H), 6.42 (s, 1H), 7.28-8.24 (m, 9H), 8.70-9.53 (m, 5H), 12.22 (s, 1H). DMSO >98 Method Z
    1047
    Figure US20170217923A1-20170803-C02007
         		1H NMR (DMSO-d6) ppm 1.69- 2.55 (m, 6H), 4.41-4.44 (m, 1H), 7.23-8.24 (m, 7H), 8.65-9.54 (m, 5H), 12.06 (s, 1H). DMSO >98 Method Z
    1048
    Figure US20170217923A1-20170803-C02008
         		1H NMR (DMSO-d6) ppm 4.55 (s, 2H), 7.17-8.21 (m, 12H), 8.65- 9.54 (m, 5H), 12.06 (s, 1H). DMSO >98 Method Z
    1049
    Figure US20170217923A1-20170803-C02009
         		1H NMR (DMSO-d6) ppm 7.02- 8.67 (m, 15H), 9.47 (s, 1H), 10.04 (s, 1H), 12.06 (s, 1H). DMSO >98 Method Z
    1050
    Figure US20170217923A1-20170803-C02010
         		1H NMR (DMSO-d6) ppm 2.75- 2.80 (m, 2H), 3.48-3.54 (m, 2H), 7.08-8.20 (m, 12H), 8.69-9.56 (m, 5H), 12.16 (s, 1H). DMSO >98 Method Z
    1051
    Figure US20170217923A1-20170803-C02011
         		1H NMR (DMSO-d6) ppm 4.01- 4.10 (m, 2H), 7.28-8.27 (m, 7H), 8.59-9.51 (m, 5H), 11.45 (s, 1H). DMSO >98 Method Z
    1052
    Figure US20170217923A1-20170803-C02012
         		1H NMR (DMSO-d6) ppm 4.38- 4.57 (m, 4H), 7.27-8.24 (m, 7H), 8.69-9.56 (m, 5H), 12.10 (s, 1H). DMSO >98 Method Z
    1053
    Figure US20170217923A1-20170803-C02013
         		1H NMR (DMSO-d6) ppm 2.85- 2.92 (br s, 3H), 7.20-8.22 (m, 7H), 8.67-9.56 (m, 5H), 12.61 (s, 1H). DMSO >98 Method Z
    1054
    Figure US20170217923A1-20170803-C02014
         		1H NMR (DMSO-d6) ppm 1.04- 1.81 (m, 10H), 3.77-3.82 (m, 1H), 7.24-8.05 (m, 8H), 8.65-9.52 (m, 4H), 12.27 (s, 1H). DMSO >98 Method Z
    1055
    Figure US20170217923A1-20170803-C02015
         		1H NMR (DMSO-d6) ppm 2.49- 2.51 (m, 2H), 3.57-3.59 (m, 2H), 7.21-8.16 (m, 12H), 8.69-9.56 (m, 5H), 12.16 (s, 1H). DMSO >98 Method Z
    1056
    Figure US20170217923A1-20170803-C02016
         		1H NMR (DMSO-d6) ppm 0.79- 1.44 (m, 11H), 3.26-3.30 (m, 2H), 7.24-7.92 (m, 7H), 8.67-9.52 (m, 5H), 12.45 (s, 1H). DMSO >98 Method Z
    1057
    Figure US20170217923A1-20170803-C02017
         		1H NMR (DMSO-d6) ppm 1.04- 1.16 (m, 3H), 3.33-3.38 (m, 2H), 7.20-8.22 (m, 7H), 8.60-9.53 (m, 5H), 12.34 (s, 1H). DMSO >98 Method Z
    1058
    Figure US20170217923A1-20170803-C02018
         		1H NMR (DMSO-d6) ppm 7.09- 8.68 (m, 15H), 9.51 (s, 1H), 10.34 (s, 1H), 12.06 (s, 1H). DMSO >98 Method Z
    1059
    Figure US20170217923A1-20170803-C02019
         		1H NMR (DMSO-d6) ppm 3.78 (s, 3H), 4.43 (s, 2H), 6.77-8.23 (m, 11H), 8.68-9.54 (m, 5H), 12.06 (s, 1H). DMSO >98 Method Z
    1060
    Figure US20170217923A1-20170803-C02020
         		1H NMR (DMSO-d6) ppm 3.69 (S, 3H), 4.48 (s, 2H), 6.89-8.15 (m, 11H), 8.68-9.54 (m, 5H), 12.44 (s, 1H). DMSO >98 Method Z
    1061
    Figure US20170217923A1-20170803-C02021
         		1H NMR (DMSO-d6) ppm 2.24 (s, 3H), 4.46 (s, 2H), 7.03-8.13 (m, 11H), 8.67-9.54 (m, 5H), 12.21 (s, 1H). DMSO >98 Method Z
    1062
    Figure US20170217923A1-20170803-C02022
         		1H NMR (DMSO-d6) ppm 4.51 (s, 2H), 7.11-8.14 (m, 11H), 8.67- 9.54 (m, 5H), 12.34 (s, 1H). DMSO >98 Method Z
    1063
    Figure US20170217923A1-20170803-C02023
         		1H NMR (DMSO-d6) ppm 4.47 (s, 2H), 7.05-8.14 (m, 11H), 8.67- 9.54 (m, 5H), 12.37 (s, 1H). DMSO >98 Method Z
    1064
    Figure US20170217923A1-20170803-C02024
         		1H NMR (DMSO-d6) ppm 3.95 (s, 3H), 4.47 (s, 2H), 7.05-8.14 (m, 11H), 8.67-9.54 (m, 5H), 12.32 (s, 1H). DMSO >98 Method Z
    1H Purity Method
    Num- Starting Starting Salt NMR per- of
    ber Material R1 Material R2 Product Type 1H NMR Solvent cent Coupling
    1065
    Figure US20170217923A1-20170803-C02025
    Figure US20170217923A1-20170803-C02026
    Figure US20170217923A1-20170803-C02027
         		1H NMR (DMSO-d6) ppm 4.52 (d, 2H, J = 5.8 Hz), 7.21-7.30 (m, 5H), 7.50 (t, J = 7.9 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.89-7.92 (m, 3H), 8.21 (d, J = 1.8 Hz, 1H), 8.65-8.70 (m, 3H), 8.99 (s, 1H), 9.52 (s, 1H), 11.88 (s, 1H) DMSO >98 Method Y, Z
    1066
    Figure US20170217923A1-20170803-C02028
    Figure US20170217923A1-20170803-C02029
    Figure US20170217923A1-20170803-C02030
         		1H NMR (DMSO-d6) ppm 4.49 (d, 2H, J = 5.6 Hz), 7.24-7.35 (m, 5H), 7.50 (t, J = 7.2 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.91-7.95 (m, 3H), 8.22 (d, J = 1.5 Hz, 1H), 8.67-8.73 (m, 3H), 9.19 (s, 1H), 9.53 (s, 1H), 11.98 (s, 1H) DMSO >98 Method Y,Z
    1067
    Figure US20170217923A1-20170803-C02031
    Figure US20170217923A1-20170803-C02032
    Figure US20170217923A1-20170803-C02033
         		1H NMR (DMSO-d6) ppm 4.58 (d, 2H, J = 5.7 Hz), 7.16-7.36 (m, 5H), 7.50 (t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.88-7.96 (m, 3H), 8.22 (d, J = 1.5 Hz, 1H), 8.65-8.69 (m, 3H), 8.98 (s, 1H), 9.52 (s, 1H), 11.87 (s, 1H) DMSO >98 Method Y,Z
    1068
    Figure US20170217923A1-20170803-C02034
    Figure US20170217923A1-20170803-C02035
    Figure US20170217923A1-20170803-C02036
         		1H NMR (DMSO-d6) ppm 4.47 (d, 2H, J = 5.6 Hz), 7.30 (br s, 5H), 7.54 (t, J = 7.7 Hz, 1H), 7.70 (t, J = 7 .8 Hz, 1H), 7.88-7.96 (m, 3H), 8.15 (d, J = 1.5 Hz, 1H), 8.68-8.81 (m, 3H), 8.98 (s, 1H), 9.52 (s, 1H), 12.29 (s, 1H) DMSO >98 Method Y, Z
    1069
    Figure US20170217923A1-20170803-C02037
    Figure US20170217923A1-20170803-C02038
    Figure US20170217923A1-20170803-C02039
         		1H NMR (DMSO-d6) ppm 4.57 (d, 2H, J = 5.6 Hz), 7.23-7.29 (m, 5H), 7.39 (t, J = 7.9 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.94-7.99 (m, 3H), 8.15 (d, J = 1.4 Hz, 1H), 8.68-8.84 (m, 3H), 9.24 (s, 1H), 9.55 (s, 1H), 12.23 (s, 1H) DMSO >98 Method Y, Z
    1070
    Figure US20170217923A1-20170803-C02040
    Figure US20170217923A1-20170803-C02041
    Figure US20170217923A1-20170803-C02042
         		1H NMR (DMSO-d6) ppm 4.50 (d, 2H, J = 5.5 Hz), 7.25-7.53 (m, 5H), 7.69 (t, J = 7.1 Hz, 1H), 7.73 (t, J = 7.0 Hz, 1H), 7.94-8.15 (m, 3H), 8.18 (d, J = 1.4 Hz, 1H), 8.68-8.82 (m, 3H), 9.24 (s, 1H), 9.54 (s, 1H), 12.21 (s, 1H) DMSO >98 Method Y, Z
    1071
    Figure US20170217923A1-20170803-C02043
    Figure US20170217923A1-20170803-C02044
    Figure US20170217923A1-20170803-C02045
         		1H NMR (DMSO-d6) ppm 3.90 (s, 3H), 4.56 (d, 2H, J = 5.6 Hz), 7.22-7.44 (m, 7H), 7.44 (t, J- 7.9 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.94-7.99 (m, 2H), 8.68-8.81 (m, 3H), 9.24 (s, 1H), 9.55 (s, 1H), 12.19 (s, 1H) DMSO >98 Method Y, Z
    1072
    Figure US20170217923A1-20170803-C02046
         		HCl 1H-NMR (400 MHz, DMSO-d6): δ 12.17 (s, 1H), 9.52 (s, 1H), 9.08 (s, 1H), 8.95 (d, J = 7.6 Hz, 1H), 8.85 (s, 1H), 8.66 (d, J = 7.8 Hz, 1H), 7.91 (t, J = 9.4 Hz, 2H), 7.84 (s, 1H), 7.75-7.67 (m, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.30 (t, J = 7.3 Hz, 1H), 4.47 (d, J = 47.3 Hz, 2H), 4.26 (d, J = 6.8 Hz, 2H), 3.58-3.50 (m, 2H), 1.47 (t, J = 6.7 Hz, 3H). DMSO   95 Method Y, Z
  • Figure US20170217923A1-20170803-C02047
    Figure US20170217923A1-20170803-C02048
  • Figure US20170217923A1-20170803-C02049
    Figure US20170217923A1-20170803-C02050
    • Method AB: Methyl 3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)acrylate (xxvi-a)
  • To a solution of 6-iodo-2-(pyridin-3-yl) quinazolin-4-ol (synthesized as described in Scheme 1 and 4, substituting 5-iodo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid) (3.00 g, 8.6 mmol, 1.0 eq.), Pd(OAc)2 (48 mg, 0.21 mmol, 0.025 eq.) and PPh3 (113 mg, 0.43 mmol, 0.05 eq.) in DMF (8 mL) was added methyl acrylate (3.22 g, 25.8 mmol, 3.0 eq.) and DIPEA (1.22 g, 9.46 mmol, 1.1 eq.) under Ar atmosphere. The mixture was stirred at 110° C. overnight. After cooling, the mixture was filtered and the solid was washed with ethyl acetate three times to afford 1.30 g of xxxvi-a as green solid (yield 49%). LCMS m/z=308.0 (M+1) (Method B) (retention time=1.41 min).
    • Methyl 3-(4-hydroxy-2-(pyridin-3-yl) quinazolin-6-yl)propanoate (xxvii-a)
  • Methyl 3-(4-hydroxy-2-(pyridin-3-yl) quinazolin-6-yl) propanoate was prepared in a manner analogous to that described for 2-amino-5-methoxybenzoic acid in Method K, replacing 5-methoxy-2-nitrobenzoic acid with methyl 3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)acrylate to afford 1.40 g of xxvii-a in quantitative yield as a yellow solid. LCMS m/z=310.0 (M+1) (Method B) (retention time=1.42 min).
    • 3-(4-Chloro-2-pyridin-3-yl-quinazolin-6-yl)-propionic acid methyl ester (xxviii-a)
  • 3-(4-Chloro-2-pyridin-3-yl-quinazolin-6-yl)-propionic acid methyl ester (prepared in a manner analogous to that described for 4-chloro-6-propoxy-2-pyridin-3-yl-quinazoline using Method F, replacing 6-propoxy-2-pyridin-3-yl-1H-quinazolin-4-one with methyl 3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)propanoate) was obtained in quantitative yield to give 1.50 g of xxvii-a as a red solid. LCMS m/z=328.1, 330.0 (M+1) (Method B) (retention time=1.86 min).
    • 3-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-propionic acid methyl ester (xxviv-a)
  • 3-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-propionic acid methyl ester (prepared in a manner analogous to that described for 2-(6-propoxy-2-pyridin-3-yl-quinazolin-4-ylamino)-benzamide in Method G1, replacing 4,7-dichloro-2-(4-chlorophenyl)quinazoline and 2-aminobenzamide with 3-(4-chloro-2-pyridin-3-yl-quinazolin-6-yl)-propionic acid methyl ester and 3-chloro-4-fluoro-phenylamine) was obtained in a 43% yield to give 1.04 g of xxviv-a as a yellow solid. LCMS m/z=437.1, 439.1 (M+1) (Method B) (retention time=1.62 min).
    • Method AC: 3-(4-(3-Chloro-4-fluorophenylamino)-2-(pyridin-3-yl) quinazolin-6-yl)propanoic acid (xxx-a)
  • To a solution of 3-[4-(3-chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-propionic acid methyl ester (1.04 g, 2.39 mmol, 1.0 eq.) in DMF (20 mL) was added a solution of NaOH (0.57 g, 14.3 mmol, 6.0 eq.) in H2O (8 mL). The mixture was stirred at room temperature for 2 h. 50 mL of water was added to the mixture. After filtration, the resulting filter cake was washed with water and dried in vacuo to give 933 mg of xxx-a as a yellow solid (yield 93%). LCMS m/z=423.1, 425.1 (M+1) (Method A) (retention time=1.51 min).
    • 3-(4-(3-Chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)-N,N-dimethyl propanamide (xxxi-a)
  • 3-(4-(3-Chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)-N,N-dimethyl propanamide (prepared in a manner analogous to that described for 2-benzamido-5-methoxy-3-methylbenzamide in Method D, replacing nicotinic acid and 2-amino-5-methoxy-3-methylbenzamide with 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propanoic acid and dimethylamine hydrochloride) was obtained in 90% yield to give 891 mg of xxxi-a as a yellow solid. LCMS m/z=450.0, 452.0 (M+1) (Method B) (retention time=1.834 min). 1H-NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 9.51 (d, J=1.6 Hz, 1H), 8.69-8.63 (m, 2H), 8.38 (s, 1H), 8.28 (dd, J=6.8, 2.4 Hz, 1H), 7.94-7.90 (m, 1H), 7.81 (s, 2H), 7.55-7.51 (m, 2H), 3.04 (t, J=7.6 Hz, 2H), 2.99 (s, 3H), 2.85 (s, 3H), 2.77 (t, J=8.0 Hz, 2H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 36, replacing dimethylamine with the appropriate amine and 4-fluoro, 3-chloro aniline with the appropriate aniline.
  • TABLE 12
    Salt Molecular 1H-NMR LCMS Purity Method for
    Number PRODUCT type Mass 1H-NMR Solvent LCMS Protocol percent Coupling
    1073
    Figure US20170217923A1-20170803-C02051
         		421.85 1H-NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.52 (s, 1H), 8.65-8.69 (m, 2H), 8.39 (s, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.92-7.93 (m, 1H), 7.82 (q, J = 8.0 Hz, 2H), 7.52-7.57 (m, 2H), 7.35 (s, 1H), 6.84 (s, 1H), 3.05 (t, J = 7.2 Hz, 2H), 2.51-2.54 (m, 2H). DMSO 422.1 (M + 1) Method B (NH4HCO3) 95 Method C
    1074
    Figure US20170217923A1-20170803-C02052
         		435.43 1H-NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.55 (d, J = 2.4 Hz, 1H), 8.68-8.70 (m, 2H), 8.47 (s, 1H), 7.97-7.99 (m, 1H), 7.79-7.86 (m, 3H), 7.50- 7.55 (m, 2H), 7.36 (s, 1H), 7.30 (t, J = 73.6 Hz, 1H), 6.99 (dd, J = 8.4, 2.4 Hz, 1H), 6.82 (s, 1H), 3.05 (t, J = 8.0 Hz, 2H), 2.52 (t, J = 8.4 Hz, 2H). DMSO 436.2 (M + 1) Method B (NH4HCO3) 95 Method C
    1075
    Figure US20170217923A1-20170803-C02053
         		435.88 1H-NMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 9.52 (s, 1H), 8.65-8.69 (m, 2H), 8.39 (s, 1H), 8.27- 8.29 (m, 1H), 7.79 (dd, J = 9.2, 2.4 Hz, 1H), 7.76- 7.85 (m, 3H), 7.52-7.57 (m, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.57 (d, J = 4.4 Hz, 3H), 2.52-2.54 (m, 2H). DMSO 436.1 (M + 1) Method B (NH4HCO3) 95 Method D
    1076
    Figure US20170217923A1-20170803-C02054
         		449.91 1H-NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 9.51 (d, J = 1.6 Hz, 1H), 8.63-8.69 (m, 2H), 8.38 (s, 1H), 8.28 (dd, J = 6.8, 2.4 Hz, 1H), 7.90-7.94 (m, 1H), 7.81 (s, 2H), 7.51-7.55 (m, 2H), 3.04 (t, J = 7.6 Hz, 2H), 2.99 (s, 3H), 2.85 (s, 3H), 2.77 (t, J = 8.0 Hz, 2H). DMSO 450.0 (M + 1) Method B (NH4HCO3) 95 Method D
    1077
    Figure US20170217923A1-20170803-C02055
         		540.01 1H-NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.52 (d, J = 1.6 Hz, 1H), 8.61-8.74 (m, 2H), 8.41 (s, 1H), 8.28 (dd, J = 6.8, 2.6 Hz, 1H), 7.80-7.99 (m, 3H), 7.46-7.63 (m, 2H), 3.89 (s, 4H), 3.20 (s, 2H), 3.08 (t, J = 7.4 Hz, 4H), 2.90 (t, J = 7.6 Hz, 2H). DMSO  540.2, 542.2 (M + 1) Method B (NH4HCO3) 95 Method D
  • Figure US20170217923A1-20170803-C02056
    Figure US20170217923A1-20170803-C02057
  • Figure US20170217923A1-20170803-C02058
    • (E)-4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-but-3-enenitrile (xxxii-a)
  • (E)-4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-but-3-enenitrile (prepared in a manner analogous to that described for (E)-methyl 3-(4-hydroxy-2-(pyridin-3-yl)quinazolin-6-yl)acrylate using Method AB, replacing 6-iodo-2-(pyridin-3-yl)quinazolin-4-ol and methyl acrylate with N-(3-chloro-4-fluorophenyl)-6-iodo-2-(pyridin-3-yl)quinazolin-4-amine and but-3-enenitrile) was obtained in a 48% yield to give 400 mg of xxxii-a as grey solid. LCMS m/z=416.0 (M+1) (Method B) (retention time=1.99 min).
    • 4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-butyronitrile (xxxiii-a)
  • 4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-butyronitrile (prepared in a manner analogous to that described for 2-amino-5-methoxybenzoic acid in Method K, replacing 5-methoxy-2-nitrobenzoic acid with (E)-4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)but-3-enenitrile) was obtained in a 95% yield to give 190 mg of xxxiii-a as a brown solid. LCMS m/z=418.1 (M+1) (Method B) (retention time=1.95 min).
    • Method AD: 4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)butanoic acid (xxxiv-a)
  • 4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-butyronitrile (190 mg, 046 mmol, 1.0 eq.) was treated with concentrated HCl (8 mL). The mixture was stirred at 100° C. for 2 days. The volatiles were removed in vacuo, and the residue was washed with water to afford 70 mg of xxxiv-a in a 35% yield as a yellow solid. LCMS m/z=437.1, 439.1 (M+1) (Method B) (retention time=1.46 min).
    • 4-(4-(3-Chloro-4-fluorophenylamino)-2-(pyridin-3-yl) quinazolin-6-yl)-1-morpholino butan-1-one (xxxv-a)
  • 4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl) quinazolin-6-yl)-1-morpholinobutan-1-one was prepared in a manner analogous to that described for 2-benzamido-5-methoxy-3-methylbenzamide in Method D, replacing nicotinic acid and 2-amino-5-methoxy-3-methylbenzamide with 4-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl) butanoic acid and morpholine to give 32 mg of xxxv-a in a 40% yield as a beige solid. LCMS m/z=506.2, 508.1 (M+1) (Method B) (retention time=1.85 min). 1H NMR (400 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.52 (d, J=1.6 Hz, 1H), 8.69-8.65 (m, 2H), 8.39-8.38 (m, 1H), 8.27 (dd, J=6.8, 2.8 Hz, 1H), 7.94-7.90 (m, 1H), 7.86-7.84 (m, 1H), 7.80-7.77 (m, 1H), 7.57-7.52 (m, 2H), 3.56-3.53 (m, 4H), 3.46-3.41 (m, 4H), 2.85 (t, J=8.0 Hz, 2H), 2.40 (t, J=7.6 Hz, 2H), 1.97 (t, J=7.6 Hz, 2H).
  • Figure US20170217923A1-20170803-C02059
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 38 in the synthesis of 4-(4-(3-Chloro-4-fluorophenyl amino)-2-(pyridin-3-yl) quinazolin-6-yl)-1-morpholino butan-1-one, replacing (E)-4-[4-(3-Chloro-4-fluoro-phenylamino)-2-pyridin-3-yl-quinazolin-6-yl]-but-3-enenitrile with 4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazoline-6-carbonitrile.
  • TABLE 13
    Salt Molecular 1H-NMR LCMS Purity Method for
    Number PRODUCT type Mass 1H-NMR Solvent LCMS Protocol percent Coupling
    1078
    Figure US20170217923A1-20170803-C02060
         		411.46 1H-NMR (400 MHz, DMSO-d6): δ 9.64 (d, J = 1.6 Hz, 1H), 8.78 (td, J = 7.9, 1.8 Hz, 1H), 8.71 (dd, J = 4.7, 1.6 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.59 (brs, 1H), 7.58 (dd, J = 7.6, 4.8 Hz, 1H), 7.52 (dd, J = 9.2, 2.8 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 6.4 Hz, 1H), 6.84 (dd, J = 8.0, 1.1 Hz, 1H), 6.69 (s, 1H), 4.36 (t, J = 6.5 Hz, 2H), 4.09 (t, J = 6.4 Hz, 2H), 3.46 (s, 3H), 2.30 (s, 3H). DMSO 412.2 (M + 1) Method B (NH4HCO3) 95 Method C, G
    1079
    Figure US20170217923A1-20170803-C02061
         		506.96 1H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H), 9.08 (d, J = 1.2 Hz, 1H), 8.73- 8.65 (m, 3H), 8.28 (dd, J = 6.8, 2.4 Hz, 1H), 7.97- 7.93 (m, 2H), 7.60-7.53 (m, 2H), 3.60-3.58 (m, 4H), 3.51-3.46 (m, 2H), 2.55-2.53 (m, 2H), 2.41- 2.48 (m, 4H). DMSO 508.1 (M + 1) 254.1 254.9 (M/2 + 1) Method B (NH4HCO3) 95 Method C, G, C
    1080
    Figure US20170217923A1-20170803-C02062
         		461.92 1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H), 8.72-8.67 (m, 2H), 8.64 (d, J = 1.2 Hz, 1H), 8.28 (dd, J = 7.0, 2.6 Hz, 1H), 7.95- 7.86 (m, 3H), 7.60-7.53 (m, 2H), 3.68 (d, J = 2.4 Hz, 2H), 3.37-3.34 (m, 2H), 1.65-1.51 (m, 6H). DMSO 462.0 464.0 (M + 1) 232.3 (M/2 + 1) Method A (TFA) 95 Method C, G, C
    1081
    Figure US20170217923A1-20170803-C02063
         		479.96 1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.53 (d, J = 1.6 Hz, 1H), 8.72-8.67 (m, 2H), 8.64 (d, J = 1.2 Hz, 1H), 8.28 (dd, J = 6.8, 2.8 Hz, 1H), 7.97- 7.90 (m, 3H), 7.60-7.54 (m, 2H), 3.97-3.94 (m, 2H), 3.66-3.60 (m, 2H), 2.77-2.67 (m, 4H). DMSO 480.0 482.0 (M + 1) 240.6 (M/2 + 1) Method A (TFA) 95 Method C, G, C
    1082
    Figure US20170217923A1-20170803-C02064
         		421.85 1H-NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.55 (d, J = 1.6 Hz, 1H), 8.79-8.64 (m, 3H), 8.29 (dd, J = 6.8, 2.6 Hz, 1H), 8.01-7.87 (m, 3H), 7.53-7.60 (m, 2H), 3.15-3.05 (m, 3H), 3.02 (s, 3H). DMSO 422.1, 424.1 (M + 1) Method B (NH4HCO3) 95 Method C, G, D
    1083
    Figure US20170217923A1-20170803-C02065
         		463.89 1H-NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 9.55 (d, J = 1.4 Hz, 1H), 8.77-8.65 (m, 3H), 8.02-7.87 (m, 3H), 7.60-7.54 (m, 2H), 3.56-3.39 (m, 2H), 3.82-3.55 (m, 6H). DMSO 464.1, 466.1 (M + 1) Method B (NH4HCO3) 95 Method C, G, D
    1084
    Figure US20170217923A1-20170803-C02066
         		407.83 1H-NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 9.08 (d, J = 1.3 Hz, 1H), 8.76- 8.63 (m, 3H), 8.32-8.20 (m, 2H), 7.96-7.93 (m, 2H), 7.63-7.50 (m, 2H), 2.88 (d, J = 4.5 Hz, 3H). DMSO 408.0, 410.0 (M + 1) Method B (NH4HCO3) 95 Method C, G, D
    1085
    Figure US20170217923A1-20170803-C02067
         		447.89 1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 9.55 (d, J = 1.5 Hz, 1H), 8.68-8.77 (m, 3H), 8.28 (dd, J = 6.9, 2.6 Hz, 1H), 8.02 (dd, J = 8.6, 1.6 Hz, 1H), 7.99-7.90 (m, 2H), 7.53-7.58 (m, 2H), 3.57 (t, J = 6.8 Hz, 2H), 3.51 (t, = 6.4 Hz, 2H), 1.85-1.95 (m, 4H). DMSO 448.1, 420.1 (M + 1) Method B (NH4HCO3) 95 Method C, G, D
    1086
    Figure US20170217923A1-20170803-C02068
         		476.93 1H-NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 8.75-8.63 (m, 3H), 8.29 (dd, J = 6.8, 2.6 Hz, 1H), 8.01-7.84 (m, 3H), 7.60-7.53 (m, 2H), 3.72 (d, J = 2.2 Hz, 2H), 3.51-3.39 (m, 2H), 2.48-2.40 (m, 2H), 2.33 (d, J = 1.3 Hz, 2H), 2.24 (s, 3H). DMSO 477.1, 479.1 (M + 1) 239.1, 239.9 (M/2 + 1) Method B (NH4HCO3) 95 Method C, G, D
    1087
    Figure US20170217923A1-20170803-C02069
         		511.96 1H-NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 9.53 (d, J = 1.6 Hz, 1H), 8.59-8.82 (m, 3H), 8.26 (dd, J = 6.8, 2.6 Hz, 1H), 7.81-8.14 (m, 3H), 7.57 (m, 2H), 3.83-4.10 (m, 4H), 3.33-3.35 (m, 4H). DMSO 512.1, 514.1 (M + 1) Method B (NH4HCO3) 95 Method C, G, D
    1088
    Figure US20170217923A1-20170803-C02070
         		481.91 1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H), 9.23 (d, J = 1.2 Hz, 1H), 8.72- 8.74 (m, 3H), 8.22-8.42 (m, 2H), 7.85-8.12 (m, 2H), 7.55-7.59 (m, 2H), 4.61 (t, J = 5.4 Hz, 1H), 3.47 (t, J = 5.2 Hz, 2H), 3.37 (s, 6H). DMSO 482.1, 484.2 (M + 1) Method B (NH4HCO3) 95 Method C, G, D
    1089
    Figure US20170217923A1-20170803-C02071
         		421.85 1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 9.59 (d, J = 1.2 Hz, 1H), 8.72-8.77 (m, 2H), 8.68 (d, J = 8.4 Hz, 1H), 8.34 (dd, = 7.2, 2.0 Hz, 1H), 7.96- 8.00 (m, 1H), 7.92 (m, 1H), 7.72-7.74 (m, 1H), 7.58-7.65 (m, 2H), 3.13 (s, 3H), 3.03 (s, 3H). DMSO 422.0 (M + 1) Method A (TFA) 95 Method C, G, D
    1090
    Figure US20170217923A1-20170803-C02072
         		394.79 1H-NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 9.54 (s, 1H), 8.68-8.70 (m, 2H), 8.60 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.32 (dd, J = 7.2, 2.8 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.93-7.97 (m, 1H), 7.51- 7.58 (m, 2H). DMSO 395.0 (M + 1) Method A (TFA) 95 Method C, G, D
    1091
    Figure US20170217923A1-20170803-C02073
         		476.93 1H-NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 9.53 (s, 1H), 8.62-8.72 (m, 3H), 8.29 (dd, J = 6.8, 2.4 Hz, 1H), 7.91-7.94 (m, 1H), 7.83 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.53-7.59 (m, 2H), 3.69-3.71 (s, 2H), 3.36-3.38 (s, 2H), 2.42-2.44 (s, 2H), 2.30- 2.32 (s, 2H), 2.23 (s, 3H). DMSO 477.2 (M + 1) 239.1 (1/2M + 1) Method B (NH4HCO3) 95 Method C, G, D
    1092
    Figure US20170217923A1-20170803-C02074
         		463.89 1H-NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.52 (s, 1H), 8.62-8.71 (m, 3H), 8.28 (d, J = 4.8 Hz, 1H), 7.87-7.96 (m, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.52-7.58 (m, 2H), 3.61-3.71 (m, 6H), 3.40 (m, 2H). DMSO 464.1 (M + 1) Method B (NH4HCO3) 95 Method G, D
    1093
    Figure US20170217923A1-20170803-C02075
         		393.8 1H-NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.54 (d, J = 1.6 Hz, 1H), 8.62-8.72 (m, 3H), 8.42 (d, J = 1.2 Hz, 1H), 8.37 (s, 1H), 8.30 (dd, J = 7.2, 2.8 Hz, 1H), 8.08 (dd, J = 8.4, 1.2 Hz, 1H), 7.91-7.95 (m, 1H), 7.71 (s, 1H), 7.53-7.60 (m, 2H). DMSO 394.1 (M + 1) Method B (NH4HCO3) 95 Method G, D
    1094
    Figure US20170217923A1-20170803-C02076
         		407.83 1H-NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 9.53 (s, 1H), 8.84 (d, J = 4.0 Hz, 1H), 8.60-8.72 (m, 3H), 8.35 (s, 1H), 8.29 (dd, J = 6.8, 2.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.90-7.93 (m, 1H), 7.52- 7.59 (m, 2H), 2.87 (d, J = 4.8 Hz, 3H). DMSO 408.1 (M + 1) Method B (NH4HCO3) 95 Method G, D
    1095
    Figure US20170217923A1-20170803-C02077
         		506.96 1H-NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.53 (d, J = 1.6 Hz, 1H), 8.85 (t, J = 5.6 Hz, 1H), 8.61- 8.72 (m, 3H), 8.36 (d, J = 1.2 Hz, 1H), 7.98 (dd, J = 6.4, 2.4 Hz, 1H), 8.03 (dd, J = 8.8, 1.6 Hz, 1H), 7.91- 7.95 (m, 1H), 7.52-7.59 (m, 2H), 3.60 (t, J = 4.4 Hz, 4H), 3.46-3.48 (q, J = 6.4 Hz, 2H), 2.51-2.54 (m, 2H), 2.42- 2.48 (m, 4H). DMSO 507.1 (M + 1) 254.1 (M/2 + 1) Method B (NH4HCO3) 95 Method G, C
    1096
    Figure US20170217923A1-20170803-C02078
         		511.96 1H-NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 9.56 (d, J = 1.8 Hz, 1H), 8.61-8.79 (m, 3H), 8.31 (dd, J = 6.8, 2.6 Hz, 1H), 7.88-8.11 (m, 2H), 7.78 (dd, J = 8.4, 1.4 Hz, 1H), 7.51-7.66 (m, 2H), 4.12 (brs, 2H), 3.76 (brs, 2H), 3.30-3.33 (m, 4H). DMSO 512.1, 514.1 (M + 1) Method B (NH4HCO3) 95 Method G, D
    1097
    Figure US20170217923A1-20170803-C02079
         		474 1H-NMR (400 MHz, DMSO-d6): δ 10.64 (brs, 1H), 9.53 (s, 1H), 9.44 (t, J = 6.4 Hz, 1H), 9.35 (s, 1H), 8.90 (d, J = 8.0 Hz, 1H), 8.85 (d, J = 4.8 Hz, 1H), 8.35 (dd, J = 8.4, 1.2 Hz, 1H), 8.27 (dd, J = 6.8, 2.4 Hz, 1H), 8.00-7.97 (m, 2H), 7.82 (dt, J = 13.2, 5.2 Hz, 1H), 7.55 (t, J = 8.8 Hz, 1H), 4.22-4.18 (m, 2H). DMSO 475.7, 476.6 (M + 1) Method B (NH4HCO3) 95 Method C, G, D
  • Figure US20170217923A1-20170803-C02080
  • Figure US20170217923A1-20170803-C02081
    • Method AE: 2-(7-(Methylamino)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (xxxvi-a)
  • A mixture of 2-(7-amino-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (160 mg, 0.449 mmol, 1.0 eq.) and HCHO (40%, 37 mg, 0.494 mmol, 1.1 eq.), acetic acid (2 drops) were stirred at room temperature for 0.5 h. NaBH3CN (34 mg, 0.449 mmol, 1.0 eq.) was added and the mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated to give the crude product, which was purified by reverse phase chromatography (MeOH/H2O=3:7) to afford 28 mg of xxxvi-a as a white solid (17%). LCMS m/z=371.1 (M+1), 372.1 (M+2) (Method B) (retention time=1.60 min). 1H-NMR (400 MHz, DMSO-d6): δ 12.71 (s, 1H), 9.58 (d, J=1.6 Hz, 1H), 9.14-9.12 (m, 1H), 8.74-8.69 (m, 2H), 8.45 (s, 1H), 7.93-7.91 (m, 1H), 7.85 (d, J=9.2 Hz, 2H), 7.67-7.71 (m, 1H), 7.59-7.55 (m, 1H), 7.12-7.16 (m, 1H), 7.06-7.03 (m, 1H), 6.82-6.81 (m, 1H), 6.70 (d, J=2.4 Hz, 1H), 2.84 (d, J=4.8 Hz, 3H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 41, replacing formaldehyde with the appropriate aldehyde and 2-aminobenzamide with the appropriate aniline.
  • TABLE 14
    Molec- Purity Method
    Salt ular 1H-NMR LCMS per- for
    Number PRODUCT type Mass 1H-NMR Solvent LCMS Protocol cent Coupling
    1098
    Figure US20170217923A1-20170803-C02082
         		370.41 1H-NMR (400 MHz, DMSO-d6): δ 12.87 (s, 1H), 9.57 (d, J = 1.2 Hz, 1H), 9.25 (d, J = 8.8 Hz, 1H), 8.65- 8.71 (m, 2H), 8.47 (s, 1H), 7.95-7.99 (m, 2H), 7.69-7.74 (m, 2H), 7.56 (dd, J = 7.7, 5.0 Hz, 1H), 7.33 (dd, J = 9.1, 1.9 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 1.2 Hz, 1H), 6.62 (d, J = 4.8 Hz, 1H), 2.88 (d, J = 4.8 Hz, 3H). DMSO 371.1 (M + 1) Method B (NH4HCO3) 95 Method AE
    1099
    Figure US20170217923A1-20170803-C02083
         		370.41 1H-NMR (400 MHz, DMSO-d6): δ 12.71 (s, 1H), 9.58 (d, J = 1.4 Hz, 1H), 9.13 (d, J = 7.7 Hz, 1H), 8.80- 8.64 (m, 2H), 8.45 (s, 1H), 7.92 (dd, J = 7.9, 1.4 Hz, 1H), 7.85 (d, J = 9.2 Hz, 2H), 7.76-7.62 (m, 1H), 7.57 (dd, J = 7.9, 4.8 Hz, 1H), 7.15 (dd, J = 11.2, 4.0 Hz, 1H), 7.04 (dd, J = 9.0, 2.3 Hz, 1H), 6.81 (q, J = 4.8 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 2.85 (d, J = 4.9 Hz, 3H). DMSO 371.1 (M + 1) Method B (NH4HCO3) 95 Method AE
  • Figure US20170217923A1-20170803-C02084
  • Figure US20170217923A1-20170803-C02085
    • Method AG: 1-(Benzyloxy)-3-chloro-7-methoxyisoquinoline (xxxvii-a)
  • 1,3-dichloro-7-methoxyisoquinoline (2.00 g, 8.8 mmol, 1.0 eq.) was dissolved in 30 mL anhydrous toluene and sodium benzyloxide (2.30 g, 17.6 mmol, 2.0 eq.) was added. The mixture was heated to 80° C. for 18 h. TLC indicated the reaction was complete. The mixture was concentrated to give the crude product, which was purified by chromatography on silica gel (eluted with petroleum ether) to give 2.20 g of xxxvii-a as a white solid (84.6%). LCMS m/z=300.1, 302.0 (M+1) (Method B) (retention time=2.23 min).
    • 1-(Benzyloxy)-7-methoxy-3-(pyridin-3-yl)isoquinoline (xxxviii-a)
  • 1-(Benzyloxy)-7-methoxy-3-(pyridin-3-yl)isoquinoline was prepared using Method N2. 1-(Benzyloxy)-3-chloro-7-methoxyisoquinoline (93 mg, 0.5 mmol, 1.0 eq.), potassium carbonate (357 mg, 2.5 mmol, 5.0 eq.), and Pd(PPh3)2Cl2 (18 mg, 0.026 mmol, 0.05 eq.) was dissolved in the mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). The resulting mixture was stirred at 120° C. for 30 min under the microwave condition. The solid was filtrated off and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=1:10) to afford 100 mg of xxxviii-a as a yellow solid (84.7%).
    • 7-Methoxy-3-(pyridin-3-yl)isoquinolin-1-ol (xxxviv-a)
  • 7-Methoxy-3-(pyridin-3-yl)isoquinolin-1-ol (prepared in a manner analogous to that described for 2-amino-5-methoxybenzoic acid in Method K, replacing 5-methoxy-2-nitrobenzoic acid with 1-(benzyloxy)-7-methoxy-3-(pyridin-3-yl) isoquinoline) was obtained in a 63.6% yield to give 280 mg of xxxviv-a as a yellow solid. This was carried on without further purification.
    • 1-Chloro-7-methoxy-3-(pyridin-3-yl)isoquinoline (xl-a)
  • 1-Chloro-7-methoxy-3-(pyridin-3-yl)isoquinoline (prepared in a manner analogous to that described for 4-chloro-6-propoxy-2-pyridin-3-yl-quinazoline in Method F1, replacing 6-propoxy-2-pyridin-3-yl-1H-quinazolin-4-one with 3-(pyridin-3-yl)isoquinolin-1-ol) was obtained in a 73.0% yield to give 60 mg of xl-a as a brown solid. MS m/z=241.1 (M+1) (Method A) (retention time=1.34 min).
    • N-(3-Chloro-4-fluorophenyl)-7-methoxy-3-(pyridin-3-yl)isoquinolin-1-amine (xli-a)
  • N—(N-(3-chloro-4-fluorophenyl)-7-methoxy-3-(pyridin-3-yl)isoquinolin-1-amine was prepared using Method J. A mixture of 1-chloro-7-methoxy-3-(pyridin-3-yl)isoquinoline (40 mg, 0.17 mmol, 1.0 eq.), 3-chloro-4-fluoro aniline (30 mg, 0.21 mmol, 1.2 eq.), Pd2(dba)3 (10 mg, 0.011 mmol, 0.06 eq.), Xantphos (15 mg, 0.026 mmol, 0.15 eq.), cesium carbonate (167 mg, 0.52 mmol, 3.0 eq.) was suspended in the mixed solvent of 1,4-dioxane (4 mL) and water (1 mL). The resulting mixture was stirred at 120° C. for 30 min under the microwave conditions. After cooling, the resulting mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was purified by prep-HPLC to afford 3 mg of xli-a as a yellow solid (yield 5.2%). LCMS m/z=380.1 (M+1) (Method B). 1H NMR (400 MHz, DMSO-d6): δ 9.35 (s, 1H), 9.30 (d, J=2.0 Hz, 1H), 8.57 (dd, J=4.7, 1.5 Hz, 1H), 8.41 (td, J=8.0, 1.8 Hz, 1H), 8.30 (dd, J=6.9, 2.6 Hz, 1H), 7.94-7.87 (m, 4H), 7.43-7.49 (m, 3H), 3.99 (s, 3H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 43, replacing with the appropriate isoquinoline and aniline.
  • TABLE 15
    Method
    Salt Molecular 1H-NMR LCMS Purity for
    Number PRODUCT type Mass 1H-NMR Solvent LCMS Protocol percent Coupling
    1100
    Figure US20170217923A1-20170803-C02086
         		379.81 1H-NMR (400 MHz, DMSO-d6): δ 9.35 (s, 1H), 9.30 (d, J = 2.0 Hz, 1H), 8.57 (dd, J = 4.7, 1.5 Hz, 1H), 8.41 (td, J = 8.0, 1.8 Hz, 1H), 8.30 (dd, J = 6.9, 2.6 Hz, 1H), 7.94-7.87 (m, 4H), 7.43-7.49 (m, 3H), 3.99 (s, 3H). DMSO 380.1, 382.0 (M + 1) Method B (NH4HCO3) 95 Method J
    1101
    Figure US20170217923A1-20170803-C02087
         		411.38 1H-NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 9.31 (d, J = 1.75 Hz, 1H), 8.57 (dd, J = 4.6, 1.3 Hz, 1H), 8.45-8.41 (m, 1H), 8.19 (s, 1H), 7.99-7.94 (m, 2H), 7.91-7.86 (m, 2H), 7.54-7.44 (m, 3H), 7.01 (d, J = 8.1 Hz, 1H), 4.00 (s, 3H). DMSO 412.1 (M + 1) Method B (NH4HCO3) 95 Method J
    1102
    Figure US20170217923A1-20170803-C02088
         		388.39 1H-NMR (400 MHz, DMSO-d6): δ 11.35 (s, 1H), 9.34 (d, J = 1.9 Hz, 1H), 8.80 (d, J = 8.4 Hz, 1H), 8.59 (dd, J = 4.7, 1.48 Hz, 1H), 8.49-8.45 (m, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.97-7.92 (m, 1H), 7.61 (td, J = 14.9, 7.5 Hz, 1H), 7.56-7.48 (m, 3H), 6.95 (dd, J = 10.3, 8.3 Hz, 1H), 3.98 (s, 3H). DMSO 389.1 (M + 1) Method B (NH4HCO3) 95 Method J
    1103
    Figure US20170217923A1-20170803-C02089
         		370.4 1H-NMR (400 MHz, CDCl3): δ 11.89 (s, 1H), 9.39 (s, 1H), 9.29 (s, 1H), 8.63-8.59 (m, 1H), 8.42-8.37 (m, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.60-7.62 (m, 4H), 7.44-7.33 (m, 3H), 7.05-7.00 (m, 1H), 4.06 (s, 3H). CDCl3 371.1 (M + 1) Method B (NH4HCO3) 95 Method J
    1104
    Figure US20170217923A1-20170803-C02090
         		407.37 1H-NMR (400 MHz, CDCl3): δ 9.28 (s, 1H), 8.60 (d, J = 4.6 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.63 (s, 1H), 7.43-7.35 (m, 2H), 7.22 (d, J = 8.6 Hz, 1H), 7.17(s, 1H), 7.09- 7.03 (m, 2H), 4.00 (s, 3H). CDCl3 408.1 (M + 1) Method B (NH4HCO3) 95 Method J
    1105
    Figure US20170217923A1-20170803-C02091
         		454.4 1H-NMR (400 MHz, DMSO-d6): δ 13.00 (s, 1H), 9.43 (d, J = 1.2 Hz, 1H), 9.35 (s, 1H), 8.63 (d, J = 3.7 Hz, 1H), 8.53 (s, 1H), 8.48-8.44 (m, 1H), 8.03-8.09 (m, 3H), 7.97 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.56-7.50 (m, 2H), 7.05 (dd, J = 8.6, 1.93 Hz, 1H), 4.01 (s, 3H). DMSO 455.1 (M + 1) Method B (NH4HCO3) 95 Method J
    1106
    Figure US20170217923A1-20170803-C02092
         		455.91 1H-NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 9.37 (d, J = 1.7 Hz, 1H), 8.83 (s, 1H), 8.63 (dd, J = 4.7, 1.3 Hz, 1H), 8.54-8.43 (m, 1H), 8.35 (dd, J = 6.9, 2.6 Hz, 1H), 8.15 (dd, J = 8.5, 1.4 Hz, 1H), 8.03 (t, J = 4.3 Hz, 2H), 7.91-7.95 (m, 1H), 7.46-7.55 (m, 5H), 7.11-7.01 (m, 1H), 3.91 (s, 3H). DMSO 456.1, 458.1 (M + 1) Method B (NH4HCO3) 95 Method J
    1107
    Figure US20170217923A1-20170803-C02093
         		1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 9.36 (d, J = 1.9 Hz, 1H), 9.19 (d, J = 1.9 Hz, 1H), 8.91 (s, 1H), 8.67 (dd, J = 4.8, 1.5 Hz, 1H), 8.62 (dd, J = 4.7, 1.5 Hz, 1H), 8.53-8.44 (m, 1H), 8.35-8.32 (m, 2H), 8.19 (dd, J = 8.5, 1.5 Hz, 1H), 8.13-8.01 (m, 2H), 7.92 (ddd, J = 9.1, 4.3, 2.7 Hz, 1H), 7.61 (dd, J = 7.9, 4.8 Hz, 1H), 7.55 (dd, J = 8.0, 4.8 Hz, 1H), 7.50 (t, J = 9.1 Hz, 1H). DMSO 426.7 428.7 (M + !) Method B (NH4HCO3) 95 Method J
  • Figure US20170217923A1-20170803-C02094
  • Figure US20170217923A1-20170803-C02095
    • Method AI: Ethyl 2-cyano-4,4-diethoxybutanoate (xlii-a)
  • 2-Bromo-1,1-diethoxyethane (4 g, 20 mmol, 1.0 eq.) was added to a mixture of ethyl 2-cyanoacetate (11.4 g, 101 mmol, 5.0 eq.), K2CO3 (2.8 g, 20 mmol, 1.0 eq.) and NaI (200 mg, 1.3 mmol, 0.06 eq.), as described in J. Chem. Soc., 1960, 131-138. The reaction mixture was refluxed for 4 h at 145° C. After cooling, the reaction mixture was purified by chromatography on silica gel (eluted with petroleum ether/ethyl acetate (80:1→40:1→10:1) to give 3.57 g of xlii-a as a colorless oil (78%). 1H NMR (400 MHz, CDCl3□□): δ 4.70 (t, J=5.6 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.78-3.64 (m, 3H), 3.62-3.45 (m, 2H), 2.35-2.14 (m, 2H), 1.34 (q, J=7.2 Hz, 3H), 1.25-1.16 (m, 6H).
    • Method AJ: 2-(Pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (xliii)
  • To a solution of nicotinimidamide (5.03 g, 41.6 mmol, 1.2 eq.) in EtOH (100 mL), was added NaOMe (4.8 g, 88.8 mmol, 2.5 eq.). The mixture was stirred at room temperature for 4 h. The reaction mixture was added to ethyl 2-cyano-4,4-diethoxybutanoate (8.00 g, 34.9 mmol, 1 eq.). This mixture was stirred at 105° C. overnight. After cooling, the reaction mixture was acidified with conc. HCl and stirred at room temperature for 2 h. A precipitate formed and was collected and washed with H2O (20 mL×2). After lyophilization, 3.10 g of product was obtained as a gray yellow solid (yield 41.8%). LCMS m/z=213.1 (M+1) (Method B) (retention time=1.07 min). 1H NMR (400 MHz, DMSO-d6□□): δ 12.26 (s, 1H), 12.04 (s, 1H), 9.23 (d, J=1.6 Hz, 1H), 8.70 (dd, J=4.8, 1.2 Hz, 1H), 8.43-8.40 (m, 1H), 7.55 (dd, J=8.0, 4.8 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 6.51 (d, J=2.8 Hz, 1H).
    • 4-Chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (xlv-a)
  • 4-Chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (prepared in a manner analogous to that described for 4-chloro-6-propoxy-2-pyridin-3-yl-quinazoline in Method F1, replacing 6-propoxy-2-pyridin-3-yl-1H-quinazolin-4-one with 2-(pyridin-3-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-ol) to give 450 mg of xliv-a in a 69.0% yield as a brown solid. LCMS m/z=231.0, 233.0 (M+1) (Method B) (retention time=1.60 min).
    • N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (xlv-a)
  • N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (prepared in a manner analogous to that described for N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-amine using Method G6, replacing 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propyl methanesulfonate with 4-chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine) to give a 11.3% yield, 10 mg of xlv-a as brown solid. LCMS m/z=340.1, 342.0 (M+1) (Method B) (retention time=1.814 min). 1H NMR (400 MHz, DMSO-d6): δ 9.48 (d, J=1.6 Hz, 1H), 8.62 (dd, J=4.8, 1.6 Hz, 1H), 8.60-8.56 (m, 1H), 8.27 (dd, J=6.4, 2.4 Hz, 1H), 8.06 (ddd, J=8.8, 4.0, 2.8 Hz, 1H), 7.71 (d, J=3.6 Hz, 1H), 7.66 (t, J=9.2 Hz, 1H), 7.50 (dd, J=8.0, 4.8 Hz, 1H), 7.41 (br s, 2H), 6.85 (d, J=3.6 Hz, 1H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 45, replacing with the appropriate aniline.
  • TABLE 16
    Purity Method
    Salt Molecular 1H-NMR LCMS per- for
    Number PRODUCT type Mass 1H-NMR Solvent LCMS Protocol cent Coupling
    1108
    Figure US20170217923A1-20170803-C02096
         		330.34 1H-NMR (400 MHz, DMSO- d6): δ 12.29 (s, 1H), 12.09 (s, 1H), 9.54 (d, J = 1.2 Hz, 1H), 9.11 (d, J = 8.4 Hz, 1H), 8.65- 8.68 (m, 1H), 8.35 (s, 1H), 7.89 (dd, J = 8.0, 1.2 Hz, 1H), 7.79 (s, 1H), 7.67 (td, J = 8.8, 1.2 Hz, 1H), 7.55 (dd, J = 7.2, 4.8 Hz, 1H), 7.43-7.41 (m, 1H), 7.10 (td, J = 8.0, 1.2 Hz, 1H), 6.49 (d, J = 3.6 Hz, 1H). DMSO 331.1 (M + 1) Method B (NH4HCO3) 95 Method AJ, F, G6
    1109
    Figure US20170217923A1-20170803-C02097
         		371.32 1H-NMR (400 MHz, DMSO- d6): δ 12.02 (d, J = 1.3 Hz, 1H), 9.75 (s, 1H), 9.50 (d, J = 1.5 Hz, 1H), 8.68- 8.53 (m, 2H), 8.29 (s, 1H), 7.94-7.75 (m, 1H), 7.61- 7.44 (m, 2H), 7.41-7.29 (m, 1H), 7.04 (s, 1H), 6.88 (dd, J = 3.4, 1.9 Hz, 1H). DMSO 372.0 (M + 1) Method A (TFA) 95 Method AJ, F, G6
    1110
    Figure US20170217923A1-20170803-C02098
         		366.32 1H-NMR (400 MHz, DMSO- d6): δ 11.98 (s, 1H), 9.69 (s, 1H), 9.48 (d, J = 1.8 Hz, 1H), 8.64-8.59 (m, 2H), 8.19 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 8.8, 2.0 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 3.0 Hz, 1H), 6. DMSO 368.1 (M + 1) Method A (TFA) 95 Method AJ, F, G6
    1111
    Figure US20170217923A1-20170803-C02099
         		339.75 1H-NMR (400 MHz, DMSO- d6): δ 11.51 (s, 1H), 8.78 (d, J = 8.0 Hz, 2H), 8.17 (d, J = 9.2 Hz, 1H), 7.80 (dd, J = 9.2, 2.8 Hz, 1H), 7.70-7.64 (m, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 4.0 Hz, 2H), 7.16-7.08 (m, 1H). DMSO 340.1, 342.0 (M + 1) Method B (NH4HCO3) 95 Method AJ, F, G6
  • Figure US20170217923A1-20170803-C02100
  • Figure US20170217923A1-20170803-C02101
    • Method AK: 4-Chloro-7-methyl-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (xliv-a)
  • To a solution of 4-chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.34 mmol, 1.0 eq.) in dry DMF (20 mL) was added Cs2CO3 (221 mg, 0.68 mmol, 2.0 eq.) and iodomethane (54.3 mg, 0.38 mmol, 1.1 eq.) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2.5 h. The reaction mixture was poured into ice water and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 8:1) to give 65 mg of xlvi-a as brown solid (56.7%).
    • N-(3-chloro-4-fluorophenyl)-7-methyl-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (xlvii-a)
  • N-(3-chloro-4-fluorophenyl)-7-methyl-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (prepared in a manner analogous to that described for N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-amine using Method G6, replacing 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propyl methanesulfonate with 4-chloro-7-methyl-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine) to give a 70.0% yield, 30 mg of xlvii-a as a brown solid. LCMS m/z=354.1, 356.1 (M+1) (Method B) (retention time=1.94 min). 1H NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 9.53 (s, 1H), 9.15 (d, J=8.0 Hz, 1H), 8.91 (d, J=5.2 Hz, 1H), 8.25 (dd, J=6.8, 2.4 Hz, 1H), 8.04 (dd, J=7.6, 5.6 Hz, 1H), 7.94-7.90 (m, 1H), 7.48-7.43 (m, 2H), 6.95 (d, J=3.2 Hz, 1H), 3.88 (s, 3H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 46, replacing with the appropriate aniline.
  • TABLE 17
    Method
    Salt Molecular 1H-NMR LCMS Purity for
    Number PRODUCT type Mass 1H-NMR Solvent LCMS Protocol percent Coupling
    1112
    Figure US20170217923A1-20170803-C02102
         		HCl 353.78 1H NMR (400 MHz, DMSO-d6): δ 9.97 (s, 1H), 9.53 (s, 1H), 9.15 (d, J = 8.0 Hz, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.25 (dd, J = 6.8, 2.4 Hz, 1H), 8.04 (dd, J = 7.6, 5.6 Hz, 1H), 7.94- 7.90 (m, 1H), 7.48-7.43 (m, 2H), 6.95 (d, J = 3.2 Hz, 1H), 3.88 (s, 3H). DMSO 354.1, 356.1 (M + 1) Method B (NH4HCO3) 95 Method AK, G6
    1113
    Figure US20170217923A1-20170803-C02103
         		385.34 1H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 9.56 (d, J = 1.6 Hz, 1H), 8.69-8.64 (m, 2H), 8.29 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.55-7.51 (m, 2H), 7.41 (d, J = 3.6 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 3.6 Hz, 1H), 3.87 (s, 3H). DMSO 386.1 (M + 1) Method B NH4HCO3 95 Method AK, G6
    1114
    Figure US20170217923A1-20170803-C02104
         		1H-NMR (400 MHz, DMSO-d6): δ 12.32 (s, 1H), 9.61 (s, 1H), 9.11 (d, J = 7.6 Hz, 1H), 9.11 (d, J = 7.6 Hz, 1H), 8.74 (dt, J = 8.0, 1.9 Hz, 1H), 8.67 (d, J = 3.6 Hz, 1H), 8.38 (s, 1H), 8.38 (s, 1H), 7.90 (dd, J = 7.9, 1.4 Hz, 1H), 7.82 (s, 1H), 7.68 (dd DMSO 344.9 (M + 1) Method B (NH4HCO3) 95 Method AK, G6
  • Figure US20170217923A1-20170803-C02105
  • Figure US20170217923A1-20170803-C02106
    • Method AL: 4-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)-2-(pyridin-3-yl)quinazoline-6-carboxamide (xlviii-a)
  • To a suspension of 4-oxo-2-(pyridin-3-yl)-1,4-dihydroquinazoline-6-carboxamide (prepared as described in scheme 4) (100 mg, 0.376 mmol, 1.0 eq.) in dry DMF (20 mL) was added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (216 mg, 0.488 mmol, 1.3 eq.) and diaza(1,3)bicyclo[5.4.0]undecene (114.5 mg, 0.752 mmol, 2.0 eq.) following a procedure outlined in J. Org. Chem., 2007, 72, 10194-10210. To the clear solution was then added 5,6-dimethyl-1H-benzo[d]imidazole (165.2 mg, 1.13 mmol, 3.0 eq.) and the mixture was stirred overnight at room temperature. The resultant precipitate was then collected by filtration and washed with dichloromethane, water, and ether. The product was dried in vacuo to give 26.3 mg of the desired product (xlviii-a) as an off-white solid (6.7%). LCMS m/z=395.1 (M+1) (Method C) (retention time=1.68 min). 1H NMR (300 MHz, DMSO) δ 9.69 (s, 1H), 8.90 (s, 1H), 8.82 (d, J=15.2 Hz, 2H), 8.66 (s, 1H), 8.54 (d, J=8.6 Hz, 1H), 8.42 (s, 1H), 8.30 (d, J=8.5 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H).
  • Figure US20170217923A1-20170803-C02107
  • Figure US20170217923A1-20170803-C02108
    • Method AM: Synthesis of 2-(6-(2-(piperidin-1-yl)ethoxy)-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (xlviv-a)
  • To 1-(2-chloroethyl)piperidine (45 μmol) was added the solution of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (30 μmol) in NMP (200 μL). PS-BEMP (90 μmol) was added to the vials by resin dispenser. After the reaction mixture was heated at 90° C. for 12 h, the residue was diluted with methanol and purified by mass triggered PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 51, replacing 1-(2-chloroethyl)piperidine with the appropriate alkyl halide.
  • TABLE 18
    Starting Starting
    Number Material 1 Material 2 Product
    1116
    Figure US20170217923A1-20170803-C02109
    Figure US20170217923A1-20170803-C02110
    Figure US20170217923A1-20170803-C02111
    1117
    Figure US20170217923A1-20170803-C02112
    Figure US20170217923A1-20170803-C02113
    Figure US20170217923A1-20170803-C02114
    1118
    Figure US20170217923A1-20170803-C02115
    Figure US20170217923A1-20170803-C02116
    Figure US20170217923A1-20170803-C02117
    1119
    Figure US20170217923A1-20170803-C02118
    Figure US20170217923A1-20170803-C02119
    Figure US20170217923A1-20170803-C02120
    1120
    Figure US20170217923A1-20170803-C02121
    Figure US20170217923A1-20170803-C02122
    Figure US20170217923A1-20170803-C02123
    1121
    Figure US20170217923A1-20170803-C02124
    Figure US20170217923A1-20170803-C02125
    Figure US20170217923A1-20170803-C02126
    1122
    Figure US20170217923A1-20170803-C02127
    Figure US20170217923A1-20170803-C02128
    Figure US20170217923A1-20170803-C02129
    1123
    Figure US20170217923A1-20170803-C02130
    Figure US20170217923A1-20170803-C02131
    Figure US20170217923A1-20170803-C02132
    Exact Mass Found Purity
    Number Salt Type Mass (M + 1) (%)
    1116 468 469 98
    1117 454 455 98
    1118 456 457 98
    1119 468 469 98
    1120 482 483 98
    1121 TFA 496 497 98
    1122 465 466 98
    1123 505 506 98
  • Figure US20170217923A1-20170803-C02133
  • To a suspension of ethyl 2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-4-phenylthiazole-5-carboxylate (1.3956 g, 2.89 mmol) in dioxane (40 mL) was added 1N NaOH (20 ml, 20.00 mmol) at room temperature to give a clear solution. The reaction mixture was stirred at room temperature for 1 h and then warmed to 50° C. overnight, however starting material remained. An additional 20 mL of 1N NaOH was added and heating was continued at 50° C. for 1 h and at 70° C. for 5 h 30 min. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The water phase was removed and adjusted to an acidic pH with 1N HCl (40 mL). A precipitate formed and was collected and washed with water. The product was dried in vacuo to give 1.20 g of a brown solid in a 91% yield. 1H NMR (DMSO-d6) ppm 12.88 (br, 2H), 9.77 (dd, J=2.12, 0.6 Hz, 1H), 8.92-8.89 (m, 1H), 8.78 (dd, J=4.8, 1.68 Hz, 1H), 8.32 (br, 1H), 7.96 (d, J=9.12 Hz, 1H), 7.82-7.80 (m, 2H), 7.70-7.67 (m, 1H), 7.63 (dd, J=9.12, 2.68 Hz, 1H), 7.50-7.44 (m, 3H), 3.98 (s, 3H).
