THERAPEUTIC COMPOUNDS AND RELATED METHODS OF USE

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 CR⁴or 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, R²and R³is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, 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;

R⁴is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R⁶;

R⁵is hydrogen; or when m is not 0, R⁵and one R¹may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;

each R⁶is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R⁷;

each R⁷is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R⁹;

each R⁹is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f;

Y is O or S;

q is 1 or 2 and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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 R¹are not taken together to form a pyrazole ring; and

when B is phenyl, R²is 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, X⁴and X⁵is independently CH or N, provided that at least two of X¹, X², X³, X⁴and X⁵are N;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

R¹is C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl or heterocyclylalkyl, each of which is optionally substituted with 1-5 R⁹; wherein R¹or R⁹is optionally taken together with one of R⁴, R⁵, R⁶or 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 R²and R³is independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f; each of which is optionally substituted with 1-3 R¹¹;

each R⁴, R⁵, R⁶and R⁷is independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f;

each R⁹, R¹⁰and R¹¹is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹²;

wherein, two R⁹, two R¹⁰or two R¹¹is optionally taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

R¹²is —OR^d;

Y is O or S;

q is 1 or 2 and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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, X⁴and X⁵is N and the others are CH;

m is 1, 2 or 3;

n is 1, 2, 3 or 4;

- R¹is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, alkoxyalkyl, hydroxyalkyl, heteroaryl, heteroarylalkyl, arylalkyl, —C(Y)R^e, cyclyl, cyclylalkyl or heterocyclyl, each of which is optionally substituted with 1-3 R⁷;
- R²is aryl or heteroaryl, each of which is optionally substituted with 1-5 R⁹;
- each R³or R⁴is independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹⁰;
- R⁶is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R¹¹;
- each R⁷, R⁹and R¹⁰is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹²; wherein two R⁷, two R⁹or two R¹⁰are optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;
- each R¹¹and R¹²is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹³;

R¹³is independently C₁-C₈alkyl, haloalkyl, halo, heterocyclyl, cyclyl, oxo or —C(Y)NR^bR^b′;

- Y is independently O or S;
- q is 1 or 2;and
- each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, acyl, haloalkyl alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl;
- with proviso R⁹is not

embedded image

Item 2. The compound according to item 1 represented by general formula(I) or a salt thereof,

wherein:

A is CR⁴or 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;

R⁵is hydrogen; or when m is not 0, R⁵and one R¹may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;

Y is O or S;

q is 1 or 2; and

wherein when B is phenyl, two R¹are not taken together to form a pyrazole ring; and

when B is phenyl, R²is 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, R²and R³is independently C₁-C₈alkyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silyloxyalkynyl, —CN, oxo, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(Y)R^c′, —SO₂NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, 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 R⁶is independently C₁-C₈alkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, oxo, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OR^dor —C(Y)R^e, each of which is optionally substituted with 1-3 R⁷;

each R⁷is oxo; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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, R²and R³is independently C₁-C₈alkyl, C₂-C₈alkynyl, phenyl, thienyl, pyrrolyl, oxadiazolyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, C₃-C₈cycloalkyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —SO₂NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R⁶;

each R⁶is independently C₁-C₈alkyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, morpholinylalkyl, dialkylaminoalkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, oxo, —CN, —NO₂, —C(O)OR^a, —NR^cC(Y)R^c′, —C(Y)NR^bR^b′, —NR^bR^b′, alkoxyalkyl, —OR^dor —C(Y)R^e; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈cycloalkyl, 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-C₈cycloalkylalkyl, 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, R²and R³is independently C₁-C₈alkyl, C₂-C₈alkynyl, phenyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C₃-C₈cycloalkyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^bR^b′, —NR^cC(Y)R^c′, —OC(O)NR^bR^b′, —SO₂NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R⁶;

R⁷is oxo; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈cycloalkyl, 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-C₈cycloalkylalkyl, oxazolidinylalkyl, haloalkyl, or alkoxyalkyl.

Item 6. The compound according to item 5 represented by general formula (I) or a salt thereof,

wherein:

R¹is C₁-C₈alkyl, phenyl, thienyl, pyrrolyl, oxazolyl, C₃-C₈cycloalkyl, dioxolanyl, phenylalkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —SO₂NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R⁶;

R²is C₁-C₈alkyl, C₂-C₈alkynyl, phenyl, thienyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C₃-C₈cycloalkyl, pyrrolidinyl, morpholinyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperiridylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^bR^b′, —OC(O)NR^bR^b′, —OR^dor —C(Y)R^e, each of which is optionally substituted with 1-3 R⁶;

R³is C₁-C₈alkyl, halo, haloalkyl, —NR^bR^b′ or —OR^d, 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:

R²is C₁-C₈alkyl, C₂-C₈alkynyl, phenyl, thienyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C₃-C₈cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperiridinylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^bR^b′, —OC(O)NR^bR^b′, —OR^d, —C(Y)R^eor —S(O)_qR^f;

R³is C₁-C₈alkyl, halo, haloalkyl, —NR^bR^b′ or —OR^d.

