THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE

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
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 described in items 1 to 42 below,

  • Item 1. A compound of formula (I):




embedded image


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′, —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)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




embedded image


a compound of formula (II):




embedded image


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 and


a compound of formula (III):




embedded image


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′, —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, 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)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 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




embedded image


  • 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)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




embedded image


  • 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 tem 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, for 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 NR′;


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)Rc;


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)Rc;

  • 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)Rc, 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):




embedded image


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′, —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;


when B is phenyl, R2 is not




embedded image


and where in the compound is not:




embedded image


  • Item 39. A compound of formula (IV):





embedded image


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;


wherein when B is phenyl, two R1 are not taken together to form a pyrazole ring; and


when B is phenyl, R2 is not




embedded image


  • Item 40. A compound of formula (V):





embedded image


wherein:


L is CR4R5, 0, C(O), NR6C(O), or NR′;


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.

  • Item 41. A compound of formula (VI):




embedded image


wherein:


A is CR5, CH or N;


L is O or NRb;


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:




embedded image


  • Item 42. A compound of formula (VI):





embedded image


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 Rb 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:




embedded image


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)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




embedded image


  • 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, for 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′, —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)Rc 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, Rc 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




embedded image


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:




embedded image


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:




embedded image


embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


In some embodiments, B is thienyl. In some embodiments, B is selected from:




embedded image


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:




embedded image


In some embodiments, B is:




embedded image


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, Rb is —C(Y)Rc. 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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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,




embedded image


In some embodiments,




embedded image


In some embodiments, L is NH, and




embedded image


is selected from




embedded image


In some embodiments R6 is halo.


In some embodiments, the compound is:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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′, —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′.


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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, R11 is —OCH2CH2OCH2CH2CH3. In some embodiments, R11 is —OCH2CH2OCH2CH2OCH3.


In some embodiments, the compound is:




embedded image


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:




embedded image


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:




embedded image


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′, —NRb′, —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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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




embedded image


In some embodiments, the compound has the following structure:




embedded image


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




embedded image


In some embodiments, the compound has the following structure:




embedded image


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,




embedded image


or 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:




embedded image


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




embedded image


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):




embedded image


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′, —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;


when B is phenyl, R2 is not




embedded image


and where in the compound is not:




embedded image


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):




embedded image


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 Rb;


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




embedded image


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):




embedded image


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′, —NRcC(O)ORc′, —SO2NRbRb′, —NRcSO2Rc′, —NRcC(Y)NRbRb′, —ORd, —SRd′, —C(Y)Rc 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;


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):




embedded image


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




embedded image


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:




embedded image


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:




embedded image


embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


In some embodiments, B is thienyl. In some embodiments, B is selected from:




embedded image


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:




embedded image


In some embodiments, B is:




embedded image


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, Rb 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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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




embedded image


In some embodiments, L and




embedded image


In some embodiments, L is NH, and




embedded image


is selected from




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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):




embedded image


wherein:


L is CR4R5, 0, 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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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, R11 is —OCH2CH2OCH2CH2CH3. In some embodiments, R11 is —OCH2CH2OCH2CH2OCH3.


In some embodiments, the compound is:




embedded image


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:




embedded image


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:




embedded image


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):




embedded image


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:




embedded image


In some embodiments, R9 is not:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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:




embedded image


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




embedded image


In some embodiments, the compound has the following structure:




embedded image


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




embedded image


In some embodiments, the compound has the following structure:




embedded image


wherein p is 1, 2, 3, 4 or 5.


In some embodiments, L is NR6. In some embodiments, L is 0. 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




embedded image


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:




embedded image


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




embedded image


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 π 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)n 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):




embedded image


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):




embedded image


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):




embedded image


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):




embedded image


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):




embedded image


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):




embedded image


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 occuring 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, schizoaffective 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 (O)

  • Pd(dppf)2Cl2: Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)

  • PdOAc: Palladium(II) acetate

  • Pd2dba3: Tris(dibenzylideneacetone)dipalladium (O)

  • 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-C18, 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



embedded image




embedded image


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)




embedded image


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).




embedded image


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
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




embedded image


embedded image


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, 2HCl (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(O) (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 2HCl 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(O) (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










Molecular


1H-NMR







Number
Product
Salt type
Mass

1H-NMR

Solvent
LCMS
LCMS Protocol
Purity percent
Method for Coupling





1


embedded image



399.45

1H-NMR (400 MHz, DMSO-d6): δ 9.59 (d, J = 2.0 Hz, 1 H), 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


embedded image


HCl
398.46

1H-NMR (400 MHz, DMSO-d6): δ13.20 (s, 1 H), 9.79 (s, 1 H), 9.02-9.08 (m, 2H), 8.87 (d, J = 3.2 Hz, 1 H), 8.53 (s, 1 H), 8.34 (d, J = 8.0 Hz, 1 H), 8.19 (d, J = 6.8 Hz, 1 H), 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


embedded image


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, 1 H), 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, 1 H), 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


embedded image



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, 1 H), 7.86 (d, J = 9.2 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.50-7.58 (m, 3H), 7.30 (t, J = 34.0 Hz, 1 H), 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


embedded image


HCl
408.86
1H-NMR (400 MHz, DMSO-d6): δ10.28 (s, 1 H), 9.48 (s, 1 H), 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, 1 H), 7.55 (t, J = 8.8 Hz, 1 H), 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


embedded image



425.31
1H-NMR (400 MHz, DMSO-d6): δ9.93 (s, 1 H), 9.51 (s, 1 H), 8.68-8.71 (m, 2H), 8.16 (d, J = 2.4 Hz, 1 H), 7.94 (d, J = 2.0 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.56- 7.60 (m, 2H), 7.37 (s, 1 H), 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


embedded image



392.4
1H-NMR (400 MHz, DMSO-d6): δ10.06 (s, 1 H), 9.49 (s, 1 H), 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, 1 H), 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


embedded image



425.31
1H-NMR (400 MHz, DMSO-d6): δ10.05 (s, 1 H), 9.51 (s, 1 H), 8.75-8.80 (m, 2H), 8.34 (d, J = 2.4 Hz, 1 H), 7.96-8.00 (m, 2H), 7.88 (d, J = 9.2 Hz, 1 H), 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


embedded image



415.44
1H-NMR (400 MHz, DMSO-d6): δ13.03 (s, 1H), 9.59 (d, J = 1.2 Hz, 1H), 9.15 (d, J = 8.4 Hz, 1 H), 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, 1 H), 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


embedded image



438.43
1H-NMR (400 MHz, DMSO-d6): δ9.86 (s, 1H), 9.53 (s, 1H), 8.66-8.68 (m, 2H), 8.02 (d, J = 2.8 Hz, 1 H), 7.95 (t, J = 2.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.79 (d, J
DMSO
439.1  (M +1)
Method B (NH4HCO3)
95
Method C, G1





11


embedded image


HCl
424.86
1H-NMR (400 MHz, DMSO-d6): δ10.27 (s, 1 H), 9.48 (s, 1 H), 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


embedded image



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, 1 H), 8.02 (d, J = 2.0 Hz, 1 H), 7.90 (d, J = 9.2 Hz, 1 H), 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


embedded image



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


embedded image



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


embedded image



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
441.0, 443.0  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





16


embedded image


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


embedded image



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


embedded image


HCl
394.79

1H-NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 9.48 (d, J = 0.8 Hz; 1H), 9.28 (cL 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


embedded image



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
423.0  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





20


embedded image


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, 1 H), 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, 1 H), 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


embedded image



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


embedded image



440.42

1H-NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.55 (d, J = 1.2 Hz, 1H)t 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


embedded image



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, 1 H), 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


embedded image



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


embedded image


TFA
369.38

1H-NMR (400 MHz, DMSO-d6): δ 11.51 (s, 1H). 878 (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


embedded image



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


embedded image



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, 1 H), 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


embedded image



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


embedded image


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


embedded image


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


embedded image



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, 1 H), 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


embedded image


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


embedded image


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


embedded image



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 Hz, 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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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, 1 H), 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


embedded image



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, G1





41


embedded image



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


embedded image



476.67

1H-NMR (400 MHz, DMSO-d6): δ10.40 (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)S 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


embedded image



429.67

1H-NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 9.49 (s, 1 H), 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


embedded image


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


embedded image


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, 1 H), 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


embedded image


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


embedded image


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


embedded image


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


embedded image



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


embedded image


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


embedded image


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, 1 H), 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


embedded image



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, 1 H), 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


embedded image


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


embedded image


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


embedded image


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, 1 H), 2.78 (s, 3H).

DMSO
415.0, 417.0, 419.0  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





56


embedded image



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 Hzr 1H), 7.29 (t, J = 74.0 Hz, 1H), 7.00 (dd, J = 8.1, 2.1 Hz, 1H), 4.23 (bis, 2H).

DMSO
380.1  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





57


embedded image


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


embedded image


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


embedded image


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.G Hz, 1 H), 3.80 (s, 3H).

DMSO
390.1  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





60


embedded image



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


embedded image



415.70

1H-NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.44 (s, 1 H), 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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



399.25

1H-NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 8.54 (s, 1 H), 871-8.67 (m, 2H)S 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


embedded image



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


embedded image


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, 1 H), 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


embedded image


HCl
422.43

1H-NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 9.51 (s, 1 H), 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


embedded image


HCl
408.86

1H-NMR (400 MHz, DMSO-d6): δ 10.61 (s, 1H), 9.48 (s, 1 H), 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


embedded image


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


embedded image


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


embedded image


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


embedded image


HCl
367.4

1H-NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.49 (s, 1 H), 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


embedded image


HCl
394.83

1H-NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 9.44 (s, 1 H), 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


embedded image


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


embedded image


HCl
411.28

1H-NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 9.48 (s, 1 H), 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  413.0  415.0  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





78


embedded image


HCl
378.37

1H-NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 9.49 (s, 1 H), 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


embedded image


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


embedded image


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


embedded image


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, 1 H), 7.53 (t, J = 9.0 Hz, 1H).

DMSO
395.0, 397.0  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





82


embedded image



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, 1 H), 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


embedded image


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


embedded image



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


embedded image



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, G10





86


embedded image



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, ?H) 7 96 (s, 1H), 7 91 (d, = 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


embedded image



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


embedded image



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 (mT 2H), 4.02 (s, 3H); 3.98 (s, 3H).

DMSO
402.1  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





89


embedded image



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), 7.14-7.1 I (m, IH), 4.00 (s, 3H), 3.99 (s, 3H).

DMSO
411.1, 413.1  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





90


embedded image



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


embedded image


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 (ss 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, 1 H), 3.98 (s, 3H).

DMSO
406.0, 408.0  (M + 1)
Method A (TFA)
95
Method C, G2





92


embedded image



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


embedded image


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


embedded image



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


embedded image



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


embedded image



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


embedded image



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, 1 H), 7.05-7.03 (m, 1H).

DMSO
399.0, 401.0  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





98


embedded image



385.22

1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.50 (s, 1 H), 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


embedded image



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


embedded image



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, 1 H), 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


embedded image



375.09

1H-NMR (400 MHz, DMSO-d6): δ 13.18 (s, 1H), 9.61 (s, 1 H), 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


embedded image



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, 1 H), 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


embedded image



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, 1 H), 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


embedded image



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, 1 H), 7.57-7.53 (m, 2H), 7.31 (t, J = 74.4 Hz, 1 H), 7.03 (dd, J = 8.0, 1.2 Hz, 1H).

DMSO
449.1  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





105


embedded image



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


embedded image



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


embedded image



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


embedded image



434.77

1H-NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.52 (s, 1 H), 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


embedded image



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


embedded image



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, 1 H), 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


embedded image



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, 1 H), 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


embedded image



434.89

1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 9.47 (s, 1 H), 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


embedded image



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


embedded image



418.44

1H-NMR (400 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.49 (s, 1 H), 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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



368.77

1H-NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 9.49 (s, 1 H), 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


embedded image



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


embedded image



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


embedded image



357.8
1H-NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1 H), 9.52 (s, 1 H), 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


embedded image



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


embedded image



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


embedded image



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, 1 H), 7.95-7.97 (m, 2H), 7.74- 7.75 (m, 1H), 7.54-7.62 (m, 2H), 4.00 (s, 3H).
DMSO
364.1  (M + 1) 183.1  (M/2 + 1)
Method A (TFA)
95
Method C, G1





127


embedded image



397.26
1H-NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 9.48 (s, 1 H), 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


embedded image



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, 1 H), 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


embedded image



362.81
1H-NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 9.51 (s, 1 H), 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


embedded image



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


embedded image



371.39
1H-NMR (300 MHz, DMSO-d6): δ 13.08 (s, 1H), 9.59 (s, 1 H), 9.07 (d, J = 8.1 Hz, 1H), 8.96(d, J = 8.1 Hz, 1H), 8.83 (d, J = 3.9 Hz, 1 H), 8.49(s, 1H), 7.89-7.99 (m, 3H), 7.80-7.84 (m, 1H), 7.72 (t, J = 7.8 Hz, 1 H), 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


embedded image



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, 1 H), 7.40-7.44 (m, 1 H), 3.86 (s, 3H).
DMSO
363.0, 365.1  (M + 1), 182.1  (M/2 + 1)
Method A (TFA)
95
Method C, G1





133


embedded image



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


embedded image



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


embedded image



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)T 3.03 (s, 3H).
DMSO
365.0, 367.0  (M + 1), 183.1  (M/2 + 1)
Method A (TFA)
95
Method C, G1





136


embedded image



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, 1 H), 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


embedded image



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, 1 H), 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


embedded image



397.26
1H-NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1 H), 9.53 (s, 1H), 8.67-8.70 (m, 2H), 8.41 (d, J = 2.4 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1H), 7.95-7.99 (m, 1H), 7.73 (d, J = 8.8 Hz, 1 H), 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


embedded image



380.8
1H-NMR (400 MHz, DMSO-d6): δ 10.21 (S, 1H), 9.48 (s, 1 H), 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, 1 H), 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


embedded image



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


embedded image



348.35
1H-NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1 H), 9.11 (s, 1 H), 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


embedded image



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


embedded image



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, 1 H), 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


embedded image



435.88
1H-NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 9.49 (s, 1 H), 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


embedded image



419.43
1H-NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1 H), 9.45 (s, 1 H), 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


embedded image



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


embedded image



452.34
1H-NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1 H), 9.42 (s, 1 H), 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


embedded image



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, 1 H), 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


embedded image



393.84
1H-NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1 H), 9.48 (s, 1 H), 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


embedded image



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, 1 H), 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


embedded image



410.3
1H-NMR (400 MHz, DMSO-d6): δ 9.72 (s, 1H), 9.49 (s, 1 H), 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


embedded image



410.3
1H-NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1 H), 9.45 (s, 1 H), 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


embedded image



366.42
1H-NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 9.48 (s, 1H), 8.55-8.64 (rn, 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


embedded image



435.23
1H-NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H), 9.53 (s, 1 H), 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


embedded image



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


embedded image



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


embedded image



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


embedded image



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, 1 H), 7.27 (t, J = 7.2 Hz, 1H).
DMSO
410.1  (M + 1)
Method B (NH4HCO3)
95
Method C, G





159


embedded image



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


embedded image



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


embedded image



416.78
1H-NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.49 (s, 1 H), 8.62-8.72 (m, 3H). 8.13 (s, 1 H), 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


embedded image



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, 1 H), 7.22 (t, J = 7.6, 1H).
DMSO
376.0, 378.0  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





163


embedded image



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, 1 H).
DMSO
377.0, 379.0  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





164


embedded image



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


embedded image


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


embedded image



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


embedded image


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


embedded image



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


embedded image


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


embedded image


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


embedded image



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


embedded image


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, 1 H), 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


embedded image



348.35
1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1 H), 9.51 (s, 1 H), 8.79-8.76 (m, 2H), 8.38 (s, 1 H), 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


embedded image



364.8
1 H-NMR (300 Hz, CD30D): 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


embedded image



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


embedded image



346.81
1 H-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


embedded image



346.81
1 H-NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.52 (s, 1 H), 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, 1 H), 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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



390.82
1H-NMR (400 MHz, DMSO-d6): δ 12.25 (S, 1H), 9.54 (s, 1H), 9.25 (s, 1 H), 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


embedded image



366.34
1 H-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


embedded image



415.7
1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.51 (s, 1 H), 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


embedded image



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, 1 H), 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


embedded image



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, 1 H), 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


embedded image



337.38
1 H-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, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.69 (t, J = 7.8 Hz, 1 H), 7.62 (d, J = 7.2 Hz, 1 H), 7.54-7.57 (m, 1H), 2.56 (s, 3H).
DMSO
338.1  (M + 1)
Method B (NH4HCO3)
95
Method C, G1





188


embedded image



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


embedded image



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, 1 H), 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


embedded image



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


embedded image



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)T 7.62-7.49 (m, 1H).
DMSO
369.0, 371.0  (M + 1)
Method B (NH4HCO3)
97
Method C, G1





192


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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, 1 H), 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


embedded image



357.80
1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1 H), 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


embedded image



435.23
1H-NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1 H), 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


embedded image



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


embedded image



375.79
1H-NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1 H), 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


embedded image



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


embedded image



381.26
1H-NMR (400 MHz, DMSO-d6): δ 10.05 (s, 1 H), 9.54 (s, 1H), 8.75-8.65 (m, 2H), 8.46 (d, J = 8.5 Hz, 1 H), 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, 1 H), 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


embedded image



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


embedded image



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, 1 H), 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


embedded image



381.26
1H-NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1 H), 9.53 (s, 1 H), 8.87-8.73 (m, 2H), 8.50 (d, J = 8.5 Hz, 1 H), 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, 1 H), 2.56 (s, 3H).
DMSO
381.1, 383.0  (M + 1)
Method B (NH4HCO3)
99
Method C, G1





208


embedded image



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, 1 H), 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


embedded image



355.39
1H-NMR (400 MHz, DMSO-d6): δ 13.09 (s, 1H), 9.60 (s, 1 H), 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, 1 H), 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, 1 H), 7.25 (t, J = 7.6 Hz, 1 H), 2.56 (s, 3H).
DMSO
356.1  (M + 1)
Method B (NH4HCO3)
99
Method C, G1





210


embedded image



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, 1 H), 7.74-7.70 (m, 1 H), 7.28-7.24 (m, 1H).
DMSO
376.1, 378.1  (M + 1)
Method B (NH4HCO3)
98
Method C, G1





211


embedded image



444.79
1H-NMR (400 MHz, DMSO-d6): δ 13.68 (bis, 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


embedded image



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, 1 H), 7.99 (d, J = 2.1 Hz, 1H), 7.92-7.86 (m, 1 H), 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


embedded image



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, 1 H), 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


embedded image



436.77
1H-NMR (400 MHz, DMSO-d6): δ 10.35 (S, 1H), 9.56 (s, 1 H), 8.84 (d, J = 8.3 Hz, 1H), 8.64 (d, J = 9.0 Hz, 1 H), 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


embedded image



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, 1 H), 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


embedded image



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, 1 H), 7.88 (d, J = 2.7 Hz, 1H), 7.84-7.77 (m, 1 H), 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


embedded image



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, 1 H), 3.96 (s, 3H).
DMSO
411.1  (M + 1)
Method B (NH4HCO3)
100
Method D, G1





218


embedded image



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, 1 H), 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


embedded image



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, 1 H), 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


embedded image



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


embedded image



387.39
1H-NMR (400 MHz, DMSO-d6): δ 14.80 (brs, 1H), 13.19 (s, 1H), 8.68 (d, J = 7.3 Hz, 1 H), 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, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 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


embedded image



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, 1 H), 7.26-7.18 (m, 1H), 6.80-6.69 (m, 1 H), 4.03 (s, 3H).
DMSO
411.1  (M + 1)
Method B (NH4HCO3)
100
Method C, G1





223


embedded image



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, 1 H), 6.44 (d, J = 9.6 Hz, 1H).
DMSO
401.0, 403.0  (M + 1)
Method B (NH4HCO3)
100
Method C, G1





224


embedded image



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, 1 H), 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


embedded image



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, 1 H), 7.17 (d, J = 7.8 Hz, 1 H), 6.44 (d, J = 9.6 Hz, 1H).
DMSO
433.0, 435.0  (M + 1)
Method B (NH4HCO3)
100
Method C, G1





226


embedded image



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


embedded image



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


embedded image



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, 1 H), 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


embedded image



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


embedded image



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


embedded image



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, 1 H), 8.19 (s, 1 H), 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, 1 H), 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


embedded image



359.12
1H-NMR (400 MHz, DMSO-d6): δ 13.10 (s, 1H), 9.54 (s, 1 H), 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


embedded image



381.26
1H-NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H), 9.08 (s, 1 H), 8.67-8.70 (m, 1 H), 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


embedded image



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 (del, J = 9.2, 2.0 Hz, 1 H), 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


embedded image



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, J1





236


embedded image



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, G1





237


embedded image



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


embedded image



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


embedded image



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


embedded image



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, 1 H), 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


embedded image



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, 1 H), 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


embedded image



337.4
1H-NMR (400 MHz, DMSO-d6): 10.12 (s, 1 H), 9.57 (s, 1 H), 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


embedded image



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, IH), 8.20 (s, IH), 7.97-7.94 (m, 1 H), 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


embedded image



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, 1 H), 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


embedded image



360.34
1 H-NMR (400 MHz, DMSO-d6): δ 11.95- 11.11 (m, 2H), 9.43 (d, J = 1.6 Hz, 1 H), 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


embedded image



393.8
1 H-NMR (400 MHz, DMSO-d6): δ 13.29 (s, 1H), 9.54 (s, 1H), 9.29 (s, 1 H), 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, 1 H), 8.72 (d, J = 3.6 Hz, 1 H), 8.67 (d, J = 7.8 Hz, 1 H), 8.64-8.53 (m, 1H).
DMSO
394.0, 396.0  (M + 1)
Method B (NH4HCO3)
95
Method C, J1





247


embedded image




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


embedded image



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


embedded image



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


embedded image



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, 1 H), 8.49 (t, J = 7.2 Hz, 1 H), 7.85 (d, J = 7.8 Hz, 1 H), 7.63-7.51 (m, 3H), 7.14 (t, J = 7.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1 H), 6.46 (t, J = 7.2 Hz, 1H).
DMSO
360.8  (M + 1)
Method B (NH4HCO3)
95
Method C, G8





251


embedded image



400.43
1H-NMR (400 MHz, DMSO-d6): δ 12.92 (s, 1H), 9.04 (d, J = 8.3 Hz, 1H), 8.66 (del, 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


embedded image



483.44
1H-NMR (400 MHz, DMSO-d6): δ 13.28 (s, 1H), 9.54 (s, 1H), 9.28 (s, 1 H), 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


embedded image




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


embedded image



469.42
1H-NMR (400 MHz, DMSO-d6): δ 13.34 (s, 1H), 9.60 (s, 1H), 9.35 (s, 1 H), 8.77 (d, J = 3.5 Hz, 1H), 8.72 (d, J = 7.9 Hz, 1H), 8.67 (s, 1H), 8.22 (s, 1 H), 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, 1 H), 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


embedded image



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






































Retention








Molecular



Time

Purity
Method of


Number
Product
Salt Type
Mass

1H NMR


1H NMR Solvent

LCMS
(min)
LCMS Protocol
percent
Coupling





256


embedded image


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 7.91 (m, 4H), 7.85 (d, J = 8.9 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.25 (1, J = 7.6 Hz, 1H).

DMSO
420   (M + 1)
1.89
Method D
100
Method G1





257


embedded image


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


embedded image


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


embedded image


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


embedded image


HCl
429.67
No Data

428.9  (M + 1)
2.35
Method C
100
Method G1





261


embedded image


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


embedded image


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


embedded image


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


embedded image



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


embedded image


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


embedded image


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


embedded image


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


embedded image


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 (1, J = 7.5 Hz, 1H), 7.0
DMSO
368.1  (M + 1)
1.98
Method C
100
Method G1





269


embedded image



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


embedded image



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


embedded image


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


embedded image


HCl
413.47

1HNMR (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


embedded image


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


embedded image


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 (1, J = 7.6 Hz, 1H), 4.00 (s, 3H), 3.

DMSO
400.3  (M + 1)
2.21
Method C
100
Method G1





275


embedded image


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


embedded image



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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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 (8, 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


embedded image


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


embedded image


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


embedded image



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


embedded image



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


embedded image


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




































Pu-










1H

rity
Method


Num-
Starting
Starting

Salt

NMR
per-
of


ber
Material 1
Material 2
Product
Type

1H NMR

Solvent
cent
Coupling





295


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 9.54-9.47 (m, 1 H), 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


embedded image




embedded image




embedded image




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, 1 H), 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, 1 H), 4.39-4.23 (m, 4H), 3.97 (s, 3H).

DMSO
>98
G1





298


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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, 1 H), 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


embedded image




embedded image




embedded image




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, 1 H), 7.16-7.04 (m, 1H), 6.54 (dd, J = 3.0, 1.9 Hz, 1H), 3.98 (s, 3H).

DMSO
>98
G1





301


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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, 1 H), 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


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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, 1 H), 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, 1 H), 7.51 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 4.19 (s, 3H), 3.98 (s, 3H).

DMSO
>98
G1





306


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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, 1 H), 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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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 (66, J = 9.1, 2.5 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 4.02 (s, 3H).

DMSO
>98
G1





311


embedded image




embedded image




embedded image


HCl

1 H 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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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, 1 H), 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


embedded image




embedded image




embedded image




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 (0.1N HCl added)





317


embedded image




embedded image




embedded image




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, 1 H), 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, 8.7, 2.1 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 4.00 (s, 3H).

DMSO
>98
G1 (0.1N HCl added)





318


embedded image




embedded image




embedded image




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, 1 H), 3.98 (s, 3H), 3.41 (s, 3H).

DMSO
>98
G1 (0.1N HCl added)





319


embedded image




embedded image




embedded image




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, 1 H), 3.98 (s, 3H), 3.40 (s, 3H).

DMSO
>98
G1 (0.1N HCl added)





320


embedded image




embedded image




embedded image




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 (0.1N HCl added)





321


embedded image




embedded image




embedded image




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 (0.1N HCl added)





322


embedded image




embedded image




embedded image




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, 1 H), 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 (0.1N HCl added)





323


embedded image




embedded image




embedded image




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 (0.1N HCl added)





324


embedded image




embedded image




embedded image


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 (0.1N HCl added)





325


embedded image




embedded image




embedded image


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, 2.7Hz, 1H), 6.44 (d, J = 9.5 Hz, 1H), 4.01 (s, 3H).

DMSO
>98
G1 (0.1N HCl added)





326


embedded image




embedded image




embedded image


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 (0.1N HCl added)





327


embedded image




embedded image




embedded image


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, 1 H), 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 (66, J = 9.1, 2.6 Hz, 1H), 4.02 (s, 3H), 3.47 (s, 3H).

DMSO
>98
G1 (0.1N HCl added)





328


embedded image




embedded image




embedded image


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 (0.1N HCl added)





329


embedded image




embedded image




embedded image


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, 1 H), 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, 1 H), 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,

DMSO
>98
G1 (0.1N HCl added)







1H), 4.06 (s, 3H).