    • Method AN: 2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-N-methyl-4-phenylthiazole-5-carboxamide
  • To a suspension of 2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-4-phenylthiazole-5-carboxylic acid (291.8 mg, 0.641 mmol) in DMF (20 mL) under nitrogen atmosphere was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (189 mg, 0.986 mmol) and 1-hydroxybenzotriazole hydrate (147 mg, 0.961 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 min to give a clear solution and methylamine in a methanol solution (4 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h 15 min. Additional methyl amine in a methanol solution (4 mL) was added at room temperature and then heated to 50° C. for 1 h followed by room temperature for 2 days. The reaction mixture was partitioned between water and ethyl acetate. The water phase was collected and a solid precipitated from the water phase. The solid was filtered and dried in an oven at 60° C. to give 107.9 mg (0.23 mmol) as the parent compound. The parent compound was suspended in methanol and 4N HCl in ethyl acetate (ca. 2 mL) was added to give a clear solution which precipitated over time. The solid was collected by filtration and dried in oven at 60° C. for 2 days to give 82.4 mg of the HCl salt as a yellow solid in 24% yield. 1H NMR (DMSO-d6) δ 12.77 (brs, 1H), 9.76 (d, J=1.72 Hz, 1H), 9.18 (d, J=7.88 Hz, 1H), 8.92 (d J=5.04 Hz, 1H), 8.35 (brs, 1H), 8.27 (brd, J=4.56 Hz, 1H), 7.99-7.965 (m, 2H), 7.79 (brd, J=7.16 Hz, 2H), 7.65 (dd, J=9.12, 2.56 Hz, 1H), 7.50-7.41 (m, 3H), 4.00 (s, 3H), 2.76 (d, J=4.56 Hz, 3H). The 1H of 2 HCl was not observed.
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 53, replacing N-methyl amine with the appropriate alkyl amine.
  • TABLE 19
    Starting Starting
    Number Material 1 Material 2 Product
    1124
    Figure US20170217923A1-20170803-C02134
    Figure US20170217923A1-20170803-C02135
    Figure US20170217923A1-20170803-C02136
    1125 NH3
    Figure US20170217923A1-20170803-C02137
    Figure US20170217923A1-20170803-C02138
    1126
    Figure US20170217923A1-20170803-C02139
    Figure US20170217923A1-20170803-C02140
    Figure US20170217923A1-20170803-C02141
    Method
    Salt 1H NMR Purity of
    Number Type 1H NMR Solvent percent Coupling
    1124 2 HCl 1H NMR (DMSO-d6) ppm 12.77 (brs, DMSO >98 Method AN
    1H), 9.76 (d, J = 1.72 Hz, 1H),
    9.18 (d, J = 7.88 Hz, 1H), 8.92 (d J =
    5.04 Hz, 1H), 8.35 (brs, 1H), 8.27
    (brd, J = 4.56 Hz, 1H), 7.99-7.965
    (m, 2H), 7.79 (brd, J = 7.16 Hz,
    2H), 7.65 (dd, J = 9.12, 2.56 Hz,
    1H), 7.50-7.41 (m, 3H), 4.00 (s,
    3H), 2.76 (d, J = 4.56 Hz, 3H). The
    1H of 2HCl was not observed.
    1125 2 HCl 1H NMR (DMSO-d6) ppm 12.75 (brs, DMSO >98 Method AN
    1H), 9.77 (d, J = 1.52 Hz, 1H), 9.13
    (brs, 1H), 8.88 (brd, J = 5.08 Hz,
    1H), 8.34 (d, J = 2.04 Hz, 1H), 7.98
    (d, J = 9.12 HZ, 1H), 7.90 (brm,
    1H), 7.83-7.80 (m, 2H), 7.66-7.53
    (brm, 3H), 7.51-7.42 (m, 3H), 4.00
    (s, 3H). The 1H of 2HCl was not
    observed.
    1126 1H NMR (DMSO-d6) ppm 12.66 (s, DMSO >98 Method AN
    1H), 9.76 (s, 1H), 8.88 (d, J = 7.76
    HZ, 1H), 8.75 (d, J = 3.68 Hz, 1H),
    8.40-8.20 (br, 2H), 7.94 (br, 1H),
    2H), 7.49-7.41 (m, 3H), 3.99 (s,
    3H), 3.24 (q, J = 7.24 Hz, 2H), 1.07
    (t, J = 7.24 Hz, 3H)
  • Figure US20170217923A1-20170803-C02142
  • Figure US20170217923A1-20170803-C02143
    • Method AO: N-tert-butyl-2-(4-(3,4-difluorophenyl-amino)-2-(pyridin-3-yl)quinazolin-6-yloxy)acetamide
  • To a solution of carboxylic acid derivative (500 mg, 1.2 mmol) in DMF was added 2-aminoisobutane (134 mg, 1.8 mmol), NMM (0.4 mL, 3.6 mmol), WSCDI (282 mg, 1.4 mmol) and HOBT (225 mg, 1.4 mmol). The reaction mixture was stirred at room temperature overnight. The resulting solution was poured into ice-water and the precipitate formed and was filtered off. The solid was washed with water and dried to give 350 mg (62% yield) of desired product. 1H NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 9.49 (d, J=1.5 Hz, 1H), 8.71-8.57 (m, 2H), 8.11 (ddd, J=13.3, 7.5, 2.5 Hz, 1H), 8.00-7.93 (m, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.67 (ddd, J=11.7, 7.1, 2.1 Hz, 2H), 7.59-7.47 (m, 3H), 4.61 (s, 2H), 1.35 (s, 9H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 54, replacing 2-aminoisobutane with the appropriate alkyl amine.
  • TABLE 20:
    1H Method
    Starting Starting Salt NMR Purity of
    Number Material R1 Material R2 Product Type 1H NMR Solvent percent Coupling
    1127
    Figure US20170217923A1-20170803-C02144
    Figure US20170217923A1-20170803-C02145
    Figure US20170217923A1-20170803-C02146
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 9.48 (d, J = 1.9 Hz, 1H), 9.14 (dt, J = 8.2, 1.6 Hz, 1H), 8.96 (dd, J = 5.5, 1.3 Hz, 1H), 8.37 (t, J = 6.0 Hz, 1H), 8.24 (d, J = 2.6 Hz, 1H), 8.11-7.97 (m, 3H), 7.74 (ddd, J =11.8, 7.4, 3.3 Hz, 2H), 7.55 (dt, J = 10.5, 9.1 Hz, 1H), 4.79 (s, 2H), 3.01 (t, J = 6.5 Hz, 2H), 1.86-1.59 (m, 1H), 0.85 (d, J = 6.7 Hz, 6H). DMSO >98 Method AO
    1128
    Figure US20170217923A1-20170803-C02147
    Figure US20170217923A1-20170803-C02148
    Figure US20170217923A1-20170803-C02149
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 9.50 (d, J = 1.9 Hz, 1H), 9.16 (d, J = 8.2 Hz, 1H), 8.98 (dd, J = 5.5, 1.3 Hz, 1H), 8.40 (d, = 2.5 Hz, 1H), 8.29 (t, J = 6.4 Hz, 1H), 8.18-7.95 (m, 3H), 7.83-7.67 (m, 2H), 7.55 (dt, J = 10.5, 9.1 Hz, 1H), 4.88 (s, 2H), 2.98 (d, J = 6.4 Hz, 1H), 0.84 (s, 9H). DMSO >98 Method AO
    1129
    Figure US20170217923A1-20170803-C02150
    Figure US20170217923A1-20170803-C02151
    Figure US20170217923A1-20170803-C02152
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 9.50 (d, J = 1.9 Hz, 1H), 9.16 (d, J = 8.2 Hz, 1H), 8.98 (dd, J = 5.5, 1.3 Hz, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.23- 7.96 (m, 4H), 7.85- 7.66 (m, 2H), 7.55 (dt, J = 10.5, 9.1 Hz, 1H), 4.85 (s, 2H), 3.80-3.43 (m, 1H), 1.65- 1.21 (m, 4H), 0.81 (t, J = 7.4 Hz, 6H). DMSO >98 Method AO
  • Figure US20170217923A1-20170803-C02153
  • 2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-N,N-dimethyl-1H-benzo[d]imidazole-1-carboxamide (334.1 mg, 0.760 mmol) was dissolved in concentrated HCl (0.063 ml, 0.760 mmol). The solution was stirred at room temperature overnight and then at 50° C. for 3 h 30 min followed by 100° C. for 3 h. The solid was collected and dried in vacuo to give 116.2 mg of a yellow solid in a yield 35%. 1H NMR (DMSO-d6) δ 13.22 (br, 1H), 9.55 (s, 1H), 8.92 (dd, J=4.96, 1.36 Hz, 1H), 8.88 (br, 1H), 8.01 (d, J=9.12 Hz, 1H), 7.92 (br, 1H), 7.83 (br, 1H), 7.67 (dd, J=9.12, 2.80 Hz, 1H), 7.61 (m, 2H), 7.38 (m, 2H), 3.97 (s, 3H). The 1H of 2 HCl and NH—were not observed.
  • Figure US20170217923A1-20170803-C02154
  • 4-(4-chlorophenyl)-2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)-N,N-dimethyl-1H-imidazole-1-carboxamide and concentrated HCl(aq) (10 mL) were added to a round bottom flask, a precipitate appeared upon refluxing the mixture for 3 h. The solid was collected (373.4 mg) and trituated with CH2Cl2/methanol overnight. The product was filtered and dried to give 261.7 mg of a solid. A suspension of the product in methanol was added to a 1N solution of NaOH(aq.) (5 mL) followed by CH2Cl2 and H2O. The solid was collected and washed with methanol to give 255.7 mg (0.596 mmol) of the parent product. The free parent was suspended in CH2Cl2/methanol and converted to the HCl salt by addition of a 0.3 ml solution of 4N HCl in ethyl acetate. The HCl salt was collected and dried in vacuo to give 248.4 mg as brown solid in a 26% yield. 1H NMR (DMSO-d6) δ 13.61 (br, 1H), 12.81 (br, 1H), 9.46 (s, 1H), 8.87 (d, J=5.24 Hz, 1H), 8.70 (br, 1H), 7.91-7.87 (m, 5H), 7.75 (m, 1H), 7.62-7.56 (m, 3H), 3.95 (s, 3H). The 1H of 2 HCl was not observed.
  • Figure US20170217923A1-20170803-C02155
  • To a mixture of N-(6-(benzyloxy)-2-(pyridin-3-yl)quinazolin-4-yl)-4-(4-chlorophenyl)thiazol-2-amine and catechol, dimethyl ether (0.16 g, 1.15 mmol) was added methanesulfonic acid (4.0 mL). The mixture was stirred for 1 hr and was then poured into water. The slurry was added to a stirring sat. NaHCO3(aq). solution slowly and allowed to stir for 30 min. The precipitate was filtered to give a brown solid which was washed with methanol to give 4-(4-(4-chlorophenyl)thiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol (0.23 g, 91.0%).
    • Scheme 59: Synthesis of 4-(4-phenylthiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol (Compound 1133)
  • Synthesis of 4-(4-phenylthiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol was performed in a similar manner to that described for 4-(4-(4-chlorophenyl)thiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol substituting for 4-(4-phenylthiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol for the N-(6-(benzyloxy)-2-(pyridin-3-yl)quinazolin-4-yl)-4-(4-chlorophenyl)thiazol-2-amine giving 4-(4-phenylthiazol-2-ylamino)-2-(pyridin-3-yl)quinazolin-6-ol. 1H NMR (300 MHz, DMSO) δ 10.06-9.22 (m, 2H), 8.95 (dt, J=7.9, 1.6 Hz, 1H), 8.62 (dd, J=4.7, 1.4 Hz, 1H), 7.99 (d, J=7.5 Hz, 2H), 7.87 (d, J=2.8 Hz, 1H), 7.59-7.47 (m, 2H), 7.45-7.32 (m, 3H), 7.30-7.09 (m, 2H).
  • Figure US20170217923A1-20170803-C02156
  • To a mixture of 4-chloro-6-methoxy-2-(pyridin-3-yl)quinazoline (0.50 g, 1.84 mmol) and 5′-fluorospiro[[1,3]dioxolane-2,3′-indolin]-2′-one (0.42 g, 2.02 mmol) in dry DMSO (4 mL) was added KOH powder (0.11 g, 2.02 mmol). The reaction mixture was stirred for 15 h at room temperature and then the reaction mixture was poured into water. The aqueous layer was washed with ethyl acetate (2×20 mL) and the resulting aqueous layer was acidified with 5N HCl to give a precipitate. The solid was filtered to give 2-(5-fluoro-2-(6-methoxy-2-(pyridin-3-yl)quinazolin-4-ylamino)phenyl)-1,3-dioxolane-2-carboxylic acid as a light yellow powder (0.27 g, 0.58 mmol, 32%). LCMS m/z=432 (M+1) (Method C) 1H NMR (300 MHz, DMSO) δ 9.50-9.38 (m, 2H), 8.69-8.59 (m, 2H), 8.42 (dd, J=9.7, 5.3 Hz, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.64 (d, J=2.6 Hz, 1H), 7.61-7.41 (m, 4H), 4.25-4.11 (m, 4H), 3.98 (s, 3H).
  • Figure US20170217923A1-20170803-C02157
  • In a 50 mL round-bottomed flask was added 2,4-dichloro-6-iodoquinazoline (0.52 g, 1.6 mmol), 3-chloro-4-fluoroaniline (0.30 g, 2.1 mmol), and sodium acetate (0.20 g, 2.4 mmol) in THF (6 mL) and water (2 mL) to give a brown suspension. After being stirred at room temperature for 6 days, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL), dried over Na2SO4, filtered and concentrated. The resulting product was washed with CH2Cl2 and dried to give 0.51 g of 2-chloro-N-(3-chloro-4-fluorophenyl)-6-iodoquinazolin-4-amine as a light brown solid in a 73% yield. 1H NMR (300 MHz, DMSO) δ 10.29 (s, 1H), 8.95 (s, 1H), 8.14 (dd, J=1.5, 9.0 Hz, 1H), 8.06 (dd, J=2.7, 6.6 Hz, 1H), 7.81-7.76 (m, 1H), 7.52-7.46 (m, 2H).
  • In a 50 mL round-bottomed flask was added 2-chloro-N-(3-chloro-4-fluorophenyl)-6-iodoquinazolin-4-amine (200 mg, 0.46 mmol), N,N-dimethylpropargylamine (99 mL, 0.92 mmol), NEt3 (0.26 mL, 1.84 mmol), CuI (0.88 mg, 4.6 mmol) and PdCl2(PPh3)2 (6.5 mg, 9.2 mmol) in DMF (3 mL) to give a light yellow suspension. The mixture was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was diluted with water (10 mL) and ethyl acetate (10 mL) and then a precipitate formed. The resulting precipitate was removed by filtration through Celite. The filtrate was extracted with ethyl acetate (2×10 mL). The combined organic layer was washed with water (1×15 mL) and brine (1×15 mL) and was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with CH2Cl2/MeOH 1:0 to 9:1). The desired product was washed with CH2Cl2 to give 61 mg of 2-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amine as pale yellow solid in a 34% yield. LCMS m/z=389 (M+1) (Method C) (retention time=2.24 min). 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 8.68 (s, 1H), 8.07 (dd, J=2.7, 6.9 Hz, 1H), 7.86 (dd, J=1.8, 8.7 Hz, 1H), 7.81-7.70 (m, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.49 (t, J=9.2 Hz, 1H), 3.52 (s, 2H), 2.28 (s, 6H).
  • In a 50 mL round-bottomed flask was added 2-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amine (61 mg, 0.16 mmol), 3-pyridineboronic acid (25 mg, 0.20 mmol), K2CO3 (0.11 mg, 0.78 mmol) and PdCl2(PPh3)2 (5.5 mg, 7.8 mM) in dioxane (2 mL) to give a yellow suspension. The mixture was heated at reflux for 3 h under argon. After cooling to room temperature, water (10 mL) and ethyl acetate (10 mL) were added to the mixture to form a precipitate. The resulting precipitate was filtered through Celite. The filtrate was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with water (1×15 mL) and brine (1×15 mL) and then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with AcOEt/MeOH 1:0 to 9:1). The desired product was washed with CH2Cl2 to give 25 mg of N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)-2-(pyridin-3-yl)quinazolin-4-amine as a light brown solid in 37% yield. LCMS m/z=432 (M+1) (Method C) (retention time=1.86 min). 1H NMR (300 MHz, DMSO) δ 10.13 (s, 1H), 9.51 (s, 1H), 8.77-8.56 (m, 3H), 8.26 (dd, J=6.9, 2.5 Hz, 1H), 8.02-7.78 (m, 3H), 7.64-7.47 (m, 2H), 3.54 (s, 2H), 2.30 (s, 6H).
  • Figure US20170217923A1-20170803-C02158
  • A mixture of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (200 mg, 0.283 mmol), (isocyanatomethyl)benzene (5 mL) and Et3N (57 mg, 0.283 mmol) in tetrahydrofuran (THF) (10 mL) was stirred at room temperature overnight. Water (10 mL) was added to the above mixture and the mixture was concentrated in vacuo. The precipitate was collected by filtration and washed with water (6 mL×2) to afford 72 mg of the desired product as a white solid in a yield 26.0%. LCMS: rt=1.829 min, [MH]+=491.1 1H-NMR (400 MHz, DMSO-d6): δ 13.05 (s, 1H), 9.63 (s, 1H), 9.07 (d, J=8.5 Hz, 1H), 8.87 (d, J=8.0 Hz, 1H), 8.79 (d, J=3.7 Hz, 1H), 8.59 (t, J=6.1 Hz, 1H), 8.49 (s, 1H), 8.02-7.89 (m, 4H), 7.82-7.68 (m, 3H), 7.46-7.22 (m, 6H), 4.35 (d, J=6.1 Hz, 2H).
  • Figure US20170217923A1-20170803-C02159
  • 4-(2-carbamoylphenylamino)-2-(pyridin-3-yl)quinazolin-6-yl ethylcarbamate was synthesized in a similar manner to that described for 4-(2-carbamoylphenylamino)-2-(pyridin-3-yl)quinazolin-6-yl benzylcarbamate substituting isocyanatoethane for (isocyanatomethyl)benzene. The resulting product was analyzed by LCMS: rt=1.11 min, [M+1]+=429.0. 1H-NMR (400 MHz, DMSO-d6): δ 13.06 (s, 1H), 9.66 (s, 1H), 9.10 (d, J=8.3 Hz, 1H), 8.87-8.80 (m, 2H), 8.51 (s, 1H), 8.06-7.94 (m, 4H), 7.88 (s, 1H), 7.79-7.63 (m, 3H), 7.24 (t, J=7.6 Hz, 1H), 3.22-3.11 (m, 2H), 1.14 (t, J=7.2 Hz, 3H).
  • Figure US20170217923A1-20170803-C02160
  • A mixture of 4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazoline-6-carbonitrile (1.5 g, 4.0 mmol) in HCl (conc, 25 mL) was heated to 100° C. and stirred overnight. After cooling and filtration, the solid was washed with water (10 mL) twice to give 1.4 g of the desired product 4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazoline-6-carboxylic acid as a yellow solid in a 89.0% yield. LCMS: r.t=1.271 min, [MH]+=394.9
  • A mixture of 4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazoline-6-carboxylic acid (900 mg, 2.4 mmol), DIPEA (620 mg, 4.8 mmol) and HATU (1.4 g, 3.6 mmol) in DMF (10 mL) was pre-stirred for 20 min, and 2,2,2-trifluoro-N-methylethanamine (360 mg, 2.4 mmol) was added in one portion. The resulting mixture was stirred at room temperature overnight. Water (80 mL) was added and a precipitate formed which was collected and purified by prep-HPLC to afford 490 mg of the desired product 4-(3-chloro-4-fluorophenylamino)-N-methyl-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamide as a white solid in 42.0% yield. LCMS: r.t=1.970 min, [MH]+=490.0 1H-NMR (400 MHz, DMSO-d6): δ 10.79 (brs, 1H), 9.59 (s, 1H), 9.19 (d, J=7.6 Hz, 1H), 9.04 (d, J=4.8 Hz, 1H), 8.90 (s, 1H), 8.22-8.00 (m, 5H), 7.62 (t, J=9.2 Hz, 1H), 4.55-4.52 (m, 2H), 3.22 (s, 3H).
  • To a mixture of 4-(3-chloro-4-fluorophenylamino)-N-methyl-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamide (60 mg, 0.12 mmol) in THF (1 mL) was added BH3-THF (2 mol/L, 1 mL). The mixture was stirred at room temperature overnight. Methanol (0.2 mL) was added to quench the reaction mixture. The mixture was purified by prep-HPLC to give the desired product N-(3-chloro-4-fluorophenyl)-6-((methyl(2,2,2-trifluoroethyl)amino)methyl)-2-(pyridin-3-yl)quinazolin-4-amine (GL001H-3309) as a white solid 15 mg in a yield of 26.0%. LCMS: r.t=2.154 min, [MH]+=476.1. 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.53 (s, 1H), 8.70-8.66 (m, 2H), 8.44 (s, 1H), 8.27-8.25 (m, 1H), 7.93-7.91 (m, 3H), 7.57-7.55 (m, 2H), 3.93 (s, 2H), 3.39-3.32 (m, 2H), 2.40 (s, 3H).
    • Synthesis of 4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamide (compound 1139)
  • 4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamide was synthesized in a similar manner to that described for 4-(3-chloro-4-fluorophenylamino)-N-methyl-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamide substituting 2,2,2-trifluoroethylamine for 2,2,2-trifluoro-N-methylethylamine. The resulting product was analyzed. LCMS: r.t=1.934 min, [M+1]+=476.0. 1H-NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.54 (s, 1H), 9.32 (t, J=6.1 Hz, 1H), 9.14 (s, 1H), 8.72 (d, J=4.6 Hz, 1H), 8.68 (d, J=8.0 Hz, 1H), 8.32 (d, J=8.7 Hz, 1H), 8.27 (dd, J=6.7, 2.2 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.96-7.90 (m, 1H), 7.62-7.51 (m, 2H), 4.27-4.14 (m, 2H).
  • Figure US20170217923A1-20170803-C02161
    • Method E for Cyclization
  • E1: Sodium methoxide/Toluene
    • E2: NaOH/EtOH Method G for Coupling Conditions
  • G1: i-PrOH/85-100° C.
    • G2: THF/reflux
  • G3: i-AmOH/100-130° C.
    • G4: MeOH/microwave/150° C.
  • G5: i-AmOH/microwave/150° C.
    • G6: THF/Et3N/reflux
  • Figure US20170217923A1-20170803-C02162
    • Method D: N-(2-carbamoylphenyl) pyridazine-4-carboxamide (iii-c)
  • A mixture of pyridazine-4-carboxylic acid (500 mg, 4.0 mmol, 1.0 eq.), 2-aminobenzamide (603 mg, 4.4 mmol, 1.1 eq.) and HBTU (3.0 g, 8.0 mmol, 2.0 eq.) was suspended in 15 mL of DMF. DIPEA (2.0 mL, 1.56 g, 12.0 mmol, 3.0 eq.) was added dropwise at room temperature and was stirred over night. After quenching with water, the resulting precipitate was collected and washed with a small amount of DCM. A white solid (388 mg) was obtained, LCMS m/z=243.1 (M+1) (Method B) (retention time=0.99 min), was used in the next step without further purification.
    • Method E1: 2-(pyridazin-4-yl) quinazolin-4(3H)-one (iv-f)
  • A 100 mL round-bottom flask equipped with a Dean-Stark trap was charged with a mixture of N-(2-carbamoylphenyl) pyridazine-4-carboxamide (300 mg, 1.0 eq.), sodium methoxide (401 mg, 7.4 mmol, 6.0 eq.) and 10 mL of anhydrous toluene. The reaction mixture was heated to 110° C. and refluxed overnight. After cooling, the volatiles were removed in vacuo and the residue was quenched with a saturated aqueous solution of NH4Cl (10 mL). The pH of the mixture was adjusted to 3 with 10% HCl in water. The solution was extracted with DCM (50 ml×3). The combined organic layers were washed with brine, dried over Na2SO4. After filtration and evaporation, 88 mg of a yellow solid was obtained, LCMS m/z=225.1 (M+1) (Method A) (retention time=1.10 min) which was used in the next step without further purification.
    • Method F5: 4-chloro-2-(pyridazin-4-yl)quinazoline (v-f)
  • A 100-mL round-bottom flask was charged with 2-(pyridazin-4-yl) quinazolin-4(3H)-one (30 mg) which was suspended in 3 mL of POCl3. The reaction mixture was heated to reflux for 1 h. The reaction mixture turned to a clear brown solution. After cooling, 50 mL of ice/water was carefully added. An aqueous ammonia solution (25% by weight in water) was added dropwise to the mixture with stirring until the pH of the mixture was adjusted to 7-8. An internal temperature of 0° C. was maintained by the addition of ice. The mixture was warmed to room temperature and extracted with DCM (50 ml×3). The combined organic layers were washed with brine, dried over Na2SO4. After filtration and evaporation, 32 mg was obtained as a light brown solid. LCMS m/z=242.9 (M+1) (Method B) (retention time=1.65 min). The solid was used directly in the next step without further purification.
    • Method G1: N-(3,4-difluorophenyl)-2-(pyridazin-4-yl)quinazolin-4-amine (vi-r)
  • (This method is representative of method G1, G2, and G3. These three methods can be implemented in a similar way except for substitution of the appropriate solvent and temperature) The mixture of 4-chloro-2-(pyridazin-4-yl)quinazoline (10 mg, 0.041 mmol, 1 eq.) and 3,4-difluorobenzenamine (11 mg, 0.082 mmol, 2 eq.) was suspended in i-PrOH. The mixture was heated at 85° C. overnight. After cooling, the resulting precipitate was filtered and purified on HPLC (Condition C). 7.3 mg of N-(3,4-difluorophenyl)-2-(pyridazin-4-yl)quinazolin-4-amine was obtained (yield 53%). LCMS m/z=336.0 (M+1) (Method B) (retention time=1.731 min). 1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 10.00 (dd, J=2.2, 1.3 Hz, 1H), 9.44 (dd, J=5.4, 1.2 Hz, 1H), 8.59 (d, J=8.1 Hz, 1H), 8.39 (dd, J=5.4, 2.4 Hz, 1H), 8.05-8.13 (m, 1H), 7.99 (s, 1H), 7.97 (d, J=3.6 Hz, 1H), 7.72-7.79 (m, 2H), 7.51-7.61 (m, 1H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 1 and 64 (prepared according to method procedure A-G as designated).
  • TABLE 21
    Molec- Purity Method
    Num- Salt ular 1H-NMR LCMS per- for
    ber Product type Mass 1H-NMR Solvent LCMS Protocol cent Coupling
    1140
    Figure US20170217923A1-20170803-C02163
         		402.66 1H-NMR (400 MHz, CD3OD): δ 9.40 (s, 1H), 9.84-9.86 (m, 2H), 8.52 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.84 (dd, J = 9.2, 2.4 Hz, 1H), 7.66-7.67 (m, 2H). CD3OD 402.0, 404.0, 405.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1141
    Figure US20170217923A1-20170803-C02164
         		386.21 1H-NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 9.49 (s, 1H), 8.89 (d, J = 10.8 Hz, 2H), 8.75 (d, J = 8.8 Hz, 1H), 8.44 (dd, J = 6.8, 2.4 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.94-7.99 (m, 1H), 7.87 (dd, J = 8.8, 2.0 Hz, 1H), 7.56 (t, J = 9.2 Hz, 1H). DMSO 386.0, 388.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1142
    Figure US20170217923A1-20170803-C02165
         		369.76 1H-NMR (400 MHz, CD3OD): δ 9.40 (s, 1H), 8.76 (d, J = 10.8 Hz, 2H), 8.40 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.80-7.86 (m, 1H), 7.68 (dd, J = 8.8, 1.6 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.33 (q, J = 9.2 Hz, 1H). CD3OD 370.0, 372.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1143
    Figure US20170217923A1-20170803-C02166
         		376.8  1H-NMR (400 MHz, CD3OD): δ 9.55 (s, 1H), 8.80 (d, J = 7.2 Hz, 3H), 8.26 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H). CD3OD 377.1, 379.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1144
    Figure US20170217923A1-20170803-C02167
         		358.78 1H-NMR (400 MHz, CD3OD): δ 9.39 (d, J = 1.6 Hz, 1H), 8.79 (d, J = 6.8 Hz, 2H), 8.47 (d, J = 9.2 Hz, 1H), 8.20 (s, 1H), 8.05-8.10 (m, 2H), 7.77 (dd, J = 8.8, 2.0 Hz, 1H), 7.63-7.65 (m, 2H). CD3OD 359.0, 361.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1145
    Figure US20170217923A1-20170803-C02168
         		399.78 1H-NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 9.52 (d, J = 1.2 Hz, 1H), 8.86 (t, J = 6.0 Hz, 2H), 8.77 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 15.6 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 74.0 Hz, 1H), 7.04 (dd, J = 8.0, 1.6 Hz, 1H). DMSO 400.0, 402.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1146
    Figure US20170217923A1-20170803-C02169
         		402.66 1H-NMR (400 MHz, CD3OD): δ 9.40 (s, 1H), 8.85-8.88 (m, 2H), 8.53 (d, J = 9.2 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.80-7.88 (m, 3H), 7.46 (s, 1H). CD3OD 401.9, 403.9, 405.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1147
    Figure US20170217923A1-20170803-C02170
         		377.78 1H-NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 9.58 (s, 1H), 9.14 (d, J = 8.4 Hz, 1H), 8.87 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.07- 8.12 (m, 2H), 7.86 (dd, J = 8.8, 2.0 Hz, 1H), 7.77 (t, J = 8.8 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H). DMSO 378.1, 380.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1148
    Figure US20170217923A1-20170803-C02171
         		381.79 1H-NMR (400 MHz, DMSO-d6): δ 11.69- 11.49 (m, 1H), 9.40 (d, J = 1.2 Hz, 1H), 9.00-8.86 (m, 3H), 8.24 (dd, J = 6.6, 2.1 Hz, 1H), 7.91 (ddd, J = 8.9, 4.2, 2.6 Hz, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.61 (t, J = 9.0 Hz, 1H), 7.49 (dd, J = 9.2, 2.3 Hz, 1H), 4.00 (s, 3H). DMSO 382.1, 384.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1149
    Figure US20170217923A1-20170803-C02172
         		395.36 1H-NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 9.57 (d, J = 1.4 Hz, 1H), 8.83-8.74 (m, 2H), 8.57 (d, J = 9.1 Hz, 1H), 8.28 (t, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.2, 1.2 Hz, 1H), 7.50-7.32 (m, 3H), 7.31 (t, J = 74.0 Hz, 1H), 6.94 (dd, J = 8.0, 2.2 Hz, 1H), 3.98 (s, 3H). DMSO 396.1, (M + 1), 397.2 (M + 2) Method B (NH4HCO3) 95 Method C, G1
    1150
    Figure US20170217923A1-20170803-C02173
         		383.33 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.57 (s, 1H), 8.80 (dd, J = 19.8, 1.7 Hz, 2H), 8.72-8.66 (m, 1H), 8.50 (s, 1H), 8.07- 7.94 (m, 3H), 7.75 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H). DMSO 384.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1151
    Figure US20170217923A1-20170803-C02174
         		385.42 1H-NMR (400 MHz, DMSO-d6): δ 13.01 (s, 1H), 10.04 (s, 1H), 9.40 (d, J = 5.4 Hz, 1H), 9.20 (d, J = 8.4 Hz, 1H), 8.48 (s, 1H), 8.42 (dd, J = 5.3, 1.9 Hz, 1H), 8.04-7.94 (m, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.13 (s, 1H), 3.15 (s, 6H). DMSO 386.0 (M + 1) Method A (TFA) 95 Method D, G1
    1152
    Figure US20170217923A1-20170803-C02175
         		HCl 394.83 1H-NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 9.97 (d, J = 1.1 Hz, 1H), 9.55 (d, J = 5.5 Hz, 1H), 8.61 (dd, J = 5.5, 2.2 Hz, 1H), 8.15 (dd, J = 6.8, 2.6 Hz, 1H), 8.08 (d, J = 9.3 Hz, 1H), 7.94 (ddd, J = 8.9, 4.3, 2.6 Hz, 1H), 7.74 (s, 1H), 7.62 (dd, J = 9.4, 2.5 Hz, 1H), 7.56 (t, J = 9.1 Hz, 1H), 3.16 (s, 6H). DMSO 395.1, 397.1 (M + 1) Method A (TFA) 95 Method D, G1
    1153
    Figure US20170217923A1-20170803-C02176
         		HCl 408.4 1H-NMR (400 MHz, DMSO-d6): δ 10.71 (brs, 1H), 10.01-9.99 (m, 1H), 9.52 (dd, J = 5.5, 1.0 Hz, 1H), 8.60 (dd, J = 5.5, 2.3 Hz, 1H), 8.07 ((d, J = 9.2 Hz 1H), 7.85-7.78 (m, 2H), 7.71 (s, 1H), 7.65 (dd, J = 9.3, 2.5 Hz, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.33 (t, J = 74.0 Hz, 1H), 7.09 (dd, J = 8.1, 2.1 Hz, 1H), 3.17 (s, 6H). DMSO 409.1 (M + 1) Method A (TFA) 95 Method D, G1
    1154
    Figure US20170217923A1-20170803-C02177
         		372.38 1H-NMR (400 MHz, DMSO-d6): δ 13.13 (s, 1H), 9.63 (d, J = 1.2 Hz, 1H), 9.34 (d, J = 7.6 Hz, 1H), 8.91-8.84 (m, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.49 (s, 1H), 8.12 (d, J = 9.6 Hz, 1H), 8.03-7.85 (m, 2H), 7.75-7.61 (m, 1H), 7.48-7.30 (m, 2H), 7.28-7.06 (m, 1H), 3.99 (s, 3H). DMSO (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1155
    Figure US20170217923A1-20170803-C02178
         		381.79 1H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.99-9.95 (m, 1H), 9.42 (dd, J = 5.2, 1.2 Hz, 1H), 8.58-8.51 (m, 1H), 8.35 (dd, J = 5.2, 2.4 Hz, 1H), 8.21 (dd, J = 6.8, 2.4 Hz, 1H), 7.93 (ddd, J = 8.8, 4.2, 2.7 Hz, 1H), 7.53 (dd, J = 11.7, 6.4 Hz, 1H), 7.32 (dd, J = 6.6, 2.6 Hz, 2H), 3.97 (s, 3H). DMSO 382.0, 384.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1156
    Figure US20170217923A1-20170803-C02179
         		395.36 1H-NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 10.01 (d, J = 1.3 Hz, 1H), 9.43 (dd, J = 5.2, 1.2 Hz, 1H), 8.55 (d, J = 10.0 Hz, 1H), 8.40 (dd, J = 5.2, 2.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.86-7.77 (m, 1H), 7.55-7.35 (m, 3H), 7.32 (t, J = 74.0 Hz, 1H), 7.01 (dd, J = 8.0, 2.0 Hz, 1H), 3.99 (s, 3H). DMSO 396.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1157
    Figure US20170217923A1-20170803-C02180
         		376.80 1H-NMR (400 MHz, DMSO-d6): δ 13.34 (s, 1H), 9.61 (s, 1H), 9.28 (d, J = 8.4 Hz, 1H), 8.87 (s, 1H), 8.80 (s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 7.94- 8.06 (m, 4H), 7.70 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H). DMSO 377.0, 379.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1158
    Figure US20170217923A1-20170803-C02181
         		358.78 1H-NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.54 (s, 1H), 8.77- 8.84 (m, 4H), 8.32 (d, J = 8.0 Hz, 1H), 8.00-8.03 (m, 2H), 7.62-7.70 (m, 2H). DMSO 359.0, 361.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1159
    Figure US20170217923A1-20170803-C02182
         		386.21 1H-NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H), 9.50 (s, 1H), 8.83 8.87 (m, 3H), 8.47-8.49 (m, 1H), 7.96-8.06 (m, 3H), 7.54 (t, J = 9.2 Hz, 1H). DMSO 386.0, 388.0, 390.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1160
    Figure US20170217923A1-20170803-C02183
         		402.66 1H-NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 9.53 (s, 1H), 8.84- 8.88 (m, 3H), 8.62 (d, J = 2.0 Hz, 1H), 8.01-8.07 (m, 3H), 7.73 (d, J = 8.8 Hz, 1H). DMSO 401.9, 403.9, 406.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1161
    Figure US20170217923A1-20170803-C02184
         		402.66 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.55 (d, J = 1.6 Hz, 1H), 8.87-8.88 (m, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 2.0 Hz, 2H), 8.00-8.07 (m, 2H), 7.40 (t, J = 1.6 Hz, 1H). DMSO 401.9, 403.8, 405.8 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1162
    Figure US20170217923A1-20170803-C02185
         		468.25 1H-NMR (400 MHz, DMSO-d6): δ 13.36 (s, 1H), 9.59 (d, J = 1.2 Hz, 1H), 9.15-9.12 (m, 1H), 8.90-8.85 (m, 2H), 8.68 (d, J = 1.2 Hz, 1H), 8.52 (s, 1H), 8.28-8.25 (m, 1H), 8.07 (s, 1H), 7.99- 7.96 (m, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.74-7.70 (m, 1H), 7.28 (t, J = 7.6 Hz, 1H). DMSO 469.0 (M + 1) Method B (NH4HCO3) 90 Method C, G1
    1163
    Figure US20170217923A1-20170803-C02186
         		491.23 1H-NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 9.32 (s, 1H), 9.07 (s, 1H), 8.74 (s, 2H), 8.16 (dd, J = 8.0, 1.6 Hz, 1H), 7.87 (s, 1H), 7.74-7.64 (m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 74.0 Hz, 1H), 6.95- 6.92 (m, 1H). DMSO 492.0 (M + 1) Method B (NH4HCO3) 90 Method C, G1
    1164
    Figure US20170217923A1-20170803-C02187
         		477.66 1H-NMR (400 MHz, DMSO-d6): δ 11.48 (s, 1H), 9.42 (s, 1H), 9.34 (s, 1H), 8.95-8.93 (m, 2H), 8.35-8.30 (m, 2H), 7.97- 7.90 (m, 2H), 7.60 (t, J = 9.0 Hz, 1H). DMSO 478.0, 480.0 (M + 1) Method B (NH4HCO3) 90 Method C, G1
    1165
    Figure US20170217923A1-20170803-C02188
         		413.81 1H-NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 9.99 (s, 1H), 9.40 (d, J = 5.6 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.36 (dd, J = 5.2, 2.0 Hz, 1H), 7.87 (m, 1H), 7.81 (m, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.30 (t, J = 74.0 Hz, 1H), 8.36 (dd, J = 8.4, 2.0 Hz, 1H), 2.70 (s, 3H). DMSO 414.1, 416.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1166
    Figure US20170217923A1-20170803-C02189
         		400.24 1H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 10.01 (s, 1H), 9.46 (d, (d, J = 5.2 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.39 (dd, J = 5.4, 2.2 Hz, 1H), 8.20 (dd, J = 7.2, 2.6 Hz, 1H), 7.95-7.91 (m, 1H), 7.89 (s, 1H), 7.57 (t, J = 9.0 Hz, 1H), 2.75 (s, 3H). DMSO 400.0, 402.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1167
    Figure US20170217923A1-20170803-C02190
         		409.39 1H-NMR (400 MHz, DMSO-d6): δ 10.05- 10.3 (m, 2H), 9.45 (dd, J = 5.2, 1.2 Hz, 1H), 8.42 (dd, J = 5.2, 1.2 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.97-7.94 (m, 2H), 7.86 (dd, J = 8.0, 1.2 Hz, 1H), 7.66-7.60 (m, 2H), 7.38 (t, J = 74.0 Hz, 1H), 7.10- 7.08 (m, 1H), 4.32 (q, J = 6.8 Hz, 2H), 1.51 (t, J = 7.0 Hz, 3H). DMSO 410.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1168
    Figure US20170217923A1-20170803-C02191
         		379.36 1H-NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 10.07 (d, J = 2.0 Hz, 1H), 9.44 (dd, J = 5.2, 2.4 Hz, 1H), 8.48-8.44 (m, 2H), 7.93 (t, J = 2.0 Hz, 1H), 7.86-7.84 (m, 2H), 7.66-7.62 (m, 1H), 7.54 (t, J = 8.4 Hz, 1H), 7.32 (t, J = 74.0 Hz, 1H), 7.02 (dd, J = 8.0, 2.4 Hz, 1H), 2.77 (s, 3H). DMSO 380.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1169
    Figure US20170217923A1-20170803-C02192
         		444.23 1H-NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 9.55 (s, 1H), 8.98 (s, 1H), 8.79 (d, J = 12.8 Hz, 2H), 8.26 (s, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.92- 7.88 (m, 2H), 7.52-7.50 (m, 1H), 7.32 (t, J = 71.6 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H). DMSO 444.0, 446.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1170
    Figure US20170217923A1-20170803-C02193
         		430.66 1H-NMR (400 MHz, DMSO-d6): δ 10.11 (s, 1H), 9.52 (s, 1H), 8.89 (d, J = 1.2 Hz, 1H), 8.83 (s, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.56 (dd, J = 6.8, 2.4 Hz, 1H), 8.05 (dd, J = 9.2, 2.0 Hz, 1H), 8.02- 7.96 (m, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.49 (t, J = 9.2 Hz, 1H). DMSO 430.0, 432.0, 434.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1171
    Figure US20170217923A1-20170803-C02194
         		386.41 1H-NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H), 9.63 (s, 2H), 9.33 (s, 1H), 8.95 (d, J = 8.0 Hz, 1H), 8.50 (s, 1H), 7.99- 7.94 (m, 3H), 7.76-7.71 (m, 1H), 7.62-7.59 (m, 2H), 7.24 (t, J = 7.4 Hz, 1H), 4.23 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H). DMSO 387.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1172
    Figure US20170217923A1-20170803-C02195
         		372.38 1H-NMR (400 MHz, DMSO-d6): δ 13.11 (s, 1H), 9.61 (s, 2H), 9.34 (s, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.49 (s, 1H), 7.98- 7.95 (m, 3H), 7.72 (t, J = 8.0 Hz, 1H), 7.62-7.60 (m, 2H), 7.24 (t, J = 7.6 Hz, 1H), 3.97 (s, 3H). DMSO 373.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1173
    Figure US20170217923A1-20170803-C02196
         		HCl 379.32 1H-NMR (400 MHz, DMSO-d6): δ 10.55 (brs, 1H), 9.59 (s, 2H), 9.35 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.09-8.07 (m, 1H), 8.00-7.96 (m, 2H), 7.76- 7.72 (m, 1H), 7.67 (dd, J = 8.8, 2.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H). DMSO 380.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1174
    Figure US20170217923A1-20170803-C02197
         		HCl 464.47 1H-NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 9.59 (s, 1H), 8.80 (m, 2H), 8.62 (d, J = 7.6 Hz, 1H), 8.30 (s, 1H), 7.90 (s, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.53-7.45 (m, 1H), 7.39-6.86 (m, 1H), 7.30 (t, J = 74.1 Hz, 1H), 3.73 (s, 2H), 3.63- 3.58 (m, 4H), 2.48-2.43 (m, 4H). DMSO 465.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1175
    Figure US20170217923A1-20170803-C02198
         		357.37 1H-NMR (400 MHz, DMSO-d6): δ 9.70 (s, 1H), 9.43 (d, J = 8.4 Hz, 1H), 8.90 (s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.60-7.65 (m, 2H), 7.09-7.13 (m, 3H), 2.76 (s, 3H). DMSO 358.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1176
    Figure US20170217923A1-20170803-C02199
         		365.79 1H-NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.62 (s, 1H), 8.85 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.03-8.07 (m, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 9.2 Hz, 1H), 2.75 (s, 3H). DMSO 366.0, 368.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1177
    Figure US20170217923A1-20170803-C02200
         		379.36 1H-NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.64 (s, 1H), 8.83 (s, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.38 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.32 (t, J = 74.0 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 2.75 (s, 3H). DMSO 380.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1178
    Figure US20170217923A1-20170803-C02201
         		382.25 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.62 (s, 1H), 8.86 (t, J = 2.4 Hz, 1H), 8.78 (t, J = 3.2 Hz, 2H), 8.52 (d, J = 8.4 Hz, 1H), 8.10-8.13 (m, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 2.75 (s, 3H). DMSO 381.9, 383.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1179
    Figure US20170217923A1-20170803-C02202
         		349.34 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.60 (s, 1H), 8.87 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.50-8.60 (m, 2H), 7.80-7.85 (m, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.46- 7.54 (m, 1H), 2.74 (s, 3H). DMSO 350.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1180
    Figure US20170217923A1-20170803-C02203
         		382.25 1H-NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.62 (s, 1H), 8.85 (s, 1H), 8.77 (d, J = 2.8 Hz, 1H), 8.47-8.52 (m, 3H), 7.81 (d, J = 3.2 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 1.6 Hz, 1H), 2.51 (s, 3H). DMSO 381.9, 383.9 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1181
    Figure US20170217923A1-20170803-C02204
         		338.37 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.64 (s, 1H), 8.86 (d, J = 9.2 Hz, 2H), 8.78 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.61-7.65 (m, 3H), 2.76 (s, 3H). DMSO 339.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1182
    Figure US20170217923A1-20170803-C02205
         		383.33 1H-NMR (400 MHz DMSO-d6): δ 10.24 (s, 1H), 9.99 (s, 1H), 9.41 (d, J = 5.2 Hz, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.36-8.38 (m, 1H), 8.10 (s, 1H), 7.95-7.98 (m, 3H), 7.73- 7.74 (m, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H). DMSO 384.2 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1183
    Figure US20170217923A1-20170803-C02206
         		365.34 1H-NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 10.01(s, 1H), 9.41- 9.43 (m, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.39-8.41 (m, 1H), 7.93-7.97 (m, 3H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (m, 1H), 7.54- 7.56 (m, 1H), 7.32 (t, J = 74.0 Hz, 1H), 7.02-7.04 (m, 1H). DMSO 366.2 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1184
    Figure US20170217923A1-20170803-C02207
         		398.25 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 9.96 (s, 1H), 9.44 (d, J = 4.8 Hz, 1H), 8.40- 8.41 (m, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.99-8.02 (m, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.56-7.58 (m, 1H), 3.99 (s, 3H). DMSO 398.0, 400.0, 402.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1185
    Figure US20170217923A1-20170803-C02208
         		381.79 1H-NMR (400 MHz, DMSO-d6): δ 9.92 (s, 1H), 9.36-9.38 (m, 1H), 8.27-8.29 (m, 1H), 8.14- 8.16 (m, 1H), 7.51 (s, 1H), 7.83-7.91 (m, 3H), 7.51-7.56 (m, 2H), 3.97 (s, 3H). DMSO 382.1, 384.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1186
    Figure US20170217923A1-20170803-C02209
         		365.34 1H-NMR (400 MHz, DMSO6-d6): δ 9.95- 10.00 (m, 2H), 9.40 (d, J = 5.6 Hz, 1H), 8.32-8.33 (m, 1H), 8.06 (m, 1H), 7.96 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.69 (m, 1H), 7.54-7.59 (m, 2H), 3.98 (s, 3H). DMSO 366.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1187
    Figure US20170217923A1-20170803-C02210
         		354.36 1H-NMR (400 MHz, DMSO-d6): δ 10.00 (s, 1H), 9.90 (m, 1H), 9.35- 9.36 (m, 1H), 8.23-8.30 (m, 3H), 7.84-7.90 (m, 2H), 7.62-7.71 (m, 2H), 7.54-7.57 (m, 1H), 3.96 (s, 3H). DMSO 355.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1188
    Figure US20170217923A1-20170803-C02211
         		413.35 1H-NMR (400 MHz, DMSO-d6): δ 9.96-10.0 (m, 2H), 8.39-8.40 (m, 1H), 8.31-8.33 (m, 1H), 8.07 (s, 1H), 7.88-7.96 (m, 3H), 7.57-7.67 (m, 2H), 7.22 (d, J = 8.0 Hz, 1H), 4.01 (s, 3H). DMSO 414.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1189
    Figure US20170217923A1-20170803-C02212
         		373.36 1H-NMR (400 MHz, DMSO-d6): δ 12.15 (s, 1H), 10.02 (s, 1H), 9.41 (d, J = 5.2 Hz, 1H), 8.94 (d, J = 7.6 Hz, 1H), 8.41 (m, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.80 (t, J = 8.4 Hz, 1H), 7.60-7.62 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H), 4.01 (s, 3H). DMSO 374.1, 376.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1190
    Figure US20170217923A1-20170803-C02213
         		398.25 1H-NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 9.54 (s, 1H), 8.81-8.82 (m, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 8.8, 2.4 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.92 (d, J = J = 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 3.40 (s, 3H). DMSO 397.9, 400.0, 401.9 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1191
    Figure US20170217923A1-20170803-C02214
         		381.79 1H-NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 9.52 (s, 1H), 8.81 (m, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.53 (dd, J = 6.8, 2.4 Hz, 1H), 7.98-8.03 (m, 2H), 7.91 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 5.2, 2.4 Hz, 1H), 7.51 (t, J = 8.8 Hz, 1H), 3.40 (s, 3H). DMSO 382.0, 384.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1192
    Figure US20170217923A1-20170803-C02215
         		365.34 1H-NMR (400 MHz, DMSO-d6): δ 9.89 (s, 1H), 9.52-9.53 (m, 1H), 8.81-8.82 (m, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.45- 8.51 (m, 1H), 7.98 (m, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.75-7.78 (m, 1H), 7.47-7.59 (m, 2H), 3.40 (s, 3H). DMSO 366.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1193
    Figure US20170217923A1-20170803-C02216
         		354.36 1H-NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.54 (s, 1H), 8.74- 8.81 (m, 3H), 8.35 (d, J = 8.4 Hz, 1H), 8.04 (m, 1H), 7.92-7.95 (m, 1H), 7.59- 7.69 (m, 3H), 3.40 (s, 3H). DMSO 355.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1194
    Figure US20170217923A1-20170803-C02217
         		398.25 1H-NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 9.55 (d, J = 1.2 Hz, 1H), 8.81 (t, J = 2.0 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.32 (t, J = 1.6 Hz, 1H), 3.40 (s, 3H). DMSO 398.0, 399.9, 402.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1195
    Figure US20170217923A1-20170803-C02218
         		395.36 1H-NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 9.55 (m, 1H), 8.74- 8.79 (m, 2H), 8.25 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 9.2, 2.4 Hz, 1H), 7.48-7.52 (m, 1H), 7.34 (t, J = 74.0 Hz, 1H), 6.96-6.98 (m, 1H), 3.40 (s, 3H). DMSO 396.1 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1196
    Figure US20170217923A1-20170803-C02219
         		377.78 1H-NMR (400 MHz, DMSO-d6): δ 12.26 (s, 1H), 9.94 (s, 1H), 9.41- 9.42 (m, 1H), 8.75 (d, J = 8.0 Hz, 1H,), 8.33-8.34 (m, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.93 (m, 1H), 7.75-7.77 (m, 2H), 7.05- 7.30 (m, 2H). DMSO 378.0, 380.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1197
    Figure US20170217923A1-20170803-C02220
         		343.34 1H-NMR (400 MHz, DMSO-d6): δ 13.86 (s, 1H), 12.39 (s, 1H), 9.62 (d, J = 0.8 Hz, 1H), 9.29 (d, J = 8.0 Hz, 1H), 8.87 (s, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.12 (dd, J = 8.0, 1.6 Hz, 1H), 7.97-8.05 (m, 3H), 7.75-7.79 (m, 2H), 7.24 (t, J = 7.6 Hz, 1H). DMSO 344.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1198
    Figure US20170217923A1-20170803-C02221
         		372.38 1H-NMR (400 MHz, DMSO-d6): δ 13.05 (s, 1H), 9.99 (s, 1H), 9.39 (d, J = 5.2 Hz, 1H), 9.05 (d, J = 8.4 Hz, 1H), 8.47 (s, 1H), 8.36-8.38 (m, 1H), 7.85-7.98 (m, 3H), 7.71 (t, J = 7.6 Hz, 1H), 7.46- 7.60 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 3.95 (s, 3H). DMSO 373.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1199
    Figure US20170217923A1-20170803-C02222
         		376.8  1H-NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 10.00 (s, 1H), 9.44 (d, J = 4.2 Hz, 1H), 8.95 (d, J = 8.4 Hz, 1H), 8.49 (s, 1H), 8.40-8.42 (m, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.91-7.97 (m, 3H), 7.80 (t, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.25 (t, J = 7.2 Hz, 1H). DMSO 377.0, 379.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1200
    Figure US20170217923A1-20170803-C02223
         		399.78 1H-NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 9.98 (s, 1H), 9.42 (d, J = 5.2 Hz, 1H), 8.66 (d, J = 9.2 Hz, 1H), 8.36-8.38 (m, 1H), 8.00 (d, J = 1.5 Hz, 1H), 7.89 (s, 1H), 7.79-7.81 (m, 2H), 7.49-7.57 (m, 1H), 7.31 (t, J = 74.0 Hz, 1H), 7.04 (dd, J = 8.0, 1.2 Hz, 1H). DMSO 400.0, 401.9 (M + 1) Method A (TFA) 95 Method D, G1
    1201
    Figure US20170217923A1-20170803-C02224
         		386.21 1H-NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.43 (d, J = 5.2 Hz, 1H), 8.72 (d, J = 8.8 Hz, 1H), 8.33 (dd, J = 5.6, 2.4 Hz, 1H), 8.21 (dd, J = 6.4, 1.6 Hz, 1H), 7.93-7.98 (m, 2H), 7.78 (dd, J = 8.8, 2.0 Hz, 1H), 7.54 (t, J = 9.2 Hz, 2H). DMSO 386.0 387.8 (M + 1) Method A (TFA) 95 Method D, G1
    1202
    Figure US20170217923A1-20170803-C02225
         		369.76 1H-NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.95 (m, 1H), 9.44- 9.45 (m, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.32-8.34 (m, 1H), 8.02-8.08 (m, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.79 (dd, J = 9.2, 2.4 Hz, 1H), 7.70-7.72 (m, 1H), 7.56 (q, J = 9.2 Hz, 1H). DMSO 369.9, 371.0 (M + 1) Method A (TFA) 95 Method D, G1
    1203
    Figure US20170217923A1-20170803-C02226
         		358.78 1H-NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.92 (s, 1H), 9.42 (d, J = 4.8 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.23-8.33 (m, 3H), 7.96 (d, J = 1.6 Hz, 1H), 7.65-7.79 (m, 3H). DMSO 359.0, 361.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1204
    Figure US20170217923A1-20170803-C02227
         		402.66 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.96 (s, 1H), 9.44 (d, J = 5.2 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.28-8.35 (m, 2H), 7.94-7.99 (m, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H). DMSO 401.9, 403.9, 405.9 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1205
    Figure US20170217923A1-20170803-C02228
         		402.66 1H-NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 9.42 (d, J = 4.8 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 8.07 (s, 2H), 7.92 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H). DMSO 401.9, 403.9, 405.9 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1206
    Figure US20170217923A1-20170803-C02229
         		351.76 1H-NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 9.43 (m, 1H), 9.07 (d, J = 5.2 Hz, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.50 (dd, J = 6.4, 2.0 Hz, 1H), 8.31 (dd, J = 5.2, 0.8 Hz, 1H), 8.00-8.09 (m, 3H), 7.80 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 9.2 Hz, 1H). DMSO 352.0, 354.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1207
    Figure US20170217923A1-20170803-C02230
         		342.35 1H-NMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H), 9.38-9.43 (m, 2H), 9.05 (d, J = 5.2 Hz, 1H), 8.52 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.95-8.04 (m, 4H), 7.82 (t, J = 7.2 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H). DMSO 343.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1208
    Figure US20170217923A1-20170803-C02231
         		365.34 1H-NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 9.37 (d, J = 1.2 Hz, 1H), 9.01 (d, J = 5.2 Hz, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.40 (dd, J = 5.2, 1.2 Hz, 1H), 8.28 (t, J = 1.2 Hz, 1H), 7.92-8.00 (m, 3H), 7.77-7.79 (m, 1H), 7.47-7.52 (m, 1H), 7.34 (t, J = 74.0 Hz, 1H), 6.97 (dd, J = 8.4, 2.4 Hz, 1H). DMSO 366.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1209
    Figure US20170217923A1-20170803-C02232
         		HCl (batch 02) 351.76 1H-NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 9.59 (s, 2H), 9.36 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.22 (dd, J = 6.8, 2.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.90-7.94 (m, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 9.2 Hz, 1H). DMSO 352.0, 354.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1210
    Figure US20170217923A1-20170803-C02233
         		342.35 1H-NMR (400 MHz, DMSO-d6): δ 13.17 (s, 1H), 9.65 (s, 2H), 9.36 (s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.51 (s, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.92- 8.02 (m, 4H), 7.72-7.79 (m, 2H), 7.26 (t, J = 7.6 Hz, 1H). DMSO 343.1 (M + 1) Method B (NH4HCO3) 95 Method D, G4
    1211
    Figure US20170217923A1-20170803-C02234
         		365.34 1H-NMR (400 MHz, DMSO-d6): δ 10.15 (s, 1H), 9.62 (s, 2H), 9.32 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 7.94-7.97 (m, 3H), 7.81 (dd, J = 8.4, 1.2 Hz, 1H), 7.69-7.74 (m, 1H), 7.50-7.55 (m, 1H), 7.31 (t, J = 74.0 Hz, 1H), 7.01 (dd, J = 8.4, 2.4 Hz, 1H). DMSO 366.1 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1212
    Figure US20170217923A1-20170803-C02235
         		399.78 1H-NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 10.01-10.02 (m, 1H), 9.44-9.46 (m, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.40 (dd, J = 5.2, 2.0 Hz, 1H), 8.04 (t, J = 1.6 Hz, 1H), 8.00 (d, J = 3.2 Hz, 2H), 7.94 (m, 1H), 7.76- 7.80 (m, 1H), 7.38 (t, J = 73.6 Hz, 1H), 7.16 (t, J = 2.0 Hz, 1H),. DMSO 400.0, 402.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1213
    Figure US20170217923A1-20170803-C02236
         		398.79 1H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 9.56 (m, 1H), 8.69- 8.72 (m, 2H), 8.59 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.94-7.97 (m, 2H), 7.69-7.73 (m, 1H), 7.55-7.58 (m, 1H), 7.36 (t, J = 73.6 Hz, 1H), 7.13 (t, J = 2.0 Hz, 1H). DMSO 399.0, 401.1 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1214
    Figure US20170217923A1-20170803-C02237
         		365.34 1H-NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.49 (s, 1H), 8.88- 8.92 (m, 3H), 8.16 (d, J = 8.0 Hz, 1H), 8.07 (t, J = 7.6 Hz, 2H), 7.84 (t, J = 8.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 74.0 Hz, 1H), 7.10-7.12 (m, 1H). DMSO 366.1 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1215
    Figure US20170217923A1-20170803-C02238
         		368.22 1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 10.00 (s, 1H), 9.44 (d, J = 5.2 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.38 (dd, J = 2.4, 5.2 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.96-8.00 (m, 3H), 7.73- 7.77 (m, 2H). DMSO 367.8, 369.8, 371.8 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1216
    Figure US20170217923A1-20170803-C02239
         		351.76 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.99 (s, 1H), 9.43 (d, J = 5.2 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.38 (dd, J = 5.2, 2.0 Hz, 1H), 8.22 (dd, J = 7.0, 2.6 Hz, 1H), 7.89-7.93 (m, 3H), 7.68- 7.72 (m, 1H), 7.55 (t, J = 8.6 Hz, 1H). DMSO 351.9, 353.8 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1217
    Figure US20170217923A1-20170803-C02240
         		324.34 1H-NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.99 (dd, J = 2.0, 1.2 Hz, 1H), 9.44 (dd, J = 5.2, 0.8 Hz, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.38-8.40 (m, 2H), 8.28-8.31 (m, 1H), 7.99 (s, 1H), 7.97 (d, J = 3.6 Hz, 1H), 7.66- 7.80 (m, 3H). DMSO 325.0 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1218
    Figure US20170217923A1-20170803-C02241
         		368.22 1H-NMR (400 MHz, DMSO-d6): δ 11.94 (s, 1H), 9.44 (d, J = 0.8 Hz, 1H), 9.06 (d, J = 8.0 Hz, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.97 (t, J = 1.8 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.12 (t, J = 7.4 Hz, 1H), 8.00 (dd, J = 8.6, 2.2 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H). DMSO 367.9, 369.9, 371.8 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1219
    Figure US20170217923A1-20170803-C02242
         		351.76 1H-NMR (400 MHz, DMSO-d6): δ 11.62 (s, 1H), 9.40 (d, J = 0.8 Hz, 1H), 8.60-8.83 (m, 3H), 8.32 (dd, J = 6.6, 2.2 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.09 (t, J = 7.4 Hz, 1H), 7.95-8.00 (m, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 9.2 Hz, 1H). DMSO 352.0, 354.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1220
    Figure US20170217923A1-20170803-C02243
         		335.31 1H-NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 9.48 (d, J = 0.8 Hz, 1H), 8.91-8.93 (m, 2H), 8.81 (d, J = 8.4 Hz, 1H), 8.28-8.33 (m, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.06 (t, J = 7.6 Hz, 1H), 7.77- 7.85 (m, 2H), 7.56-7.63 (m, 1H) DMSO 336.1 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1221
    Figure US20170217923A1-20170803-C02244
         		324.34 1H-NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H), 9.40 (d, J = 1.6 Hz, 1H), 9.10 (d, J = 8.4 Hz, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.97 (t, J = 2.0 Hz, 1H), 8.49 (s, 1H), 8.26- 8.30 (m, 2H), 8.12-8.06 (m, 1H), 7.87-7.91 (m, 1H), 7.76-7.84 (m, 2H) DMSO 324.9 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1222
    Figure US20170217923A1-20170803-C02245
         		368.22 1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.59 (d, J = 1.2 Hz, 1H), 8.85 (t, J = 1.8 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 1.6 Hz, 2H), 7.96-8.02 (m, 2H), 7.74-7.78 (m, 1H), 7.35 (d, J = 1.6 Hz, 1H). DMSO 368.0, 370.0, 372.0 (M + 1) Method B (NH4HCO3) 95 Method D, G6
    1223
    Figure US20170217923A1-20170803-C02246
         		368.22 1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 10.00 (s, 1H), 9.45 (d, J = 5.2 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.38 (dd, J = 5.0, 1.8 Hz, 1H), 8.09 (s, 2H), 7.94 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.70-7.74 (m, 1H), 7.35 (s, 1H). DMSO 368.1, 370.1 (M + 1) Method B (NH4HCO3) 95 Method D, G1
    1224
    Figure US20170217923A1-20170803-C02247
         		413.81 1H-NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1H), 9.63 (s, 1H), 8.82 (s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 7.89- 7.91 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 73.6 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 2.74 (s, 3H). DMSO 414.0 416.0 (M + 1) Method B (NH4HCO3) 95 Method C, G3
    1225
    Figure US20170217923A1-20170803-C02248
         		400.24 1H-NMR (400 MHz, DMSO-d6): δ 9.90 (s, 1H), 9.54 (s, 1H), 8.77- 8.80 (m, 2H), 8.60 (s, 1H), 8.50 (s, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 7.44 (s, 1H), 2.67 (s, 3H). DMSO 400.0 401.9 (M + 1) Method B (NH4HCO3) 95 Method C, G3
    1226
    Figure US20170217923A1-20170803-C02249
         		390.83 1H-NMR (400 MHz, DMSO-d6): δ 13.33 (s, 1H), 9.67 (s, 1H), 9.38 (d, J = 8.0 Hz, 1H), 8.88 (s, 1H), 8.79 (s, 1H), 8.52 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.88 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 2.75 (s, 3H). DMSO 391.0 392.0 (M + 1) Method A (TFA) 95 Method C, G3
    1227
    Figure US20170217923A1-20170803-C02250
         		391.81 1H-NMR (400 MHz, DMSO-d6): δ 16.00 (s, 1H), 9.69 (s, 1H), 9.39 (d, J = 8.4 Hz, 1H), 8.90 (s, 1H), 8.79 (s, 1H), 8.29 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 2.73 (s, 3H). DMSO 392.0 393.1 (M + 1) Method B (TFA) 95 Method C, G3
    1228
    Figure US20170217923A1-20170803-C02251
         		372.81 1H-NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 9.57 (s, 1H), 8.82 (s, 2H), 8.76 (s, 1H), 8.57 (s, 1H), 8.32 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.57- 7.63 (m, 2H), 2.70 (s, 3H). DMSO 373.0 374.0 (M + 1) Method B (NH4HCO3) 95 Method C, G3
    1229
    Figure US20170217923A1-20170803-C02252
         		416.69 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.63 (d, J = 1.2 Hz, 1H), 8.85 (dd, J = 2.4, 1.6 Hz, 1H), 8.78 (d, J = 2.4 Hz,2H), 8.63 (d, J = 1.6 Hz, 1H), 8.45 (s, 2H), 7.34 (t, J = 2.0 Hz, 1H), 2.74 (s, 3H). DMSO 416.9 417.9 (M + 1) Method B (NH4HCO3) 95 Method C, G3
    1230
    Figure US20170217923A1-20170803-C02253
         		HCl 351.76 1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.60 (s, 2H), 9.34 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.24 (dd, J = 8.4, 2.4 Hz, 1H), 7.98-7.92 (m, 3H), 7.76-7.71 (m, 1H), 7.56 (t, J = 8.8 Hz, 1H). DMSO 352.0, 354.0 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1231
    Figure US20170217923A1-20170803-C02254
         		HCl 383.33 1H-NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 9.61 (s, 2H), 9.34 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.13 (s, 1H), 8.04- 7.93 (m, 3H), 7.78-7.73 (m, 1H), 7.62 (t, J = 8.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H). DMSO 384.1 (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1232
    Figure US20170217923A1-20170803-C02255
         		421.25 1H-NMR (400 MHz, DMSO-d6): 10.34 (s, 1H), 9.58 (s, 1H), 9.27-9.25 (m, 1H), 8.84-8.77 (m, 2H), 9.52 (s, 1H), 8.35 (s, 1H), 8.07-7.67 (m, 5H), 7.20 (t, J = 7.5 Hz, 1H). DMSO 421.0, 423.0 (M + 1) Method B (NH4HCO3) 95 Method C, G6
    1233
    Figure US20170217923A1-20170803-C02256
         		1H-NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 10.00 (s, 1H), 9.44 (d, J = 5.2 Hz, 1H), 8.95 (d, J = 8.4 Hz, 1H), 8.48 (s, 1H), 8.42-8.40 (m, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.97-7.91 (m, 3H), 7.81-7.73 (m, 2H), 7.25 (t, J = 2.4 Hz, 1H). DMSO 377.0 (M + 1) Method B (NH4HCO3) 95 Method G
    1234
    Figure US20170217923A1-20170803-C02257
         		1H-NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 9.54 (s, 1H), 8.82 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.07 (dd, J = 8.8, 2.4 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.4 Hz, 1H), 4.00 (s, 3H). DMSO 397.9, 400.0 (M + 1) Method B (NH4HCO3) 95 Method G
  • Figure US20170217923A1-20170803-C02258
    Figure US20170217923A1-20170803-C02259
    • Method C: 5-Nitro-2-(pyrazine-2-carboxamido)benzoic acid (li-a)
  • To a solution of pyrazine-2-carboxylic acid (1.36 g, 10.9 mmol, 1 eq.) in SOCl2 (20 mL) was added DMF (2 drops). The mixture was stirred at 60° C. for 20 min. The volatiles were removed in vacuo to give crude pyrazine-2-carbonyl chloride, which was used in the next step directly. To a suspension of 2-amino-5-nitrobenzoic acid (2.00 g, 10.9 mmol, 1.0 eq.) in THF (50 mL) was added Et3N (1.09 g) and pyrazine-2-carbonyl chloride in anhydrous THF (50 mL) dropwise. The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the volatiles were removed. The residue was suspended in H2O (10 mL) and the pH was adjusted to 5 by slow addition of 2N HCl in water. The resulting solid was collected and dried in vacuo to give 3.12 g of 5-nitro-2-(pyrazine-2-carboxamido)benzoic acid as a brown solid (99%). LCMS m/z=289.0 (M+1) (Method B) (retention time=1.24 min).