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;

R¹is C₁-C₈alkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —SO₂NR^bR^b′, —OR^d, or —S(O)_qR^f;

R²is C₁-C₈alkyl, C₃-C₈cycloalkyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^bR^b′, —OR^d, —C(Y)R^eor —S(O)_qR^f;

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈cycloalkyl, phenyl, dihydroindenyl, morpholinyl, tetrahydropyranyl, piperidyl, pyrrolidinyl, thiomorpholinyl, phenylalkyl, thienylalkyl, pyridylalkyl, tetrahydropyranylalkyl, dihydroindenylalkyl, tetrahydrofurylalkyl, hydroxyalkyl, morpholinylalkyl, pyrrolidinylalkyl, dialkylaminoalkyl, piperidylalkyl, benzodioxolilalkyl, dihydrobenzodioxinylalkyl, C₃-C₈cycloalkylalkyl, 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, X⁴and X⁵is independently CH or N, provided that at least two of

X¹, X², X³, X⁴and X⁵are N;

- n is 0, 1, 2, 3 or 4;
- p is 0, 1, 2 or 3;

R¹is C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl or heterocyclylalkyl, each of which is optionally substituted with 1-5 R⁹; wherein R¹or R⁹is optionally taken together with one of R⁴, R⁵, R⁶or 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 R²and R³is independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹¹;

R¹²is —OR^d;

Y is O or S;

q is 1 or 2; and

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;

R¹is C₁-C₈alkyl, aryl or heteroaryl;

each R²and R³is independently hydrogen, C₁-C₈alkyl, aryl, halo, heterocyclylalkyl, —NR^cC(Y)R^c′, —NR^bR^b′ or —OR^d, each of which is optionally substituted with 1-3 R¹¹;

R⁷is hydrogen; and

each R⁹, R¹⁰and R¹¹is independently C₁-C₈alkyl, heterocyclyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR^a, —C(Y)NR^bR^b′, —OR^dor —C(Y)R^c;

Y is O;

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently hydrogen, C₁-C₈alkyl, cyclyl, heterocyclyl, aryl, or heteroaryl.

Item 11. The compound according to item 10 represented by general formula (II) or a salt thereof,

wherein:

R¹is C₁-C₈alkyl, phenyl or benzodioxolyl;

each R²and R³is independently hydrogen, C₁-C₈alkyl, phenyl, halo, morholinylalkyl, —NR^cC(Y)R^c′, —NR^bR^b′ or —OR^d;

R⁹is independently C₁-C₈alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR^a, —C(Y)NR^bR^b′, —OR^dor —C(Y)R^e; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently hydrogen, C₁-C₈alkyl, C₃-C₈cycloalkyl, tetrahydropyranyl, phenyl, or pyridyl.

Item 12. The compound according to item 10 represented by general formula (II) or a salt thereof,

wherein:

R¹is C₁-C₈alkyl, phenyl or benzodioxolyl;

each R²and R³is independently hydrogen, C₁-C₈alkyl, phenyl, halo, morholinylalkyl, —NR^cC(Y)R^c′, —NR^bR^b′ or —OR^d, each of which is optionally substituted with 1-3 R¹¹;

each R⁹, R¹⁰and R¹¹is independently C₁-C₈alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR^a, —C(Y)NR^bR^b′, —OR^dor —C(Y)R^e; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently hydrogen, C₁-C₈alkyl, C₃-C₈cycloalkyl, tetrahydropyranyl, phenyl, or pyridyl.

Item 13. The compound according to item 12 represented by general formula (II) or a salt thereof, wherein:

R²is C₁-C₈alkyl, phenyl, halo, morholinylalkyl, —NR^cC(Y)R^c′,′ —NR^bR^b′ or —OR^d, each of which is optionally substituted with 1-3 R¹¹;

R³is hydrogen;

R⁹is halo, haloalkoxy, —CN, —C(O)OR^aor —C(Y)NR^bR^b′; and

R¹¹is C₁-C₈alkyl, morpholinyl, tetrahydropyranyl, halo, —CN, —OR^dor —C(Y)R^c;

Item 14. The compound according to item 11 or 13 represented by general formula (II) or a salt thereof, wherein:
R²is C₁-C₈alkyl, phenyl, halo, morholinylalkyl, —NR^cC(Y)R^c′,′ —NR^bR^b′ or —OR^d;

R³is hydrogen; and

R⁹is halo, haloalkoxy, —CN, —C(O)OR^aor —C(Y)NR^bR^b′.

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, X⁴and X⁵is N and the others are CH;

m is 1, 2 or 3;

n is 1, 2, 3 or 4;

R¹is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, alkoxyalkyl, hydroxyalkyl, heteroaryl, heteroarylalkyl, arylalkyl, —C(Y)R^e, cyclyl, cyclylalkyl or heterocyclyl, each of which is optionally substituted with 1-3 R⁷;

R²is aryl or heteroaryl, each of which is optionally substituted with 1-5 R⁹;

each R³or R⁴is independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹⁰;

each R⁷, R⁹and R¹⁰is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹²; wherein two R⁷or two R⁹are optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

R¹²is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹³;

R¹³is independently C₁-C₈alkyl, haloalkyl, halo, heterocyclyl, cyclyl, oxo or —C(Y)NR^bR^b′;

Y is O or S;

q is 1 or 2; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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;

R¹is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, heteroaryl, heterocyclyl, arylalkyl, cyclylalkyl, heteroarylalkyl, alkoxyalkyl, hydroxyalkyl or —C(O)R^e, each of which is optionally substituted with 1-3 R⁷;

R²is aryl, heteroaryl or benzofuryl, each of which is optionally substituted with 1-5 R⁹;

each R³or R⁴is independently hydrogen, C₁-C₈alkyl, halo, haloalkyl or —OR^d;

R⁶is hydrogen or C₁-C₈alkyl;

each R⁷and R⁹is independently C₁-C₈alkyl, aryl, heteroaryl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO₂, —C(O)OR^a, —C(O)NR^bR^b′, —NR^bR^b′, —OR^d, —C(O)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹²;