330


embedded image




embedded image




embedded image


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, IH), 4.02 (S, 3H).

DMSO
>98
G1 (0.1N HCl added)





331


embedded image




embedded image




embedded image


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 (0.1N HCl added)





332


embedded image




embedded image




embedded image


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 (0.1N HCl added)





333


embedded image




embedded image




embedded image


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 (0.1N HCl added)





334


embedded image




embedded image




embedded image


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 (0.1N HCl added)





335


embedded image




embedded image




embedded image


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 (0.1N HCl added)





336


embedded image




embedded image




embedded image


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, 1 H), 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 (0.1N HCl added)





337


embedded image




embedded image




embedded image


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 =

DMSO
>98
G1 (0.1N HCl added)







7.0 Hz, 3H).








338


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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, 1 H), 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


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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, 1 H); 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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


HCl

1H NM R (400 MHz, DMSO) δ 9.35- 9.29 (m, 1H), 8.87-8.78 (m, 2H), 8.19 (d, J = 9.4 Hz, 1 H), 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


embedded image




embedded image




embedded image


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, 1 H), 4.02 (s, 3H).

DMSO
>98
G12 at room temper- ature





347


embedded image




embedded image




embedded image


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, 1 H), 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


embedded image




embedded image




embedded image


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, 1 H), 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


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 9.23 (dd, J = 2.1, 0.7 Hz, 1 H); 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


embedded image




embedded image




embedded image


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 = 92 Hz, 1H), 7.92-7.79 (m, 1H), 7.74 (dd, J = 9.1, 2.9 Hz, 1 H), 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


embedded image




embedded image




embedded image


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, 1 H), 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, 1 H), 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,

DMSO
>98
G1







3H).








352


embedded image




embedded image




embedded image


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, 1 H), 7.81-7.72 (m, 2H), 6.47 (d, J = 9.5 Hz, 1H).

DMSO
>98
G1





353


embedded image




embedded image




embedded image


HCl
1H NMR (300 MHz, DMSO) δ 10.90 (s, 1 H), 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, 1 H), 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


embedded image




embedded image




embedded image


HCl
1H NMR (300 MHz, DMSO) δ 11.44 (s, 1 H), 9.58 (d, J = 1.8 Hz, 1 H), 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, 1 H), 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


embedded image




embedded image




embedded image


HCl
1H NMR (300 MHz, DMSO) δ 11.38 (s, 1 H), 9.53 (s, 1H), 9.18 (d, J = 8.1 Hz, 1H), 8.97 (d, J = 5.3 Hz, 1 H), 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


embedded image




embedded image




embedded image


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, 1 H), 7.26 (s, 1H), 7.21 (d, J = 7.4 Hz, 1H), 3.98 (s, 3H), 2.41 (s, 3H).
DMSO
>98
G1





357


embedded image




embedded image




embedded image


HCl
1H NMR (300 MHz, DMSO) δ 11.21 (s, 1 H), 9.59 (d, J = 1.7 Hz, 1 H), 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, 1 H), 3.98 (s, 3H).
DMSO
>98
G1





358


embedded image




embedded image




embedded image


HCl
1H NMR (300 MHz, DMSO) δ 10.87 (s, 1H), 9.65-9.55 (m, 1 H), 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, 1 H), 7.60-7.46 (m, 4H), 7.44- 7.35 (m, 1H), 7.32 (s, 1 H), 3.98 (s, 3H).
DMSO
>98
G1





359


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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.G Hz, 1H), 7.29 (s, 1H), 3.96 (s, 3H).
DMSO
>98
G1





366


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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, 1 H); 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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


2 HCl
1H NMR (300 MHz, DMSO) δ 11.32 (s, 1 H), 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


embedded image




embedded image




embedded image


2 HCl
1H NMR (300 MHz, DMSO) δ 11.38 (s, 1 H), 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


embedded image




embedded image




embedded image


2 HCl
1H NMR (300 MHz, DMSO) δ 11.29 (s, 1 H), 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


embedded image




embedded image




embedded image


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, 1 H), 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, 1 H), 7.64-7.35 (m, 9H), 5.23 (s, 2H).
DMSO
>98
J NaOtBu, Pd(OAc)2, Tri-t- butyl- phospho- nium tetra- fluoro- borate, Toluene





376


embedded image




embedded image




embedded image


2 HCl
1H NMR (300 MHz, DMSO) δ 12.49 (s, 1 H), 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, 1 H), 7.64-7.35 (m, 9H), 5.21 (s, 2H).
DMSO
>98
J NaOtBu, Pd(OAc)2, Tri-t- butyl- phospho- nium tetra- fluoro- borate, Toluene





377


embedded image




embedded image




embedded image


2 HCl
1H NMR (300 MHz, DMSO) δ 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, 1 H), 4.69 (t, J = 7.9 Hz, 2H), 3.92 (s, 3H), 3.26 (t, J = 7.8 Hz, 2H).
DMSO
>98
G8





378


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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 (1, J = 8.0 Hz, 2H), 3.92 (s, 3H), 3.22 (t, J = 7.8 Hz, 2H).
DMSO
>98
G8 at 50° C.





380


embedded image




embedded image




embedded image


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, 1 H), 7.12 (td, J = 9.0, 2.7 Hz, 1 H), 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


embedded image




embedded image




embedded image


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, 1 H), 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


embedded image




embedded image




embedded image


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 (1. 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


embedded image




embedded image




embedded image


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 (Id, J = 9.2, 2.7 Hz, 1H), 7.02-6.89 (m, 1H), 3.91 (s, 3H).
DMSO
>98
G8 at 50° C.





384


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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, 1 H), 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


embedded image




embedded image




embedded image


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 (1, J = 6.9 Hz, 3H).
DMSO
>98
G8 at 50° C.





389


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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 in- stead of THF





391


embedded image




embedded image




embedded image


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, 1 H), 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 in- stead of THF





392


embedded image




embedded image




embedded image


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, 1 H); 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 in- stead of THF





393


embedded image




embedded image




embedded image


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 in- stead of THF





394


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 9.43- 9.29 (m, 1H), 8.75-8.64 (m, 2H), 8.60-8.48 (m, 1 H); 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 in- stead of THF





395


embedded image




embedded image




embedded image


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 in- stead of THF





396


embedded image




embedded image




embedded image


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

DMSO
>98
G12





397


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image




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, 1 H), 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


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 12.52 (s, 1 H); 9.78 (d, J = 1.56 Hz, 1 H), 8.91 8.88 (m, 1H), 8.74 (dd, J = 4.74, 1.69 Hz, 1H), 8.33 (brs, 1H), 8.96 (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


embedded image




embedded image




embedded image


2 HCl
1H NMR (DMSO-d6) ppm 12.80- 12.40 (br, 1H), 977 (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, 1 H), 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


embedded image




embedded image




embedded image


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 (bit, 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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


HCl
1H NMR (DMS0-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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


HCl
1H NMR (DMSO-d6) ppm 10.31 (s, 1H), 9.37 (s, 1 H), 8.88 (m, 2H), 8.04 (d J = 2.60 Hz, 1 H), 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 = 1.88Hz, 1H), 3.98 (s, 3H), 3.74 (s, 3H). The 1H of HCl was not observed.
DMSO
>98
J2





407


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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 (bit 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 Tempera- ture at 100° C.





409


embedded image




embedded image




embedded image


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 (bit 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 Tempera- ture at 100° C.





410


embedded image




embedded image




embedded image


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, 1 H), 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 obseived.
DMSO
>98
J2 Tempera- ture at 100° C.





411


embedded image




embedded image




embedded image



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 Tempera- ture at 100° C.





412


embedded image




embedded image




embedded image


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, 1 H), 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 Tempera- ture at 100° C.





413


embedded image




embedded image




embedded image



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, 1 H), 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 Tempera- ture at 100° C.







































1H

Pu-
Meth-











NMR
rity
od of

Reten-



Num-
Starting
Starting

Salt

Sol-
per-
Cou-

tion
LCMS


ber
Material 1
Material 2
Product
type

1H NMR

vent
cent
pling
LCMS
Time
Method





414


embedded image




embedded image




embedded image


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 Tem- pera- ture at 100° C.








415


embedded image




embedded image




embedded image


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 Tem- pera- ture at 100° C.








416


embedded image




embedded image




embedded image


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,
DMSO
>98
G12 Tem- pera- ture at 100° C.










3H). The 1H of HCl













was not observed.











417


embedded image




embedded image




embedded image


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 Tem- pera- ture at 100° C.








418


embedded image




embedded image




embedded image


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),
DMSO
>98
G12 Tem- pera- ture at 100° C.










7.77-7.75 (br,













2H), 7.62 (dd, J =













9.08, 2.72 Hz, 1H),













7.50 (m, 2H), 7.37













(m, 1H), 3.99 (s,3H).













The 1H of HCl was













not observed.











419


embedded image




embedded image




embedded image


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 (bit, 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 Tem- pera- ture at 100° C.








420


embedded image




embedded image




embedded image


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 Tem- pera- ture at 100° C.








421


embedded image




embedded image




embedded image



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


embedded image




embedded image




embedded image


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-
DMSO
>98
J3 using Na2CO3 instead of K2CO3










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.











423


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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
DMSO
>98
J3










(brm, 1H), 7.55













(d, J = 8.56 Hz, 2H),













4.01 (s, 3H).The 1H













of HCl was not ob-













served.











425


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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 120° C.








427


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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 ob- served.
DMSO
>98
G13 using K2CO3 instead of Cs2CO3








430


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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, H), 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 HClwas not observed.
DMSO
>98
G13 using K2CO3 instead of Cs2CO3








434


embedded image




embedded image




embedded image


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,lH), 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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image



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
DMSO
>98
G13 using K2CO3 instead of Cs2CO3










(m, 1H), 3.96 (s,













3H).











438


embedded image




embedded image




embedded image


HCl
1H NMR (DMSO- d6) ppm 10.48 (br, 1H), 9.23 (s,lH), 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


embedded image




embedded image




embedded image


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
DMSO
>98
G13 at 100° C.










of HCl was not













observed.











440


embedded image




embedded image




embedded image


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 (bit, 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,
DMSO
>98
G13 at 100° C.










J = 7.48 Hz, 1H),













4.02 (s, 3H),













2.40 (s, 3H).













The 1H of HCl













was not observed.











441


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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
DMSO
>98
G13 at 100° C.










not observed.











443


embedded image




embedded image




embedded image


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 = 2.60Hz, 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


embedded image




embedded image




embedded image


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
MeOD
>98
G13










observed.











445


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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,
DMSO
>98
G13










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.











448


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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
DMSO
>98
G13 at 100° C.










observed.











450


embedded image




embedded image




embedded image


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),
DMSO
>98
G13 at 100° C.










7.45 (s, 1H), 3.98













(s, 3H). The 1H













of 2HCl was not













observed.











451


embedded image




embedded image




embedded image


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
DMSO
>98
G13










of HCl was not













observed.











452


embedded image




embedded image




embedded image


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
DMSO
>98
G13










observed.











453


embedded image




embedded image




embedded image


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,
DMSO
>98
G13










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.











454


embedded image




embedded image




embedded image


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
DMSO
>98
G13










Hz, 1H), 7.55













(m, 3H), 4.02 (s,













3H). The 1H of













2HCl was not













observed.











455


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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).
DMSO
>98
G13










The 1H of HCl was













not observed.











459


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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
DMSO
>98
G13










was not observed.











462


embedded image




embedded image




embedded image


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
DMSO
>98
G13










(brs, 2H), 3.96













(brs, 3H). The













1H of 2HCl was













not observed.











463


embedded image




embedded image




embedded image


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
DMSO
>98
G13










Hz, 2H), 1.49 (t,













J = 7.40 Hz, 3H).













The 1H of 2HCl













was not observed.











464


embedded image




embedded image




embedded image


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
DMSO
>98
G13










was not observed.













The CH proton of













iPr group was not













observed because













of overlapping













the H2O peak.











465


embedded image




embedded image




embedded image


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, H), 7.51 (t, J = 7.36 Hz, 2H),
DMSO
>98
G13










7.42 (t, J = 7.36













Hz, 1H), 3.99 (s,













3H), 2.96 (t, J =













7.52 Hz, 2H),













1.78 (m, 2H),













1.01 (t, J = 7.24













Hz, 3H). The 1H













of 2HCl was













not observed.











466


embedded image




embedded image




embedded image


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,
DMSO
>98
G13










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).













The 1H of 2HCl













was not observed.











467


embedded image




embedded image




embedded image


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,
DMSO
>98
G13










J =6.88 Hz,2H),













1.47 (t, J = 6.88













Hz, 3H). The 1H













of HCl was not













observed.











468


embedded image




embedded image




embedded image


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
DMSO
>98
G13










2HCl was not













observed.











469


embedded image




embedded image




embedded image


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
DMSO
>98
G13










and NH—













were not observed.











470


embedded image




embedded image




embedded image


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
DMSO
>98
G13










(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, 2H), 1.47













(t, J = 7.00 Hz, 3H).













The 1H of HCl was













not observed.











471


embedded image




embedded image




embedded image


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),
DMSO
>98
G13










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, J =













6.92 Hz, 2H),













1.47 (t, J = 6.92













Hz, 3H). The 1H













of 2HCl was not













observed.











472


embedded image




embedded image




embedded image


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,
DMSO
>98
G13










J = 6.92 Hz, 2H),













1.47 (t, J = 6.92













Hz, 3H). The 1H













of 3HCl was not













observed.











473


embedded image




embedded image




embedded image


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,
DMSO
>98
G13










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













observed.











474


embedded image




embedded image




embedded image



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


embedded image




embedded image




embedded image


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



embedded image




embedded image


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



embedded image




embedded image


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
DMSO
  95
Method G1
482.1 (M + 1)

Method C







(s, 3H), 1.42 (t,













J = 6.9 Hz, 3H).











478



embedded image




embedded image


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



embedded image




embedded image


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



embedded image




embedded image


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



embedded image




embedded image


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



embedded image




embedded image


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



embedded image




embedded image


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



embedded image




embedded image


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 =
DMSO
  95
Method G1
422.1 (M + 1)

Method C







6.9 Hz, 2H), 2.90













(d, J = 4.7 Hz,













3H), 1.44 (t, J =













6.9 Hz, 3H).











485



embedded image




embedded image


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



embedded image




embedded image


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-
DMSO
  99
Method G1
382.5 (M + 1)

Method C







7.03 (m, 2H), 3.74













(s, 3H), 3.69 (s, 3H).











487



embedded image




embedded image


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



embedded image




embedded image


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



embedded image




embedded image


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



embedded image




embedded image



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,
DMSO
  99
Method G1
464.2 (M + 1)

Method C







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 Hz, 2H), 3.34













(s, 3H), 1.44 (t,













J = 6.9 Hz, 3H).











491



embedded image




embedded image



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
DMSO
  99
Method G1
427.5 (M + 1)

Method C







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).











492




embedded image



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




embedded image


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




embedded image




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 ft, 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




embedded image




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
402.2 (M + 1)
t = 1.746 min
Method B (NH4HCO3)





496




embedded image




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




embedded image


2 HCl

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),

DMSO
  95
Method G1
418.2 (M + 1)
1.782 min
Method B (NH4HCO3)







1.45 (t, J = 6.9 Hz,













3H).











498




embedded image




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

DMSO
  95
Method G1
530.0 (M + 1)
1.856 min
Method B (NH4HCO3)







(s, 4H).











499




embedded image


2 HCl

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),

DMSO
  95
Method G1
420.1 (M + 1)
t = 1.478 min
Method B (NH4HCO3)







7.32 (t, J = 7.6 Hz,













1H), 3.38 (s, 3H).











501




embedded image


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




embedded image




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, J = 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




embedded image




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




embedded image


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
DMSO
  95
Method G1
396.1 (M + 1)

Method C







Hz, 2H), 7.47 (d,













J = 5.4 Hz, 1H),













4.02(s, 3H).











505


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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),

DMSO
>98
G1 (0.1N HCl added)










4.64 (s, 2H), 3.97













(s, 3H).











507


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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 (4, 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

DMSO
>98
G1










(s, 3H), 3.90 (s,













3H).











509


embedded image




embedded image




embedded image




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

DMSO
>98
G1 (0.1N HCl added)










Hz, 1H), 3.98













(s, 3H), 3.47 (s,













3H).











510


embedded image




embedded image




embedded image




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,

DMSO
>98
G1 (0.1N HCl added)










2.0 Hz, 1H), 7.01













(d, J = 8.3 Hz, 1H),













3.97 (s, 3H).











511


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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-

DMSO
>98
G1










7.49 (m, 2H), 4.22













(s, 3H), 3.99 (s, 3H).











513


embedded image




embedded image




embedded image




1H NMR (100 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),

DMSO
>98
J2










7.60 (d, J = 8.5 Hz,













1H), 7.57-7.49 (m,













2H), 4.21 (s, 3H),













3.98 (s, 3H).











514


embedded image




embedded image




embedded image


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 =

DMSO
>98
G1










9.2 Hz, 1H), 7.70-













7.63 (m, 2H),













4.21 (s, 3H), 4.02













(s, 3H).











515


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 10.45 (s, 1H), 9.46 (d, J = 1.7Hz, 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-

DMSO
>98
G1 (0.1N HCl added)










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 = 9.4 Hz, 1H),













4.00 (s, 3H).











516


embedded image




embedded image




embedded image




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

DMSO
>98
G1










(dd, J = 8.7, 2.1













Hz, 1H), 7.58-













7.50 (m, 2H),













4.20 (s, 3H), 3.99













(s, 3H).











517


embedded image




embedded image




embedded image


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,

DMSO
>98
G1










J = 7.8 Hz, 1H),













7.58 (dd, J =8.8,













2.0 Hz, 2H), 7.52-













7.46 (m, 1H), 7.28













(s, 1H), 3.98 (d,













J = 9.2 Hz, 3H).











518


embedded image




embedded image




embedded image


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-

DMSO
>98
G1










7.36 (m, 4H), 7.32













(s, 1H), 7.06-













6.90 (m, 1H), 3.99













(s, 3H), 3.86 (s,













3H).











519


embedded image




embedded image




embedded image


2 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 (66, 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 =
DMSO
>98
G1










9.1, 2.6 Hz, 1H),













7.44 (d, J = 8.8













Hz, 1H), 6.58 (d,













J = 9.4 Hz, 1H),













4.00 (s, 3H).











520


embedded image




embedded image




embedded image


HCl

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

DMSO
>98
G1










(dd, J = 8.7,













2.1 Hz, 1H), 7.58-













7.50 (m, 2H),













4.20 (s, 3H), 3.99













(s, 3H).











521


embedded image




embedded image




embedded image


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),

DMSO
>98
G1










7.52-7.46 (m, 1H),













7.28 (s, 1H), 3.98













(d, J = 9.2 Hz, 3H).











1758


embedded image




embedded image




embedded image


3 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
G13








1759


embedded image




embedded image




embedded image


3 HCl
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
DMSO
>98
J2










1H of 3HCl













was not observed.











embedded image


embedded image




embedded image


embedded image


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








Mole-


1H



Purity
Method


Num-

Salt
cular

NMR

LCMS
per-
for


ber
Product
type
Mass

1H-NMR

Solvent
LCMS
Protocol
cent
Coupling







522


embedded image



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


embedded image



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


embedded image



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


embedded image


HCl
429.47 
1H-NMR (400 MHz, DMSO- d6): δ 12.96 (s, 1H), 9.60 (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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image


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 (NH4CO3)
95
Method N, G1





532


embedded image



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


embedded image


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


embedded image



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


embedded image


HCl
468.45 
1H-NMR (400 MHz, DMSO- 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


embedded image



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


embedded image



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


embedded image



397.26 
1H-NMR (400 MHz, DMSO- d6): δ 10.00 (s, 1H), 8.54 (d, J = 1.3 Hz, 1H), 8.71-8.56 (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


embedded image



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


embedded image



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


embedded image



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 = 7.6 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


embedded image



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


embedded image



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 9m, 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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



433.24 
1H-NMR (400 MHz, DMSO- d6): δ 10.30 (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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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), 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


embedded image



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


embedded image



397.43 
1H-NMR (400 MHz, DMSO- d6): δ 10.67 (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


embedded image



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


embedded image



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


embedded image



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


embedded image



427.28 
1H-NMR (400 MHz, DMSO- d6): δ 9.70 (s, 1H), 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


embedded image


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 (NH4HCO3)
95
Method N, G1





565


embedded image


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











embedded image


embedded image




embedded image


embedded image


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 μl, 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).




embedded image


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












Re-












ten-

Pu-
Method





Mole-


1H-


tion

rity
for


Num-

Salt
cular

NMR

Time
LCMS
per-
Coup-


ber
Product
type
Mass

1H-NMR

Solvent
LCMS
(Min)
Protocol
cent
ling







566


embedded image



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
Method O1





567


embedded image



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
Methods O1, P





568


embedded image



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
Methods O1, P, Q





569


embedded image


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.
DMSO
436 (M + 1)
1.68
Method C
100
Method G4





570


embedded image



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
Methods O1, P, Q





571


embedded image


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
Method G4





572


embedded image



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
Method G4





573


embedded image


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), 8.08-7.78 (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
Method G4





574


embedded image


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
Method G4 follow- ed by acyla- tion with acetyl chlo- ride/ TEA/ DCM, rt





575


embedded image


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
Method G4





576


embedded image



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
Method O1





577


embedded image



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
Methods O1, P





578


embedded image



519.09 
1H NMR (300 MHz, DMSO) δ 10.17 (s, 1H), 9.67-9.43 (m, 1H), 8.68 (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
Method O1





579


embedded image



404.82 
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
Methods O1, Q





580


embedded image



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
Methods O1, P





581


embedded image



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
Methods O1, P





582


embedded image



408.86 
1H NMR (300 MHz, CD3OD) δ 9.50 (d, J = 1.3 Hz, 1H), 8.77 (d, J = 8.0 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
Methods O1, P, Q





583


embedded image



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
Method G4





584


embedded image



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
Method O2





585


embedded image



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
Methods O2, P





586


embedded image


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 (Ammon- ium formate)
100
Method O2





587


embedded image


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 (Ammon- ium formate)
100
Method O2





588


embedded image



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
Method O1





589


embedded image



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
Method O1, P





590


embedded image



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).
DMSO
  410.5 (M + 1)

Method C
 95
Method O1





591


embedded image



413.47 

DMSO
  415.5 (M + 1)

Method C
 95
Method O1, P











embedded image


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




embedded image


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).




embedded image


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).




embedded image


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).




embedded image


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).




embedded image


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







Salt
Molecular


1H-NMR


Retention
LCMS
Purity
Method for


Number
PRODUCT
type
Mass

1H-NMR

Solvent
LCMS
Time (min)
Protocol
percent
Coupling

























592


embedded image


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
Method C
100
Method N3





593


embedded image


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, 1 H), 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, 2H), 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
Method D
97
Method N3





594


embedded image



448.920

1H NMR (300 MHz, DMSO) δ 10.10 (s, 1H, 9.51 (s, 1 H), 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
Method D
92
Method N3





595


embedded image



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
Method C
100
Method N1





596


embedded image



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
Method C
100
Method N3





597


embedded image



456.9

DMSO
456.0 (M + 1)
2.64
Method C
100
Method N1





598


embedded image



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, 1 H), 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
Method C
100
Method N1





599


embedded image



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
Method C
100
Method N1





600


embedded image



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
Method C
100
Method N1





601


embedded image



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
Method C
100
Method N1





602


embedded image



445.85

1H NMR (300 MHz, DMSO) δ 10.09 (s, 1H), 9.50 (s, 1 H). 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
Method C
99
Method N1





603


embedded image



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
Method C
100
Method N1





604


embedded image



456.9

1H NMR (300 MHz, DMSO) δ 10.16 (s, 1H), 9.53 (s, 1H), 8.81 (s, 1H), 8.73-8.60 (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
Method C
100
Method N1





605


embedded image



486.92

1H NMR (300 MHz, DMSO) δ 10.16 (s, 1H), 9.54 (s, 1H), 8.79 (d, J = 9.7 Hz, 1 H), 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
Method C
100
Method N1





606


embedded image



486.92

DMSO
487.1 (M + 1)
2.58
Method C
100
Method N1





607


embedded image



390.84

DMSO
390.9 (M + 1)
2.48
Method C
100
Method N1





608


embedded image



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
Method C
100
Method N1





609


embedded image



526


526.16 (M + 1)
2.55
Method C
94
Method N1





610


embedded image



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, 1 H), 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
Method C
100
Method N1





611


embedded image



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
Method C
100
Method N1





612


embedded image



442.88

DMSO
443.1 (M + 1)
2.37
Method C
100
Method N1





613


embedded image



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
Method C
100
Method N1





614


embedded image



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
Method C
100
Method N1





615


embedded image



514.93

1H NMR (300 MHz, DMSO) d 10.19 (s, 1H), 9.52(s, 1H), 8.86 (s, 1H), 8.67 (dd, J = 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
Method C
100
Method N1





616


embedded image



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, 11.1, 6.0 Hz, 2H).
DMSO
452.0 (M + 1)
2.61
Method C
96
Method N1





617


embedded image



436.47


437.2 (M + 1)
2.08
Method C
95
Method N1





618


embedded image



421.45


422.2 (M + 1)
1.8
Method C
100
Method N1





619


embedded image



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
Method C
100
Method N3





620


embedded image



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
Method C
100
Method N2





621


embedded image



462.95

1H NMR (300 MHz, CD3OD) δ 9.40 (s, 1H), 8.66 (d, J = 8.0 Hz, 1 H), 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
Method C
100
Method N3





622


embedded image



433.91


434.0 (M + 1)
1.73
Method C
100
Method N3





623


embedded image



435.92


436.0 (M + 1)
1.84
Method C
100
Method N3





624


embedded image



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
Method C
100
Method N2





625


embedded image



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
Method C
94
Method N3





626


embedded image



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
Method C
93
Method N1





627


embedded image



463.93

1H NMR (300 MHz, DMSO) δ 9.99 (s, 1H), 9.54 (s, 1 H), 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
Method C
100
Method N3





628


embedded image



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, 1 H), 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, 1 H).

DMSO
420.1 (M + 1)
2.12
Method C
99
Method N4


































1H

Purity
Method


Num-
Starting
Starting

Salt

NMR
Per-
of


ber
Material 1
Material 2
Product
type

1H NMR

Solvent
cent
Coupling







629


embedded image




embedded image




embedded image




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).

DMSO
>98
N5





630


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.20 (s, 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).

DMSO
>98
N5





631


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.20 (s, 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).

DMSO
>98
N5





632


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.22- 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).

DMSO
>98
N5





633


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.20 (s, 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)

DMSO
>98
N5





634


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.20 (s, 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).

DMSO
>98
N5





635


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.27 (s, 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).

DMSO
>98
N5





636


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.13 (s, 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).

DMSO
>98
N5





637


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.10 (s, 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).

DMSO
>98
N5





638


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.16 (s, 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).

DMSO
>98
N5





639


embedded image




embedded image




embedded image



1H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 9.57 (s, 1H), 8.80 (d, J = 1.8 Hz, 1H), 8.76-8.69 (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-
DMSO
>98
N5







7.52 (m, 2H).