    • Method A: N-(2-carbamoyl-4-nitrophenyl)pyrazine-2-carboxamide (iii-d)
  • A mixture of 5-nitro-2-(pyrazine-2-carboxamido)benzoic acid (3.12 g, 10.8 mmol) in SOCl2 (20 mL) was stirred at 80° C. for 2 h. After cooling, the volatiles were removed and the residue was suspended in DCM (150 mL), and a solution of NH3.H2O (25% by weight in water, 40 mL) was added and stirred for 4 h. The resulting precipitate was collected and dried in vacuo to give 2.42 g of N-(2-carbamoyl-4-nitrophenyl)pyrazine-2-carboxamide as a dark red solid (74.6%). LCMS m/z=288.0 (M+1) (Method B) (retention time=1.11 min).
    • Method E2: 6-nitro-2-(pyrazin-2-yl)quinazolin-4(1H)-one (iv-g)
  • To a mixture of N-(2-carbamoyl-4-nitrophenyl)pyrazine-2-carboxamide (2.42 g, 8.43 mmol, 1.0 eq.) in EtOH (60 mL) was added NaOH (1.98 g, 49.5 mmol, 5.0 eq.). The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the volatiles were removed in vacuo. The residue was partitioned between H2O (50 mL) and ethyl acetate (50 mL). The aqueous layer was neutralized to pH 5 by slow addition of aqueous citric acid. The resulting precipitate was collected and dried to give 2.00 g of 6-nitro-2-(pyrazin-2-yl)quinazolin-4(3H)-one as a yellow solid (88%). LCMS m/z=270.1 (M+1) (Method A) (retention time=1.36 min).
    • Method F2: 4-Chloro-6-nitro-2-(pyrazin-2-yl)quinazoline (v-g)
  • To a mixture of 6-nitro-2-(pyrazin-2-yl)quinazolin-4(3H)-one (1.00 g, 3.7 mmol) in POCl3 (10 mL) was added N,N-dimethylbenzenamine (0.1 mL). The resulting mixture was stirred at 120° C. for 2 h. After the reaction was completed, POCl3 was removed in vacuo, and the residue was co-evaporated with toluene twice to give a dark crude product, which was used for the next step without further purification.
    • Method G6: N-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl)quinazolin-4-amine (vi-s)
  • A mixture of 4-chloro-6-nitro-2-(pyrazin-2-yl)quinazoline (1.00 g, crude, 3.7 mmol, 1.0 eq.), 3-(difluoromethoxy)benzenamine (600 mg, 3.7 mmol, 1.0 eq.) and Et3N (1.00 g, 10 mmol, 3.0 eq) in THF (80 mL) was stirred at 75° C. for 18 h. After cooling, the volatiles were removed in vacuo and the residue was washed with H2O (100 mL×2). The solid was dried in vacuo to afford 1.40 g of N-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl)quinazolin-4-amine as a black solid (90.2% of two steps). LCMS m/z=411.0 (M+1) (Method A) (retention time=1.61 min).
    • Method B: N4-(3-(difluoromethoxy)phenyl)-2-(pyrazin-2-yl)quinazoline-4,6-diamine (lii-a)
  • To a mixture of N-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl) quinazolin-4-amine (1.40 g, 3.4 mmol, 1.0 eq.) in MeOH—H2O (v/v, 3:1, 110 mL) was added NH4Cl (1.80 g, 34 mmol, 10.0 eq.) and Fe (1.91 g, 34 mmol, 10.0 eq.). The resulting mixture was stirred at 60° C. for 3 h. After the reaction was completed, the mixture was cooled to room temperature, and the iron was filtered off. The filtrate was concentrated to 15 mL and a precipitate formed and was collected and dried in vacuo to give 1.13 g of N4-(3-(difluoromethoxy)phenyl)-2-(pyrazin-2-yl)quinazoline-4,6-diamine as a pale yellow solid (87.5%). LCMS m/z=381.1 (M+1) (Method B) (retention time=1.60 min). 1H-NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 9.52 (d, J=1.2 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.30 (s, 1H), 7.87 (dd, J=8.4, 0.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.49-7.42 (m, 2H), 7.33-7.32 (m, 1H), 7.31 (t, J=74 Hz, 1H), 5.85 (s, 2H).
    • Method C: N-(4-(3-(difluoromethoxy)phenylamino)-2-(pyrazin-2-yl)quinazolin-6-yl)-6-methoxynicotinamide (liii-a)
  • To a solution of 6-methoxynicotinic acid (100 mg, 0.65 mmol) in SOCl2 (2 mL) was added DMF (1 drop). The mixture was stirred at 60° C. for 20 min. The volatiles were removed in vacuo to give 6-methoxynicotinoyl chloride, which was used for the next step directly. To a suspension of N4-(3-(difluoromethoxy)phenyl)-2-(pyrazin-2-yl)quinazoline-4,6-diamine (130 mg, 0.34 mmol, 0.5 eq.) in THF (5 mL) and Et3N (101 mg, 1 mmol, 3.0 eq) was added 6-methoxynicotinoyl chloride in anhydrous THF (5 mL) dropwise. The resulting mixture was stirred at room temperature for 18 h. The volatiles were removed in vacuo. The residue was washed with MeOH and re-crystallized from THF/MeOH twice, and purified by reverse phase chromatography PREP-HPLC (A=NH4HCO3—H2O, 10 mmol/L, B=MeOH) to afford 33 mg of N-(4-(3-(difluoromethoxy)phenylamino)-2-(pyrazin-2-yl)quinazolin-6-yl)-6-methoxynicotinamide as a pale yellow solid (18.8%). LCMS m/z=516.1 (M+1), 258.6 (M/2+1) (Method A) (retention time=1.57 min). 1H-NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H), 10.18 (s, 1H), 9.57 (d, J=1.6 Hz, 1H), 9.01 (d, J=1.6 Hz, 1H), 8.91 (d, J=2.4 Hz, 1H), 8.81 (t, J=2.0 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.34 (dd, J=8.8, 2.8 Hz, 1H), 8.23 (s, 1H), 8.08 (dd, J=8.8, 2.0 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.46-7.50 (m, 1H), 7.32 (t, J=74.4 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.95 (dd, J=8.0, 2.0 Hz, 1H), 3.97 (s, 3H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 67 (prepared according to method procedure A-G as designated).
  • TABLE 22
    Molec- 1H- Purity Method
    Num- Salt ular NMR LCMS per- for
    ber PRODUCT type Mass 1H-NMR Solvent LCMS Protocol cent Coupling
    1242
    Figure US20170217923A1-20170803-C02260
         		422.39 1H-NMR (400 MHz, DMSO-d6): δ 10.10- 10.45 (m, 2H), 9.68 (s, 1H), 8.45-9.10 (m, 2H), 7.68-8.37 (m, 4H), 7.36-7.52 (m, 2H), 7.02-7.08 (m, 1H), 2.21 (s, 3H). DMSO 423.0 (M + 1) Method A (TFA) 95 Method C, G4, C
    1243
    Figure US20170217923A1-20170803-C02261
         		515.47 1H-NMR (400 MHz, DMSO-d6): δ 10.71 (s, 1H), 10.18 (s, 1H), 9.57 (d, J = 1.6 Hz, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.91 (d, J = 2.4 Hz, 1H), 8.81 (t, J = 2.0 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.34 (dd, J = 8.8, 2.8 Hz, 1H), 8.23 (s, 1H), 8.08 (dd, J = 8.8, 2.0 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.90 (d, DMSO 516.2 (M + 1) Method B (NH4HCO3) 95 Method C, G4, C
    J = 9.2 Hz, 1H), 7.46-
    7.50 (m, 1H), 7.32 (t,
    J = 74.4 Hz, 1H), 7.02
    (d, J = 8.8 Hz, 1H),
    6.95 (dd, J = 8.0, 2.0 Hz,
    1H), 3.97 (s, 3H).
    1244
    Figure US20170217923A1-20170803-C02262
         		514.48 1H-NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 10.16 (s, 1H), 9.57 (s, 1H), 9.00 (d, J = 1.6 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.76 (d, J = 2.8 Hz, 1H), 8.23 (s, 1H), 8.07-8.12 (m, 3H), 7.99 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.46-7.50 (m, 1H), 7.32 (t, J = 72.8 Hz, 1H), 7.11-7.13 (m, 2H), 6.95 (dd, J = 8.4, 2.4 Hz, 1H), 3.87 DMSO 515.2 (M + 1) Method B (NH4HCO3) 95 Method C, G4, C
    (s, 3H).
    1245
    Figure US20170217923A1-20170803-C02263
         		520.53 1H-NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 10.16 (s, 1H), 9.54 (s, 1H), 8.89 (s, 1H), 8.79 (t, J = 2.4 Hz, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.20 (s, 1H), 7.93 (s, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 10.0, 2.0 Hz, 1H), 7.31 (t, J = 74.0 Hz, 1H), 6.94 (dd, J = 8.4, 2.0 Hz, 1H), 3.26 (s, 3H), 3.18-3.22 (m, 1H), DMSO 521.2 (M + 1) Method B (NH4HCO3) 95 Method C, G4, C
    1.91-1.96 (m, 2H),
    1.66-1.78 (m, 2H),
    1.53-1.63 (m, 2H),
    1.38-1.49 (m, 2H).
    1246
    Figure US20170217923A1-20170803-C02264
         		492.48 1H-NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 10.15 (s, 1H), 9.54 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.80 (dd, J = 2.4, 1.2 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.86-7.91 (m, 2H), 7.48 (dd, J = 10.8, 2.8 Hz, 1H), 7.31 (t, J = 74.4 Hz, 1H), 6.94 (dd, J = 7.6, 2.0 Hz, 1H), 3.94-3.97 (m, 2H), 3.40-3.43 (m, 2H), 2.70-2.73 DMSO 493.2 (M + 1) Method B (NH4HCO3) 95 Method C, G4, C
    (m, 1H), 1.65-1.78
    (m, 4H).
  • Figure US20170217923A1-20170803-C02265
    • Method BF: 6-(3-methoxyphenyl)-N-methyl-2-(pyrimidin-5-yl)quinazolin-4-amine (compound 1247)
  • In a 10 mL microwave vial was added 2-chloro-6-(3-methoxyphenyl)-N-methylquinazolin-4-amine (0.080 g, 0.267 mmol), pyrimidine-5-boronic acid (0.099 g, 0.801 mmol), dichlorobis(triphenylphosphine)palladium (II) (Pd(PPh3)2Cl2) (9.37 mg, 0.013 mmol), and potassium carbonate (0.111 g, 0.801 mmol) in DME (3 mL), EtOH (1.286 mL), and water (0.857 mL) to give a yellow suspension. The vial was irradiated at 120° C. for 15 min under argon. Water (10 mL) was added to the mixture and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL) and then dried over MgSO4, filtered and concentrated. The residue was washed with MeOH—CH2Cl2 and dried to give 35 mg of 6-(3-methoxyphenyl)-N-methyl-2-(pyrimidin-5-yl)quinazolin-4-amine as a white solid (38%). LCMS m/z=344 (M+1) (Method D) (retention time=1.78 min). 1H NMR (300 MHz, DMSO) δ 9.79-9.59 (m, 2H), 9.30 (s, 1H), 8.72 (d, J=4.6 Hz, 1H), 8.59 (s, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.53-7.28 (m, 3H), 7.00 (d, J=6.8 Hz, 1H), 3.86 (s, 3H), 3.18 (d, J=3.9 Hz, 3H).
  • Figure US20170217923A1-20170803-C02266
  • In a 100 mL round-bottomed flask was added 6-iodo-2-(pyrazin-2-yl)quinazolin-4(3H)-one (0.500 g, 1.428 mmol), BOP (0.821 g, 1.857 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.426 ml, 2.86 mmol) in DMF (10 mL) to give a colorless solution. Methylamine, 2M in THF (2.142 ml, 4.28 mmol) was added and stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and then a precipitate formed. The resulting solid was collected by filtration and dried to give 0.515 g of 6-iodo-N-methyl-2-(pyrazin-2-yl)quinazolin-4-amine as a pale brown solid in a 99% yield. LCMS m/z=364 (M+1) (Method D) (retention time=1.25 min). 1H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 8.89-8.65 (m, 3H), 8.65-8.48 (m, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 3.11 (d, J=4.2 Hz, 3H).
  • In a 50 mL round-bottomed flask was added 6-iodo-N-methyl-2-(pyrazin-2-yl)quinazolin-4-amine (0.100 g, 0.275 mmol), 3-methoxyphenylboronic acid (0.063 g, 0.413 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) (0.016 g, 0.022 mmol), and potassium phosphate tribasic monohydrate (0.190 g, 0.826 mmol) in dioxane (5 mL) and water (0.5 mL) to give a brown suspension. The reaction mixture was heated at 80° C. overnight under argon. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and then a precipitate formed. The resulting solid was collected by filtration and washed with ethyl acetate and dried to give 25 mg of 6-(3-methoxyphenyl)-N-methyl-2-(pyrazin-2-yl)quinazolin-4-amine as a pale yellow solid in a 26% yield. LCMS m/z=344 (M+1) (Method D) (retention time=1.43 min). 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.85-8.78 (m, 1H), 8.77-8.71 (m, 1H), 8.70-8.63 (m, 1H), 8.63-8.55 (m, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.9 Hz, 1H), 7.53-7.31 (m, 3H), 7.09-6.92 (m, 1H), 3.86 (s, 3H), 3.17 (d, J=3.6 Hz, 3H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 69 (prepared according to method described for 6-(3-methoxyphenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine).
  • TABLE 23
    Molec- 1H- Purity Method
    Num- Salt ular NMR LCMS per- for
    ber PRODUCT type Mass 1H-NMR Solvent LCMS Protocol cent Coupling
    1235
    Figure US20170217923A1-20170803-C02267
         		343.38 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.85-8.78 (m, 1H), 8.77-8.71 (m, 1H), 8.70- 8.63 (m, 1H), 8.63- 8.55 (m, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.53- 7.31 (m, 3H), 7.09-6.92 (m, 1H), 3.86 (s, 3H), 3.17 (d, J = 3.6 Hz, 3H). DMSO 344  (M + 1) Method D 100 Method AP/AQ
    1236
    Figure US20170217923A1-20170803-C02268
         		338.37 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.87-8.61 (m, 4H), 8.24 (d, J = 8.8 Hz, 1H), 8.15-7.98 (m, 4H), 7.92 (d, J = 8.7 Hz, 1H), 3.17 (d, J = 4.0 Hz, 3H). DMSO 339  (M + 1) Method D 100 Method C, G1
    1237
    Figure US20170217923A1-20170803-C02269
         		2HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 9.54 (d, J = 5.2 Hz, 1H), 9.36 (s, 1H), 8.63 (s, 2H), 8.13- 8.06 (m, 2H), 7.58-7.51 (m, 2H), 7.43-7.38 (m, 1H), 3.23 (d, J = 4.0 Hz, 3H). DMSO 350.1, 351.1, (M + 1) Method B (NH4HCO3)  95 Method C, G1
    1238
    Figure US20170217923A1-20170803-C02270
         		2HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 9.50 (d, J = 5.2 Hz, 1H), 9.24 (s, 1H), 8.60 (dd, J = 5.4, 1.8 Hz, 1H), 8.55 (s, 1H), 8.04 (q, J = 8.8 Hz, 2H), 7.76 (dd, J = 15.4, 9.0 Hz, 1H), 7.51-7.45 (m, 1H), 7.32 (dt, J = 8.4, 2.0 Hz, 1H), 3.23 (d, J = 4.4 Hz, 3H). DMSO 350.0, 351.0, (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1239
    Figure US20170217923A1-20170803-C02271
         		1H-NMR (400 MHz, DMSO-d6): δ 9.73 (s, 1H), 9.32 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.51 (s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.54- 7.49 (m, 2H), 7.42-7.37 (m, 1H), 4.12 (q, J = 5.2 Hz, 1H), 3.17 (t, J = 4.5 Hz, 3H). DMSO 350.1  (M + 1) Method B (NH4HCO3)  95 Method C, G1
    1240
    Figure US20170217923A1-20170803-C02272
         		2HCl 1H-NMR (400 MHz, CD3OD): δ 9.77 (s, 1H), 8.85 (d, J = 11.4 Hz, 2H), 8.42 (s, 1H), 8.19- 8.03 (m, 2H), 7.60 (dd, J = 15.6, 7.8 Hz, 1H), 7.10 (t, J = 8.4 Hz, 2H), 3.38 (s, 3H). CD3OD 350.1  (M + 1) Method B (NH4HCO3) 95 Method C, G1
    1241
    Figure US20170217923A1-20170803-C02273
         		2HCl 1H-NMR (400 MHz, DMSO): δ 10.84 (d, J = 1.8 Hz, 1H), 9.87 (s, 1H), 9.06 (d, J = 13.6 Hz, 2H), 8.90 (s, 1H), 8.32 (t, J = 9.8 Hz, 2H), 7.67-7.35 (m, 3H), 3.39 (s, 3H). DMSO 349.9  (M + 1) Method B (NH4HCO3)  95 Method C, G1
  • Figure US20170217923A1-20170803-C02274
  • Figure US20170217923A1-20170803-C02275
    • Method B2: 2-Amino-3-methylbenzoic acid (lv-a)
  • Pd/C catalyst (150 mg) was suspended in a solution of 3-methyl-2-nitrobenzoic acid (1.50 g, 8.28 mmol. 1.0 eq) in THF (60 mL), the mixture was stirred under H2 atmosphere at room temperature overnight. The Pd/C was removed by filtration over Celite and the THF was removed in vacuo to give 1.23 g of lv-a as a white solid (yield 98%). LCMS m/z=152.1 (M+1) (Method B) (retention time=0.73 min). The product was used further without purification.
    • Method AZ: 2-Amino-5-bromo-3-methylbenzoic acid (lvi-a)
  • To a solution of 2-amino-3-methylbenzoic acid (1.23 g, 8.14 mmol, 1.0 eq) in 15 mL of DMSO was added 40% HBr (6.00 mL, 44.7 mmol, 5 eq). The resulting mixture was stirred at room temperature overnight. A white precipitate formed during the course of the reaction. The reaction mixture was quenched with saturated aqueous NaHCO3 resulting in a white solid that was filtered and dried in vacuo to yield 950 mg in 51% yield of lvi-a as white solid. LCMS m/z=229.9 (M+1) (Method B) (retention time=1.20 min).
    • Method C: 2-Amino-5-bromo-3-methylbenzamide (ii-c)
  • A mixture of 2-amino-5-bromo-3-methylbenzoic acid (950 mg, 4.15 mmol) and SOCl2 (20 mL) was stirred at 80° C. for 2 h. After the reaction was completed, the mixture was cooled to room temperature. The SOCl2 was removed in vacuo and the residue was dissolved in anhydrous THF (10 mL). The THF solution was then added dropwise to a 28% by weight solution of NH3—H2O (10 mL). After 1 h, the resulting precipitate was collected and dried in vacuo to give 820 mg of ii-c as a yellow solid (87%). LCMS m/z=288.9, 230.9 (M+1) (Method B) (retention time=1.49 min).
  • Figure US20170217923A1-20170803-C02276
    • Method G for Coupling Conditions
  • G1: i-PrOH/85-100° C.
    • G2: THF/heat
  • G3: i-AmOH/100-130° C.
    • G4: MeOH/microwave/150° C.
  • G5: i-AmOH/microwave/150° C.
    • G6: THF/Et3N/reflux G7: THF-H2O/NaOAc/rt-60° C. G8: NaH/THF
  • G9: n-BuLi/THF
    • G10: LHMDS/THF G11: LDA/THF
  • G12: K2CO3/DMF/60° C.
    G13: Cs2CO3/DMA/80° C.
    • G14: NaOtBu/DMF/Microwave/100° C. Method AQ for Coupling Conditions
  • AQ1: Pd(PPh3)2Cl2/K2CO3/Dioxane-H2O
    AQ2: Pd2(APhos)2Cl2/K3PO4/Dioxane-H2O
    AQ3: Pd(PPh3)4/K3PO4/Dioxane-H2O
    AQ4: Pd(dppf)Cl2—CH2Cl2/K3PO4/Dioxane-H2O
    AQ5: Pd(OAc)2Cl2/S-Phos/K3PO4/Dioxane-H2O
    AQ6: Pd(dppf)Cl2—CH2Cl2/Na2CO3/Dioxane-H2O
  • Figure US20170217923A1-20170803-C02277
    • Method C: N-(4-bromo-2-carbamoyl-6-methylphenyl)nicotinamide (iii-e)
  • To a solution of 2-amino-5-bromo-3-methylbenzamide (820 mg, 3.55 mmol, 1.0 eq.) in THF (15 mL) and Et3N (0.7 mL) was added nicotinoyl chloride (551 mg, 3.91 mmol, 1.1 eq.) in anhydrous THF (15 mL) dropwise. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the resultant precipitate was filtered and dried in vacuo to give 1.74 g of crude iii-e as a yellow solid. LCMS m/z=333.8, 335.8 (M+1) (Method B) (retention time=1.42 min).
    • Method E: 6-Bromo-8-methyl-2-(pyridin-3-yl)quinazolin-4-ol (iv-h)
  • A mixture of N-(4-bromo-2-carbamoyl-6-methylphenyl)nicotinamide (1.74 g salt, 5.22 mmol, 1.0 eq) in EtOH (50 mL) was treated with NaOH (1.04 g, 26.1 mmol, 5.0 eq). The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the volatiles were removed in vacuo. Water (30 mL) was added to the residue and the mixture was adjusted to pH ˜1 or 2 by slow addition of aqueous HCl. The resultant precipitate was collected and dried to give 870 mg of iv-h as a yellow solid (77% yield after two steps). LCMS m/z=315.7, 317.7 (M+1) (Method B) (retention time=1.74 min).
    • Method F5: 6-Bromo-4-chloro-8-methyl-2-(pyridin-3-yl)quinazoline (v-h)
  • 6-Bromo-8-methyl-2-(pyridin-3-yl)quinazolin-4-ol (870 mg, 2.76 mmol) was added to POCl3 (10 mL). The resulting mixture was stirred at 120° C. overnight. After the reaction was completed, the mixture was carefully poured into ice-water. The pH was adjusted to 7 by slow addition of NH4OH at 0° C. The resultant solid was collected to give 1.00 g of v-h as a beige solid (quantitative yield). LCMS m/z=333.9, 335.9 (M+1) (Method B) (retention time=2.23 min).
    • Method G6: 6-Bromo-N, 8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (vi-t)
  • A mixture of 6-bromo-4-chloro-8-methyl-2-(pyridin-3-yl)quinazoline (200 mg, 0.60 mmol, 1.0 eq.), methylamine (81 mg, 1.20 mmol, 2.0 eq.) and Et3N (0.2 mL) in i-PrOH (10 mL) was stirred at 85° C. overnight. The resultant yellow precipitate was collected to afford 125 mg of vi-t as a beige solid (63.4%). LCMS m/z=328.8, 330.8 (M+1) (Method B) (retention time=1.95 min).
    • Method G2: 7-bromo-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (vi-u)
  • To a suspension of 7-bromo-4-chloro-2-(pyridin-3-yl)quinazoline (5.0 g, 0.0156 mol) in THF (100 mL) was added dropwise a methylamine solution (40 wt. % in H2O) (24 ml, 0.272 mmol) with cooling. The suspension was stirred at 60° C. for 3 h, cooled, filtered, and dried to give the title compound. (3.62 g, 73.5%)
    • Method AQ1: 6-(3-Methoxyphenyl)-N, 8-dimethyl-2-(pyridin-3-yl) quinazolin-4-amine (lviii-a)
  • (This method is representative of method AQ2 and can be implemented in a similar way except for substitution of the appropriate catalyst and base) To a mixture of 6-bromo-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (130 mg, 0.396 mmol, 1.0 eq), 3-methoxyphenylboronic acid (60 mg, 0.396 mmol, 1.0 eq), K2CO3 (295 mg, 2.14 mmol, 5.4 eq.) in dioxane (8 mL) and H2O (4 mL) was added Pd(PPh3)2Cl2 (15 mg, 0.021 mmol, 0.054 eq) under N2 atmosphere. The resulting mixture was stirred at 120° C. under N2 atmosphere overnight. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC column to afford 11 mg of lviii-a as a white solid (yield 7.8%). LCMS m/z=357.2, (M+1) (Method B (retention time=2.11 min). 1H NMR (400 MHz, DMSO-d6): δ 9.68 (d, J=1.2 Hz, 1H), 8.75 (d, J=8.0 Hz, 1H), 8.62 (d, J=4.6 Hz, 1H), 8.49 (d, J=4.4 Hz, 1H), 8.35 (s, 1H), 7.97 (s, 1H), 7.49 (dd, J=7.8, 4.8 Hz, 1H), 7.44-7.29 (m, 3H), 6.93 (dd, J=6.8, 2.4 Hz, 1H), 3.81 (s, 3H), 3.12 (d, J=4.4 Hz, 3H), 2.68 (s, 3H).
    • Method AQ3: 6-(4-Fluorophenyl)-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride (lviii-b)
  • 6-Bromo-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (340 mg, 1.03 mmol), 3-fluorobenzeneboronic acid (217 mg, 1.55 mmol), K3PO4 (658 mg, 3.10 mmol) and Pd(PPh3)4 (59.7 mg, 0.052 mmol) were dissolved in the mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). The resulting mixture was stirred at 90° C. for 6 hours under a nitrogen atmosphere. After the reaction was completed, water was added to the mixture and stirred for 30 minutes. The resulting precipitate was collected by filtration and purified by column chromatography on NH-silica gel (eluted with THF) to give a yellow powder. The solid was suspended in ethanol and 5N HCl (1 mL) was added to the mixture. The mixture was sonicated for 10 min and the resulting precipitate was collected by filtration and dried to give 304 mg of 6-(3-fluorophenyl)-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride as a yellow powder in 71% yield.
    • Method AQ4: 6-(2,4-Difluorophenyl)-N,5-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (lviii-c)
  • 6-Bromo-N,5-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (350 mg, 1.06 mmol), 2,4-difluorophenylboronic acid (252 mg, 1.595 mmol), K3PO4 (677 mg, 3.19 mmol) and Pd(dppf)Cl2—CH2Cl2 (87 mg, 0.106 mmol) were dissolved in the mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). The resulting mixture was stirred at 90° C. for 2.5 hours under N2. After the reaction was completed, water was added to the mixture and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4. After filtration and evaporation, the crude product was purified by column chromatography on NH-silica gel (eluted with isocratic 33% ethyl acetate/67% hexane) to give a white powder. The solid was suspended in ethanol and 5N HCl (1.0 mL) was added to the mixture. The mixture was sonicated for 10 min and the resultant precipitate was collected by filtration and dried to give 139 mg of 6-(2,4-difluorophenyl)-N,5-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride as a pale yellow powder in a 30% yield.
    • Method AQ5: 7-(3-fluorophenyl)-N,6-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride (lviii-d)
  • A mixture of 7-chloro-N,6-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (400 mg, 1.40 mmol), 3-fluorophenylboronic acid (294 g, 2.10 mmol), Pd(OAc)2 (15.8 mg, 0.070 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (86.7 mg, 0.211 mmol), K3PO4 (900 mg, 4.23 mmol) in dioxane (10 mL) and water (2 mL) was stirred under reflux for 2.5 h. Ethyl acetate (20 mL) was added to the cooled mixture and a precipiate formed and was filtered. The solid was recrystallized from DMF and water to give the title compound as free form. The solid was suspended in ethyl acetate (10 mL) and 4N HCl in ethyl acetate (1.0 mL) was added. The resulting solid was subjected to sonication for 20 min, filtered and dried to give the title compound as the bis-HCl salt (0.10 g, 18.7%).
    • Method AQ6:7-(3,4-difluorophenyl)-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride (lviii-e)
  • To a suspension of 3,4-difluorophenylboronic acid (389 mg, 2.46 mmol) and 7-bromo-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (395.4 mg, 1.201 mmol) in dioxane/H2O (2/1) (30 mL) under a nitrogen atmosphere was added Na2CO3 (633.2 mg, 5.97 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (98 mg, 0.120 mmol) at room temperature. The mixture was stirred at 100° C. for 1.5 h. Water was added to the reaction mixture and then a precipitate formed. The solid was filtered and washed with water and dried. The dried solid was then heated in a methanol/dioxane mixture to give a clear solution and filtered through Celite. The filtrate was concentrated to give the crude product. The crude product was sonicated in methanol/CH2Cl2 for ca. 15 min and filtered to give 305.2 mg of a pale brown solid as the parent compound. To a suspension of parent compound in methanol was added 4N HCl in ethyl acetate (ca. 4 mL) to give a clear solution. The solution was concentrated and recystallized from ethanol to give the HCl salt. The salt was collected and dried in an oven at 60° C. to give 231.3 mg in a 44% yield as pale yellow solid. 1H NMR (DMSO-d6) δ 9.73 (s, 1H), 9.37 (brd, J=8.08 Hz, 1H), 8.97 (brd, J=5.24 Hz, 1H), 8.77 (brs, 1H), 8.20 (d, J=8.48 Hz, 1H), 8.10-8.07 (brm, 1H), 7.63-7.55 (brm, 2H), 7.47 (d, J=8.48 Hz, 1H), 7.32 (brm, 1H), 3.20 (d, J=4.20 Hz, 3H), 2.65 (s, 3H). The 1H of 2 HCl was not observed.
  • Figure US20170217923A1-20170803-C02278
  • Figure US20170217923A1-20170803-C02279
    • Method AP: 6-bromo-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine (vi-u)
  • To a solution of 6-bromo-2-(pyridin-3-yl)quinazolin-4(3H)-one (5.00 g, 16.6 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (9.52 g, 21.5 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.94 ml, 33.1 mmol) in DMF (50 mL) was added methylamine, 2M in THF (16.6 mL, 33.1 mmol). The mixture was stirred overnight at room temperature. Water (100 mL) was added to the mixture and stirred. The resultant precipitate was collected by filtration and dried to give 5.15 g of 6-bromo-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine as pale yellow solid (99%). LCMS m/z=315 (M+1) (Method D) (retention time=1.34 min). 1H NMR (300 MHz, DMSO) δ 9.60 (dd, J=2.1, 0.8 Hz, 1H), 8.79-8.70 (m, 1H), 8.67 (dd, J=4.8, 1.7 Hz, 1H), 8.57 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 7.90 (dd, J=8.9, 2.1 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.52 (ddd, J=7.9, 4.8, 0.9 Hz, 1H), 3.13 (d, J=4.5 Hz, 3H).
    • Method AQ2: 6-(6-methoxypyridin-3-yl)-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine (lviii-f)
  • To a 1 dram reaction vial was added 6-bromo-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine (35 mg, 0.111 mmol), 6-methoxypyridin-3-ylboronic acid (20.4 mg, 0.133 mmol), Pd(APhos)2Cl2 (3.2 mg, 0.004 mmol) and potassium phosphate monohydrate (77 mg, 0.33 mmol) in a mixture of dioxane-water (9:1, 2 mL). The reaction mixture was heated to 90° C. for 14 h after which it was cooled to room temperature and diluted with water (5 mL). The resultant precipitate was collected by filtration and recrystallized from methanol to give 6-(6-methoxypyridin-3-yl)-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine as a pale yellow solid (19.1 mg, 51%). LCMS m/z=344 (M+1) (Method C) (retention time=2.01 min). 1H NMR (300 MHz, DMSO) δ 9.64 (d, J=1.3 Hz, 1H), 8.84-8.74 (m, 1H), 8.68 (dd, J=6.2, 1.7 Hz, 2H), 8.57 (d, J=1.6 Hz, 2H), 8.16 (ddd, J=14.4, 8.7, 2.2 Hz, 2H), 7.85 (d, J=8.7 Hz, 1H), 7.54 (dd, J=7.9, 4.8 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 3.93 (s, 3H), 3.18 (d, J=4.3 Hz, 3H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 72 or 74, replacing methylamine with the appropriate amine and 6-methoxypyridin-3-ylboronic acid with the appropriate boronic acid.
  • TABLE 24
    Number Product Salt Molecular Mass
    1248
    Figure US20170217923A1-20170803-C02280
         		HCl 342.4
    1249
    Figure US20170217923A1-20170803-C02281
         		372.4
    1250
    Figure US20170217923A1-20170803-C02282
         		356.4
    1251
    Figure US20170217923A1-20170803-C02283
         		356.4
    1252
    Figure US20170217923A1-20170803-C02284
         		329.3
    1253
    Figure US20170217923A1-20170803-C02285
         		HCl 342.4
    1254
    Figure US20170217923A1-20170803-C02286
         		330.3
    1255
    Figure US20170217923A1-20170803-C02287
         		312.4
    1256
    Figure US20170217923A1-20170803-C02288
         		HCl 337.4
    1257
    Figure US20170217923A1-20170803-C02289
         		337.4
    1258
    Figure US20170217923A1-20170803-C02290
         		346.8
    1259
    Figure US20170217923A1-20170803-C02291
         		346.8
    1260
    Figure US20170217923A1-20170803-C02292
         		372.4
    1261
    Figure US20170217923A1-20170803-C02293
         		348.3
    1262
    Figure US20170217923A1-20170803-C02294
         		313.4
    1263
    Figure US20170217923A1-20170803-C02295
         		343.4
    1264
    Figure US20170217923A1-20170803-C02296
         		356.4
    1265
    Figure US20170217923A1-20170803-C02297
         		342.4
    1266
    Figure US20170217923A1-20170803-C02298
         		344.4
    1267
    Figure US20170217923A1-20170803-C02299
         		329.4
    1268
    Figure US20170217923A1-20170803-C02300
         		342.4
    1269
    Figure US20170217923A1-20170803-C02301
         		342.4
    1270
    Figure US20170217923A1-20170803-C02302
         		2HCl 374.5
    1271
    Figure US20170217923A1-20170803-C02303
         		374.5
    1272
    Figure US20170217923A1-20170803-C02304
         		2HCl 425.5
    1273
    Figure US20170217923A1-20170803-C02305
         		HCl 342.4
    1274
    Figure US20170217923A1-20170803-C02306
         		329.4
    1275
    Figure US20170217923A1-20170803-C02307
         		343.4
    1276
    Figure US20170217923A1-20170803-C02308
         		331.3
    1277
    Figure US20170217923A1-20170803-C02309
         		425.5
    1278
    Figure US20170217923A1-20170803-C02310
         		343.4
    1H-NMR Retention LCMS Purity Method for
    Number 1H-NMR Solvent LCMS Time Protocol percent Coupling
    1248 1H-NMR (400 MHz, DMSO-d6): δ 9.66 (s, DMSO 343.1 Method B  95 Method
    1H), 8.50-8.89 (m, 3H), 8.16 (d, J = 8.2 Hz, (M + 1) (NH4HCO3) AQ1
    1H), 7.86 (d, J = 8.6 Hz, 1H), 7.30-7.61 (m,
    4H), 7.01 (d, J = 6.4 Hz, 1H), 3.88 (s, 3H),
    3.32 (brs, 1H), 3.19 (s, 3H).
    1249 1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, DMSO 372.9 Method B  95 Method
    1H), 8.77 (d, J = 7.9 Hz, 1H), 8.67 (d, J = 3.7 (M + 1) (NH4HCO3) AQ1
    Hz, 1H), 8.50 (s, 1H), 8.11 (s, 1H), 7.56-7.53
    (m, 2H), 7.48-7.40 (m, 3H), 7.01 (d, J = 3.9
    Hz, 1H), 4.07 (s, 3H), 3.88 (s, 3H), 3.17 (d, J =
    4.0 Hz, 3H).
    1250 1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, DMSO 357.1 Method B  95 Method
    1H), 8.79-8.74 (m, 1H), 8.69 (d, J = 4.0 Hz, (M + 1) (NH4HCO3) AQ1
    1H), 7.67 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.8
    Hz, 1H), 7.57-7.51 (m, 1H), 7.42 (t, J = 8.0
    Hz, 1H), 7.37-7.30 (m,1H), 7.02-6.92 (m,
    3H), 3.82 (s, 3H), 3.18 (d, J = 4.0 Hz, 3H),
    2.69 (s, 3H).
    1251 1H-NMR (400 MHz, DMSO-d6): δ 9.68 (d, J = DMSO 357.2 Method B  95 Method
    1.2 Hz, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.62 (M + 1) (NH4HCO3) AQ1
    (d, J = 4.6 Hz, 1H), 8.49 (d, J = 4.4 Hz, 1H),
    8.35 (s, 1H), 7.97 (s, 1H), 7.49 (dd, J = 7.8,
    4.8 Hz, 1H), 7.44-7.29 (m, 3H), 6.93 (dd, J =
    6.8, 2.4 Hz, 1H), 3.81 (s, 3H), 3.12 (d, J =
    4.4 Hz, 3H), 2.68 (s, 3H).
    1252 1H NMR (300 MHz, DMSO) δ 9.31 (s, 1H), DMSO 330   1.76 Method D 100
    8.76 (d, J = 4.7 Hz, 1H), 8.51 (d, J = 8.0 Hz, (M + 1)
    1H), 8.37 (d, J = 2.0 Hz, 1H), 8.18 (dd, J =
    8.5, 2.2 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H),
    7.59 (dd, J = 7.9, 4.8 Hz, 1H), 7.49-7.23 (m,
    3H), 6.99 (d, J = 6.7 Hz, 1H), 3.85 (s, 3H).
    1253 1H NMR (300 MHz, DMSO) δ 10.11 (s, 1H), DMSO 343   1.47 Method D 100 Method
    9.63 (s, 1H), 9.07-8.86 (m, 2H), 8.58 (s, (M + 1) AQ2
    1H), 8.16 (s, 2H), 7.92-7.77 (m, 1H), 7.54-
    7.36 (m, 2H), 7.20 (d, J = 8.6 Hz, 1H), 7.16-
    7.07 (m, 1H), 3.81 (s, 3H), 3.29 (d, J = 3.9
    Hz, 3H).
    1254 1H NMR (300 MHz, DMSO) δ 9.59 (s, 1H), DMSO 331   1.52 Method D 100 Method
    8.73 (d, J = 8.3 Hz, 1H), 8.65 (d, J = 4.7 Hz, (M + 1) AQ2
    1H), 8.37-8.22 (m, 1H), 8.18-8.05 (m, 1H),
    7.76 (d, J = 9.0 Hz, 1H), 7.71 (s, 1H), 7.56-
    7.43 (m, 2H), 4.58 (s, 2H), 3.14 (d, J = 4.4
    Hz, 3H), 2.69 (d, J = 4.6 Hz, 3H).
    1255 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), DMSO 313   1.48 Method D 100 Method
    8.88-8.47 (m, 4H), 8.25-8.05 (m, 1H), (M + 1) AQ2
    7.97-7.72 (m, 3H), 7.67-7.35 (m, 4H),
    3.18 (d, J = 4.4 Hz, 3H).
    1256 1H NMR (300 MHz, DMSO) δ 9.93 (s, 1H), DMSO 338   1.50 Method D 100 Method
    9.63 (s, 1H), 9.00 (d, J = 8.3 Hz, 1H), 8.95- (M + 1) AQ2
    8.82 (m, 2H), 8.46-8.32 (m, 2H), 8.25 (d, J =
    7.0 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.92
    (d, J = 7.2 Hz, 1H), 7.88-7.70 (m, 2H), 3.29
    (d, J = 4.2 Hz, 3H).
    1257 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), DMSO 338   1.50 Method D 100 Method
    8.77 (d, J = 7.9 Hz, 1H), 8.73-8.59 (m, 3H), (M + 1) AQ2
    8.21 (d, J = 8.8 Hz, 1H), 8.11-7.94 (m, 4H),
    7.87 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 7.9, 4.8
    Hz, 1H), 3.18 (d, J = 4.0 Hz, 3H).
    1258 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), DMSO 347   1.60 Method D 100 Method
    8.77 (d, J = 7.9 Hz, 1H), 8.72-8.52 (m, 3H), (M + 1) AQ2
    8.14 (d, J = 8.7 Hz, 1H), 7.97-7.74 (m, 3H),
    7.68-7.45 (m, 3H), 3.18 (d, J = 4.0 Hz, 3H).
    1259 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), DMSO 347   1.66 Method D 100 Method
    8.78 (d, J = 8.0 Hz, 1H), 8.72-8.54 (m, 3H), (M + 1) AQ2
    8.17 (d, J = 8.7 Hz, 1H), 7.94 (s, 1H), 7.90-
    7.78 (m, 2H), 7.61-7.42 (m, 3H), 3.19 (d,
    J = 4.4 Hz, 3H).
    1260 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), DMSO 373   1.49 Method D 100 Method
    8.77 (dd, J = 7.9, 1.8 Hz, 1H), 8.67 (d, J = 4.7 (M + 1) AQ2
    Hz, 1H), 8.46 (d, J = 4.4 Hz, 1H), 8.26 (s,
    1H), 7.95-7.84 (m, 1H), 7.75 (d, J = 8.6 Hz,
    1H), 7.53 (dd, J = 7.9, 4.8 Hz, 1H), 7.35 (d,
    J = 8.3 Hz, 1H), 6.77-6.60 (m, 2H), 3.80 (ss,
    6H), 3.14 (d, J = 4.3 Hz, 3H).
    1261 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), DMSO 349   1.61 Method D 100 Method
    8.77 (dd, J = 8.0, 1.9 Hz, 1H), 8.68 (d, J = 4.6 (M + 1) AQ2
    Hz, 1H), 8.59 (s, 2H), 8.21-8.09 (m, 1H),
    8.02-7.88 (m, 1H), 7.84 (d, J = 8.7 Hz, 1H),
    7.71 (s, 1H), 7.67-7.58 (m, 1H), 7.53 (dd, J =
    7.6, 5.1 Hz, 1H), 3.18 (d, J = 4.4 Hz, 3H).
    1262 1H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), DMSO 314   1.70 Method C  96 Method
    9.09 (s, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.73- (M + 1) AQ2
    8.55 (m, 4H), 8.30-8.14 (m, 2H), 7.89 (d, J =
    8.6 Hz, 1H), 7.63-7.47 (m, 2H), 3.19 (d, J =
    4.3 Hz, 3H).
    1263 1H NMR (300 MHz, DMSO) δ 9.64 (d, J = 1.3 DMSO 344.1 1.94 Method C  95 Method
    Hz, 1H), 8.84-8.74 (m, 1H), 8.68 (dd, J = (M + 1) AQ2
    6.2, 1.7 Hz, 2H), 8.57 (d, J = 1.6 Hz, 2H),
    8.16 (ddd, J = 14.4, 8.7, 2.2 Hz, 2H), 7.85 (d,
    J = 8.7 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz,
    1H), 7.00 (d, J = 8.7 Hz, 1H), 3.93 (s, 3H),
    3.18 (d, J = 4.3 Hz, 3H).
    1264 1H NMR (300 MHz, DMSO) δ 10.76 (s, 1H), DMSO 357.1 2.13 Method C 100 Method
    9.75 (d, J = 1.6 Hz, 1H), 9.23 (d, J = 8.2 Hz, (M + 1) AQ2
    1H), 9.05-8.86 (m, 2H), 8.41-8.24 (m, 2H),
    8.24-8.05 (m, 2H), 7.96 (dd, J = 8.1, 5.2 Hz,
    1H), 6.56 (d, J = 9.5 Hz, 1H), 4.81 (s, 2H),
    3.34 (s, 3H), 3.29 (d, J = 4.3 Hz, 3H).
    1265 1H NMR (300 MHz, DMSO) d 9.64 (s, 1H), DMSO 343.1 1.78 Method C  99 Method
    8.78 (dd, J = 8.0, 1.9 Hz, 1H), 8.67 (dd, J = (M + 1) AQ2
    6.3, 4.7 Hz, 2H), 8.58 (s, 1H), 8.17-8.06 (m,
    1H), 7.86 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H),
    7.72 (d, J = 7.6 Hz, 1H), 7.60-7.44 (m, 2H),
    7.37 (d, J = 7.5 Hz, 1H), 5.31 (t, J = 5.4 Hz, 1H),
    4.62 (d, J = 4.9 Hz, 2H), 3.18 (d, J = 4.4 Hz, 3H).
    1266 1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 2.1 DMSO 345.1 2.32 Method C 100 Method
    Hz, 1H), 8.92-8.59 (m, 3H), 8.59-8.47 (m, (M + 1) AQ2
    1H), 8.40-8.11 (m, 2H), 8.04 (d, J = 8.5 Hz,
    1H), 7.58 (dd, J = 7.9, 4.8 Hz, 1H), 6.95 (d,
    J = 8.6 Hz, 1H), 4.29 (s, 3H), 3.93 (s, 3H).
    1267 1H NMR (300 MHz, DMSO) δ 12.77 (s, 1H), DMSO 330   1.78 Method C 100 Method
    9.33 (d, J = 1.7 Hz, 1H), 8.77 (dd, J = 4.7, 1.5 (M + 1) AQ2
    Hz, 1H), 8.60-8.46 (m, 1H), 8.23 (d, J = 8.3
    Hz, 1H), 8.04 (d, J = 1.5 Hz, 1H), 7.87 (dd,
    J = 8.3, 1.8 Hz, 1H), 7.67-7.53 (m, 1H), 7.52-
    7.29 (m, 3H), 7.04 (ddd, J = 7.7, 2.4, 1.5 Hz,
    1H), 3.57 (s, 3H).
    1268 1H NMR (300 MHz, DMSO) δ 9.65 (dd, J = DMSO 343.3 2.09 Method C Method
    2.1, 0.8 Hz, 1H), 8.84-8.74 (m, 1H), 8.68 (M + 1) AQ2
    (dd, J = 4.7, 1.7 Hz, 1H), 8.52 (d, J = 4.4 Hz,
    1H), 8.30 (d, J = 8.6 Hz, 1H), 8.03 (d, J = 1.7
    Hz, 1H), 7.85 (dd, J = 8.5, 1.8 Hz, 1H), 7.54
    (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.47-7.34
    (m, 3H), 7.08-6.96 (m, 1H), 3.34 (s, 3H),
    3.17 (d, J = 4.4 Hz, 3H).
    1269 1H NMR (300 MHz, DMSO) δ 9.53 (d, J = 2.0 DMSO 343.3 2.16 Method C 100 Method
    Hz, 1H), 8.65 (dd, J = 5.9, 3.5 Hz, 2H), 8.51 (M + 1) AQ2
    (d, J = 4.2 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H),
    7.84 (d, J = 7.3 Hz, 1H), 7.65-7.25 (m, 5H),
    7.00 (dd, J = 8.1, 2.6 Hz, 1H), 3.33 (s, 3H),
    3.17 (d, J = 4.2 Hz, 3H).
    1270 1H NMR (300 MHz, DMSO) δ 10.67 (s, 1H), DMSO 375.1 1.67 Method C  95 Method
    9.69 (s, 1H), 9.12 (d, J = 11.6 Hz, 2H), 8.97 (M + 1) AQ2
    (d, J = 5.0 Hz, 1H), 8.43 (d, J = 7.4 Hz, 1H),
    8.31 (d, J = 8.6 Hz, 1H), 8.20 (s, 1H), 8.07 (s,
    1H), 7.98-7.86 (m, 1H), 7.77 (s, 2H), 3.31
    (d, J = 3.9 Hz, 3H), 2.90 (s, 3H).
    1271 1H NMR (300 MHz, DMSO) δ 9.70-9.57 (m, DMSO 375.1 1.64 Method C  95 Method
    1H), 8.84-8.72 (m, 1H), 8.73-8.62 (m, 3H), (M + 1) AQ2
    8.19 (dd, J = 8.7, 1.9 Hz, 1H), 8.06 (d, J = 8.4
    Hz, 2H), 7.86 (dd, J = 10.6, 8.5 Hz, 3H), 7.60-
    7.49 (m, 1H), 3.19 (d, J = 4.4 Hz, 2H), 2.81 (s, 3H).
    1272 1H NMR (300 MHz, DMSO) δ 10.54 (s, 1H), DMSO 426.2 1.72 Method C  95 Method
    9.70 (d, J = 1.7 Hz, 1H), 9.12 (d, J = 8.1 Hz, (M + 1) AQ2
    1H), 8.98 (dd, J = 5.5, 4.0 Hz, 2H), 8.37 (dd,
    J = 26.8, 7.9 Hz, 2H), 8.09-7.84 (m, 3H),
    7.63 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 7.6 Hz,
    1H), 3.67 (bs, 8H), 3.31 (d, J = 4.3 Hz, 3H).
    1273 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), DMSO 343.1 2.06 Method C 100 Method
    8.77 (d, J = 7.9 Hz, 1H), 8.71-8.65 (m, 1H), (M + 1) AQ2
    8.60 (s, 1H), 8.53 (s, 1H), 8.10 (d, J = 8.7 Hz,
    1H), 7.87-7.77 (m, 3H), 7.59-7.49 (m, 1H),
    7.10 (d, J = 8.7 Hz, 2H), 3.83 (d, J = 0.9 Hz,
    3H), 3.19 (s, 3H).
    1274 1H NMR (300 MHz, DMSO) δ 9.34 (d, J = 1.5 DMSO 330.0 1.75 Method C 100 Method
    Hz, 1H), 8.74 (dd, J = 4.8, 1.6 Hz, 1H), 8.53 (M + 1) AQ2
    (d, J = 8.0 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.10
    (dd, J = 8.5, 2.3 Hz, 1H), 7.79 (d, J = 8.6 Hz,
    1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.58 (dd, J = 8.0,
    4.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H).
    1275 1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 1.5 DMSO 344.1 1.95 Method C  95 Method
    Hz, 1H), 8.84-8.65 (m, 4H), 8.31 (d, J = 5.4 Hz, (M + 1) AQ2
    1H), 8.24 (dd, J = 8.7, 1.9 Hz, 1H), 7.87 (d,
    J = 8.7 Hz, 1H), 7.59-7.46 (m, 2H), 7.33 (d, J =
    0.9 Hz, 1H), 3.93 (s, 3H), 3.20 (d, J = 4.4 Hz, 3H).
    1276 1H NMR (300 MHz, DMSO) δ 9.63 (d, J = 1.4 DMSO 332.1 1.89 Method C 100 Method
    Hz, 1H), 8.81-8.74 (m, 1H), 8.73 (d, J = 2.3 (M + 1) AQ2
    Hz, 1H), 8.68 (dd, J = 4.7, 1.7 Hz, 1H), 8.66-
    8.56 (m, 2H), 8.44 (td, J = 8.2, 2.6 Hz, 1H),
    8.18 (dd, J = 8.7, 2.0 Hz, 1H), 7.87 (d, J = 8.7
    Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.38
    (dd, J = 8.5, 2.9 Hz, 1H), 3.18 (d, J = 4.4 Hz, 3H).
    1277 1H NMR (300 MHz, DMSO) δ 9.63 (d, J = 1.4 DMSO 426.2 1.69 Method C 100 Method
    Hz, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.70-8.59 (M + 1) AQ2
    (m, 3H), 8.15 (dd, J = 8.7, 1.6 Hz, 1H), 7.92
    (d, J = 8.2 Hz, 2H), 7.85 (d, J = 8.7 Hz, 1H),
    7.62-7.48 (m, 3H), 3.62 (s, J = 54.7 Hz, 8H),
    3.17 (d, J = 4.2 Hz, 3H).
    1278 1H NMR (300 MHz, DMSO) δ 9.67 (d, J = 1.5 DMSO 344.2 2.47 Method C 100 Method
    Hz, 1H), 8.86-8.77 (m, 1H), 8.74 (dd, J = (M + 1) AQ2
    4.7, 1.6 Hz, 1H), 8.37-8.25 (m, 2H), 8.06 (d,
    J = 8.7 Hz, 1H), 7.60 (dd, J = 7.9, 4.1 Hz,
    1H), 7.50-7.30 (m, 3H), 7.02 (dd, J = 7.9,
    1.4 Hz, 1H), 4.31 (s, 3H), 3.87 (s, 3H).
  • 1H Purity Method
    Num- Starting Starting Salt NMR per- of Cou- LCMS
    ber Material 1 Material 2 Product type 1H NMR Solvent cent pling LCMS Method
    1279
    Figure US20170217923A1-20170803-C02311
    Figure US20170217923A1-20170803-C02312
    Figure US20170217923A1-20170803-C02313
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.69 (d, J = 1.8 Hz, 1H), 9.40- 9.33 (m, 1H), 9.03-8.93 (m, 2H), 8.64-8.59 (m, 1H), 8.18-8.14 (m, 1H), 8.13-8.05 (m, 3H), 8.04-7.97 (m, 2H), 3.21 (d, J = 4.4 Hz, 3H), 2.77 (s, 3H). DMSO >98 AQ3
    1280
    Figure US20170217923A1-20170803-C02314
    Figure US20170217923A1-20170803-C02315
    Figure US20170217923A1-20170803-C02316
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.71-9.65 (m, 1H), 9.44-9.36 (m, 1H), 9.06-8.94 (m, 2H), 8.59-8.54 (m, 1H), 8.19-8.10 (m, 2H), 7.79-7.71 (m, 2H), 7.61-7.54 (m, 1H), 7.29-7.22 (m, 1H), 3.21 (d, J = 3.9 Hz, 3H), 2.76 (s, 3H). DMSO >98 AQ3
    1281
    Figure US20170217923A1-20170803-C02317
    Figure US20170217923A1-20170803-C02318
    Figure US20170217923A1-20170803-C02319
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.72-9.65 (m, 1H), 9.43-9.36 (m, 1H), 9.04-8.91 (m, 2H), 8.63-8.55 (m, 1H), 8.36-8.31 (m, 1H), 8.26-8.20 (m, 1H), 8.20-8.11 (m, 2H), 7.91-7.85 (m, 1H), 7.78-7.70 (m, 1H), DMSO >98 AQ3
    3.22 (d, J = 4.2 Hz, 3H),
    2.76 (s, 3H).