R¹²is independently C₁-C₈alkyl, oxo, halo, haloalkyl, —CN, —C(O)NR^bR^b′ or —C(O)R^eeach of which is optionally substituted with 1-3 R¹³;

R¹³is independently C₁-C₈alkyl, halo or heterocyclyl; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, 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:

R¹is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, alkoxyalkyl, hydroxyalkyl, imidazolyl, pyridylalkyl, phenylalkyl, oxazolylalkyl, thienylalkyl, thiazolidinyl isoindolyl, —C(O)R^c, dihydroindenyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkylalkyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-3 R⁷;

R²is 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 R³or R⁴is independently hydrogen, C₁-C₈alkyl, halo, haloalkyl or —OR^d;

R⁶is hydrogen or C₁-C₈alkyl;

each R⁷and R⁹is independently C₁-C₈alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO₂, —C(O)OR^a, —C(O)NR^bR^b′, —NR^bR^b′, —OR^d, —C(O)R^eor —S(O)_qR^f; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₃-C₈cycloalkyl, 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:

R¹is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, alkoxyalkyl, hydroxyalkyl, imidazolyl, furylalkyl, pyridylalkyl, phenylalkyl, oxazolylalkyl, thienylalkyl, thiazolidinyl, isoindolyl, —C(O)R^e, dihydroindenyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkylalkyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-3 R⁷;

R²is 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 R³or R⁴is independently hydrogen, C₁-C₈alkyl, halo, haloalkyl or —OR^d;

R⁶is hydrogen or C₁-C₈alkyl;

- each R⁷and R⁹is independently C₁-C₈alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO₂, —C(O)OR^a, —C(O)NR^bR^b′, —NR^bR^b′, —OR^d, —C(O)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹²;

R¹²is independently C₁-C₈alkyl, oxo, halo, haloalkyl, —CN, —C(O)NR^bR^b′ or —C(O)R^e, each of which is optionally substituted with 1-3 R¹³;

R¹³is independently C₁-C₈alkyl, halo or pyrrolidinyl; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₃-C₈cycloalkyl, 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;

R³is hydrogen, C₁-C₈alkyl, halo, haloalkyl, or —OR^d;

R⁴is hydrogen, C₁-C₈alkyl, halo, or —OR^d;

R⁷is C₁-C₈alkyl, phenyl, halo, haloalkyl, oxo, —C(O)OR^a, —C(O)NR^bR^b′ or —OR^deach of which is optionally substituted with 1-3 R¹²;

R⁹is C₁-C₈alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, —CN, —NO₂, —C(O)NR^bR^b′, —C(O)OR^a, —NR^bR^b′, —OR^d, —C(O)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹²; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₃-C₈cycloalkyl, 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;

R³is hydrogen, C₁-C₈alkyl, halo, haloalkyl, or —OR^d;

R⁴is hydrogen, C₁-C₈alkyl, halo, or —OR^d;

R⁷is C₁-C₈alkyl, phenyl, halo, haloalkyl, oxo, —C(O)OR^a, —C(O)NR^bR^b′ or —OR^d;

R⁹is C₁-C₈alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, —CN, —NO₂, —C(O)NR^bR^b′, —C(O)OR^a, —NR^bR^b′, —OR^d, —C(O)R^eor —S(O)_qR^f; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₃-C₈cycloalkyl, 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:

R¹is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, alkoxyalkyl, hydroxyalkyl, imidazolyl, furylalkyl, pyridylalkyl, phenylalkyl, oxazolylalkyl, thienylalkyl, isoindolyl, —C(O)R^e, dihydroindenyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkylalkyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-3 R⁷;

R²is phenyl, which is optionally substituted with 1-5 R⁹; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, 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, CR⁴or 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 NR⁵or O;

one of X and Z is N and the other is CH;

p is 0, 1, 2, 3 or 4;

each R¹, R²and R³is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, 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;

R⁴is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which may be optionally substituted with 1-3 R⁶;

R⁵is hydrogen; or when m is not 0, R⁵and 1 R¹may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;

each R⁶is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which may be optionally substituted with 1-3 R⁷;

each R⁷is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f;

each Y is independently O or S;

q is 1 or 2; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently selected from hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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 R^band R^b′, 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 R¹are not taken together to form a pyrazole ring;

when B is phenyl, R²is 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, CR⁴or N;

B is aryl or a 5-membered heteroaryl;

E is aryl or a 5-membered heteroaryl;

L is NR⁵or 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 R¹and R³is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, 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 R²is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, 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;

R⁵is hydrogen; or when m is not 0, R⁵and 1 R¹may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;

Y is O or S;

q is 1 or 2; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently selected from hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of which may be optionally further substituted with 1-3 R⁶, wherein R^band R^b′, together with the atoms to which they are attached, may form an optionally substituted cyclyl or heterocyclyl ring;

wherein when B is phenyl, two R¹are not taken together to form a pyrazole ring; and

when B is phenyl, R²is 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, X⁴and X⁵is independently CH or N, provided that at least two of X¹, X², X³, X⁴and X⁵are N;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

R¹is C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl or heterocyclylalkyl, each of which may be optionally substituted with 1-5 R⁹; wherein R¹or R⁹may optionally be taken together with one of R⁴, R⁵, R⁶or 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 R²and R³is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f; each of which is optionally substituted with 1-3 R¹¹;

each R⁴, R⁵, R⁶and R⁷is independently H, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f;

each R⁸, R⁹, R¹⁰and R¹¹is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which may be optionally further substituted; wherein two R⁸, two R⁹, two R¹⁰or two R¹¹may 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 R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently selected from hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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 NR^b;