640


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.12 (s, 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).

DMSO
>98
N5





641


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 8.85-8.55 (m, 3H), 8.20-7.95 (m, 3H), 7.85-7.20 (m, 7H)

DMSO
>98
N5





642


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.19 (s, 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).

DMSO
>98
N5





643


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.18 (s, 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).

DMSO
>98
N5





644


embedded image




embedded image




embedded image



1H NMR (400 MHz, DMSO) δ 10.14 (s, 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
DMSO
>98
N5







(dd, J = 7.6, 1.6 Hz,










1H), 3.89 (s, 3H),










3.58 (s, 3H).








645


embedded image




embedded image




embedded image



1H NMR (400 MHz, DMSO) δ 10.09 (s, 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
DMSO
>98
N5







Hz, 1H), 3.81 (s,










3H), 3.76 (s, 3H).








646


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 9.99 (s, 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,

DMSO
>98
N5







2H), 3.77-3.66 (m,










6H).








647


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.06- 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).

DMSO
>98
N5





648


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.10 (s, 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).

DMSO
>98
N5





649


embedded image




embedded image




embedded image



1H NMR (400 MHz, DMSO) δ 10.20 (s, 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).
DMSO
>98
N5





650


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.12 (s, 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).

DMSO
>98
N5





651


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.22 (s, 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).

DMSO
>98
N5





652


embedded image




embedded image




embedded image



1H NMR (400 MHz, DMSO) δ 10.05 (s, 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


embedded image




embedded image




embedded image




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).

DMSO
>98
N5





654


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.09 (s, 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


embedded image




embedded image




embedded image




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).

DMSO
>98
N5





656


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.21 (s, 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).

DMSO
>98
N5





657


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.21 (s, 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).

DMSO
>98
N5





658


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.20 (s, 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).

DMSO
>98
N5





659


embedded image




embedded image




embedded image



1H NMR (400 MHz, DMSO) δ 10.06 (s, 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).
DMSO
>98
N5





660


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.15 (s, 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).

DMSO
>98
N5





661


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.06 (s, 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).

DMSO
>98
N5





662


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.11 (s, 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),

DMSO
>98
N5







7.11 (d, J = 8.1 Hz,










1H), 6.13 (s, 2H).








663


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.19 (s, 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).

DMSO
>98
N5





664


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 9.52 (d, J = 1.3 Hz, 1H), 8.89- 8.81 (m, 1H), 8.73- 8.64 (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).

DMSO
>98
N5





665


embedded image




embedded image




embedded image



1H NMR (400 MHz, DMSO) δ 10.19 (s, 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).
DMSO
>98
N5





666


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.57 (s, 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).

DMSO
>98
N5





667


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.78 (s, 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).

DMSO
>98
N5





668


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.49 (s, 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),

DMSO
>98
N5







7.47 (t, J = 7.6 Hz,










1H), 7.29 (d, J =










7.5 Hz, 1H), 2.45










(s, 6H).








669


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.22 (s, 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),

DMSO
>98
N5







2.41 (s, 3H).








670


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.77 (s, 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),

DMSO
>98
N5







7.32 (d, J = 8.2 Hz,










1H), 3.97 (s, 3H),










2.23 (s, 3H).








671


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.77 (s, 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),

DMSO
>98
N5







7.32 (d, J = 8.2 Hz,










1H), 3.97 (s, 3H),










2.23 (s, 3H).








672


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.67 (s, 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,

DMSO
>98
N5







1H), 7.53 (t, J =










9.1 Hz, 1H).








673


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.82 (s, 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 =

DMSO
>98
N5







11.7, 5.9 Hz, 1H),










1.33 (d, J = 6.0 Hz,










6H).








674


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.60 (s, 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,

DMSO
>98
N5







J = 9.1 Hz, 1H).








675


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.51 (s, 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-

DMSO
>98
N5







7.31 (m, 1H).








676


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.63 (s, 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

DMSO
>98
N5





677


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.52 (s, 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).

DMSO
>98
N5





678


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.42 (s, 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), 8.76 (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),

DMSO
>98
N5







7.52 (t, J = 9.1 Hz,










1H).








679


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.47 (s, 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

DMSO
>98
N5







Hz, 1H), 4.02 (s, 3H).








680


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.09 (s, 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,

DMSO
>98
N5





681


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.05 (s, 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,

DMSO
>98
N5







3H).








682


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.09 (s, 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).

DMSO
>98
N5





683


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.10 (s, 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).

DMSO
>98
N5





684


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.16 (s, 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).

DMSO
>98
N5





685


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.21 (s, 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).

DMSO
>98
N5





686


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.18 (s, 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).

DMSO
>98
N5





687


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.18 (s, 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).

DMSO
>98
N5





688


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.14 (s, 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).

DMSO
>98
N5





689


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.13 (s, 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).

DMSO
>98
N5





690


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.14 (s, 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).

DMSO
>98
N5





691


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.45 (s, 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-

DMSO
>98
N5







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


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.38 (s, 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 =

DMSO
>98
N5







7.8, 5.0 Hz, 1H),










7.64-7.46 (m, 4H).








693


embedded image




embedded image




embedded image


3 HCl

1H NMR (400 MHz, DMSO) δ 10.91 (s, 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),

DMSO
>98
N5







3.18 (s, 6H).








694


embedded image




embedded image




embedded image


3 HCl

1H NMR (400 MHz, DMSO) δ 10.99 (s, 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),

DMSO
>98
N5







7.09 (s, 2H), 3.05










(s, 6H).








695


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.67 (s, 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),

DMSO
>98
N5







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


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.48 (s, 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),

DMSO
>98
N5







2.40 (s, 3H).








697


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.68 (s, 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).

DMSO
>98
N5


698


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.47 (s, 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).

DMSO
>98
N5





699


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.12 (s, 1H), 9.59 (s, 1H), 9.10 (d, J = 8.1 Hz, 1H), 9.00-8.86 (m, 2H), 8.50 (s, 1H), 8.22-8.07 (m, 2H), 8.03-7.86 (m, 4H), 7.72 (t, J = 7.9 Hz, 1H), 7.28 (t, J = 7.1 Hz, 1H).

DMSO
>98
Scheme 4 synthesis using method N6 coupling





700


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.64 (s, 1H), 9.21-9.08 (m, 1H), 0.07-8.89 (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).

DMSO
>98
N6





701


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.17 (s, 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).

DMSO
>98
N6





702


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.19 (s, 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).

DMSO
>98
N6





703


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.17 (s, 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).

DMSO
>98
N6





704


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.19 (s, 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,

DMSO
>98
N6







1H), 7.37-7.19 (m,










2H).








705


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.20 (s, 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).

DMSO
>98
N6





706


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 9.64 (d, J = 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).

DMSO
>98
N6





707


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.18 (s, 1H), 9.62 (d, J = 1.6 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).

DMSO
>98
N6





708


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 9.56 (d, J = 1.6 Hz, 1H), 9.04 (d, J = 7.8 Hz, 1H), 8.92 (d, J = 4.8 Hz, 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,

DMSO
>98
N6/F5 followed by G1







1H), 7.63 (t, J =










8.2 Hz, 1H), 7.42 (t,










J = 8.8 Hz, 2H),










7.28-7.15 (m, 1H).








709


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.60 (s, 1H), 9.56 (s, 1H), 9.07 (d, J = 7.9 Hz, 1H), 8.93 (d, J = 4.3 Hz, 1H), 8.77 (d, 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),

DMSO
>98
N6/F5 followed by G1







7.41 (t, J = 8.8 Hz,










2H).








710


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.81(s, 3H), 3.88 (s, 3H), 7.11- 7.71 (m, 9H), 7.91 (d, 1H, J = 8.7 Hz), 8.23 (d, 1H, J = 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)
DMSO
>98
N6/F5 followed by G1





711


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.04 (d, 1H, J = 4.1 Hz), 7.48-7.57 (m, 5H), 7.98 (dd, 1H, J = 7.1, 1.7 Hz), 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)
DMSO
>98
N6/F5 followed by G1





712


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.05 (d, 1H, J = 4.1 Hz), 7.48-7.57 (m, 4H), 7.88 (dd, 1H, J = 7.1, 1.7 Hz), 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)
DMSO
>98
N6/F5 followed by G1





713


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.88 (s, 3H), 7.05-7.51 (m, 9H), 7.95 (d, 1H, J = 8.7 Hz), 8.26 (d, 1H, J = 8.7 Hz), 8.54- 8.88 (m, 3H), 9.38 (s, 1H), 10.19 (s, 1H)
DMSO
>98
N6/F5 followed by G1





714


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.04-7.06 (m, 2H), 7.46-7.76 (m, 8H), 7.95 (d, 2H, J = 8.6 Hz), 8.24 (d, 1H, J = 1.7 Hz), 8.69- 8.87 (m, 3H), 9.56 (s, 1H), 10.18 (s, 1H)
DMSO
>98
N6/F5 followed by G1





715


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.84 (s, 3H), 3.89 (s, 3H), 6.81- 7.56 (m, 2H), 7.40- 7.70 (m, 7H), 7.95 (d, 1H, J = 8.5 Hz), 8.23 (d, 1H, J = 1.5 Hz), 8.69-8.89 (m, 3H), 9.58 (s, 1H), 10.06 (s, 1H)
DMSO
>98
N6/F5 followed by G1





716


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.88 (s, 3H), 7.03-7.06 (m, 1H), 7.50-8.39 (m, 10H), 8.86-8.98 (m, 3H), 9.58 (s, 1H), 10.06 (s, 1H)
DMSO
>98
N6/F5 followed by G1





717


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.02-7.07 (m, 2H), 7.31 (s, 1H), 7.47- 7.56 (m, 5H), 7.81- 8.26 (m, 4H), 8.26- 8.90 (m, 3H), 9.57 (s, 1H), 10.27 (s, 1H)
DMSO
>98
N6/F5 followed by G1





718


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 7.03-7.50 (m, 8H), 7.98 (d, 1H, J = 8.7 Hz), 8.30 (d, 1H, J = 8.7 Hz), 8.48- 8.91 (m, 3H), 9.30 (s, 1H), 10.19 (s, 1H)
DMSO
>98
N6/F5 followed by G1





719


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.88 (s, 3H), 7.03-7.54 (m, 8H), 7.97 (d, 1H, J = 8.7 Hz), 8.28 (d, 1H, J = 8.7 Hz), 8.56- 8.86 (m, 3H), 9.40 (s, 1H), 10.23 (s, 1H)
DMSO
>98
N6/F5 followed by G1





720


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.88 (s, 3H), 7.03-7.52 (m, 8H), 7.95 (d, 1H, J = 8.7 Hz), 8.26 (d, 1H, J = 8.7 Hz), 8.52- 8.85 (m, 3H), 9.38 (s, 1H), 10.17 (s, 1H)
DMSO
>98
N6/F5 followed by G1





721


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 7.05-7.54 (m, 8H), 8.00 (d, 1H, J = 8.7 Hz), 8.27 (d, 1H, J = 8.7 Hz), 8.55- 8.87 (m, 3H), 9.38 (s, 1H), 10.34 (s, 1H)
DMSO
>98
N6/F5 followed by G1





722


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.05-7.53 (m, 7H), 7.93 (s, 1H), 7.96 (d, 1H, J = 8.7 Hz), 8.16 (s, 1H), 8.26 (d, 1H, J = 8.7 Hz), 8.74-8.89 (m, 3H), 9.55 (s, 1H), 10.27 (s, 1H)
DMSO
>98
N6/F5 followed by G1





723


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.88 (s, 3H), 7.03-7.54 (m, 7H), 7.92 (s, 1H), 7.97 (d, 1H, J = 8.7 Hz), 8.28 (d, 1H, J = 8.7 Hz), 8.56-8.85 (m, 3H), 9.40 (s, 1H), 10.25 (s, 1H)
DMSO
>98
N6/F5 followed by G1





724


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.88 (s, 3H), 7.03-7.74 (m, 8H), 7.98 (d, 1H, J = 8.7 Hz), 8.27 (d, 1H, J = 8.7 Hz), 8.52- 8.87 (m, 3H), 9.32 (s, 1H), 10.22 (s, 1H)
DMSO
>98
N6/F5 followed by G1





725


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.05-7.71 (m, 8H), 7.99 (d, 1H, J = 8.6 Hz), 8.30 (d, 1H, J = 8.7 Hz), 8.67- 8.92 (m, 3H), 9.37 (s, 1H), 10.52 (s, 1H)
DMSO
>98
N6/F5 followed by G1





726


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.03-7.71 (m, 9H), 7.99 (d, 1H, J = 8.7 Hz), 8.29 (d, 1H, J = 8.7 Hz), 8.67- 8.92 (m, 3H), 9.37 (s, 1H), 10.52 (s, 1H)
DMSO
>98
N6/F5 followed by G1





727


embedded image




embedded image




embedded image



1H NMR (DMSO-d6 at 70° C.) ppm 3.89 (s, 3H), 7.02-7.52 (m, 8H), 7.90 (d, 1H, J = 8.5 Hz), 7.93 (s, 1H), 7.99 (d, 1H, J = 8.6 Hz), 8.22 (s, 1H), 8.74- 8.91 (m, 3H), 9.52 (s, 1H), 10.23 (s, 1H)
DMSO
>98
N6/F5 followed by G1





728


embedded image




embedded image




embedded image



1H NMR (DMSO-d6) ppm 2.50 (s, 3H), 3.89 (s, 3H), 7.06 (s, 1H), 7.49-7.85 (m, 9H), 8.01-8.96 (m, 4H), 9.58 (s, 1H), 10.50 (s, 1H)
DMSO
>98
N6/F5 followed by G1





729


embedded image




embedded image




embedded image




1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.04 (br s, 1H), 7.22 (s, 1H), 7.49-8.30 (m, 9H), 8.77-8.91 (m, 3H), 9.55 (s, 1H), 10.37 (s, 1H)

DMSO
>98
N6/F5 followed by G1





730


embedded image




embedded image




embedded image




1H NMR (DMSO-d6) ppm 3.89 (s, 3H), 7.04 (s, 1H), 7.49- 8.32 (m, 9H), 8.91- 9.04 (m, 3H), 9.54 (s, 1H), 10.63 (s, 1H)

DMSO
>98
N6/F5 followed by G1





731


embedded image




embedded image




embedded image




1H NMR (DMSO-d6) ppm 3.87 (s, 3H), 7.03 (s, 1H), 7.44- 8.25 (m, 9H), 8.71- 8.84 (m, 3H), 9.52 (s, 1H), 10.23 (s, 1H)

DMSO
>98
N6/F5 followed by G1





732


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 12.02 (s, 1H), 10.53 (s, 1H), 9.49 (s, 1H), 9.02- 8.72 (m, 3H), 8.30 (dd, J = 8.7, 1.6 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).

DMSO
>98
N6/F5 followed by G1





733


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 9.43 (s, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.64 (dd, J = 21.1, 5.9 Hz, 2H), 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).

DMSO
>98
N6/F5 followed by G1





734


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 13.18 (s, 1H), 10.57 (s, 1H), 9.48 (s, 1H), 8.98 (d, J = 1.3 Hz, 1H), 8.78 (t, J = 7.1 Hz, 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,

DMSO
>98
N6/F5 followed by G1







2H), 7.09-7.01 (m,










1H), 3.90 (s, 3H).








735


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 10.11 (s, 1H), 9.51 (d, J = 1.2 Hz, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.71- 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).

DMSO
>98
N6/F5 followed by G1





736


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 10.65 (s, 1H), 10.08 (s, 1H), 9.55 (d, J = 2.0 Hz, 1H), 8.88 (d, J = 1.8 Hz, 1H), 8.76-8.66 (m, 2H), 8.24 (dd, J = 8.7, 1.9 Hz, 1H), 7.94 (d, J8.7 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,

DMSO
>98
N6/F5 followed by G1







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


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 9.40 (s, 1H), 8.86 (d, J = 1.7 Hz, 1H), 8.64 (dd, J = 28.9, 5.8 Hz, 2H), 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,

DMSO
>98
N6/F5 followed by G1







1H), 7.09-6.98 (m,










1H), 3.89 (d, J =










2.9 Hz, 1H), 3.83










(s, 3H).








738


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.56 (s, 1H), 8.88 (d, J = 1.7 Hz, 1H), 8.75 (t, J = 7.2 Hz, 2H), 8.27 (dd, 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-

DMSO
>98
N6/F5 followed by G1







6.98 (m, 1H), 3.89










(s, 3H), 3.83 (s, 3H).








739


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 9.55 (s, 1H), 8.85 (s, 1H), 8.70 (d, J = 5.5 Hz, 2H), 8.24 (dd, J = 8.7, 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),

DMSO
>98
N6/F5 followed by G1







2.29 (s, 3H).








740


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 9.60 (s, 1H), 8.89 (d, J = 1.8 Hz, 1H), 8.71 (dd, J = 12.8, 6.3 Hz, 2H), 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).

DMSO
>98
N6/F5 followed by G1





741


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 9.60 (s, 1H), 8.89 (d, J = 1.7 Hz, 1H), 8.71 (dd, J = 12.7, 6.3 Hz, 2H), 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).

DMSO
>98
N6/F5 followed by G1





742


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 9.73 (s, 1H), 9.37 (s, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.63 (d, J = 3.4 Hz, 1H), 8.54 (d, 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,

DMSO
>98
N6/F5 followed by G1







3H), 3.79 (s, 3H).








743


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.56 (s, 1H), 8.84 (d, J = 1.7 Hz, 1H), 8.71 (d, J = 9.1 Hz, 1H), 8.27 (dd, 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).

DMSO
>98
N6/F5 followed by G1





744


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 9.55 (s, 1H), 8.87 (d, J = 26.7 Hz, 3H), 8.31 (dd, J = 8.7, 1.7 Hz, 2H), 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).

DMSO
>98
N6/F5 followed by G1





745


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 14.27 (s, 1H), 9.79 (s, 1H), 9.32 (d, J = 8.4 Hz, 1H), 8.98 (d, J = 5.2 Hz, 1H), 8.34 (dd, 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,

DMSO
>98
N6/F5 followed by G1







1H), 7.08 (dd, J =










8.2, 1.8 Hz, 1H),










3.86 (s, 3H).








746


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.36 (s, 1H), 9.11 (s, 1H), 9.00 (dd, J = 23.2, 6.7 Hz, 2H), 8.41 (d, J = 9.1 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 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).

DMSO

N6/F5 followed by G1





747


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 12.92 (d, J = 17.9 Hz, 1H), 9.64 (s, 1H), 9.09 (d, J = 7.9 Hz, 1H), 8.92 (d, J = 4.9 Hz, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.38 (s, 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 =

DMSO
>98
N6/F5 followed by G1







8.2, 1.8 Hz, 2H),










3.89 (s, 3H).






































Pu-
Method











1H

rity
of




Num-
Starting
Starting

Salt

NMR
per-
Cou-

LCMS


ber
Material 1
Material 2
Product
type

1H NMR

Solvent
cent
pling
LCMS
Method





748


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.71 (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

DMSO
>98
Method N6









Hz, 1H).










749


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.12 (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).

DMSO
>98
Method N6







750


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 9.55 (d, J = 1.5 Hz, 1H), 9.33 (s, 1 H), 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 =

DMSO
>98
Method N6









8.7 Hz, 1H), 8.01-












7.93 (m, 1H),












7.84 (d, J = 9.0 Hz,












1H), 7.57 (dd,












J = 19.7, 9.1 Hz,












1H), 4.03 (s, 3H).










751


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.57 (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,

DMSO
>98
Method N6









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


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.05 (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,

DMSO
>98
Method N6









2H), 4.02 (s, 3H).










753


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.17 (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


embedded image




embedded image




embedded image




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 =

DMSO
>98
Method N6









8.1 Hz, 1H), 6.13












(s, 2H).










755


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 11.36 (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, 1 H), 8.19 (ddd, J = 13.0, 7.5, 2.5 Hz, 1H), 8.09 (d,

DMSO
>98
Method N6









J = 8.8 Hz, 1 H),












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


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.19 (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),

DMSO
>98
Method N6









7.62-7.53 (m, 4H),












7.47 (t, J = 7.4












Hz, 1H).










757


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.84 (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).

DMSO
>98
Method N6







758


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.78 (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).

DMSO
>98
Method N6







759


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.41 (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).

DMSO
>98
Method N6







760


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.51 (s, 1H), 9.55 (d, J = 1.6 Hz, 1H), 9.04 (d, J = 8.1 Hz, 1 H), 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).

DMSO
>98
Method N6







761


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.51 (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-

DMSO
>98
Method N6









7.44 (m, 2H), 7.39-












7.28 (m, 1H).










762


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.75 (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 =

DMSO
>98
Method N6









12.9, 1.6 Hz, 2H),












6.99-6.90 (m,












1H), 3.90 (s, 3H).










763


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.54 (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,

DMSO
>98
Method N6









3H), 3.89 (s, 3H).










764


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.68 (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

DMSO
>98
Method N6









(m, 2H).










765


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.43 (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,

DMSO
>98
Method N6









J = 8.1 Hz, 1H),












6.12 (s, 2H).










766


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.33 (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. 1 H), 3.95 (s, 3H).

DMSO
>98
Method N6







767


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.71 (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).

DMSO
>98
Method N6







768


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.53 (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).

DMSO
>98
Method N6







769


embedded image




embedded image




embedded image


3 HCl

1H NMR (400 MHz, DMSO) δ 11.13 (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),

DMSO
>98
Method N6









7.93-7.84 (m, 1H),












7.53 (dd, J =












19.7, 9.2 Hz, 1H).










770


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.69 (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-

DMSO
>98
Method N6









7.47 (m, 4H).










771


embedded image




embedded image




embedded image


3 HCl

1H NMR (400 MHz, DMSO) δ 10.89 (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).

DMSO
>98
Method N6







772


embedded image




embedded image




embedded image


3 HCl

1H NMR (400 MHz, DMSO) δ 10.67 (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-

DMSO
>98
Method N6









7.74 (m, 1H), 7.56












(dd, J = 19.7, 9.2












Hz, 1H).










773


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.81 (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).

DMSO
>98
Method N6







774


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.32 (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).

DMSO
>98
Method N6







775


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.59 (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).

DMSO
>98
Method N6







776


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.46 (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,

DMSO
>98
Method N6












2H), 7.65-7.48 (m,












2H), 7.39-












7.25 (m, 1H).










777


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.62 (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),

DMSO
>98
Method N6









7.41 (t, J = 8.8 Hz,












1H).










778


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.65 (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).

DMSO
>98
Method N6







779


embedded image




embedded image




embedded image


HCl

1H NMR (400 MHz, DMSO) δ 10.40 (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,

DMSO
>98
Method N6









2H), 7.69-7.49 (m,












2H).










780


embedded image




embedded image




embedded image


2 HCl

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-

DMSO
>98
Method N6









7.35 (m, 1H).










781


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 10.47 (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).

DMSO
>98
Method N6







782


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.20 (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,

DMSO
>98
Method N6









J = 10.4, 4.8 Hz,












2H), 7.53-7.46












(m, 2H), 7.34-7.25












(m, 1H).










783


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.22 (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).

DMSO
>98
Method N6







784


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.15 (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).

DMSO
>98
Method N6







785


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 MHz, DMSO) δ 13.10 (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 =

DMSO
>98
Method N6









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


embedded image




embedded image




embedded image


2 HCl
1H NMR (DMSO- d6) ppm 9.79 (d, J = 1.56 Hz, 1H), 9.26 (brd, J = 7.2 Hz, 1H), 9.00-8.90 (brm, 2H), 8.18 (d, J = 8.64 Hz, 1H), 8.11 (d, J = 8.64 Hz, 1 H), 8.01 (brt, J = 6.28 Hz, 1H), 7.86-7.80 (brm, 1H), 7.72 (d, J = 3.96 Hz, 1H),
DMSO
>98
N6 using Na2CO3 instead of K3PO4









7.53-7.46 (m, 2H),












7.37-7.32 (brm,












1H). The 1H of












2HCl and NH-












were not observed.










787


embedded image




embedded image




embedded image



1H NMR (DMSO- d6) ppm 12.63 (brs, 1H), 9.80 (d, J = 1.64 Hz, 1H), 9.05- 8.91 (brm, 2H), 8.76 (brd, J = 4.6 Hz, 1H), 8.10 (brd, J = 8.64 Hz, 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
DMSO
>98
N6 using Na2CO3 instead of K3PO4









(brs, 1H), 2.35 (brs,












3H).










788




embedded image



1H NMR (300 MHz, CD3OD) δ 9.40 (s, 1H), 8.65 (d, J = 8.0 Hz, 1H), 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).
CD3OD
99
Method N3
463.0 (M + 1)
Method C





789




embedded image





99
Method N3
434.0 (M + 1)
Method C





790




embedded image





99
Method N3
436.0 (M + 1)
Method C





791




embedded image




1H-NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1H), 9.64 (s, 1H), 9.58 (s, 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,

DMSO
95
Method N1
422.2 (M + 1)
Method B (NH4HCO3)







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




embedded image


HCl

1H-NMR (400 MHz, DMSO-d6): δ 13.42 (s, 1H), 8.99 (d, J = 8.0 Hz, 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).

DMSO
95
Method N1
404.0 (M + 1)
Method B (NH4HCO3)





793




embedded image


HCl

1H-NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 9.13 (d, J = 2.0 Hz, 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,

DMSO
95
Method N1
445.0 (M + 1)
Method B (NH4HCO3)







2.4 Hz, 1H), 7.22












(d, J = 8.0 Hz, 1 H),












4.28 (q, J = 6.8












Hz, 2H), 1.47 (t,












J = 6.8 Hz, 3H).










794




embedded image


2HCl

DMSO
95
Method N1
382.5 (M + 1)
Method C





795




embedded image


3HCl
1H-NMR (300 MHz, DMSO): δ 13.10 (s, 1H), 9.61 (s, 1H), 9.12 (d, 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).
DMSO
95
Method N1
449.4 (M + 1)
Method C





796




embedded image


3HCl
1H-NMR (300 MHz, DMSO): δ 12.79 (s, 1H), 9.54 (d, J = 1.6 Hz, 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, 1 H), 7.68 (t, J = 7.1 Hz, 1H), 7.32 (t,
DMSO
95
Method N1
419.1 (M + 1)
Method C







J = 7.2 Hz, 1H).










797




embedded image


3HCl
1H-NMR (300 MHz, DMSO): δ 12.81 (s, 1H), 9.54 (s, 1H), 9.45 (s, 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,
DMSO
95
Method N1
419.1 (M + 1)
Method C







1H), 7.32 (t, J =












7.2 Hz, 1H).










798




embedded image


2HCl
1H-NMR (300 MHz, DMSO): δ 13.20 (s, 1H), 9.62 (s, 1H), 9.13 (d, 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,
DMSO
95
Method N1
448.1 (M + 1)
Method C







3H).










799




embedded image



1H-NMR (300 MHz, DMSO): δ 13.13 (s, 1H), 9.60 (d, J = 1.4 Hz, 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 =
DMSO
95
Method N1
422.2 (M + 1)
Method C







7.1 Hz, 1H), 3.94 (s,












3H).