    1282
    Figure US20170217923A1-20170803-C02320
    Figure US20170217923A1-20170803-C02321
    Figure US20170217923A1-20170803-C02322
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.70-9.65 (m, 1H), 9.37 (d, J = 8.2 Hz, 1H), 9.03-8.90 (m, 2H), 8.49-8.42 (m, 1H), 8.12 (dd, J = 8.1, 5.6 Hz, 1H), 8.08-8.03 (m, 1H), 7.88-7.78 (m, 2H), 7.15-7.04 (m, 2H), 3.84 (s, 3H), 3.21 (d, J = 3.9 Hz, 3H), 2.76 (s, 3H). DMSO >98 AQ3
    1283
    Figure US20170217923A1-20170803-C02323
    Figure US20170217923A1-20170803-C02324
    Figure US20170217923A1-20170803-C02325
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.73-9.67 (m, 1H), 9.36 (d, J = 7.4 Hz, 1H), 9.02-8.96 (m, 1H), 8.82 (s, 1H), 8.26-8.19 (m, 1H), 8.15-8.07 (m, 1H), 7.89- 7.83 (m, 1H), 7.47-7.38 (m, 2H), 7.21-7.15 (m, 1H), 7.14-7.06 (m, 1H), 3.81 (s, 3H), 3.19 (d, J = 4.5 Hz, 3H), DMSO >98 AQ3
    2.77 (s, 3H).
    1284
    Figure US20170217923A1-20170803-C02326
    Figure US20170217923A1-20170803-C02327
    Figure US20170217923A1-20170803-C02328
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.72 (d, J = 1.8 Hz, 1H), 9.34- 9.28 (m, 1H), 8.95 (dd, J = 5.4, 1.4 Hz, 1H), 8.88-8.78 (m, 1H), 8.38 (d, J = 1.5 Hz, 1H), 8.07- 8.00 (m, 2H), 7.95-7.90 (m, 1H), 7.90-7.83 (m, 1H), 7.76 (dd, J = 7.8, 0.7 Hz, 1H), 7.68- DMSO >98 AQ3
    7.63 (m, 1H), 3.19 (d, J = 4.5 Hz,
    3H), 2.77 (s, 3H).
    1285
    Figure US20170217923A1-20170803-C02329
    Figure US20170217923A1-20170803-C02330
    Figure US20170217923A1-20170803-C02331
         		1H NMR (400 MHz, DMSO) δ 9.63 (dd, J = 2.1, 0.8 Hz, 1H), 8.80-8.75 (m, 1H), 8.69 (dd, J = 3.7, 1.8 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.58-7.49 (m, 2H), 7.46-7.40 (m, 1H), 7.39-7.32 (m, 1H), DMSO >98 AQ4
    7.28-7.18 (m, 1H), 3.18 (d, J =
    4.4 Hz, 3H), 2.64 (s, 3H).
    1286
    Figure US20170217923A1-20170803-C02332
    Figure US20170217923A1-20170803-C02333
    Figure US20170217923A1-20170803-C02334
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.67-9.60 (m, 1H), 9.06-8.88 (m, 3H), 8.12 (d, J = 8.8 Hz, 1H), 7.91-7.79 (m, 2H), 7.53-7.40 (m, 2H), 7.34-7.24 (m, 1H), 3.34 (d, J = 4.6 Hz, 3H), 2.66 (s, 3H). DMSO >98 AQ4
    1287
    Figure US20170217923A1-20170803-C02335
    Figure US20170217923A1-20170803-C02336
    Figure US20170217923A1-20170803-C02337
         		HCl 1H NMR (400 MHz, DMSO) δ 9.62-9.57 (m, 1H), 8.94-8.86 (m, 2H), 8.62 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.86-7.75 (m, 2H), 7.52-7.36 (m, 2H), 7.35-7.28 (m, 1H), 3.31 (d, J = 4.5 Hz, 3H), 2.67 (s, 3H). DMSO >98 AQ4
    1288
    Figure US20170217923A1-20170803-C02338
    Figure US20170217923A1-20170803-C02339
    Figure US20170217923A1-20170803-C02340
         		HCl 1H NMR (400 MHz, DMSO) δ 9.63-9.58 (m, 1H), 8.95-8.86 (m, 2H), 8.73 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.87-7.75 (m, 2H), 7.61-7.50 (m, 1H), 7.45-7.33 (m, 3H), 3.32 (d, J = 4.5 Hz, 3H), 2.66 (s, 3H). DMSO >98 AQ4
    1289
    Figure US20170217923A1-20170803-C02341
    Figure US20170217923A1-20170803-C02342
    Figure US20170217923A1-20170803-C02343
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.64-9.60 (m, 1H), 9.00-8.86 (m, 3H), 8.06 (d, J = 8.5 Hz, 1H), 7.91-7.79 (m, 2H), 7.65-7.55 (m, 1H), 7.37-7.29 (m, 1H), 7.29-7.22 (m, 2H), 3.35 (d, J = 4.6 Hz, 3H), 2.72 (s, 3H). DMSO >98 AQ4
    1290
    Figure US20170217923A1-20170803-C02344
    Figure US20170217923A1-20170803-C02345
    Figure US20170217923A1-20170803-C02346
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.69-9.64 (m, 1H), 9.14-8.99 (m, 2H), 8.96 (dd, J = 5.0, 1.5 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.90-7.81 (m, 2H), 7.50-7.34 (m, 4H), 3.35 (d, J = 4.6 Hz, 3H), 2.72 (s, 3H). DMSO >98 AQ4
    1291
    Figure US20170217923A1-20170803-C02347
    Figure US20170217923A1-20170803-C02348
    Figure US20170217923A1-20170803-C02349
         		HCl 1H NMR (300 MHz, CDCl3) δ 9.63 (s, 2H), 8.96 (d, J = 8.2 Hz, 1H), 8.90 (d, J = 5.0 Hz, 1H), 8.50 (s, 1H), 8.16-7.99 (m, 2H), 7.82 (dd, J = 8.0, 4.9 Hz, 1H), 7.71-7.62 (m, 1H), 7.61-7.47 (m, 3H), 3.26 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3
    1292
    Figure US20170217923A1-20170803-C02350
    Figure US20170217923A1-20170803-C02351
    Figure US20170217923A1-20170803-C02352
         		2 HCl 1H NMR (300 MHz, CDCl3) δ 10.27 (s, 1H), 9.69 (s, 1H), 9.09 (d, J = 8.1 Hz, 1H), 8.97 (d, J = 5.0 Hz, 1H), 8.56 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.89 (dd, J = 8.0, 5.1 Hz, 1H), 7.45-7.26 (m, 4H), 3.29 (d, J = 4.2 Hz, DMSO >98 G2/AQ3
    3H), 2.32 (s, 3H).
    1293
    Figure US20170217923A1-20170803-C02353
    Figure US20170217923A1-20170803-C02354
    Figure US20170217923A1-20170803-C02355
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.40 (s, 1H), 9.73 (s, 1H), 9.15 (d, J = 7.9 Hz, 1H), 8.98 (d, J = 5.1 Hz, 1H), 8.67 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.91 (dd, J = 7.9, 5.2 Hz, 1H), 7.45 (m, 2H), 7.20 (d, J = 8.2 Hz, DMSO >98 G2/AQ3
    1H), 7.12 (t, J = 7.5 Hz, 1H),
    3.82 (s, 3H), 3.29 (d, J =
    4.1 Hz, 3H).
    1294
    Figure US20170217923A1-20170803-C02356
    Figure US20170217923A1-20170803-C02357
    Figure US20170217923A1-20170803-C02358
         		1H NMR (300 MHz,CDCl3) δ 9.66 (s, 1H), 8.80 (d, J = 7.9 Hz, 1H), 8.74-8.67 (m, 1H), 8.60 (m, 1H), 8.49 (s, 1H), 8.00 (dd, J = 18.5, 10.4 Hz, 2H), 7.96-7.81 (m, 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.56 (dd, J = 7.6, 5.0 Hz, 1H), 3.18 (d, J = 4.2 Hz, 3H). DMSO >98 G2/AQ3
    1295
    Figure US20170217923A1-20170803-C02359
    Figure US20170217923A1-20170803-C02360
    Figure US20170217923A1-20170803-C02361
         		2 HCl 1H NMR (300 MHz, CDCl3) δ 9.88 (s, 1H), 9.66 (s, 1H), 9.01 (d, J = 8.3 Hz, 1H), 8.90 (d, J = 4.2 Hz, 1H), 8.70 (s, 1H), 8.27-8.08 (m, 2H), 7.81 (dd, J = 8.0, 5.1 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.60-7.48 (m, 1H), 7.48-7.27 (m, 2H), 3.27 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1296
    Figure US20170217923A1-20170803-C02362
    Figure US20170217923A1-20170803-C02363
    Figure US20170217923A1-20170803-C02364
         		2 HCl 1H NMR (300 MHz, CDCl3) δ 9.63 (m, 2H), 8.93 (d, J = 7.7 Hz, 1H), 8.88 (d, J = 4.1 Hz, 1H), 8.76 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.94 (dd, J = 8.6, 5.5 Hz, 2H), 7.82-7.73 (m, 1H), 7.41 (t, J = 8.7 Hz, 2H), 3.28 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1297
    Figure US20170217923A1-20170803-C02365
    Figure US20170217923A1-20170803-C02366
    Figure US20170217923A1-20170803-C02367
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.82 (s, 1H), 9.64 (d, J = 1.7 Hz, 1H), 9.00 (d, J = 8.0 Hz, 1H), 8.95-8.86 (m, 2H), 8.69 (t, J = 1.9 Hz, 1H), 8.51-8.34 (m, 2H), 8.30 (dd, J = 7.9, 1.8 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.93-7.76 (m, 2H), 3.30 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3
    1298
    Figure US20170217923A1-20170803-C02368
    Figure US20170217923A1-20170803-C02369
    Figure US20170217923A1-20170803-C02370
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.30 (s, 1H), 9.70 (d, J = 2.1 Hz, 1H), 9.11 (d, J = 8.2 Hz, 1H), 9.04-8.83 (m, 1H), 8.56 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.01-7.80 (m, 3H), 7.78-7.64 (m, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 3.29 (d, J = DMSO >98 G2/AQ3
    4.4 Hz, 3H), 2.44 (s, 3H).
    1299
    Figure US20170217923A1-20170803-C02371
    Figure US20170217923A1-20170803-C02372
    Figure US20170217923A1-20170803-C02373
         		1H NMR (300 MHz, DMSO) δ 10.50 (s, 1H), 9.66 (s, 1H), 9.09 (d, J = 8.2 Hz, 1H), 9.01 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.40 (d, J = 8.7 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.13-8.00 (m, 4H), 7.88 (dd, J = 8.0, 5.2 Hz, 1H), 3.30 (d, J = 4.1 Hz, 3H), 2.62 (s, 3H). DMSO >98 G2/AQ3
    1300
    Figure US20170217923A1-20170803-C02374
    Figure US20170217923A1-20170803-C02375
    Figure US20170217923A1-20170803-C02376
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.49 (s, 1H), 9.66 (s, 1H), 9.09 (d, J = 7.9 Hz, 1H), 9.01 (s, 1H), 8.95 (d, J = 5.0 Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 8.15-7.94 (m, 4H), 7.88 (dd, J = 7.9, 5.2 Hz, 1H), 3.31 (d, J = 4.1 Hz, 3H), 2.63 (s, 3H). DMSO >98 G2/AQ3
    1301
    Figure US20170217923A1-20170803-C02377
    Figure US20170217923A1-20170803-C02378
    Figure US20170217923A1-20170803-C02379
         		3 HCl 1H NMR (300 MHz, DMSO) δ 10.97 (s, 1H), 9.71 (d, J = 2.0 Hz, 1H), 9.29 (s, 1H), 9.15 (d, J = 8.0 Hz, 1H), 8.98 (dd, J = 5.0, 1.3 Hz, 1H), 8.49-8.38 (m, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.21 (s, 1H), 7.92 (dd, J = 8.1, 5.1 Hz, 1H), 7.84 (s, 1H), DMSO >98 G2/AQ3
    7.69-7.52 (m, 2H), 3.31 (d, J =
    4.3 Hz, 3H), 3.23 (s, 6H).
    1302
    Figure US20170217923A1-20170803-C02380
    Figure US20170217923A1-20170803-C02381
    Figure US20170217923A1-20170803-C02382
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 9.73 (d, J = 1.7 Hz, 1H), 9.20 (d, J = 8.0 Hz, 1H), 9.00 (d, J = 4.2 Hz, 1H), 8.68 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.01-7.93 (m, 2H), 7.90 (t, J = 7.2 Hz, DMSO >98 G2/AQ3
    1H), 7.74 (dd, J = 15.4, 7.7
    Hz, 2H), 3.24 (t, J = 18.2 Hz, 3H).
    1303
    Figure US20170217923A1-20170803-C02383
    Figure US20170217923A1-20170803-C02384
    Figure US20170217923A1-20170803-C02385
         		HCl 1H NMR (300 MHz, DMSO) δ 10.46 (s, 1H), 9.76 (d, J = 2.1 Hz, 1H), 9.21 (d, J = 8.2 Hz, 1H), 9.00 (dd, J = 5.1, 1.2 Hz, 1H), 8.58 (d, J = 1.3 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 8.08-7.86 (m, 2H), 7.36-7.09 (m, 3H), 3.29 (d, J = 4.3 Hz, 3H), 2.33 (s, 3H), 2.17 (s, 3H). DMSO >98 G2/AQ3
    1304
    Figure US20170217923A1-20170803-C02386
    Figure US20170217923A1-20170803-C02387
    Figure US20170217923A1-20170803-C02388
         		1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 2.1 Hz, 1H), 8.79 (dt, J = 8.0, 1.9 Hz, 1H), 8.69 (dd, J = 4.7, 1.6 Hz, 1H), 8.46 (d, J = 4.5 Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.75 (dd, J = 8.5, 1.6 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), DMSO >98 G2/AQ3
    7.28-7.02 (m, 3H), 3.33 (s, 6H),
    3.15 (d, J = 4.4 Hz, 3H),
    2.51 (dt, J = 3.6, 1.7 Hz,
    1H), 2.35 (s, 3H), 2.27 (s, 3H).
    1305
    Figure US20170217923A1-20170803-C02389
    Figure US20170217923A1-20170803-C02390
    Figure US20170217923A1-20170803-C02391
         		HCl 1H NMR (300 MHz, DMSO) δ 10.48 (s, 1H), 9.70 (s, 1H), 9.11 (d, J = 7.8 Hz, 1H), 8.97 (d, J = 4.7 Hz, 1H), 8.90 (s, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 7.98-7.80 (m, 1H), DMSO >98 G2/AQ3
    7.74 (s, 1H), 7.65 (d, J =
    7.5 Hz, 1H), 7.30 (d, J =
    7.8 Hz, 1H), 3.32 (d, J =
    4.0 Hz, 3H), 2.33 (d, J =
    10.0 Hz, 3H), 2.29 (s, 3H).
    1306
    Figure US20170217923A1-20170803-C02392
    Figure US20170217923A1-20170803-C02393
    Figure US20170217923A1-20170803-C02394
         		HCl 1H NMR (300 MHz, DMSO) δ 10.45-10.35 (m, 1H), 9.69 (s, 1H), 9.09 (s, 1H), 8.99 (s, 1H), 8.88 (s, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 8.7 Hz, 1H), 7.94 (s, 1H), 7.54 (s, 1H), 7.11 (s, 1H), 3.34 (d, J = 4.3 Hz, 3H), 2.40 (s, 3H). DMSO >98 G2/AQ3
    1307
    Figure US20170217923A1-20170803-C02395
    Figure US20170217923A1-20170803-C02396
    Figure US20170217923A1-20170803-C02397
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.28 (s, 1H), 9.84-9.66 (m, 1H), 9.17 (d, J = 8.1 Hz, 1H), 7.98-7.80 (m, 2H), 7.41 (t, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 3.71 (s, 6H), 3.29 (d, J = 4.2 Hz, 3H). DMSO >98 G2/AQ3
    1308
    Figure US20170217923A1-20170803-C02398
    Figure US20170217923A1-20170803-C02399
    Figure US20170217923A1-20170803-C02400
         		HCl 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.96-8.91 (m, 1H), 8.89-8.83 (m, 2H), 8.41 (d, J = 9.1 Hz, 2H), 8.38-8.32 (m, 1H), 8.16 (d, J = 9.0 Hz, 2H), 8.02 (d, J = 9.1 Hz, 1H), 7.81-7.73 (m, 1H), 3.27 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1309
    Figure US20170217923A1-20170803-C02401
    Figure US20170217923A1-20170803-C02402
    Figure US20170217923A1-20170803-C02403
         		1H NMR (300 MHz, DMSO) δ 9.64 (d, J = 2.0 Hz, 1H), 8.78 (ddd, J = 14.6, 8.2, 6.5 Hz, 1H), 8.70 (dd, J = 4.7, 1.4 Hz, 1H), 8.56 (d, J = 4.3 Hz, 1H), 8.33 (d, J = 1.5 Hz, 1H), 8.06 (dd, J = 8.6, 1.4 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.56 (dd, J = 7.9, 4.8 Hz, DMSO >98 G2/AQ3
    1H), 7.34 (t, J = 7.5 Hz, 2H),
    7.20-7.00 (m, 2H), 3.16 (d, J =
    4.4 Hz, 3H).
    1310
    Figure US20170217923A1-20170803-C02404
    Figure US20170217923A1-20170803-C02405
    Figure US20170217923A1-20170803-C02406
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.63 (s, 1H), 9.69 (s, 1H), 9.16 (s, 1H), 9.10 (d, J = 7.9 Hz, 1H), 8.97 (d, J = 5.0 Hz, 1H), 8.52 (s, 1H), 8.45 (d, J = 8.7 Hz, 1H), 8.29 (d, J = 8.7 Hz, 2H), 8.07 (d, J = 7.8 Hz, 1H), 8.01-7.84 (m, 2H), 7.63 (t, J = 7.8 Hz, 1H), 7.54 (s, 1H), 3.31 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1311
    Figure US20170217923A1-20170803-C02407
    Figure US20170217923A1-20170803-C02408
    Figure US20170217923A1-20170803-C02409
         		HCl 1H NMR (300 MHz, DMSO) δ 10.20 (s, 1H), 9.65 (s, 1H), 9.02 (s, 1H), 8.95 (s, 2H), 8.43 (d, J = 8.7 Hz, 1H), 8.26-8.14 (m, 1H), 8.04 (dd, J = 18.8, 8.1 Hz, 4H), 7.88 (s, 1H), 7.47 (s, 1H), 3.32 (s, 3H), 3.17 (d, J = 1.8 Hz, 9H). DMSO >98 G2/AQ3
    1312
    Figure US20170217923A1-20170803-C02410
    Figure US20170217923A1-20170803-C02411
    Figure US20170217923A1-20170803-C02412
         		HCl 1H NMR (300 MHz, DMSO) δ 9.79 (s, 1H), 9.66 (d, J = 1.7 Hz, 1H), 9.02 (d, J = 8.1 Hz, 1H), 8.96-8.86 (m, 1H), 8.57 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.05 (dd, J = 8.7, 1.4 Hz, 1H), 7.82 (dd, J = 8.1, 5.0 Hz, 1H), 7.79-7.72 (m, 1H), 7.64-7.45 DMSO >98 G2/AQ3
    (m, 2H), 3.25
    (d, J = 4.4 Hz, 3H).
    1313
    Figure US20170217923A1-20170803-C02413
    Figure US20170217923A1-20170803-C02414
    Figure US20170217923A1-20170803-C02415
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 9.65 (s, 1H), 9.06 (d, J = 7.8 Hz, 1H), 8.95 (d, J = 4.8 Hz, 1H), 8.59 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.95-7.77 (m, 2H), 7.66-7.52 (m, 2H), 3.27 (d, J = 4.3 Hz, 3H), 3.17 (d, J = 0.7 Hz, 1H). DMSO >98 G2/AQ3
    1314
    Figure US20170217923A1-20170803-C02416
    Figure US20170217923A1-20170803-C02417
    Figure US20170217923A1-20170803-C02418
         		HCl 1H NMR (300 MHz, DMSO) δ 10.10 (s, 1H), 9.69 (s, 1H), 9.13 (d, J = 8.0 Hz, 1H), 8.98 (d, J = 5.1 Hz, 1H), 8.62 (s, 1H), 8.27 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 8.02-7.83 (m, 1H), 7.77-7.65 (m, 2H), 7.60 (d, J = 8.5 Hz, 1H), 3.29 (d, J = 3.9 Hz, 3H). DMSO >98 G2/AQ3
    1315
    Figure US20170217923A1-20170803-C02419
    Figure US20170217923A1-20170803-C02420
    Figure US20170217923A1-20170803-C02421
         		HCl 1H NMR (300 MHz, DMSO) δ 9.62 (s, 1H), 9.02-8.93 (m, 1H), 8.89 (d, J = 4.5 Hz, 1H), 8.80 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.18 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.96-7.75 (m, 2H), 3.29 (d, J = 4.2 Hz, 3H). DMSO >98 G2/AQ3
    1316
    Figure US20170217923A1-20170803-C02422
    Figure US20170217923A1-20170803-C02423
    Figure US20170217923A1-20170803-C02424
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.36 (s, 1H), 9.67 (s, 1H), 9.13 (d, J = 8.2 Hz, 1H), 9.01-8.82 (m, 2H), 8.40 (d, J = 9.1 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 7.97 (s, 2H), 7.90 (dd, J = 8.0, 5.2 Hz, 1H), 7.65 (s, 1H), 3.31 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1317
    Figure US20170217923A1-20170803-C02425
    Figure US20170217923A1-20170803-C02426
    Figure US20170217923A1-20170803-C02427
         		1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 1.9 Hz, 1H), 8.89-8.75 (m, 1H), 8.74-8.67 (m, 1H), 8.67-8.56 (m, 1H), 8.48 (s, 1H), 8.06-7.94 (m, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.68-7.51 (m, 2H), 7.46 (td, J = 9.6, 4.7 Hz, 1H), 7.39-7.21 (m, 1H), 3.18 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1318
    Figure US20170217923A1-20170803-C02428
    Figure US20170217923A1-20170803-C02429
    Figure US20170217923A1-20170803-C02430
         		HCl 1H NMR (300 MHz, DMSO) δ 10.57 (s, 1H), 9.69 (d, J = 2.0 Hz, 1H), 9.15 (d, J = 8.0 Hz, 1H), 9.02 (s, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 7.91 (dd, J = 8.0, 5.2 Hz, 1H), 7.77-7.63 (m, 2H), 7.37-7.18 (m, 1H), 3.29 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1319
    Figure US20170217923A1-20170803-C02431
    Figure US20170217923A1-20170803-C02432
    Figure US20170217923A1-20170803-C02433
         		1H NMR (300 MHz, CDCl3) δ 9.58 (d, J = 2.0 Hz, 1H), 8.78-8.60 (m, 2H), 8.35 (d, J = 1.7 Hz, 1H), 8.11-7.84 (m, 3H), 7.78 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.48-7.34 (m, 2H), 7.17 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 3.81 (s, 3H). DMSO >98 G2/AQ3
    1320
    Figure US20170217923A1-20170803-C02434
    Figure US20170217923A1-20170803-C02435
    Figure US20170217923A1-20170803-C02436
         		1H NMR (300 MHz, CDCl3) δ 9.62 (d, J = 2.1 Hz, 1H), 8.82-8.72 (m, 1H), 8.72-8.66 (m, 1H), 8.30 (s, 1H), 7.93 (dd, J = 8.7, 1.2 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.50-7.33 (m, 2H), 7.18 (d, DMSO >98 G2/AQ3
    J = 8.3 Hz, 1H), 7.09
    (t, J = 7.5 Hz, 1H), 3.82
    (s, 3H), 3.46 (s, 6H).
    1321
    Figure US20170217923A1-20170803-C02437
    Figure US20170217923A1-20170803-C02438
    Figure US20170217923A1-20170803-C02439
         		1H NMR (300 MHz, CDCl3) δ 9.59 (d, J = 2.1 Hz, 1H), 8.76-8.66 (m, 2H), 8.50 (s, 2H), 8.06 (brs, 1H), 7.99 (dt, J = 8.6, 1.7 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.75-7.63 (m, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.52-7.44 (m, 1H), 7.44-7.32 (m, 2H). DMSO >98 G2/AQ3
    1322
    Figure US20170217923A1-20170803-C02440
    Figure US20170217923A1-20170803-C02441
    Figure US20170217923A1-20170803-C02442
         		1H NMR (300 MHz, CDCl3) δ 9.59 (d, J = 2.1 Hz, 1H), 8.79-8.62 (m, 3H), 8.21 (dd, J = 8.8, 1.9 Hz, 1H), 8.10 (brs, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.80-7.69 (m, 2H), 7.68-7.49 (m, 2H), 7.32-7.20 (m, 1H). DMSO >98 G2/AQ3
    1323
    Figure US20170217923A1-20170803-C02443
    Figure US20170217923A1-20170803-C02444
    Figure US20170217923A1-20170803-C02445
         		1H NMR (300 MHz, CDCl3) δ 9.58 (d, J = 2.0 Hz, 1H), 8.80-8.64 (m, 2H), 8.62 (d, J = 1.8 Hz, 1H), 8.14 (dd, J = 8.7, 1.9 Hz, 1H), 8.07 (brs, 2H), 7.98-7.87 (m, 2H), 7.85 (d, J = 8.7 Hz, 1H), DMSO >98 G2/AQ3
    7.54 (dd, J = 7.9, 4.8
    Hz, 1H), 7.38 (t, J = 8.8 Hz, 2H).
    1324
    Figure US20170217923A1-20170803-C02446
    Figure US20170217923A1-20170803-C02447
    Figure US20170217923A1-20170803-C02448
         		1H NMR (300 MHz,CDCl3) δ 9.65-9.57 (m, 1H), 8.82-8.70 (m, 1H), 8.70-8.63 (m, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.11 (dd, J = 8.7, 1.7 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.72-7.60 (m, 2H), 7.60-7.47 DMSO >98 G2/AQ3
    (m, 2H), 7.32-7.18
    (m, 1H), 3.49 (s, 6H).
    1325
    Figure US20170217923A1-20170803-C02449
    Figure US20170217923A1-20170803-C02450
    Figure US20170217923A1-20170803-C02451
         		1H NMR (400 MHz, DMSO) δ 9.64 (d, J = 1.4 Hz, 1H), 8.78 (dt, J = 8.3, 1.8 Hz, 1H), 8.69 (dd, J = 4.7, 1.8 Hz, 1H), 8.61-8.46 (m, 2H), 8.40 (d, J = 1.6 Hz, 1H), 7.99 (dd, J = 9.0, 1.8 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.54 DMSO >98 G2/AQ3
    (dd, J = 8.4, 4.5 Hz, 1H),
    3.99 (d, J = 8.9 Hz, 6H),
    3.17 (d, J = 4.6 Hz, 3H).
    1326
    Figure US20170217923A1-20170803-C02452
    Figure US20170217923A1-20170803-C02453
    Figure US20170217923A1-20170803-C02454
         		1H NMR (300 MHz, DMSO) δ 9.64-9.55 (m, 1H), 8.81-8.62 (m, 3H), 8.40 (s, 1H), 8.23 (dd, J = 8.8, 1.4 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), DMSO >98 G2/AQ3
    7.54 (dd, J = 7.9, 4.8
    Hz, 1H), 2.71 (s, 3H).
    1327
    Figure US20170217923A1-20170803-C02455
    Figure US20170217923A1-20170803-C02456
    Figure US20170217923A1-20170803-C02457
         		1H NMR (300 MHz, DMSO) δ (d, J = 2.1 Hz, 1H), 8.76-8.65 (m, 3H), 8.24 (dd, J = 8.7, 1.8 Hz, 1H), 8.19-7.93 (m, 6H), 7.88 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 2.65 (s, 3H). DMSO >98 G2/AQ3
    1328
    Figure US20170217923A1-20170803-C02458
    Figure US20170217923A1-20170803-C02459
    Figure US20170217923A1-20170803-C02460
         		1H NMR (300 MHz, DMSO) δ 9.60 (d, J = 1.8 Hz, 1H), 8.73 (dt, J = 8.0, 1.8 Hz, 1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 (s, 1H), 7.99 (brs, 2H), 7.92-7.81 (m, 2H), 7.67-7.60 (m, 1H), 7.60-7.52 (m, 2H), 7.52-7.43 (m, 2H), DMSO >98 G2/AQ3
    1329
    Figure US20170217923A1-20170803-C02461
    Figure US20170217923A1-20170803-C02462
    Figure US20170217923A1-20170803-C02463
         		1H NMR (300 MHz, DMSO) δ 9.60 (d, J = 2.0 Hz, 1H), 8.77-8.65 (m, 3H), 8.19 (dd, J = 8.7, 1.8 Hz, 1H), 8.09 (brs, 2H), 7.99-7.94 (m, 1H), 7.90-7.79 (m, 2H), 7.63-7.51 (m, 2H), 7.48 (d, J = 8.1 Hz, 1H). DMSO >98 G2/AQ3
    1330
    Figure US20170217923A1-20170803-C02464
    Figure US20170217923A1-20170803-C02465
    Figure US20170217923A1-20170803-C02466
         		1H NMR (300 MHz, DMSO) δ (s, 1H), 8.87-8.75 (m, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.09-7.76 (m, 3H), 7.62-7.44 (m, 1H), 7.18 (s, 1H), 3.93 (s, 3H), 3.17 (s, 3H). DMSO >98 G2/AQ3
    1331
    Figure US20170217923A1-20170803-C02467
    Figure US20170217923A1-20170803-C02468
    Figure US20170217923A1-20170803-C02469
         		1H NMR (300 MHz, DMSO) δ (s, 1H), 8.75 (d, J = 7.6 Hz, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H), 8.01-7.87 (m, 3H), 7.55 (s, 1H), 3.51 (s, 6H), 2.63 (s, 3H). DMSO >98 G2/AQ3
    1332
    Figure US20170217923A1-20170803-C02470
    Figure US20170217923A1-20170803-C02471
    Figure US20170217923A1-20170803-C02472
         		1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 8.83-8.72 (m, 1H), 8.70 (d, J = 3.8 Hz, 1H), 8.21 (s, 1H), 7.89 (q, J = 8.6 Hz, 2H), 7.74- 7.41 (m, 5H), 3.47 (s, 6H). DMSO >98 G2/AQ3
    1333
    Figure US20170217923A1-20170803-C02473
    Figure US20170217923A1-20170803-C02474
    Figure US20170217923A1-20170803-C02475
         		1H NMR (300 MHz, DMSO) δ 9.62 (d, J = 2.0 Hz, 1H), 8.76 (dt, J = 7.9, 1.8 Hz, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.38 (d, J = 1.9 Hz, 1H), 8.13 (dd, J = 8.7, 1.9 Hz, 1H), 7.98- 7.84 (m, 2H), 7.78 (d, J = 7.6 Hz, 1H), 7.66- 7.41 (m, 3H), 3.51 (s, 6H). DMSO >98 G2/AQ3
    1334
    Figure US20170217923A1-20170803-C02476
    Figure US20170217923A1-20170803-C02477
    Figure US20170217923A1-20170803-C02478
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.81-9.63 (m, 1H), 9.18 (d, J = 8.4 Hz, 1H), 9.07-8.89 (m, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.31 (d, J = 1.7 Hz, 1H), 8.22-8.07 (m, 1H), 8.02 (dd, J = 8.7, 1.7 Hz, 1H), 7.98-7.91 (m, 1H), 7.91- DMSO >98 G2/AQ3
    7.83 (m, 1H), 7.80-7.68 (m,
    2H), 3.65 (s, 6H).
    1335
    Figure US20170217923A1-20170803-C02479
    Figure US20170217923A1-20170803-C02480
    Figure US20170217923A1-20170803-C02481
         		1H NMR (300 MHz, DMSO) δ 9.65-9.62 (m, 1H), 8.82-8.75 (m, 1H), 8.73-8.68 (m, 1H), 8.61-8.56 (m, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.34-8.20 (m, 3H), 7.97 (d, J = 8.7 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.57 DMSO >98 G2/AQ3
    (dd, J = 8.3, 5.2 Hz,
    1H), 3.54 (s, 6H).
    1336
    Figure US20170217923A1-20170803-C02482
    Figure US20170217923A1-20170803-C02483
    Figure US20170217923A1-20170803-C02484
         		1H NMR (300 MHz, DMSO) δ 9.61 (d, J = 1.8 Hz, 1H), 8.80-8.72 (m, 1H), 8.72-8.67 (m, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.39-8.29 (m, 2H), 8.19 (dd, J = 8.7, 1.8 Hz, 1H), 8.14-8.07 (m, 2H), 7.94 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 3.52 (s, 6H). DMSO >98 G2/AQ3
    1337
    Figure US20170217923A1-20170803-C02485
    Figure US20170217923A1-20170803-C02486
    Figure US20170217923A1-20170803-C02487
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.61-9.61 (m, 1H), 8.82-8.73 (m, 1H), 8.73- 8.65 (m, 1H), 8.39 (s, 1H), 8.03-7.96 (m, 3H), 7.90-7.72 (m, 2H), 7.72-7.60 (m, 1H), 7.56 (dd, J = 7.6, 5.1 Hz, 1H), 3.53 (s, 6H), DMSO >98 G2/AQ3
    1338
    Figure US20170217923A1-20170803-C02488
    Figure US20170217923A1-20170803-C02489
    Figure US20170217923A1-20170803-C02490
         		1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 2.1 Hz, 1H), 8.78 (dt, J = 8.1, 1.8 Hz, 1H), 8.71-8.59 (m, 3H), 8.19 (dd, J = 8.6, 1.7 Hz, 1H), 8.07-7.95 (m, 2H), 7.93- 7.81 (m, 2H), 7.54 (dd, J = 7.9, 4.7 Hz, 1H), 7.47-7.34 (m, 2H), 3.23-3.20 (m, 3H). DMSO >98 G2/AQ3
    1339
    Figure US20170217923A1-20170803-C02491
    Figure US20170217923A1-20170803-C02492
    Figure US20170217923A1-20170803-C02493
         		1H NMR (300 MHz, DMSO) δ 9.68-9.64 (m, 1H), 8.83-8.75 (m, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.56-8.45 (m, 2H), 8.17-8.05 (m, 1H), 8.05-7.87 (m, 4H), 7.58-7.40 (m, 3H), 3.18 (d, J = 4.1 Hz, 3H). DMSO >98 G2/AQ3
    1340
    Figure US20170217923A1-20170803-C02494
    Figure US20170217923A1-20170803-C02495
    Figure US20170217923A1-20170803-C02496
         		1H NMR (300 MHz, DMSO) δ 9.67 (d, J = 1.5 Hz, 1H), 8.80 (dt, J = 7.9, 1.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.57-8.41 (m, 2H), 8.08 (dd, J = 6.1, 2.6 Hz, 1H), 7.99 (dd, J = 8.6, 1.8 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.62- 7.44 (m, 4H), 3.17 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3
    1341
    Figure US20170217923A1-20170803-C02497
    Figure US20170217923A1-20170803-C02498
    Figure US20170217923A1-20170803-C02499
         		1H NMR (300 MHz, DMSO) δ 9.66 (d, J = 1.5 Hz, 1H), 8.79 (dt, J = 7.9, 1.9 Hz, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.65 (d, J = 1.9 Hz, 1H), 8.61-8.53 (m, 1H), 8.35 (d, J = 1.6 Hz, 1H), 8.21 (dd, J = 8.7, 2.0 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.92-7.80 (m, 3H), 7.59-7.48 (m, 2H), 3.21 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3
    1342
    Figure US20170217923A1-20170803-C02500
    Figure US20170217923A1-20170803-C02501
    Figure US20170217923A1-20170803-C02502
         		1H NMR (300 MHz, DMSO) δ 9.66 (d, J = 1.6 Hz, 1H), 8.79 (dt, J = 8.0, 1.9 Hz, 1H), 8.73-8.61 (m, 3H), 8.50 (s, 1H), 8.24 (dd, J = 8.7, 1.9 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.96-7.82 (m, 3H), 7.60-7.50 (m, 2H), 3.21 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1343
    Figure US20170217923A1-20170803-C02503
    Figure US20170217923A1-20170803-C02504
    Figure US20170217923A1-20170803-C02505
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.41 (brs, 1H), 9.75 (d, J = 1.7 Hz, 1H), 9.24-9.19 (m, 1H), 9.01 (dd, J = 5.2, 1.5 Hz, 1H), 8.90 (d, J = 1.5 Hz, 1H), 8.46 (d, J = 8.7 Hz, 1H), 8.39 (dd, J = 8.7, 1.7 Hz, 1H), 8.06-7.91 (m, 2H), 7.86 (d, J = 5.5 Hz, 1H), 7.66-7.52 (m, 3H), 3.29 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3
    1344
    Figure US20170217923A1-20170803-C02506
    Figure US20170217923A1-20170803-C02507
    Figure US20170217923A1-20170803-C02508
         		HCl 1H NMR (300 MHz, DMSO) δ 10.33 (brs, 1H), 9.78 (d, J = 2.0 Hz, 1H), 9.23 (d, J = 8.1 Hz, 1H), 9.01 (d, J = 5.0 Hz, 1H), 8.73 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.95 (dd, J = 8.1, 5.2 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.72-7.50 (m, 4H), 3.27 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1345
    Figure US20170217923A1-20170803-C02509
    Figure US20170217923A1-20170803-C02510
    Figure US20170217923A1-20170803-C02511
         		1H NMR (300 MHz, DMSO) δ 9.68 (d, J = 1.4 Hz, 1H), 8.85-8.77 (m, 1H), 8.77- 8.62 (m, 3H), 8.40 (s, 1H), 8.30 (dd, J = 8.7, 1.6 Hz, 1H), 8.14-7.95 (m, 4H), 7.91 (d, J = 8.7 Hz, 1H), 7.63-7.50 (m, 3H), 3.22 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1346
    Figure US20170217923A1-20170803-C02512
    Figure US20170217923A1-20170803-C02513
    Figure US20170217923A1-20170803-C02514
         		1H NMR (300 MHz, DMSO) δ 9.67 (d, J = 2.0 Hz, 1H), 8.80 (dt, J = 8.0, 1.9 Hz, 1H), 8.69 (dd, J = 4.7, 1.7 Hz, 1H), 8.67-8.55 (m, 2H), 8.25 (dd, J = 8.7, 1.8 Hz, 1H), 8.13-8.09 (m, 1H), 7.92- 7.77 (m, 4H), 7.71 (d, J = 7.8 Hz, 1H), 7.67-7.47 (m, 4H), 7.47- 7.37 (m, 1H), 3.20 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1347
    Figure US20170217923A1-20170803-C02515
    Figure US20170217923A1-20170803-C02516
    Figure US20170217923A1-20170803-C02517
         		1H NMR (300 MHz, DMSO) δ 9.68- 9.65 (m, 1H), 8.79 (dt, J = 8.0, 1.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.68-8.60 (m, 2H), 8.20 (dd, J = 8.7, 1.9 Hz, 1H), 7.99-7.95 (m, 2H), 7.92-7.81 (m, 3H), 7.80-7.73 (m, 2H), 7.61-7.46 (m, 3H), 7.46-7.36 (m, 1H), 3.20 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1348
    Figure US20170217923A1-20170803-C02518
    Figure US20170217923A1-20170803-C02519
    Figure US20170217923A1-20170803-C02520
         		1H NMR (300 MHz, DMSO) δ 9.66 (d, J = 1.5 Hz, 1H), 8.80 (dt, J = 7.9, 1.9 Hz, 1H), 8.70 (dd, J = 4.7, 1.7 Hz, 1H), 8.55 (d, J = 4.6 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.92- 7.84 (m, 3H), 7.60-7.50 (m, 3H), 7.50-7.42 (m, 1H), 3.18 (d, J = 4.5 Hz, 3H). DMSO >98 G2/AQ3
    1349
    Figure US20170217923A1-20170803-C02521
    Figure US20170217923A1-20170803-C02522
    Figure US20170217923A1-20170803-C02523
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.23 (brs, 1H), 9.67 (d, J = 2.1 Hz, 1H), 9.04 (d, J = 7.7 Hz, 1H), 8.98-8.91 (m, 1H), 8.57 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.91-7.76 (m, 3H), 7.22-7.10 (m, 2H), 3.85 (s, 3H), 3.31 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1350
    Figure US20170217923A1-20170803-C02524
    Figure US20170217923A1-20170803-C02525
    Figure US20170217923A1-20170803-C02526
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.48 (brs, 1H), 9.74 (d, J = 1.9 Hz, 1H), 9.19 (d, J = 8.3 Hz, 1H), 9.07-8.97 (m, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.64 (s, 1H), 8.36 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.16-8.06 (m, 2H), 7.95 (dd, J = 8.1, 5.0 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 3.31 (d, J = 4.4 Hz, 3H), 2.71 (s, 3H). DMSO >98 G2/AQ3
    1351
    Figure US20170217923A1-20170803-C02527
    Figure US20170217923A1-20170803-C02528
    Figure US20170217923A1-20170803-C02529
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.47 (brs, 1H), 9.73 (d, J = 1.3 Hz, 1H), 9.19 (d, J = 8.3 Hz, 1H), 9.03-8.94 (m, 1H), 8.69-8.62 (m, 2H), 8.15-8.07 (m, 3H), 8.02-7.77 (m, 3H), 3.29 (d, J = 4.3 Hz, 3H), 2.65 (s, 3H). DMSO >98 G2/AQ3
    1352
    Figure US20170217923A1-20170803-C02530
    Figure US20170217923A1-20170803-C02531
    Figure US20170217923A1-20170803-C02532
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.44 (brs, 1H), 9.74 (s, 1H), 9.19 (d, J = 7.3 Hz, 1H), 8.99 (d, J = 5.2 Hz, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.03-7.90 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.72-7.62 (m, 1H), 7.53 (d, J = 9.6 Hz, 3H), 3.32 (d, J = 4.0 Hz, 3H). DMSO >98 G2/AQ3
    1353
    Figure US20170217923A1-20170803-C02533
    Figure US20170217923A1-20170803-C02534
    Figure US20170217923A1-20170803-C02535
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.48 (brs, 1H), 9.77 (s, 1H), 9.29- 9.23 (m, 1H), 9.05-8.97 (m, 1H), 8.74-8.59 (m, 2H), 8.20- 8.08 (m, 1H), 8.02-7.95 (m, 1H), 7.90 (s, 1H), 7.84-7.79 (m, 1H), 7.68-7.57 (m, 2H), 3.35- 3.29 (m, 3H). DMSO >98 G2/AQ3
    1354
    Figure US20170217923A1-20170803-C02536
    Figure US20170217923A1-20170803-C02537
    Figure US20170217923A1-20170803-C02538
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.35 (brs, 1H), 9.72 (d, J = 2.0 Hz, 1H), 9.21-9.11 (m, 1H), 8.98 (dd, J = 5.1, 1.4 Hz, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.59 (s, 1H), 8.09 (dd, J = 8.8, 1.7 Hz, 1H), 7.95-7.82 (m, 3H), 7.70- 7.60 (m, 2H), 3.30 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1355
    Figure US20170217923A1-20170803-C02539
    Figure US20170217923A1-20170803-C02540
    Figure US20170217923A1-20170803-C02541
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.51 (brs, 1H), 9.77 (d, J = 1.9 Hz, 1H), 9.22 (d, J = 8.2 Hz, 1H), 9.01 (dd, J = 5.1, 1.4 Hz, 1H), 8.69 (s, 1H), 8.40 (d, J = 8.7 Hz, 1H), 8.17 (dd, J = 8.7, 1.6 Hz, 1H), 7.96 (dd, J = 8.1, 5.2 Hz, DMSO >98 G2/AQ3
    1H), 7.30-7.15 (m, 2H), 7.10
    (dd, J = 7.3, 1.9 Hz, 1H), 3.89 (s,
    3H), 3.59 (s, 3H), 3.30 (d, J = 4.5
    Hz, 3H).
    1356
    Figure US20170217923A1-20170803-C02542
    Figure US20170217923A1-20170803-C02543
    Figure US20170217923A1-20170803-C02544
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.42 (s, 1H), 9.71 (d, J = 1.8 Hz, 1H), 9.12 (d, J = 8.1 Hz, 1H), 8.97 (dd, J = 5.1, 1.5 Hz, 1H), 8.71 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.19 (dd, J = 8.7, 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 5.1 Hz, 1H), 7.18-7.06 (m, 2H), 7.01 (dd, J = 8.9, 3.1 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.30 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1357
    Figure US20170217923A1-20170803-C02545
    Figure US20170217923A1-20170803-C02546
    Figure US20170217923A1-20170803-C02547
         		HCl 1H NMR (300 MHz, DMSO) δ 10.21 (brs, 1H), 9.63 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.93 (d, J = 3.7 Hz, 1H), 8.87 (s, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.91-7.78 (m, 1H), 7.05 (d, J = 2.1 Hz, 2H), 6.66- 6.58 (m, 1H), 3.87 (s, 6H), 3.31 (d, J = 4.2 Hz, 3H). DMSO >98 G2/AQ3
    1358
    Figure US20170217923A1-20170803-C02548
    Figure US20170217923A1-20170803-C02549
    Figure US20170217923A1-20170803-C02550
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.43 (brs, 1H), 9.73 (d, J = 1.8 Hz, 1H), 9.17 (d, J = 8.2 Hz, 1H), 8.99 (dd, J = 5.0, 1.3 Hz, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.49 (s, 1H), 8.05-7.88 (m, 2H), 7.71 (t, J = 7.9 Hz, 1H), 7.64-7.50 (m, 1H), 7.50-7.33 (m, 2H), 3.32 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1359
    Figure US20170217923A1-20170803-C02551
    Figure US20170217923A1-20170803-C02552
    Figure US20170217923A1-20170803-C02553
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.29 (s, 1H), 9.70 (d, J = 1.7 Hz, 1H), 9.14 (d, J = 8.3 Hz, 1H), 8.97 (dd, J = 5.1, 1.3 Hz, 1H), 8.63 (d, J = 8.7 Hz, 1H), 8.58 (s, 1H), 8.15-8.04 (m, 1H), 7.90 (dd, J = 8.0, 5.1 Hz, 1H), 7.75- 7.57 (m, 3H), 7.43-7.30 (m, 1H), 3.30 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1360
    Figure US20170217923A1-20170803-C02554
    Figure US20170217923A1-20170803-C02555
    Figure US20170217923A1-20170803-C02556
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.41 (brs, 1H), 9.73 (d, J = 1.9 Hz, 1H), 9.16 (d, J = 8.3 Hz, 1H), 8.98 (dd, J = 5.1, 1.4 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.60 (s, 1H), 8.12-8.02 (m, 1H), 8.00- 7.84 (m, 3H), 7.49-7.33 (m, 2H), 3.30 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1361
    Figure US20170217923A1-20170803-C02557
    Figure US20170217923A1-20170803-C02558
    Figure US20170217923A1-20170803-C02559
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.39 (s, 1H), 9.71 (d, J = 1.8 Hz, 1H), 9.17-9.08 (m, 1H), 8.97 (dd, J = 5.1, 1.5 Hz, 1H), 8.64 (d, J = 8.7 Hz, 1H), 8.58 (s, 1H), 8.07 (dd, J = 8.6, 1.7 Hz, 1H), 7.88 (dd, J = 8.1, 5.2 Hz, 1H), DMSO >98 G2/AQ3
    7.70-7.58 (m, 2H), 7.46 (t, J =
    7.6 Hz, 1H), 7.33 (d, J = 7.4 Hz,
    1H), 3.30 (d, J = 4.4 Hz, 3H),
    2.43 (s, 3H).
    1362
    Figure US20170217923A1-20170803-C02560
    Figure US20170217923A1-20170803-C02561
    Figure US20170217923A1-20170803-C02562
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.37 (brs, 1H), 9.70 (d, J = 1.7 Hz, 1H), 9.10 (d, J = 8.1 Hz, 1H), 8.96 (dd, J = 5.0, 1.4 Hz, 1H), 8.62 (d, J = 8.7 Hz, 1H), 8.58 (s, 1H), 8.08 (dd, J = 8.6, 1.6 Hz, 1H), 7.87 (dd, J = 7.9, 5.0 Hz, 1H), 7.74 (d, J = 8.2 Hz, 2H), DMSO >98 G2/AQ3
    7.39 (d, J = 8.0 Hz, 2H), 3.30 (d,
    J = 4.4 Hz, 3H), 2.40 (s, 3H).
    1363
    Figure US20170217923A1-20170803-C02563
    Figure US20170217923A1-20170803-C02564
    Figure US20170217923A1-20170803-C02565
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.82 (brs, 1H), 9.65 (s, 1H), 9.14- 9.02 (m, 1H), 9.02-8.90 (m, 1H), 8.64-8.51 (m, 1H), 8.20 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.00-7.85 (m, 3H), 7.85-7.66 (m, 2H), 3.30 (s, 3H). DMSO >98 G2/AQ3
    1364
    Figure US20170217923A1-20170803-C02566
    Figure US20170217923A1-20170803-C02567
    Figure US20170217923A1-20170803-C02568
         		HCl 1H NMR (300 MHz, DMSO) δ 9.83 (brs, 1H), 9.68-9.63 (m, 1H), 9.12-9.02 (m, 1H), 9.01-8.91 (m, 1H), 8.56 (d, J = 9.2 Hz, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 9.3 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.93-7.84 (m, 1H), 7.79 (t, DMSO >98 G2/AQ3
    J = 8.2 Hz, 1H), 3.28 (d, J = 4.5
    Hz, 3H).
    1365
    Figure US20170217923A1-20170803-C02569
    Figure US20170217923A1-20170803-C02570
    Figure US20170217923A1-20170803-C02571
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.27 (brs, 1H), 9.72 (s, 1H), 9.23- 9.10 (m, 1H), 8.98 (s, 1H), 8.77- 8.55 (m, 2H), 8.18-7.86 (m, 6H), 3.34-3.27 (m, 3H). DMSO >98 G2/AQ3
    1366
    Figure US20170217923A1-20170803-C02572
    Figure US20170217923A1-20170803-C02573
    Figure US20170217923A1-20170803-C02574
         		1H NMR (300 MHz, DMSO) δ 9.66 (d, J = 2.0 Hz, 1H), 8.79 (dt, J = 7.9, 1.9 Hz, 1H), 8.69 (dd, J = 4.7, 1.6 Hz, 1H), 8.65-8.53 (m, 2H), 8.22-8.12 (m, 3H), 7.92 (dd, J = 8.8, 1.5 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 4.11 (s, 3H), 3.20 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1367
    Figure US20170217923A1-20170803-C02575
    Figure US20170217923A1-20170803-C02576
    Figure US20170217923A1-20170803-C02577
         		1H NMR (300 MHz, DMSO) δ 11.10 (s, 1H), 9.63 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.81-8.70 (m, 2H), 8.39 (dd, J = 8.9, 1.9 Hz, 1H), 8.15-8.02 (m, 5H), 7.60 (dd, J = 8.0, 4.8 Hz, 1H), 2.65 (s, 3H), 2.61 (s, 3H). DMSO >98 G2/AQ3
    1368
    Figure US20170217923A1-20170803-C02578
    Figure US20170217923A1-20170803-C02579
    Figure US20170217923A1-20170803-C02580
         		HCl 1H NMR (300 MHz, DMSO) δ 9.72 (d, J = 1.8 Hz, 1H), 9.27-9.21 (m, 1H), 8.97 (dd, J = 5.3, 1.4 Hz, 1H), 8.50 (dd, J = 8.8, 2.1 Hz, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.15- 8.09 (m, 2H), 8.09-7.98 (m, 3H), 3.55 (s, 3H), 2.65 (s, 3H), 2.22 (s, 3H). DMSO >98 G2/AQ3
    1369
    Figure US20170217923A1-20170803-C02581
    Figure US20170217923A1-20170803-C02582
    Figure US20170217923A1-20170803-C02583
         		HCl 1H NMR (300 MHz, DMSO) δ 11.16 (s, 1H), 9.67 (s, 1H), 9.20 (d, J = 8.2 Hz, 1H), 8.97 (d, J = 4.3 Hz, 1H), 8.75 (s, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.02 (dd, J = 8.0, 5.5 Hz, 1H), 7.66-7.47 (m, 2H), 7.47- 7.34 (m, 1H), 2.56 (s, 3H). DMSO >98 G2/AQ3
    1370
    Figure US20170217923A1-20170803-C02584
    Figure US20170217923A1-20170803-C02585
    Figure US20170217923A1-20170803-C02586
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.17 (brs, 1H), 9.68 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 8.0 Hz, 1H), 8.95 (dd, J = 5.0, 1.4 Hz, 1H), 8.77 (s, 1H), 8.31 (s, 2H), 8.16 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 7.8, 5.2 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.61-7.47 (m, 2H), 7.19 (d, J = 1.4 Hz, 1H), 3.31 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1371
    Figure US20170217923A1-20170803-C02587
    Figure US20170217923A1-20170803-C02588
    Figure US20170217923A1-20170803-C02589
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.28 (brs, 1H), 9.71 (s, 1H), 9.16 (d, J = 7.9 Hz, 1H), 8.98 (d, J = 4.2 Hz, 1H), 8.67 (d, J = 8.9 Hz, 1H), 8.45 (s, 1H), 8.01-7.83 (m, 2H), 7.68-7.50 (m, 2H), 7.50- 7.35 (m, 1H), 3.31 (d, J = 4.1 Hz, 3H). DMSO >98 G2/AQ3
    1372
    Figure US20170217923A1-20170803-C02590
    Figure US20170217923A1-20170803-C02591
    Figure US20170217923A1-20170803-C02592
         		HCl 1H NMR (300 MHz, DMSO) δ 9.72- 9.45 (m, 2H), 8.9 (d, J = 7.6 Hz, 1H), 8.88 (d, J = 3.8 Hz, 1H), 8.49 (d, J = 8.5 Hz, 1H), 8.13 (s, 1H), 7.91-7.75 (m, 3H), 7.53- 7.43 (m, 1H), 7.36-7.25 (m, 1H), 3.27 (d, J = 4.3 Hz, 3H). DMSO >98 G2/AQ3
    1373
    Figure US20170217923A1-20170803-C02593
    Figure US20170217923A1-20170803-C02594
    Figure US20170217923A1-20170803-C02595
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.04 (brs, 1H), 9.70 (s, 1H), 9.22- 9.07 (m, 1H), 8.93 (s, 1H), 8.62 (d, J = 7.6 Hz, 1H), 8.55 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.99- 7.79 (m, 2H), 7.79-7.55 (m, 2H), 3.33-3.27 (m, 3H). DMSO >98 G2/AQ3
    1374
    Figure US20170217923A1-20170803-C02596
    Figure US20170217923A1-20170803-C02597
    Figure US20170217923A1-20170803-C02598
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 9.34 (brs, 1H), 9.06- 8.92 (m, 1H), 8.86 (s, 1H), 8.50- 8.37 (m, 1H), 8.25 (s, 1H), 8.11- 7.95 (m, 1H), 7.85-7.74 (m, 1H), 7.74-7.57 (m, 2H), 7.43- 7.29 (m, 1H), 3.28-3.21 (m, 3H). DMSO >98 G2/AQ3
    1375
    Figure US20170217923A1-20170803-C02599
    Figure US20170217923A1-20170803-C02600
    Figure US20170217923A1-20170803-C02601
         		HCl 1H NMR (300 MHz, DMSO) δ 9.63 (d, J = 1.6 Hz, 1H), 9.38 (brs, 1H), 9.01-8.91 (m, 1H), 8.84 (dd, J = 5.0, 1.6 Hz, 1H), 8.60 (s, 1H), 8.08 (s, 2H), 7.76 (dd, J = 7.9, 5.1 Hz, 1H), 7.64-7.38 (m, 2H), 3.26 (d, J = 3.7 Hz, 3H). DMSO >98 G2/AQ3
    1376
    Figure US20170217923A1-20170803-C02602
    Figure US20170217923A1-20170803-C02603
    Figure US20170217923A1-20170803-C02604
         		HCl 1H NMR (300 MHz, DMSO) δ 9.88 (brs, 1H), 9.65 (s, 1H), 9.18- 8.99 (m, 1H), 8.90 (s, 1H), 8.70 (s, 1H), 8.31-8.03 (m, 2H), 7.94- 7.77 (m, 2H), 7.77-7.57 (m, 1H), 3.28 (s, 3H). DMSO >98 G2/AQ3
    1377
    Figure US20170217923A1-20170803-C02605
    Figure US20170217923A1-20170803-C02606
    Figure US20170217923A1-20170803-C02607
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 9.67 (s, 1H), 9.10 (d, J = 7.8 Hz, 1H), 9.02 (s, 1H), 8.92 (d, J = 5.0 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.03-7.76 (m, 3H), 3.31 (s, 3H). DMSO >98 G2/AQ3
    1378
    Figure US20170217923A1-20170803-C02608
    Figure US20170217923A1-20170803-C02609
    Figure US20170217923A1-20170803-C02610
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.66 (d, J = 1.7 Hz, 1H), 9.56-9.34 (m, 1H), 9.26-9.10 (m, 1H), 9.05 (d, J = 4.7 Hz, 1H), 8.44 (s, 1H), 8.19 (dd, J = 8.1, 5.7 Hz, 1H), 7.95 (d, J = 11.5 Hz, 1H), 7.63-7.45 (m, 2H), 7.45-7.26 (m, 1H), 3.19 (d, J = 4.4 Hz, 3H). DMSO >98 G2/AQ3
    1379
    Figure US20170217923A1-20170803-C02611
    Figure US20170217923A1-20170803-C02612
    Figure US20170217923A1-20170803-C02613
         		HCl 1H NMR (300 MHz, DMSO) δ 9.67- 9.59 (m, 1H), 9.38 (d, J = 8.3 Hz, 1H), 9.22-9.10 (m, 1H), 9.03 (d, J = 4.9 Hz, 1H), 8.37 (s, 1H), 8.16 (dd, J = 8.1, 5.6 Hz, 1H), 7.89 (d, J = 11.6 Hz, 1H), 7.78 (td, J = 8.9, 6.6 Hz, 1H), 7.54-7.36 (m, 1H), 7.30 (td, J = DMSO >98 G2/AQ3
    8.3, 2.0 Hz, 1H), 3.18 (d, J = 4.4
    Hz, 3H).
    1380
    Figure US20170217923A1-20170803-C02614
    Figure US20170217923A1-20170803-C02615
    Figure US20170217923A1-20170803-C02616
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.72 (d, J = 1.6 Hz, 1H), 9.25-9.14 (m, 1H), 8.99 (dd, J = 5.2, 1.5 Hz, 1H), 8.51 (s, 1H), 8.44 (d, J = 8.7 Hz, 1H), 8.26-8.11 (m, 1H), 7.94 (dd, J = 8.0, 5.2 Hz, 1H), 7.65-7.49 (m, 2H), 7.49-7.29 (m, 1H), 3.69 (s, 6H). DMSO >98 G2/AQ3
    1381
    Figure US20170217923A1-20170803-C02617
    Figure US20170217923A1-20170803-C02618
    Figure US20170217923A1-20170803-C02619
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.71 (s, 1H), 9.18 (d, J = 8.0 Hz, 1H), 8.98 (d, J = 5.1 Hz, 1H), 8.49- 8.36 (m, 2H), 8.16 (d, J = 8.8 Hz, 1H), 7.99-7.86 (m, 1H), 7.86- 7.72 (m, 1H), 7.46 (t, J = 10.2 Hz, 1H), 7.29 (t, J = 8.5 Hz, 1H), 3.69 (s, 6H). DMSO >98 G2/AQ3
    1382
    Figure US20170217923A1-20170803-C02620
    Figure US20170217923A1-20170803-C02621
    Figure US20170217923A1-20170803-C02622
         		HCl 1H NMR (300 MHz, DMSO) δ 10.25 (brs, 1H), 9.66 (d, J = 1.6 Hz, 1H), 9.04 (d, J = 8.2 Hz, 1H), 8.94 (dd, J = 5.0, 1.6 Hz, 1H), 8.70 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.16 (dd, J = 8.7, 1.5 Hz, 1H), 7.84 (dd, J = 8.0, 5.1 Hz, 1H), 7.71 (dd, J = 8.0, 1.4 Hz, 1H), 7.65-7.55 (m, 2H), 3.90 (s, DMSO >98 G2/AQ3
    3H), 3.29 (d, J = 4.5 Hz, 3H),
    2.64 (s, 3H).
    1383
    Figure US20170217923A1-20170803-C02623
    Figure US20170217923A1-20170803-C02624
    Figure US20170217923A1-20170803-C02625
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.18 (brs, 1H), 9.68 (d, J = 1.8 Hz, 1H), 9.17 (d, J = 8.0 Hz, 1H), 8.99 (dd, J = 5.2, 1.4 Hz, 1H), 8.86 (s, 1H), 8.31 (d, J = 8.7 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.97 (dd, J = 8.0, 5.3 Hz, 1H), 7.64-7.49 (m, 2H), 7.49-7.34 DMSO >98 G2/AQ3
    (m, 1H), 4.06-3.92 (m, 2H),
    3.73 (t, J = 5.5 Hz, 2H), 3.33 (s,
    3H).