1, 2 or 3 of X¹, X², X³, X⁴and X⁵are N and the others are CH;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3 or 4;

R¹is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R⁷; or when L is NR⁶, R¹or R⁷may be taken together with R⁶and the atoms to which they are attached to form a heterocyclyl or heteroaryl ring that is optionally substituted with 1-3 R⁸;

R²is aryl or heteroaryl, each of which is optionally substituted with 1-5 R⁹;

each R³, R⁴and R⁵is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹⁰;

R⁶is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R¹¹;

each R⁷, R⁸, R⁹and R¹⁰is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹²; wherein two R⁷, two R⁸, two R⁹or two R¹⁰may optionally be taken together with the atoms to which they are attached to form an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl ring;

each R¹¹and R¹²is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f;

each Y is independently O or S;

q is 1 or 2; and

or a pharmaceutically acceptable derivative or prodrug thereof,

wherein when R¹is cyclopropyl, R⁹is 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, X⁴and X⁵are N and the others are CH;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3 or 4;

R¹is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R⁷; or when L is NR⁶, R¹or R⁷may be taken together with R^band the atoms to which they are attached to form a heterocyclyl or heteroaryl ring that is optionally substituted with 1-3 R⁸;

R²is aryl or heteroaryl, each of which is optionally substituted with 1-5 R⁹;

R⁶is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R¹¹;

each Y is independently O or S;

q is 1 or 2; and

wherein R⁹is 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 CR⁴or 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;

R⁵is hydrogen; or when m is not 0, R⁵and one R¹may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;

each R⁷is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f,each of which is optionally substituted with 1-3 R⁹;

Y is O or S;

q is 1 or 2; and

wherein when B is phenyl, two R¹are not taken together to form a pyrazole ring; and

when B is phenyl, R²is 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 R⁷is oxo; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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:

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;

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 R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈cycloalkyl, 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-C₈cycloalkylalkyl, oxazolidinylalkyl, haloalkyl, or alkoxyalkyl.

Item 6. The compound according to item 5 represented by general formula (I) or a salt thereof,

wherein:

R²is C₁-C₈alkyl, C₂-C₈alkynyl, phenyl, thienyl, pyridyl, benzodioxolyl, furyl, pyrimidinyl, isoxazolyl, pyrazolyl, C₃-C₈cycloalkyl, pyrrolidinyl, morpholinyl, thiomorpholinylalkyl, pyrrolidinylalkyl, morpholinylalkyl, piperiridylalkyl, piperazinylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxyalkyl, silyloxyalkynyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —OC(O)NR^bR^b′, —OR^dor —C(Y)R^e, each of which is optionally substituted with 1-3 R⁶;

R³is C₁-C₈alkyl, halo, haloalkyl, —NR^bR^b′ or —OR^d, 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:

R³is C₁-C₈alkyl, halo, haloalkyl, —NR^bR^b′ or —OR^d.

Item 8. The compound according to item 7 represented by general formula (I) or a salt thereof,

wherein:

m is 1, 2, 3 or 4;

R¹is C₁-C₈alkyl, halo, haloalkyl, haloalkoxy, alkoxyalkyl, —CN, oxo, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —SO₂NR^bR^b′, —OR^d, or —S(O)_qR^f;

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, R¹is in the ortho position. In some embodiments, R¹is in the meta position. In some embodiments, R¹is in the para position.

In some embodiments, R¹is C₁-C₈alkyl (e.g., methyl or tert-butyl). In some embodiments, R¹is heteroaryl (e.g., oxazolyl, oxadiazolyl or quinazolinyl).

In some embodiments, R¹is heteroaryl substituted with 1-3 R⁶(e.g., 1 R⁶).

In some embodiments, R¹is oxadiazolyl substituted with 1 R⁶. some embodiments, R⁶is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R¹is heteroaryl substituted with 2 R⁶. In some embodiments, R¹is quinazolinyl substituted with 2 R⁶. In some embodiments, one R⁶is halo (e.g., bromo) and the other is heteroaryl (e.g., pyridyl).

In some embodiments, m is 1 and R¹is halo (e.g., fluoro, chloro or bromo). In some embodiments, m is 2 and each R¹is halo (e.g., fluoro, chloro or bromo). In some embodiments, m is 3 and each R¹is halo (e.g., fluoro, chloro or bromo). In some embodiments, R¹is haloalkyl (e.g., trifluoromethyl). In some embodiments, R¹is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).

In some embodiments, R¹is haloalkoxy substituted with 1 R⁶. In some embodiments, R¹is —O—CF₂—R⁶. In some embodiments, R⁶is —C(Y)NR^bR^b′. In some embodiments, Y is O, R^bis hydrogen and R^b′ is C₁-C₈alkyl (e.g., methyl). In some embodiments, R¹is —O—CF₂—CH₂—R⁶. In some embodiments, R⁶is —OR^d. In some embodiments, R^dis hydrogen. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁶is —NR^bR^b′. In some embodiments, R^band R^b′ are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl). In some embodiments, R⁶is heterocyclyl (e.g., morpholino).

In some embodiments, R¹is aminoalkyl. In some embodiments, R¹is —CH₂NH₂. In some embodiments, R¹is alkylaminoalkyl. In some embodiments, R¹is —CH₂NHCH₂CH₂CH₃. In some embodiments, R¹is dialkylaminoalkyl. In some embodiments, R¹is —CH₂N(CH(CH₃)₂)₂.

In some embodiments, R¹is hydroxyalkyl. In some embodiments, R¹is —CH₂OH.

In some embodiments, R¹is —CN.

In some embodiments, R¹is —NO₂.