800


embedded image




embedded image




embedded image




1H NMR (400 MHz, DMSO) δ 10.08 (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,

DMSO
>98
N5









2H).










801


embedded image




embedded image




embedded image


MsOH
1H NMR (DMSO- d6) ppm 9.78 (brs, 1H), 9.20- 8.80 (br, 3H), 8.14 (brd, J = 8.64 Hz, 1H), 8.04 (d, J = 8.64 Hz, 1H), 7.83 ′brm, 2H), 7.52- 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.
DMSO
>98
N6 using Na2CO3 instead of K3PO4




























Number
PRODUCT
Salt type
Molecular Mass

1H-NMR


1H-NMR Solvent

LCMS
LCMS Protocol
Purity percent
Method for Coupling







802


embedded image



494.87

1H-NMR (400 MHz, DMSO-d6): δ 10.18 (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


embedded image



458.89

1H-NMR (400 MHz, DMSO-d6): δ 10.14 (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


embedded image



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


embedded image



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


embedded image



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


embedded image



456.9

1H-NMR (400 MHz, DMSO-d6): δ 10.10 (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











embedded image




embedded image


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).




embedded image


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







Salt
Molecular


1H-NMR


Retention
LCMS
Purity
Method for


Number
Product
type
Mass

1H-NMR

Solvent
LCMS
Time (min.)
Protocol
Percent
Coupling







808


embedded image



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 (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,
DMSO
477.4 (M + 1)
1.68
Method C
95
Method S





809


embedded image



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, 2H), 7.32 (dd, J = 9.1, 2.2 Hz, 1H), 7.20 (s, 1H), 6.38 (s
DMSO
493 (M + 1)
1.97
Method C
100
Method S





810


embedded image



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, 2.2 Hz, 1H), 7.25 (s, 1H), 6.40 (t
DMSO
423.9 (M + 1)
2.16
Method C
100
Method S





811


embedded image



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, 1H), 6.77 (t, J = 5.3 Hz, 1H), 6.72
DMSO
464.0 (M + 1)
2.19
Method C
100
Method S





812


embedded image



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), 6.79 (d, J = 2.1 Hz,
DMSO
449.9 (M + 1)
2.12
Method C
100
Method S





813


embedded image



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), 3.42
DMSO
409.9 (M + 1)
1.86
Method C
100
Method S





814


embedded image



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, J = 9.1 Hz, 1H), 7.19 (s, 1H), 6.38 (s
DMSO
464.0 (M + 1)
2.19
Method C
95
Method S





815


embedded image



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, 1H), 7.57-7.47 (m, 3H), 4.25 (t, J = 5.8 Hz, 2H).
DMSO
480.0 (M + 1)
2.09
Method C
91
Method T





816


embedded image



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 = 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).
DMSO
423.9 (M + 1)

Method C
99
Method S





817


embedded image



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 = 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).
DMSO
438.1 (M + 1)

Method C
99
Method S





818


embedded image



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, 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, 7.7 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).
DMSO
449.9 (M + 1)

Method C
94
Method S





819


embedded image




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), 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).
DMSO
463.9 (M + 1)

Method C
95
Method S











embedded image




embedded image


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).




embedded image


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).




embedded image


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













1H-


Reten-

Puri-
Meth-





Molecu-

NMR

tion
LCMS
ty
od for


Num-

Salt
lar

Sol-

Time
Proto-
Per-
Coupl-


ber
Product
type
Mass

1H-NMR

vent
LCMS
(min.)
col
cent
ing





820


embedded image



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, J = 7.6 Hz, 1H), 4.29- 4.16 (m, 2H), 3.65-3.51 (m
DMSO
485 (M + 1)
1.71
Method C
100
Methods V, G4





821


embedded image



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 (m, 2H), 3.07-2.77 (m, 3H), 2.2
DMSO
471 (M + 1)
1.75
Method C
100
Methods V, G4 followed by acylation with acetyl chloride/ TEA in DCM at rt.





822


embedded image



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, 3H).
DMSO
443 (M + 1)
1.63
Method C
100
Method W





823


embedded image


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, 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).
DMSO
526 (M + 1)
2.02
Method C
100
Method W





824


embedded image


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), 8.07-7.93 (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
DMSO
526 (M + 1)
2.25
Method C
100
Methods V, G4





825


embedded image



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, 1H), 7.17 (d, J = 8.3 Hz, 1H), 4.69 (s, 2H), 2.71 (d, J = 4.5 Hz, 3H).
DMSO
470 (M + 1)
2.04
Method C
100
Method W





826


embedded image



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, 1H), 5.03 (s, 2H), 3.06 (s, 3H), 2.88 (s, 3H).
DMSO
484 (M + 1)
1.71
Method D
1.00
Method W





827


embedded image


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, 2H), 4.41- 4.27 (m, 2H), 3.55-3.43 (m, 2H), 3.34-3.20 (m, 2H), 3.03- 2.
DMSO
492 (M + 1)
1.81
Method C
1.00
Methods V, G4





828


embedded image



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
Method D
1.00
Method W





829


embedded image



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
Method C
98
Method W





830


embedded image



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, 4H), 1.37-0.88 (m, 6H).
DMSO
480 (M + 1)
2.20
Method C
100
Method W





831


embedded image


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), 4.39- 4.18 (m, 2H), 4.05-3.89 (m, 2H), 3.79 (t, J = 11.9 Hz, 2H), 3.53-
DMSO
508 (M + 1)
2.14
Method C
100
Methods V, G4





832


embedded image



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
Method C
100
Method W





833


embedded image


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), 8.12-7.89 (m, 3H), 7.63 (d, J = 9.1 Hz, 1H), 7.54 (t, J = 9.1 Hz, 1H), 4.45-4.26 (m,
DMSO
494 (M + 1)
2.10
Method C
100
Methods V, G4





834


embedded image



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
Method D
100
Method U





835


embedded image



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
Method C
100
Method W





836


embedded image



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 (s, 1H), 3.79-3.40 (m, 8H).
DMSO
485 (M + 1)
1.72
Method C
 91
Method W





837


embedded image



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
Method C
100
Method W





838


embedded image



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
Method C
100
Method U





839


embedded image


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, 1H), 6.55 (d, J = 9.5 Hz, 1H).
DMSO
443.9 (M + 1)
1.87
Method C
100
Method U





840


embedded image


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, 1H), 6.52 (d, J = 9.6 Hz, 1H), 2.71 (s, 3H).
DMSO
458.0 (M + 1)
2.12
Method D
100
Method U





841


embedded image



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
Method C
 96
Method X





842


embedded image



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
Method C
100
Method X





843


embedded image



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 = 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).
DMSO
426.2
2.46
Method C
100
Method X





844


embedded image



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, 2.5 Hz, 1H), 7.64- 7.47 (m, 3H), 5.37 (s, 2H).
DMSO
458.1, 460.1 (M + 1) 229.6, 230.3 (m/2 + 1)

Method A
 95
Method X





845


embedded image



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, 3H), 7.53-7.30 (m, 3H), 6.82-6.68 (m, 1H), 5.07 (s, 2H), 3.71 (s, 3H).
DMSO
488.1, 490.1 (M + 1) 244.6, 245.4 (M/2 + 1)

Method A
 95
Method X














Starting
Starting



Number
Material R1
Material R3
Product





846


embedded image




embedded image




embedded image







847


embedded image




embedded image




embedded image







848


embedded image




embedded image




embedded image







849


embedded image




embedded image




embedded image







850


embedded image




embedded image




embedded image







851


embedded image




embedded image




embedded image







852


embedded image




embedded image




embedded image







853


embedded image




embedded image




embedded image







854


embedded image




embedded image




embedded image







855


embedded image




embedded image




embedded image







856


embedded image




embedded image




embedded image







857


embedded image




embedded image




embedded image







858


embedded image




embedded image




embedded image







859


embedded image




embedded image




embedded image







860


embedded image




embedded image




embedded image







861


embedded image




embedded image




embedded image







862


embedded image




embedded image




embedded image







863


embedded image




embedded image




embedded image







864


embedded image




embedded image




embedded image







865


embedded image




embedded image




embedded image







866


embedded image




embedded image




embedded image







867


embedded image




embedded image




embedded image







868




embedded image







869




embedded image







870




embedded image







871




embedded image







872




embedded image







873




embedded image







874




embedded image







875




embedded image







876




embedded image







1757


embedded image




embedded image




embedded image




















Salt


1H NMR

Purity
Method



Number
Type

1H NMR

Solvent
percent
of Coupling






846
HCl
1H NMR (400 MHz, DMSO) δ 9.31 (d, J = 1.7 Hz,
DMSO
>98
Method X using K2CO3 instead of





1H), 8.83-8.76 (m, 1H), 8.76-8.67 (m, 1H),


Cs2CO3





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).






847

1H NMR (400 MHz, DMSO) δ 9.28 (dd, J = 2.2, 0.8
DMSO
>98
Method X using K2CO3 instead of Cs2CO3





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).






848


1H NMR (400 MHz, CDCl3) δ 9.45 (dd, J = 2.1, 0.8

CDCl3
>98
Method X using K2CO3 instead of Cs2CO3





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).






849
2 HCl
1H NMR (300 MHz, DMSO) δ 13.01-11.72 (m,
DMSO
>98
W





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).






850
2 HCl
1H NMR (300 MHz, DMSO) δ 9.74 (d, J = 1.8 Hz,
DMSO
>98
W





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).






851
2 HCl
1H NMR (300 MHz, DMSO) δ 12.67 (s, 1H), 9.31-
DMSO
>98
W





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).






852
3 HCl
1H NMR (300 MHz, DMSO) δ 9.56 (d, J = 1.8 Hz,
DMSO
>98
W





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).






853
3 HCl
1H NMR (300 MHz, DMSO) δ 9.56 (d, J = 1.8 Hz,
DMSO
>98
W





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).






854
2 HCl
1H NMR (300 MHz, DMSO) δ 9.55 (d, J = 1.8 Hz,
DMSO
>98
W





1H), 9.30-99.18 (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).






855
2 HCl
1H NMR (300 MHz, DMSO) δ 9.55 (d, J = 1.7 Hz,
DMSO
>98
W





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).






856
2 HCl
1H NMR (300 MHz, DMSO) δ 9.54 (d, J = 1.7 Hz,
DMSO
>98
W





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).






857
HCl

1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.49

DMSO
>98
Method W





(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).






858


1H NMR (400 MHz, DMSO) δ 9.77 (br s, J = 81.7

DMSO
>98
Method W





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).






859
HCl

1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.50

DMSO
>98
Method W





(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).






860
2 HCl

1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 9.51

DMSO
>98
Method W





(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).






861
3 HCl

1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 9.50

DMSO
>98
Method W





(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, 2H),








7.68 (dd, J = 9.1, 2.3 Hz, 1H), 7.55 (dd, J = 19.5,








9.3 Hz, 1H), 4.67 (s, 2H), 3.23-3.05 (m, 6H),








2.10-1.78 (m, 4H).






862
2 HCl

1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 9.49

DMSO
>98
Method W





(d, J = 1.6 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).






863
2 HCl

1H NMR (400 MHz, CDCl3) δ10.71 (s, 1H), 9.80 (s,

DMSO
>98
Method W





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).






864
2 HCl
1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.50
DMSO
>98
Method W





(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).






865
3 HCl

1H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 9.51

DMSO
>98
Method W





(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).






866
4 HCl

1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.50

DMSO
>98
Method W





(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).






867
HCl
1H NMR (300 MHz, DMSO) d 9.58 (s, 1H), 9.05 (d,
DMSO
94
Method X (K2CO3,





J = 8.2 Hz, 1H), 8.98 (d, J = 8.1 Hz, 1H), 8.88 (d,


DMF-THF (1:1), rt)





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).






868
2 HCl
1H NMR (300 MHz, DMSO) δ 13.07 (s, 1H), 9.59
DMSO
99
Method W





(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).






869
3HCl

1H-NMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 9.40

DMSO
98
Method X





(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).






870
2HCl

1H-NMR (400 MHz, CD3OD): δ 9.62 (d, J = 6.9 Hz,

MeOD
95
Method W





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).






871
4HCl

1H-NMR (400 MHz, DMSO-d6): δ 12.96 (s, 1H),

DMSO-
95
Method X





9.59 (s, 1H), 9.24 (d, J = 8.1 Hz, 1H), 9.00 (s,
d6







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).






872
2HCl

1H-NMR (400 MHz, DMSO-d6): δ 12.82 (s, 1H),

DMSO
95
Method X





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).






873
3HCl

1H-NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H),

DMSO
95
Method X





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).






874
2HCl

1H-NMR (400 MHz, DMSO-d6): δ 12.89 (s, 1h),

DMSO
95
Method X





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).






875
3HCl

1H-NMR (400 MHz, DMSO-d6): δ 12.88 (s, 1H),

DMSO
95
Method X





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).






876
CF3COOH

1H-NMR (400 MHz, DMSO-d6): δ 12.93 (s, 1H),

DMSO
95
Method W





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).






1757 


1H NMR (400 MHz, DMSO) δ 9.32-9.27 (m, 1H),

DMSO
>98
Method W using K2CO3





8.66 (dd, J = 4.8, 1.7 Hz, 1H), 8.64-8.60 (m,


instead of Cs2CO3





1H), 8.50-8.43 (m, 1H), 8.30-8.03 (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).











embedded image




embedded image


Method Y: 2-Amino-N-cyclohexyl-benzamide (ii-b)

To a dry reaction vial was added cyclohexylamine (40 μmol, 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 μLl) 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


embedded image


489
490
Methods Y, Z





878


embedded image


453
454
Methods Y, Z





879


embedded image


495
496
Methods Y, Z





880


embedded image


495
496
Methods Y, Z





881


embedded image


491
492
Methods Y, Z





882


embedded image


491
492
Methods Y, Z





883


embedded image


493
494
Methods Y, Z





884


embedded image


467
468
Methods Y, Z





885


embedded image


441
442
Methods Y, Z





886


embedded image


529
530
Methods Y, Z





887


embedded image


543
544
Methods Y, Z





888


embedded image


543
544
Methods Y, Z





889


embedded image


543
544
Methods Y, Z





890


embedded image


487
488
Methods Y, Z





891


embedded image


493
494
Methods Y, Z





892


embedded image


467
468
Methods Y, Z





893


embedded image


441
442
Methods Y, Z





894


embedded image


529
530
Methods Y, Z





895


embedded image


543
544
Methods Y, Z





896


embedded image


543
544
Methods Y, Z





897


embedded image


543
544
Methods Y, Z





898


embedded image


487
488
Methods Y, Z





899


embedded image


467
468
Methods Y, Z





900


embedded image


501
502
Methods Y, Z





901


embedded image


465
466
Methods Y, Z





902


embedded image


435
436
Methods Y, Z





903


embedded image


519
520
Methods Y, Z





904


embedded image


487
488
Methods Y, Z





905


embedded image


487
488
Methods Y, Z





906


embedded image


467
468
Methods Y, Z





907


embedded image


501
502
Methods Y, Z





908


embedded image


465
466
Methods Y, Z





909


embedded image


435
436
Methods Y, Z





910


embedded image


519
520
Methods Y, Z











embedded image




embedded image


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


embedded image


362
363
Method Z





912


embedded image


358
359
Method Z





913


embedded image


396
397
Method Z





914


embedded image


392
393
Method Z





915


embedded image


388
389
Method Z





916


embedded image


372
373
Method Z





917


embedded image


388
389
Method Z





918


embedded image


342
343
Method Z





919


embedded image


353
354
Method Z





920


embedded image


416
417
Method Z





921


embedded image


396
397
Method Z





922


embedded image


396
397
Method Z





923


embedded image


356
357
Method Z





924


embedded image


364
365
Method Z





925


embedded image


372
373
Method Z





926


embedded image


392
393
Method Z





927


embedded image


376
377
Method Z





928


embedded image


426
427
Method Z





929


embedded image


407
408
Method Z





930


embedded image


430
431
Method Z





931


embedded image


440
441
Method Z





932


embedded image


392
393
Method Z





933


embedded image


380
381
Method Z





934


embedded image


380
381
Method Z





935


embedded image


380
381
Method Z





936


embedded image


434
435
Method Z





937


embedded image


421
422
Method Z





938


embedded image


378
379
Method Z





939


embedded image


376
377
Method Z





940


embedded image


387
388
Method Z





941


embedded image


414
415
Method Z





942


embedded image


392
393
Method Z





943


embedded image


380
381
Method Z





944


embedded image


390
391
Method Z





945


embedded image


428
429
Method Z





946


embedded image


428
429
Method Z





947


embedded image


391
392
Method Z





948


embedded image


356
357
Method Z





949


embedded image


377
378
Method Z





950


embedded image


392
393
Method Z





951


embedded image


368
369
Method Z





952


embedded image


397
398
Method Z





953


embedded image


441
442
Method Z





954


embedded image


379
380
Method Z





955


embedded image


401
402
Method Z





956


embedded image


383
384
Method Z





957


embedded image


382
383
Method Z





958


embedded image


379
380
Method Z





959


embedded image


393
394
Method Z





960


embedded image


411
412
Method Z





961


embedded image


379
380
Method Z





962


embedded image


370
371
Method Z





963


embedded image


385
386
Method Z





964


embedded image


427
428
Method Z





965


embedded image


395
396
Method Z





966


embedded image


379
380
Method Z





967


embedded image


402
403
Method Z





968


embedded image


384
385
Method Z











embedded image




embedded image


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


Number
Product
Mass
(M + 1)
Coupling







969


embedded image


366
367
Method Z





970


embedded image


362
363
Method Z





971


embedded image


366
367
Method Z





972


embedded image


346
347
Method Z





973


embedded image


392
393
Method Z





974


embedded image


392
393
Method Z





975


embedded image


419
420
Method Z





976


embedded image


392
393
Method Z





977


embedded image


346
347
Method Z





978


embedded image


350
351
Method Z





979


embedded image


350
351
Method Z





980


embedded image


350
351
Method Z





981


embedded image


376
377
Method Z





982


embedded image


420
421
Method Z





983


embedded image


360
361
Method Z





984


embedded image


360
361
Method Z





985


embedded image


360
361
Method Z





986


embedded image


360
361
Method Z





987


embedded image


368
369
Method Z





988


embedded image


368
369
Method Z





989


embedded image


380
381
Method Z





990


embedded image


376
377
Method Z





991


embedded image


396
397
Method Z





992


embedded image


380
381
Method Z





993


embedded image


430
431
Method Z





994


embedded image


392
393
Method Z





995


embedded image


396
397
Method Z





996


embedded image


380
381
Method Z





997


embedded image


382
383
Method Z





998


embedded image


384
385
Method Z





999


embedded image


465
466
Method Z





1000 


embedded image


357
358
Method Z





1001 


embedded image


396
397
Method Z





1002 


embedded image


425
426
Method Z





1003 


embedded image


380
381
Method Z





1004 


embedded image


434
435
Method Z





1005 


embedded image


396
397
Method Z





1006 


embedded image


384
385
Method Z





1007 


embedded image


446
447
Method Z





1008 


embedded image


415
416
Method Z





1009 


embedded image


381
382
Method Z





1010 


embedded image


381
382
Method Z





1011 


embedded image


396
397
Method Z











embedded image


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-l)

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









Salt
Molecular



Number
PRODUCT
type
Mass

1H-NMR






1012


embedded image



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, J = 7.2 Hz, 1H).





1013


embedded image



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).





1014


embedded image



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)





1015


embedded image



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), 827 (dd, J = 6.8, 2.6 Hz, 1H), 7.76-7.93 (m, 3H), 7.54-7.57 (m, 2H).















Number

1H-NMR Solvent

LCMS
LCMS Protocol
Purity percent
Method for Coupling





1012
DMSO
348.1
Method B
95
Method C, G3




(M + 1)
(NH4HCO3)




1013
DMSO
371.0
Method B
95
Method C, G3




(M + 1)
(NH4HCO3)




1014
DMSO
389.0
Method B
95
Method C, G3




(M + 1)
(NH4HCO3)




1015
DMSO
357.0, 359.0
Method B
95
Method C, G3




(M + 1)
(NH4HCO3)











embedded image




embedded image


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 x 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 (3eq) 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











1H NMR

Purity
Method of


Number
Product

1H NMR

Solvent
percent
Coupling





1016


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image



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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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














Starting
Starting



Number
Material R1
Material R3
Product





1065


embedded image




embedded image




embedded image







1066


embedded image




embedded image




embedded image







1067


embedded image




embedded image




embedded image







1068


embedded image




embedded image




embedded image







1069


embedded image




embedded image




embedded image







1070


embedded image




embedded image




embedded image







1071


embedded image




embedded image




embedded image







1072




embedded image





















1H NMR





Number
Salt Type

1H NMR

Solvent
Purity percent
Method of Coupling





1065


1H NMR (DMSO-d6) ppm 4.52 (d, 2H, J = 5.8 Hz),

DMSO
>98
Method Y, Z




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)





1066


1H NMR (DMSO-d6) ppm 4.49 (d, 2H, J = 5.6 Hz),

DMSO
>98
Method Y, Z




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)





1067


1H NMR (DMSO-d6) ppm 4.58 (d, 2H, J = 5.7 Hz),

DMSO
>98
Method Y, Z




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)





1068


1H NMR (DMSO-d6) ppm 4.47 (d, 2H, J = 5.6 Hz),

DMSO
>98
Method Y, Z




7.30 (br s, 5H), 7.54 (t, J = 7.7 Hz, 1 H), 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)





1069


1H NMR (DMSO-d6) ppm 4.57 (d, 2H, J = 5.6 Hz),

DMSO
>98
Method Y, Z




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)





1070


1H NMR (DMSO-d6) ppm 4.50 (d, 2H, J = 5.5 Hz),

DMSO
>98
Method Y, Z




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)





1071


1H NMR (DMSO-d6) ppm 3.90 (s, 3H), 4.56 (d,

DMSO
>98
Method Y, Z




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)





1072
HCl

1H-NMR (400 MHz, DMSO-d6): δ 12.17 (s, 1H),

DMSO
 95
Method Y, Z




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).











embedded image




embedded image


embedded image


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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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











embedded image




embedded image


(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).




embedded image


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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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, J = 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


embedded image



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


embedded image



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, C





1088


embedded image



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


embedded image



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, J = 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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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











embedded image




embedded image


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-


1H-




Method


Num-

Salt
ular

NMR

LCMS
Purity
for


ber
PRODUCT
type
Mass

1H-NMR

Solvent
LCMS
Protocol
percent
Coupling







1098


embedded image



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, 1 H), 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


embedded image



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











embedded image




embedded image


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













Pu-
Method





Molec-


1H-



rity
for


Num-

Salt
ular

NMR

LCMS
per-
Cou-


ber
PRODUCT
type
Mass

1H-NMR

Solvent
LCMS
Protocol
cent
pling
























1100


embedded image



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


embedded image



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, 1 H), 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


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



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, 1 H), 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


embedded image





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 + 1)
Method B (NH4HCO3)
95
Method J











embedded image




embedded image


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→40:1) 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








Molec-


1H-




Method


Num-

Salt
ular

NMR

LCMS
Purity
for


ber
PRODUCT
type
Mass

1H-NMR

Solvent
LCMS
Protocol
percent
Coupling
























1108


embedded image



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


embedded image



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


embedded image



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


embedded image



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











embedded image




embedded image


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 x 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








Molec-


1H-




Method


Num-

Salt
ular

NMR

LCMS
Purity
for


ber
PRODUCT
type
Mass

1H-NMR

Solvent
LCMS
Protocol
percent
Coupling
























1112


embedded image


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


embedded image



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


embedded image




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











embedded image




embedded image


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).




embedded image




embedded image


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











Mass



Num-
Starting
Starting

Salt
Exact
Found
Purity


ber
Material 1
Material 2
Product
Type
Mass
(M + 1)
(%)







1116


embedded image




embedded image




embedded image



468
469
98





1117


embedded image




embedded image




embedded image



454
455
98





1118


embedded image




embedded image




embedded image



456
457
98





1119


embedded image




embedded image




embedded image



468
469
98





1120


embedded image




embedded image




embedded image



482
483
98





1121


embedded image




embedded image




embedded image


TFA
496
497
98





1122


embedded image




embedded image




embedded image



465
466
98





1123


embedded image




embedded image




embedded image



505
506
98











embedded image


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 2HCl 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







Number
Starting Material 1
Starting Material 2
Product





1124


embedded image




embedded image




embedded image







1125
NH3


embedded image




embedded image







1126


embedded image




embedded image




embedded image
























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), 7.52-7.42 (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),








7.80 (d, J = 7.16 Hz, 2H), 7.63 (m,








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)











embedded image




embedded image


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







Num-
Starting
Starting



ber
Material R1
Material R3
Product





1127


embedded image




embedded image




embedded image







1128


embedded image




embedded image




embedded image







1129


embedded image




embedded image




embedded image
























Method




Salt


1H NMR

Purity
of



Number
Type

1H NMR

Solvent
percent
Coupling






1127
3 HCl

1H NMR (400 MHz, DMSO) δ 10.60

DMSO
>98
Method AO





(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).






1128
3 HCl

1H NMR (400 MHz, DMSO) δ 10.81

DMSO
>98
Method AO





(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, J = 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).






1129
2 HCl

1H NMR (400 MHz, DMSO) δ 10.87

DMSO
>98
Method AO





(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).











embedded image


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 2HCl and NH—were not observed.




embedded image


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 2HCl was not observed.




embedded image


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).




embedded image


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).




embedded image


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).




embedded image


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).




embedded image


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).




embedded image


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, NM+=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, lmL). 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).




embedded image


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



embedded image


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 x 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, 2eq.) 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













Pu-






Molec-




rity
Method


Num-

Salt
ular


1H-NMR


LCMS
per-
for


ber
Product
type
Mass

1H-NMR

Solvent
LCMS
Protocol
cent
Coupling
























1140


embedded image



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


embedded image



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,
DMSO
386.0, 388.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






J = 8.8, 2.0 Hz,











1H), 7.56











(t, J = 9.2 Hz,











1H).










1142


embedded image



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),
CD3OD
370.0, 372.1 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






7.33 (q, J =











9.2 Hz, 1H).










1143


embedded image



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 =
CD3OD
377.1, 379.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






7.6 Hz, 1H).










1144


embedded image



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


embedded image



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,
DMSO
400.0, 402.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






J = 8.0, 1.6











Hz, 1H).










1146


embedded image



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


embedded image



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,
DMSO
378.1, 380.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






1H), 7.77 (t,











J = 8.8 Hz,











1H), 7.26 (t,











J = 7.6 Hz,











1H).










1148


embedded image



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),
DMSO
382.1, 384.1 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






7.61 (t, J =











9.0 Hz, 1H),











7.49 (dd, J =











9.2, 2.3 Hz,











1H) 4.00 (s,











3H).










1149


embedded image



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 =
DMSO
396.1, (M + 1), 397.2 (M + 2)
Method B (NH4HCO3)
95
Method C, G1






8.0, 2.2 Hz,











1H), 3.98 (s,











3H).










1150


embedded image



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,
DMSO
384.1, (M + 1)
Method B (NH4HCO3)
95
Method C, G1






1H), 7.57 (t,











J = 8.2 Hz,











1H), 7.14 (d,











J = 8.8 Hz,











1H).