    1384
    Figure US20170217923A1-20170803-C02626
    Figure US20170217923A1-20170803-C02627
    Figure US20170217923A1-20170803-C02628
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.18 (brs, 1H), 9.67 (d, J = 1.6 Hz, 1H), 9.14 (d, J = 8.1 Hz, 1H), 8.99 (dd, J = 5.2, 1.5 Hz, 1H), 8.80 (s, 1H), 8.29 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.95 (dd, J = 8.2, 5.2 Hz, 1H), 7.79 (td, J = 8.9, 6.6 Hz, 1H), DMSO >98 G2/AQ3
    7.50 (ddd, J = 11.6, 9.3, 2.6 Hz,
    1H), 7.33 (td, J = 8.3, 2.3 Hz,
    1H), 4.08-3.94 (m, 3H), 3.73 (t,
    J = 5.5 Hz, 3H), 3.32 (s, 3H).
    1385
    Figure US20170217923A1-20170803-C02629
    Figure US20170217923A1-20170803-C02630
    Figure US20170217923A1-20170803-C02631
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.33 (brs, 1H), 9.70 (d, J = 1.7 Hz, 1H), 9.15 (d, J = 8.2 Hz, 1H), 8.99 (dd, J = 5.2, 1.5 Hz, 1H), 8.81 (s, 1H), 8.33 (d, s = 8.7 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.95 (dd, J = 8.1, 5.2 Hz, 1H), 7.81 (td, J = 8.9, 6.6 Hz, 1H), DMSO >98 G2/AQ3
    7.49 (ddd, J = 11.5, 9.3, 2.5 Hz,
    1H), 7.32 (td, J = 8.5, 2.2 Hz,
    1H), 3.96-3.78 (m, 2H), 3.48 (t,
    J = 6.1 Hz, 2H), 3.27 (s, 3H),
    2.14-1.93 (m, 2H).
    1386
    Figure US20170217923A1-20170803-C02632
    Figure US20170217923A1-20170803-C02633
    Figure US20170217923A1-20170803-C02634
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.73 (s, 1H), 9.17 (d, s = 8.4 Hz, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 8.43 (d, s = 8.8 Hz, 1H), 8.21 (d, s = 9.0 Hz, 1H), 8.02-7.90 (m, 1H), 7.87-7.78 (m, 1H), 7.57-7.38 (m, 1H), 7.38-7.24 (m, 1H), 4.31-4.18 (m, 4H), 2.08 (s, 4H). DMSO >98 G2/AQ3
    1387
    Figure US20170217923A1-20170803-C02635
    Figure US20170217923A1-20170803-C02636
    Figure US20170217923A1-20170803-C02637
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.68 (d, J = 1.7 Hz, 1H), 9.17 (d, J = 8.3 Hz, 1H), 8.99 (dd, J = 5.2, 1.5 Hz, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.24-8.12 (m, 2H), 7.97 (dd, J = 8.0, 5.2 Hz, 1H), 7.81 (td, J = 8.9, 6.6 Hz, 1H), 7.49 (ddd, J = 11.6, 9.3, 2.5 Hz, 1H), 7.30 (td, J = 8.4, 2.1 Hz, 1H), 4.16 (brs, 4H), 1.80 (brs, 6H). DMSO >98 G2/AQ3
    1388
    Figure US20170217923A1-20170803-C02638
    Figure US20170217923A1-20170803-C02639
    Figure US20170217923A1-20170803-C02640
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.70 (d, J = 1.7 Hz, 1H), 9.26 (d, J = 8.3 Hz, 1H), 9.01 (dd, J = 5.3, 1.4 Hz, 1H), 8.37-8.19 (m, 2H), 8.15 (d, J = 8.7 Hz, 1H), 8.02 (dd, J = 8.1, 5.3 Hz, 1H), 7.81 (td, J = 8.9, 6.5 Hz, 1H), 7.48 (ddd, J = 11.6, 9.3, 2.6 Hz, 1H), 7.30 (td, J = 8.4, 2.3 Hz, 1H), DMSO >98 G2/AQ3
    4.23-4.12 (m, 4H), 3.90-3.80
    (m, 4H).
    1389
    Figure US20170217923A1-20170803-C02641
    Figure US20170217923A1-20170803-C02642
    Figure US20170217923A1-20170803-C02643
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.68 (d, J = 1.7 Hz, 1H), 9.17 (d, J = 8.2 Hz, 1H), 8.99 (dd, J = 5.2, 1.5 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.27-8.13 (m, 2H), 7.97 (dd, J = 8.1, 5.4 Hz, 1H), 7.67-7.48 (m, 2H), 7.41 (ddd, J = 14.7, 9.9, 4.9 Hz, 1H), 4.16 (brs, 4H), 1.80 (brs, 6H). DMSO >98 G2/AQ3
    1390
    Figure US20170217923A1-20170803-C02644
    Figure US20170217923A1-20170803-C02645
    Figure US20170217923A1-20170803-C02646
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.70 (d, J = 1.8 Hz, 1H), 9.26 (d, J = 8.3 Hz, 1H), 9.01 (dd, J = 5.3, 1.4 Hz, 1H), 8.36-8.23 (m, 2H), 8.18 (d, J = 8.7 Hz, 1H), 8.03 (dd, J = 8.0, 5.4 Hz, 1H), 7.64- 7.46 (m, 2H), 7.46-7.29 (m, 1H), 4.23-4.16 (m, 4H), 3.85 (d, J = 4.7 Hz, 4H). DMSO >98 G2/AQ3
    1391
    Figure US20170217923A1-20170803-C02647
    Figure US20170217923A1-20170803-C02648
    Figure US20170217923A1-20170803-C02649
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.68 (d, J = 1.7 Hz, 1H), 9.18 (d, J = 8.2 Hz, 1H), 9.00 (dd, J = 5.2, 1.2 Hz, 1H), 8.62 (s, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.98 (dd, J = 8.0, 5.2 Hz, 1H), 7.64-7.47 (m, 2H), 7.46- 7.27 (m, 1H), 4.26 (t, J = 5.2 Hz, DMSO >98 G2/AQ3
    2H), 3.85 (t, J = 5.3 Hz, 2H), 3.72
    (s, 3H), 3.33 (s, 3H).
    1392
    Figure US20170217923A1-20170803-C02650
    Figure US20170217923A1-20170803-C02651
    Figure US20170217923A1-20170803-C02652
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.67 (d, J = 1.7 Hz, 1H), 9.15 (d, J = 8.1 Hz, 1H), 8.99 (d, J = 4.1 Hz, 1H), 8.56 (s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.96 (dd, J = 8.1, 5.2 Hz, 1H), 7.86-7.70 (m, 1H), 7.55-7.40 (m, 1H), 7.30 (td, J = 8.5, 2.2 Hz, DMSO >98 G2/AQ3
    1H), 4.36-4.18 (m, 2H), 3.88-
    3.77 (m, 2H), 3.72 (s, 3H), 3.33
    (s, 3H).
    1393
    Figure US20170217923A1-20170803-C02653
    Figure US20170217923A1-20170803-C02654
    Figure US20170217923A1-20170803-C02655
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.70 (d, J = 1.7 Hz, 1H), 9.24-9.06 (m, 1H), 8.99 (dd, J = 5.1, 1.5 Hz, 1H), 8.52 (s, 1H), 8.40 (d, J = 8.7 Hz, 1H), 8.30-8.14 (m, 1H), 7.93 (dd, J = 8.0, 5.2 Hz, 1H), 7.63-7.46 (m, 2H), 7.46-7.25 (m, 1H), 4.22-4.11 (m, 2H), DMSO >98 G2/AQ3
    3.73 (s, 3H), 3.59 (t, J = 5.9 Hz,
    2H), 2.10-1.92 (m, 2H).
    1394
    Figure US20170217923A1-20170803-C02656
    Figure US20170217923A1-20170803-C02657
    Figure US20170217923A1-20170803-C02658
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.68 (d, J = 1.7 Hz, 1H), 9.11 (d, J = 8.3 Hz, 1H), 8.97 (dd, J = 5.1, 1.5 Hz, 1H), 8.46 (s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 8.1, 5.2 Hz, 1H), 7.80 (td, J = 8.9, 6.6 Hz, 1H), 7.47 (ddd, J = 11.6, 9.3, 2.6 DMSO >98 G2/AQ3
    Hz, 1H), 7.29 (td, J = 8.4, 2.1 Hz,
    1H), 4.22-4.08 (m, 2H), 3.72 (s,
    3H), 3.59 (t, J = 5.9 Hz, 2H), 2.10-
    1.94 (m, 2H).
    1395
    Figure US20170217923A1-20170803-C02659
    Figure US20170217923A1-20170803-C02660
    Figure US20170217923A1-20170803-C02661
         		HCl 1H NMR (300 MHz, DMSO) δ 9.97- 9.66 (m, 2H), 9.66-9.58 (m, 1H), 9.17-9.05 (m, 1H), 8.99 (dd, J = 5.2, 1.5 Hz, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.50 (s, 1H), 8.01-7.88 (m, 2H), 7.62 (ddd, J = 9.1, 6.1, 3.1 Hz, 1H), 7.58- 7.36 (m, 2H). DMSO >98 G2/AQ3
    1396
    Figure US20170217923A1-20170803-C02662
    Figure US20170217923A1-20170803-C02663
    Figure US20170217923A1-20170803-C02664
         		HCl 1H NMR (300 MHz, DMSO) δ 9.70 (d, J = 1.8 Hz, 1H), 9.16 (d, J = 8.3 Hz, 1H), 8.98 (d, J = 3.9 Hz, 1H), 8.58-8.42 (m, 2H), 8.00- 7.82 (m, 2H), 7.69-7.38 (m, 3H), 3.69 (s, 6H). DMSO >98 G2/AQ3
    1397
    Figure US20170217923A1-20170803-C02665
    Figure US20170217923A1-20170803-C02666
    Figure US20170217923A1-20170803-C02667
         		HCl 1H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 9.68 (d, J = 1.8 Hz, 1H), 9.11 (d, J = 8.0 Hz, 1H), 9.04 (s, 1H), 8.96 (dd, J = 5.1, 1.4 Hz, 1H), 8.41 (dd, J = 8.8, 1.6 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.4 Hz, 3H), 3.34 (t, J = 17.1 Hz, 3H). DMSO >98 AQ4
    1398
    Figure US20170217923A1-20170803-C02668
    Figure US20170217923A1-20170803-C02669
    Figure US20170217923A1-20170803-C02670
         		HCl 1H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 9.65 (d, J = 1.7 Hz, 1H), 9.06 (d, J = 7.9 Hz, 1H), 8.99-8.90 (m, 2H), 8.44 (d, J = 7.2 Hz, 1H), 8.28-8.17 (m, 3H), 7.94-7.76 (m, 3H), 3.32 (d, J = 4.5 Hz, 3H). DMSO >98 AQ4
    1399
    Figure US20170217923A1-20170803-C02671
    Figure US20170217923A1-20170803-C02672
    Figure US20170217923A1-20170803-C02673
         		HCl 1H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 9.65 (d, J = 2.1 Hz, 1H), 9.10-9.00 (m, 1H), 8.96 (dd, J = 5.1, 1.5 Hz, 1H), 8.65 (s, 1H), 8.26-8.17 (m, 1H), 8.16- 8.07 (m, 1H), 7.90 (dd, J = 7.8, 5.3 Hz, 1H), 7.77-7.69 (m, 1H), 7.68-7.55 (m, 3H), 3.29 (d, J = 4.6 Hz, 3H). DMSO >98 AQ4
    1400
    Figure US20170217923A1-20170803-C02674
    Figure US20170217923A1-20170803-C02675
    Figure US20170217923A1-20170803-C02676
         		HCl 1H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 9.63 (d, J = 1.7 Hz, 1H), 9.04-8.85 (m, 2H), 8.63 (s, 1H), 8.12 (q, J = 8.7 Hz, 2H), 7.83 (dd, J = 7.8, 4.9 Hz, 1H), 7.38- 7.25 (m, 2H), 7.25-7.17 (m, 1H), 3.92 (s, 3H). DMSO >98 AQ4
    1401
    Figure US20170217923A1-20170803-C02677
    Figure US20170217923A1-20170803-C02678
    Figure US20170217923A1-20170803-C02679
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 9.64 (d, J = 1.7 Hz, 1H), 9.04 (d, J = 7.6 Hz, 1H), 8.99-8.92 (m, 1H), 8.89 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.33- 8.20 (m, 2H), 8.16 (d, J = 8.6 Hz, 1H), 7.94-7.84 (m, 1H), 7.81- 7.68 (m, 1H), 3.32 (d, J = 4.5 Hz, 3H). DMSO >98 AQ4
    1402
    Figure US20170217923A1-20170803-C02680
    Figure US20170217923A1-20170803-C02681
    Figure US20170217923A1-20170803-C02682
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 9.68 (d, J = 1.8 Hz, 1H), 9.15-9.05 (m, 1H), 8.97 (dd, J = 5.1, 1.4 Hz, 1H), 8.52 (s, 1H), 8.10 (s, 1H), 7.96-7.82 (m, 1H), 7.67-7.55 (m, 1H), 7.42- 7.26 (m, 3H), 3.31 (d, J = 4.5 Hz, 3H), 2.40 (s, 3H). DMSO >98 AQ5
    1403
    Figure US20170217923A1-20170803-C02683
    Figure US20170217923A1-20170803-C02684
    Figure US20170217923A1-20170803-C02685
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 9.59 (d, J = 1.5 Hz, 1H), 9.00-8.89 (m, 2H), 8.42 (s, 1H), 7.93-7.80 (m, 2H), 7.62-7.54 (m, 1H), 7.49-7.36 (m, 3H), 3.30 (d, J = 4.6 Hz, 3H), 2.32 (s, 3H). DMSO >98 AQ5
    1404
    Figure US20170217923A1-20170803-C02686
    Figure US20170217923A1-20170803-C02687
    Figure US20170217923A1-20170803-C02688
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.68-9.61 (m, 1H), 9.05-8.98 (m, 1H), 8.94 (dd, J = 5.0, 1.6 Hz, 1H), 8.48 (d, J = 5.7 Hz, 1H), 8.02 (s, 1H), 7.91-7.82 (m, 1H), 7.59-7.50 (m, 2H), 7.43-7.36 (m, 2H), 3.31 (d, J = 4.6 Hz, 3H), 2.40 (s, 3H). DMSO >98 AQ5
    1405
    Figure US20170217923A1-20170803-C02689
    Figure US20170217923A1-20170803-C02690
    Figure US20170217923A1-20170803-C02691
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 9.69-9.61 (m, 1H), 9.11-9.02 (m, 1H), 8.95 (dd, J = 5.1, 1.5 Hz, 1H), 8.52 (s, 1H), 8.05 (s, 1H), 7.89 (dd, J = 8.1, 5.1 Hz, 1H), 7.68-7.56 (m, 1H), 7.48-7.38 (m, 1H), 7.33- 7.25 (m, 1H), 3.31 (d, J = 4.6 Hz, 3H), 2.33 (s, 3H). DMSO >98 AQ5
    1406
    Figure US20170217923A1-20170803-C02692
    Figure US20170217923A1-20170803-C02693
    Figure US20170217923A1-20170803-C02694
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 9.63 (dd, J = 2.2, 0.7 Hz, 1H), 9.09-9.00 (m, 1H), 8.95 (dd, J = 5.1, 1.6 Hz, 1H), 8.48 (s, 1H), 8.00 (s, 1H), 7.89 (dd, J = 7.9, 5.2 Hz, 1H), 7.54- 7.35 (m, 3H), 3.30 (d, J = 4.6 Hz, 3H), 2.33 (s, 3H). DMSO >98 AQ5
    1407
    Figure US20170217923A1-20170803-C02695
    Figure US20170217923A1-20170803-C02696
    Figure US20170217923A1-20170803-C02697
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.09 (s, 1H), 9.63 (d, J = 1.6 Hz, 1H), 9.08-8.98 (m, 1H), 8.95 (dd, J = 5.1, 1.5 Hz, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.87 (dd, J = 8.1, 5.1 Hz, 1H), 7.64 (ddt, J = 16.8, 14.3, 5.3 Hz, 2H), 7.40- 7.30 (m, 1H), 3.30 (d, J = 4.6 Hz, 3H), 2.41 (s, 3H). DMSO >98 AQ5
    1408
    Figure US20170217923A1-20170803-C02698
    Figure US20170217923A1-20170803-C02699
    Figure US20170217923A1-20170803-C02700
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.92 (s, 1H), 9.61 (d, J = 1.6 Hz, 1H), 9.03-8.97 (m, 1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.42 (s, 1H), 7.93 (s, 1H), 7.87 (dd, J = 8.1, 5.0 Hz, 1H), 7.44-7.36 (m, 1H), 7.33-7.23 (m, 2H), 3.29 (d, J = 4.6 Hz, 3H), 2.41 (s, 3H). DMSO >98 AQ5
    1409
    Figure US20170217923A1-20170803-C02701
    Figure US20170217923A1-20170803-C02702
    Figure US20170217923A1-20170803-C02703
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 9.64 (d, J = 2.2 Hz, 1H), 9.10-9.03 (m, 1H), 8.96 (dd, J = 5.1, 1.5 Hz, 1H), 8.49 (s, 1H), 8.05-7.94 (m, 3H), 7.94- 7.88 (m, 1H), 7.88-7.82 (m, 1H), 7.77 (t, J = 7.7 Hz, 1H), 3.31 (d, J = 4.5 Hz, 3H), 2.40 (s, 3H). DMSO >98 AQ5
    1410
    Figure US20170217923A1-20170803-C02704
    Figure US20170217923A1-20170803-C02705
    Figure US20170217923A1-20170803-C02706
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 9.67 (d, J = 1.6 Hz, 1H), 9.14-9.07 (m, 1H), 8.97 (dd, J = 5.1, 1.5 Hz, 3H), 8.52 (s, 1H), 8.10-8.00 (m, 3H), 7.91 (dd, J = 7.9, 5.3 Hz, 1H), 7.75- 7.67 (m, 2H), 3.31 (d, J = 4.5 Hz, 3H), 2.39 (s, 3H). DMSO >98 AQ5
    1411
    Figure US20170217923A1-20170803-C02707
    Figure US20170217923A1-20170803-C02708
    Figure US20170217923A1-20170803-C02709
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.20-9.85 (m, 1H), 9.58 (s, 1H), 8.94-8.85 (m, 2H), 8.38 (s, 1H), 7.88-7.76 (m, 2H)(7.54- 7.44 (m, 1H), 7.24-7.16 (m, 2H), 7.12 (td, J = 7.4, 0.9 Hz, 1H), 3.76 (s, 3H), 3.31 (d, J = 4.5 Hz, 3H), 2.24 (s, 3H). DMSO >98 AQ5
    1412
    Figure US20170217923A1-20170803-C02710
    Figure US20170217923A1-20170803-C02711
    Figure US20170217923A1-20170803-C02712
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.69-9.61 (m, 1H), 9.01 (d, J = 7.8 Hz, 1H), 8.93 (dd, J = 5.0, 1.6 Hz, 1H), 8.49 (s, 1H), 8.06 (s, 1H), 7.83 (dd, J = 8.0, 5.1 Hz, 1H), 7.51- 7.41 (m, 1H), 7.13-7.05 (m, 1H), 7.05-6.95 (m, 2H), 3.81 (d, DMSO >98 AQ5
    J = 10.8 Hz, 3H), 3.31 (d, J = 4.6
    Hz, 3H), 2.41 (s, 3H).
    1413
    Figure US20170217923A1-20170803-C02713
    Figure US20170217923A1-20170803-C02714
    Figure US20170217923A1-20170803-C02715
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.09 (s, 1H), 9.60 (s, 1H), 9.00- 8.88 (m, 2H), 8.42 (s, 1H), 7.94 (s, 1H), 7.86-7.78 (m, 1H), 7.48- 7.39 (m, 2H), 7.16-7.06 (m, 2H), 3.85 (s, 3H), 3.31 (d, J = 4.6 Hz, 3H), 2.43 (s, 3H). DMSO >98 AQ5
    1414
    Figure US20170217923A1-20170803-C02716
    Figure US20170217923A1-20170803-C02717
    Figure US20170217923A1-20170803-C02718
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 9.63 (s, 1H), 9.05- 8.91 (m, 2H), 8.36 (s, 1H), 8.10- 7.99 (m, 1H), 7.91-7.80 (m, 1H), 7.59-7.50 (m, 2H), 7.44- 7.32 (m, 2H), 3.27 (d, J = 4.5 Hz, 3H), 2.45 (s, 3H). DMSO >98 AQ5
    1415
    Figure US20170217923A1-20170803-C02719
    Figure US20170217923A1-20170803-C02720
    Figure US20170217923A1-20170803-C02721
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.01 (s, 1H), 9.65 (s, 1H), 9.10- 8.99 (m, 1H), 8.97 (d, J = 5.0 Hz, 1H), 8.41 (s, 1H), 8.09 (s, 1H), 7.97-7.83 (m, 1H), 7.61-7.41 (m, 2H), 7.31 (td, J = 8.4, 2.2 Hz, 1H), 3.26 (d, J = 4.5 Hz, 3H), 2.35 (s, 3H). DMSO >98 AQ5
    1416
    Figure US20170217923A1-20170803-C02722
    Figure US20170217923A1-20170803-C02723
    Figure US20170217923A1-20170803-C02724
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.01-9.69 (m, 1H), 9.61 (s, 1H), 8.94 (m, J = 5.0 Hz, 2H), 8.36 (s, 1H), 7.99 (s, 1H), 7.92- 7.81 (m, 1H), 7.71-7.57 (m, 2H), 7.41-7.31 (m, 1H), 3.26 (d, J = 4.5 Hz, 3H), 2.47 (s, 3H). DMSO >98 AQ5
    1417
    Figure US20170217923A1-20170803-C02725
    Figure US20170217923A1-20170803-C02726
    Figure US20170217923A1-20170803-C02727
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 9.63 (d, J = 1.8 Hz, 1H), 9.08-8.89 (m, 2H), 8.40 (s, 1H), 8.02 (s, 1H), 7.92-7.81 (m, 1H), 7.44-7.25 (m, 3H), 3.27 (d, J = 4.5 Hz, 3H), 2.49 (s, 3H). DMSO >98 AQ5
    1418
    Figure US20170217923A1-20170803-C02728
    Figure US20170217923A1-20170803-C02729
    Figure US20170217923A1-20170803-C02730
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.99 (s, 1H), 9.62 (s, 1H), 8.95 (d, J = 5.0 Hz, 2H), 8.27 (s, 1H), 8.11- 7.99 (m, 1H), 7.89-7.80 (m, 1H), 7.53-7.45 (m, 1H), 7.24 (dd, J = 7.4, 1.7 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (td, J = 7.4, 0.9 Hz, 1H), 3.74 (d, J = 8.9 Hz, DMSO >98 AQ5
    3H), 3.26 (d, J = 4.6 Hz, 3H),
    2.28 (s, 3H).
    1419
    Figure US20170217923A1-20170803-C02731
    Figure US20170217923A1-20170803-C02732
    Figure US20170217923A1-20170803-C02733
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 9.72 (d, J = 1.6 Hz, 1H), 9.20-9.10 (m, 1H), 8.98 (dd, J = 5.1, 1.5 Hz, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 7.91 (dd, J = 8.0, 5.1 Hz, 1H), 7.48-7.40 (m, 1H), 7.08-7.01 (m, 3H), 3.84 (s, 3H), 3.26 (d, J = 4.5 Hz, 3H), 2.45 (s, 3H). DMSO >98 AQ5
    1420
    Figure US20170217923A1-20170803-C02734
    Figure US20170217923A1-20170803-C02735
    Figure US20170217923A1-20170803-C02736
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.08-9.71 (m, 1H), 9.58 (d, J = 2.0 Hz, 1H), 8.96-8.83 (m, 2H), 8.31 (s, 1H), 7.94 (s, 1H), 7.87- 7.79 (m, 1H), 7.47-7.39 (m, 2H), 7.10 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.27 (d, J = 4.5 Hz, 3H), 2.47 (s, 3H). DMSO >98 AQ5
    1421
    Figure US20170217923A1-20170803-C02737
    Figure US20170217923A1-20170803-C02738
    Figure US20170217923A1-20170803-C02739
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.69-9.63 (m, 1H), 9.10-8.93 (m, 3H), 8.12 (d, J = 8.4 Hz, 1H), 7.90-7.82 (m, 2H), 7.68-7.58 (m, 1H), 7.56-7.48 (m, 1H), 7.30-7.22 (m, 1H), 3.35 (d, J = 4.6 Hz, 3H), 2.73 (s, 3H). DMSO >98 AQ4
    1422
    Figure US20170217923A1-20170803-C02740
    Figure US20170217923A1-20170803-C02741
    Figure US20170217923A1-20170803-C02742
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.62 (s, 1H), 8.95 (d, J = 5.0 Hz, 3H), 8.03 (s, 1H), 7.85 (t, J = 9.9 Hz, 2H), 7.44-7.34 (m, 1H), 7.17 (dd, J = 8.2, 2.2 Hz, 2H), 3.34 (d, J = 4.5 Hz, 3H), 2.73 (s, 3H). DMSO >98 AQ4
    1423
    Figure US20170217923A1-20170803-C02743
    Figure US20170217923A1-20170803-C02744
    Figure US20170217923A1-20170803-C02745
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.62 (d, J = 2.1 Hz, 1H), 9.00-8.75 (m, 3H), 8.08-7.99 (m, 1H), 7.99-7.93 (m, 1H), 7.93-7.79 (m, 3H), 7.79-7.73 (m, 2H), 3.34 (d, J = 4.5 Hz, 3H), 2.70 (s, 3H). DMSO >98 AQ4
    1424
    Figure US20170217923A1-20170803-C02746
    Figure US20170217923A1-20170803-C02747
    Figure US20170217923A1-20170803-C02748
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 8.99-8.63 (m, 3H), 8.07- 7.98 (m, 3H), 7.89-7.78 (m, 2H), 7.65-7.59 (m, 2H), 3.33 (d, J = 4.5 Hz, 3H), 2.70 (s, 3H). DMSO >98 AQ4
    1425
    Figure US20170217923A1-20170803-C02749
    Figure US20170217923A1-20170803-C02750
    Figure US20170217923A1-20170803-C02751
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 9.56 (s, 1H), 9.19 (s, 1H), 8.95 (d, J = 5.3 Hz, 1H), 8.83 (d, J = 5.5 Hz, 1H), 8.73 (d, J = 6.4 Hz, 1H), 8.41 (d, J = 5.6 Hz, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 8.02-7.91 (m, 2H), 7.85 (s, 1H), 7.78-7.68 (m, 1H), 7.61- DMSO >98 Method AQ3
    7.51 (m, 1H), 7.48-7.36 (m,
    2H), 5.36 (s, 2H).
    1426
    Figure US20170217923A1-20170803-C02752
    Figure US20170217923A1-20170803-C02753
    Figure US20170217923A1-20170803-C02754
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 9.67 (d, J = 1.8 Hz, 1H), 9.32 (dd, J = 5.8, 4.1 Hz, 1H), 8.97 (dd, J = 5.4, 1.4 Hz, 1H), 8.75 (d, J = 8.7 Hz, 1H), 8.35 (t, J = 7.9 Hz, 1H), 8.24 (d, J = 13.5 Hz, 1H), 8.03 (dd, J = 8.1, 5.4 Hz, 1H), 7.92 (dd, J = 13.5, 4.8 Hz, 2H), 7.85-7.73 (m, 2H), DMSO >98 Method AQ3
    7.53-7.43 (m, 1H), 7.36-7.25
    (m, 1H), 5.40 (d, J = 5.6 Hz, 2H),
    2.85 (s, 3H).
    1427
    Figure US20170217923A1-20170803-C02755
    Figure US20170217923A1-20170803-C02756
    Figure US20170217923A1-20170803-C02757
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 9.64 (d, J = 1.7 Hz, 1H), 9.26 (d, J = 8.1 Hz, 1H), 8.95 (dd, J = 5.3, 1.4 Hz, 1H), 8.71 (d, J = 8.7 Hz, 1H), 8.30 (d, J = 18.0 Hz, 2H), 8.04-7.84 (m, 3H), 7.74 (dd, J = 7.8, 6.0 Hz, 2H), 7.62-7.33 (m, 3H), 5.38 (d, J = 5.5 Hz, 2H), 2.84 (s, 3H). DMSO >98 Method AQ3
    1428
    Figure US20170217923A1-20170803-C02758
    Figure US20170217923A1-20170803-C02759
    Figure US20170217923A1-20170803-C02760
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.63 (d, J = 1.6 Hz, 1H), 9.24 (d, J = 8.1 Hz, 1H), 8.95 (dd, J = 5.3, 1.4 Hz, 1H), 8.69 (d, J = 8.7 Hz, 1H), 8.41- 8.22 (m, 2H), 8.09 (dd, J = 8.7, 1.8 Hz, 1H), 8.01-7.84 (m, 4H), 7.74 (d, J = 7.8 Hz, 1H), 7.46- DMSO >98 Method AQ3
    7.33 (m, 2H), 5.36 (d, J = 5.5 Hz,
    2H), 2.83 (s, 3H).
    1429
    Figure US20170217923A1-20170803-C02761
    Figure US20170217923A1-20170803-C02762
    Figure US20170217923A1-20170803-C02763
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 9.62 (s, 1H), 9.19 (d, J = 7.8 Hz, 1H), 8.93 (d, J = 4.6 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.26 (dd, J = 28.0, 20.1 Hz, 2H), 8.04-7.80 (m, 3H), 7.72 (d, J = 7.8 Hz, 1H), 7.64-7.50 (m, 2H), 7.46-7.33 (m, 1H), 5.33 (d, DMSO >98 Method AQ3
    J = 5.3 Hz, 2H), 2.81 (s, 3H).
    1430
    Figure US20170217923A1-20170803-C02764
    Figure US20170217923A1-20170803-C02765
    Figure US20170217923A1-20170803-C02766
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 9.66 (d, J = 1.8 Hz, 1H), 9.31 (d, J = 8.2 Hz, 1H), 8.96 (dd, J = 5.4, 1.4 Hz, 1H), 8.73 (d, J = 8.7 Hz, 1H), 8.33 (t, J = 7.9 Hz, 1H), 8.23 (s, 1H), 8.03 (dd, J = 8.1, 5.4 Hz, 1H), 7.93 (dd, J = 11.7, 8.3 Hz, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.70-7.60 DMSO >98 Method AQ3
    (m, 1H), 7.54-7.35 (m, 2H),
    5.38 (d, J = 5.5 Hz, 2H), 2.85
    (s, 3H).
    1431
    Figure US20170217923A1-20170803-C02767
    Figure US20170217923A1-20170803-C02768
    Figure US20170217923A1-20170803-C02769
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 9.61 (s, 1H), 9.22 (t, J = 7.3 Hz, 1H), 8.98-8.90 (m, 1H), 8.65 (dd, J = 8.6, 3.0 Hz, 1H), 8.36-8.26 (m, 2H), 8.13 (dd, J = 8.7, 1.9 Hz, 1H), 8.05-7.95 (m, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.76-7.64 (m, 3H), 7.43-7.33 (m, 1H), 5.33 (s, 2H), 2.82 (s, 3H). DMSO >98 Method AQ3
    1432
    Figure US20170217923A1-20170803-C02770
    Figure US20170217923A1-20170803-C02771
    Figure US20170217923A1-20170803-C02772
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.26 (s, 1H), 9.62 (d, J = 1.8 Hz, 1H), 9.23 (d, J = 8.2 Hz, 1H), 8.94 (dd, J = 5.4, 1.5 Hz, 1H), 8.78 (s, 1H), 8.30 (t, J = 7.9 Hz, 1H), 8.20-8.15 (m, 1H), 8.10 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 7.9, 5.3 Hz, 1H), 7.88 (d, J = 7.9 DMSO >98 Method AQ3
    Hz, 1H), 7.80-7.71 (m, 2H),
    7.59-7.50 (m, 1H), 7.47-7.35
    (m, 2H), 5.35 (d, J = 5.5 Hz, 2H),
    2.82 (s, 3H).
    1433
    Figure US20170217923A1-20170803-C02773
    Figure US20170217923A1-20170803-C02774
    Figure US20170217923A1-20170803-C02775
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 9.61 (d, J = 1.7 Hz, 1H), 9.19 (d, J = 8.2 Hz, 1H), 9.01 (d, J = 1.8 Hz, 1H), 8.93 (dd, J = 5.3, 1.5 Hz, 1H), 8.38 (dd, J = 8.8, 1.9 Hz, 1H), 8.29 (t, J = 7.9 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.97 (dd, J = 8.1, 5.3 Hz, 1H), 7.92-7.80 (m, 3H), 7.72 (d, DMSO >98 Method AQ3
    J = 7.8 Hz, 1H), 7.66-7.57 (m,
    1H), 7.35-7.26 (m, 1H), 5.36 (d,
    J = 5.5 Hz, 2H), 2.81 (s, 3H).
    1434
    Figure US20170217923A1-20170803-C02776
    Figure US20170217923A1-20170803-C02777
    Figure US20170217923A1-20170803-C02778
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 9.60 (d, J = 1.9 Hz, 1H), 9.19 (d, J = 8.2 Hz, 1H), 9.01-8.89 (m, 2H), 8.36-8.25 (m, 2H), 8.10 (d, J = 8.7 Hz, 1H), 8.05-7.94 (m, 3H), 7.88 (dd, J = 12.8, 5.4 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.46-7.35 (m, 2H), DMSO >98 Method AQ3
    5.36 (d, J = 5.5 Hz, 2H), 2.82 (s,
    3H).
    1435
    Figure US20170217923A1-20170803-C02779
    Figure US20170217923A1-20170803-C02780
    Figure US20170217923A1-20170803-C02781
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 9.63 (d, J = 1.8 Hz, 1H), 9.24 (d, J = 8.2 Hz, 1H), 8.95 (d, 1H), 8.83 (s, 1H), 8.30 (t, J = 7.9 Hz, 1H), 8.19 (dd, J = 8.7, 1.8 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 8.1, 5.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.64- DMSO >98 Method AQ3
    7.51 (m, 2H), 7.46-7.37 (m,
    1H), 5.36 (d, J = 5.5 Hz, 2H),
    2.82 (s, 3H).
    1436
    Figure US20170217923A1-20170803-C02782
    Figure US20170217923A1-20170803-C02783
    Figure US20170217923A1-20170803-C02784
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 9.56 (d, J = 1.6 Hz, 1H), 9.06 (d, J = 8.0 Hz, 1H), 8.88 (dd, J = 5.2, 1.5 Hz, 1H), 8.75 (s, 1H), 8.25-8.13 (m, 2H), 8.04 (d, J = 8.7 Hz, 1H), 7.89 (dd, J = 7.8, 5.3 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.70-7.60 (m, 2H), DMSO >98 Method AQ3
    7.53-7.44 (m, 1H), 7.38 (ddd,
    J = 12.2, 8.4, 3.5 Hz, 1H), 5.27
    (d, J = 5.3 Hz, 2H), 2.77 (s, 3H).
    1437
    Figure US20170217923A1-20170803-C02785
    Figure US20170217923A1-20170803-C02786
    Figure US20170217923A1-20170803-C02787
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 9.60 (d, J = 1.7 Hz, 1H), 9.19 (d, J = 8.1 Hz, 1H), 8.93 (dd, J = 5.4, 1.5 Hz, 1H), 8.75 (s, 1H), 8.29 (t, J = 7.9 Hz, 1H), 8.17-8.05 (m, 2H), 7.98 (dd, J = 8.0, 5.4 Hz, 1H), 7.83 (ddd, J = 15.5, 8.4, 6.0 Hz, 2H), DMSO >98 Method AQ3
    7.72 (d, J = 7.8 Hz, 1H), 7.54-
    7.44 (m, 1H), 7.38-7.28 (m,
    1H), 5.33 (d, J = 5.5 Hz, 2H),
    2.81 (s, 3H).
    1438
    Figure US20170217923A1-20170803-C02788
    Figure US20170217923A1-20170803-C02789
    Figure US20170217923A1-20170803-C02790
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 9.62 (d, J = 1.7 Hz, 1H), 9.21 (d, J = 8.1 Hz, 1H), 9.03 (d, J = 1.7 Hz, 1H), 8.93 (dd, J = 5.3, 1.4 Hz, 1H), 8.39- 8.26 (m, 2H), 8.15-8.04 (m, 2H), 8.00-7.81 (m, 3H), 7.76- 7.59 (m, 2H), 5.36 (d, J = 5.5 Hz, 2H), 2.82 (s, 3H). DMSO >98 Method AQ3
    1439
    Figure US20170217923A1-20170803-C02791
    Figure US20170217923A1-20170803-C02792
    Figure US20170217923A1-20170803-C02793
         		3 HCl 1H NMR (400 MHz, DMSO) δ 10.29 (s, 1H), 9.53 (d, J = 1.8 Hz, 1H), 9.12 (d, J = 8.0 Hz, 1H), 8.93 (dd, J = 5.3, 1.4 Hz, 1H), 8.78 (d, J = 2.5 Hz, 2H), 8.31 (t, J = 7.8 Hz, 1H), 8.13 (q, J = 8.7 Hz, 2H), 8.04-7.89 (m, 2H), 7.87-7.68 (m, 2H), 7.50 (ddd, DMSO >98 Method AQ3
    J = 11.6, 9.3, 2.6 Hz, 1H), 7.33 (td,
    J = 8.3, 1.9 Hz, 1H), 5.30 (d, J =
    5.4 Hz, 2H).
    1440
    Figure US20170217923A1-20170803-C02794
    Figure US20170217923A1-20170803-C02795
    Figure US20170217923A1-20170803-C02796
         		2 HCl 1H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 9.63 (d, J = 1.7 Hz, 1H), 9.15 (d, J = 8.1 Hz, 1H), 8.97 (dd, J = 5.2, 1.4 Hz, 1H), 8.83 (s, 1H), 8.20 (s, 2H), 7.97 (dd, J = 8.0, 5.3 Hz, 1H), 7.73- 7.56 (m, 2H), 7.54-7.28 (m, 4H), 5.03 (d, J = 5.7 Hz, 2H). DMSO >98 Method AQ3
    1441
    Figure US20170217923A1-20170803-C02797
    Figure US20170217923A1-20170803-C02798
    Figure US20170217923A1-20170803-C02799
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.59 (d, J = 1.6 Hz, 1H), 9.07-8.94 (m, 2H), 8.84 (s, 1H), 8.76 (s, 1H), 8.22-8.13 (m, 2H), 7.96 (dd, J = 8.0, 5.3 Hz, 1H), 7.66 (ddd, J = 9.2, 6.1, 3.2 Hz, 1H), 7.53-7.32 (m, 2H), 1.69 (s, 9H). DMSO >98 Method AQ3
    1442
    Figure US20170217923A1-20170803-C02800
    Figure US20170217923A1-20170803-C02801
    Figure US20170217923A1-20170803-C02802
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 9.62 (d, J = 1.6 Hz, 1H), 9.06-8.87 (m, 2H), 8.39 (s, 1H), 8.06-7.98 (m, 3H), 7.87 (dd, J = 8.0, 5.1 Hz, 1H), 7.77-7.67 (m, 2H), 3.26 (d, J = 4.6 Hz, 3H), 2.45 (s, 3H). DMSO >98 Method AQ3
    1443
    Figure US20170217923A1-20170803-C02803
    Figure US20170217923A1-20170803-C02804
    Figure US20170217923A1-20170803-C02805
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 9.64 (s, 1H), 8.99 (dd, J = 27.3, 6.4 Hz, 2H), 8.41 (s, 1H), 8.10-7.93 (m, 3H), 7.88 (dd, J = 7.7, 6.0 Hz, 2H), 7.76 (t, J = 7.8 Hz, 1H), 3.27 (d, J = 4.5 Hz, 3H), 2.46 (s, 3H). DMSO >98 Method AQ3
    1444
    Figure US20170217923A1-20170803-C02806
    Figure US20170217923A1-20170803-C02807
    Figure US20170217923A1-20170803-C02808
         		2 HCl 1H NMR (400 MHz, DMSO) δ 9.76-9.69 (m, 1H), 9.37 (t, J = 5.4 Hz, 1H), 8.99 (dd, J = 11.7, 7.5 Hz, 1H), 8.81 (dt, J = 7.9, 4.0 Hz, 1H), 8.70 (t, J = 7.3 Hz, 1H), 8.52 (d, J = 9.2 Hz, 1H), 8.35-8.27 (m, 1H), 8.10 (dd, J = 12.8, 7.3 Hz, 1H), 8.01-7.90 (m, 2H), 7.77-7.71 (m, 1H), 7.50-7.37 (m, 3H), 7.06-7.01 (m, 1H), 5.19 DMSO >98 Method AQ3, F, G2 (reflux)
    (t, J = 17.9 Hz, 2H),
    3.88 (s, 3H).
    1445
    Figure US20170217923A1-20170803-C02809
    Figure US20170217923A1-20170803-C02810
    Figure US20170217923A1-20170803-C02811
         		2 HCl 1H NMR (DMSO-d6) ppm 9.73 (s, 1H), 9.37 (brd, J = 8.08 Hz, 1H), 8.97 (brd, J = 5.24 Hz, 1H), 8.77 (brs, 1H), 8.20 (d, J = 8.48 Hz, 1H), 8.10-8.07 (brm, 1H), 7.63- 7.55 (brm, 2H), 7.47 (d, J = 8.48 Hz, 1H), 7.32 (brm, 1H), 3.20 (d, J = 4.20 Hz, 3H), 2.65 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 AQ6
    1446
    Figure US20170217923A1-20170803-C02812
    Figure US20170217923A1-20170803-C02813
    Figure US20170217923A1-20170803-C02814
         		3 HCl 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.76 Hz, 1H), 9.39 (brd, J = 8.16 Hz, 1H), 8.98 (dd, J = 5.44, 1.20 Hz, 1H), 8.80 'brs, 1H), 8.22 (d, J = 8.48 Hz, 1H), 8.12-8.08 (brm, 1H), 7.57-7.51 (m, 1H), 7.46-7.35 (m, 4H), 3.21 (d, J = 4.32 Hz, 3H), 2.55 (s, 3H). The 1H of 3HCl was not observed. DMSO >98 AQ6
    1447
    Figure US20170217923A1-20170803-C02815
    Figure US20170217923A1-20170803-C02816
    Figure US20170217923A1-20170803-C02817
         		3 HCl 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.68 Hz, 1H), 9.26 (brd, J = 8.48 Hz, 1H), 8.91 (dd, J = 5.28, 1.40 Hz, 1H), 8.69 (brs, 1H), 8.18 (d, J = 8.56 Hz, 1H), 8.00-7.96 (brm, 1H), 7.53-7.49 (m, 2H), 7.44 (d, J = 8.56 Hz, 1H), 7.38- 7.33 (m, 2H), 3.20 (d, J = 4.40 DMSO >98 AQ6
    Hz, 3H), 2.63 (s, 3H). The 1H of
    3HCl was not observed.
    1448
    Figure US20170217923A1-20170803-C02818
    Figure US20170217923A1-20170803-C02819
    Figure US20170217923A1-20170803-C02820
         		2 HCl 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.44 Hz, 1H), 9.36 (brd, J = 7.88 Hz, 1H), 8.96 (d, J = 5.04 Hz, 1H), 8.77 (brs, 1H), 8.21 (d, J = 8.56 Hz, 1H), 8.07 (brm, 1H), 7.48 (d, J = 8.56 Hz, 1H), 7.38- 7.32 (m, 1H), 7.27-7.22 (m, 2H), 3.20 (d, J = 4.4 Hz, 3H), 2.65 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 AQ6
    1449
    Figure US20170217923A1-20170803-C02821
    Figure US20170217923A1-20170803-C02822
    Figure US20170217923A1-20170803-C02823
         		3 HCl 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.72 Hz, 1H), 9.32 (brd, J = 7.56 Hz, 1H), 8.94 (brd, J = 5.48 Hz, 1H), 8.74 (brs, 1H), 8.20 (d, J = 8.56 Hz, 1H), 8.08-8.02 (m, 1H), 7.60-7.54 (m, 1H), 7.47 (d, J = 7.35-7.27 (m, 3H), 3.20 (d, J = 4.4 Hz, 3H), 2.65 (s, 3H). The 1H of 3HCl was not observed. DMSO >98 AQ6
    1450
    Figure US20170217923A1-20170803-C02824
    Figure US20170217923A1-20170803-C02825
    Figure US20170217923A1-20170803-C02826
         		2 HCl 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.76 Hz, 1H), 9.37 (brd, J = 8.16 Hz, 1H), 8.97 (brdd, J = 5.44, 1.24 Hz, 1H), 8.79 (brs, 1H), 8.22 (d, J = 8.52 Hz, 1H), 8.10-8.06 (brm, 1H), 7.48-7.35 (m, 4H), 3.21 (d, J = 4.36 Hz, 3H), 2.56 (brs, 3H). The 1H of 2HCl was not observed. DMSO >98 AQ6
    1451
    Figure US20170217923A1-20170803-C02827
    Figure US20170217923A1-20170803-C02828
    Figure US20170217923A1-20170803-C02829
         		3 HCl 1H NMR (DMSO-d6) ppm 9.74 (d, J = 1.52 Hz, 1H), 9.37 (d, J = 8.08 Hz, 1H), 8.97 (dd, J = 5.54, 1.16 Hz, 1H), 8.80 (brs, 1H), 8.23 (d, J = 8.52 Hz, 1H), 8.10- 8.07 (m, 1H), 7.60-7.53 (m, 1H), 7.48 (d, J = 8.52 Hz, 1H), 7.41- 7.36 (m, 1H), 7.30-7.26 (m, 1H), DMSO >98 AQ6
    3.21 (d, J = 4.36 Hz, 3H), 2,56 (s,
    3H). The 1H of 3HCl was not
    observed.
    1452
    Figure US20170217923A1-20170803-C02830
    Figure US20170217923A1-20170803-C02831
    Figure US20170217923A1-20170803-C02832
         		3 HCl 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.68 Hz, 1H), 9.26 (brd, J = 7.8 Hz, 1H), 8.91 (brdd, J = 5.28, 1.36 Hz, 1H), 8.71 (brs, 1H), 8.21 (d, J = 8.52 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.99-7.95 (m, 1H), 7.69 (d, 8.4 Hz, 2H),7.46 (d, J = 8.52 Hz, 1H), 3.20 (d, J = 4.4 Hz, 3H), 2.63 (s, 3H). The 1H of 3HCl was not observed. DMSO >98 AQ6
    1453
    Figure US20170217923A1-20170803-C02833
    Figure US20170217923A1-20170803-C02834
    Figure US20170217923A1-20170803-C02835
         		2 HCl 1H NMR (DMSO-d6) ppm 9.73 (d, J = 1.72 Hz, 1H), 9.33 (brd, J = 7.64 Hz, 1H), 8.95 (brd, J = 5.28 Hz, 1H), 8.76 (brs, 1H), 8.22 (d, J = 8.48 Hz, 1H), 8.05 (brm, J = 7.64, 5.28 Hz, 1H), 7.98-7.93 (m, 2H), 7.84-7.81 (m, 1H), 7.74 (dd, J = 7.84, 7.76 Hz, 1H), 7.49 (d, J = 8.84 Hz, 1H), 3.21 (d, J = 4.4 Hz, 3H), 2.63 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 AQ6
    1454
    Figure US20170217923A1-20170803-C02836
    Figure US20170217923A1-20170803-C02837
    Figure US20170217923A1-20170803-C02838
         		2 HCl 1H NMR (DMSO-d6) ppm 9.72 (d, J = 1.76 Hz, 1H), 9.42 (brd, J = 8.00 Hz, 1H), 9.00 (d, J = 5.52 Hz, 1H), 8.83 (bsr, 1H), 8.22 (d, J = 8.56 Hz, 1H), 8.13 (brm, 1H), 7.55-7.51 (m, 2H), 7.48-7.43 (m, 4H), 3.21 (brd, J = 4.16 Hz, 3H), 2.64 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 AQ6
    1455
    Figure US20170217923A1-20170803-C02839
    Figure US20170217923A1-20170803-C02840
    Figure US20170217923A1-20170803-C02841
         		2 HCl 1H NMR (DMSO-d6) ppm 9.72 (s, (d, 1H), 9.33 (d, J = 8.24 Hz, 1H), 8.96 (d, J = 5.40 Hz, 1H), 8.75 (brs, 1H), 8.17 (d, J = 8.60 Hz, 1H), 8.06 (brm, 1H), 7.45 (d, J = 8.80 Hz, 1H), 7.40 (d, J = 8.64 Hz, 2H), 7.08 (d, J = 8.64 Hz, 2H), 3.84 (s, 3H), 3.20 (d, J = 4.20 Hz, 3H), 2.66 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 AQ6
    1456
    Figure US20170217923A1-20170803-C02842
    Figure US20170217923A1-20170803-C02843
    Figure US20170217923A1-20170803-C02844
         		2 HCl 1H NMR (DMSO-d6) ppm 9.72 (d, J = 1.64 Hz, 1H), 9.38 (d, J = 8.04 Hz, 1H), 8.98 (dd, J = 5.48, 1.24 Hz, 1H), 8.79 (brs, 1H), 8.20 (d, J = 8.52 Hz, 1H), 8.12-8.09 (m, 1H), 7.48-7.42 (m, 2H), 7.04-6.97 (m, 3H), 3.82 (s, 3H), 3.21 (d, J = 4.28 Hz, 3H), 2.65 (s, 3H). The 1H of 2HCl was not observed. DMSO >98 AQ6
    1457
    Figure US20170217923A1-20170803-C02845
    Figure US20170217923A1-20170803-C02846
    Figure US20170217923A1-20170803-C02847
         		2 HCl 1H NMR (DMSO-d6) ppm 9.71 (d, J = 1.32 Hz, 1H), 9.40 (d, J = 7.64 Hz, 1H), 8.99 (dd, J = 5.52, 1.16 Hz, 1H), 8.82 (brs, 1H), 8.17 (d, J = 8.48 Hz, 1H), 8.13 (m, 1H), 7.47-7.43 (m, 1H), 7.37 (d, J = 8.48 Hz, 1H), 7.22-7.16 (m, 2H), 7.11-7.07 (m, 1H), 3.73 (s, 3H), DMSO >98 AQ6
    3.21 (d, J = 4.12 Hz, 3H), 2.47 (s,
    3H). The 1H of 2HCl was not
    observed.
    1458
    Figure US20170217923A1-20170803-C02848
    Figure US20170217923A1-20170803-C02849
    Figure US20170217923A1-20170803-C02850
         		2 HCl 1H NMR (DMSO-d6) ppm 9.57 (d, J = 1.88 Hz, 1H), 8.93 (dd, J = 4.88, 1.56 Hz, 1H), 8.87 (brd, J = 6.52 Hz, 1H), 7.95 (d, J = 8.36 Hz, 1H), 7.84 (d, J = 8.36 Hz, 1H), 7.81 (m, 1H), 7.34 (d, J = 8.72 Hz, 2H), 7.11 (d, J = 8.72 Hz, 2H), 3.84 (s, 3H), 3.34 (d, J = DMSO >98 AQ6
    4.56 Hz, 3H), 2.72 (s, 3H). The
    1H of 2HCl and NH— were not
    observed.
    1459
    Figure US20170217923A1-20170803-C02851
    Figure US20170217923A1-20170803-C02852
    Figure US20170217923A1-20170803-C02853
         		2 HCl 1H NMR (DMSO-d6) ppm 9.59 (s, 1H), 8.94 (dd, J = 4.92, 1.48 Hz, 1H), 8.89 (br, 1H), 7.98 (d, J = 8.48 Hz, 1H), 7.86 (d, J = 8.48 Hz, 1H), 7.82 (m, 1H), 7.46 (t, J = 7.96 Hz, 1H), 7.06-7.03 (m, 1H), 6.98-6.94 (m, 2H), 3.83 (s, 3H), 3.34 (d, J = 4.56 Hz, 3H), DMSO >98 AQ6
    2.72 (s, 3H). The 1H of 2HCl and
    NH— were not observed.
    1460
    Figure US20170217923A1-20170803-C02854
    Figure US20170217923A1-20170803-C02855
    Figure US20170217923A1-20170803-C02856
         		1H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 8.84-8.57 (m, 3H), 8.30 (d, J = 7.0 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.12-7.93 (m, 4H), 7.85 (dd, J = 8.7, 1.5 Hz, 1H), 7.60-7.46 (m, 1H), 4.85-4.58 (m, 1H), 1.37 (d, J = 6.5 Hz, 6H). DMSO 100 AQ1 366   (M + 1) Method A (Formic acid)
    1461
    Figure US20170217923A1-20170803-C02857
    Figure US20170217923A1-20170803-C02858
    Figure US20170217923A1-20170803-C02859
         		HCl 1H NMR (300 MHz, DMSO) δ 9.81 (s, 1H), 9.60 (s, 1H), 8.95 (s, 3H), 8.39 (d, J = 8.9 Hz, 1H), 8.19 (s, 1H), 7.96-7.73 (m, 3H), 7.68- 7.55 (m, 1H), 7.39-7.25 (m, 1H), 4.99-4.81 (m, 1H), 1.42 (d, J = 6.5 Hz, 6H). DMSO 100 AQ1 359   (M + 1) Method A (Formic acid)
    1462
    Figure US20170217923A1-20170803-C02860
    Figure US20170217923A1-20170803-C02861
    Figure US20170217923A1-20170803-C02862
         		1H NMR (300 MHz, DMSO) δ 9.43 (s, 1H), 8.75-8.47 (m, 3H), 8.29 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 7.1 Hz, 1H), 7.72-7.54 (m, 2H), 7.48 (dd, J = 7.8, 4.9 Hz, 1H), 7.44-7.32 (m, 1H), 7.30-7.12 (m, 1H), 3.32 (s, 3H), 3.16 (d, J = 4.3 Hz, 3H). DMSO 100 AQ1 349   (M + 1) Method A (Formic acid)
    1463
    Figure US20170217923A1-20170803-C02863
    Figure US20170217923A1-20170803-C02864
         		1H NMR (300 MHz, DMSO) δ 9.68 (dd, J = 2.1, 0.8 Hz, 1H), 8.86- 8.78 (m, 1H), 8.74 (dd, J = 4.8, 1.7 Hz, 1H), 8.34-8.25 (m, 2H), 8.09-8.02 (m, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.60 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.09 (d, J = 8.9 Hz, 2H), 4.31 (s, 3H), 3.83 (s, 3H). DMSO  99 Method AQ2 344.0 (M + 1) Method C
    1464
    Figure US20170217923A1-20170803-C02865
    Figure US20170217923A1-20170803-C02866
         		1H NMR (300 MHz, DMSO) δ 9.67 (d, J = 2.1 Hz, 1H), 8.82 (d, J = 7.9 Hz, 1H), 8.74 (dd, J = 4.8, 1.7 Hz, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.36 (dd, J = 8.8, 2.2 Hz, 1H), 8.15-7.94 (m, 5H), 7.60 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 4.31 (s, 3H). DMSO  99 Method AQ2 338.9 (M + 1) Method C
    1465
    Figure US20170217923A1-20170803-C02867
    Figure US20170217923A1-20170803-C02868
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.71 (d, J = 1.8 Hz, 1H), 9.15 (d, J = 8.0 Hz, 1H), 8.90 (dd, J = 5.2, 1.4 Hz, 1H), 8.58 (s, J = 1.8 Hz, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 8.7, 2.2 Hz, 1H), 8.32 (dd, J = 7.8, 0.9 Hz, 1H), 8.28 (dd, J = 8.2, 2.2 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.92 (dd, J = DMSO  99 Method AQ2 359.0 (M + 1) Method C
    8.0, 5.2 Hz, 1H), 7.81 (t, J =
    8.0 Hz, 1H), 4.34 (s, 3H).
    1466
    Figure US20170217923A1-20170803-C02869
    Figure US20170217923A1-20170803-C02870
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.71 (d, J = 2.0 Hz, 1H), 9.12 (dd, J = 8.0, 1.4 Hz, 1H), 8.89 (dd, J = 5.2, 1.5 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.42 (dd, J = 8.8, 2.2 Hz, 1H), 8.34 (d, J = 9.0 Hz, 2H), 8.14 (dd, J = 9.2, 2.4 Hz, 3H), 7.88 (dd, J = 7.8, 5.5 Hz, 1H), 4.34 (s, 3H). DMSO  99 Method AQ2 359.0 (M + 1) Method C
    1467
    Figure US20170217923A1-20170803-C02871
    Figure US20170217923A1-20170803-C02872
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.36 (s, 1H), 9.00 (d, J = 6.5 Hz, 2H), 8.78 (d, J = 4.5 Hz, 2H), 8.58 (s, 1H), 8.06 (s, 2H), 7.75 (dd, J = 15.6, 8.9 Hz, 1H), 7.47 (ddd, J = 11.7, 9.4, 2.6 Hz, 1H), 7.31 (td, J = 8.4, 2.7 Hz, 3H), 3.22 (d, J = 4.2 Hz, 3H). DMSO  99 Method AQ2 349.6 (M + 1) Method C
    1468
    Figure US20170217923A1-20170803-C02873
    Figure US20170217923A1-20170803-C02874
         		3 HCl 1H NMR (300 MHz, DMSO) δ 9.97 (s, 1H), 9.63 (d, J = 1.6 Hz, 1H), 9.04 (d, J = 7.0 Hz, 1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.76 (d, J = 0.7 Hz, 1H), 8.41-8.05 (m, 4H), 7.89 (dd, J = 7.1, 4.8 Hz, 1H), 7.59 (ddd, J = 7.1, 4.9, 1.8 Hz, 1H), 3.27 (d, J = 4.3 Hz, 3H). DMSO  99 Method AQ2 332.4 (M + 1) Method C
    1469
    Figure US20170217923A1-20170803-C02875
    Figure US20170217923A1-20170803-C02876
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.04 (s, 1H), 9.65 (d, J = 1.5 Hz, 1H), 9.06 (d, J = 7.3 Hz, 1H), 8.95 (dd, J = 5.1, 1.5 Hz, 1H), 8.71 (s, 1H), 8.19 (s, 2H), 7.89 (dd, J = 7.6, 5.1 Hz, 1H), 7.76- 7.61 (m, 2H), 7.42 (td, J = 7.9, 0.9 Hz, 1H), 3.27 (d, J = 4.4 Hz, 3H). DMSO  95 Method AQ2 365.3 (M + 1) Method C
    1470
    Figure US20170217923A1-20170803-C02877
    Figure US20170217923A1-20170803-C02878
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.03 (s, 1H), 9.63 (d, J = 1.5 Hz, 1H), 9.04 (d, J = 7.9 Hz, 1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.68 (s, 1H), 8.16 (s, 2H), 7.88 (dd, J = 7.6, 5.1 Hz, 1H), 7.74 (t, J = 8.5 Hz, 1H), 7.67 (dd, J = 10.8, 2.0 Hz, 1H), 7.51 (dd, J = DMSO  94 Method AQ2 365.3 (M + 1) Method C
    8.3, 1.6 Hz, 1H), 3.27 (d, J = 4.4
    Hz, 3H).
    1471
    Figure US20170217923A1-20170803-C02879
    Figure US20170217923A1-20170803-C02880
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.95 (s, 1H), 9.64 (d, J = 1.6 Hz, 1H), 9.07 (d, J = 7.9 Hz, 1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.75 (s, 1H), 8.18 (s, 2H), 8.09 (d, J = 11.1 Hz, 1H), 7.92 (d, J = 4.0 Hz, 3H), 3.27 (d, J = 4.4 Hz, 3H). DMSO  96 Method AQ2 356.4 (M + 1) Method C
    1472
    Figure US20170217923A1-20170803-C02881
    Figure US20170217923A1-20170803-C02882
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 9.63 (d, J = 1.5 Hz, 1H), 9.03 (d, J = 7.8 Hz, 1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.73 (s, 1H), 8.25-8.12 (m, 3H), 7.93-7.76 (m, 4H), 7.63 (d, J = 0.8 Hz, 1H), 3.28 (d, J = 4.4 Hz, 3H). DMSO  95 Method AQ2 374.4 (M + 1) Method C
    1473
    Figure US20170217923A1-20170803-C02883
    Figure US20170217923A1-20170803-C02884
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.97 (s, 1H), 9.61 (d, J = 2.1 Hz, 1H), 8.98 (d, J = 4.6 Hz, 1H), 8.93 (dd, J = 5.1, 1.5 Hz, 1H), 8.68-8.60 (m, 1H), 8.13 (d, J = 6.1 Hz, 2H), 7.85 (dd, J = 7.7, 5.2 Hz, 1H), 7.63 (t, J = 8.3 Hz, 1H), 7.37-7.23 (m, DMSO  95 Method AQ2 377.5 (M + 1) Method C
    2H), 3.27 (d, J = 4.5 Hz, 3H),
    2.56 (s, J = 5.2 Hz, 3H).