In some embodiments, R¹is —C(O)OR^a. In some embodiments, R^ais hydrogen. In some embodiments, R^ais C₁-C₈alkyl (e.g., methyl or ethyl).

In some embodiments, R¹is —NR^cC(Y)R^c′. In some embodiments, one of R^cand R^c′ is hydrogen and the other is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R¹is —OR^d. In some embodiments, R^dis hydrogen. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl or ethyl).

In some embodiments, R¹is —SO₂NR^bR^b′. In some embodiments, R^band R^b′ are both hydrogen.

In some embodiments, R¹is —C(Y)R^e. In some embodiments, Y is O. In some embodiments, R^cis C₁-C₈alkyl (e.g., methyl). In some embodiments, R^eis heterocyclyl (e.g., pyrrolidinyl, piperidinyl or morpholino).

In some embodiments, R¹is —C(Y)NR^bR^b′. In some embodiments, Y is S. In some embodiments, Y is O. In some embodiments, R^band R^b′ are both hydrogen. In some embodiments, R^bis hydrogen. In some embodiments, R^bis hydrogen and R^b′ is aralkyl. In some embodiments, R^bis hydrogen and R^b′ is optionally substituted benzyl. In some embodiments, R^b′ is C₁-C₈alkyl, e.g., methyl, ethyl, C₃alkyl (e.g., n-propyl or isopropyl), C₄alkyl (e.g., n-butyl, sec-butyl or tert-butyl), C₅alkyl (e.g., n-pentyl, isopentyl or pentan-3-yl), C₆alkyl (e.g., n-hexyl or 3,3-dimethylbutan-2-yl), or C₇alkyl (e.g., n-heptyl or 2-heptyl).

In some embodiments, R^b′ is bicyclyl (e.g., indanyl). In some embodiments, R^b′ is heterocyclyl, e.g., a 6-membered heterocyclyl. In some embodiments, R^b′ is a 6-membered oxygen-containing heterocyclyl (e.g., tetrahydropyranyl). In some embodiments, R^b′ is a 6-membered nitrogen-containing heterocyclyl (e.g., piperidinyl).

In some embodiments, R^b′ is cyclylalkyl. In some embodiments, the alkyl is a C₁-C₈alkyl (e.g., C₁alkyl). 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, R^b′ is heterocyclylalkyl. In some embodiments, the alkyl is a C₁-C₈alkyl (e.g., C₁alkyl). In some embodiments, the heterocyclyl group is tetrahydropyranyl.

In some embodiments, R^b′ is haloalkyl (e.g., fluoroethyl, difluoroethyl, trifluoroethyl or trifluoropropyl).

In some embodiments, R^b′ is alkoxyalkyl. In some embodiments, the alkyl is a C₁-C₈alkyl (e.g., C₁, C₂, C₃or C₄alkyl). 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, R^band R^b′ are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl, both ethyl, or both isopropyl).

In some embodiments, two R¹and B are taken together to form a bicyclic heteroaryl or heterocyclic ring.

In some embodiments, two R¹and B are taken together to form

embedded image

In some embodiments, R¹is halo. In some embodiments, R¹is at the 6, 7, or 8 position.

In some embodiments, two R¹and B are taken together to form a group selected from:

embedded image

In some embodiments, R²is aryl.

In some embodiments, each R¹is independently C₁-C₈alkyl (e.g., each R¹is methyl). In some embodiments, each R¹is independently halo (e.g., each R¹is fluoro or each R¹is chloro). In some embodiments, one R¹is fluoro and the other is chloro. In some embodiments, one R¹is chloro and the other is bromo.

In some embodiments, each R¹is independently —OR^d. In some embodiments, each R^dis independently C₁-C₈alkyl (e.g., each R^dis methyl).

In some embodiments, one R¹is halo (e.g., chloro) and the other is C₁-C₈alkyl (e.g., methyl). In some embodiments, one R¹is 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, R⁶is C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹is halo (e.g., fluoro or chloro) and the other is haloalkyl (e.g., trifluoromethyl).

In some embodiments, one R¹is halo (e.g., chloro) and the other is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).

In some embodiments, one R¹is halo (e.g., chloro) and the other is —C(O)OR^a. In some embodiments, R^ais hydrogen.

In some embodiments, one R¹is halo (e.g., fluoro or chloro) and the other is —C(Y)NR^bR^b′. In some embodiments, Y is O. In some embodiments, R^band R^b′ are both hydrogen. In some embodiments, one of R^band R^b′ is hydrogen and the other is C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹is halo (e.g., chloro) and the other is —NR^cC(Y)R^c′. In some embodiments, Y is O. In some embodiments, R^cis hydrogen and R^c′ is C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹is halo (e.g., fluoro or chloro) and the other is —OR^d. In some embodiments, R^dis hydrogen. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹is halo (e.g., fluoro or chloro) and the other is —CN.

In some embodiments, one R¹is halo (e.g., chloro) and the other is —NO₂.

In some embodiments, one R¹is —C(O)OR^aand the other is —NO₂. In some embodiments, R^ais hydrogen.

In some embodiments, one R¹is —C(O)OR^aand the other is —OR^d. In some embodiments, each R^aand R^dis hydrogen.

In some embodiments, one R¹is —C(Y)NR^bR^b′ and the other is haloalkyl (e.g., trifluoromethyl). In some embodiments, R^band R^b′ are both hydrogen.

In some embodiments, one R¹is —C(Y)NR^bR^b′ and the other is haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R^band R^b′ are both hydrogen.