1151


embedded image



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
DMSO
386.0 (M + 1)
Method A (TFA)
95
Method D, G1






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).










1152


embedded image


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 =
DMSO
395.1, 397.1 (M + 1)
Method A (TFA)
95
Method D, G1






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).










1153


embedded image


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 =
DMSO
409.1 (M + 1)
Method A (TFA)
95
Method D, G1






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).










1154


embedded image



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
DMSO
373.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






(m, 2H), 7.75-











7.61 (m,











1H), 7.48-











7.30 (m, 2H),











7.28-7.06 (m,











1H), 3.99











(s, 3H).










1155


embedded image



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 =
DMSO
382.0, 384.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






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).










1156


embedded image



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,
DMSO
396.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






J = 74.0 Hz,











1H), 7.01 (dd,











J = 8.0, 2.0











Hz, 1H), 3.99











(s, 3H).










1157


embedded image



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 =
DMSO
377.0, 379.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






7.6 Hz, 1H).










1158


embedded image



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


embedded image



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


embedded image



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


embedded image



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


embedded image



468.2
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-
DMSO
469.0 (M + 1)
Method B (NH4HCO3)
90
Method C, G1






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).










1163


embedded image



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
DMSO
492.0 (M + 1)
Method B (NH4HCO3)
90
Method C, G1






(m, 2H), 7.39











(t, J = 8.0











Hz, 1H), 7.16











(t, J = 74.0











Hz, 1H), 6.95-











6.92 (m,











1H).










1164


embedded image



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


embedded image



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
DMSO
414.1, 416.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






(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).










1166


embedded image



400.24
1H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 10.01 (s, 1H), 9.46 (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,
DMSO
400.0, 402.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






1H), 7.95-











7.91 (m, 1H),











7.89 (s, 1H),











7.57 (t, J =











9.0 Hz, 1H),











2.75 (s, 3H).










1167


embedded image



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),
DMSO
410.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






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).










1168


embedded image



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
DMSO
380.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






Hz, 1H), 7.02











(dd, J = 8.0,











2.4 Hz, 1H),











2.77 (s, 3H).










1169


embedded image



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-
DMSO
444.0, 446.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






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).










1170


embedded image



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 =
DMSO
430.0, 432.0, 434.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






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).










1171


embedded image



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,
DMSO
387.1 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






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).










1172


embedded image



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
DMSO
373.1 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






Hz, 1H), 3.97











(s, 3H).










1173


embedded image


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,
DMSO
380.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






J = 8.8, 2.0











Hz, 1H), 7.53











(d, J = 8.8











Hz, 1H).










1174


embedded image


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
DMSO
465.1 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






(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).










1175


embedded image



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
DMSO
358.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






(m, 2H), 7.09-











7.13 (m,











3H), 2.76











(s, 3H).










1176


embedded image



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,
DMSO
366.0, 368.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






1H), 7.49 (t,











J = 9.2 Hz,











1H), 2.75 (s,











3H).










1177


embedded image



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,
DMSO
380.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






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).










1178


embedded image



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
DMSO
381.9, 383.9 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






Hz, 1H), 7.63











(t, J = 7.6











Hz, 1H), 2.75











(s. 3H).










1179


embedded image



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,
DMSO
350.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






3H).










1180


embedded image



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),
DMSO
381.9, 383.9 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






2.51 (s, 3H).










1181


embedded image



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,
DMSO
339.0 (M + 1)
Method B (NH4HCO3)
95
Method C, G1






J = 7.2 Hz,











1H), 7.61-











7.65 (m, 3H),











2.76 (s,











3H).










1182


embedded image



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-
DMSO
384.2 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






7.74 (m, 1H),











7.62 (t, J =











8.0 Hz, 1H),











7.20 (d, J =











8.0 Hz, 1H).










1183


embedded image



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,
DMSO
366.2 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






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).










1184


embedded image



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
DMSO
398.0, 400.0, 402.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






Hz, 1H), 7.71











(d, J = 8.8











Hz, 1H), 7.56-











7.58 (m,











1H), 3.99 (s,











3H).










1185


embedded image



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


embedded image



365.34
1H-NMR (400 MHz, DMSO-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
DMSO
366.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






(s, 3H).










1187


embedded image



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


embedded image



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


embedded image



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
DMSO
374.1, 376.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






Hz, 1H),











7.60-7.62 (m,











2H), 7.25 (t,











J = 7.6 Hz,











1H), 4.01 (s,











3H).










1190


embedded image



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,
DMSO
397.9, 400.0, 401.9 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






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).










1191


embedded image



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,
DMSO
382.0, 384.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






1H), 7.51 (t,











J = 8.8 Hz,











1H), 3.40 (s,











3H).










1192


embedded image



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),
DMSO
366.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






7.47-7.59











(m, 2H), 3.40











(s, 3H).










1193


embedded image



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


embedded image



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,
DMSO
398.0, 399.9, 402.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






1H), 7.59 (dd,











J = 8.8, 2.4











Hz, 1H), 7.32











(t, J = 1.6











Hz. 1H), 3.40











(s, 3H).










1195


embedded image



395.36
1H-NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 9.55 (m, 1H), 874- 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,
DMSO
396.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






J = 74.0 Hz,











1H), 6.96-











6.98 (m, 1H),











3.40 (s, 3H).










1196


embedded image



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),
DMSO
378.0, 380.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






7.75-7.77 (m,











2H), 7.05-











7.30 (m, 2H).










1197


embedded image



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,
DMSO
344.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






1.6 Hz, 1H),











7.97-8.05











(m, 3H),











7.75-7.79 (m,











2H), 7.24 (t,











J = 7.6 Hz,











1H).










1198


embedded image



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-
DMSO
373.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






7.60 (m, 2H),











7.20 (t, J =











7.6 Hz, 1H),











3.95 (s, 3H).










1199


embedded image



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),
DMSO
377.0, 379.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






7.80 (t, J =











7.6 Hz, 1H),











7.73 (t, J =











7.6 Hz, 1H),











7.25 (t, J =











7.2 Hz, 1H).










1200


embedded image



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),
DMSO
400.0, 401.9 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






7.04 (dd,











J = 8.0, 1.2 Hz,











1H).










1201


embedded image



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
DMSO
386.0, 387.8 (M + 1)
Method A (TFA)
95
Method D, G1






(m, 2H), 7.78











(dd, J = 8.8,











2.0 Hz, 1H),











7.54 (t, J =











9.2 Hz, 2H).










1202


embedded image



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,
DMSO
369.9, 371.0 (M + 1)
Method A (TFA)
95
Method D, G1






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).










1203


embedded image



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,
DMSO
359.0, 361.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






3H).










1204


embedded image



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,
DMSO
401.9, 403.9, 405.9 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






1H), 7.73 (d,











J = 8.8 Hz,











1H).










1205


embedded image



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


embedded image



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),
DMSO
352.0, 354.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






7.80 (t, J =











7.2 Hz, 1H),











7.53 (t, J =











9.2 Hz, 1H).










1207


embedded image



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
DMSO
343.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






Hz, 1H), 7.70











(t, J = 7.6











Hz, 1H), 7.22











(t, J = 7.6











Hz, 1H).










1208


embedded image



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,
DMSO
366.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






1H), 7.34











(t, J = 74.0











Hz, 1H), 6.97











(dd, J = 8.4,











2.4 Hz, 1H).










1209


embedded image


HCl (batch 02)
351.6
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,
DMSO
352.0, 354.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






1H), 7.75 (t,











J = 7.2 Hz,











1H), 7.56 (t,











J = 9.2 Hz,











1H).










1210


embedded image



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
DMSO
343.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G4






Hz, 1H).










1211


embedded image



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,
DMSO
366.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






2.4 Hz, 1H).










1212


embedded image



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,
DMSO
400.0, 402.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






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),.










1213


embedded image



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,
DMSO
399.0, 401.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






1H), 7.55-











7.58 (m, 1H),











7.36 (t, J =











73.6 Hz, 1H),











7.13 (t, J =











2.0 Hz, 1H).










1214


embedded image



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


embedded image



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),
DMSO
367.8, 369.8, 371.8 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






7.96-8.00











(m, 3H), 7.73-











7.77 (m, 2H).










1216


embedded image



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),
DMSO
351.9, 353.8 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






7.89-7.93 (m,











3H), 7.68-











7.72 (m, 1H),











7.55 (t, J =











8.6 Hz, 1H).










1217


embedded image



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,
DMSO
325.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






1H), 7.99 (s,











1H), 7.97











(d, J = 3.6 Hz,











1H), 7.66-











7.80 (m, 3H).










1218


embedded image



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,
DMSO
367.9, 369.9, 371.8 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






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).










1219


embedded image



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,
DMSO
352.0, 354.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






1H), 7.95-











8.00 (m, 1H),











7.85 (t, J =











7.8 Hz, 1H),











7.61 (t, J =











9.2 Hz, 1H).










1220


embedded image



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
DMSO
336.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






(t, J = 7.6 Hz,











1H), 7.77-











7.85 (m, 2H),











7.56-7.63











(m, 1H)










1221


embedded image



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-
DMSO
324.9 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






8.30 (m, 2H),











8.12-8.06











(m, 1H), 7.87-











7.91 (m,











1H), 7.76-











7.84 (m, 2H)










1222


embedded image



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), 3.78 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 3.42 (d, J = 1.6 Hz, 2H), 7.96- 8.02 (m, 2H),
DMSO
368.0, 370.0, 372.0 (M + 1)
Method B (NH4HCO3)
95
Method D, G6






7.74-7.78











(m, 1H), 7.35











(d, J = 1.6 Hz,











1H).










1223


embedded image



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),
DMSO
368.1, 370.1 (M + 1)
Method B (NH4HCO3)
95
Method D, G1






7.70-7.74











(m, 1H), 7.35











(s,1H).










1224


embedded image



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


embedded image



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


embedded image



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,
DMSO
391.0 392.0 (M + 1)
Method A (TFA)
95
Method C, G3






J = 7.2 Hz,











1H), 7.21 (t,











J = 7.6 Hz,











1H), 2.75 (s,











3H).










1227


embedded image



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,
DMSO
392.0 393.1 (M + 1)
Method A (TFA)
95
Method C, G3






J = 7.2 Hz,











1H), 2.73 (s,











3H).










1228


embedded image



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


embedded image



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),
DMSO
416.9 417.9 (M + 1)
Method B (NH4HCO3)
95
Method C, G3






2.74 (s, 3H).










1230


embedded image


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


embedded image


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


embedded image



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


embedded image




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
DMSO
377.0 (M + 1)
Method B (NH4HCO3)
95
Method G






(m, 2H), 7.25











(t, J = 2.4 Hz,











1H).










1234


embedded image




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
DMSO
397.9, 400.0 (M + 1)
Method B (NH4HCO3)
95
Method G






(d, J = 8.8











Hz, 1H), 7.60











(dd, J = 8.8,











2.4 Hz, 1H),











4.00 (s, 3H).











embedded image


embedded image


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













Pu-
Method





Molec-


1H-



rity
for


Num-

Salt
ular

NMR

LCMS
per-
Cou-


ber
PRODUCT
type
Mass

1H-NMR

Solvent
LCMS
Protocol
cent
pling
























1242


embedded image



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


embedded image



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, J = 9.2 Hz,

DMSO
516.2 (M + 1)
Method B (NH4HCO3)
95
Method C, G4, C






1 H), 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


embedded image



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

DMSO
515.2 (M + 1)
Method B (NH4HCO3)
95
Method C, G4, C






(dd, J = 8.4, 2.4 Hz,











1H), 3.87 (s, 3H).










1245


embedded image



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,

DMSO
521.2 (M + 1)
Method B (NH4HCO3)
95
Method C, G4, C






1H), 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


embedded image



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),

DMSO
493.2 (M + 1)
Method B (NH4HCO3)
95
Method C, G4, C






3.94-3.97 (m, 2H),











3.40-3.43 (m, 2H),











2.70-2.73 (m, 1H),











1.65-1.78 (m, 4H).











embedded image


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).




embedded image


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








Molecular


1H-NMR







Number
PRODUCT
Salt type
Mass

1H-NMR

Solvent
LCMS
LCMS Protocol
Purity percent
Method for Coupling
























1235


embedded image



343.38
1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.85-8.78 (m, 1 H), 8.77-8.71 (m, 1H), 8.70-8.63 (m, 1 H), 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


embedded image



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


embedded image


2HCl


1H-NMR (400 MHz, DMSO-d6): δ 10.17 (s, 1H), 9.54 (6, 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


embedded image


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, 1 H), 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


embedded image





1H-NMR (400 MHz, DMSO-d6): δ 9.73(s, 1H), 9.32 (s, 1H), 8.74 (d, J = 4.4Hz, 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


embedded image


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


embedded image


2HCl


1H-NMR (400 MHz, DMSO): δ 10.84 (d, J = 1.8 Hz, 1 H), 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











embedded image




embedded image


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).




embedded image


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



embedded image


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 mmo 1), 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 2HCl was not observed.




embedded image




embedded image


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












Reten-


Method


Num-


Molecular


1H-NMR


tion
LCMS
Purity
for


ber
Product
Salt
Mass

1H-NMR

Solvent
LCMS
Time
Protocol
percent
Coupling

























1248


embedded image


HCl
342.4

1H-NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.50-8.89 (m, 3H), 8.16 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.30-7.61 (m, 4H), 7.01 (d, J = 6.4 Hz, 1 H), 3.88 (s, 3H), 3.32 (brs, 1H), 3.19 (s, 3H).

DMSO
343.1 (M + H)

Method B (NH4HCO3)
95
Method AQ1





1249


embedded image



372.4
1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.77 (d, J = 7.9 Hz, 1H), 8.67 (d, J = 3.7 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).
DMSO
372.9 (M + H)

Method B (NH4HCO3)
95
Method AQ1





1250


embedded image



356.4
1H-NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.79-8.74 (m, 1H), 8.69 (d, J = 4.0 Hz, 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).
DMSO
357.1 (M + H)

Method B (NH4HCO3)
95
Method AQ1





1251


embedded image



356.4
1H-NMR (400 MHz, DMSO-d6): δ 9.68 (d, J = 1.2 Hz, 1H), 8.75 (d, J = 8.0 Hz, 1 H), 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).
DMSO
357.2 (M + H)

Method B (NH4HCO3)
95
Method AQ1





1252


embedded image



329.3
1H NMR (300 MHz, DMSO) δ 9.31 (s, 1H), 8.76 (d, J = 4.7 Hz, 1H), 8.51 (d, J = 8.0 Hz, 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).
DMSO
330 (M + H)
1.76
Method D
100






1253


embedded image


HCl
342.4
1H NMR (300 MHz, DMSO) δ 10.11 (s, 1H), 9.63 (s, 1H), 9.07-8.86 (m, 2H), 8.58 (s, 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).
DMSO
343 (M + H)
1.47
Method D
100
Method AQ2





1254


embedded image



330.3
1H NMR (300 MHz, DMSO) δ 9.59 (s, 1H), 8.73 (d, J = 8.3 Hz, 1H), 8.65 (d, J = 4.7 Hz, 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).
DMSO
331 (M + H)
1.52
Method D
100
Method AQ2





1255


embedded image



312.4
1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.88-8.47 (m, 4H), 8.25-8.05 (m, 1H), 7.97-7.72 (m, 3H), 7.67-7.35 (m, 4H), 3.18 (d, J = 4.4 Hz, 3H).
DMSO
313 (M + H)
1.48
Method D
100
Method AQ2





1256


embedded image


HCl
337.4
1H NMR (300 MHz, DMSO) δ 9.93 (s, 1H), 9.63 (s, 1H), 9.00 (d, J = 8.3 Hz, 1H), 8.95- 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).
DMSO
338 (M + H)
1.50
Method D
100
Method AQ2





1257


embedded image



337.4
1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J = 7.9 Hz, 1H), 8.73-8.59 (m, 3H), 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).
DMSO
338 (M + H)
1.50
Method D
100
Method AQ2





1258


embedded image



346.8
1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.77 (d, J = 7.9 Hz, 1H), 8.72-8.52 (m, 3H), 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).
DMSO
347 (M + H)
1.60
Method D
100
Method AQ2





1259


embedded image



346.8
1H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.72-8.54 (m, 3H), 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).
DMSO
347 (M + H)
1.66
Method D
100
Method AQ2





1260


embedded image



372.4
1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 8.77 (dd, J = 7.9, 1.8 Hz, 1H), 8.67 (d, J = 4.7 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).
DMSO
373 (M + H)
1.49
Method D
100
Method AQ2





1261


embedded image



348.3
1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 8.77 (dd, J = 8.0, 1.9 Hz, 1H), 8.68 (d, J = 4.6 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).
DMSO
349 (M + H)
1.61
Method D
100
Method AQ2





1262


embedded image



313.4
1H NMR (300 MHz, DMSO) δ 9.65 (s, 1H), 9.09 (s, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.73- 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).
DMSO
314 (M + H)
1.70
Method C
96
Method AQ2





1263


embedded image



343.4
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).
DMSO
344.1 (M + H)
1.94
Method C
95
Method AQ2





1264


embedded image



356.4
1H NMR (300 MHz, DMSO) δ 10.76 (s, 1H), 9.75 (d, J = 1.6 Hz, 1H), 9.23 (d, J = 8.2 Hz, 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).
DMSO
357.1 (M + H)
2.13
Method C
100
Method AQ2





1265


embedded image



342.4
1H NMR (300 MHz, DMSO) d 9.64 (s, 1H), 8.78 (dd, J = 8.0, 1.9 Hz, 1H), 8.67 (dd, J = 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).
DMSO
343.1 (M + H)
1.78
Method C
99
Method AQ2





1266


embedded image



344.4
1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 2.1 Hz, 1H), 8.92-8.59 (m, 3H), 8.59-8.47 (m, 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).
DMSO
345.1 (M + H)
2.32
Method C
100
Method AQ2





1267


embedded image



329.4
1H NMR (300 MHz, DMSO) δ 12.77 (s, 1H), 9.33 (d, J = 1.7 Hz, 1H), 8.77 (dd, J = 4.7, 1.5 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).
DMSO
330 (M + H)
1.78
Method C
100
Method AQ2





1268


embedded image



342.4
1H NMR (300 MHz, DMSO) δ 9.65 (dd, J = 2.1, 0.8 Hz, 1H), 8.84-8.74 (m, 1H), 8.68 (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, 1 H), 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).
DMSO
343.3 (M + H)
2.09
Method C

Method AQ2





1269


embedded image



342.4
1H NMR (300 MHz, DMSO) δ 9.53 (d, J = 2.0 Hz, 1 H), 8.65 (dd, J = 5.9, 3.5 Hz, 2H), 8.51 (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).
DMSO
343.3 (M + H)
2.16
Method C
100
Method AQ2





1270


embedded image


2HCl
374.5
1H NMR (300 MHz, DMSO) δ 10.67 (s, 1H), 9.69 (s, 1H). 9.12 (d, J = 11.6 Hz. 2H), 8.97 (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).
DMSO
375.1 (M + H)
1.67
Method C
95
Method AQ2





1271


embedded image



374.5
1H NMR (300 MHz, DMSO) δ 9.70-9.57 (m, 1H), 8.84-8.72 (m, 1H), 8.73-8.62 (m, 3H), 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).
DMSO
375.1 (M + H)
1.64
Method C
95
Method AQ2





1272


embedded image


2HCl
425.5
1H NMR (300 MHz, DMSO) δ 10.54 (s, 1H), 9.70 (d, J = 1.7 Hz, 1H), 9.12 (d, J = 8.1 Hz, 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).
DMSO
426.2 (M + H)
1.72
Method C
95
Method AQ2





1273


embedded image


HCl
342.4
1H NMR (300 MHz, DMSO) δ 9.64 (s, 1 H), 8.77 (d, J = 7.9 Hz, 1H), 8.71-8.65 (m, 1H), 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).
DMSO
343.1 (M + H)
2.06
Method C
100
Method AQ2





1274


embedded image



329.4
1H NMR (300 MHz, DMSO) δ 9.34 (d, J = 1.5 Hz, 1 H), 8.74 (dd, J = 4.8, 1.6 Hz, 1H), 8.53 (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).
DMSO
330.0 (M + H)
1.75
Method C
100
Method AQ2





1275


embedded image



343.4
1H NMR (300 MHz, DMSO) δ 9.65 (d, J = 1.5 Hz, 1H), 8.84-8.65 (m, 4H), 8.31 (d, J = 5.4 Hz, 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).
DMSO
344.1 (M + H)
1.95
Method C
95
Method AQ2





1276


embedded image



331.3
1H NMR (300 MHz, DMSO) δ 9.63 (d, J = 1.4 Hz, 1H), 8.81-8.74 (m, 1H), 8.73 (d, J = 2.3 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).
DMSO
332.1 (M + H)
1.89
Method C
100
Method AQ2





1277


embedded image



425.5
1H NMR (300 MHz, DMSO) δ 9.63 (d, J = 1.4 Hz, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.70-8.59 (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).
DMSO
426.2 (M + H)
1.69
Method C
100
Method AQ2





1278


embedded image



343.4
1H NMR (300 MHz, DMSO) δ 9.67 (d, J = 1.5 Hz, 1H), 8.86-8.77 (m, 1H), 8.74 (dd, J = 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).
DMSO
344.2 (M + H)
2.47
Method C
100
Method AQ2






































1H

Pu-
Method










NMR
rity
of




Num-
Starting
Starting

Salt

Sol-
Per-
Cou-

LCMS


ber
Material 1
Material 2
Product
type

1H NMR

vent
cent
pling
LCMS
Method





1279


embedded image




embedded image




embedded image


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,

DMSO
>98
AQ3
  
  







2H), 3.21 (d, J =












4.4 Hz, 3H), 2.77












(s, 3H).










1280


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ3









2.76 (s, 3H).










1281


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ3









7.91-7.85 (m,












1H), 7.78-7.70












(m, 1H), 3.22 (d,












J = 4.2 Hz, 3H),












2.76 (s, 3H).










1282


embedded image




embedded image




embedded image


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

DMSO
>98
AQ3









(m, 2H), 7.15-












7.04 (m, 2H), 3.84












(s, 3H), 3.21












(d, J = 3.9 Hz, 3H),












2.76 (s, 3H).










1283


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ3









7.21-7.15 (m,












1H), 7.14-7.06












(m, 1H), 3.81 (s,












3H), 3.19 (d,












J = 4.5 Hz, 3H),












2.77 ( s, 3H).










1284


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ3









7.95-7.90 (m,












1H), 7.90-7.83












(m, 1H), 7.76












(dd, J = 7.8, 0.7












Hz, 1H), 7.68-












7.63 (m, 1H),












3.19 (d, J = 4.5












Hz, 3H), 2.77 (s,












3H).










1285


embedded image




embedded image




embedded image




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,

DMSO
>98
AQ4









2H), 7.46-7.40












(m, 1H), 7.39-












7.32 (m, 1H),












7.28-7.18 (m,












1H), 3.18 (d, J =












4.4 Hz, 3H), 2.64












(s, 3H).










1286


embedded image




embedded image




embedded image


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

DMSO
>98
AQ4









Hz, 3H), 2.66 (s,












3H).










1287


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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,

DMSO
>98
AQ4









J = 4.5 Hz, 3H),












2.66 (s, 3H).










1289


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ4









2.72 (s, 3H).










1290


embedded image




embedded image




embedded image


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,

DMSO
>98
AQ4









J = 4.6 Hz, 3H),












2.72 (s, 3H).










1291


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









(m, 3H), 3.26 (d, J =












4.5 Hz, 3H).










1292


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









8.0, 5.1 Hz, 1H),












7.45-7.26 (m,












4H), 3.29 (d, J =












4.2 Hz, 3H), 2.32












(s, 3H).










1293


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









1H), 7.45 (m,












2H), 7.20 (d, J =












8.2 Hz, 1H), 7.12












(t, J = 7.5 Hz,












1H), 3.82 (s, 3H),












3.29 (d, J = 4.1












Hz, 3H).










1294


embedded image




embedded image




embedded image




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,

DMSO
>98
G2/AQ3









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).










1295


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









(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).










1296


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









Hz, 2H), 7.82-












7.73 (m, 1H),












7.41 (t, J = 8.7 Hz,












2H), 3.28 (d, J =












4.3 Hz, 3H).










1297


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









Hz, 1H), 8.13 (d,












J = 8.7 Hz, 1H),












7.93-7.76 (m,












2H), 3.30 (d, J =












4.5 Hz, 3H).










1298


embedded image




embedded image




embedded image


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),

DMSO
>98
G2/AQ3









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 =












4.4 Hz, 3H), 2.44












(s, 3H).










1299


embedded image




embedded image




embedded image




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-

DMSO
>98
G2/AQ3









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).










1300


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









7.9, 5.2 Hz, 1H),












3.31 (d, J = 4.1












Hz, 3H), 2.63 (s,












3H).










1301


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









J = 8.8 Hz, 1H),












8.21 (s, 1H),












7.92 (dd, J = 8.1,












5.1 Hz, 1H),












7.84 (s, 1H),












7.69-7.52 (m, 2H),












3.31 (d, J = 4.3












Hz, 3H), 3.23 (s,












6H).










1302


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









Hz, 1H), 8.01-












7.93 (m, 2H),












7.90 (t, J = 7.2 Hz,












1H), 7.74 (dd, J =












15.4, 7.7 Hz,












2H), 3.24 (t, J =












18.2 Hz, 3H).










1303


embedded image




embedded image




embedded image


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),

DMSO
>98
G2/AQ3









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).










1304


embedded image




embedded image




embedded image




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

DMSO
>98
G2/AQ3









Hz, 1H), 7.75












(dd, J = 8.5, 1.6












Hz, 1H), 7.54












(dd, J = 7.9, 4.8












Hz, 1H), 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


embedded image




embedded image




embedded image


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-

DMSO
>98
G2/AQ3









7.80 (m, 1H),












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


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









4.3 Hz, 3H),












2.40 (s, 3H).










1307


embedded image




embedded image




embedded image


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), 8.99 (d, J = 5.0 Hz, 1H), 8.46 (s, 1H), 8.36 (d, J = 8.6 Hz, 1H), 7.98-7.80 (m,

DMSO
>98
G2/AQ3









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).










1308


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









4.3 Hz, 3H).










1309


embedded image




embedded image




embedded image




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

DMSO
>98
G2/AQ3









(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, 1H),












7.34 (t, J = 7.5












Hz, 2H), 7.20-












7.00 (m, 2H),












3.16 (d, J = 4.4 Hz,












3H).










1310


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









2H), 7.63 (t, J =












7.8 Hz, 1H), 7.54












(s, 1H), 3.31 (d,












J = 4.3 Hz, 3H).










1311


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









3H), 3.17 (d, J =












1.8 Hz, 9H).










1312


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









1H), 7.82 (dd, J =












8.1, 5.0 Hz, 1H),












7.79-7.72 (m,












1H), 7.64-7.45












(m, 2H), 3.25 (d,












J = 4.4 Hz, 3H).










1313


embedded image




embedded image




embedded image


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-

DMSO
>98
G2/AQ3









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).