    1474
    Figure US20170217923A1-20170803-C02885
    Figure US20170217923A1-20170803-C02886
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.98 (s, 1H), 9.64 (d, J = 1.6 Hz, 1H), 9.06 (d, J = 8.8 Hz, 1H), 8.94 (dd, J = 5.1, 1.5 Hz, 1H), 8.75 (s, 1H), 8.26-8.11 (m, 2H), 8.04-7.85 (m, 5H), 3.35 (s, 3H), 3.27 (d, J = 4.1 Hz, 3H). DMSO  96 Method AQ2 409.5 (M + 1) Method C
    1475
    Figure US20170217923A1-20170803-C02887
    Figure US20170217923A1-20170803-C02888
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.25 (s, 1H), 9.63 (d, J = 1.6 Hz, 1H), 9.00 (d, J = 7.1 Hz, 1H), 8.93 (dd, J = 5.0, 1.5 Hz, 1H), 8.79 (s, 1H), 8.31 (dd, J = 8.8, 1.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 7.5, 4.8 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.40 (dd, J = 8.2, 1.9 Hz, 1H), DMSO  99 Method AQ2 357.5 (M + 1) Method C
    7.09 (d, J = 8.1 Hz, 1H), 6.10 (s,
    2H), 3.29 (d, J = 4.3 Hz, 3H).
    1476
    Figure US20170217923A1-20170803-C02889
    Figure US20170217923A1-20170803-C02890
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.26 (s, 1H), 9.63 (d, J = 1.6 Hz, 1H), 9.01 (d, J = 8.6 Hz, 1H), 8.93 (dd, J = 5.0, 1.5 Hz, 1H), 8.77 (s, 1H), 8.31 (dd, J = 8.8, 1.4 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.84 (dd, J = 6.9, 5.8 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.39 (dd, J = 8.4, 2.3 Hz, 1H), DMSO  99 Method AQ2 371.5 (M + 1) Method C
    7.01 (d, J = 8.4 Hz, 1H), 4.30 (s,
    4H), 3.29 (d, J = 4.4 Hz, 3H).
    1477
    Figure US20170217923A1-20170803-C02891
    Figure US20170217923A1-20170803-C02892
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.19 (s, 1H), 9.61 (d, J = 1.6 Hz, 1H), 8.98 (d, J = 8.8 Hz, 1H), 8.93 (dd, J = 5.0, 1.5 Hz, 1H), 8.82 (s, 1H), 8.35 (dd, J = 8.8, 1.3 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.85 (dd, J = 8.1, 5.2 Hz, 1H), 7.76-7.66 (m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.7 DMSO  99 Method AQ2 357.5 (M + 1) Method C
    Hz, 1H), 3.69 (t, J = 7.0 Hz, 2H),
    3.31 (d, J = 4.4 Hz, 3H), 2.84 (t,
    J = 7.0 Hz, 2H).
    1478
    Figure US20170217923A1-20170803-C02893
    Figure US20170217923A1-20170803-C02894
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.11 (s, 1H), 9.60 (d, J = 1.9 Hz, 1H), 8.93 (dd, J = 10.3, 5.4 Hz, 2H), 8.80 (d, J = 0.6 Hz, 1H), 8.34 (dd, J = 8.0, 0.5 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.88- 7.75 (m, 3H), 7.40 (d, J = 8.3 Hz, 2H), 3.65 (t, J = 6.9 Hz, 2H), 3.30 (d, J = 4.4 Hz, 3H), 2.79 (t, J = DMSO  99 Method AQ2 357.5 (M + 1) Method C
    6.9 Hz, 2H).
    1479
    Figure US20170217923A1-20170803-C02895
    Figure US20170217923A1-20170803-C02896
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.27 (s, 1H), 9.62 (d, J = 1.5 Hz, 1H), 8.99 (s, 1H), 8.96-8.88 (m, 2H), 8.37 (d, J = 8.9 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.85 (s, 1H), 7.70 (d, J = 8.5 Hz, 2H), 3.30 (d, J = 4.3 Hz, 3H), 1.74 (s, 6H). DMSO  99 Method AQ2 380.5 (M + 1) Method C
    1480
    Figure US20170217923A1-20170803-C02897
    Figure US20170217923A1-20170803-C02898
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.23 (s, 1H), 9.62 (d, J = 1.8 Hz, 1H), 9.02 (d, J = 6.6 Hz, 1H), 8.93 (dd, J = 5.0, 1.5 Hz, 1H), 8.88 (d, J = 0.5 Hz, 1H), 8.33 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.86 (dd, J = 7.4, 5.1 Hz, 1H), 7.75 (dd, J = 8.5, 1.8 Hz, 1H), DMSO  99 Method AQ2 393.4 (M + 1) Method C
    7.60 (d, J = 8.5 Hz, 1H), 3.29 (d,
    J = 4.3 Hz, 3H).
    1481
    Figure US20170217923A1-20170803-C02899
    Figure US20170217923A1-20170803-C02900
    Figure US20170217923A1-20170803-C02901
         		1H NMR (300 MHz, DMSO) δ 9.63 (d, J = 1.4 Hz, 1H), 8.81-8.73 (m, 1H), 8.68 (dd, J = 4.7, 1.7 Hz, 1H), 8.61 (d, J = 4.3 Hz, 1H), 8.45 (s, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.86 (d, J = DMSO  99 Method AQ2, fol- lowed by hydro- lysis 374.5 (M + 1) Method C
    8.7 Hz, 2H), 7.77-7.61 (m, with
    3H), 7.53 (dd, J = 7.9, 30%
    4.8 Hz, 3H), 7.40 (t, J = 7.6 H2O2
    Hz, 1H), 3.15 (d, J = 4.3 and
    Hz, 3H). NaOH
    in
    ethanol
    1482
    Figure US20170217923A1-20170803-C02902
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.60 (s, 1H), 10.29 (s, 1H), 9.62 (d, J = 1.5 Hz, 1H), 9.00 (d, J = 7.1 Hz 1H), 8.92 (dd, J = 4.9, 1.4 Hz, 1H), 8.76 (s, 1H), 8.29 (d, J = 8.9 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.84 (dd, J = 7.8, 4.8 Hz, 1H), 7.79-7.68 (m, 2H), 6.95 (d, DMSO  94 Method AQ1, except that dioxane water was replaced 365.5 (M + 1) Method C
    J = 8.0 Hz, 1H), 3.57 (s, 2H), with
    3.29 (d, J = 4.3 Hz, 3H). DME/
    water/
    EtOH
    in the
    micro-
    wave
    at
    120° C.
    for 10
    min
    1483
    Figure US20170217923A1-20170803-C02903
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.67 (s, 1H), 9.60 (d, J = 2.4 Hz, 1H), 8.99-8.88 (m, 2H), 8.73 (d, J = 1.0 Hz, 1H), 8.27 (d, J = 9.2 Hz, 1H), 8.10 (d, J = 7.5 Hz, 1H), 7.83 (dd, J = 6.9, 4.3 Hz, 1H), 7.40 (q, J = 8.3 Hz, 2H), 7.20 (s, 1H), 3.56 (s, 2H), 3.29 (d, J = 4.1 DMSO  99 Method AQ1, except that dioxane water was replaced 368.5 (M + 1) Method C
    Hz, 3H). with
    DME/
    water/
    EtOH
    in the
    micro-
    wave
    at
    120° C.
    for 10
    min
    1484
    Figure US20170217923A1-20170803-C02904
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.61 (d, J = 1.9 Hz, 1H), 9.04-8.89 (m, 2H), 8.84 (d, J = 1.2 Hz, 1H), 8.36 (dd, J = 8.7, 1.3 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.94-7.78 (m, 3H), 7.50 (d, J = 8.3 Hz, 2H), 4.49 (s, 2H), 3.39-3.23 (m, 6H). DMSO  99 Method AQ1, except that dioxane water was replaced 357.5 (M + 1) Method C
    with
    DME/
    water/
    EtOH
    in the
    micro-
    wave
    at
    120° C.
    for 10
    min
    1485
    Figure US20170217923A1-20170803-C02905
         		1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.76 (td, J = 8.0, 1.6 Hz, 1H), 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 8.37 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.59-7.54 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.06-6.98 (m, 3H), 3.82 (s, 3H), DMSO  95 Method G1, AQ1 377.0 379.0 (M + 1) Method B (NH4HCO3)
    1486
    Figure US20170217923A1-20170803-C02906
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 9.38 (d, J = 8.4 Hz, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.69 (d, J = 1.6 Hz, 1H), 8.41 (dd, J = 8.8, 2.0 Hz, 1H), 8.29- 8.26 (m, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.50-7.41 (m, 3H), 7.11- 7.08 (m, 1H), 4.80-4.76 (m, 1H), 3.66-3.57 (m, 2H), 3.50 (s, DMSO  95 Method G1, AQ1 401.1 (M + 1) Method B (NH4HCO3)
    3H), 3.44 (s, 3H), 1.35 (d, J = 6.4
    Hz, 3H).
    1487
    Figure US20170217923A1-20170803-C02907
         		2 HCl 1H-NMR (400 MHz, CD3OD): δ 9.55 (s, 1H), 8.92 (d, J = 4.9 Hz, 1H), 8.89 (dt, J = 8.2, 1.8 Hz, 1H), 8.62 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 8.0, 5.0 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 7.43 (s, 2H), 7.10 (d, J = 7.6 Hz, 1H), 4.01 (s, 2H), 3.46 (s, 3H), 3.35 (s, DMSO  95 Method G1, AQ1 415.1 (M + 1) Method B (NH4HCO3)
    3H), 1.37 (s, 6H).
    1488
    Figure US20170217923A1-20170803-C02908
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.65 (s, 1H), 9.04 (d, J = 6.9 Hz, 1H), 8.99-8.87 (m, 2H), 8.39 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.86 (s, 1H), 7.47-7.43 (m, 3H), 7.05 (d, J = 6.8 Hz, 1H), 4.26-4.22 (m, DMSO  95 Method G1, AQ1 400.9 (M + 1) Method B (NH4HCO3)
    2H), 3.77-3.73 (m, 2H), 3.56-
    3.50 (m, 2H), 3.32 (d, J = 4.3 Hz,
    3H), 1.15 (t, J = 7.0 Hz, 3H).
    1489
    Figure US20170217923A1-20170803-C02909
         		1H-NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 8.81-8.78 (m, 2H), 8.71 (d, J = 3.6 Hz, 1H), 8.54 (s, 1H), 8.32 (d, J = 1.2 Hz, 1H), 7.57 (dd, J = 7.6, 4.8 Hz, 1H), 7.46-7.42 (m, 3H), 7.04-7.01 (m, 1H), 3.88 (s, 3H), 3.19 (d, J = 4.0 Hz, 3H). DMSO  95 Method G1, AQ1 377.1, 379.1 (M + 1) Method B (NH4HCO3)
    1490
    Figure US20170217923A1-20170803-C02910
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.50 (brs, 1H), 9.68 (d, J = 2.0 Hz, 1H), 9.09 (d, J = 8.0 Hz, 1H), 8.96 (dd, J = 5.2, 1.2 Hz, 1H), 8.94 (s, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.89 (dd, J = 8.0, 1.6 Hz, 1H), 7.48-7.43 (m, 3H), 7.03 (d, J = 7.2 Hz, 1H), 4.06-4.05 (m, 2H), DMSO  95 Method G1, AQ1 427.2 (M + 1) Method B (NH4HCO3)
    3.92 (d, J = 11.6 Hz, 1H), 3.69-
    3.66 (m, 1H), 3.42-3.39 (m,
    1H), 3.32 (d, J = 4.4 Hz, 3H),
    1.86-1.83 (m, 1H), 1.69 (d, J =
    12.4 Hz, 1H), 1.52-1.51 (m,
    3H), 1.38-1.35 (m, 1H).
    1492
    Figure US20170217923A1-20170803-C02911
         		3 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 9.70 (s, 1H), 9.13 (d, J = 8.0 Hz, 1H), 9.07 (s, 1H), 8.97 (d, J = 4.4 Hz, 1H), 8.94 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.90 (t, J = 6.2 Hz, 1H), DMSO  95 Method G1, AQ1 488.0 (M + 1) Method B (NH4HCO3)
    7.68 (s, 1H), 7.53 (d, J = 8.0 Hz,
    1H), 7.46 (d, J = 7.8 Hz, 1H),
    7.12 (d, J = 8.0 Hz, 1H), 5.50 (s,
    2H), 3.30 (d, J = 2.4 Hz, 3H).
    1493
    Figure US20170217923A1-20170803-C02912
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 9.71 (s, 1H), 9.14 (d, J = 7.6 Hz, 1H), 8.98 (d, J = 8.0 Hz, 2H), 8.40 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 7.92 (t, J = 6.2 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.47-7.43 (m, 3H), 7.02 (d, J = 7.2 Hz, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.53 (d, DMSO  95 Method G1, AQ1 496.2 (M + 1) Method B (NH4HCO3)
    J = 6.4 Hz, 1H), 3.32 (d, J = 2.4
    Hz, 3H), 2.26 (t, J = 7.0 Hz, 2H),
    2.00-1.93 (m, 2H), 1.73-1.63
    (m, 4H), 1.55-1.51 (m, 1H),
    1.28-1.02 (m, 5H).
    1494
    Figure US20170217923A1-20170803-C02913
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 9.60 (s, 1H), 8.92 (d, J = 4.4 Hz, 2H), 8.76 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.85-7.83 (m, 4H), 7.11 (d, J = 8.8 Hz, 2H), 4.04 (t, J = 6.4 Hz, 2H), 3.30 (d, J = 4.0 Hz, 3H), 2.58 (d, J = 4.0 Hz, 3H), 2.26 (t, J = 7.4 Hz, 2H), 2.00-1.93 (m, 2H). DMSO  95 Method G1, AQ1 428.1, 429.1 (M + 1) Method B (NH4HCO3)
    1495
    Figure US20170217923A1-20170803-C02914
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 9.73 (s, 1H), 9.17 (d, J = 7.6 Hz, 1H), 8.99 (s, 1H), 8.91 (s, 1H), 8.34 (s, 2H), 7.93 (t, J = 6.0 Hz, 1H), 7.88 (d, J = 7.2 Hz, 2H), 7.09 (d, J = 7.6 Hz, 2H), 4.08-4.06 (m, 2H), 3.32 (s, 3H), 2.98 (s, 3H), 2.84 (s, 3H), 2.47- 2.46 (m, 2H), 1.98-1.94 (m, 2H). DMSO  95 Method G1, AQ1 442.1, 443.1, (M + 1) Method B (NH4HCO3)
    1496
    Figure US20170217923A1-20170803-C02915
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.64 (s, 1H), 9.01 (d, J = 7.0 Hz, 1H), 8.94 (s, 1H), 8.89 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.47 (d, J = 5.8 Hz, 3H), 7.05 (d, J = 3.4 Hz, 1H), DMSO  95 Method G1, AQ1 413.1, 414.1 (M + 1) Method B (NH4HCO3)
    4.21 (dt, J = 10.8, 5.5 Hz, 1H),
    4.08 (qd, J = 10.1, 5.2 Hz, 2H),
    3.82 (dd, J = 14.4, 7.0 Hz, 1H),
    3.71 (dd, J = 14.1, 7.4 Hz, 1H),
    3.31 (d, J = 4.2 Hz, 3H), 2.08-
    2.00 (m, 1H), 1.98-1.79 (m,
    2H), 1.72-1.68 (m, 1H).
    1497
    Figure US20170217923A1-20170803-C02916
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 9.68 (s, 1H), 9.09 (d, J = 7.7 Hz, 1H), 8.96 (d, J = 5.9 Hz, 2H), 8.39 (d, J = 8.7 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.94-7.79 (m, 1H), 7.48-7.45 (m, 3H), 7.04 (d, J = 7.5 Hz, 1H), 4.30-4.18 (m, 2H), 3.80-3.70 (m, 2H), 3.44 (t, J = 6.6 Hz, 2H), DMSO- d6  95 Method G1, AQ1 415.1 (M + 1) Method B (NH4HCO3)
    3.31 (d, J = 4.2 Hz, 3H), 1.56-1.54
    (m, 2H), 0.89 (t, J = 7.4 Hz, 3H).
    1498
    Figure US20170217923A1-20170803-C02917
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 9.67 (s, 1H), 9.03 (d, J = 8.0 Hz, 1H), 8.95 (d, J = 4.5 Hz, 1H), 8.51 (s, 1H), 7.85 (s, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.18 (dd, J = 7.8, 5.1 Hz, 2H), 7.02 (dd, J = 8.2, 2.3 Hz, 1H), 3.97 (s, 3H), 3.84 (s, 3H), DMSO  95 Method G1, AQ1 373.1 (M + 1) Method B (NH4HCO3)
    1499
    Figure US20170217923A1-20170803-C02918
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.66 (s, 1H), 9.02 (d, J = 7.5 Hz, 1H), 8.95 (s, 1H), 8.89 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.85 (dd, J = 7.0, 5.4 Hz, 1H), 7.52-7.43 (m, 3H), 7.09-7.01 (m, 1H), 4.17-4.15 (m, 2H), DMSO  95 Method G1, AQ1 415.1 (M + 1) Method B (NH4HCO3)
    3.32-3.30 (m, 4H), 3.25 (s, 3H),
    1.98-1.82 (m, 2H), 1.17 (d, J =
    6.1 Hz, 3H).
    1500
    Figure US20170217923A1-20170803-C02919
         		2 HCl 1H-NMR (400 MHz, CD3OD): δ 9.80 (s, 1H), 9.37 (d, J = 8.2 Hz, 1H), 9.13 (d, J = 5.3 Hz, 1H), 8.90 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.25 (dd, J = 7.9, 5.6 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J = 5.1 Hz, 2H), 7.17 (dd, J = 7.5, 3.6 Hz, CD3OD  95 Method G1, AQ1 468.1 (M + 1) Method B (NH4HCO3)
    1H), 4.70-4.62 (m, 2H), 4.42 (q,
    J = 9.0 Hz, 2H), 3.93-3.86 (m,
    2H), 3.51 (s, 3H), 3.24 (s, 3H).
    1501
    Figure US20170217923A1-20170803-C02920
         		2 HCl 1H-NMR (400 MHz, DMSO): δ 10.45 (brs, 1H), 9.72 (s, 1H), 9.12 (d, J = 7.6 Hz, 1H), 8.97 (d, J = 4.0 Hz, 1H), 8.70 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.90-7.87 (m, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 8.4 DMSO  95 Method G1, AQ1 428.1 (M + 1) Method B (NH4HCO3)
    Hz, 1H), 7.11 (t, J = 7.2 Hz, 1H),
    4.03 (t, J = 6.4 Hz, 2H), 3.30 (d,
    J = 4.4 Hz, 3H), 2.54 (d, J = 4.0
    Hz, 3H), 2.19 (t, J = 7.4 Hz,
    2H), 1.93-1.86 (m, 2H).
    1502
    Figure US20170217923A1-20170803-C02921
         		1H-NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 8.88 (s, 1H), 8.81 (d, J = 8 Hz, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 8.19 (d, J = 8 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.61- 7.58 (m, 1H), 7.47-7.44 (m, 3H), 7.06-7.04 (m, 1H), 4.56-4.54 (m, 1H), 3.87 (dd, J = 11.2, 2.0 Hz, DMSO  95 Method G1, AQ1 413.1 (M + 1) Method B (NH4HCO3)
    1H), 3.68-3.64 (m, 1H), 3.56-3.53
    (m, 2H), 3.21 (d, J = 4.4 Hz,
    3H), 2.09-2.05 (m, 1H), 1.83-1.72
    (m, 2H), 1.61-1.55 (m, 1H).
    1503
    Figure US20170217923A1-20170803-C02922
         		2 HCl 1H-NMR (400 MHz, CD3OD): δ 9.77 (s, 1H), 9.43 (d, J = 8.1 Hz, 1H), 9.08 (d, J = 5.6 Hz, 1H), 8.46 (s, 1H), 8.34-8.25 (m, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 3.98 (t, J = 6.1 Hz, CD3OD  95 Method G1, AQ1 496.2 (M + 1) Method B (NH4HCO3)
    2H), 3.44 (t, J = 11.1 Hz, 1H),
    3.35 (s, 3H), 2.17 (t, J = 7.3 Hz,
    2H), 1.93-1.89 (m, 2H), 1.70-
    1.53 (m, 4H), 1.48 (d, J = 12.5
    Hz, 1H), 1.22-1.12 (m, 2H),
    1.08-1.02 (m, 3H).
    1504
    Figure US20170217923A1-20170803-C02923
         		1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.67 (d, J = 3.6 Hz, 1H), 8.50 (d, J = 4.0 Hz, 1H), 8.10 (s, 1H), 7.56-7.53 (m, 2H), 7.46- 7.42 (m, 3H), 7.03-7.01 (m, 1H), 4.07 (s, 3H), 3.88 (s, 3H), 3.17 (d, J = 4.0 Hz, 1H). DMSO  95 Method G1, AQ1 372.9 (M + 1) Method B (NH4HCO3)
    1505
    Figure US20170217923A1-20170803-C02924
         		1H-NMR (400 MHz, DMSO): δ 9.28 (s, 1H), 8.94 (t, J = 7.6 Hz, 1H), 8.62 (d, J = 4.2 Hz, 1H), 8.42 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.73-7.71 (m, 1H), 7.46 (t, J = 10.0 Hz, 1H), 7.33-7.27 (m, 2H), 3.16 (d, J = 4.4 Hz, 3H). DMSO  95 Method G1, AQ1 367.0 (M + 1) Method B (NH4HCO3)
    1506
    Figure US20170217923A1-20170803-C02925
         		1H-NMR (400 MHz, DMSO): δ 8.77 (s, 1H), 8.66 (t, J = 8.6 Hz, 1H), 8.52 (s, 1H), 8.44-8.31 (m, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.62- 7.49 (m, 3H), 7.42-7.37 (m, 1H), 3.12 (d, J = 3.0 Hz, 3H). DMSO  95 Method G1, AQ1 366.9 (M + 1) Method B (NH4HCO3)
    1507
    Figure US20170217923A1-20170803-C02926
         		1H-NMR (400 MHz, DMSO): δ 9.29 (d, J = 2.0 Hz, 1H), 8.95 (dt, J = 8.4, 2.4 Hz, 1H), 8.65 (d, J = 4.4 Hz, 1H), 8.49 (s, 1H), 7.94- 7.93 (m, 2H), 7.60-7.26 (m, 4H), 3.16 (d, J = 4.4 Hz, 3H). DMSO  95 Method G1, AQ1 367.1 (M + 1) Method B (NH4HCO3)
    1508
    Figure US20170217923A1-20170803-C02927
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 8.77 (s, 1H), 8.65 (t, J = 8.5 Hz, 1H), 8.55 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.79 (dd, J = 15.8, 7.8 Hz, 1H), 7.71-7.66 (m, 1H), 7.51 (t, J = 10.2 Hz, 1H), 7.34 (t, J = 8.5 Hz, 1H), 3.23 (d, J = 3.3 Hz, 3H). DMSO  95 Method G1, AQ1 367.0 (M + 1) Method B (NH4HCO3)
    1509
    Figure US20170217923A1-20170803-C02928
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 9.55 (d, J = 1.8 Hz, 1H), 9.07 (d, J = 72 Hz, 1H), 8.67 (s, 1H), 8.16 (dd, J = 18.0, 8.4 Hz, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.78 (td, J = 8.9, 6.6 Hz, 1H), 7.55-7.45 (m, 1H), 7.33 (td, J = 8.4, 2.0 Hz, 1H), 3.28 (d, J = 4.4 Hz, 3H), 2.74 (s, 3H). DMSO  95 Method G1, AQ1 363.1 (M + 1) Method B (NH4HCO3)
    1510
    Figure US20170217923A1-20170803-C02929
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 8.82 (dd, J = 7.9, 6.7 Hz, 2H), 8.65 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.80 (s, 1H), 7.65-7.50 (m, 2H), 7.42 (dd, J = 12.7, 7.6 Hz, 1H), 3.20 (d, J = 4.4 Hz, 3H), 2.94 (s, 3H). DMSO  95 Method G1, AQ1 363.0 (M + 1) Method B (NH4HCO3)
    1511
    Figure US20170217923A1-20170803-C02930
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 8.84 (d, J = 4.0 Hz, 1H), 8.77 (s, 1H), 8.64 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.79 (td, J = 8.9, 6.6 Hz, 2H), 7.57-7.46 (m, 1H), 7.34 (td, J = 8.5, 2.2 Hz, 1H), 3.20 (d, J = 4.5 Hz, 3H), 2.93 (s, 3H). DMSO  95 Method G1, AQ1 362.9 (M + 1) Method B (NH4HCO3)
    1512
    Figure US20170217923A1-20170803-C02931
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.57 (s, 1H), 8.83 (dd, J = 8.0, 1.6 Hz, 1H), 8.63 (dd, J = 4.8, 2.0 Hz, 1H), 8.38 (s, 1H), 7.95-7.86 (m, 2H), 7.67-7.57 (m, 2H), 7.15-7.09 (m, 2H), 4.44 (brs, 1H), 2.17 (t, J = 7.6 Hz, 1H), 1.91-1.89 (m, 1H), 1.78 (d, J = 12.0 Hz, 1H), 1.56-1.48 (m, 4H), 1.32-1.28 (m, 1H). DMSO  95 Method G1, AQ1 417.1 (M + 1) Method B (NH4HCO3)
    1513
    Figure US20170217923A1-20170803-C02932
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.94-8.89 (m, 2H), 8.58 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.85 (t, J = 6.8 Hz, 1H), 7.73 (dd, J = 14.4, 8.0 Hz, 1H), 7.25-7.19 (m, 2H), 4.01 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H). DMSO  95 Method G1, AQ1 363.1 (M + 1) Method B (NH4HCO3)
    1514
    Figure US20170217923A1-20170803-C02933
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 9.21 (d, J = 8.4 Hz, 1H), 9.08 (d, J = 4.4 Hz, 1H), 8.68 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.15-8.12 (m, 2H), 7.50- 7.38 (m, 3H), 4.04 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H). DMSO  95 Method G1, AQ1 363.1 (M + 1) Method B (NH4HCO3)
    1515
    Figure US20170217923A1-20170803-C02934
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 9.25 (d, J = 8.0 Hz, 1H), 9.03 (d, J = 5.2 Hz, 1H), 8.60 (s, 1H), 8.21-8.14 (m, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.40- 7.26 (m, 3H), 4.26 (brs, 4H), 2.14 (brs, 4H). DMSO- d6  95 Method G1, AQ1 389.1 (M + 1) Method B (NH4HCO3)
    1516
    Figure US20170217923A1-20170803-C02935
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 9.14 (d, J = 8.0 Hz, 1H), 9.10 (d, J = 5.2 Hz, 1H), 8.69 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 8.0, 5.2 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.39-7.27 (m, 3H), 4.60-4.50 (m, 1H), 2.08 (d, J = 11.6 Hz, 2H), 1.84 (d, J = 12.0 Hz, 2H), 1.69 (d, J = 8.4 Hz, 1H), 1.57- 1.45 (m, 4H), 1.18-1.10 (m, 1H). DMSO  95 Method G1, AQ1 417.1 (M + 1) Method B (NH4HCO3)
    1517
    Figure US20170217923A1-20170803-C02936
         		1H-NMR (400 MHz, DMSO-d6): δ 12.04 (brs, 1H), 9.58 (s, 1H), 9.38 (brs, 1H), 8.84 (d, J = 5.6 Hz, 2H), 8.72 (s, 1H), 8.28 (d, J = 9.2 Hz, 1H), 7.75 (t, J = 6.8 Hz, 1H), 7.51-7.41 (m, 3H), 7.07-7.03 (m, 1H), 3.88 (s, 3H), 3.80 (q, J = 5.6 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.86-1.74 (m, 2H), 1.73- 1.64 (m, 2H). DMSO  95 Method G1, AQ1 428.9 (M + 1) Method B (NH4HCO3)
    1518
    Figure US20170217923A1-20170803-C02937
         		1H-NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.74 (td, J = 8.0, 1.6 Hz, 1H), 8.71-8.66 (m, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.08 (dd, J = 8.8, 2.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.87-7.81 (m, 2H), 7.58-7.49 (m, 1H), 7.39- 7.30 (m, 2H), 3.49 (s, 6H). DMSO  95 Method G1, AQ1 345.1 (M + 1) Method B (NH4HCO3)
    1519
    Figure US20170217923A1-20170803-C02938
         		1H-NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.74 (d, J = 7.2 Hz, 1H), 8.69 (d, J = 3.6 Hz, 1H), 8.32 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.62- 7.48 (m, 3H), 3.48 (s, 6H). DMSO  95 Method G1, AQ1 361.1 363.1 (M + 1) Method B (NH4HCO3)
    1520
    Figure US20170217923A1-20170803-C02939
         		1H-NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.74 (td, J = 8.0, 1.6 Hz, 1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 8.8, 2.0 Hz, 1H), 8.04-7.89 (m, 5H), 7.54 (q, J = 5.2 Hz, 1H), 3.51 (s, 6H). DMSO  95 Method G1, AQ1 352.1 (M + 1) Method B (NH4HCO3)
    1521
    Figure US20170217923A1-20170803-C02940
         		1H-NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.68-8.60 (m, 2H), 8.15 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.56 (q, J = 4.8 Hz, 1H), 7.49-7.40 (m, 3H), 7.30 (s, 1H), 7.06-6.97 (m, 1H), 6.73 (s, 1H), 3.87 (s, 5H), 2.14 (t, J = 7.2 Hz, 2H), 1.80-1.71 (m, 2H), 1.71-1.62 (m, 2H). DMSO  95 Method G1, AQ1 428.1 (M + 1) Method B (NH4HCO3)
    1522
    Figure US20170217923A1-20170803-C02941
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 9.39 (d, J = 8.2 Hz, 1H), 9.02 (d, J = 5.3 Hz, 1H), 8.31 (d, J = 9.3 Hz, 2H), 8.24- 8.10 (m, 3H), 7.88 (d, J = 7.7 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 3.54 (s, 6H), 2.78 (s, 3H). DMSO  95 Method G1, AQ1 366.1 (M + 1) Method B (NH4HCO3)
    1523
    Figure US20170217923A1-20170803-C02942
         		1H-NMR (400 MHz, DMSO-d6): δ 9.63 (d, J = 1.7 Hz, 1H), 8.88- 8.32 (m, 4H), 8.16 (dd, J = 8.7, 1.8 Hz, 1H), 7.86 (t, J = 9.2 Hz, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 7.50-7.34 (m, 3H), 7.01 (dt, J = 7.3, 2.1 Hz, 1H), 3.96- 3.84 (m, 5H), 2.78 (t, J = 6.9 Hz, 2H). DMSO  95 Method G1, AQ1 400.9 (M + 1) Method B (NH4HCO3)
    1524
    Figure US20170217923A1-20170803-C02943
         		1H-NMR (400 MHz, DMSO-d6): 9.63 (s, 1H), 8.77 (d, J = 8 Hz, 1H), 8.66-8.63 (m, 3H), 8.15 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.45-7.41 (m, 3H), 7.33 (s, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.79 (s, 1H), 3.88 (s, 3H), 3.72 (d, J = 6.0 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 2.04-1.94 (m, 2H). DMSO  95 Method G1, AQ1 414.1 (M + 1) Method B (NH4HCO3)
    1525
    Figure US20170217923A1-20170803-C02944
         		1H-NMR (400 MHz, DMSO-d6): δ 9.58 (d, J = 1.2 Hz, 1H), 8.73- 8.68 (m, 3H), 8.37 (s, 1H), 8.27- 8.22 (m, 4H), 7.89-7.87 (m, 2H), 7.75 (t, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.0, 5.2 Hz, 1H). DMSO  95 Method G1, AQ1 324.1 (M + 1) Method B (NH4HCO3)
    1526
    Figure US20170217923A1-20170803-C02945
         		1H-NMR (400 MHz, DMSO-d6): δ 9.57 (d, J = 1.6 Hz, 1H), 8.72- 8.66 (m, 2H), 8.57 (d, J = 1.6 Hz, 1H), 8.19-7.91 (m, 3H), 7.83 (d, J = 8.0 Hz, 3H), 7.54 (dd, J = 7.6, 4.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 3.83 (s, 3H). DMSO  95 Method G1, AQ1 329.1 (M + 1) Method B (NH4HCO3)
    1527
    Figure US20170217923A1-20170803-C02946
         		1H-NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.72-8.66 (m, 3H), 8.16 (d, J = 8.4 Hz, 3H), 7.91 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 7.6, 4.8 Hz, 1H). DMSO  95 Method G1, AQ1 333.1, 335.0 (M + 1) Method B (NH4HCO3)
    1528
    Figure US20170217923A1-20170803-C02947
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H), 9.28 (d, J = 8.0 Hz, 1H), 9.01 (d, J = 5.6 Hz, 1H), 8.65 (s, 2H), 8.37 (s, 2H), 8.25 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 8.13 (t, J = 6.8 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 2.77 (s, 3H). DMSO  95 Method G1, AQ1 338.1 (M + 1) Method B (NH4HCO3)
    1529
    Figure US20170217923A1-20170803-C02948
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.78 (s, 1H), 9.72 (d, J = 1.8 Hz, 1H), 9.18 (d, J = 8.1 Hz, 1H), 8.98 (dd, J = 5.1, 1.2 Hz, 1H), 8.78 (s, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.95 (dd, J = 7.9, 5.3 Hz, 1H), 7.80 (td, J = 8.9, 6.6 Hz, 1H), 7.55-7.45 (m, 1H), 7.34 (td, J = 8.4, 2.3 Hz, 1H), 7.26 (s, 1H), 6.96 (s, 1H), 3.98 (d, J = 6.1 Hz, 2H), 1.24 (s, 6H). DMSO  95 Method G1, AQ1 434.1 (M + 1) Method B (NH4HCO3)
    1530
    Figure US20170217923A1-20170803-C02949
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 9.04-8.89 (m, 2H), 8.71-8.66 (m, 1H), 8.15- 8.11 (m, 2H), 7.82-7.76 (m, 2H), 7.51 (t, J = 9.2 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 4.64 (s, 2H), 3.19 (s, 3H), 2.91 (s, 3H). DMSO  95 Method G1, AQ1 420.1 (M + 1) Method B (NH4HCO3)
    1531
    Figure US20170217923A1-20170803-C02950
         		1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.78 (d, J = 7.9 Hz, 1H), 8.72 (d, J = 3.2 Hz, 1H), 8.19 (s, 2H), 8.08-7.97 (m, 2H), 7.80 (dd, J = 15.5, 8.9 Hz, 1H), 7.58 (dd, J = 7.6, 4.9 Hz, 1H), 7.52-7.41 (m, 1H), 7.29 (td, J = 8.3, 1.9 Hz, 1H), 4.48 (s, 2H), 4.15 (s, 2H), 3.48 (s, 2H). DMSO  95 Method G1, AQ1 418.1 (M + 1) Method B (NH4HCO3)
    1532
    Figure US20170217923A1-20170803-C02951
         		1H-NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 8.87 (s, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.70 (s, 1H), 8.59 (s, 1H), 8.23 (s, 1H), 8.05- 7.89 (m, 3H), 7.75 (dd, J = 15.1, 7.6 Hz, 1H), 7.56 (s, 1H), 7.48 (t, J = 9.9 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H), 4.46 (t, J = 13.4 Hz, 2H). DMSO  95 Method G1, AQ1 442.0 (M + 1) Method B (NH4HCO3)
    1533
    Figure US20170217923A1-20170803-C02952
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.95-9.03 (m, 2H), 8.78 (s, 1H), 8.14-8.24 (m, 2H), 7.88 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.54-7.48 (m, 1H), 7.35-7.32 (m, 1H), 4.89 (m, 1H), 1.39 (d, J = 1.2 Hz, 6H). DMSO  95 Method G1, AQ1 377.1 (M + 1) Method B (NH4HCO3)
    1534
    Figure US20170217923A1-20170803-C02953
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.69-8.74 (m, 2H), 8.59 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.71-7.77 (m, 1H), 7.66 (s, 1H), 7.56-7.60 (m, 1H), 7.42-7.48 (m, 1H), 7.27-7.32 (m, 1H), 1.66 (s, 9H). DMSO  95 Method G1, AQ1 391.1 (M + 1) Method B (NH4HCO3)
    1535
    Figure US20170217923A1-20170803-C02954
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H), 9.66 (s, 1H), 9.22 (d, J = 7.6 Hz, 1H), 8.99 (d, J = 4.8 Hz, 1H), 8.83 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.95 (t, J = 6.2 Hz, 1H), 7.58 (q, J = 8.6 Hz, 1H), 7.51 (t, J = 7.0 Hz, 1H), 7.46-7.41 (m, 1H), 7.25 (s, 1H), 6.72 (s, 1H), 5.13-5.06 (m, 1H), 3.21 (q, J = 7.3 Hz, 1H), 2.22-1.92 (m, 5H), 1.68-1.57 (m, 1H). DMSO  95 Method G1, AQ1 446.0 (M + 1) Method B (NH4HCO3)
    1536
    Figure US20170217923A1-20170803-C02955
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.81 (s, 2H), 9.32 (d, J = 8.0 Hz, 1H), 9.02 (d, J = 5.2 Hz, 1H), 8.81 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.00 (dd, J = 7.8, 5.8 Hz, 1H), 7.76 (dd, J = 15.4, 8.6 Hz, 1H), 7.51 (t, J = 10.0 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.29 (s, 1H), 6.73 (s, 1H), 5.15-5.07 (m, 1H), 3.21 (q, J = 7.3 Hz, 1H), 2.23- 1.87 (m, 5H), 1.68-1.57 (m, 1H). DMSO  95 Method G1, AQ1 446.1 (M + 1) Method B (NH4HCO3)
    1537
    Figure US20170217923A1-20170803-C02956
         		1H-NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.69 (dd, J = 4.4, 1.2 Hz, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 7.2 Hz, 1H), 8.13 (dd, J = 8.6, 1.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 7.6, 4.8 Hz, 1H), 7.49-7.40 (m, 3H), 7.11 (s, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.69 (s, 1H), 5.03-4.96 (m, 1H), 3.87 (s, 3H), 3.20 (dd, J = 15.0, 7.4 Hz, 1H), 2.22-1.88 DMSO  95 Method G1, AQ1 Method B (NH4HCO3)
    (m, 5H), 1.70-1.56 (m, 1H).
    1538
    Figure US20170217923A1-20170803-C02957
         		1H-NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 8.86 (d, J = 7.7 Hz, 1H), 8.74 (d, J = 8.0 Hz, 1H), 8.69 (d, J = 3.3 Hz, 1H), 8.65 (s, 1H), 8.19 (d, J = 7.4 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.54 (dd, J = 7.8, 4.8 Hz, 1H), 7.50- 7.40 (m, 3H), 7.01 (dd, J = 7.3, 3.9 Hz, 1H), 4.85 (dd, J = 16.9, 8.7 Hz, 1H), 3.88 (s, 3H), 2.16 (s, 2H), 1.96 (s, 2H). DMSO  95 Method G1, AQ1 426.1, 427.1 (M + 1) Method B (NH4HCO3)
    1539
    Figure US20170217923A1-20170803-C02958
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.67 (s, 1H), 9.07 (s, 1H), 8.97 (d, J = 5.0 Hz, 1H), 8.92 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 7.4 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.48 (d, J = 5.8 Hz, 3H), 7.09-6.99 (m, 1H), 4.03 (d, J = 6.1 Hz, 2H), 3.89 (s, 3H), 2.65 (t, J = 6.8 Hz, 2H), 2.56 (d, J = 4.4 Hz, 3H). DMSO  95 Method G1, AQ1 414.0, 415.0 (M + 1) Method B (NH4HCO3)
    1540
    Figure US20170217923A1-20170803-C02959
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 9.64 (s, 1H), 9.05 (d, J = 7.9 Hz, 1H), 9.01-8.92 (m, 2H), 8.38 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 8.6 Hz, 1H), 7.93- 7.83 (m, 1H), 7.55-7.43 (m, 3H), 7.08-6.98 (m, 1H), 4.04 (dd, J = 12.4, 6.6 Hz, 2H), 3.89 (s, 3H), 2.98 (s, 3H), 2.89 (t, J = 7.0 Hz, 2H), 2.84 (s, 3H). DMSO  95 Method G1, AQ1 428.1, 429.1 (M + 1) Method B (NH4HCO3)
    1541
    Figure US20170217923A1-20170803-C02960
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.02 (brs, 1H), 9.75 (d, J = 1.6 Hz, 1H), 9.07 (dd, J = 8.0, 1.6 Hz, 1H), 8.83 (s, 1H), 8.35 (d, J = 9.2 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.48-7.46 (m, 3H), 7.06-7.03 (m, 1H), 3.89 (s, 3H), 3.30 (d, J = 4.0 Hz, 3H). DMSO  95 Method G1, AQ1 411.1 (M + 1) Method B (NH4HCO3)
    1542
    Figure US20170217923A1-20170803-C02961
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.22 (brs, 1H), 9.64 (s, 1H), 9.01 (d, J = 6.4 Hz, 1H), 8.95 (d, J = 4.0 Hz, 1H), 8.89 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 5.2 Hz, 1H), 7.52-7.42 (m, 4H), 7.08-7.05 (m, 1H), 6.89 (s, 1H), 3.89 (s, 4H), 3.83-3.76 (m, 2H), 2.83- 2.79 (m, 1H), 1.65-1.56 (m, 7H), 1.24-1.07 (m, 6H), 0.89- 0.81 (m, 2H). DMSO  95 Method G1, AQ1 510.2 (M + 1) Method B (NH4HCO3)
    1543
    Figure US20170217923A1-20170803-C02962
         		1H-NMR (400 MHz, DMSO-d6): δ 9.67 (d, J = 1.6 Hz, 1H), 8.80 (dt, J = 8.0, 2.0 Hz, 1H), 8.70 (dd, J = 4.4, 2.0 Hz, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.71-7.67 (m, 1H), 7.58-7.55 (m, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.34 (m, 2H), 3.45 (s, 6H), 2.76 (s, 3H). DMSO  95 Method G1, AQ1 359.1 (M + 1) Method B (NH4HCO3)
    1544
    Figure US20170217923A1-20170803-C02963
         		1H-NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.82-8.79 (m, 1H), 8.70 (d, J = 4.0 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.02 (s, 1H), 7.86-7.84 (m, 2H), 7.58-7.55 (m, 3H), 3.48 (s, 6H), 2.77 (s, 3H). DMSO  95 Method G1, AQ1 375.1 (M + 1) Method B (NH4HCO3)
    1545
    Figure US20170217923A1-20170803-C02964
         		1H-NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.82 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.03 (s, 1H), 7.88-7.84 (m, 2H), 7.80- 7.77 (m, 1H), 7.37-7.33 (m, 2H), 3.50 (s, 6H), 2.78 (s, 3H). DMSO  95 Method G1, AQ1 359.1 (M + 1) Method B (NH4HCO3)
    1546
    Figure US20170217923A1-20170803-C02965
         		1H-NMR (400 MHz, CD3OD): δ 9.51 (s, 1H), 8.81 (d, J = 7.8 Hz, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.29 (dt, J = 11.2, 4.8 Hz, 3H), 6.88 (d, J = 7.5 Hz, 1H), 4.43 (dd, J = 7.1, 4.0 Hz, 1H), 4.16 (dd, J = 13.8, 4.0 Hz, 1H), CD3OD  95 Method G1, AQ1 416.1 (M + 1) Method B (NH4HCO3)
    3.86 (dd, J = 13.7, 7.4 Hz, 1H),
    3.80 (s, 3H).
    1547
    Figure US20170217923A1-20170803-C02966
         		2 HCl 1H-NMR (400 MHz, CD3OD): δ 9.74 (s, 1H), 9.44 (d, J = 8.2 Hz, 1H), 9.02 (d, J = 5.5 Hz, 1H), 8.50 (s, 1H), 8.24 (dd, J = 8.0, 5.9 Hz, 1H), 8.16 (q, J = 8.7 Hz, 2H), 7.70-7.58 (m, 1H), 7.12- 7.00 (m, 2H), 6.13 (s, 1H), 4.44- 4.41 (m, 1H), 4.29-4.27 (m, 1H), 2.37-2.16 (m, 3H), 2.09- 2.07 (m, 1H). CD3OD  95 Method G1, AQ1 457.0 (M + 1) Method B (NH4HCO3)
    1548
    Figure US20170217923A1-20170803-C02967
         		2 HCl 1H-NMR (400 MHz, CD3OD): δ 9.85 (s, 1H), 9.57 (d, J = 8.0 Hz, 1H), 9.10 (d, J = 4.8 Hz, 1H), 8.64 (s, 1H), 8.34-8.22 (m, 3H), 7.51 (t, J = 6.9 Hz, 1H), 7.47- 7.33 (m, 2H), 6.23 (s, 1H), 4.53- 4.51 (m, 1H), 4.38-4.36 (m, 1H), 2.51-2.30 (m, 3H), 2.19- 2.18 (m, 1H). CD3OD  95 Method G1, AQ1 457.1 (M + 1) Method B (NH4HCO3)
    1549
    Figure US20170217923A1-20170803-C02968
         		2 HCl 1H-NMR (400 MHz, DMSO): δ 10.38 (brs, 1H), 9.63 (d, J = 1.6 Hz, 1H), 9.00 (d, J = 8.0 Hz, 1H), 8.95-8.94 (m, 2H), 8.39 (d, J = 9.2 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.88-7.85 (m, 1H), 7.49- 7.48 (m, 3H), 7.07-7.04 (m, 1H), 3.94-3.89 (m, 5H), 3.60- 3.57 (m, 2H), 1.96-1.93 (m, 2H). DMSO  95 Method G1, AQ1 387.1 (M + 1) Method B (NH4HCO3)
    1550
    Figure US20170217923A1-20170803-C02969
         		1H-NMR (400 MHz, DMSO): δ 9.62 (s, 1H), 8.72-8.70 (m, 2H), 8.40 (s, 1H), 8.11-7.94 (m, 2H), 7.91-7.74 (m, 3H), 7.54 (dd, J = 7.6, 4.8 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 3.83 (s, 3H), 2.74 (s, 3H). DMSO  95 Method G1, AQ1 343.1 (M + 1) Method B (NH4HCO3)
    1551
    Figure US20170217923A1-20170803-C02970
         		1H-NMR (400 MHz, DMSO): δ 9.64 (s, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.70 (d, J = 4.4 Hz, 1H), 8.46 (s, 1H), 8.12-7.83 (m, 5H), 7.57 (dd, J = 7.8, 4.8 Hz, 1H), 7.39 (t, J = 8.7 Hz, 2H), 2.84 (s, 3H). DMSO  95 Method G1, AQ1 331.1 (M + 1) Method B (NH4HCO3)
    1552
    Figure US20170217923A1-20170803-C02971
         		1H-NMR (400 MHz, DMSO): δ 9.62 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 8.07- 8.00 (m, 2H), 7.60-7.50 (m, 3H), 7.40-7.37 (m, 1H), 4.48 (s, 2H), 4.12-4.10 (m, 2H), 3.48- 3.46 (m, 2H). DMSO  95 Method G1, AQ1 418.1 (M + 1) Method B (NH4HCO3)
    1553
    Figure US20170217923A1-20170803-C02972
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H), 9.45 (s, 1H), 9.27 (d, J = 8.8 Hz, 1H), 8.97 (s, 1H), 8.69 (s, 1H), 8.12-8.00 (m, 3H), 7.83-7.76 (m, 1H), 7.51-7.32 (m, 2H), 480-4.64 (m, 2H). DMSO  95 Method G1, AQ1 417.1 (M + 1) Method B (NH4HCO3)
    1554
    Figure US20170217923A1-20170803-C02973
         		2 HCl 1H-NMR (400 MHz, CD3OD): δ 9.86 (s, 1H), 9.48 (d, J = 8.8 Hz, 1H), 9.18 (d, J = 5.2 Hz, 1H), 8.72 (s 1H), 8.92 (s, 1H), 8.37- 8.31 (m, 2H), 8.22 (d, J = 8.8 Hz, 1H), 7.80-7.55 (m, 1H), 7.26- 7.20 (m, 2H), 4.92 (d, J = 4.8 Hz, 1H), 4.81 (t, J = 4.8 Hz, 1H), 4.39-4.30 (m, 2H). CD3OD  95 Method G1, AQ1 380.9 (M + 1) Method B (NH4HCO3)
    1555
    Figure US20170217923A1-20170803-C02974
         		1H-NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 8.7-8.68 (m, 2H), 8.32 (s, 1H), 7.97-7.93 (m, 2H), 7.91-7.36 (m, 5H), 347 (s, 6H). DMSO  95 Method G1, AQ1 345.1 (M + 1) Method B (NH4HCO3)
    1556
    Figure US20170217923A1-20170803-C02975
         		1H-NMR (400 MHz, DMSO-d6): δ 9.61 (s, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.67 (d, J = 3.6 Hz, 1H), 8.48 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.59-7.49 (m, 3H), 7.45-7.30 (m, 5H), 7.02-6.92 (m, 1H), 4.50 (q, J = 3.2 Hz, 1H), 4.39- 4.20 (m, 2H), 4.14-4.09 (m, 1H), 3.98-3.83 (m, 1H), 3.38 (s, 3H), 2.49-2.40 (m, 1H), 2.35- 2.18 (m, 1H). DMSO  95 Method G1, AQ1 493.0 495.0 (M + 1) Method B (NH4HCO3)
    1557
    Figure US20170217923A1-20170803-C02976
         		1H-NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 8.73 (dd, J = 7.6, 1.2 Hz, 1H), 8.67 (dd, J = 8.4, 1.2 Hz, 1H), 8.47 (s, 1H), 8.11 (dd, J = 8.4, 1.6 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.54-7.50 (m, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.38- 7.32 (m, 2H), 7.32-7.23 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 7.00-6.92 (m, 2H), 4.45 (t, J = 8.4 Hz, 1H), 4.24 (s, 2H), 4.08- 3.95 (m, 1H), 3.88-3.80 (m, DMSO  95 Method G1, AQ1 489.1 (M + 1) Method B (NH4HCO3)
    7H), 2.44-2.33 (m, 1H), 2.29-
    2.15 (m, 1H).
    1558
    Figure US20170217923A1-20170803-C02977
         		1H-NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H), 9.02 (s, 1H), 8.19 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.58 (dd, J = 7.7, 4.9 Hz, 1H), 7.52-7.37 (m, 3H), 7.37-7.24 (m, 3H), 7.12 (t, J = 8.8 Hz, 2H), 7.02 (d, J = 7.5 Hz, 1H), 6.84 (s, 1H), 3.89-3.78 (m, 4H), 3.72-3.66 (m, 1H), 3.13 (s, 1H), 2.97-2.90 (m, 1H), 2.86- 2.78 (m, 1H). DMSO  95 Method G1, AQ1 506.1 (M + 1) Method B (NH4HCO3)
    1559
    Figure US20170217923A1-20170803-C02978
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.48-10.00 (m, 1H), 9.70 (s, 1H), 9.12-8.77 (m, 3H), 8.42- 8.32 (m, 1H), 8.30-8.17 (m, 1H), 7.95-7.79 (m, 1H), 7.55- 7.44 (m, 6H), 7.26 (d, J = 7.2 Hz, 1H), 7.05 (s, 1H), 6.94 (s, 1H), 3.89 (s, 5H), 3.22 (s, 1H), 2.97-2.81 (m, 2H). DMSO  95 Method G1, AQ1 558.1 560.0 562.0 (M + 1) Method B (NH4HCO3)
    1560
    Figure US20170217923A1-20170803-C02979
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 9.61 (d, J = 1.5 Hz, 1H), 8.96 (d, J = 4.0 Hz, 1H), 8.87 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 7.87 (s, 1H), 7.52-7.44 (m, 4H), 7.36 (t, J = 7.6 Hz, 1H), 7.28 (dd, J = 13.5, 6.0 Hz, 1H), 7.22-7.10 (m, 2H), 7.06 (d, J = 7.5 Hz, 1H), 6.89 (s, 1H), 3.95-3.81 (m, 5H), 3.21 (d, J = 9.0 Hz, 1H), 2.94 (d, J = 7.3 Hz, 2H). DMSO  95 Method G1, AQ1 508.2 (M + 1) Method B (NH4HCO3)
    1561
    Figure US20170217923A1-20170803-C02980
         		1H-NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.74 (m, 2H), 8.69 (d, J = 3.5 Hz, 1H), 8.64 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.58-7.49 (m, 1H), 7.43 (m, 4H), 7.28-7.18 (m, 4H), 7.15 (m, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.94 (s, 1H), 3.82-3.73 (m, 5H), 2.90-2.87 (m, 1H), 2.68-2.65 (m, 2H), 1.89-1.86 (m, 2H). DMSO  95 Method G1, AQ1 503.9 (M + 1) Method B (NH4HCO3)
    1562
    Figure US20170217923A1-20170803-C02981
         		1H-NMR (400 MHz, DMSO-d6): 9.85 (s, 1H), 8.76 (s, 1H), 8.65 (d, J = 3.6 Hz, 1H), 8.64 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.51 (dd, J = 8.0, 4.7 Hz, 1H), 7.45 (d, J = 6.7 Hz, 2H), 7.40 (s, 1H), 7.31-7.27 (m, 5H), 7.24 (d, J = 6.6 Hz, 1H), 7.00 (d, J = 6.9 Hz, 1H), 6.80 (s, 1H), 3.77-3.70 (m, 5H), 3.17-3.15 (m, 1H). 2.98-2.81 (m, 2H). DMSO  95 Method G1, AQ1 489.9 (M + 1) Method B (NH4HCO3)
    1563
    Figure US20170217923A1-20170803-C02982
         		1H-NMR (400 MHz, DMSO-d6): δ 9.57 (s, 1H), 8.74-8.68 (m, 2H), 8.21 (s, 1H), 8.15 (dd, J = 8.7, 1.6 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.56-7.52 (m, 2H), 7.46- 7.31 (m, 4H), 7.12 (d, J = 6.5 Hz, 2H), 6.95-6.93 (m, 1H), 5.16 (s, 2H), 3.78 (s, 3H), 3.53 (s, 3H). DMSO  95 Method G1, AQ1 467.1, 469.1 (M + 1) Method B (NH4HCO3)
    1564
    Figure US20170217923A1-20170803-C02983
         		1H-NMR (400 MHz, DMSO-d6): δ 9.64 (d, J = 1.4 Hz, 1H), 8.75 (d, J = 7.9 Hz, 1H), 8.70 (d, J = 4.6 Hz, 1H), 8.32 (s, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.36- 7.29 (m, 2H), 7.01-6.98 (m, 1H), 6.88 (s, 1H), 6.83 (s, 2H), 4.12-4.03 (m, 2H), 3.85 (s, 3H), DMSO  95 Method G1, AQ1 507.2 (M + 1) Method B (NH4HCO3)
    3.69 (s, 3H), 3.62 (s, 3H), 3.56(d,
    J = 8.0 Hz, 3H), 3.16-3.02 (m, 2H).
    1565
    Figure US20170217923A1-20170803-C02984
         		1H-NMR (400 MHz, DMSO-d6): δ 9.64 (d, J = 2.0 Hz, 1H), 8.77- 8.69 (m, 2H), 8.68 (d, J = 1.6 Hz, 1H), 8.64 (d, J = 1.6 Hz, 1H), 8.16 (dd, J = 8.8, 1.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.55- 7.52 (m, 1H), 7.46-7.41 (m, 4H), 7.29 (t, J = 7.2 Hz, 1H), 7.23- 7.19 (m, 1H), 7.14-7.06 (m, 2H), 7.01 (dt, J = 9.2, 2.0 Hz, 1H), 6.96 (s, 1H), 3.87-3.76 (m, 5H), 2.94-2.93 (m, 1H), 2.68 (t, J = 7.8 Hz, 2H), 1.89- 1.83 (m, 2H). DMSO  95 Method G1, AQ1 522.3 (M + 1) Method B (NH4HCO3)
    1566
    Figure US20170217923A1-20170803-C02985
         		1H-NMR (400 MHz, DMSO-d6): δ 9.59 (s, 1H), 8.76 (t, J = 5.2 Hz, 1H), 8.69 (dd, J = 4.4, 1.2 Hz, 1H), 8.63 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.15 (dd, J = 8.8, 1.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.53-7.50 (m, 1H), 7.48-7.40 (m, 3H), 7.36-7.32 (m, 3H), 7.30-7.24 (m, 2H), 7.02-7.00 (m, 1H), 6.85 (s, 1H), 3.92-3.83 (m, 4H), 3.72-3.69 (m, 1H), 3.18-3.14 (m, 1H), 2.96-2.84 (m, 2H). DMSO  95 Method G1, AQ1 524.2, 526.2 (M + 1) Method B (NH4HCO3)
    1567
    Figure US20170217923A1-20170803-C02986
         		1H-NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 9.08 (s, 1H), 8.79- 8.69 (m, 2H), 8.51 (s, 1H), 8.31 (s, 1H), 8.00-7.89 (m, 2H), 7.85- 7.69 (m, 1H), 7.67-7.42 (m, 2H), 7.30-7.21 (m, 2H), 5.00 (d, J = 5.1 Hz, 2H). DMSO  95 Method G1, AQ1 416.0 (M + 1) Method B (NH4HCO3)
    1568
    Figure US20170217923A1-20170803-C02987
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 10.09 (d, J = 4.4 Hz, 1H), 9.65 (s, 1H), 9.05-9.02 (m, 2H), 8.95 (d, J = 4.4 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.30- 8.27 (m, 1H), 7.85 (t, J = 6.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.49-7.43 (m, 3H), 7.24 (t, J = 7.8 Hz, 2H), 7.03-6.97 (m, 2H), DMSO  95 Method G1, AQ1 504.1 (M + 1) Method B (NH4HCO3)
    3.89 (s, 3H), 3.86-3.84 (m, 2H),
    2.44 (t, J = 7.0 Hz, 2H), 1.87-
    1.77 (m, 4H).
    1569
    Figure US20170217923A1-20170803-C02988
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 9.67 (s, 1H), 9.08 (d, J = 7.2 Hz, 1H), 9.03 (s, 1H), 8.97 (d, J = 5.2 Hz, 1H), 8.44 (t, J = 5.6 Hz, 1H), 8.40 (dd, J = 8.8, 0.8 Hz, 1H), 8.32 (dd, J = 9.2, 2.8 Hz, 1H), 7.89 (t, J = 6.4 Hz, 1H), 7.50-7.44 (m, 3H), 7.25-7.14 (m, 5H), 7.03 (d, J = 7.2 Hz, 1H), 4.24 (d, J = 6.0 Hz, 2H), 3.89 (s, DMSO  95 Method G1, AQ1 518.1 (M + 1) Method B (NH4HCO3)
    3H), 3.87-3.82 (m, 2H), 2.26 (t,
    J = 7.0 Hz, 2H), 1.84-1.69 (m, 4H).
    1570
    Figure US20170217923A1-20170803-C02989
         		1H-NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.69 (dd, J = 11.3, 6.2 Hz, 2H), 8.23 (s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.59-7.50 (m, 2H), 7.44-7.26 (m, 3H), 7.23 (t, J = 7.5 Hz, 1H), 7.15 (s, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 5.18 (s, 2H), 3.79 (s, 3H), 3.54 (s, 3H). DMSO  95 Method G1, AQ1 451.2, 452.2, 453.2 (M + 1) Method B (NH4HCO3)
    1571
    Figure US20170217923A1-20170803-C02990
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 9.60 (s, 1H), 8.88 (d, J = 4.3 Hz, 1H), 8.82 (s, 1H), 8.78 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.75 (dd, J = 7.8, 5.1 Hz, 1H), 7.53-7.39 (m, 4H), 7.33 (dd, J = 14.3, 7.9 Hz, 1H), 7.12 (t, J = 7.8 Hz, 2H), 7.03 (dd, J = 11.0, 6.3 Hz, 2H), 6.90 (s, 1H), 3.97-3.90 (m, 4H), 3.82 (dd, J = 18.0, 9.5 Hz, 1H), 3.19 (dd, J = 13.4, 7.5 Hz, 1H), 2.98 (dd, J = DMSO  95 Method G1, AQ1 508.1, 509.1, 510.1 (M + 1) Method B (NH4HCO3)
    13.6, 7.9 Hz, 1H), 2.87 (dd, J =
    13.6, 6.7 Hz, 1H).