In some embodiments, one R¹is —C(Y)NR^bR^b′ and the other is —S(O)_qR^f. In some embodiments, R^band R^b′ are both hydrogen. In some embodiments, R^fis C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹is —C(Y)NR^bR^b′and the other is —CN. In some embodiments, R^band R^b′ are both hydrogen.

In some embodiments, one R¹is —OR^dand the other is C₁-C₈alkyl (e.g., methyl). In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹is —OR^dand the other is haloalkyl (e.g., trifluoromethyl). In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹is —OR^dand the other is —C(O)OR^a. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, R^ais hydrogen. In some embodiments, R^ais C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹is —OR^dand the other is —NR^cC(O)R^c′. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, R^cis hydrogen and R^c′ is C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R¹is 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 R¹and ring B are taken together to form a group selected from:

embedded image

In some embodiments, R²is aryl.

In some embodiments, each R¹is independently halo (e.g., all three R¹are fluoro or all three R¹are chloro).

In some embodiments, two R¹are independently halo (e.g., both are chloro) and the other is C₁-C₈alkyl (e.g., methyl). In some embodiments, two R¹are independently halo (e.g., both are chloro) and the other is heteroaryl (e.g., pyrrolyl). In some embodiments, two R¹are independently halo (e.g., both are fluoro) and the other is —C(Y)NR^bR^b′ (e.g., —C(O)NH₂). In some embodiments, two R¹are independently C₁-C₈alkyl (e.g., both are methyl) and the other is halo (e.g., chloro or bromo).

In some embodiments, one R¹is C₁-C₈alkyl (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 R¹is —OR^d, and two R¹, together with the atoms to which they are attached, are taken together to form a heterocyclyl ring. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, three R¹and 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, m is 3. In some embodiments, one R¹is —OR^d, 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, R^dis 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, R¹is aryl (e.g., phenyl).

In some embodiments, R¹is phenyl substituted with 1 R⁶.

In some embodiments, R⁶is halo (e.g., chloro). In some embodiments, R¹is selected from:

embedded image

In some embodiments, m is 2.

In some embodiments, one R¹is C₁-C₈alkyl (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, R⁶is halo (e.g., chloro). In some embodiments, R¹is:

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, R¹is —C(O)OR_a. In some embodiments, R^ais C₁-C₈alkyl (e.g., ethyl).

In some embodiments, R¹is —C(Y)NR^bR^b′. In some embodiments, Y is O. In some embodiments, R^band R^b′ are both hydrogen.

In some embodiments, m is 2.

In some embodiments, one R¹is C₁-C₈alkyl (e.g., methyl) and the other is —C(Y)NR^bR^b′. In some embodiments, Y is O. In some embodiments, R^band R^b′are both hydrogen.

In some embodiments, B is thiazolyl.

In some embodiments, m is 1.

In some embodiments, R¹is 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)R^e. In some embodiments, Y is O. In some embodiments, R^eis C₁-C₈alkyl (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, R²is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R²is C₁-C₈alkyl substituted with 1-3 R⁶. In some embodiments, R²is C₁alkyl substituted with 1 R⁶.

In some embodiments, R⁶is —NR^bR^b′. In some embodiments, R^band R^b′ are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl, or R^band R^b′ are both ethyl). In some embodiments, one of R^band R^b′ is hydrogen and the other is haloalkyl (e.g., trifluoroethyl).

In some embodiments, R⁶is —OR^d. In some embodiments, R^dis cyclyl (e.g., cyclopentyl). In some embodiments, R^dis heterocyclylalkyl (e.g., —CH₂— tetrahydropyranyl).

In some embodiments, R²is C₂alkyl substituted with 1 R⁶.

In some embodiments, R⁶is —C(Y)NR^bR^b′. In some embodiments, Y is O. In some embodiments, R^band R^b′ are both hydrogen. In some embodiments, R^band R^b′ are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl). In some embodiments, one of R^band R^b′ is hydrogen and the other is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R^bis —C(Y)R^c. In some embodiments, Y is O. In some embodiments, R^eis heterocyclyl (e.g., morpholino or thiomorpholino). In some embodiments, R^eis thiomorpholino substituted with 2 R⁷. In some embodiments, each R⁷is oxo. In some embodiments, R^eis:

embedded image

In some embodiments, R²is C₃alkyl substituted with 1 R⁶.

In some embodiments, R⁶is —C(Y)NR^bR^b′. In some embodiments, Y is O. In some embodiments, R^band R^b′are both hydrogen. In some embodiments, R^band R^b′ are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl). In some embodiments, one of R^band R^b′ is hydrogen and the other is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R⁶is —NR^cC(Y)R^c′. In some embodiments, Y is O. In some embodiments, R^cand R^c′ are each independently C₁-C₈alkyl (e.g., R^cand R^c′ are both methyl).

In some embodiments, R⁶is —OR^d. In some embodiments, R^dis hydrogen. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, R⁶is silyloxy (e.g., tert-butyldimethylsilyloxy).

In some embodiments, R⁶is —C(Y)R^e. In some embodiments, Y is O. In some embodiments, R^eis heterocyclyl (e.g., morpholino).

In some embodiments, R²is C₂-C₈alkynyl. In some embodiments, R²is C₂-C₈alkynyl substituted with 1 R⁶(e.g., C₃alkynyl substituted with 1 R⁶). In some embodiments, R²is —C≡C—CH₂—R⁶. In some embodiments, R⁶is —NR^bR^b′. In some embodiments, R^band R^b′are each independently C₁-C₈alkyl (e.g., R^band R^b′are both methyl). In some embodiments, R⁶is —OR^d. In some embodiments, R^dis hydrogen. In some embodiments, R⁶is silyloxy (e.g., tert-butyldimethylsilyloxy). In some embodiments, R⁶is heterocyclyl (e.g., morpholino or thiomorpholino). In some embodiments, R⁶is thiomorpholino substituted with 2 R⁷. In some embodiments, each R⁷is oxo. In some embodiments, R⁶is:

embedded image

In some embodiments, R²is aryl (e.g., phenyl). In some embodiments, R²is unsubstituted phenyl.