1314


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









2H), 7.60 (d, J =












8.5 Hz, 1H), 3.29












(d, J = 3.9 Hz,












3H).










1315


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









2H), 3.29 (d, J =












4.2 Hz, 3H).










1316


embedded image




embedded image




embedded image


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),

DMSO
>98
G2/AQ3









3.31 (d, J = 4.3












Hz, 3H).










1317


embedded image




embedded image




embedded image




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,

DMSO
>98
G2/AQ3









4.7 Hz, 1H),












7.39-7.21 (m,












1H), 3.18 (d, J =












4.4 Hz, 3H).










1318


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









Hz, 1H), 7.77-












7.63 (m, 2H),












7.37-7.18 (m,












1H), 3.29 (d, J =












4.3 Hz, 3H).










1319


embedded image




embedded image




embedded image




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-

DMSO
>98
G2/AQ3









7.34 (m, 2H),












7.17 (d, J = 8.1












Hz, 1H), 7.10 (t,












J = 7.4 Hz, 1H),












3.81 (s, 3H).































1320


embedded image




embedded image




embedded image




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 =

DMSO
>98
G2/AQ3
  
  







7.9, 4.8 Hz,












1H), 7.50-7.33












(m, 2H), 7.18 (d,












J = 8.3 Hz, 1H),












7.09 (t, J = 7.5












Hz, 1H), 3.82












(s, 3H), 3.46 (s,












6H).










1321


embedded image




embedded image




embedded image




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,

DMSO

>98

G2/AQ3









1H), 7.54 (dd, J =












7.9, 4.8 Hz, 1H),












7.52-7.44 (m,












1H), 7.44-7.32












(m, 2H).










1322


embedded image




embedded image




embedded image




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,

DMSO

>98

G2/AQ3









2H), 7.32-












7.20 (m, 1H).










1323


embedded image




embedded image




embedded image




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 =

DMSO
>98
G2/AQ3









8.7 Hz, 1H),












7.54 (dd, J =












7.9, 4.8 Hz, 1H),












7.38 (t, J = 8.8 Hz,












2H).










1324


embedded image




embedded image




embedded image




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-

DMSO
>98
G2/AQ3









7.60 (m, 2H),












7.60-7.47 (m,












2H), 7.32-7.18












(m, 1H), 3.49 (s,












6H).










1325


embedded image




embedded image




embedded image




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 =

DMSO
>98
G2/AQ3









9.0, 1.8 Hz, 1H),












7.83 (d, J = 9.0












Hz, 1H), 7.54












(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


embedded image




embedded image




embedded image




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),

DMSO
>98
G2/AQ3









7.89 (d, J = 8.7












Hz, 1H), 7.69 (t,












J = 7.7 Hz, 1H),












7.54 (dd, J = 7.9,












4.8 Hz, 1H), 2.71












(s, 3H).










1327


embedded image




embedded image




embedded image




1H NMR (300 MHz, DMSO) δ 9.58 (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


embedded image




embedded image




embedded image




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

DMSO
>98
G2/AQ3









(m, 1H), 7.60-












7.52 (m, 2H),












7.52-7.43 (m,












2H).










1329


embedded image




embedded image




embedded image




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

DMSO
>98
G2/AQ3









(m, 2H), 7.48 (d,












J = 8.1 Hz, 1H).










1330


embedded image




embedded image




embedded image




1H NMR (300 MHz, DMSO) δ 9.65 (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),

DMSO
>98
G2/AQ3









3.17 (s, 3H).










1331


embedded image




embedded image




embedded image




1H NMR (300 MHz, DMSO) δ 9.61 (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


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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

DMSO
>98
G2/AQ3









(m, 2H), 7.78 (d,












J = 7.6 Hz, 1H),












7.66-7.41 (m,












3H), 3.51 (s, 6H).










1334


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









J = 8.7, 1.7 Hz,












1H), 7.98-7.91












(m, 1H), 7.91-












7.83 (m, 1H),












7.80-7.68 (m,












2H), 3.65 (s, 6H).










1335


embedded image




embedded image




embedded image




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),

DMSO
>98
G2/AQ3









7.82 (t, J = 8.0












Hz, 1H), 7.57












(dd, J = 8.3, 5.2 Hz,












1H), 3.54 (s, 6H).










1336


embedded image




embedded image




embedded image




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

DMSO
>98
G2/AQ3









Hz, 1H), 7.55












(dd, J = 7.9, 4.8












Hz, 1H), 3.52 (s,












6H).










1337


embedded image




embedded image




embedded image


2 HCl

1H NMR (300 MHz, DMSO) δ 9.67- 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,

DMSO
>98
G2/AQ3









J = 7.6, 5.1 Hz,












1H), 3.53 (s, 6H).










1338


embedded image




embedded image




embedded image




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,

DMSO
>98
G2/AQ3









4.7 Hz, 1H),












7.47-7.34 (m, 2H),












3.23-3.20 (m, 3H).










1339


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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,

DMSO
>98
G2/AQ3









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).










1341


embedded image




embedded image




embedded image




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

DMSO
>98
G2/AQ3









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).










1342


embedded image




embedded image




embedded image




1H NMR (300 MHz, DMSO) δ 9.66 (d, J = 1.6 Hz, 1H), 8.79 (dt, 7 = 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,

DMSO
>98
G2/AQ3









2H), 3.21 (d, J =












4.4 Hz, 3H).










1343


embedded image




embedded image




embedded image


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),

DMSO
>98
G2/AQ3









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).










1344


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









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).










1345


embedded image




embedded image




embedded image




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


embedded image




embedded image




embedded image




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

DMSO
>98
G2/AQ3









(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).










1347


embedded image




embedded image




embedded image




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

DMSO
>98
G2/AQ3









(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).










1348


embedded image




embedded image




embedded image




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

DMSO
>98
G2/AQ3









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).










1349


embedded image




embedded image




embedded image


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),

DMSO
>98
G2/AQ3









7.91-7.76 (m,












3H), 7.22-7.10












(m, 2H), 3.85 (s,












3H), 3.31 (d, J =












4.4 Hz, 3H).










1350


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









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).










1351


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









(s, 3H).










1352


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









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).










1353


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









1H), 7.84-7.79 (m,












1H), 7.68-7.57












(m, 2H), 3.35-












3.29 (m, 3H).










1354


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









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).










1355


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









J = 8.7, 1.6 Hz,












1H), 7.96 (dd,












J = 8.1, 5.2 Hz,












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


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









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).










1357


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









Hz, 2H), 6.66-












6.58 (m, 1H),












3.87 (s, 6H), 3.31












(d, J = 4.2 Hz,












3H).










1358


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









(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).










1359


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









(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).










1360


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









(m, 1H), 8.00-












7.84 (m, 3H),












7.49-7.33 (m,












2H), 3.30 (d,












J = 4.4 Hz, 3H).































1361


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3
  
  







1.7 Hz, 1H),












7.88 (dd, J = 8.1,












5.2 Hz, 1H),












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


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









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),












7.39 (d, J = 8.0












Hz, 2H), 3.30 (d,












J = 4.4 Hz, 3H),












2.40 (s, 3H).










1363


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









3H), 7.85-7.66












(m, 2H), 3.30












(s, 3H).










1364


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









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,












J = 8.2 Hz, 1H),












3.28 (d, J = 4.5












Hz, 3H).










1365


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image




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),

DMSO
>98
G2/AQ3









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).










1367


embedded image




embedded image




embedded image




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),

DMSO
>98
G2/AQ3









2.61 (s, 3H).










1368


embedded image




embedded image




embedded image


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),

DMSO
>98
G2/AQ3









8.09-7.98 (m,












3H), 3.55 (s, 3H),












2.65 (s, 3H),












2.22 (s, 3H).










1369


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









(m, 2H), 7.47-












7.34 (m, 1H), 2.56












(s, 3H).










1370


embedded image




embedded image




embedded image


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),

DMSO
>98
G2/AQ3









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).










1371


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









(m, 2H), 7.50-












7.35 (m, 1H), 3.31












(d, J = 4.1 Hz,












3H).










1372


embedded image




embedded image




embedded image


HCl

1H NMR (300 MHz, DMSO) δ 9.72-9.45 (m, 2H), 8.95 (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),

DMSO
>98
G2/AQ3









7.36-7.25 (m,












1H), 3.27 (d, J =












4.3 Hz, 3H).










1373


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









2H), 7.79-7.55 (m,












2H), 3.33-3.27












(m, 3H).










1374


embedded image




embedded image




embedded image


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-

DMSO
>98
G2/AQ3









3.21 (m, 3H).










1375


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









3.7 Hz, 3H).










1376


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









11.5 Hz, 1H),












7.63-7.45 (m,












2H), 7.45-7.26












(m, 1H), 3.19 (d,












J = 4.4 Hz, 3H).










1379


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









11.6 Hz, 1H),












7.78 (td, J = 8.9,












6.6 Hz, 1H),












7.54-7.36 (m,












1H), 7.30 (td, J =












8.3, 2.0 Hz, 1H),












3.18 (d, J = 4.4












Hz, 3H).










1380


embedded image




embedded image




embedded image


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, Hz, 1H), 8.51 (s, 1H), 8.44 (d, J = 8.7 Hz, 1H), 8.26-8.11 (m, 1H), 7.94 (dd,

DMSO
>98
G2/AQ3









J = 8.0, 5.2 Hz,












1H), 7.65-7.49












(m, 2H), 7.49-












7.29 (m, 1H),












3.69 (s, 6H).










1381


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









1H), 7.46 (t, J =












10.2 Hz, 1H), 7.29












(t, J = 8.5 Hz,












1H), 3.69 (s, 6H).










1382


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









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,












3H), 3.29 (d, J =












4.5 Hz, 3H),












2.64 (s, 3H).










1383


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









8.8 Hz, 1H),












7.97 (dd, J =












8.0, 5.3 Hz, 1H),












7.64-7.49 (m,












2H), 7.49-7.34












(m, 1H), 4.06-












3.92 (m, 2H),












3.73 (t, J = 5.5












Hz, 2H), 3.33 (s,












3H).










1384


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









8.7 Hz, 1H),












7.95 (dd, J = 8.2,












5.2 Hz, 1H),












7.79 (td, J = 8.9,












6.6 Hz, 1H),












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


embedded image




embedded image




embedded image


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, J = 8.7 Hz, 1H), 8.18 (d, J =

DMSO
>98
G2/AQ3









8.7 Hz, 1H),












7.95 (dd, J = 8.1,












5.2 Hz, 1H),












7.81 (td, J = 8.9,












6.6 Hz, 1H),












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


embedded image




embedded image




embedded image


2 HCl

1H NMR (300 MHz, DMSO) δ 9.73 (s, 1H), 9.17 (d, J = 8.4 Hz, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 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

DMSO
>98
G2/AQ3









(m, 1H), 4.31-4.18












(m, 4H), 2.08 (s,












4H).










1387


embedded image




embedded image




embedded image


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 =

DMSO
>98
G2/AQ3









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).










1388


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









(ddd, J = 11.6,












9.3, 2.6 Hz, 1H),












7.30 (td, J = 8.4,












2.3 Hz, 1H),












4.23-4.12 (m,












4H), 3.90-3.80












(m, 4H).










1389


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









Hz, 1H), 4.16 (brs,












4H), 1.80 (brs, 6H).










1390


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









1H), 4.23-4.16












(m, 4H), 3.85 (d,












J = 4.7 Hz, 4H).










1391


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









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,












2H), 3.85 (t, J =












5.3 Hz, 2H), 3.72












(s, 3H), 3.33 (s, 3H).










1392


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









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,












1H), 4.36-4.18












(m, 2H), 3.88-












3.77 (m, 2H), 3.72












(s, 3H), 3.33 (s, 3H).










1393


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/AQ3









5.2 Hz, 1H),












7.63-7.46 (m,












2H), 7.46-7.25












(m, 1H), 4.22-












4.11 (m, 2H),












3.73 (s, 3H),












3.59 (t, J = 5.9 Hz,












2H), 2.10-1.92












(m, 2H).










1394


embedded image




embedded image




embedded image


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

DMSO
>98
G2/AQ3









(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












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


embedded image




embedded image




embedded image


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),

DMSO
>98
G2/AQ3









8.01-7.88 (m,












2H), 7.62 (ddd, J =












9.1, 6.1, 3.1












Hz, 1H), 7.58-












7.36 (m, 2H).










1396


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ4
   
   







8.14 (d, J = 8.2












Hz, 2H), 7.90 (d,












J = 8.4 Hz, 3H),












3.34 (t, J = 17.1












Hz, 3H).










1398


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ4









7.77-7.69 (m, 1H),












7.68-7.55 (m,












3H), 3.29 (d, J =












4.6 Hz, 3H).










1400


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ4









7.25-7.17 (m,












1H), 3.92 (s, 3H).










1401


embedded image




embedded image




embedded image


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

DMSO
>98
AQ4









(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).










1402


embedded image




embedded image




embedded image


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

DMSO
>98
AQ5









(m, 1H), 7.42-












7.26 (m, 3H), 3.31












(d, J = 4.5 Hz,












3H), 2.40 (s, 3H).










1403


embedded image




embedded image




embedded image


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

DMSO
>98
AQ5









Hz, 3H), 2.32 (s,












3H).










1404


embedded image




embedded image




embedded image


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,

DMSO
>98
AQ5









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).










1405


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ5









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).










1406


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ5









3.30 (d, J = 4.6 Hz,












3H), 2.33 (s, 3H).










1407


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ5









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).










1408


embedded image




embedded image




embedded image


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,

DMSO
>98
AQ5









2H), 3.29 (d, J =












4.6 Hz, 3H),












2.41 (s, 3H).










1409


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ5









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).










1410


embedded image




embedded image




embedded image


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, 1H), 8.52 (s, 1H), 8.10-8.00 (m, 3H), 7.91 (dd, J = 7.9, 5.3

DMSO
>98
AQ5









Hz, 1H), 7.75-












7.67 (m, 2H),












3.31 (d, J = 4.5 Hz,












3H), 2.39 (s, 3H).










1411


embedded image




embedded image




embedded image


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,

DMSO
>98
AQ5









J = 7.4, 0.9 Hz,












1H), 3.76 (s, 3H),












3.31 (d, J = 4.5












Hz, 3H), 2.24 (s,












3H).










1412


embedded image




embedded image




embedded image


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

DMSO
>98
AQ5









(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,












J = 10.8 Hz,












3H), 3.31 (d, J =












4.6 Hz, 3H), 2.41












(s, 3H).










1413


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ5









3.31 (d, J = 4.6












Hz, 3H), 2.43 (s,












3H).










1414


embedded image




embedded image




embedded image


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

DMSO
>98
AQ5









(d, J = 4.5 Hz,












3H), 2.45 (s, 3H).










1415


embedded image




embedded image




embedded image


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,

DMSO
>98
AQ5









J = 8.4, 2.2 Hz,












1H), 3.26 (d, J =












4.5 Hz, 3H),












2.35 (s, 3H).










1416


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ5









2.47 (s, 3H).










1417


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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

DMSO
>98
AQ5









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,












3H), 3.26 (d, J =












4.6 Hz, 3H), 2.28












(s, 3H).










1419


embedded image




embedded image




embedded image


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,

DMSO
>98
AQ5









3H), 3.26 (d, J =












4.5 Hz, 3H),












2.45 (s, 3H).










1420


embedded image




embedded image




embedded image


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 =

DMSO
>98
AQ5









8.8 Hz, 2H),












3.84 (s, 3H), 3.27












(d, J = 4.5 Hz,












3H), 2.47 (s, 3H).










1421


embedded image




embedded image




embedded image


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

DMSO
>98
AQ4








(s, 3H).










1422


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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

DMSO
>98
Method AQ3









(s, 1H), 8.09 (s,












1H), 8.02-7.91












(m, 2H), 7.85 (s,












1H), 7.78-7.68












(m, 1H), 7.61-












7.51 (m, 1H),












7.48-7.36 (m,












2H), 5.36 (s, 2H).










1426


embedded image




embedded image




embedded image


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

DMSO
>98
Method AQ3









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),












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


embedded image




embedded image




embedded image


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),

DMSO
>98
Method AQ3









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).










1428


embedded image




embedded image




embedded image


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),

DMSO
>98
Method AQ3









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-












7.33 (m, 2H),












5.36 (d, J = 5.5 Hz,












2H), 2.83 (s, 3H).










1429


embedded image




embedded image




embedded image


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

DMSO
>98
Method AQ3









(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,












J = 5.3 Hz, 2H),












2.81 (s, 3H).










1430


embedded image




embedded image




embedded image


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),

DMSO
>98
Method AQ3









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












(m, 1H), 7.54-












7.35 (m, 2H),












5.38 (d, J = 5.5












Hz, 2H), 2.85 (s,












3H).










1431


embedded image




embedded image




embedded image


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,

DMSO
>98
Method AQ3









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).










1432


embedded image




embedded image




embedded image


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

DMSO
>98
Method AQ3









(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












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


embedded image




embedded image




embedded image


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),

DMSO
>98
Method AQ3









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,












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


embedded image




embedded image




embedded image


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,

DMSO
>98
Method AQ3









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),












5.36 (d, J = 5.5












Hz, 2H), 2.82 (s,












3H).










1435


embedded image




embedded image




embedded image


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,

DMSO
>98
Method AQ3









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-












7.51 (m, 2H),












7.46-7.37 (m,












1H), 5.36 (d, J =












5.5 Hz, 2H),












2.82 (s, 3H).










1436


embedded image




embedded image




embedded image


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

DMSO
>98
Method AQ3









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), 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


embedded image




embedded image




embedded image


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

DMSO
>98
Method AQ3









(m, 2H), 7.98












(dd, J = 8.0, 5.4












Hz, 1H), 7.83












(ddd, J = 15.5,












8.4, 6.0 Hz, 2H),












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


embedded image




embedded image




embedded image


4 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),

DMSO
>98
Method AQ3









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).










1439


embedded image




embedded image




embedded image


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),

DMSO
>98
Method AQ3









8.13 (q, J = 8.7












Hz, 2H), 8.04-












7.89 (m, 2H),












7.87-7.68 (m,












2H), 7.50 (ddd, 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


embedded image




embedded image




embedded image


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),

DMSO
>98
Method AQ3









7.54-7.28 (m,












4H), 5.03 (d, J =












5.7 Hz, 2H).










1441


embedded image




embedded image




embedded image


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,

DMSO
>98
Method AQ3









2H), 1.69 (s, 9H).










1442


embedded image




embedded image




embedded image


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 =

DMSO
>98
Method AQ3









4.6 Hz, 3H),












2.45 (s, 3H).










1443


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image


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

DMSO
>98
Method AQ3, F, G2 (reflux)









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 (t, J = 17.9












Hz, 2H), 3.88 (s,












3H).










1445


embedded image




embedded image




embedded image


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),
DMSO
>98
AQ6









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.










1446


embedded image




embedded image




embedded image


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-
DMSO
>98
AQ6









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.










1447


embedded image




embedded image




embedded image


3 HCl
1H NMR (DMSO- d6) ppm 9.72 (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-
DMSO
>98
AQ6









7.49 (m, 2H),












7.44 (d, J = 8.56












Hz, 1H), 7.38-












7.33 (m, 2H),












3.20 (d, J = 4.40












Hz, 3H), 2.63 (s,












3H). The 1H of












3HCl was not












observed.










1448


embedded image




embedded image




embedded image


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),
DMSO
>98
AQ6









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.










1449


embedded image




embedded image




embedded image


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-
DMSO
>98
AQ6









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.










1450


embedded image




embedded image




embedded image


2 HCl
1H NMR (DMSO- d6) ppm 9.74 (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
DMSO
>98
AQ6









(d, J = 4.36 Hz,












3H), 2.56 (brs,












3H). The 1H of












2HCl was not












observed.










1451


embedded image




embedded image




embedded image


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),
DMSO
>98
AQ6









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),












3.21 (d, J = 4.36












Hz, 3H), 2.56 (s,












3H). The 1H of












3HCl was not












observed.










1452


embedded image




embedded image




embedded image


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),
DMSO
>98
AQ6









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.










1453


embedded image




embedded image




embedded image


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, 2 H), 7.84-7.81 (m, 1H), 7.74 (dd, J = 7.84,
DMSO
>98
AQ6









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.










1454


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ6









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.










1455


embedded image




embedded image




embedded image


2 HCl

1H NMR (DMSO- d6) ppm 9.72 (s, 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,

DMSO
>98
AQ6









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.










1456


embedded image




embedded image




embedded image


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 =

DMSO
>98
AQ6









4.28 Hz, 3H),












2.65 (s, 3H). The












1H of 2HCl was












not observed.










1457


embedded image




embedded image




embedded image


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,

DMSO
>98
AQ6









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),












3.21 (d, J = 4.12












Hz, 3H), 2.47 (s,












3H). The 1H of












2HCl was not












observed.










1458


embedded image




embedded image




embedded image


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,

DMSO
>98
AQ6









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 =












4.56 Hz, 3H),












2.72 (s, 3H). The












1H of 2HCl and












NH- were not












observed.










1459


embedded image




embedded image




embedded image


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),

DMSO
>98
AQ6









7.06-7.03 (m,












1H), 6.98-6.94












(m, 2H), 3.83 (s,












3H), 3.34 (d, J =












4.56 Hz, 3H),












2.72 (s, 3H). The












1H of 2HCl and












NH- were not












observed.










1460


embedded image




embedded image




embedded image




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

DMSO
100
AQ1
366 (M + 1)
Method A (Formic acid)







(m, 1H), 1.37 (d,












J = 6.5 Hz, 6H).










1461


embedded image




embedded image




embedded image


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


embedded image




embedded image




embedded image




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



embedded image




embedded image



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
DMSO
99
Method AQ2
344.0 (M + 1)
Method C







(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).










1464



embedded image




embedded image



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 =
DMSO
99
Method AQ2
338.9 (M + 1)
Method C







8.0, 4.8, 0.8 Hz,












1H), 4.31 (s, 3H).










1465



embedded image




embedded image


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
DMSO
99
Method AQ2
359.0 (M + 1)
Method C







(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 =












8.0, 5.2 Hz, 1H),












7.81 (t, J = 8.0












Hz, 1H), 4.34 (s,












3H).










1466



embedded image




embedded image


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),
DMSO
99
Method AQ2
359.0 (M + 1)
Method C







8.14 (dd, J =












9.2, 2.4 Hz, 3H),












7.88 (dd, J =












7.8, 5.5 Hz, 1H),












4.34 (s, 3H).










1467



embedded image




embedded image


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,
DMSO
99
Method AQ2
349.6 (M + 1)
Method C







1H), 7.31 (td,












J = 8.4, 2.7 Hz,












1H), 3.22 (d, J =












4.2 Hz, 3H).































1468



embedded image




embedded image


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,
DMSO
99
Method AQ2
332.4 (M + 1)
Method C







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).










1469



embedded image




embedded image


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
DMSO
95
Method AQ2
365.3 (M + 1)
Method C







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).










1470



embedded image




embedded image


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
DMSO
94
Method AQ2
365.3 (M + 1)
Method C







Hz, 1H), 7.74 (t,












J = 8.5 Hz, 1H),












7.67 (dd, J =












10.8, 2.0 Hz, 1H),












7.51 (dd, J =












8.3, 1.6 Hz, 1H),












3.27 (d, J = 4.4












Hz, 3H).










1471



embedded image




embedded image


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
DMSO
96
Method AQ2
356.4 (M + 1)
Method C







(d, J = 4.0 Hz,












3H), 3.27 (d, J =












4.4 Hz, 3H).










1472



embedded image




embedded image


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 =
DMSO
95
Method AQ2
374.4 (M + 1)
Method C







0.8 Hz, 1H), 3.28












(d, J = 4.4 Hz,












3H).










1473



embedded image




embedded image


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,
DMSO
95
Method AQ2
377.5 (M + 1)
Method C







J = 7.7, 5.2 Hz,












1H), 7.63 (t, J =












8.3 Hz, 1H), 7.37-












7.23 (m, 2H),












3.27 (d, J = 4.5












Hz, 3H), 2.56 (s,












J = 5.2 Hz, 3H).










1474



embedded image




embedded image


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,
DMSO
96
Method AQ2
409.5 (M + 1)
Method C







3H).










1475



embedded image




embedded image


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
DMSO
99
Method AQ2
357.5 (M + 1)
Method C







(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),












7.09 (d, J = 8.1












Hz, 1H), 6.10 (s,












2H), 3.29 (d, J =












4.3 Hz, 3H).










1476



embedded image




embedded image


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
DMSO
99
Method AQ2
371.5 (M + 1)
Method C







(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),












7.01 (d, J = 8.4












Hz, 1H), 4.30 (s,












4H), 3.29 (d, J =












4.4 Hz, 3H).










1477



embedded image




embedded image


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,
DMSO
99
Method AQ2
357.5 (M + 1)
Method C







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












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



embedded image




embedded image


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),
DMSO
99
Method AQ2
357.5 (M + 1)
Method C







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 =












6.9 Hz, 2H).










1479



embedded image




embedded image


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),
DMSO
99
Method AQ2
380.5 (M + 1)
Method C







7.85 (s, 1H),












7.70 (d, J = 8.5












Hz, 2H), 3.30 (d,












J = 4.3 Hz, 3H),












1.74 (s, 6H).










1480



embedded image




embedded image


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,
DMSO
99
Method AQ2
393.4 (M + 1)
Method C







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),












7.60 (d, J = 8.5












Hz, 1H), 3.29 (d,












J = 4.3 Hz, 3H).










1481


embedded image




embedded image




embedded image



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,
DMSO
99
Method AQ2, fol- lowed by hydrol- ysis with 30% H2O2
374.5 (M + 1)
Method C







1H), 7.86 (d, J =


and









8.7 Hz, 2H),


NAOH









7.77-7.61 (m,


in









3H), 7.53 (dd, J =


ethanol









7.9, 4.8 Hz, 1H),












7.40 (t, J = 7.6












Hz, 1H), 3.15 (d,












J = 4.3 Hz, 3H).










1482




embedded image


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 =
DMSO
94
Method AQ1, except that dioxane water was replaced with DME/
368.5 (M + 1)
Method C







8.9 Hz, 1H), 8.20


water/









(d, J = 8.4 Hz,


EtOH in









1H), 7.84 (dd, J =


the









7.8, 4.8 Hz,


micro-









1H), 7.79-7.68


wave









(m, 2H), 6.95 (d,


at 120°









J = 8.0 Hz, 1H),


C. for









3.57 (s, 2H),


10 min









3.29 (d, J = 4.3












Hz, 3H).










1483




embedded image


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),
DMSO
99
Method AQ1, except that dioxane water was replaced with DME/
368.5 (M + 1)
Method C







7.83 (dd, J = 6.9,


water/









4.3 Hz, 1H),


EtOH in









7.40 (q, J = 8.3


the









Hz, 2H), 7.20 (s,


micro-









1H), 3.56 (s, 2H),


wave









3.29 (d, J = 4.1


at 120°









Hz, 3H).