    1572
    Figure US20170217923A1-20170803-C02991
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.61 (s, 1H), 8.94 (d, J = 4.8 Hz, 1H), 8.86 (s, 2H), 8.37 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 7.56-7.32 (m, 6H), 7.31-7.19 (m, 2H), 7.06 (d, J = 7.2 Hz, 1H), 6.89 (s, 1H), 4.03-3.93 (m, 1H), 3.88 (s, 3H), 3.82 (dd, J = 14.4, 5.5 Hz, 1H), 3.22 (s, 1H), 3.02 (d, J = 7.2 Hz, 2H). DMSO  95 Method G1, AQ1 524.1, 525.1, 526.0 (M + 1) Method B (NH4HCO3)
    1573
    Figure US20170217923A1-20170803-C02992
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 9.63 (s, 1H), 8.96 (d, J = 4.4 Hz, 1H), 8.90 (s, 1H), 8.84 (d, J = 7.7 Hz, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.91-7.80 (m, 1H), 7.48 (dd, J = 15.6, 7.7 Hz, 3H), 7.36 (s, 1H), 7.24-7.03 (m, 5H), 6.85 (s, 1H), 4.03-3.93 (m, 1H), 3.88 (s, 3H), 3.83 (dd, J = 14.7, 7.6 Hz, 1H), 3.15 (s, 1H), 2.94 (dd, J = 13.8, 8.0 Hz, 1H), 2.84 (dd, J = 13.8, 6.6 Hz, 1H), 2.29 (s, 3H). DMSO  95 Method G1, AQ1 504.1, 505.2, 506.1 (M + 1) Method B (NH4HCO3)
    1574
    Figure US20170217923A1-20170803-C02993
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.71 (s, 1H), 9.05 (d, J = 4.7 Hz, 1H), 9.01 (d, J = 7.6 Hz, 1H), 8.96 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.99-7.89 (m, 1H), 7.61-7.41 (m, 4H), 7.23 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.6 Hz, 3H), 6.93 (s, 1H), 4.01-3.84 (m, 5H), 3.31-3.21 (m, 1H), 3.02- 2.97 (m, 7.5 Hz, 1H), 2.87-2.81 (m, 1H), 2.29 (s, 3H). DMSO  95 Method G1, AQ1 504.1 (M + 1) Method B (NH4HCO3)
    1575
    Figure US20170217923A1-20170803-C02994
         		1H-NMR (400 MHz, CD3OD): δ 9.39 (s, 1H), 8.69 (d, J = 8.0 Hz, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.60-7.53 (m, 1H), 7.35-7.25 (m, 5H), 7.18 (dd, J = 13.6, 7.2 Hz, 2H), 7.12 (s, 1H), 6.88 (dd, J = 7.9, 2.1 Hz, 1H), 4.49 (dd, J = 11.3, 7.9 Hz, 1H), 4.36-4.17 (m, 2H), 4.04 (t, J = 10.4 Hz, 1H), 3.74 (s, 3H), 3.60-3.49 (m, 1H), 2.50-2.39 (m, 1H), 2.27-2.14 (m, 1H). CD3OD  95 Method G1, AQ1 459.0 (M + 1) Method B (NH4HCO3)
    1576
    Figure US20170217923A1-20170803-C02995
         		1H-NMR (400 MHz, DMSO-d6): δ 9.67 (d, J = 1.7 Hz, 1H), 9.05 (s, 1H), 8.94 (d, J = 3.7 Hz, 1H), 8.59 (s, 1H), 8.40-8.22 (m, 2H), 7.85 (s, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.52-7.36 (m, 4H), 7.04 (d, J = 7.6 Hz, 1H), 4.74-4.72 (m, 2H), 4.48-4.43 (m, 3H), 3.85 (s, 3H), 3.74-3.60 (m, 1H), 2.25-2.23 (m, 1H). DMSO  95 Method G1, AQ1 527.0, 529.0 (M + 1) Method B (NH4HCO3)
    1577
    Figure US20170217923A1-20170803-C02996
         		2 HCl 1H-NMR (400 MHz, DMSO): δ 9.69 (d, J = 1.6 Hz, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.79 (d, J = 1.6 Hz, 1H), 8.73 (s, 1H), 8.21 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 7.6, 4.8 Hz, 1H), 7.56-7.38 (m, 7H), 7.05-7.02 (m, 1H), 5.59 (s, 4H), 3.89 (s, 3H). DMSO  95 Method G1, AQ1 431.1 (M + 1) Method B (NH4HCO3)
    1578
    Figure US20170217923A1-20170803-C02997
         		1H-NMR (400 MHz, DMSO): δ 9.59 (d, J = 1.6 Hz, 1H), 8.81-8.64 (m, 2H), 8.28-8.10 (m, 2H), 7.96 (d, J = 8.6 Hz, 1H), 7.55 (td, J = 8.5, 5.0 Hz, 3H), 7.40-7.06 (m, 5H), 6.94 (dd, J = 8.2, 2.0 Hz, 1H), 5.15 (s, 2H), 3.78 (s, 3H), 3.51 (s, 3H). DMSO  95 Method G1, AQ1 451.2 (M + 1) Method B (NH4HCO3)
    1579
    Figure US20170217923A1-20170803-C02998
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 10.61 (s, 1H), 9.66 (s, 1H), 9.00 (d, J = 13.5 Hz, 3H), 8.43-8.31 (m, 2H), 7.89 (s, 1H), 7.48 (dd, J = 14.6, 7.2 Hz, 3H), 7.33-7.22 (m, 4H), 7.21-7.14 (m, 1H), 7.05 (d, J = 7.2 Hz, 1H), 4.10- 3.85 (m, 2H), 3.90 (s, 3H), 3.37- 3.27 (m, 1H), 3.07-2.91 (m, 2H). DMSO  95 Method G1, AQ1 491.2 (M + 1) Method B (NH4HCO3)
    1580
    Figure US20170217923A1-20170803-C02999
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 9.60 (s, 1H), 9.11 (s, 1H), 8.95 (s, 1H), 8.66 (s, 1H), 8.20-8.02 (m, 3H), 7.97 (s, 1H), 7.78 (dd, J = 13.3, 6.5 Hz, 1H), 7.50 (t, J = 11.3 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.21 (s, 1H), 5.08 (d, J = 3.8 Hz, 2H). DMSO  95 Method G1, AQ1 416.0 (M + 1) Method B (NH4HCO3)
    1581
    Figure US20170217923A1-20170803-C03000
         		2 HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.84 (s, 1H), 9.71 (s, 1H), 9.12 (d, J = 6.2 Hz, 1H), 8.96 (d, J = 4.8 Hz, 1H), 8.91 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 7.88 (s, 1H), 7.57-7.38 (m, 3H), 7.24 (s, 1H), 7.08 (d, J = 7.9 Hz, 1H), 6.73 (s, 1H), 5.18-5.05 (m, 1H), 3.88 (s, 3H), 3.23 (dd, J = 14.8, 7.4 Hz, 1H), 2.31-2.17 (m, 1H), 2.15-1.89 (m, 4H), 1.71- 1.57 (m, 1H). DMSO  95 Method G1, AQ1 440.2 (M + 1) Method B (NH4HCO3)
    1583
    Figure US20170217923A1-20170803-C03001
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.39 (s, 1H), 9.71 (s, 1H), 9.14 (d, J = 8.1 Hz, 1H), 8.98 (d, J = 4.0 Hz, 1H), 8.71 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.25-8.19 (m, 1H), 7.96-7.89 (m, 1H), 7.38 (dd, J = 9.2, 3.0 Hz, 1H), 7.34- 7.14 (m, 2H), 3.81 (s, 4H), 3.30 (d, J = 4.4 Hz, 4H). DMSO  95 Method AQ2, AP 361.7 (M + 1) Method C
    1584
    Figure US20170217923A1-20170803-C03002
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.84 (s, 1H), 9.01 (s, 1H), 8.95 (d, J = 3.9 Hz, 1H), 8.72 (d, J = 7.8 Hz, 1H), 8.50-8.40 (m, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.24 (td, J = 7.8, 1.7 Hz, 1H), 7.85 (dd, J = 6.5, 4.8 Hz, 1H), 7.57-7.43 (m, 3H), 7.09-7.02 (m, 1H), 3.90 (s, 3H), 3.38 (s, 3H) DMSO  95 Method AQ2, AP 343.5 (M + 1) Method C
    1585
    Figure US20170217923A1-20170803-C03003
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.44-10.13 (m, 1H), 9.66 (s, 1H), 9.08 (d, J = 10.1 Hz, 2H), 8.96 (d, J = 3.7 Hz, 1H), 8.44 (d, J = 8.9 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.13 (dd, J = 13.3, 5.3 Hz, 2H), 8.00 (d, J = 8.2 Hz, 1H), 7.91 (s, 1H), 3.30 (d, J = 4.4 Hz, 3H). DMSO  95 Method AQ2, AP 356.4 (M + 1) Method C
    1586
    Figure US20170217923A1-20170803-C03004
         		1H-NMR (300 MHz, DMSO): δ 9.64 (s, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.73-8.69 (m, 1H), 8.63 (s, 2H), 8.47-8.37 (m, 1H), 8.32- 8.25 (m, 1H), 8.23-8.12 (m, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.73 (t, J = 9.0 Hz, 1H), 7.55 (dd, J = 7.9, 4.7 Hz, 1H), 3.20 (d, J = 4.3 Hz, 3H). DMSO  95 Method AQ2, AP 356.4 (M + 1) Method C
    1587
    Figure US20170217923A1-20170803-C03005
         		1H-NMR (300 MHz, DMSO): δ 9.65 (s, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.72-8.57 (m, 2H), 8.24 (d, J = 8.7 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 10.9 Hz, 2H), 7.45-7.36 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.21 (d, J = 4.1 Hz, 3H). DMSO  95 Method AQ2, AP 401.5 (M + 1) Method C
    1588
    Figure US20170217923A1-20170803-C03006
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.77 (s, 1H), 9.66 (s, 1H), 9.06 (s, 2H), 8.95 (d, J = 3.8 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.38 (dd, J = 22.8, 11.6 Hz, 2H), 4.03 (s, 3H), 3.31 (d, J = 4.1 Hz, 3H). DMSO  95 Method AQ2, AP 361.5 (M + 1) Method C
    1589
    Figure US20170217923A1-20170803-C03007
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.23-10.05 (m, 1H), 9.64 (s, 1H), 9.00 (s, 1H), 8.94 (s, 1H), 8.89 (s, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.36 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 10.9 Hz, 1H), 3.90 (s, 1H), 3.30 (d, J = 4.3 Hz, 3H). DMSO  95 Method AQ2, AP 361.5 (M + 1) Method C
    1590
    Figure US20170217923A1-20170803-C03008
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.34 (s, 1H), 9.70 (s, 1H), 9.14 (d, J = 7.4 Hz, 1H), 8.98 (d, J = 3.9 Hz, 1H), 8.75 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 4.8 Hz, 1H), 7.27 (dd, J = 19.5, 6.3 Hz, 3H), 3.88 (s, 3H), 3.28 (d, J = 4.1 Hz, 3H). DMSO  95 Method AQ2, AP 361.3 (M + 1) Method C
    1591
    Figure US20170217923A1-20170803-C03009
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.21 (s, 1H), 9.66 (d, J = 1.6 Hz, 1H), 9.04 (d, J = 7.3 Hz, 1H), 8.96 (d, J = 3.5 Hz, 1H), 8.67 (s, 1H), 8.28-8.12 (m, 2H), 7.88 (s, 1H), 7.66 (t, J = 8.8 Hz, 1H), 7.11- 6.97 (m, 2H), 3.86 (s, 3H), 3.30 (d, J = 4.4 Hz, 3H). DMSO  95 Method AQ2, AP 361.3 (M + 1) Method C
    1592
    Figure US20170217923A1-20170803-C03010
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.77 (s, 1H), 9.69 (s, 1H), 9.39 (s, 1H), 9.16 (d, J = 7.8 Hz, 1H), 9.04 (s, 1H), 8.97 (d, J = 3.6 Hz, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.53 (s, 2H), 8.31 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 5.4 Hz, 1H), 4.11 (s, 3H), 3.30 (d, J =4.4 Hz, 3H). DMSO  95 Method AQ2, AP 343.1 (M + 1) Method C
    1593
    Figure US20170217923A1-20170803-C03011
         		2 HCl DMSO  95 Method AQ2, AP 359.1 (M + 1) Method C
    1594
    Figure US20170217923A1-20170803-C03012
         		1H-NMR (300 MHz, DMSO): δ 9.64 (d, J = 1.3 Hz, 1H), 8.82- 8.75 (m, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.60 (s, 1H), 8.53 (d, J = 1.7 Hz, 1H), 8.10 (dd, J = 8.7, 1.9 Hz, 1H), 7.86-7.77 (m, 4H), 7.58-7.48 (m, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 3.99 (d, J = 6.0 Hz, 2H), DMSO  95 Method AQ2, AP 371.1 (M + 1) Method C
    3.18 (d, J = 4.4 Hz, 3H), 1.82-
    1.69 (m, 2H), 1.07 (d, J = 6.7 Hz,
    3H).
    1595
    Figure US20170217923A1-20170803-C03013
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.24-10.10 (bs, 1H), 9.65 (s, 1H), 9.02 (s, 1H), 8.96 (d, J = 3.8 Hz, 1H), 8.90 (s, 1H), 8.39 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.54 (t, J = 9.1 Hz, 1H), 3.70 (bs, 4H), 3.59 (bs, 4H), 3.32 (d, J = 4.4 Hz, 3H). DMSO  95 Method AQ2, AP 443.5 (M + 1) Method C
    1596
    Figure US20170217923A1-20170803-C03014
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.37 (s, 1H), 9.69 (d, J = 1.7 Hz, 1H), 9.10 (d, J = 7.0 Hz, 1H), 9.03-8.93 (m, 2H), 8.42 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 9.3 Hz, 1H), 8.05 (d, J = 3.5 Hz, 1H), 7.99 (dd, J = 6.2, 2.4 Hz, 2H), 7.52 (t, J = 9.1 Hz, 1H), 3.54- 3.43 (m, 4H), 3.30 (t, J = 10.4 DMSO  95 Method AQ2, AP 428.5 (M + 1) Method C
    Hz, 3H), 1.98-1.81 (m, 4H).
    1597
    Figure US20170217923A1-20170803-C03015
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.71 (s, 1H), 8.96 (d, J = 3.9 Hz, 1H), 8.81 (s, 1H), 8.74 (d, J = 7.9 Hz, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.29-8.19 (m, 2H), 7.87 (dd, J = 6.5, 4.7 Hz, 1H), 7.80 (dd, J = 15.5, 8.9 Hz, 1H), 7.61-7.50 (m, 1H), 7.36 (d, J = 8.1 Hz, 1H), 3.37 (d, J = 4.5 Hz, 3H). DMSO  95 Method AQ2, AP 349.4 (M + 1) Method C
    1598
    Figure US20170217923A1-20170803-C03016
         		1H-NMR (300 MHz, DMSO): δ 9.27 (d, J = 1.5 Hz, 1H), 8.61 (dd, J = 12.6, 3.0 Hz, 2H), 8.41 (d, J = 2.9 Hz, 1H), 8.34-8.27 (m, 1H), 8.16 (dd, J = 8.7, 1.9 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.45 (dd, J = 16.0, 9.2 Hz, 3H), 7.05-6.97 (m, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.19 (d, J = 4.3 Hz, 3H). DMSO  95 Method AQ2, AP 373.4 (M + 1) Method C
    1599
    Figure US20170217923A1-20170803-C03017
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 10.44-10.13 (m, 1H), 9.65 (s, 1H), 9.02 (s, 1H), 8.96 (d, J = 3.5 Hz, 1H), 8.87 (s, 1H), 8.37 (d, J = 9.1 Hz, 1H), 8.24 (s, 1H), 7.86 (s, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.43 (d, DMSO  95 Method AQ2, AP 343.5 (M + 1) Method C
    J = 7.5 Hz, 1H), 4.64 (s, 2H),
    3.33 (d, J = 4.2 Hz, 3H), 3.17 (s,
    1H).
    1600
    Figure US20170217923A1-20170803-C03018
         		MSA 1H-NMR (300 MHz, DMSO): δ 9.90 (s, 1H), 9.57 (d, J = 1.6 Hz, 1H), 8.93 (dd, J = 5.0, 1.5 Hz, 2H), 8.73 (s, 1H), 8.32 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 10.1, 7.0 Hz, 2H), 7.73 (d, J = 7.5 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 7.5 DMSO  95 Method AQ2, AP 343.5 (M + 1) Method C
    Hz, 1H), 4.63 (s, 2H), 3.30 (d, J =
    4.3 Hz, 3H), 2.32 (s, 3H).
    1601
    Figure US20170217923A1-20170803-C03019
    Figure US20170217923A1-20170803-C03020
    Figure US20170217923A1-20170803-C03021
         		MsOH 1H NMR (300 MHz, DMSO) δ 9.72 (brs, 1H), 9.58 (d, J = 1.6 Hz, 1H), 9.03-8.89 (m, 2H), 8.45 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.99-7.84 (m, 2H), 7.64 (ddd, J = 9.2, 6.1, 3.1 Hz, 1H), 7.58- 7.31 (m, 2H), 3.28 (d, J = DMSO >98 G2/ AQ3
    4.5 Hz, 3H), 2.39 (s, 3H).
    1602
    Figure US20170217923A1-20170803-C03022
    Figure US20170217923A1-20170803-C03023
    Figure US20170217923A1-20170803-C03024
         		1H NMR (300 MHz, DMSO) δ 9.59 (d, J = 2.0 Hz, 1H), 9.33 (s, 2H), 9.24 (s, 1H), 8.79 (d, J = 1.5 Hz, 1H), 8.76-8.64 (m, 2H), 8.30 (dd, J = 8.7, 1.5 Hz, 1H), 8.12 (brs, 2H), 7.91 (d, J = 8.7 Hz, 1H), 7.55 DMSO >98 G2/ AQ3
    (dd, J = 7.9, 4.8 Hz, 1H).
    1603
    Figure US20170217923A1-20170803-C03025
    Figure US20170217923A1-20170803-C03026
    Figure US20170217923A1-20170803-C03027
         		1H NMR (300 MHz, DMSO) δ 9.64-9.53 (m, 1H), 8.77-8.58 (m, 2H), 8.53 (s, 1H), 8.43 (d, J = 1.5 Hz, 1H), 8.11-7.90 (m, 3H), 7.82 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 4.00 (s, DMSO >98 G2/ AQ3
    3H), 3.98 (s, 3H).
    1604
    Figure US20170217923A1-20170803-C03028
    Figure US20170217923A1-20170803-C03029
    Figure US20170217923A1-20170803-C03030
         		1H NMR (300 MHz, DMSO) δ 9.59 (d, J = 2.0 Hz, 1H), 8.83-8.66 (m, 2H), 8.55 (s, 1H), 8.27-7.99 (m, 4H), 7.99-7.82 (m, 2H), 7.77 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.56 (dd, J = 7.9, 4.8 Hz, 1H). DMSO >98 G2/ AQ3
    1605
    Figure US20170217923A1-20170803-C03031
    Figure US20170217923A1-20170803-C03032
    Figure US20170217923A1-20170803-C03033
         		1H NMR (300 MHz, DMSO) δ 9.58 (d, J = 2.1 Hz, 1H), 8.80-8.64 (m, 2H), 8.25 (dd, J = 8.7, 1.6 Hz, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.7 Hz, 1H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H). DMSO >98 G2/ AQ3
    1606
    Figure US20170217923A1-20170803-C03034
    Figure US20170217923A1-20170803-C03035
    Figure US20170217923A1-20170803-C03036
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.95-9.43 (m, 3H), 9.05 (d, J = 8.2 Hz, 1H), 8.99 (dd, J = 5.1, 1.5 Hz, 1H), 8.74 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 7.93 (dd, J = 8.0, 5.1 Hz, 1H), 7.79 (td, DMSO >98 G2/ AQ3
    J = 8.9, 6.6 Hz, 1H), 7.51
    (ddd, J = 11.5, 9.3, 2.6 Hz, 1H),
    7.33 (td, J = 8.3, 1.9 Hz, 1H).
    1607
    Figure US20170217923A1-20170803-C03037
    Figure US20170217923A1-20170803-C03038
    Figure US20170217923A1-20170803-C03039
         		3 HCl 1H NMR (300 MHz, DMSO) δ 11.88 (s, 1H), 9.77 (d, J = 1.7 Hz, 1H), 9.56-9.28 (m, 1H), 9.19-9.01 (m, 1H), 8.31- 8.11 (m, 4H), 7.75-7.47 (m, 2H), 7.47-7.23 (m, 1H), 4.83-4.67 (m, 2H), 3.96 (t, J = 12.2 Hz, 2H), 3.57 (d, J = 11.9 Hz, 2H), 3.46- 3.19 (m, 2H), 2.83 (d, J = 3.1 Hz, 3H). DMSO >98 G2/ AQ3
    1608
    Figure US20170217923A1-20170803-C03040
    Figure US20170217923A1-20170803-C03041
    Figure US20170217923A1-20170803-C03042
         		HCl 1H NMR (300 MHz, DMSO) δ 14.45 (s, 1H), 10.36 (s, 1H), 9.31 (d, J = 2.2 Hz, 1H), 8.82 (s, 1H), 8.73 (ddd, J = 8.8, 2.5, 0.9 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.56-7.36 (m, 3H), 7.11 (d, J = 8.4 Hz, DMSO 100 Method AQ2/ BF
    1H), 7.03 (d, J = 7.1 Hz,
    1H), 3.99 (s, 3H), 3.87 (s,
    3H), 3.30 (d, J = 3.9 Hz, 3H).
    1609
    Figure US20170217923A1-20170803-C03043
    Figure US20170217923A1-20170803-C03044
    Figure US20170217923A1-20170803-C03045
         		HCl 1H NMR (300 MHz, DMSO) δ 10.97 (s, 1H), 9.56-9.35 (m, 2H), 9.04-8.81 (m, 2H), 8.66 (t, J = 7.7 Hz, 1H), 8.61-8.45 (m, 2H), 8.15 (d, J = 8.6 Hz, 1H), 8.10-7.96 (m, 1H), 7.77-7.58 (m, 1H), 3.25 (d, J = 4.1 Hz, 3H). DMSO 100 Method AQ2/ BF
    1610
    Figure US20170217923A1-20170803-C03046
    Figure US20170217923A1-20170803-C03047
    Figure US20170217923A1-20170803-C03048
         		2 MsOH 1H NMR (300 MHz, CDCl3) δ 9.93 (brs, 1H), 9.61 (d, J = 1.8 Hz, 1H), 9.10-8.96 (m, 2H), 8.64 (s, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 8.0, 5.3 Hz, 1H), 7.69-7.47 (m, 2H), 7.47-7.34 DMSO >98 G2/ AQ3 Method 3
    (m, 1H), 3.30 (d, J = 4.5
    Hz, 3H), 2.42 (s, 6H).
    1611
    Figure US20170217923A1-20170803-C03049
    Figure US20170217923A1-20170803-C03050
    Figure US20170217923A1-20170803-C03051
         		2 HCl 1H NMR (300 MHz, CDCl3) δ 10.42 (brs, 1H), 9.71 (d, J = 1.9 Hz, 1H), 9.17 (d, J = 8.1 Hz, 1H), 8.99 (dd, J = 5.1, 1.3 Hz, 1H), 8.78 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.94 (dd, DMSO >98 G2/ AQ3
    J = 8.1, 5.2 Hz, 1H), 7.79
    (td, J = 8.9, 6.7 Hz, 1H),
    7.55-7.37 (m, 1H), 7.31
    (td, J = 8.4, 2.2 Hz, 1H),
    3.29 (d, J = 4.4 Hz, 3H).
    1612
    Figure US20170217923A1-20170803-C03052
    Figure US20170217923A1-20170803-C03053
    Figure US20170217923A1-20170803-C03054
         		HCl 1H NMR (300 MHz, DMSO) δ 9.95 (brs, 1H), 9.65 (s, 1H), 9.18-9.02 (m, 1H), 8.95 (d, J = 4.7 Hz, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.28 (s, 1H), 8.09-7.70 (m, 4H), 3.29 (d, J = 4.4 Hz, 3H). DMSO >98 G2/ AQ3
    1613
    Figure US20170217923A1-20170803-C03055
    Figure US20170217923A1-20170803-C03056
    Figure US20170217923A1-20170803-C03057
         		1H NMR (300 MHz, DMSO) δ 9.64 (d, J = 1.5 Hz, 1H), 8.77 (dt, J = 7.9, 1.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.61-8.48 (m, 1H), 8.31 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 8.00-7.83 (m, 3H), 7.55 (dd, J = 7.9, 4.8 Hz, 1H), 3.17 (d, DMSO >98 G2/ AQ3
    J = 4.4 Hz, 3H).
    1614
    Figure US20170217923A1-20170803-C03058
    Figure US20170217923A1-20170803-C03059
    Figure US20170217923A1-20170803-C03060
         		1H NMR (300 MHz, DMSO) δ 9.65 (dd, J = 2.1, 0.8 Hz, 1H), 8.78 (dt, J = 8.0, 1.9 Hz, 1H), 8.69 (dd, J = 4.8, 1.7 Hz, 1H), 8.65-8.50 (m, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.04-7.85 (m, 1H), 7.69 (dt, J = 8.5, 1.8 Hz, 1H), 7.65-7.37 (m, 3H), 3.18 (d, J = 4.5 Hz, 3H). DMSO >98 G2/ AQ3 Method 3
    1615
    Figure US20170217923A1-20170803-C03061
    Figure US20170217923A1-20170803-C03062
    Figure US20170217923A1-20170803-C03063
         		1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 1.7 Hz, 1H), 8.84-8.74 (m, 1H), 8.69 (dd, J = 4.7, 1.5 Hz, 1H), 8.65-8.52 (m, 1H), 8.34 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.69-7.43 (m, 3H), 3.18 (d, J = 4.3 Hz, 3H). DMSO >98 G2/ AQ3 Method 3
    1760
    Figure US20170217923A1-20170803-C03064
    Figure US20170217923A1-20170803-C03065
    Figure US20170217923A1-20170803-C03066
         		2 HCl 1H NMR (300 MHz, DMSO) δ 10.04 (s, 1H), 9.65 (s, 1H), 9.11-8.99 (m, 1H), 8.96 (dd, J = 5.0, 1.4 Hz, 1H), 8.41 (s, 1H), 8.13-8.05 (m, 1H), 7.92-7.82 (m, 1H), 7.64-7.55 (m, 1H), 7.44- 7.26 (m, 3H), 3.27 (d, J = 4.6 Hz, 3H), 2.47 (s, 3H). DMSO >98 AQ5 ND 4
  • Figure US20170217923A1-20170803-C03067
  • Figure US20170217923A1-20170803-C03068
    • 6-(3-methoxyphenyl)-2-(pyridine-3-yl)quinazoline-4-ol (lix-a)
  • 6-(3-methoxyphenyl)-2-(pyridine-3-yl)quinazoline-4-ol was prepared from 6-bromo-2-(pyridin-3-yl)quinazolin-4-ol (synthesized following Scheme 70 substituting 2-amino-5-bromobenzamide for 2-amino-5-bromo-3-methylbenzamide) and 3-methoxylphenylboronic acid as described in Scheme 72 using method AQ2. The resultant product, 6-(6-methoxypyridin-3-yl)-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine, was a pale yellow solid (19.1 mg, 51%). LCMS m/z=344 (M+1) (Method C) (retention time=2.01 min). 1H NMR (300 MHz, DMSO) δ 9.64 (d, J=1.3 Hz, 1H), 8.84-8.74 (m, 1H), 8.68 (dd, J=6.2, 1.7 Hz, 2H), 8.57 (d, J=1.6 Hz, 2H), 8.16 (ddd, J=14.4, 8.7, 2.2 Hz, 2H), 7.85 (d, J=8.7 Hz, 1H), 7.54 (dd, J=7.9, 4.8 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 3.93 (s, 3H), 3.18 (d, J=4.3 Hz, 3H).
    • Method AP: 6-(3-methoxyphenyl)-2-(pyridine-3-yl)-4-(pyrrolidin-1-yl)quinazoline (lviii-g)
  • 6-(3-methoxyphenyl)-2-(pyridine-3-yl)-4-(pyrrolidin-1-yl)quinazoline was prepared from 6-(3-methoxyphenyl)-2-(pyridine-3-yl)quinazoline-4-ol and pyrrolidine in a manner analogous to that described for 6-bromo-N-methyl-2-(pyridine-3-yl)quinazoline-4-amine using Method AP in Scheme 72. 6-(3-methoxyphenyl)-2-(pyridine-3-yl)-4-(pyrrolidin-1-yl)quinazoline was a pale yellow solid (43 mg, 31%). LCMS m/z=383 (M+1) (Method C) (retention time=2.49 min). 1H NMR (300 MHz, DMSO) δ 9.62 (s, 1H), 8.94 (d, J=5.0 Hz, 2H), 8.56 (s, 1H), 8.32 (dd, J=19.9, 8.5 Hz, 2H), 7.83 (s, 1H), 7.56-7.30 (m, 3H), 7.04 (d, J=6.8 Hz, 1H), 4.27 (s, 4H), 3.86 (s, 3H), 2.08 (s, 4H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 76, replacing pyrrolidine with the appropriate amine and 3-methoxyphenylboronic acid with the appropriate boronic acid.
  • TABLE 25
    1H- Re- Puri- Method
    NMR ten- LCMS ty for
    Num- Sol- tion Proto- Per- Coup-
    ber Product Salt 1H-NMR vent LCMS Time col cent ling
    1616
    Figure US20170217923A1-20170803-C03069
         		HCl 1H NMR (300 MHz, DMSO) δ 9.82 (s, 1H), 9.59 (s, 1H), 9.08-8.81 (m, 3H), 8.36 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.95- 7.77 (m, 1H), 7.58- 7.37 (m, 3H), 7.05 (d, J = 6.5 Hz, 1H), 5.01- 4.79 (m, 1H), 3.87 (s, 3H), 1.42 (d, J = 6.5 Hz, 6H). DMSO 371 (M + 1) 2.36 Meth- od C 100 Method AP
    1617
    Figure US20170217923A1-20170803-C03070
         		HCl 1H NMR (300 MHz, DMSO) δ 10.38 (s, 1H), 9.64 (s, 1H), 9.43 (s, 1H), 9.28 (s, 1H), 9.07 (d, J = 7.9 Hz, 1H), 9.00- 8.76 (m, 3H), 8.48 (d, J = 7.5 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.08- 7.95 (m, 1H), 7.94-7.81 (m, 1H), 3.97-3.74 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H). DMSO 328 (M + 1) 1.82 Meth- od C 100 Method AP
    1618
    Figure US20170217923A1-20170803-C03071
         		HCl 1H NMR (300 MHz, DMSO) δ 10.11 (s, 1H), 9.58 (s, 1H), 9.03-8.79 (m, 3H), 8.35 (d, J = 8.7 Hz, 1H), 8.23-8.09 (m, 1H), 7.90-7.75 (m, 1H), 7.58-7.36 (m, 3H), 7.04 (d, J = 3.3 Hz, 1H), 3.88 (s, 3H), 3.65 (t, J = 6.0 Hz, 2H), 2.29-2.09 (m, 1H), 1.02 (d, J = 6.7 Hz, 6H). DMSO 385 (M + 1) 1.76 Meth- od D 100 Method AP
    1619
    Figure US20170217923A1-20170803-C03072
         		HCl 1H NMR (300 MHz, DMSO) δ 9.83-9.52 (m, 2H), 9.27 (d, J = 7.1 Hz, 1H), 8.95 (d, J = 5.1 Hz, 1H), 8.87 (s, 1H), 8.32 (d, J = 8.9 Hz, 1H), 8.15- 7.92 (m, 2H), 7.59- 7.33 (m, 3H), 7.04 (d, J = 3.4 Hz, 1H), 4.86- 4.57 (m, 2H), 3.88 (s, 3H). DMSO 411 (M + 1) 1.99 Meth- od D 100 Method AP
    1620
    Figure US20170217923A1-20170803-C03073
         		HCl 1H NMR (300 MHz, DMSO) δ 10.50 (s, 1H), 9.64 (d, J = 1.4 Hz, 1H), 9.12-8.85 (m, 3H), 8.46-8.33 (m, 1H), 8.27 (d, J = 8.9 Hz, 1H), 7.88 (dd, J = 7.9, 5.1 Hz, 1H), 7.57-7.37 (m, 3H), 7.11-6.94 (m, 1H), 4.00-3.76 (m, 5H), 1.37 (t, J = 7.2 DMSO MS not work 1.56 Meth- od D 100 Method AP
    Hz, 3H).
    1621
    Figure US20170217923A1-20170803-C03074
         		1H NMR (300 MHz, DMSO) δ 9.57 (s, 1H), 8.78-8.50 (m, 3H), 8.33-7.89 (m, 3H), 7.83 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 7.9, 4.8 Hz, 1H), 7.47-7.32 (m, 3H), 7.04-6.91 (m, 1H), 3.86 (s, 3H). DMSO 329 (M + 1) 1.47 Meth- od D 100 Method AP
    1622
    Figure US20170217923A1-20170803-C03075
         		HCl 1H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.14-8.87 (m, 2H), 8.50 (s, 1H), 8.33 (s, 2H), 7.94-7.77 (m, 1H), 7.52-7.25 (m, 3H), 7.02 (d, J = 7.9 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 6H). DMSO 357 (M + 1) 1.55 Meth- od D 100 Method AP
    1623
    Figure US20170217923A1-20170803-C03076
         		1H NMR (300 MHz, DMSO) δ 9.60 (d, J = 1.4 Hz, 1H), 8.81- 8.55 (m, 3H), 8.42 (d, J = 1.8 Hz, 1H), 8.11 (ddd, J = 18.8, 8.7, 2.2 Hz, 2H), 7.86 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 7.9, 4.8 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 4.27 (s, 4H), 3.92 (s, 3H), 2.08 (s, 4H). DMSO 384.1 (M + 1) 2.33 Meth- od C 100 Method AP
    1624
    Figure US20170217923A1-20170803-C03077
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.62 (s, 1H), 8.94 (d, J = 5.0 Hz, 2H), 8.56 (s, 1H), 8.32 (dd, J = 19.9, 8.5 Hz, 2H), 7.83 (s, 1H), 7.56- 7.30 (m, 3H), 7.04 (d, J = 6.8 Hz, 1H), 4.27 (s, 4H), 3.86 (s, 3H), 2.08 (s, 4H). DMSO 383.2 (M + 1) 2.47 Meth- od C  95 Method AP
    1625
    Figure US20170217923A1-20170803-C03078
         		1H NMR (300 MHz, DMSO) δ 9.70 (d, J = 1.4 Hz, 1H), 8.85 (d, J = 7.9 Hz, 1H), 8.80-8.72 (m, 2H), 8.45 (d, J = 8.7 Hz, 1H), 8.27 (dd, J = 14.9, 5.9 Hz, 3H), 7.63 (dd, J = 7.3, 4.8 Hz, 1H), 7.52-7.33 (m, 4H), 7.04 (d, J = 7.1 Hz, 1H), 3.88 (s, 3H). DMSO 380.1 (M + 1) 2.01 Meth- od C 100 Method AP
    1626
    Figure US20170217923A1-20170803-C03079
         		HCl 1H NMR (300 MHz, DMSO) δ 9.61 (s, 1H), 8.75 (d, J = 7.7 Hz, 1H), 8.68 (d, J = 4.6 Hz, 1H), 8.30 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.54 (dd, J = 7.6, 5.0 Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 3.82 (s, 4H), 3.49 (s, DMSO 358.0 (M + 1) 2.25 Meth- od C 100 Method AP
    7H).
    1627
    Figure US20170217923A1-20170803-C03080
         		HCl 1H NMR (300 MHz, DMSO) δ 9.62 (s, 1H), 8.76 (d, J = 7.9 Hz, 1H), 8.73-8.66 (m, 1H), 8.19-8.09 (m, 2H), 7.97 (d, J = 8.6 Hz, 1H), 7.82-7.73 (m, 2H), 7.61-7.52 (m, 1H), 7.14-7.05 (m, 2H), 3.94 (s, 5H), 3.89-3.80 (m, 9H). DMSO 399.2 (M + 1) 2.19 Meth- od C 100 Method AP
    1628
    Figure US20170217923A1-20170803-C03081
         		1H NMR (300 MHz, DMSO) δ 9.55 (dd, J = 2.1, 0.8 Hz, 1H), 8.76-8.62 (m, 3H), 8.60 (d, J = 1.7 Hz, 1H), 8.24-8.10 (m, 2H), 8.02 (s, 2H), 7.83 (d, J = 8.7 Hz, 1H), 7.56- 7.46 (m, 1H), 6.98 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H). DMSO 330.1 (M + 1) 1.72 Meth- od C 100 Method AP
    1629
    Figure US20170217923A1-20170803-C03082
         		1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 2.1 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.73 (dd, J = 4.7, 1.6 Hz, 1H), 8.36-8.25 (m, 2H), 8.06 (d, J = 8.7 Hz, 1H), 7.59 (dd, J = 7.6, 4.4 Hz, 1H), 7.48- 7.40 (m, 1H), 7.41- 7.29 (m, 2H), 7.01 (dd, J = 8.0, 2.4 Hz, 1H), 4.80 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), DMSO 358 (M + 1) Meth- od C  99 Method AP
    1.53 (t, J = 7.0 Hz,
    3H).
    1630
    Figure US20170217923A1-20170803-C03083
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.68 (d, J = 1.8 Hz, 1H), 9.07 (d, J = 5.5 Hz, 1H), 8.96 (d, J = 3.5 Hz, 1H), 8.90 (s, 1H), 8.37 (d, J = 7.5 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.94-7.83 (m, 1H), 7.57-7.39 (m, 3H), 7.22 (d, J = 1.0 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.72 (s, 1H), 5.18-5.04 (m, 1H), 3.88 (s, J = 2.7 Hz, 3H), 3.23 (dd, J = 13.7, 6.1 Hz, 1H), 2.31-2.17 (m, 1H), 2.17-1.88 (m, 4H), 1.74-1.55 (m, 1H). DMSO 440.6 (M + 1) Meth- od C  99 Method AP
    1631
    Figure US20170217923A1-20170803-C03084
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.70 (d, J = 1.6 Hz, 1H), 9.24 (d, J = 7.4 Hz, 1H), 8.99 (dd, J = 5.3, 1.4 Hz, 1H), 8.34 (dd, J = 15.7, 6.1 Hz, 3H), 8.21 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 7.7, 5.1 Hz, 1H), 7.51- 7.33 (m, 3H), 7.04 (dd, J = 7.8, 2.4 Hz, 1H), 4.67 (s, 2H), 4.33 (s, 2H), 3.87 (s, J = 3.6 Hz, 3H), 3.50 (s, 2H). DMSO 412.4 (M + 1) Meth- od C  99 Method AP
    1632
    Figure US20170217923A1-20170803-C03085
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.00 (d, J = 6.5 Hz, 2H), 8.78 (d, J = 6.5 Hz, 2H), 8.46- 8.32 (m, 2H), 8.15 (d, J = 8.4 Hz, 1H), 7.53- 7.30 (m, 3H), 7.02 (d, J = 7.8 Hz, 1H), 4.34 (s, J = 2.4 Hz, 3H), 3.86 (s, J = 2.5 Hz, 3H). DMSO 344.4 (M + 1) Meth- od C  99 Method AP
    1633
    Figure US20170217923A1-20170803-C03086
         		1H NMR (300 MHz, DMSO) δ 9.55 (dd, J = 2.1, 0.8 Hz, 1H), 8.76-8.62 (m, 3H), 8.60 (d, J = 1.7 Hz, 1H), 8.24-8.10 (m, 2H), 8.02 (s, 2H), 7.83 (d, J = 8.7 Hz, 1H), 7.56-7.46 (m, 1H), 6.98 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H). DMSO 330.1 (M + 1) Meth- od C  99 Method AP
  • 1H Purity
    Starting Starting Salt NMR per- Method of
    Number Material R1 Material R3 Product Type 1H NMR Solvent cent Coupling
    1634
    Figure US20170217923A1-20170803-C03087
    Figure US20170217923A1-20170803-C03088
    Figure US20170217923A1-20170803-C03089
         		1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 4.78 (d, 2H, J = 5.4 Hz), 6.58 (d, 1H, J = 1.1 Hz), 7.00-7.75 (m, 8H), 7.85 (d, 1H, J = 8.6 Hz), 8.64-8.97 (m, 4H), 9.64 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1635
    Figure US20170217923A1-20170803-C03090
    Figure US20170217923A1-20170803-C03091
    Figure US20170217923A1-20170803-C03092
         		1H NMR (DMSO-d6) ppm 3.84-3.95 (m, 11H), 7.01 (d, 1H, J = 8.1 Hz), 7.32-7.46 (m, 3H), 7.56 (dd, 1H, J = 6.1, 8.1 Hz), 7.97 (d, 1H, J = 8.2 Hz), 8.16-8.76 (m, 4H), 9.61 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1636
    Figure US20170217923A1-20170803-C03093
    Figure US20170217923A1-20170803-C03094
    Figure US20170217923A1-20170803-C03095
         		1H NMR (DMSO-d6) ppm 2.23 (m, 2H), 3.85 (s, 3H), 4.71 (br s, 4H), 6.98 (dd, 1H, J = 2.1, 8.0 Hz), 7.31-7.55 (m, 4H), 7.87 (d, 1H, J = 8.2 Hz), 8.12-8.74 (m, 4H), 9.59 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1637
    Figure US20170217923A1-20170803-C03096
    Figure US20170217923A1-20170803-C03097
    Figure US20170217923A1-20170803-C03098
         		1H NMR (DMSO-d6) ppm 1.77 (br s, 6H), 3.86-3.89 (br m, 7H), 6.99 (dd, 1H, J = 1.4, 8.6 Hz), 7.31-7.57 (m, 4H), 7.93 (d, 1H, J = 1.4, 8.6 Hz), 8.11-8.16 (m, 2H), 8.69-8.76 (m, 2H), 9.61 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1638
    Figure US20170217923A1-20170803-C03099
    Figure US20170217923A1-20170803-C03100
    Figure US20170217923A1-20170803-C03101
         		1H NMR (DMSO-d6) ppm 2.18-2.22 (m, 1H), 3.00-3.09 (m, 1H), 3.11-3.22 (m, 2H), 3.31-3.34 (m, 1H), 3.86 (s, 3H), 6.29-6.31 (m, 1H), 7.17-8.82 (m, 14H), 9.63 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1639
    Figure US20170217923A1-20170803-C03102
    Figure US20170217923A1-20170803-C03103
    Figure US20170217923A1-20170803-C03104
         		1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 4.10-4.13 (m, 2H), 4.35-4.38 (m, 2H), 6.92-7.46 (m, 10H), 7.85 (d, 1H, J = 8.6 Hz), 8.16 (d, 1H, J = 8.6 Hz), 8.66- 8.75 (m, 4H), 9.61 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1640
    Figure US20170217923A1-20170803-C03105
    Figure US20170217923A1-20170803-C03106
    Figure US20170217923A1-20170803-C03107
         		1H NMR (DMSO-d6) ppm 3.07 (t, 2H, J = 6.9 Hz), 3.37 (s, 3H), 3.92-3.96 (m, 2H), 7.00-7.58 (m, 10H), 7.84 (d, 1H, J = 8.6 Hz), 8.14 (d, 1H, J = 8.6 Hz), 8.59-8.78 (m, 4H), 9.64 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1641
    Figure US20170217923A1-20170803-C03108
    Figure US20170217923A1-20170803-C03109
    Figure US20170217923A1-20170803-C03110
         		1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 4.95 (d, 2H, J = 5.6 Hz), 7.01-7.51 (m, 10H), 7.85 (d, 1H, J = 8.6 Hz), 8.16 (d, 1H, J = 3.6 Hz), 8.65-8.73 (m, 4H), 9.56 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1642
    Figure US20170217923A1-20170803-C03111
    Figure US20170217923A1-20170803-C03112
    Figure US20170217923A1-20170803-C03113
         		1H NMR (DMSO-d6) ppm 1.66-1.781 (m, 6H), 2.16-2.19 (m, 2H), 3.87 (s, 3H), 4.78 (br s, 1H), 7.00-7.55 (m, 5H), 7.83 (d, 1H, J = 8.6 Hz), 8.12 (d, 1H, J = 8.6 Hz), 8.29 (s, 1H), 8.67-8.77 (m, 3H), 9.62 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1643
    Figure US20170217923A1-20170803-C03114
    Figure US20170217923A1-20170803-C03115
    Figure US20170217923A1-20170803-C03116
         		HCl 1H NMR (DMSO-d6) ppm 0.81 (t, 3H, J = 7.4 Hz), 1.47-1.54 (m, 2H), 2.00- 2.05 (m, 2H), 3.32-3.37 (m, 4H), 3.86- 3.91 (m, 5H), 7.03-7.80 (m, 5H), 8.16 (d, 1H, J = 8.7 Hz), 8.34 (d, 1H, J = 8.7 Hz), 8.86-8.96 (m, 3H), 9.61 (s, 1H), 10.03 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1644
    Figure US20170217923A1-20170803-C03117
    Figure US20170217923A1-20170803-C03118
    Figure US20170217923A1-20170803-C03119
         		1H NMR (DMSO-d6) ppm 0.38-0.54 (m, 4H), 1.30-1.32 (m, 1H), 3.58-3.62 (m, 2H), 3.87 (s, 3H), 7.00-7.54 (m, 5H), 7.86 (d, 1H, J = 8.6 Hz), 8.14 (d, 1H, J = 3.6 Hz), 8.64-8.76 (m, 4H), 9.62 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1645
    Figure US20170217923A1-20170803-C03120
    Figure US20170217923A1-20170803-C03121
    Figure US20170217923A1-20170803-C03122
         		1H NMR (DMSO-d6) ppm 1.83-1.88 (m, 2H), 2.21-2.27 (m, 2H), 2.49 (br s, 2H), 3.87 (s, 3H), 4.88-4.91 (m, 1H), 7.03-7.57 (m, 5H), 7.83 (d, 1H, J = 8.6 Hz), 8.13 (d, 1H, J = 8.6 Hz), 8.62-8.77 (m, 4H), 9.63 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1646
    Figure US20170217923A1-20170803-C03123
    Figure US20170217923A1-20170803-C03124
    Figure US20170217923A1-20170803-C03125
         		1H NMR (DMSO-d6) ppm 3.21 (s, 1H), 3.88 (s, 3H), 4.52 (dd, 2H, J = 2.2, 5.2 Hz), 7.01-7.58 (m, 5H), 7.88 (d, 1H, J = 8.7 Hz), 8.19 (d, 1H, J = 8.6 Hz), 8.64- 9.01 (m, 4H), 9.66 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1647
    Figure US20170217923A1-20170803-C03126
    Figure US20170217923A1-20170803-C03127
    Figure US20170217923A1-20170803-C03128
         		1H NHR (DMSO-d6) ppm 3.87 (s, 3H), 4.37 (br s, 2H), 5.19 (dd, 1H, J = 1.5, 10.2 Hz), 5.31 (dd, 1H, J = 1.5, 17.2 Hz), 6.01-6.22 (m, 1H), 7.00-7.56 (m, 5H), 7.85 (d, 1H, J = 8.6 Hz), 8.16 (d, 1H, J = 8.6 Hz), 8.67-8.82 (m, 4H), 9.61 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1648
    Figure US20170217923A1-20170803-C03129
    Figure US20170217923A1-20170803-C03130
    Figure US20170217923A1-20170803-C03131
         		1H NMR (DMSO-d6) ppm 0.94-0.99 (t, 6H, J = 7.4 Hz), 1.68-1.80 (m, 4H), 3.87 (s, 3H), 4.49-4.52 (m, 1H), 7.01- 7.47 (m, 5H), 7.83 (d, 1H, J = 8.6 Hz), 8.11-8.15 (m, 2H), 8.67-8.75 (m, 3H), 9.63 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1649
    Figure US20170217923A1-20170803-C03132
    Figure US20170217923A1-20170803-C03133
    Figure US20170217923A1-20170803-C03134
         		1H NMR (DMSO-d6) ppm 1.68 (s, 9H), 3.87 (s, 3H), 7.01-7.70 (m, 6H), 7.82 (d, 1H, J = 8.6 Hz), 8.11 (d, 1H, J = 8.6 Hz), 8.67-8.74 (m, 3H), 9.60 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1650
    Figure US20170217923A1-20170803-C03135
    Figure US20170217923A1-20170803-C03136
    Figure US20170217923A1-20170803-C03137
         		1H NMR (DMSO-d6) ppm 0.97 (t, 3H, J = 7.2 Hz), 1.44-1.48 (m, 2H), 1.74- 1.78 (m, 2H), 3.71-3.75 (m, 2H), 3.89 (s, 3H), 7.00-7.56 (m, 5H), 7.83 (d, 1H, J = 8.6 Hz), 8.15 (d, 1H, J = 8.6 Hz), 8.59-8.76 (m, 4H), 9.62 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1651
    Figure US20170217923A1-20170803-C03138
    Figure US20170217923A1-20170803-C03139
    Figure US20170217923A1-20170803-C03140
         		1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 4.98 (d, 2H, J = 5.6 Hz), 7.02-7.46 (m, 7H), 7.87 (d, 1H, J = 8.7 Hz), 8.51 (dd, 1H, J = 1.5, 4.5 Hz), 8.50-8.71 (m, 5H), 9.26 (s, 1H), 9.48 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1652
    Figure US20170217923A1-20170803-C03141
    Figure US20170217923A1-20170803-C03142
    Figure US20170217923A1-20170803-C03143
         		1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 4.98 (d, 2H, J = 5.5 Hz), 7.00-7.46 (m, 6H), 7.86-7.90 (m, 2H), 8.16 (d, 1H, J = 1.7 Hz), 8.46 (d, 1H, J = 1.7 Hz), 8.66-8.76 (m, 4H), 9.22 (s, 1H), 9.56 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1653
    Figure US20170217923A1-20170803-C03144
    Figure US20170217923A1-20170803-C03145
    Figure US20170217923A1-20170803-C03146
         		1H NMR (DMSO-d6) ppm 3.22-3.27 (m, 2H), 3.87 (s, 3H), 4.04-4.11 (m, 2H), 7.02-7.46 (m, 8H), 7.83 (d, 1H, J = 8.6 Hz), 8.13 (d, 1H, J = 1.6 Hz), 8.67-8.78 (m, 5H), 9.64 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1654
    Figure US20170217923A1-20170803-C03147
    Figure US20170217923A1-20170803-C03148
    Figure US20170217923A1-20170803-C03149
         		1H NMR (DMSO-d6) ppm 1.76-1.88 (m, 4H), 2.66 (br s, 1H), 3.37-3.48 (m, 2H), 3.86 (s, 3H), 4.39-4.47 (m, 2H), 6.95-7.57 (m, 7H), 7.95 (d, 1H, J = 8.7 Hz), 8.15-8.19 (m, 2H), 8.69-8.76 (m, 2H), 9.61 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1655
    Figure US20170217923A1-20170803-C03150
    Figure US20170217923A1-20170803-C03151
    Figure US20170217923A1-20170803-C03152
         		1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 4.97 (d, 2H, J = 5.6 Hz), 7.00-7.50 (m, 8H), 7.85 (d, 1H, J = 8.7 Hz), 8.16 (s, 1H), 8.66-8.77 (m, 3H), 9.11 (s, 1H), 9.61 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1656
    Figure US20170217923A1-20170803-C03153
    Figure US20170217923A1-20170803-C03154
    Figure US20170217923A1-20170803-C03155
         		1H NMR (DMSO-d6) ppm 2.28 (s, 3H), 3.87 (s, 3H), 4.91 (d, 2H, J = 5.5 Hz), 7.00-7.52 (m, 9H), 7.86 (d, 1H, J = 8.6 Hz), 8.17 (dd, 1H, J = 8.6, 1.8 Hz), 8.66-9.16 (m, 3H), 9.18-9.16 (m, 1H), 9.57 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1657
    Figure US20170217923A1-20170803-C03156
    Figure US20170217923A1-20170803-C03157
    Figure US20170217923A1-20170803-C03158
         		1H NMR (DMSO-d6) ppm 3.71 (s, 3H), 3.87 (s, 3H), 4.91 (d, 2H, J = 5.7 Hz), 6.82-7.52 (m, 9H), 7.86 (d, 1H, J = 8.7 Hz), 8.17 (dd, 1H, J = 8.7, 1.8 Hz), 8.66-9.15 (m, 3H), 9.17-9.19 (m, 1H), 9.57 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1658
    Figure US20170217923A1-20170803-C03159
    Figure US20170217923A1-20170803-C03160
    Figure US20170217923A1-20170803-C03161
         		1H NMR (DMSO-D6) ppm 2.25 (s, 3H), 3.87 (s, 3H), 4.91 (d, 2H, J = 5.7 Hz), 7.00-7.53 (m, 9H), 7.86 (d, 1H, J = 8.6 Hz), 8.17 (dd, 1H, J = 8.6, 1.8 Hz), 8.66-9.15 (m, 3H), 9.17-9.19 (m, 1H), 9.57 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1659
    Figure US20170217923A1-20170803-C03162
    Figure US20170217923A1-20170803-C03163
    Figure US20170217923A1-20170803-C03164
         		1H NMR (DMSO-D6) ppm 2.44 (s, 3H), 3.86 (s, 3H), 4.95 (d, 2H, J = 5.7 Hz), 7.01-7.53 (m, 9H), 7.86 (d, 1H, J = 8.6 Hz), 8.17 (dd, 1H, J = 8.6, 1.8 Hz), 8.65-9.02 (m, 3H), 9.50-9.52 (m, 1H), 9.54 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1660
    Figure US20170217923A1-20170803-C03165
    Figure US20170217923A1-20170803-C03166
    Figure US20170217923A1-20170803-C03167
         		1H NMR (DMSO-D6) ppm 3.87 (s, 3H), 7.03 (s, 1H), 7.44-7.94 (m, 10H), 8.07- 8.70 (m, 4H), 9.41 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1661
    Figure US20170217923A1-20170803-C03168
    Figure US20170217923A1-20170803-C03169
    Figure US20170217923A1-20170803-C03170
         		1H NMR (DMSO-D6) ppm 3.87 (s, 3H), 4.91 (d, 2H, J = 5.5 Hz), 7.00-7.04 (m, 1H), 7.04-7.55 (m, 7H), 7.87 (d, 1H, J = 8.6 Hz), 8.18 (dd, 1H, J = 8.6, 1.8 Hz), 8.66-9.18 (m, 3H), 9.18-9.21 (m, 1H), 9.55 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1662
    Figure US20170217923A1-20170803-C03171
    Figure US20170217923A1-20170803-C03172
    Figure US20170217923A1-20170803-C03173
         		1H NMR (DMSO-D6) ppm 3.87 (s, 3H), 4.99 (d, 2H, J = 5.5 Hz), 7.01-7.05 (m, 2H), 7.15-7.56 (m, 6H), 7.88 (d, 1H, J = 8.6 Hz), 8.20 (dd, 1H, J = 8.6, 1.8 Hz), 8.64-9.18 (m, 3H), 9.19-9.21 (m, 1H), 9.50 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1663
    Figure US20170217923A1-20170803-C03174
    Figure US20170217923A1-20170803-C03175
    Figure US20170217923A1-20170803-C03176
         		1H NMR (DMSO-D6) ppm 3.49 (s, 3H), 3.74 (s, 3H), 5.15 (s, 2H), 6.90 (d, J = 8.2 Hz, 1H), 7.04-7.29 (m, 2H), 7.33- 7.54 (m, 7H), 7.93 (d, 1H, J = 8.6 Hz), 8.15 (dd, 1H, J = 8.6, 1.8 Hz), 8.21 (s, 1H), 8.68-8.75 (m, 2H), 9.59 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1664
    Figure US20170217923A1-20170803-C03177
    Figure US20170217923A1-20170803-C03178
    Figure US20170217923A1-20170803-C03179
         		1H NMR (DMSO-D6) ppm 3.87 (s, 3H), 4.94 (d, 2H, J = 5.5 Hz), 7.01-7.03 (m, 1H), 7.35-7.57 (m, 7H), 7.88 (d, 1H, J = 8.6 Hz), 8.20 (dd, 1H, J = 8.6, 1.8 Hz), 8.66-9.22 (m, 3H), 9.19-9.21 (m, 1H), 9.50 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1665
    Figure US20170217923A1-20170803-C03180
    Figure US20170217923A1-20170803-C03181
    Figure US20170217923A1-20170803-C03182
         		1H NMR (DMSO-D6) ppm 3.87 (s, 3H), 4.96 (d, 2H, J = 5.5 Hz), 7.00-7.03 (m, 2H), 7.33-7.52 (m, 7H), 7.88 (d, 1H, J = 8.6 Hz), 8.19 (dd, 1H, J = 8.6, 1.8 Hz), 8.65-9.20 (m, 3H), 9.19-9.21 (m, 1H), 9.54 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1666
    Figure US20170217923A1-20170803-C03183
    Figure US20170217923A1-20170803-C03184
    Figure US20170217923A1-20170803-C03185
         		1H NMR (DMSO-D6) ppm 3.87 (s, 3H), 4.93 (d, 2H, J = 5.5 Hz), 7.00-7.19 (m, 3H), 7.41-7.55 (m, 6H), 7.88 (d, 1H, J = 8.6 Hz), 8.17 (dd, 1H, J = 8.6, 1.8 Hz), 8.65-9.18 (m, 3H), 9.19-9.21 (m, 1H), 9.57 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1667
    Figure US20170217923A1-20170803-C03186
    Figure US20170217923A1-20170803-C03187
    Figure US20170217923A1-20170803-C03188
         		1H NMR (DMSO-D6) ppm 3.87 (s, 3H), 4.92 (d, 2H, J = 5.5 Hz), 7.01-7.03 (d, 1H, J = 7.0 Hz), 7.37-7.53 (m, 6H), 7.72 (d, 1H, J = 8.6 Hz), 8.18 (dd, 1H, J = 8.6, 1.8 Hz), 8.66-9.19 (m, 3H), 9.20-9.23 (m, 1H), 9.56 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1668
    Figure US20170217923A1-20170803-C03189
    Figure US20170217923A1-20170803-C03190
    Figure US20170217923A1-20170803-C03191
         		1H NMR (DMSO-D6) ppm 1.68 (d, 3H, J = 7.0 Hz), 3.87 (s, 3H), 4.92 (d, 2H, J = 5.5 Hz), 5.75-5.78 (m, 1H), 7.02 (d, 1H, J = 7.0 Hz), 7.32-7.56 (m, 9H), 7.84 (d, 1H, J = 8.6 Hz), 8.15 (dd, 1H, J = 8.6, 1.8 Hz), 8.64-8.84 (m, 4H), 9.51 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1669
    Figure US20170217923A1-20170803-C03192
    Figure US20170217923A1-20170803-C03193
    Figure US20170217923A1-20170803-C03194
         		1H NMR (DMSO-D6) ppm 3.70 (s, 3H), 3.86 (s, 3H), 4.92 (d, J = 5.1 Hz, 2H), 6.89-7.01 (m, 3H), 7.41-7.54 (m, 6H), 7.85 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 8.67-8.75 (m, 3H), 9.19 (s, 1H), 9.56 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1670
    Figure US20170217923A1-20170803-C03195
    Figure US20170217923A1-20170803-C03196
    Figure US20170217923A1-20170803-C03197
         		1H NMR (DMSO-D6) ppm 3.87 (s, 3H), 3.91 (s, 3H), 4.92 (d, J = 5.0 Hz, 2H), 6.87-7.52 (m, 9H), 7.85 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.64-8.73 (m, 3H), 9.05 (s, 1H), 9.52 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1671
    Figure US20170217923A1-20170803-C03198
    Figure US20170217923A1-20170803-C03199
    Figure US20170217923A1-20170803-C03200
         		1H NMR (DMSO-D6) ppm 3.87 (s, 3H), 4.93 (d, J = 5.6 Hz, 2H), 7.02 (s, 1H), 7.41-7.61 (m, 7H), 7.83 (d, J = 8.9 Hz, 1H), 8.18 (d, J = 8.9 Hz, 1H), 8.66-8.71 (m, 3H), 9.21 (s, 1H), 9.54 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1672
    Figure US20170217923A1-20170803-C03201
    Figure US20170217923A1-20170803-C03202
    Figure US20170217923A1-20170803-C03203
         		1H NMR (DMSO-D6) ppm 3.69 (s, 6H), 3.87 (s, 3H), 4.93 (d, J = 5.6 Hz, 2H), 6.90 (s, 1H), 7.00-7.54 (m, 7H), 7.85 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 8.66-8.78 (m, 3H), 9.14 (s, 1H), 9.63 (s, 1H) DMSO >98 Method AQ3, F5, G2 (reflux)
    1673
    Figure US20170217923A1-20170803-C03204
         		DMSO   95 Method AQ3, AP
    1674
    Figure US20170217923A1-20170803-C03205
         		2 HCl 1H-NMR (300 MHz, DMSO): δ 9.71 (d, J = 1.6 Hz, 1H), 9.16 (d, J = 8.2 Hz, 1H), 8.98 (dd, J = 5.1, 1.5 Hz, 1H), 8.58 (s, 1H), 8.48-8.34 (m, 3H), 8.20 (d, J = 8.0 Hz, 1H), 7.98-7.87 (m, 2H), 7.75 (t, J = 7.8 Hz, 1H), 3.73 (s, 6H). DMSO   95 Method AQ3, AP
    1675
    Figure US20170217923A1-20170803-C03206
         		1H-NMR (300 MHz, DMSO): δ 9.59 (s, 1H), 8.78-8.62 (m, 2H), 8.38 (s, 1H), 8.05 (dd, J = 8.6, 1.8 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.52 (dd, J = 7.8, 4.7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 4.04 (s, 4H), 3.82 (s, 3H), 2.02 (s, 4H). DMSO   95 Method AQ3, AP
    1676
    Figure US20170217923A1-20170803-C03207
         		3 HCl 1H-NMR (300 MHz, DMSO): δ 10.40 (s, 1H), 9.48 (d, J = 2.0 Hz, 1H), 8.95 (s, 2H), 8.88 (d, J = 5.2 Hz, 1H), 8.72 (d, J = 4.3 Hz, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.94-7.81 (m, 2H), 7.64 (s, 1H), 7.54-7.45 (m, 3H), 7.06-7.00 (m, 1H), 5.25 (d, J = 5.1 Hz, 2H), 3.88 (s, 3H). DMSO   95 Method AQ3, AP
    1677
    Figure US20170217923A1-20170803-C03208
         		1H-NMR (300 MHz, DMSO): δ 12.83 (s, 1H), 9.32 (d, J = 2.2 Hz, 1H), 8.77 (dd, J = 4.8, 1.5 Hz, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.56-8.49 (m, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.23-8.14 (m, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.60 (dd, J = 8.0, 4.8 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 3.92 (s, 3H). DMSO   95 Method AQ3, AP
    1678 NH3
    Figure US20170217923A1-20170803-C03209
         		2 HCl 1H NMR (300 MHz, DMSO) δ 9.79 (brs, 1H), 9.60 (s, 2H), 9.07 (d, J = 7.4 Hz, 1H), 9.00 (d, J = 4.5 Hz, 1H), 8.80 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.02-7.88 (m, 1H), 7.67-7.48 (m, 2H), 7.49-7.37 (m, 1H). DMSO >98 Method AQ3, F5, G2 (reflux)
  • Figure US20170217923A1-20170803-C03210
    • Method AT for Alkylation Method AT1: NaOMe/MeOH/microwave/150° C. Method AT2: MeOH/microwave/150° C. Method AT3: DIPEA/KI/DMF/microwave/150° C.