In some embodiments, R²is phenyl substituted with 1 R⁶.

In some embodiments, R⁶is heterocyclylalkyl (e.g., —CH₂-morpholino). In some embodiments, R⁶is haloalkyl (e.g., trifluoromethyl). In some embodiments, R⁶is —CN. In some embodiments, R⁶is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁶is —C(Y)R^e. In some embodiments, Y is O. In some embodiments, R^eis heterocyclyl (e.g., morpholino).

In some embodiments, R²is phenyl substituted with 2 R⁶.

In some embodiments, each R⁶is independently —OR^d. In some embodiments, each R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, one R⁶is halo (e.g., fluoro) and the other is C₁-C₈alkyl (e.g., methyl). In some embodiments, one R⁶is —C(O)OR^aand the other is —OR^d. In some embodiments, R^aand R^dare each independently C₁-C₈alkyl (e.g., R^aand R^dare both methyl).

In some embodiments, R²is heteroaryl.

In some embodiments, R²is isoxazolyl. In some embodiments, R²is isoxazolyl substituted with 2 R⁶. In some embodiments, each R⁶is independently C₁-C₈alkyl (e.g., R⁶is methyl).

In some embodiments, R²is pyrazolyl. In some embodiments, R²is pyrazolyl substituted with 1 R⁶. In some embodiments, R⁶is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R²is pyridyl. In some embodiments, R²is unsubstituted pyridyl. In some embodiments, R²is pyridyl substituted with 1 R⁶. In some embodiments, R⁶is halo (e.g., fluoro). In some embodiments, R⁶is —NR^bR^b′. In some embodiments, R^band R^b′ are each hydrogen. In some embodiments, R⁶is —OR^d. In some embodiments, R^dis hydrogen. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁶is heterocyclyl (e.g., morpholino or piperazinyl). In some embodiments, R⁶is piperazinyl substituted with 1 R⁷. In some embodiments, R⁷is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R²is pyrimidinyl.

In some embodiments, R²is pyridazinyl.

In some embodiments, R²is cyclyl (e.g., cyclopropyl).

In some embodiments, R²is heterocyclyl (e.g., morpholino or pyrrolidinyl).

In some embodiments, R²is aralkyl (e.g., benzyl).

In some embodiments, R²is heterocyclylalkyl. In some embodiments, the alkyl is C₁alkyl. In some embodiments, the alkyl is C₂alkyl. In some embodiments, the alkyl is C₃alkyl. 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, R⁶is C₁-C₈alkyl (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 R⁶is oxo. In some embodiments, the heterocyclyl is:

embedded image

In some embodiments, R²is halo (e.g., fluoro, chloro, bromo or iodo).

In some embodiments, R²is haloalkyl (e.g., trifluoromethyl).

In some embodiments, R²is haloalkoxy (e.g., trifluoromethoxy).

In some embodiments, R²is —CN.

In some embodiments, R²is —NO₂.

In some embodiments, R²is —C(O)OR^a. In some embodiments, R^ais hydrogen. In some embodiments, R^ais C₁-C₈alkyl (e.g., methyl).

In some embodiments, R²is —C(Y)NR^bR^b′. In some embodiments, Y is O. In some embodiments, R^band R^b′ are each hydrogen. In some embodiments, R^band R^b′ are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl). In some embodiments, one of R^band R^b′ is hydrogen and the other is C₁-C₈alkyl (e.g., methyl or ethyl). In some embodiments, one of R^band R^b′ is hydrogen and the other is heterocyclylalkyl (e.g., —CH₂—CH₂-morpholino). In some embodiments, one of R^band R^b′ is hydrogen and the other is haloalkyl (e.g., trifluoroethyl).

In some embodiments, R²is —NR^bR^b′. In some embodiments, R^band R^b′ are both hydrogen. In some embodiments, R^band R^b′ are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl). In some embodiments, one of R^band R^b′ is hydrogen and the other is C₁-C₈alkyl (e.g., methyl). In some embodiments, one of R^band R^b′ is hydrogen and the other is heterocyclyl (e.g., tetrahydropyranyl). In some embodiments, one of R^band R^b′ is hydrogen and the other is heterocyclylalkyl. In some embodiments, the alkyl is C₁alkyl. In some embodiments, the alkyl is C₂alkyl. In some embodiments, the alkyl is C₃alkyl. 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 R^band R^b′ is hydrogen and the other is hydroxyalkyl. In some embodiments, the alkyl is C₂alkyl. In some embodiments, one of R^band R^b′ is hydrogen and the other is alkoxyalkyl. In some embodiments, the alkyl is C₂alkyl. In some embodiments, the alkyl is C₃alkyl. In some embodiments, the alkoxy is methoxy. In some embodiments, one of R^band R^b′ is hydrogen and the other is —C(Y)R^e. In some embodiments, Y is O. In some embodiments, R^eis C₁-C₈alkyl (e.g., methyl). In some embodiments, R^eis heterocyclyl. In some embodiments, R^eis tetrahydropyranyl.

In some embodiments, R²is —OR^d.