C. for












10 min







1484




embedded image


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
DMSO
99
Method AQ1, except that dioxane water was replaced with DME/
357.5 (M + 1)
Method C







Hz, 1H), 7.94-


water/









7.78 (m, 3H), 7.50


EtOH in









(d, J = 8.3 Hz,


the









2H), 4.49 (s, 2H),


micro-









3.39-3.23 (m, 6H).


wave












at 120°












C. for












10 min







1485




embedded image



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),
DMSO
95
Method G1, AQ1
377.0 379.0 (M + 1)
Method C







7.43 (t, J =












8.0 Hz, 1H), 7.06-












6.98 (m, 3H),












3-82 (s, 3H),










1486




embedded image


2HCl
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
DMSO
95
Method G1, AQ1
401.1 (M + 1)
Method B (NH4HCO3)







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,












3H), 3.44 (s, 3H),












1.35 (d, J = 6.4












Hz, 3H).










1487




embedded image


2HCl
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,
MeOD
95
Method G1, AQ1
415.1 (M + 1)
Method B (NH4HCO3)







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,












3H), 1.37 (s, 6H).










1488




embedded image


2HCl
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),
DMSO
95
Method G1, AQ1
400.9 (M + 1)
Method B (NH4HCO3)







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,












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




embedded image



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,
DMSO
95
Method G1, AQ1
377.1, 379.1 (M + 1)
Method B (NH4HCO3)







3H), 7.04-7.01












(m, 1H), 3.88 (s,












3H), 3.19 (d, J =












4.0 Hz, 3H).










1490




embedded image


2HCl
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),
DMSO
95
Method G1, AQ1
427.2 (M + 1)
Method B (NH4HCO3)







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),












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




embedded image


3HCl
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,
DMSO
95
Method G1, AQ1
488.0 (M + 1)
Method B (NH4HCO3)







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),












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




embedded image


2HCl
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 =
DMSO
95
Method G1, AQ1
496.2 (M + 1)
Method B (NH4HCO3)







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,












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




embedded image


2HCl
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,
DMSO
95
Method G1, AQ1
428.1, 429.1, (M + 1)
Method B (NH4HCO3)







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).










1495




embedded image


2HCl
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
DMSO
95
Method G1, AQ1
442.1, 443.1, (M + 1)
Method B (NH4HCO3)







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).










1496




embedded image


2HCl
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 =
DMSO
95
Method G1, AQ1
413.1, 414.1 (M + 1)
Method B (NH4HCO3)







8.1 Hz, 1H),












7.85 (s, 1H), 7.47












(d, J = 5.8 Hz,












3H), 7.05 (d,












J = 3.4 Hz, 1H),












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




embedded image


2HCl
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),
DMSO- d6
95
Method G1, AQ1
415.1 (M + 1)
Method B (NH4HCO3)







4.30-4.18 (m,












2H), 3.80-3.70












(m, 2H), 3.44 (t,












J = 6.6 Hz, 2H),












3.31 (d, J = 4.2












Hz, 3H), 1.56-












1.54 (m, 2H),












0.89 (t, J = 7.4 Hz,












3H).










1498




embedded image


2HCl
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
DMSO
95
Method G1, AQ1
373.1 (M + 1)
Method B (NH4HCO3)







Hz, 2H), 7.02












(dd, J = 8.2, 2.3












Hz, 1H), 3.97 (s,












3H), 3.84 (s, 3H),










1499




embedded image


2HCl
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, 2 = 8.5 Hz, 1H), 8.22 (d, J =
DMSO
95
Method G1, AQ1
415.1 (M + 1)
Method B (NH4HCO3)







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),












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




embedded image


2HCl
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,
CD3OD
95
Method G1, AQ1
468.1 (M + 1)
Method B (NH4HCO3)







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,












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




embedded image


2HCl
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),
DMSO
95
Method G1, AQ1
428.1 (M + 1)
Method B (NH4HCO3)







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












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
  
  


embedded image



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), 788 (d, J = 9.2 Hz, 1H), 7.61-
DMSO
95
Method G1, AQ1
413.1 (M + 1)
Method B (NH4HCO3)







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, 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




embedded image


2HCl
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),
CD3OD
95
Method G1, AQ1
496.2 (M + 1)
Method B (NH4HCO3)







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,












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




embedded image



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-
DMSO
95
Method G1, AQ1
372.9 (M + 1)
Method B (NH4HCO3)







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).










1505




embedded image



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, 7 = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.73-7.71 (m,
DMSO
95
Method G1, AQ1
367.0 (M + 1)
Method B (NH4HCO3)







1H), 7.46 (t, J =












10.0 Hz, 1H),












7.33-7.27 (m,












2H), 3.16 (d,












J = 4.4 Hz, 3H).










1506




embedded image



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),
DMSO
95
Method G1, AQ1
366.9 (M + 1)
Method B (NH4HCO3)







7.42-7.37 (m,












1H), 3.12 (d,












J = 3.0 Hz, 3H).










1507




embedded image



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,
DMSO
95
Method G1, AQ1
367.1 (M + 1)
Method B (NH4HCO3)







J = 4.4 Hz, 3H).










1508




embedded image


2HCl

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,

DMSO
95
Method G1, AQ1
367.0 (M + 1)
Method B (NH4HCO3)







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).










1509




embedded image


2HCl

1H-NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 9.55 (d, J = 1.8 Hz, 1H), 9.07 (d, J = 7.2 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 =

DMSO
95
Method G1, AQ1
363.1 (M + 1)
Method B (NH4HCO3)







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).










1510




embedded image


2HCl

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,

DMSO
95
Method G1, AQ1
363.0 (M + 1)
Method B (NH4HCO3)







J = 12.7, 7.6












Hz, 1H), 3.20 (d,












J = 4.4 Hz, 3H),












2.94 (s, 3H).










1511




embedded image


2HCl

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-

DMSO
95
Method G1, AQ1
362.9 (M + 1)
Method B (NH4HCO3)







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).










1512




embedded image


2HCl

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),

DMSO
95
Method G1, AQ1
417.1 (M + 1)
Method B (NH4HCO3)







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).










1513




embedded image


2HCl

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,

DMSO
95
Method G1, AQ1
363.1 (M + 1)
Method B (NH4HCO3)







J = 7.2 Hz, 2H),












1.48 (t, J = 7.2












Hz, 3H).










1514




embedded image


2HCl

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 =

DMSO
95
Method G1, AQ1
363.1 (M + 1)
Method B (NH4HCO3)







7.2 Hz, 3H).










1515




embedded image


2HCl

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




embedded image


2HCl

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

DMSO
95
Method G1, AQ1
417.1 (M + 1)
Method B (NH4HCO3)







(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).










1517




embedded image




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,

DMSO
95
Method G1, AQ1
428.9 (M + 1)
Method B (NH4HCO3)







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).










1518




embedded image




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),

DMSO
95
Method G1, AQ1
345.1 (M + 1)
Method B (NH4HCO3)







7.87-7.81 (m,












2H), 7.58-7.49












(m, 1H), 7.39-












7.30 (m, 2H),












3.49 (s, 6H).










1519




embedded image




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

DMSO
95
Method G1, AQ1
361.1 363.1 (M + 1)
Method B (NH4HCO3)







Hz, 2H), 7.62-












7.48 (m, 3H),












3.48 (s, 6H).










1520




embedded image




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 =

DMSO
95
Method G1, AQ1
352.1 (M + 1)
Method B (NH4HCO3)







5.2 Hz, 1H), 3.51












(s, 6H).










1521




embedded image




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,

DMSO
95
Method G1, AQ1
428.1 (M + 1)
Method B (NH4HCO3)







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).










1522




embedded image


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




embedded image




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,

DMSO
95
Method G1, AQ1
400.9 (M + 1)
Method B (NH4HCO3)







2H).










1524




embedded image




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),

DMSO
95
Method G1, AQ1
414.1 (M + 1)
Method B (NH4HCO3)







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).










1525




embedded image




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

DMSO
95
Method G1, AQ1
324.1 (M + 1)
Method B (NH4HCO3)







Hz, 1H).










1526




embedded image




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),

DMSO
95
Method G1, AQ1
329.1 (M + 1)
Method B (NH4HCO3)







7.10 (d, J = 8.4












Hz, 2H), 3.83 (s,












3H).










1527




embedded image




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,

DMSO
95
Method G1, AQ1
333.1, 335.0 (M + 1)
Method B (NH4HCO3)







4.8 Hz, 1H).










1528




embedded image


2HCl

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

DMSO
95
Method G1, AQ1
338.1 (M + 1)
Method B (NH4HCO3)







Hz, 1H), 7.88 (d,












J = 7.6 Hz, 1H),












7.74 (t, J = 8.0












Hz, 1H), 2.77 (s,












3H).










1529




embedded image


2HCl

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),

DMSO
95
Method G1, AQ1
434.1 (M + 1)
Method B (NH4HCO3)







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).










1530




embedded image


2HCl

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,

DMSO
95
Method G1, AQ1
420.1 (M + 1)
Method B (NH4HCO3)







3H).










1531




embedded image




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),

DMSO
95
Method G1, AQ1
418.1 (M + 1)
Method B (NH4HCO3)







4.48 (s, 2H),












4.15 (s, 2H), 3.48












(s, 2H).










1532




embedded image




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,

DMSO
95
Method G1, AQ1
442.0 (M + 1)
Method B (NH4HCO3)







J = 13.4 Hz, 2H).










1533




embedded image


2HCl

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,

DMSO
95
Method G1, AQ1
377.1 (M + 1)
Method B (NH4HCO3)







J = 1.2 Hz, 6H).










1534




embedded image


2HCl

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),

DMSO
95
Method G1, AQ1
391.1 (M + 1)
Method B (NH4HCO3)







1.66 (s, 9H).










1535




embedded image


2HCl

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,

DMSO
95
Method G1, AQ1
446.0 (M + 1)
Method B (NH4HCO3)







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).










1536




embedded image


2HCl

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),

DMSO
95
Method G1, AQ1
446.1 (M + 1)
Method B (NH4HCO3)







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).










1537




embedded image




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),

DMSO
95
Method G1, AQ1

Method B (NH4HCO3)







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












(m, 5H), 1.70-1.56












(m, 1H).










1538




embedded image




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),

DMSO
95
Method G1, AQ1
426.1, 427.1 (M + 1)
Method B (NH4HCO3)







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).































1539
  
  


embedded image


2HCl

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

DMSO
95
Method G1, AQ1
414.0, 415.0 (M + 1)
Method B (NH4HCO3)







(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).










1540




embedded image


2HCl

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,

DMSO
95
Method G1, AQ1
428.1, 429.1 (M + 1)
Method B (NH4HCO3)







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).










1541




embedded image


2HCl

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 =

DMSO
95
Method G1, AQ1
411.1 (M + 1)
Method B (NH4HCO3)







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).










1542




embedded image


2HCl

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,

DMSO
95
Method G1, AQ1
510.2 (M + 1)
Method B (NH4HCO3)







7H), 1.24-1.07












(m, 6H), 0.89-












0.81 (m, 2H).










1543




embedded image




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,

DMSO
95
Method G1, AQ1
359.1 (M + 1)
Method B (NH4HCO3)







1H), 7.47 (d, J =












2.4 Hz, 1H), 7.34












(m, 2H), 3.45












(s, 6H), 2.76 (s, 3H).










1544




embedded image




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,

DMSO
95
Method G1, AQ1
375.1 (M + 1)
Method B (NH4HCO3)







6H), 2.77 (s,












3H).










1545




embedded image




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),

DMSO
95
Method G1, AQ1
359.1 (M + 1)
Method B (NH4HCO3)







7.37-7.33 (m,












2H), 3.50 (s, 6H),












2.78 (s, 3H).










1546




embedded image




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

CD3OD
95
Method G1, AQ1
416.1 (M + 1)
Method B (NH4HCO3)







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),












3.86 (dd, J = 13.7,












7.4 Hz, 1H),












3.80 (s, 3H).










1547




embedded image


2HCl

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-

CD3OD
95
Method G1, AQ1
457.0 (M + 1)
Method B (NH4HCO3)







4.41 (m, 1H),












4.29-4.27 (m,












1H), 2.37-2.16












(m, 3H), 2.09-












2.07 (m, 1H).










1548




embedded image


2HCl

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,

CD3OD
95
Method G1, AQ1
457.1 (M + 1)
Method B (NH4HCO3)







1H), 2.51-2.30












(m, 3H), 2.19-












2.18 (m, 1H).










1549




embedded image


2HCl

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, 1 H), 7.49- 7.48 (m, 3H), 7.07-7.04 (m, 1H), 3.94-3.89 (m, 5H), 3.60-

DMSO
95
Method G1, AQ1
387.1 (M + 1)
Method B (NH4HCO3)







3.57 (m, 2H),












1.96-1.93 (m,












2H).










1550




embedded image




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,

DMSO
95
Method G1, AQ1
343.1 (M + 1)
Method B (NH4HCO3)







3H), 2.74 (s, 3H).










1551




embedded image




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),

DMSO
95
Method G1, AQ1
331.1 (M + 1)
Method B (NH4HCO3)







2.84 (s, 3H).










1552




embedded image



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




embedded image


2HCl

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




embedded image


2HCl

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 (s1H), 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,

CD3OD
95
Method G1, AQ1
380.9 (M + 1)
Method B (NH4HCO3)







1H), 4.81 (t, J =












4.8 Hz, 1H),












4.39-4.30 (m,












2H).










1555




embedded image




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




embedded image




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,

DMSO
95
Method G1, AQ1
493.0 495.0 (M + 1)
Method B (NH4HCO3)







1H), 3.98-3.83












(m, 1H), 3.38 (s,












3H), 2.49-2.40












(m, 1H), 2.35-












2.18 (m, 1H).










1557




embedded image




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 =

DMSO
95
Method G1, AQ1
489.1 (M + 1)
Method B (NH4HCO3)







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,












7H), 2.44-2.33












(m, 1H), 2.29-












2.15 (m, 1H).










1558




embedded image




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,

DMSO
95
Method G1, AQ1
506.1 (M + 1)
Method B (NH4HCO3)







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).










1559




embedded image


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




embedded image


2HCl

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-

DMSO
95
Method G1, AQ1
508.2 (M + 1)
Method B (NH4HCO3)







3.81 (m, 5H),












3.21 (d, J = 9.0












Hz, 1H), 2.94 (d,












J = 7.3 Hz, 2H).










1561




embedded image




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,

DMSO
95
Method G1, AQ1
503.9 (M + 1)
Method B (NH4HCO3)







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).










1562




embedded image




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),

DMSO
95
Method G1, AQ1
489.9 (M + 1)
Method B (NH4HCO3)







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).










1563




embedded image




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




embedded image




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 =

DMSO
95
Method G1, AQ1
507.2 (M + 1)
Method B (NH4HCO3)







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),












3.69 (s, 3H), 3.62












(s, 3H), 3.56












(d, J = 8.0 Hz,












3H), 3.16-3.02












(m, 2H).










1565




embedded image




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 =

DMSO
95
Method G1, AQ1
522.3 (M + 1)
Method B (NH4HCO3)







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).










1566




embedded image




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,

DMSO
95
Method G1, AQ1
524.2, 526.2 (M + 1)
Method B (NH4HCO3)







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).










1567




embedded image




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




embedded image


2HCl

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),

DMSO
95
Method G1, AQ1
504.1 (M + 1)
Method B (NH4HCO3)







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),












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




embedded image


2HCl

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),

DMSO
95
Method G1, AQ1
518.1 (M + 1)
Method B (NH4HCO3)







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,












3H), 3.87-3.82 (m,












2H), 2.26 (t,












J = 7.0 Hz, 2H),












1.84-1.69 (m,












4H).










1570




embedded image




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

DMSO
95
Method G1, AQ1
451.2, 452.2, 453.2 (M + 1)
Method B (NH4HCO3)







(s, 2H), 3.79 (s,












3H), 3.54 (s, 3H).










1571




embedded image


2HCl

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,

DMSO
95
Method G1, AQ1
508.1, 509.1, 510.1 (M + 1)
Method B (NH4HCO3)







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 =












13.6, 7.9 Hz,












1H), 2.87 (dd, J =












13.6, 6.7 Hz, 1H).










1572




embedded image


2HCl

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

DMSO
95
Method G1, AQ1
524.1, 525.1, 526.0 (M + 1)
Method B (NH4HCO3)







(d, J = 7.2 Hz,












2H).










1573




embedded image


2HCl

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),

DMSO
95
Method G1, AQ1
504.1, 505.2, 506.1 (M + 1)
Method B (NH4HCO3)







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).










1574




embedded image


2HCl

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,

DMSO
95
Method G1, AQ1
504.1 (M + 1)
Method B (NH4HCO3)







1H), 2.87-2.81












(m, 1H), 2.29 (s,












3H).































1575




embedded image




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 =

CD3OD
95
Method G1, AQ1
459.0 (M + 1)
Method B (NH4HCO3)







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).










1576




embedded image




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-

DMSO
95
Method G1, AQ1
527.0, 529.0 (M + 1)
Method B (NH4HCO3)







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).










1577




embedded image


2HCl

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




embedded image




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




embedded image


2HCl

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),

DMSO
95
Method G1, AQ1
491.2 (M + 1)
Method B (NH4HCO3)







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).










1580




embedded image


2HCl

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




embedded image


2HCl

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),

DMSO
95
Method G1, AQ1
440.2 (M + 1)
Method B (NH4HCO3)







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).










1583




embedded image


2HCl
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
DMSO
95
Method AQ2, AP
361.7 (M + 1)
Method C







(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).










1584




embedded image


2HCl
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,
DMSO
95
Method AQ2, AP
343.5 (M + 1)
Method C







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)










1585




embedded image


2HCl
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
DMSO
95
Method AQ2, AP
356.4 (M + 1)
Method C







Hz, 2H), 8.00 (d,












J = 8.2 Hz, 1H),












7.91 (s, 1H), 3.30












(d, J = 4.4 Hz,












3H).










1586




embedded image



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 =
DMSO
95
Method AQ2, AP
356.4 (M + 1)
Method C







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).










1587




embedded image



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,
DMSO
95
Method AQ2, AP
401.5 (M + 1)
Method C







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).










1588




embedded image


2HCl
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
DMSO
95
Method AQ2, AP
361.5 (M + 1)
Method C







Hz, 1H), 7.38












(dd, J = 22.8,












11.6 Hz, 2H), 4.03












(s, 3H), 3.31 (d,












J = 4.1 Hz, 3H).










1589




embedded image


2HCl
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 =
DMSO
95
Method AQ2, AP
361.5 (M + 1)
Method C







10.9 Hz, 1H),












3.90 (s, 1H), 3.30












(d, J = 4.3 Hz, 3H).










1590




embedded image


2HCl
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,
DMSO
95
Method AQ2, AP
361.3 (M + 1)
Method C







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).










1591




embedded image


2HCl
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 =
DMSO
95
Method AQ2, AP
361.3 (M + 1)
Method C







8.8 Hz, 1H), 7.11-












6.97 (m, 2H), 3.86












(s, 3H), 3.30












(d, J = 4.4 Hz, 3H).










1592




embedded image


3HCl
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
DMSO
95
Method AQ2, AP
343.1 (M + 1)
Method C







(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).










1593




embedded image


2HCl

DMSO
95
Method AQ2, AP
359.1 (M + 1)
Method C





1594




embedded image



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),
DMSO
95
Method AQ2, AP
371.1 (M + 1)
Method C







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),












3.18 (d, J = 4.4












Hz, 3H), 1.82-












1.69 (m, 2H),












1.07 (d, J = 6.7 Hz,












3H).










1595




embedded image


2HCl
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,
DMSO
95
Method AQ2, AP
443.5 (M + 1)
Method C







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).










1596




embedded image


2HCl
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),
DMSO
95
Method AQ2, AP
428.5 (M + 1)
Method C







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












Hz, 3H), 1.98-1.81












(m, 4H).










1597




embedded image


2HCl
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),
DMSO
95
Method AQ2, AP
349.4 (M + 1)
Method C







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).










1598




embedded image



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),
DMSO
95
Method AQ2, AP
373.4 (M + 1)
Method C







7.05-6.97 (m, 1H),












3.96 (s, 3H),












3.87 (s, 3H), 3.19












(d, J = 4.3 Hz,












3H).










1599




embedded image


2HCl
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 =
DMSO
95
Method AQ2, AP
343.5 (M + 1)
Method C







7.9 Hz, 1H),












7.54 (d, J = 7.6












Hz, 1H), 7.43 (d,












J = 7.5 Hz, 1H),












4.64 (s, 2H),












3.33 (d, J = 4.2 Hz,












3H), 3.17 (s, 1H).










1600




embedded image


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,
DMSO
95
Method AQ2, AP
343.5 (M + 1)
Method C







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 Hz, 1H),












4.63 (s, 2H), 3.30












(d, J = 4.3 Hz, 3H),












2.32 (s, 3H).










1601


embedded image




embedded image




embedded image


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),

DMSO
>98
G2/ AQ3









7.64 (ddd,












J = 9.2, 6.1, 3.1












Hz, 1H), 7.58-












7.31 (m, 2H), 3.28












(d, J = 4.5 Hz,












3H), 2.39 (s, 3H).










1602


embedded image




embedded image




embedded image




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

DMSO
>98
G2/ AQ3









Hz, 1H), 8.12












(brs, 2H), 7.91 (d,












J = 8.7 Hz,












1H), 7.55 (dd, J =












7.9, 4.8 Hz, 1H).










1603


embedded image




embedded image




embedded image




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

DMSO
>98
G2/ AQ3









Hz, 1H), 7.54












(dd, J = 7.9, 4.8












Hz, 1H), 4.00 (s,












3H), 3.98 (s, 3H).










1604


embedded image




embedded image




embedded image




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

DMSO
>98
G2/ AQ3









Hz, 1H), 7.66 (t,












J = 7.6 Hz, 1H),












7.56 (dd, J = 7.9,












4.8 Hz, 1H).










1605


embedded image




embedded image




embedded image




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

DMSO
>98
G2/ AQ3









Hz, 2H), 7.88 (d,












J = 8.7 Hz, 1H),












7.55 (dd, J =












7.9, 4.8 Hz, 1H).










1606


embedded image




embedded image




embedded image


2HCl

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

DMSO
>98
G2/ AQ3









Hz, 1H), 8.21 (d,












J = 8.7 Hz, 1H),












7.93 (dd, J = 8.0,












5.1 Hz, 1H),












7.79 (td, 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


embedded image




embedded image




embedded image


3HCl

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 =

DMSO
>98
G2/ AQ3









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).










1608


embedded image




embedded image




embedded image


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,

DMSO
100
Method AQ2/BF









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,












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


embedded image




embedded image




embedded image


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,

DMSO
100
Method AQ2/BF









1H), 7.77-7.58












(m, 1H), 3.25 (d,












J = 4.1 Hz, 3H).










1610


embedded image




embedded image




embedded image


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

DMSO
>98
G2/ AQ3
Method 3








(dd, J = 8.0, 5.3












Hz, 1H), 7.69-












7.47 (m, 2H),












7.47-7.34 (m,












1H), 3.30 (d, J =












4.5 Hz, 3H),












2.42 (s, 6H).










1611


embedded image




embedded image




embedded image


2HCl

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 =

DMSO
>98
G2/ AQ3









8.7 Hz, 1H),












7.94 (dd, 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


embedded image




embedded image




embedded image


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,

DMSO
>98
G2/ AQ3









3H).










1613


embedded image




embedded image




embedded image




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

DMSO
>98
G2/ AQ3









(dd, J = 7.9,












4.8 Hz, 1H), 3.17












(d, J = 4.4 Hz,












3H).










1614


embedded image




embedded image




embedded image




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

DMSO
>98
G2/ AQ3
Method 3








(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).