  • Figure US20170217923A1-20170803-C03211
    • Method AR: 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (lxi-a)
  • To a suspension of 6-(3-methoxyphenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (prepared in a similar method described for 6-(3-methoxyphenyl)-2-(pyridine-3-yl)-4-(pyrrolidin-1-yl)quinazoline using Scheme 74, substituting N-methylamine for pyrrolidine) (1.00 g, 2.9 mmol) in CH2Cl2 (15 mL) and boron tribromide 1M solution in dichloromethane (8.76 ml, 8.76 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature after which it was carefully poured into a vigorously stirring mixture of ice and saturated aqueous solution of NaHCO3. The resultant solid was collected by filtration, dried and then dissolved in a mixture of K2CO3 (2 g) and methanol (50 mL). The solution was then acidified using aqueous NH4Cl solution. (50 mL) and the precipitate which formed was collected by filtration and dried to give 0.95 g of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol as pale yellow solid (99%). LCMS m/z=329 (M+1) (Method D) (retention time=1.30 min). 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 9.60 (s, 1H), 8.77 (d, J=8.0 Hz, 1H), 8.74-8.59 (m, 2H), 8.54 (s, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.54 (dd, J=7.9, 4.8 Hz, 1H), 7.38-7.12 (m, 3H), 6.82 (d, J=7.8 Hz, 1H), 3.17 (d, J=4.3 Hz, 3H).
    • Method AS: 6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (lxii-a)
  • A suspension of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (0.30 g, 0.914 mmol), 1-bromo-2-chloroethane (0.38 ml, 4.57 mmol), and potassium carbonate (0.38 g, 2.74 mmol) in DMF (10 mL) was stirred for 2 days at room temperature. Water (10 mL) and ethyl acetate (10 mL) were added to the mixture and extracted. The organic layer was separated and concentrated in vacuo to leave a solid, which was collected by filtration and washed with hexane and dried to give 0.30 g of 6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine as brown solid (83%). The product was used without further purification.
    • Method AT1: 6-(3-(2-methoxyethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (lxiii-a)
  • A solution of 6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (70 mg, 0.18 mmol) and sodium methoxide (97 mg, 1.8 mmol) in methanol (3 mL) was placed in a microwave reaction vial. The mixture was heated under microwave irradiation conditions at 150° C. for 30 minutes after which the solvent was removed in vacuo. The crude product was obtained, which was purified by column chromatography on basic silica gel (eluted with hexane/ethyl acetate 3:1-1:4) to give 20 mg of 6-(3-(2-methoxyethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine as an off-white powder (29%). LCMS m/z=387 (M+1) (Method D) (retention time=1.49 min). 1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J=8.2 Hz, 1H), 8.73-8.51 (m, 3H), 8.16 (d, J=8.7 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.60-7.32 (m, 4H), 7.01 (s, 1H), 4.21 (s, 2H), 3.70 (s, 2H), 3.33 (s, 3H), 3.19 (s, 3H).
    • Method AT2: N-Methyl-6-(4-(2-morpholinoethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine (lxiii-b)
  • Figure US20170217923A1-20170803-C03212
  • In a 10 mL microwave vial 6-(4-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (70.0 mg, 0.179 mmol) and morpholine (0.155 ml, 1.791 mmol) were added in methanol (3 mL) to give a yellow suspension. The vial was irradiated at 150° C. in the microwave for 30 min. The volatiles were evaporated in vacuo. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL), then dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on basic silica gel (eluted with hexane/ethyl acetate 3:2 to 0:1). The product was obtained as the parent and converted to the HCl salt by addition of 4 M HCl-dioxane, then crystallized from EtOH-H2O to give 55 mg of N-methyl-6-(4-(2-morpholinoethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine as a yellow powder (60% yield). LCMS m/z=442 (M+1) (Method D) (retention time=1.12 min). 1H NMR (300 MHz, DMSO) δ 11.31 (s, 1H), 10.41 (s, 1H), 9.63 (s, 1H), 9.10-8.79 (m, 3H), 8.34 (d, J=8.2 Hz, 1H), 8.28-8.12 (m, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.87-7.74 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 4.60-4.46 (m, 2H), 4.06-3.91 (m, 2H), 3.91-3.74 (m, 2H), 3.67-3.41 (m, 4H), 3.38-3.09 (m, J=10.1 Hz, 5H).
    • Method AT3: N-methyl-2-(pyridin-3-yl)-6-(3-(2-(2,2,2 trifluoroethylamino)ethoxy) phenyl)quinazolin-4-amine (lxiii-c)
  • Figure US20170217923A1-20170803-C03213
  • In a 10 mL microwave vial was added 6-(3-(2-chloroethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (50.0 mg, 0.128 mmol), 2,2,2-trifluoroethylamine (0.100 ml, 1.279 mmol), potassium iodide (42.5 mg, 0.256 mmol), and N,N′-diisopropylethylamine (0.045 ml, 0.256 mmol) in DMF (3 mL) to give a yellow suspension. The vial was irradiated at 150° C. in the microwave for 20 min. Water (10 mL) was added to the mixture and extracted with ethyl acetate (2×20 mL). The organic layers were combined and washed with water (1×20 mL) and brine (1×20 mL), dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with CH2Cl2/CH2Cl2-MeOH—NH4OH=100:20:1 1:0 to 0:1). The product was converted to the HCl salt by addition of 4 M HCl-dioxane, then crystallization from IPA-H2O to give 30 mg of N-methyl-2-(pyridin-3-yl)-6-(3-(2-(2,2,2-trifluoroethylamino)ethoxy)phenyl)quinazolin-4-amine as a yellow powder (42%). LCMS m/z=454 (M+1) (Method C) (retention time=2.26 min). 1H NMR (300 MHz, DMSO) δ 10.73-10.36 (m, 1H), 9.65 (s, 1H), 9.13-8.98 (m, 2H), 8.93 (d, J=5.0 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.24 (d, J=7.7 Hz, 1H), 7.94-7.75 (m, 1H), 7.69-7.41 (m, 3H), 7.09 (d, J=8.1 Hz, 1H), 4.61-4.43 (m, 2H), 4.28-4.07 (m, 2H), 3.59-3.39 (m, 2H), 3.30 (d, J=2.8 Hz, 3H).
    • Scheme 80: Method AU: N-(2-(4-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenoxy)ethyl)acetamide (lxiv-a)
  • Figure US20170217923A1-20170803-C03214
  • In a 50 mL round-bottomed flask was added 6-(4-(2-aminoethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (15.0 mg, 0.040 mmol) and triethylamine (0.017 ml, 0.121 mmol) in CH2Cl2 (5 mL) to give a yellow solution. Acetic anhydride (4.58 μl, 0.048 mmol) was added and the mixture was stirred for 2 h at room temperature. Water (10 mL) was added to the mixture and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL), dried over Mg2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with CH2Cl2/MeOH 1:0 to 9:1). The product was converted to the HCl salt by addition of 4 M HCl-dioxane, then dissolved in a small amount of methanol, followed by ethyl acetate. The resulting solid was filtered and dried to give 10 mg of N-(2-(4-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenoxy)ethyl)acetamide as a HCl salt as a yellow solid in a 51% yield. LCMS m/z=414 (M+1) (Method C) (retention time=1.28 min). 1H NMR (300 MHz, DMSO) δ 10.26 (s, 1H), 9.62 (s, 1H), 9.06-8.90 (m, 2H), 8.81 (s, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.17 (d, J=6.6 Hz, 2H), 7.86 (d, J=8.0 Hz, 3H), 7.13 (d, J=7.9 Hz, 2H), 4.06 (t, J=5.4 Hz, 2H), 3.52-3.38 (m, 2H), 3.30 (d, J=4.1 Hz, 3H), 1.84 (s, 3H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 78, replacing 1-bromo-2-chloroethane with the corresponding alkyl halide.
  • TABLE 26
    Method
    1H-NMR Retention LCMS Purity for
    Number PRODUCT Salt 1H-NMR Solvent LCMS Time Protocol percent Coupling
    1679
    Figure US20170217923A1-20170803-C03215
         		HCl 1H NMR (300 MHz, DMSO) δ 10.36 (s, 1H), 9.65 (s, 1H), 9.13-8.99 (m, 1H), 8.99- 8.83 (m, 2H), 8.38 (d, J = 8.8 Hz, 1H), 8.30- 8.16 (m, 1H), 7.94-7.80 (m, 1H), 7.55-7.35 (m, 3H), 7.09-6.97 (m, 1H), 4.16 (q, J = 7.0 Hz, 2H), 3.31 (d, J = 4.3 Hz, 3H), 1.37 (t, J = 6.9 Hz, 3H). DMSO 357   (M + 1) 1.62 Method D 100 Method AR/AS/AT1
    1680
    Figure US20170217923A1-20170803-C03216
         		1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J = 8.2 Hz, 1H), 8.73-8.51 (m, 3H), 8.16 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.60-7.32 (m, 4H), 7.01 (s, 1H), 4.21 (s, 2H), 3.70 (s, 2H), 3.33 (s, 3H), 3.19 (s, 3H). DMSO 387   (M + 1) 1.49 Method D 100 Method AR/AS/AT1
    1681
    Figure US20170217923A1-20170803-C03217
         		1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.78 (d, J = 7.9 Hz, 1H), 8.72-8.49 (m, 3H), 8.22-8.01 (m, 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.62-7.36 (m, 4H), 7.01 (s, 1H), 4.59 (s, 2H), 3.19 (d, J = 4.0 Hz, 3H), 2.68 (d, J = 4.5 Hz, 3H). DMSO 400   (M + 1) 1.31 Method D 100 Method AR/W with KI
    1682
    Figure US20170217923A1-20170803-C03218
         		2HCl 1H NMR (300 MHz, DMSO) d 10.47 (s, 1H), 9.65 (d, J = 1.7 Hz, 1H), 9.05 (d, J = 7.9 Hz, 1H), 9.01-8.88 (m, 2H), 8.39 (m, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.0, 5.3 Hz, 1H), 7.65-7.39 (m, 3H), 7.09 (m, 1H), 6.44 (m, 1H), 4.47 (td, J = 14.7, 3.4 Hz, 2H), 3.29 (d, J = 4.5 Hz, 3H). DMSO 393.4 (M + 1) Method C (NH4HCO3) 100 Method AR/AS (K2CO3, DMF—THF (1:1), 60° C.) then Method AT
    1683
    Figure US20170217923A1-20170803-C03219
         		HCl 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.60 (s, 1H), 9.03-8.87 (m, 2H), 8.77 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.21-8.02 (m, 1H), 7.92-7.69 (m, 3H), 7.20-7.02 (m, 2H), 4.93 (s, 2H), 3.70-3.40 (m, 8H), 3.29 (d, J = 3.5 Hz, 3H). DMSO 456   (M + 1) 1.73 Method B (Ammonium formate) 100 Method AR/W with KI
    1684
    Figure US20170217923A1-20170803-C03220
         		HCl 1H NMR (300 MHz, DMSO) δ 10.38 (s, 1H), 9.64 (s, 1H), 9.02 (d, J = 6.7 Hz, 1H), 8.93 (d, J = 4.9 Hz, 1H), 8.84 (s, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 7.98-7.70 (m, 3H), 7.11 (d, J = 7.3 Hz, 2H), 4.26-4.05 (m, 2H), 3.78-3.57 (m, 2H), 3.45- 3.19 (m, 6H). DMSO 387   (M + 1) 1.47 Method A (Formic acid) 100 Method AR/AS/AT1
    1685
    Figure US20170217923A1-20170803-C03221
         		HCl 1H NMR (300 MHz, DMSO) δ 11.31 (s, 1H), 10.41 (s, 1H), 9.63 (s, 1H), 9.10-8.79 (m, 3H), 8.34 (d, J = 8.2 Hz, 1H), 8.28-8.12 (m, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.87-7.74 (m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 4.60-4.46 (m, 2H), 4.06-3.91 (m, 2H), 3.91-3.74 (m, 2H), 3.67-3.41 (m, 4H), 3.38-3.09 (m, J = 10.1 Hz, 5H). DMSO 442   (M + 1) 1.22 Method A (Formic acid) 100 Method AR/AS/AT2
    1686
    Figure US20170217923A1-20170803-C03222
         		HCl 1H NMR (300 MHz, DMSO) δ 10.32-9.70 (m, 1H), 9.61 (s, 1H), 9.13-8.70 (m, 5H), 8.29 (d, J = 8.5 Hz, 1H), 8.20-8.01 (m, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.83-7.67 (m, 1H), 7.16 (d, J = 8.8 Hz, 2H), 4.38-4.27 (m, 2H), 3.43-3.32 (m, 2H), 3.27 (d, J = 3.7 Hz, 3H), 2.63 (t, J = 4.8 Hz, 3H). DMSO 386   (M + 1) 1.46 Method B (Ammonium formate) 100 Method AR/AS/AT2
    1687
    Figure US20170217923A1-20170803-C03223
         		HCl 1H NMR (300 MHz, DMSO) δ 9.95 (s, 1H), 9.62 (s, 1H), 9.13-8.86 (m, J = 5.2 Hz, 3H), 8.39 (d, J = 8.7 Hz, 1H), 8.26 (s, 1H), 7.97- 7.80 (m, 1H), 7.61-7.37 (m, 3H), 7.14-6.98 (m, 1H), 5.01-4.81 (m, 1H), 4.31-4.13 (m, 2H), 3.79-3.63 (m, 2H), 1.42 (d, J = 6.5 Hz, 6H). DMSO 415   (M + 1) 1.65 Method A (Formic acid) 100 Method AR/AS/AT1
    1688
    Figure US20170217923A1-20170803-C03224
         		HCl 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.63 (s, 1H), 9.10-8.88 (m, 2H), 8.72 (s, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 7.6, 4.8 Hz, 1H), 7.52 (d, J = 6.3 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.22-7.04 (m, 2H), 4.97 (s, 2H), 3.30 (d, J = 4.1 Hz, 3H), 2.97 (s, 3H), 2.85 (s, 3H). DMSO 414   (M + 1) 1.28 Method A (Formic acid) 100 Method AR/W with KI
    1689
    Figure US20170217923A1-20170803-C03225
         		HCl 1H NMR (300 MHz, DMSO) δ 10.22 (s, 1H), 9.63 (s, 1H), 9.10-8.87 (m, 2H), 8.75 (s, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 4.2 Hz, 1H), 7.93-7.77 (m, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 4.54 (s, 2H), 3.29 (d, J = 3.9 Hz, 3H), 2.64 (d, J = 4.4 Hz, 3H). DMSO 400   (M + 1) 1.33 Method A (Formic acid) 100 Method AR/W with KI
    1690
    Figure US20170217923A1-20170803-C03226
         		HCl 1H NMR (300 MHz, DMSO) δ 10.09 (s, 1H), 9.62 (s, 1H), 9.05-8.87 (m, 2H), 8.60 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.90-7.77 (m, 1H), 7.54- 7.36 (m, 2H), 7.26-7.06 (m, 2H), 4.23-4.11 (m, 2H), 3.70-3.58 (m, 2H), 3.29 (d, J = 4.4 Hz, 3H), 3.24 (s, 3H). DMSO 387   (M + 1) 1.51 Method A (Formic acid) 100 Method AR/AS/AT1
    1691
    Figure US20170217923A1-20170803-C03227
         		HCl 1H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.04 (d, J = 7.8 Hz, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.50 (s, 1H), 8.39-8.22 (m, 2H), 7.97-7.80 (m, 1H), 7.53-7.31 (m, 3H), 7.03 (d, J = 6.8 Hz, 1H), 4.26-4.13 (m, 2H), 3.82-3.59 (m, 8H), 3.32 (s, 3H). DMSO 401   (M + 1) 1.47 Method A (Formic acid) 100 Method AR/AS/AT1
    1692
    Figure US20170217923A1-20170803-C03228
         		HCl 1H NMR (300 MHz, DMSO) δ 9.83-9.26 (m, 3H), 9.00-8.76 (m, 3H), 8.40 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.89-7.72 (m, 1H), 7.58-7.36 (m, 3H), 7.04 (d, J = 3.4 Hz, 1H), 4.30-4.18 (m, 2H), 3.79-3.66 (m, 2H), 3.33 (s, 3H). DMSO 373   (M + 1) 1.42 Method A (Formic acid) 100 Method AR/AS/AT1
    1693
    Figure US20170217923A1-20170803-C03229
         		HCl 1H NMR (300 MHz, DMSO) δ 10.73-10.36 (m, 1H), 9.65 (s, 1H), 9.13-8.98 (m, 2H), 8.93 (d, J = 5.0 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.94-7.75 (m, 1H), 7.69-7.41 (m, 3H), 7.09 (d, J = 8.1 Hz, 1H), 4.61-4.43 (m, 2H), 4.28-4.07 (m, 2H), 3.59-3.39 (m, 2H), 3.30 (d, J = 2.8 Hz, 3H). DMSO 454   (M + 1) 2.26 Method B (Ammonium formate) 100 Method AR/AS/AT3
    1694
    Figure US20170217923A1-20170803-C03230
         		HCl 1H NMR (300 MHz, DMSO) δ 10.35 (s, 1H), 9.67 (s, 1H), 9.04 (d, J = 7.3 Hz, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.78 (s, 1H), 8.24 (s, 2H), 7.96-7.77 (m, 1H), 7.60-7.40 (m, 2H), 7.33-7.10 (m, 2H), 4.50-4.36 (m, 2H), 4.05-3.85 (m, 2H), 3.53-3.37 (m, 2H), 3.28 (d, J = 3.6 Hz, 3H). DMSO 454   (M + 1) 2.11 Method B (Ammonium formate) 100 Method AR/AS/AT3
    1695
    Figure US20170217923A1-20170803-C03231
         		1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.73-8.50 (m, 3H), 8.14 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H), 7.48- 7.34 (m, 3H), 6.96 (d, J = 3.2 Hz, 1H), 4.91 (s, 2H), 3.18 (d, J = 4.3 Hz, 3H), 3.03 (s, 3H), 2.86 (s, 3H). DMSO 414   (M + 1) 1.30 Method A (Formic acid) 100 Method AR/W with KI
  • Figure US20170217923A1-20170803-C03232
  • Figure US20170217923A1-20170803-C03233
    • Method AV: 1-(Benzyloxy)-7-bromo-3-chloroisoquinoline (lxv-a)
  • To 20 mL of benzylalcohol was slowly added Na (2.00 g, 86.9 mmol) at 0° C., the mixture was then stirred at room temperature for 4 h. 7-bromo-1,3-dichloroisoquinoline (2.00 g, 7.2 mmol) in toluene (50 mL) was added to the mixture with stirring. The reaction mixture was heated at 80° C. overnight. The solvent was removed under reduced pressure, the residue was purified with chromatography on silica gel (petroleum ether) to give 2.00 g xiv-a as a white solid (yield 80%). LCMS m/z=257.9, 259.9 (M+1) (Method B) (retention time=1.62 min).
    • Method AQ1: 1-(Benzyloxy)-3-chloro-7-(3-methoxyphenyl) isoquinoline (lxvi-a)
  • To a mixture of 1-(benzyloxy)-7-bromo-3-chloroisoquinoline (1.00 g, 2.86 mmol, 1.0 eq), 3-methoxyphenylboronic acid (435 mg, 2.86 mmol, 1.0 eq), K2CO3 (2.13 g, 15.4 mmol, 5.4 eq) in dioxane (10 mL) and H2O (5 mL) was added Pd(PPh3)2Cl2 (100 mg, 0.15 mmol, 0.05 eq) under N2 atmosphere. The resulting mixture was stirred at 110° C. under N2 atmosphere overnight. The solvent was removed in vacuo and the residue was purified with chromatography on silica gel (hexane/ethyl acetate 250:1) to give 550 mg of lxvi-a as white solid (yield 37%). LCMS m/z=376.0 (M+1) (Method B) (retention time=2.43 min).
    • Method AQ3: 1-(Benzyloxy)-7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinoline (lxvii-a)
  • To a mixture of 1-(benzyloxy)-3-chloro-7-(3-methoxyphenyl)isoquinoline (150 mg, 0.40 mmol, 1.0 eq), pyridin-3-ylboronic acid (74 mg, 0.60 mmol, 1.5 eq), K2CO3 (166 mg, 1.20 mmol, 3.0 eq) in dioxane (2 mL) and H2O (1 mL) was added Pd(PPh3)2Cl2 (14 mg, 0.02 mmol, 0.05 eq) under N2 atmosphere. The sealed tube was irradiated in the CEM microwave at 130° C. for 1 h. After the reaction was completed, the volatiles were removed in vacuo and the residue was purified with chromatography on silica gel (hexane/ethyl acetate 50:1) to give 200 mg of crude lxvii-a as a brown oil, which was used directly in the next step without purification. LCMS m/z=419.0 (M+1) (Method B) (retention time=2.25 min).
    • Method AW: 7-(3-Methoxyphenyl)-3-(pyridin-3-yl)isoquinolin-1-ol (lxviii-a)
  • A mixture of 1-(benzyloxy)-7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinoline (200 mg, 0.48 mmol), and concentrated HCl (10 mL) in ethanol (20 mL) was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered and concentrated to afford 130 mg of lxviii-a as a yellow solid (yield 90% for two steps). LCMS m/z=329.0 (M+1) (Method B) (retention time=1.66 min).
    • Method AX: 1-Chloro-7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinoline (lxix-a)
  • To a mixture of 7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinolin-1-ol (130 mg, 0.395 mmol) in phenylphosphonic dichloride (5 mL) was stirred at 120° C. overnight. After the reaction was completed, the mixture was added to ice-water slowly. The pH was adjusted to 7 by slow addition of NH3.H2O at 0° C. Then the mixture was extracted with dichloromethane (100 mL×3). The combined organic layer were dried over MgSO4, filtered and concentrated in vacuo to give 130 mg of crude lxix-a as a white solid, which was used directly in the next step without purification. LCMS m/z=346.9 (M+1) (Method B) (retention time=1.80 min).
    • Method AY: 7-(3-Methoxyphenyl)-N-methyl-3-(pyridin-3-yl)isoquinolin-1-amine (lxx-a)
  • A mixture of 1-chloro-7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinoline (90 mg, 0.26 mmol), methylamine hydrochloride (200 mg, 2.96 mmol, 10.0 eq) and Et3N (0.5 mL) was added to a sealed tube with i-AmOH (2 mL). The sealed tube was irradiated in the CEM microwave at 160° C. for 1 h. After the reaction was completed, the i-AmOH was removed in vacuo and the residue was dissolved in 10 mL of water and dichloromethane, the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo and the residue was washed with MeOH to give 5 mg of lxx-a as a brown solid (yield 6%). LCMS m/z=342.1 (M+1) (Method B) (retention time=2.02 min). 1H NMR (400 MHz, DMSO-d6): δ 9.40 (d, J=0.9 Hz, 1H), 8.67-8.47 (m, 3H), 8.08-7.95 (m, 1H), 7.89-7.84 (m, 2H), 7.66 (s, 1H), 7.57-7.49 (m, 1H), 7.46-7.42 (m, 3H), 7.08-6.95 (m, 1H), 3.88 (s, 3H), 3.14 (d, J=4.3 Hz, 3H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 81, replacing with the appropriate isoquinoline and aniline.
  • TABLE 27
    Molec- Method
    Salt ular 1H-NMR LCMS Purity for
    Number PRODUCT type Mass 1H-NMR Solvent LCMS Protocol percent Coupling
    1697
    Figure US20170217923A1-20170803-C03234
         		341.41 1H-NMR (400 MHz, DMSO- d6): δ 9.40 (d, J = 0.9 Hz, 1H), 8.67-8.47 (m, 3H), 8.08-7.95 (m, 1H), 7.89-7.84 (m, 2H), 7.66 (s, 1H), 7.57-7.49 (m, 1H), 7.46-7.42 (m, 3H), 7.08-6.95 DMSO 342.1 (M + 1) Method B (NH4HCO3) 95 Method AX, H1
    (m, 1H), 3.88 (s, 3H), 3.14 (d,
    J = 4.3 Hz, 3H).
    1698
    Figure US20170217923A1-20170803-C03235
         		312.37 1H-NMR (400 MHz, DMSO- d6): δ 9.40 (d, J = 1.8 Hz, 1H), 9.12 (d, J = 2.1 Hz, 1H), 8.66 (s, 1H), 8.60 (m, 2H), 8.54 (dt, J = 8.0, 1.9 Hz, 1H), 8.29-8.23 (m, 1H), 8.08 (dd, J = 8.5, 1.6 DMSO 312.9 (M + 1) Method B (NH4HCO3) 95 Method AX, H1
    Hz, 1H), 7.92 (d, J = 8.5 Hz,
    1H), 7.87 (d, J = 4.5 Hz, 1H),
    7.68 (s, 1H), 7.56 (dd, J = 7.8,
    4.8 Hz, 1H), 7.51 (dd, J = 7.8,
    4.8 Hz, 1H), 3.14 (d, J = 4.4
    Hz, 3H).
  • Figure US20170217923A1-20170803-C03236
  • Figure US20170217923A1-20170803-C03237
    • Method BA: Synthesis of 5-[3-(4-Methylamino-2-pyridin-3-yl-quinazolin-6-yl)-phenoxymethyl]-oxazolidin-2-one (lxxi-a)
  • To 5-(chloromethyl)oxazolidin-2-one (45 μmol) was added the solution of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (30 μmol) in NMP (200 μL). PS-BEMP (90 μmol) was added to the vials by resin dispenser. After the reaction mixture was heated at 90° C. for 12 h, the residue was diluted with methanol and purified by PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 80, replacing 5-(chloromethyl)oxazolidin-2-one with the appropriate alkyl halide.
  • TABLE 28
    Mass
    Starting Starting Salt Exact Found Purity
    Number Material 1 Material 2 Product Type Mass (M + 1) (%)
    1699
    Figure US20170217923A1-20170803-C03238
    Figure US20170217923A1-20170803-C03239
    Figure US20170217923A1-20170803-C03240
         		427 428 98
    1700
    Figure US20170217923A1-20170803-C03241
    Figure US20170217923A1-20170803-C03242
    Figure US20170217923A1-20170803-C03243
         		421 422 98
    1701
    Figure US20170217923A1-20170803-C03244
    Figure US20170217923A1-20170803-C03245
    Figure US20170217923A1-20170803-C03246
         		TFA 467 468 98
    1702
    Figure US20170217923A1-20170803-C03247
    Figure US20170217923A1-20170803-C03248
    Figure US20170217923A1-20170803-C03249
         		515 516 98
    1703
    Figure US20170217923A1-20170803-C03250
    Figure US20170217923A1-20170803-C03251
    Figure US20170217923A1-20170803-C03252
         		2TFA 468 469 98
    1704
    Figure US20170217923A1-20170803-C03253
    Figure US20170217923A1-20170803-C03254
    Figure US20170217923A1-20170803-C03255
         		TFA 436 437 98
    1705
    Figure US20170217923A1-20170803-C03256
    Figure US20170217923A1-20170803-C03257
    Figure US20170217923A1-20170803-C03258
         		455 456 98
    1706
    Figure US20170217923A1-20170803-C03259
    Figure US20170217923A1-20170803-C03260
    Figure US20170217923A1-20170803-C03261
         		438 439 98
    1707
    Figure US20170217923A1-20170803-C03262
    Figure US20170217923A1-20170803-C03263
    Figure US20170217923A1-20170803-C03264
         		421 422 98
    1708
    Figure US20170217923A1-20170803-C03265
    Figure US20170217923A1-20170803-C03266
    Figure US20170217923A1-20170803-C03267
         		453 454 98
    1709
    Figure US20170217923A1-20170803-C03268
    Figure US20170217923A1-20170803-C03269
    Figure US20170217923A1-20170803-C03270
         		TFA 467 468 98
    1710
    Figure US20170217923A1-20170803-C03271
    Figure US20170217923A1-20170803-C03272
    Figure US20170217923A1-20170803-C03273
         		487 488 98
    1711
    Figure US20170217923A1-20170803-C03274
    Figure US20170217923A1-20170803-C03275
    Figure US20170217923A1-20170803-C03276
         		TFA 515 516 98
    1712
    Figure US20170217923A1-20170803-C03277
    Figure US20170217923A1-20170803-C03278
    Figure US20170217923A1-20170803-C03279
         		TFA 436 437 98
    1713
    Figure US20170217923A1-20170803-C03280
    Figure US20170217923A1-20170803-C03281
    Figure US20170217923A1-20170803-C03282
         		TFA 422 423 98
    1714
    Figure US20170217923A1-20170803-C03283
    Figure US20170217923A1-20170803-C03284
    Figure US20170217923A1-20170803-C03285
         		TFA 476 477 98
    1715
    Figure US20170217923A1-20170803-C03286
    Figure US20170217923A1-20170803-C03287
    Figure US20170217923A1-20170803-C03288
         		2TFA 438 439 98
  • Figure US20170217923A1-20170803-C03289
  • Figure US20170217923A1-20170803-C03290
  • Method BB: Synthesis of 3-methyl-6-((3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenoxy)methyl)benzo[d]oxazol-2(3H)-one (lxxi-b)
  • To 6-(hydroxymethyl)-3-methylbenzo [d]oxazol-2(3H)-one (45 μmol) was added the solution of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (30 μmol) in THF (400 μL). After PS-triphenylphosphine (60 μmol) was added, the solution of DBAD (di-tert-butyl azodicarboxylate, 66 μmol) in THF was dispensed to the vials. The mixture was heated at 50° C. for 8 h. After the solvent was removed, the residue was diluted with methanol and purified by Mass triggered PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 85, replacing 6-(hydroxymethyl)-3-methylbenzo[d]oxazol-2(3H)-one with the appropriate alkyl alcohol.
  • TABLE 29
    Mass
    Num- Starting Starting Salt Exact Found Purity
    ber Material 1 Material 2 Product Type Mass (M + 1) (%)
    1716
    Figure US20170217923A1-20170803-C03291
    Figure US20170217923A1-20170803-C03292
    Figure US20170217923A1-20170803-C03293
         		TFA 489 490 100
    1717
    Figure US20170217923A1-20170803-C03294
    Figure US20170217923A1-20170803-C03295
    Figure US20170217923A1-20170803-C03296
         		TFA 448 449 100
    1718
    Figure US20170217923A1-20170803-C03297
    Figure US20170217923A1-20170803-C03298
    Figure US20170217923A1-20170803-C03299
         		TFA 422 423 100
    1719
    Figure US20170217923A1-20170803-C03300
    Figure US20170217923A1-20170803-C03301
    Figure US20170217923A1-20170803-C03302
         		TFA 422 423 100
    1720
    Figure US20170217923A1-20170803-C03303
    Figure US20170217923A1-20170803-C03304
    Figure US20170217923A1-20170803-C03305
         		TFA 472 473 100
    1721
    Figure US20170217923A1-20170803-C03306
    Figure US20170217923A1-20170803-C03307
    Figure US20170217923A1-20170803-C03308
         		TFA 489 490 100
    1722
    Figure US20170217923A1-20170803-C03309
    Figure US20170217923A1-20170803-C03310
    Figure US20170217923A1-20170803-C03311
         		TFA 489 490 100
    1723
    Figure US20170217923A1-20170803-C03312
    Figure US20170217923A1-20170803-C03313
    Figure US20170217923A1-20170803-C03314
         		TFA 466 467 100
    1724
    Figure US20170217923A1-20170803-C03315
    Figure US20170217923A1-20170803-C03316
    Figure US20170217923A1-20170803-C03317
         		TFA 425 426  94
    1725
    Figure US20170217923A1-20170803-C03318
    Figure US20170217923A1-20170803-C03319
    Figure US20170217923A1-20170803-C03320
         		TFA 453 454 100
    1726
    Figure US20170217923A1-20170803-C03321
    Figure US20170217923A1-20170803-C03322
    Figure US20170217923A1-20170803-C03323
         		TFA 489 490 100
    1727
    Figure US20170217923A1-20170803-C03324
    Figure US20170217923A1-20170803-C03325
    Figure US20170217923A1-20170803-C03326
         		TFA 489 490 100
    1728
    Figure US20170217923A1-20170803-C03327
    Figure US20170217923A1-20170803-C03328
    Figure US20170217923A1-20170803-C03329
         		TFA 448 449 100
    1729
    Figure US20170217923A1-20170803-C03330
    Figure US20170217923A1-20170803-C03331
    Figure US20170217923A1-20170803-C03332
         		TFA 422 423 100
    1730
    Figure US20170217923A1-20170803-C03333
    Figure US20170217923A1-20170803-C03334
    Figure US20170217923A1-20170803-C03335
         		TFA 504 505 100
    1731
    Figure US20170217923A1-20170803-C03336
    Figure US20170217923A1-20170803-C03337
    Figure US20170217923A1-20170803-C03338
         		TFA 424 425 100
    1732
    Figure US20170217923A1-20170803-C03339
    Figure US20170217923A1-20170803-C03340
    Figure US20170217923A1-20170803-C03341
         		TFA 433 434 100
    1733
    Figure US20170217923A1-20170803-C03342
    Figure US20170217923A1-20170803-C03343
    Figure US20170217923A1-20170803-C03344
         		TFA 484 485 100
    1734
    Figure US20170217923A1-20170803-C03345
    Figure US20170217923A1-20170803-C03346
    Figure US20170217923A1-20170803-C03347
         		TFA 466 467 100
    1735
    Figure US20170217923A1-20170803-C03348
    Figure US20170217923A1-20170803-C03349
    Figure US20170217923A1-20170803-C03350
         		TFA 425 426 100
    1736
    Figure US20170217923A1-20170803-C03351
    Figure US20170217923A1-20170803-C03352
    Figure US20170217923A1-20170803-C03353
         		TFA 464 465  95
    1737
    Figure US20170217923A1-20170803-C03354
    Figure US20170217923A1-20170803-C03355
    Figure US20170217923A1-20170803-C03356
         		TFA 466 467 100
    1738
    Figure US20170217923A1-20170803-C03357
    Figure US20170217923A1-20170803-C03358
    Figure US20170217923A1-20170803-C03359
         		TFA 489 490 100
  • Figure US20170217923A1-20170803-C03360
    • Synthesis of N-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)acetamide (lxxii-a)
  • A 100 mL round bottom flask was fitted with a reflux condenser and charged with 6-bromo-2-(pyridin-3-yl)quinazolin-4-amine (2.45 g, 8.14 mmol), acetic anhydride (5.81 g, 57.0 mmol) and acetic acid (30 mL). The reaction mixture was stirred at 90° C. for 20 min and then cooled to room temperature. A precipitate formed during the reaction and was collected by filtration and washed with water (100 mL). The solid was dried at 60° C. to give N-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)acetamide as a white powder (1.83 g, 66%). 1H NMR (300 MHz, CDCl3) δ 9.72 (s, 1H), 8.84-8.69 (m, 3H), 8.22 (s, 1H), 8.02-7.90 (m, 2H), 7.53-7.41 (m, 1H), 2.83 (s, 3H).
  • Figure US20170217923A1-20170803-C03361
    • Synthesis of N-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)-N-methylacetamide (lxxiii-a)
  • To a solution of 6-bromo-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (1.20 g, 3.81 mmol) in acetic acid (10 mL) was added acetic anhydride (1.94 g, 19.0 mmol) and stirred at 195° C. using microwave for 6 h. The reaction mixture was checked by LC-MS, no starting material was observed, ice was added into the reaction. The precipitate was collected by filtration and washed with water. The product was dried at 60° C. to give N-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)-N-methylacetamide (711 mg, 52%) as a light brown powder. 1H NMR (300 MHz, CDCl3) δ 9.76 (dd, J=2.2, 0.8 Hz, 1H), 8.85-8.79 (m, 1H), 8.76 (dd, J=4.8, 1.7 Hz, 1H), 8.09 (dd, J=1.8, 0.8 Hz, 1H), 8.05-8.01 (m, 2H), 7.46 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 3.52 (s, 3H), 2.11 (s, 3H).
  • Figure US20170217923A1-20170803-C03362
    • Method BC: Synthesis of 6-(2,3-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride (lxxv-a) (Compound 1742)
  • To a solution of the hydroxyl derivative (520 mg, 1.27 mmol) in DMF (20 mL) was added methyl iodide (262 mg, 1.84 mmol) and NaH (55% in oil; 69 mg, 1.9 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h and the ice water was added into the reaction mixture. The resulting solution was extracted with ethyl acetate (3 times), dried over Na2SO4, concentrated and purified by column chromatography (NH-silica gel, 50% hexane/50% ethyl acetate). The resulting product was dissolved in isopropyl alcohol and 1N-HCl (5 mL) was added and a precipitate formed which was collected by filtration and dried at 60° C. to give 6-(2,3-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride as an orange powder (130 mg, 21%). 1H NMR (300 MHz, DMSO) δ 9.66 (d, J=1.6 Hz, 1H), 9.09 (d, J=8.1 Hz, 1H), 8.96 (dd, J=5.1, 1.5 Hz, 1H), 8.51 (s, 1H), 8.33 (d, J=8.7 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 7.90 (dd, J=8.1, 5.1 Hz, 1H), 7.66-7.47 (m, 2H), 7.47-7.32 (m, 1H), 4.22-4.07 (m, 2H), 3.70 (s, 3H), 3.48 (t, J=5.8 Hz, 2H), 3.22 (s, 3H), 2.19-2.01 (m, 2H).
  • Figure US20170217923A1-20170803-C03363
    • Method BD: 2-(3-(4-(dimethylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenyl)ethanol, 2 HCl (lxxvi-a)
  • To a reaction vial containing 2-(3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenyl)ethanol (89.0 mg, 0.25 mmol) in DMF (1 mL) was added 60% sodium hydride (13 mg, 0.325 mmol) and iodomethane (0.02 mL, 0.325 mmol). The reaction mixture was allowed to stir at ambient temperature for 12 h. Water (20 mL) was added to the reaction mixture, and the crude product was extracted with ethyl acetate (4×15 mL). The crude material was purified via ISCO (silica, 4 g column, 95% CH2Cl2—5% MeOH—0.1% NH4OH) to give the product as an off-white solid. The free base was then converted to the HCl salt to yield the final product as a yellow solid (24.6 mg, 0.055 mmol, 22%). LC-MS m/z=371.5 (M+1) (retention time=1.86)1H NMR (300 MHz, DMSO) δ 9.61 (d, J=2.1 Hz, 1H), 8.99 (d, J=7.5 Hz, 1H), 8.93 (dd, J=5.0, 1.5 Hz, 1H), 8.48 (d, J=1.0 Hz, 1H), 8.28 (dd, J=17.4, 9.4 Hz, 2H), 7.84 (dd, J=7.7, 5.1 Hz, 1H), 7.69-7.60 (m, 2H), 7.44 (t, J=7.5 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 3.78-3.61 (m, 9H), 2.82 (t, J=7.0 Hz, 2H).
    • Synthesis of 6-(2,4-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride (lxxvii-a)
  • (Compound 1744) 6-(2,4-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride was synthesized in a similar manner to that described for 6-(2,3-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride substituting the appropriate hydroxyl derivative. 6-(2,4-difluorophenyl)-N-(3-methoxypropyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine was obtained as the dihydrochloride salt 1H NMR (300 MHz, DMSO) δ 9.69 (d, J=2.0 Hz, 1H), 9.14 (d, J=8.3 Hz, 1H), 8.97 (dd, J=5.1, 1.2 Hz, 1H), 8.45 (s, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.92 (dd, J=8.0, 5.2 Hz, 1H), 7.86-7.73 (m, 1H), 7.57-7.38 (m, 1H), 7.36-7.23 (m, 1H), 4.19-4.04 (m, 2H), 3.71 (s, 3H), 3.48 (t, J=5.7 Hz, 2H), 3.23 (s, 3H), 2.21-1.96 (m, 2H).
  • Figure US20170217923A1-20170803-C03364
    • Method BE: 4-(3,4-dichlorophenyl)-1-(6-(3-methoxyphenyl)-2-(pyridin-3-yl)quinazolin-4-yl)pyrrolidin-2-one (lxxviii-a)
  • To a mixture of 4-chloro-6-(3-methoxyphenyl)-2-(pyridin-3-yl)quinazoline (40 mg, 0.12 mmol), 4-(3,4-dichlorophenyl)pyrrolidin-2-one (100 mg, 0.437 mmol) and Cs2CO3 (42 mg, 0.127 mmol) in dry toluene (6 mL) was added Pd(OAc)2 (3 mg, 0.01 mmol) and Xantphos (10 mg, 0.02 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 12 h. After cooling, the mixture was filtered through a pad of celite. The residue was purified by silica gel chromatography, eluted with petroleum ether/ethyl acetate (5:4) to give the desired product as a yellow solid. 14 mg of the desired product was obtained in a 22.5%. yield, LCMS: retention time=1.802 min, [MH]+=541.0, 543.0. 1H-NMR (400 MHz, DMSO-d6): δ 9.73 (s, 1H), 9.05-9.04 (m, 1H), 8.86-8.85 (m, 1H), 8.42-8.38 (m, 2H), 8.19 (d, J=8.8 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.82-7.81 (m, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.58 (dd, J=8.0, 1.6 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.41-7.36 (m, 2H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 4.57-4.46 (m, 2H), 4.06-4.03 (m, 1H), 3.20-3.01 (m, 2H), 3.88 (s, 3H).
  • The compounds in the following table were prepared in a manner analogous to that described in Scheme 91, replacing 4-(3,4-dichlorophenyl)pyrrolidin-2-one with the appropriate amide
  • TABLE 30
    Method
    Num- Salt 1H NMR Purity of LCMS
    ber Product type 1H NMR Solvent percent Coupling LCMS Method
    1745
    Figure US20170217923A1-20170803-C03365
         		1H-NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 8.90 (d, J = 8.0 Hz, 1H), 8.78 (d, J = 4.0 Hz, 1H), 8.35 (s, 1H), 8.28-8.19 (m, 2H), 7.92 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 5.0 Hz, 2H), 7.73-7.70 (m, 1H), 7.68-7.61 (m, 2H), 7.52- 7.42 (m, 1H), 7.29 (t, J = 8.4 Hz, 1H), 5.61 (s, 2H). DMSO 95 Method BE 451.0 (M + 1) Method B (NH4HCO3)
    1746
    Figure US20170217923A1-20170803-C03366
         		1H-NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.77 (d, J = 3.8 Hz, 1H), 8.45 (s, 1H), 8.39 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.83 (s, 2H), 7.72-7.56 (m, 2H), 7.52-7.27 (m, 3H), 7.03 (d, J = 7.9 Hz, 1H), 5.60 (s, 2H), 3.85 (s, 3H). DMSO 95 Method BE 445.1 (M + 1) Method B (NH4HCO3)
    1747
    Figure US20170217923A1-20170803-C03367
         		1H-NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 8.91 (d, J = 6.4 Hz, 1H), 8.79 (s, 1H), 8.41 (s, 1H), 8.30-8.23 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 (s, 2H), 7.65 (d, J = 3.6 Hz, 2H), 7.55- 7.49 (m, 2H), 7.40 (s, 1H), 5.61 (s, 2H). DMSO 95 Method BE 451.0, 452.0, (M + 1) Method B (NH4HCO3)
    1748
    Figure US20170217923A1-20170803-C03368
         		2HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.73 (s, 1H), 9.05-9.04 (m, 1H), 8.86-8.85 (m, 1H), 8.42- 8.38 (m, 2H), 8.19 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.82-7.81 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.58 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.41-7.36 (m, 2H), 7.07 (dd, J = 8.0, 2.0 Hz, 1H), 4.57- 4.46 (m, 2H), 4.06-4.03 (m, 1H), 3.20-3.01 (m, 2H), 3.88 (s, 3H). DMSO 95 Method BE 541.0, 543.0 (M + 1) Method B (NH4HCO3)
    1749
    Figure US20170217923A1-20170803-C03369
         		2HCl 1H-NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 8.83 (d, J = 8.0 Hz, 1H), 8.76 (s, 1H), 8.39-8.37 (m, 2H), 8.17 (d, J = 10.0 Hz, 1H), 7.63-7.31 (m, 9H), 7.06 (dd, J = 8.4, 2.0 Hz, 1H), 4.56-4.45 (m, 2H), 4.03-3.99 (m, 1H), 3.88 (s, 3H), 3.19-2.97 (m, 2H). DMSO 95 Method BE 472.9 (M + 1) Method B (NH4HCO3)
    1750
    Figure US20170217923A1-20170803-C03370
         		1H-NMR (400 MHz, DMSO-d6): δ 9.74 (d, J = 8.4 Hz, 1H), 8.89 (dt, J = 8.4, 1.6 Hz, 1H), 8.78 (dd, J = 4.4, 1.2 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.41 (dd, J = 8.8, 1.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.88 (s, 2H), 7.65- 7.62 (m, 1H), 7.48-7.44 (m, 1H), 7.41-7.37 (m, 2H), 7.04 (dd, J = 8.0, 1.6 Hz, 1H), 5.59 (s, 2H), 3.86 (s, 3H). DMSO 95 Method BE 479.0 (M + 1) Method B (NH4HCO3)
    1751
    Figure US20170217923A1-20170803-C03371
         		1H-NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.78 (d, J = 4.4 Hz, 1H), 8.46 (s, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.91-7.87 (m, 1H), 7.77-7.62 (m, 3H), 7.48-7.37 (m, 3H), 7.03 (d, J = 6.4 Hz, 1H), 5.58 (s, 2H), 3.86 (s, 3H). DMSO 95 Method BE 463.1 (M + 1) Method B (NH4HCO3)
    • Scheme 91: Synthesis of N-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine methanesulfonate (lxxix-a) (Compound 1752)
  • Figure US20170217923A1-20170803-C03372
  • N-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (1.51 g, 3.87 mmol) was dissolved in CH2Cl2/MeOH (20 mL/20 mL). Methanesulfonic acid (0.251 mL, 3.87 mmol) was added to the solution. The volatiles were evaporated in vacuo. The resultant residue was crystallized from EtOH (30 mL) to give 1.35 g of N-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine methanesulfonate as a light yellow powder (72%). LCMS m/z=391 (M+1) (Method D) (Retention time=1.91 min). 1H NMR (300 MHz, DMSO) δ 9.52 (s, 1H), 9.01-8.83 (m, 2H), 8.75 (s, 1H), 8.58 (s, 1H), 8.09 (d, J=7.2 Hz, 1H), 8.03-7.85 (m, 2H), 7.83-7.68 (m, 1H), 7.59-7.43 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 2.31 (s, 3H), 1.66 (s, 9H).
    • Scheme 92: Synthesis of N-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine fumarate (lxxx) (Compound 1753)
  • Figure US20170217923A1-20170803-C03373
  • N-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (1.22 g, 3.12 mmol) was dissolved in CH2Cl2/MeOH (20 mL/20 mL). Fumaric acid (0.363 g, 3.12 mmol) was added to the solution. The mixture was sonicated until fumaric acid was dissolved. Then, the volatiles were evaporated in vacuo. The resultant solid was washed with MeOH and dried to give 1.28 g of N-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine ½ fumarate as a light yellow powder (91%). LCMS m/z=391 (M+1) (Method D) (Retention time=1.95 min). 1H NMR (300 MHz, DMSO) δ 13.14 (s, 1H), 9.59 (s, 1H), 8.82-8.65 (m, 2H), 8.57 (s, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.79-7.62 (m, 2H), 7.61-7.52 (m, 1H), 7.51-7.38 (m, 1H), 7.28 (t, J=8.6 Hz, 1H), 6.61 (s, 1H), 1.64 (s, 9H).
    • Scheme 93: Synthesis of N-methyl-6-(3-(2-propoxyethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine fumarate (lxxxi) (Compound 1754)
  • Figure US20170217923A1-20170803-C03374
  • N-methyl-6-(3-(2-propoxyethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine fumarate was synthesized in a similar manner to that described N-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine fumarate. LCMS m/z=415.5 (M+1) (Method C (NH4HCO3) (Retention time=2.43 min). 1H NMR (300 MHz, CD3OD) δ 9.57 (s, 1H), 8.84 (m, 1H), 8.63 (s, 1H), 8.35 (m, 1H), 8.07 (m, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.58 (m, 1H), 7.48-7.24 (m, 4H), 7.00 (m, 1H), 6.74 (s, 1H), 4.36-4.05 (m, 2H), 4.00-3.70 (m, 2H), 3.53 (t, J=6.6 Hz, 2H), 3.29-3.13 (m, 3H), 1.75-1.51 (m, 2H), 0.95 (t, J=7.4 Hz, 3H).
    • Scheme 94: Synthesis of N-methyl-6-(3-(2-propoxyethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine methanesulfonate (lxxxii-a) (Compound 1755)
  • Figure US20170217923A1-20170803-C03375
  • N-methyl-6-(3-(2-propoxyethoxy)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine methanesulfonate was synthesized in a similar manner to that described N-tert-butyl-6-(2,4-difluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine methanesulfonate. LCMS m/z=415.5 (M+1) (Method C (NH4HCO3) (Retention time=2.43 min). 1H NMR (300 MHz, CD3OD) δ 9.49 (s, 1H), 9.00-8.72 (m, 1H), 8.53 (s, 1H), 8.29 (m, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.80 (dd, J=8.0, 5.1 Hz, 1H), 7.52-7.25 (m, 3H), 7.02 (m, 1H), 4.38-4.06 (m, 2H), 3.98-3.72 (m, 2H), 3.61-3.48 (m, 2H), 3.42 (d, J=0.6 Hz, 3H), 3.34-3.26 (m, 2H), 2.71 (s, 3H), 1.80-1.47 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).
    • Biological Testing: STEP46 Biochemical Assays
  • Serial dilutions of compounds were performed in 100% DMSO and 1 uL of compounds were dispensed into 384-well black polystyrene plates (Corning, N.Y.). Compounds were incubated with 24 uL of buffer containing 50 mM Hepes, 1 mM DTT, 0.02% Brij35, 1 ng/well purified STEP46 enzyme for 30 min at room temperature. The reaction was initiated by addition of 25 uL of DiFMUP (6, 8-difluoro-4-methylumbelliferyl phosphate) (InVitrogen, CA) with a final concentration of 10 μM and incubated at 27° C. for 90 min. Final DMSO concentration is 2%. Plates were read with florescence intensity at excitation/emission of 360/460 nm using a PheraStar plate reader (BMG Labtech, NC).
    • Data Analysis
  • Data were expressed as percentage (%) inhibition of enzyme activity. 0% inhibition is defined as the RFUs (relative fluorescence units) in the absence of compounds and 100% inhibition is defined as RFUs in the absence of STEP46 enzyme. IC50 values of compounds with inhibitory activity against STEP46 were determined by GraphPad Prism (version 4.03) using four parameter logistic equation. Some compounds act as activators. For compounds showing STEP46 enzymatic activation, data are represented as percentage of inhibition but with negative values at three representative concentrations (25, 50 and 100 uM).
  • Compounds 1-1760 show either inhibition or activation >50% at 100 uM, 50 or 25 uM.
  • STEP STEP STEP STEP
    IC50 IC50 IC50 IC50
    Number (μM) Number (μM) Number (μM) Number (μM)
     73 ++  327 ++  391 ++  427 ++
     296 ++  329 +++  392 ++  428 ++
     297 +  330 ++  393 ++  429 +++
     300 +  332 +++  396 ++  430 +++
     303 ++  333 +++  399 +++  431 +++
     306 +  334 ++  400 ++  433 ++
     309 ++  335 +++  403 ++  434 ++
     312 +++  336 +++  407 ++  435 +++
     313 +++  337 +++  412 +++  436 ++
     314 ++  339 ++  415 ++  437 ++
     315 ++  341 ++  416 +++  439 +++
     316 +++  342 ++  418 ++  440 ++
     317 ++  343 +  419 +++  441 ++
     318 ++  344 ++  421 +  442 +++
     320 ++  346 ++  423 ++  443 +++
     322 +  348 ++  424 ++  444 +++
     325 +++  352 ++  425 ++  445 +++
     326 ++  390 ++  426 +  446 ++
     447 ++  470 ++  642 +++  663 +++
     448 +++  471 ++  643 +++  664 ++
     449 ++  472 ++  644 ++  665 ++
     451 +++  473 ++  645 ++  666 +++
     452 +++  474 ++  647 ++  667 +++
     453 +++  629 ++  648 ++  668 +++
     454 ++  630 ++  649 ++  669 +++
     455 ++  631 ++  650 +++  670 +++
     456 +++  632 +++  651 +++  671 ++
     457 ++  633 ++  652 +++  672 ++
     458 +++  634 ++  653 +++  673 ++
     459 +++  635 +++  655 +++  674 ++
     460 ++  636 +  656 +++  675 +++
     461 ++  637 ++  657 +++  676 +++
     463 ++  638 ++  658 ++  677 +
     466 ++  639 +++  660 +++  678 ++
     467 ++  640 ++  661 +++  679 +++
     468 +++  641 +++  662 +++  680 ++
     681 ++  699 +++  900 ++ 1150 +
     682 ++  700 +++  901 ++ 1151 ++
     683 ++  701 ++  923 ++ 1152 ++
     684 ++  702 +++  932 ++ 1153 ++
     685 +++  703 +++  933 ++ 1155 ++
     686 +++  704 +++  934 +++ 1157 ++
     687 +++  705 +++  962 +++ 1158 ++
     688 +++  706 +++ 1124 +++ 1159 ++
     689 +++  707 +++ 1125 ++ 1160 ++
     690 ++  708 ++ 1126 ++ 1161 ++
     691 +++  709 +++ 1140 +++ 1165 +++
     692 +++  846 ++ 1141 +++ 1167 ++
     693 +++  847 +++ 1142 ++ 1168 ++
     694 +++  884 + 1143 ++ 1171 ++
     695 +++  888 + 1144 ++ 1172 ++
     696 +++  889 ++ 1145 ++ 1173 +
     697 ++  898 + 1146 ++ 1176 ++
     698 +++  899 ++ 1148 ++ 1178 ++
    1180 ++ 1204 + 1226 ++ 1324 ++
    1181 ++ 1205 ++ 1227 ++ 1327 +
    1182 ++ 1206 ++ 1228 ++ 1328 +
    1183 ++ 1208 + 1229 ++ 1330 +
    1184 ++ 1211 + 1230 ++ 1332 ++
    1185 ++ 1212 ++ 1234 ++ 1333 +
    1186 ++ 1213 ++ 1237 ++ 1334 +
    1187 +++ 1214 ++ 1238 ++ 1335 ++
    1188 ++ 1215 +++ 1239 ++ 1336 ++
    1191 ++ 1216 +++ 1248 ++ 1337 ++
    1192 ++ 1217 ++ 1279 ++ 1339 ++
    1193 ++ 1218 ++ 1280 ++ 1340 ++
    1194 +++ 1219 ++ 1281 +++ 1341 ++
    1198 ++ 1220 + 1282 ++ 1346 ++
    1200 ++ 1221 + 1283 + 1348 +
    1201 ++ 1222 ++ 1284 ++ 1350 ++
    1202 ++ 1223 +++ 1285 + 1351 ++
    1203 ++ 1225 ++ 1286 ++ 1352 +
    1353 ++ 1374 ++ 1410 ++ 1448 ++
    1354 ++ 1375 ++ 1411 + 1449 +
    1356 ++ 1376 ++ 1412 ++ 1450 ++
    1357 ++ 1380 ++ 1413 ++ 1451 ++
    1358 ++ 1381 ++ 1414 ++ 1452 +++
    1359 ++ 1382 +++ 1415 + 1453 ++
    1360 ++ 1391 + 1416 ++ 1454 +
    1361 + 1395 ++ 1419 ++ 1455 ++
    1362 ++ 1396 ++ 1420 ++ 1456 ++
    1363 ++ 1400 ++ 1422 ++ 1458 +
    1364 ++ 1401 ++ 1423 + 1467 ++
    1365 ++ 1402 ++ 1424 + 1497 ++
    1366 ++ 1403 + 1425 ++ 1516 +
    1369 ++ 1404 + 1430 ++ 1601 ++
    1370 ++ 1406 ++ 1437 ++ 1611 ++
    1371 ++ 1407 ++ 1445 ++ 1680 ++
    1372 ++ 1408 ++ 1446 ++
    1373 ++ 1409 ++ 1447 +
    Key
    +IC50 > 10 uM
    ++IC50 1-10 uM
    +++IC50 < 1 uM
  • Having thus described several aspects of at least one embodiment of this invention, it is to be appreciated various alterations, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description and drawings are by way of example only.

Claims (6)

1. A compound represented by general formula (II):
Figure US20170217923A1-20170803-C03376
or a salt thereof,
wherein:
L is CR4R5, O, C(O), NR6C(O) or NR7;
A is N;
each X1, X2, X3, X4 and X5 is independently CH or N, provided that at least two of X1, X2, X3, X4 and X5 are N;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2 or 3;
R1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl or heterocyclylalkyl, each of which is optionally substituted with 1-5 R9; wherein R1 or R9 is optionally taken together with one of R4, R5, R6 or R7, and the atoms to which they are attached to form a cyclyl, heterocyclyl, aryl or heteroaryl ring that is optionally substituted with 1-3 R10;
each R2 and R3 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R11;
each R4, R5, R6 and R7 is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf;
each R9, R10 and R11 is independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, oxo, thioxo, —CN, —NO2, —C(O)ORa, —C(Y)NRbRb′, —NRcC(Y)Rc′, —NRbRb′, —OC(O)NRbRb′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Re or —S(O)qRf, each of which is optionally substituted with 1-3 R12; wherein two R9, two R10 or two R11 is optionally taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
R12 is —ORd;
Y is O or S;
q is 1 or 2; and
each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl.
2. The compound according to claim 1 represented by general formula (II) or a salt thereof,
L is NR7;
n is 0, 1 or 2;
p is 0;
R1 is C1-C8 alkyl, aryl or heteroaryl;
each R2 and R3 is independently hydrogen, C1-C8 alkyl, aryl, halo, heterocyclylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R11;
R7 is hydrogen; and
each R9, R10 and R11 is independently C1-C8 alkyl, heterocyclyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)ORa, —C(Y)NRbRb′, —ORd or —C(Y)Re;
Y is O;
each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, cyclyl, heterocyclyl, aryl or heteroaryl.
3. The compound according to claim 2 represented by general formula (II) or a salt thereof,
wherein:
R1 is C1-C8 alkyl, phenyl or benzodioxolyl;
each R2 and R3 is independently hydrogen, C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd;
R9 is independently C1-C8 alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)ORa, —C(Y)NRbRb′, —ORd or —C(Y)Re; and
each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, tetrahydropyranyl, phenyl or pyridyl.
4. The compound according to claim 2 represented by general formula (II) or a salt thereof,
wherein:
R1 is C1-C8 alkyl, phenyl or benzodioxolyl;
each R2 and R3 is independently hydrogen, C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R11;
each R9, R10 and R11 is independently C1-C8 alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)ORa, —C(Y)NRbRb′, —ORd or —C(Y)Re; and
each Ra, Rb, Rb′, Rc, Rc′, Rd, Rd′, Re, Re′ and Rf is independently hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, tetrahydropyranyl, phenyl or pyridyl.
5. The compound according to claim 4 represented by general formula (II) or a salt thereof, wherein:
R2 is C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc′, —NRbRb′ or —ORd, each of which is optionally substituted with 1-3 R11;
R3 is hydrogen;
R9 is halo, haloalkoxy, —CN, —C(O)ORa or —C(Y)NRbRb′; and
R11 is C1-C8 alkyl, morpholinyl, tetrahydropyranyl, halo, —CN, —ORd or —C(Y)Re;
6. The compound according to claim 3 or 5 represented by general formula (II) or a salt thereof, wherein:
R2 is C1-C8 alkyl, phenyl, halo, morholinylalkyl, —NRcC(Y)Rc′, —NRbRb′ or —ORd;
R3 is hydrogen; and
R9 is halo, haloalkoxy, —CN, —C(O)ORa or —C(Y)NRbRb′.
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