1615


embedded image




embedded image




embedded image




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),

DMSO
>98
G2/ AQ3
Method 3








3.18 (d, J =












4.3 Hz, 3H).










1760


embedded image




embedded image




embedded image


2 HCl

1H NMR (400 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

DMSO
>98
AQ5
ND
4







(d, J = 4.6 Hz,












3H), 2.47 (s, 3H).











embedded image




embedded image


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















Pur-
Method







1H-


Re-

ity
for


Num-



NMR

tention
LCMS
Per-
Coup-


ber
Product
Salt

1H-NMR

Solvent
LCMS
Time
Protocol
cent
ling





1616


embedded image


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
Method C
100
Method AP





1617


embedded image


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
Method C
100
Method AP





1618


embedded image


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
Method D
100
Method AP





1619


embedded image


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
Method D
100
Method AP





1620


embedded image


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 Hz, 3H).
DMSO
MS not work
1.56
Method D
100
Method AP





1621


embedded image



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
Method D
100
Method AP





1622


embedded image


HCl
1H NMR (300 MHz, DMSO) δ 9.56 (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
Method D
100
Method AP





1623


embedded image



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
Method C
100
Method AP





1624


embedded image


2HCl
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
Method C
 95
Method AP





1625


embedded image



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
Method C
100
Method AP





1626


embedded image


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, 7H).
DMSO
358.0 (M + 1)
2.25
Method C
100
Method AP





1627


embedded image


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
Method C
100
Method AP





1628


embedded image



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
Method C
100
Method AP





1629


embedded image



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), 1.53 (t, J = 7.0 Hz, 3H).
DMSO
358 (M + 1)

Method C
 99
Method AP





1630


embedded image


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)

Method C
 99
Method AP





1631


embedded image


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)

Method C
 99
Method AP





1632


embedded image


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)

Method C
 99
Method AP





1633


embedded image



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)

Method C
 99
Method AP













Num-





ber
Starting Material R1
Starting Material R3
Product





1634


embedded image




embedded image




embedded image







1635


embedded image




embedded image




embedded image







1636


embedded image




embedded image




embedded image







1637


embedded image




embedded image




embedded image







1638


embedded image




embedded image




embedded image







1639


embedded image




embedded image




embedded image







1640


embedded image




embedded image




embedded image







1641


embedded image




embedded image




embedded image







1642


embedded image




embedded image




embedded image







1643


embedded image




embedded image




embedded image







1644


embedded image




embedded image




embedded image







1645


embedded image




embedded image




embedded image







1646


embedded image




embedded image




embedded image







1647


embedded image




embedded image




embedded image







1648


embedded image




embedded image




embedded image







1649


embedded image




embedded image




embedded image







1650


embedded image




embedded image




embedded image







1651


embedded image




embedded image




embedded image







1652


embedded image




embedded image




embedded image







1653


embedded image




embedded image




embedded image







1654


embedded image




embedded image




embedded image







1655


embedded image




embedded image




embedded image







1656


embedded image




embedded image




embedded image







1657


embedded image




embedded image




embedded image







1658


embedded image




embedded image




embedded image







1659


embedded image




embedded image




embedded image







1660


embedded image




embedded image




embedded image







1661


embedded image




embedded image




embedded image







1662


embedded image




embedded image




embedded image







1663


embedded image




embedded image




embedded image







1664


embedded image




embedded image




embedded image







1665


embedded image




embedded image




embedded image







1666


embedded image




embedded image




embedded image







1667


embedded image




embedded image




embedded image







1668


embedded image




embedded image




embedded image







1669


embedded image




embedded image




embedded image







1670


embedded image




embedded image




embedded image







1671


embedded image




embedded image




embedded image







1672


embedded image




embedded image




embedded image







1673




embedded image







1674




embedded image







1675




embedded image







1676




embedded image







1677




embedded image







1678
NH3



embedded image




















Salt


1HNMR

Purity
Method



Number
Type

1H NMR

Solvent
percent
of Coupling






1634


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





4.78 (d, 2H, J = 5.4 Hz), 6.58 (d, 1H, J =


F5, G2





1.1 Hz), 7.00-7.75 (m, 8H), 7.85 (d,


(reflux)





1H, J = 8.6 Hz), 8.64-8.97 (m, 4H),








9.64 (s, 1H)






1635


1H NMR (DMSO-d6) ppm 3.84-3.95 (m,

DMSO
>98
Method AQ3,





11H), 7.01 (d, 1H, J = 8.1 Hz), 7.32-


F5, G2





7.46 (m, 3H), 7.56 (dd, 1H, J = 6.1, 8.1


(reflux)





Hz), 7.97 (d, 1H, J = 8.2 H), 8.16-








8.76 (m, 4H), 9.61 (s, 1H)






1636


1H NMR (DMSO-d6) ppm 2.23 (m, 2H),

DMSO
>98
Method AQ3,





3.85 (s, 3H), 4.71 (br s, 4H), 6.98 (dd,


F5, G2





1H, J = 2.1, 8.0 Hz), 7.31-7.55 (m, 4H),


(reflux)





7.87 (d, 1H, J = 8.2 Hz), 8.12-8.74 (m,








4H), 9.59 (s, 1H)






1637

1H NMR (DMSO-d6) ppm 1.77 (br s,
DMSO
>98
Method AQ3,





6H), 3.86-3.89 (br m, 7H), 6.99 (dd,


F5, G2





1H, J = 1.4, 8.6 Hz), 7.31-7.57 (m, 4H),


(reflux)





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)






1638

1H NMR (DMSO-d6) ppm 2.18-2.22
DMSO
>98
Method AQ3,





(m, 1H), 3.00-3.09 (m, 1H), 3.11-3.22


F5, G2





(m, 2H), 3.31-3.34 (m, 1H), 3.86 (s,


(relux)





3H), 6.29-6.31 (m, 1H), 7.17-8.82 (m,








14H), 9.63 (s, 1H)






1639

1H NMR (DMSO-d6) ppm 3.87 (s, 3H),
DMSO
>98
Method AQ3,





4.10-4.13 (m, 2H), 4.35-4.38 (m, 2H),


F5, G2





6.92-7.46 (m, 10H), 7.85 (d, 1H, J =


(reflux)





8.6 Hz), 8.16 (d, 1H, J = 8.6 Hz), 8.66-








8.75 (m, 4H), 9.61 (s, 1H)






1640

1H NMR (DMSO-d6) ppm 3.07 (t, 2H,
DMSO
>98
Method AQ3,





J = 6.9 Hz), 3.87 (s, 3H), 3.92-3.96 (m,


F5, G2





2H), 7.00-7.58 (m, 10H), 7.84 (d, 1H, J =


(reflux)





8.6 Hz), 8.14 (d, 1H, J = 8.6 Hz),








8.59-8.78 (m, 4H), 9.64 (s, 1H)






1641

1H NMR (DMSO-d6) ppm 3.87 (s, 3H),
DMSO
>98
Method AQ3,





4.95 (d, 2H, J = 5.6 Hz), 7.01-7.51 (m,


F5, G2





10H), 7.85 (d, 1H, J = 8.6 Hz), 8.16 (d,


(reflux)





1H, J = 8.6 Hz), 8.65-8.73 (m, 4H),








9.56 (s, 1H)






1642

1H NMR (DMSO-d6) ppm 1.66-1.781
DMSO
>98
Method AQ3,





(m, 6H), 2.16-2.19 (m, 2H), 3.87 (s,


F5, G2





3H), 4.78 (br s, 1H), 7.00-7.55 (m, 5H),


(reflux)





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)






1643
HCl
1H NMR (DMSO-d6) ppm 0.81 (t, 3H,
DMSO
>98
Method AQ3,





J = 7.4 Hz), 1.47-1.54 (m, 2H), 2.00-


F5, G2





2.05 (m, 2H), 3.32-3.37 (m, 4H), 3.86-


(reflux)





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)






1644

1H NMR (DMSO-d6) ppm 0.38-0.54
DMSO
>98
Method AQ3,





(m, 4H), 1.30-1.32 (m, 1H), 3.58-3.62


F5, G2





(m, 2H), 3.87 (s, 3H), 7.00-7.54 (m,


(reflux)





5H), 7.86 (d, 1H, J = 8.6 Hz), 8.14 (d,








1H, J = 8.6 Hz), 8.64-8.76 (m, 4H),








9.62 (s, 1H)






1645

1H NMR (DMSO-d6) ppm 1.83-1.88
DMSO
>98
Method AQ3,





(m, 2H), 2.21-2.27 (m, 2H), 2.49 (br s,


F5, G2





2H), 3.87 (s, 3H), 4.88-4.91 (m, 1H),


(reflux)





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)






1646

1H NMR (DMSO-d6) ppm 3.21 (s, 1H),
DMSO
>98
Method AQ3,





3.88 (s, 3H), 4.52 (dd, 2H, J = 2.2, 5.2


F5, G2





Hz), 7.01-7.58 (m, 5H), 7.88 (d, 1H, J =


(reflux)





8.7 Hz), 8.19 (d, 1H, J = 8.6 Hz), 8.64-








9.01 (m, 4H), 9.66 (s, 1H)






1647

1H NMR (DMSO-d6) ppm 3.87 (s, 3H),
DMSO
>98
Method AQ3,





4.37 (br s, 2H), 5.19 (dd, 1H, J = 1.5,


F5, G2





10.2 Hz), 5.31 (dd, 1H, J = 1.5, 17.2


(reflux)





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)






1648

1H NMR (DMSO-d6) ppm 0.94-0.99 (t,
DMSO
>98
Method AQ3,





6H, J = 7.4 Hz), 1.68-1.80 (m, 4H),


F5, G2





3.87 (s, 3H), 4.49-4.52 (m, 1H), 7.01-


(reflux)





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)






1649

1H NMR (DMSO-d6) ppm 1.68 (s, 9H),
DMSO
>98
Method AQ3,





3.87 (s, 3H), 7.01-7.70 (m, 6H), 7.82


F5, G2





(d, 1H, J = 8.6 Hz), 8.11 (d, 1H, J = 8.6


(reflux)





Hz), 8.67-8.74 (m, 3H), 9.60 (s, 1H)






1650

1H NMR (DMSO-d6) ppm 0.97 (t, 3H,
DMSO
>98
Method AQ3,





J = 7.2 Hz), 1.44-1.48 (m, 2H), 1.74-


F5, G2





1.78 (m, 2H), 3.71-3.75 (m, 2H), 3.89


(reflux)





(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)






1651

1H NMR (DMSO-d6) ppm 3.87 (s, 3H),
DMSO
>98
Method AQ3,





4.98 (d, 2H, J = 5.6 Hz), 7.02-7.46 (m,


F5, G2





7H), 7.87 (d, 1H, J = 8.7 Hz), 8.51 (dd,


(reflux)





1H, J = 1.5, 4.5 Hz), 8.50-8.71 (m, 5H),








9.26 (s, 1H), 9.48 (s, 1H)






1652

1H NMR (DMSO-d6) ppm 3.87 (s, 3H),
DMSO
>98
Method AQ3,





4.98 (d, 2H, J = 5.5 Hz), 7.00-7.46 (m,


F5, G2





6H), 7.86-7.90 (m, 2H), 8.16 (d, 1H, J =


(reflux)





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)






1653

1H NMR (DMSO-d6) ppm 3.22-3.27
DMSO
>98
Method AQ3,





(m, 2H), 3.87 (s, 3H), 4.04-4.11 (m,


F5, G2





2H), 7.02-7.46 (m, 8H), 7.83 (d, 1H, J =


(reflux)





8.6 Hz), 8.13 (d, 1H, J = 1.6 Hz),








8.67-8.78 (m, 5H), 9.64 (s, 1H)






1654

1H NMR (DMSO-d6) ppm 1.76-1.88
DMSO
>98
Method AQ3,





(m, 4H), 2.66 (br s, 1H), 3.37-3.48 (m,


F5, G2





2H), 3.86 (s, 3H), 4.39-4.47 (m, 2H),


(reflux)





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)






1655


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





4.97 (d, 2H, J = 5.6 Hz), 7.00-7.50 (m,


F5, G2





8H), 7.85 (d, 1H, J = 8.7 Hz), 8.16 (s,


(reflux)





1H), 8.66-8.77 (m, 3H), 9.11 (s, 1H),








9.61 (s, 1H)






1656


1H NMR (DMSO-d6) ppm 2.28 (s, 3H),

DMSO
>98
Method AQ3,





3.87 (s, 3H), 4.91 (d, 2H, J = 5.5 Hz),


F5, G2





7.00-7.52 (m, 9H), 7.86 (d, 1H, J = 8.6


(reflux)





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)






1657


1H NMR (DMSO-d6) ppm 3.71 (s, 3H),

DMSO
>98
Method AQ3,





3.87 (s, 3H), 4.91 (d, 2H, J = 5.7 Hz),


F5, G2





6.82-7.52 (m, 9H), 7.86 (d, 1H, J = 8.7


(reflux)





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)






1658


1H NMR (DMSO-d6) ppm 2.25 (s, 3H),

DMSO
>98
Method AQ3,





3.87 (s, 3H), 4.91 (d, 2H, J = 5.7 Hz),


F5, G2





7.00-7.53 (m, 9H), 7.86 (d, 1H, J = 8.6


(reflux)





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)






1659


1H NMR (DMSO-d6) ppm 2.44 (s, 3H),

DMSO
>98
Method AQ3,





3.86 (s, 3H), 4.95 (d, 2H, J = 5.7 Hz),


F5, G2





7.01-7.53 (m, 9H), 7.86 (d, 1H, J = 8.6


(reflux)





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)






1660


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





7.03 (s, 1H), 7.44-7.94 (m, 10H), 8.07-


F5, G2





8.70 (m, 4H), 9.41 (s, 1H)


(reflux)



1661


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





4.91 (d, 2H, J = 5.5 Hz), 7.00-7.04 (m,


F5, G2





1H), 7.04-7.55 (m, 7H), 7.87 (d, 1H, J =


(reflux)





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)






1662


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





4.99 (d, 2H, J = 5.5 Hz), 7.01-7.05 (m,


F5, G2





2H), 7.15-7.56 (m, 6H), 7.88 (d, 1H, J =


(reflux)





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)






1663


1H NMR (DMSO-d6) ppm 3.49 (s, 3H),

DMSO
>98
Method AQ3,





3.74 (s, 3H), 5.15 (s, 2H), 6.90 (d, J =


F5, G2





8.2 Hz, 1H), 7.04-7.29 (m, 2H), 7.33-


(reflux)





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)






1664


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





4.94 (d, 2H, J = 5.5 Hz), 7.01-7.03 (m,


F5, G2





1H), 7.35-7.57 (m, 7H), 7.88 (d, 1H, J =


(reflux)





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)






1665


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





4.96 (d, 2H, J = 5.5 Hz), 7.00-7.03 (m,


F5, G2





2H), 7.33-7.52 (m, 7H), 7.88 (d, 1H, J =


(reflux)





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)






1666


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





4.93 (d, 2H, J = 5.5 Hz), 7.00-7.19 (m,


F5, G2





3H), 7.41-7.55 (m, 6H), 7.88 (d, 1H, J =


(reflux)





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)






1667


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





4.92 (d, 2H, J = 5.5 Hz), 7.01-7.03 (d,


F5, G2





1H, J = 7.0 Hz), 7.37-7.53 (m, 6H),


(reflux)





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)






1668


1H NMR (DMSO-d6) ppm 1.68 (d, 3H, J =

DMSO
>98
Method AQ3,





7.0 Hz), 3.87 (s, 3H), 4.92 (d, 2H, J =


F5, G2





5.5 Hz), 5.75-5.78 (m, 1H), 7.02 (d,


(reflux)





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)






1669


1H NMR (DMSO-d6) ppm 3.70 (s, 3H),

DMSO
>98
Method AQ3,





3.86 (s, 3H), 4.92 (d, J = 5.1 Hz, 2H),


F5, G2





6.89-7.01 (m, 3H), 7.41-7.54 (m, 6H),


(reflux)





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)






1670


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





3.91 (s, 3H), 4.92 (d, J = 5.0 Hz, 2H),


F5, G2





6.87-7.52 (m, 9H), 7.85 (d, J = 8.5 Hz,


(reflux)





1H), 8.17 (d, J = 8.5 Hz, 1H), 8.64-8.73








(m, 3H), 9.05 (s, 1H), 9.52 (s, 1H)






1671


1H NMR (DMSO-d6) ppm 3.87 (s, 3H),

DMSO
>98
Method AQ3,





4.93 (d, J = 5.6 Hz, 2H), 7.02 (s, 1H),


F5, G2





7.41-7.61 (m, 7H), 7.83 (d, J = 8.9 Hz,


(reflux)





1H), 8.18 (d, J = 8.9 Hz, 1H), 8.66-8.71








(m, 3H), 9.21 (s, 1H), 9.54 (s, 1H)






1672


1H NMR (DMSO-d6) ppm 3.69 (s, 6H),

DMSO
>98
Method AQ3,





3.87 (s, 3H), 4.93 (d, J = 5.6 Hz, 2H),


F5, G2





6.90 (s, 1H), 7.00-7.54 (m, 7H), 7.85


(reflux)





(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)






1673


DMSO
 95
Method AQ3,








AP



1674
2HCl
1H-NMR (300 MHz, DMSO): δ 9.71 (d,
DMSO
 95
Method AQ3,





J = 1.6 Hz, 1H), 9.16 (d, J = 8.2 Hz,


AP





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).






1675

1H-NMR (300 MHz, DMSO): δ 9.59 (s,
DMSO
 95
Method AQ3,





1H), 8.78-8.62 (m, 2H), 8.38 (s, 1H),


AP





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).






1676
3HCl
1H-NMR (300 MHz, DMSO): δ 10.40
DMSO
 95
Method AQ3,





(s, 1H), 9.48 (d, J = 2.0 Hz, 1H), 8.95


AP





(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).






1677

1H-NMR (300 MHz, DMSO): δ 12.83
DMSO
 95
Method AQ3,





(s, 1H), 9.32 (d, J = 2.2 Hz, 1H), 8.77


AP





(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).






1678
2HCl

1H NMR (300 MHz, DMSO) δ 9.79

DMSO
>98
Method AQ3,





(brs, 1H), 9.60 (s, 2H), 9.07 (d, J = 7.4


F5, G2





Hz, 1H), 9.00 (d, J = 4.5 Hz, 1H), 8.80


(reflux)





(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).











embedded image


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.



embedded image


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-chloroethoxyl)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-chloroethoxyl)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-methoxyethoxyl)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (lxiii-a)

A solution of 6-(3-(2-chloroethoxyl)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-methoxyethoxyl)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)



embedded image


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-morpholinoethoxyl)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)



embedded image


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)



embedded image


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










1H-


Re-

Pur-
Method






NMR

ten-

ity
for


Num-



Sol-

tion
LCMS
per-
Coup-


ber
PRODUCT
Salt

1H-NMR

vent
LCMS
Time
Protocol
cent
ling







1679


embedded image


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


embedded image



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


embedded image



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


embedded image


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


embedded image


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 (M + 1)
Method B (Ammon- ium formate)
100
Method AR/W with KI





1684


embedded image


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


embedded image


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


embedded image


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 (Ammon- ium formate)
100
Method AR/AS/ AT2





1687


embedded image


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


embedded image


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 (d, 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


embedded image


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


embedded image


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


embedded image


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


embedded image


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


embedded image


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 (Ammon- ium formate)
100
Method AR/AS/ AT3





1694


embedded image


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 (Ammon- ium formate)
100
Method AR/AS/ AT3





1695


embedded image




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











embedded image




embedded image


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 NH3H2O at 0° C. Then the mixture was extracted with dichloromethane (100 mL x 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








Mole-


1H-




Method


Num-

Salt
cular

NMR

LCMS
Purity
for


ber
PRODUCT
type
Mass

1H-NMR

Solvent
LCMS
Protocol
percent
Coupling







1697


embedded image



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 (m, 1H), 3.88 (s, 3H), 3.14 (d, J = 4.3 Hz, 3H).
DMSO
342.1 (M + 1)
Method B (NH4HCO3)
95
Method AX, H1





1698


embedded image



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 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).
DMSO
312.9 (M + 1)
Method B (NH4HCO3)
95
Method AX, H1











embedded image




embedded image


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








Starting
Starting


Number
Material 1
Material 2





1699


embedded image




embedded image







1700


embedded image




embedded image







1701


embedded image




embedded image







1702


embedded image




embedded image







1703


embedded image




embedded image







1704


embedded image




embedded image







1705


embedded image




embedded image







1706


embedded image




embedded image







1707


embedded image




embedded image







1708


embedded image




embedded image







1709


embedded image




embedded image







1710


embedded image




embedded image







1711


embedded image




embedded image







1712


embedded image




embedded image







1713


embedded image




embedded image







1714


embedded image




embedded image







1715


embedded image




embedded image





















Mass





Salt
Exact
Found
Purity


Number
Product
Type
Mass
(M + 1)
(%)





1699


embedded image



427
428
98





1700


embedded image



421
422
98





1701


embedded image


TFA
467
468
98





1702


embedded image



515
516
98





1703


embedded image


2TFA
468
469
98





1704


embedded image


TFA
436
437
98





1705


embedded image



455
456
98





1706


embedded image



438
439
98





1707


embedded image



421
422
98





1708


embedded image



453
454
98





1709


embedded image


TFA
467
468
98





1710


embedded image



487
488
98





1711


embedded image


TFA
515
516
98





1712


embedded image


TFA
436
437
98





1713


embedded image


TFA
422
423
98





1714


embedded image


TFA
476
477
98





1715


embedded image


2TFA
438
439
98











embedded image




embedded image


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







Number
Starting Material 1
Starting Material 2





1716


embedded image




embedded image







1717


embedded image




embedded image







1718


embedded image




embedded image







1719


embedded image




embedded image







1720


embedded image




embedded image







1721


embedded image




embedded image







1722


embedded image




embedded image







1723


embedded image




embedded image







1724


embedded image




embedded image







1725


embedded image




embedded image







1726


embedded image




embedded image







1727


embedded image




embedded image







1728


embedded image




embedded image







1729


embedded image




embedded image







1730


embedded image




embedded image







1731


embedded image




embedded image







1732


embedded image




embedded image







1733


embedded image




embedded image







1734


embedded image




embedded image







1735


embedded image




embedded image







1736


embedded image




embedded image







1737


embedded image




embedded image







1738


embedded image




embedded image



















Salt

Mass Found



Number
Product
Type
Exact Mass
(M + 1)
Purity (%)





1716


embedded image


TFA
489
490
100





1717


embedded image



448
449
100





1718


embedded image


TFA
422
423
100





1719


embedded image


TFA
422
423
100





1720


embedded image


TFA
472
473
100





1721


embedded image


TFA
489
490
100





1722


embedded image


TFA
489
490
100





1723


embedded image


TFA
466
467
100





1724


embedded image


TFA
425
426
 94





1725


embedded image


TFA
453
454
100





1726


embedded image


TFA
489
490
100





1727


embedded image


TFA
489
490
100





1728


embedded image


TFA
448
449
100





1729


embedded image


TFA
422
423
100





1730


embedded image


TFA
504
505
100





1731


embedded image


TFA
424
425
100





1732


embedded image


TFA
433
434
100





1733


embedded image


TFA
484
485
100





1734


embedded image


TFA
466
467
100





1735


embedded image


TFA
425
426
100





1736


embedded image


TFA
464
465
 95





1737


embedded image


TFA
466
467
100





1738


embedded image


TFA
489
490
100











embedded image


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).




embedded image


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).




embedded image


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).




embedded image


Method BD: 2-(3-(4-(dimethylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenyl)ethanol, 2HCl (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).




embedded image


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










1H


Method




Num-

Salt

NMR
Purity
of

LCMS


ber
Product
type

1H NMR

Solvent
percent
Coupling
LCMS
Method







1745


embedded image




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


embedded image




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


embedded image




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


embedded image


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


embedded image


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


embedded image




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


embedded image




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)











embedded image


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).




embedded image


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).




embedded image


N-methyl-6-(3-(2-propoxyethoxyl)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).




embedded image


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, NY). 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 IC50



Number
(μM)



















73
++



296
++



297
+



300
+



303
++



306
+



309
++



312
+++



313
+++



314
++



315
++



316
+++



317
++



318
++



320
++



322
+



325
+++



326
++



327
++



329
+++



330
++



332
+++



333
+++



334
++



335
+++



336
+++



337
+++



339
++



341
++



342
++



343
+



344
++



346
++



348
++



352
++



390
++



391
++



392
++



393
++



396
++



399
+++



400
++



403
++



407
++



412
+++



415
++



416
+++



418
++



419
+++



421
+



423
++



424
++



425
++



426
+



427
++



428
++



429
+++



430
+++



431
+++



433
++



434
++



435
+++



436
++



437
++



439
+++



440
++



441
++



442
+++



443
+++



444
+++



445
+++



446
++



447
++



448
+++



449
++



451
+++



452
+++



453
+++



454
++



455
++



456
+++



457
++



458
+++



459
+++



460
++



461
++



463
++



466
++



467
++



468
+++



470
++



471
++



472
++



473
++



474
++



629
++



630
++



631
++



632
+++



633
++



634
++



635
+++



636
+



637
++



638
++



639
+++



640
++



641
+++



642
+++



643
+++



644
++



645
++



647
++



648
++



649
++



650
+++



651
+++



652
+++



653
+++



655
+++



656
+++



657
+++



658
++



660
+++



661
+++



662
+++



663
+++



664
++



665
++



666
+++



667
+++



668
+++



669
+++



670
+++



671
++



672
++



673
++



674
++



675
+++



676
+++



677
+



678
++



679
+++



680
++



681
++



682
++



683
++



684
++



685
+++



686
+++



687
+++



688
+++



689
+++



690
++



691
+++



692
+++



693
+++



694
+++



695
+++



696
+++



697
++



698
+++



699
+++



700
+++



701
++



702
+++



703
+++



704
+++



705
+++



706
+++



707
+++



708
++



709
+++



846
++



847
+++



884
+



888
+



889
++



898
+



899
++



900
++



901
++



923
++



932
++



933
++



934
+++



962
+++



1124
+++



1125
++



1126
++



1140
+++



1141
+++



1142
++



1143
++



1144
++



1145
++



1146
++



1148
++



1150
+



1151
++



1152
++



1153
++



1155
++



1157
++



1158
++



1159
++



1160
++



1161
++



1165
+++



1167
++



1168
++



1171
++



1172
++



1173
+



1176
++



1178
++



1180
++



1181
++



1182
++



1183
++



1184
++



1185
++



1186
++



1187
+++



1188
++



1191
++



1192
++



1193
++



1194
+++



1198
++



1200
++



1201
++



1202
++



1203
++



1204
+



1205
++



1206
++



1208
+



1211
+



1212
++



1213
++



1214
++



1215
+++



1216
+++



1217
++



1218
++



1219
++



1220
+



1221
+



1222
++



1223
+++



1225
++



1226
++



1227
++



1228
++



1229
++



1230
++



1234
++



1237
++



1238
++



1239
++



1248
++



1279
++



1280
++



1281
+++



1282
++



1283
+



1284
++



1285
+



1286
++



1324
++



1327
+



1328
+



1330
+



1332
++



1333
+



1334
+



1335
++



1336
++



1337
++



1339
++



1340
++



1341
++



1346
++



1348
+



1350
++



1351
++



1352
+



1353
++



1354
++



1356
++



1357
++



1358
++



1359
++



1360
++



1361
+



1362
++



1363
++



1364
++



1365
++



1366
++



1369
++



1370
++



1371
++



1372
++



1373
++



1374
++



1375
++



1376
++



1380
++



1381
++



1382
+++



1391
+



1395
++



1396
++



1400
++



1401
++



1402
++



1403
+



1404
+



1406
++



1407
++



1408
++



1409
++



1410
++



1411
+



1412
++



1413
++



1414
++



1415
+



1416
++



1419
++



1420
++



1422
++



1423
+



1424
+



1425
++



1430
++



1437
++



1445
++



1446
++



1447
+



1448
++



1449
+



1450
++



1451
++



1452
+++



1453
++



1454
+



1455
++



1456
++



1458
+



1467
++



1497
++



1516
+



1601
++



1611
++



1680
++







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
  • 1-41. (canceled)
  • 42. A compound of formula (III):
  • 43. The compound according to claim 42 represented by general formula (III) or a salt thereof,wherein: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; and
  • 44. The compound according to claim 43 represented by general formula (III) or a salt thereof,wherein: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
  • 45. The compound according to claim 44 represented by general formula (III) or a salt thereof,wherein:R2 is phenyl, which is optionally substituted with 1-5 R9; andeach 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, tetrahydrofurylalkyl, alkylaminoalkyl or phenyl.
  • 46. The compound according to claim 45 represented by general formula (III) or a salt thereof, wherein:n is 0;R1 is hydrogen, C1-C8 alkyl or pyridylalkyl, each of which is optionally substituted with 1-3 R7;R7 is C1-C8 alkyl or halo;R9 is C1-C8 alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, —CN, —NO2, —C(O)NRbRb′, —C(O)ORa, —NRbRb′, —ORd, —C(O)Re or —S(O)qRf; andeach 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 or tetrahydrofurylalkyl.
  • 47. The compound according to claim 46 represented by general formula (III) or a salt thereof, wherein:
  • 48. The compound according to claim 42 or a salt thereof, wherein the compound of formula (III) is a compound selected from the group consisting of
  • 49. A pharmaceutical composition comprising the compound according to claim 42 or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • 50. The pharmaceutical composition according to claim 49 for preventing or treating central nervous system diseases.
  • 51. The pharmaceutical composition according to claim 50 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.
  • 52. 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 claim 42.
  • 53. The method of claim 52, wherein the disorder is schizophrenia.
  • 54. The method of claim 52, wherein the disorder is cognitive deficit.
  • 55. The method of claim 52, wherein the compound of formula (I), (II) or (III) is administered in combination with an additional therapeutic agent.
  • 56. The method of claim 52, wherein the additional therapeutic agent is an atypical antipsychotic.
  • 57. The method of claim 52, 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.
  • 58. The method of claim 52, wherein the additional therapeutic agent is a typical antipsychotic.
  • 59. The method of claim 52, 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.
  • 60. A kit comprising a composition comprising a compound or a salt thereof according to claim 42 and an acceptable carrier.
  • 61. A kit comprising a pharmaceutical composition comprising a compound or a salt thereof according to claim 42 and a pharmaceutically acceptable carrier.
RELATED APPLICATIONS

This application 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.

Provisional Applications (3)
Number Date Country
61291544 Dec 2009 US
61291550 Dec 2009 US
61291554 Dec 2009 US
Continuations (1)
Number Date Country
Parent 13520018 Sep 2012 US
Child 14692434 US