In some embodiments, R^dis hydrogen. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, R^dis ethyl. In some embodiments, R^dis C₃alkyl (e.g., isopropyl or n-propyl). In some embodiments, R^dis optionally substituted heteroaralkyl. In some embodiments, R^dis optionally substituted pyrindinalkyl.

In some embodiments, R^dis n-propyl. In some embodiments, R^dis cyclyl (e.g., cyclopentyl).

In some embodiments, R^dis heteroaralkyl (e.g., —CH₂-pyridyl).

In some embodiments, R^dis heterocyclylalkyl. In some embodiments, the alkyl is C₁alkyl. In some embodiments, the alkyl is C₂alkyl. In some embodiments, the alkyl is C₃alkyl. In some embodiments, the alkyl is C₄alkyl. In some embodiments, the heterocyclyl is morpholino. In some embodiments, the heterocyclyl is piperidyl. In some embodiments, the heterocyclyl is tetrahydrofuranyl. In some embodiments, R^dis cyclylalkyl (e.g., —CH₂-cyclobutyl).

In some embodiments, R^dis alkoxyalkyl. In some embodiments, the alkyl is C₂alkyl. In some embodiments, the alkyl is C₃alkyl. In some embodiments, the alkoxy is methoxy.

In some embodiments, R^dis dialkylaminoalkyl. In some embodiments, the alkyl is C₂alkyl. In some embodiments, the alkyl is C₃alkyl. In some embodiments, the dialkylamino is dimethylamino.

In some embodiments, R²is —C(Y)R^e. In some embodiments, Y is O. In some embodiments, R^eis heterocyclyl. In some embodiments, R^eis piperidyl. In some embodiments, R^eis pyrrolidinyl. In some embodiments, R^eis piperazinyl. In some embodiments, R^eis morpholino. In some embodiments, R^eis thiomorpholino.

In some embodiments, n is 2.

In some embodiments, each R²is independently halo (e.g., each R²is chloro).

In some embodiments, each R²is independently —OR^d.

In some embodiments, each R^dis C₁-C₈alkyl.

In some embodiments, each R²is methoxy. In some embodiments, one R²is methoxy and the other is ethoxy. In some embodiments, one R²is methoxy and the other is propoxy. In some embodiments, one R²is methoxy and the other is isopropoxy.

In some embodiments, one R²is methoxy and the other is ethoxy substituted with 1 R⁶. In some embodiments, R⁶is —NR^bR^b′. In some embodiments, R^band R^b′ are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl). In some embodiments, R⁶is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R²is methoxy and the other is propoxy substituted with 1 R⁶. In some embodiments, R⁶is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R²is —OR^dand the other is C₁-C₈alkyl (e.g., methyl). In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl or ethyl).

In some embodiments, one R²is —OR^dand the other is halo (e.g., chloro). In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R²is —OR^dand the other is —CN. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R²is —OR^dand the other is —C(O)OR^a. In some embodiments, R^dand R^aare both hydrogen.

In some embodiments, one R²is —OR^dand the other is C₁-C₈alkyl (e.g., methyl). In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R²is —OR^dand the other is —C(Y)R^e. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, Y is O. In some embodiments, R^eis heterocyclyl (e.g., morpholino).

In some embodiments, one R²is halo (e.g., chloro or bromo) and the other is C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R²is C₁-C₈alkyl (e.g., methyl) and the other is —CN.

In some embodiments, one R²is C₁-C₈alkyl (e.g., methyl) and the other is heteroaryl (e.g., pyridyl). In some embodiments, the pyridyl is substituted with 1 R⁶. In some embodiments, R⁶is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, one R²is C₁-C₈alkyl (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, R³is C₁-C₈alkyl (e.g., methyl). In some embodiments, R³is halo (e.g., chloro). In some embodiments, R³is haloalkyl (e.g., trifluoromethyl). In some embodiments, R³is oxo.

In some embodiments, R³is —OR^d. In some embodiments, R^dis hydrogen. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, R³is —NR^bR^b′. In some embodiments, R^band R^b′ are both hydrogen. In some embodiments, one of R^band R^b′ is hydrogen and the other is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R³is heterocyclyl (e.g., piperazinyl). In some embodiments, R³is piperazinyl substituted with 1 R⁶. In some embodiments, R⁶is C₁-C₈alkyl (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, R²is C₁-C₈alkyl (e.g., methyl). In some embodiments, E is an N-methylpyrrole ring.

In some embodiments, L is NR⁵. In some embodiments, R⁵is hydrogen.

In some embodiments, L is O.

In some embodiments, the compound is:

embedded image

In some embodiments, R²is C₁-C₄alkoxy. In some embodiments, R²is halo. In some embodiments, R¹is —C(Y)NR^bR^b′.

In some embodiments, the compound is:

embedded image

In some embodiments, R²is C₁-C₄alkoxy. In some embodiments, R²is halo. In some embodiments, R¹is —C(Y)NR^bR^b′.

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 R⁶is halo.

In some embodiments, the compound is:

embedded image

In some embodiments, R¹is —C(Y)NR^bR^b′. In some embodiments, R¹is halo. In some embodiments, R²is C₁-C₄alkoxy. In some embodiments, R²is halo. In some embodiments, m is 2 and two R¹are 3,4-dichloro; 3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro,4-fluoro; or 3-chloro,5-fluoro. In some embodiments, R²is —C(O)NR^bR^b′ and R³is H. In some embodiments, R^band R^b′ are H. In some embodiments, R^band R^b′ are independently C₁-C₄alkyl or halo-substituted C₁-C₄alkyl. In some embodiments, R^bis methyl and R^b′ is trifluoroethyl. In some embodiments, R¹is C₁-C₄alkoxy or halo-substituted C₁-C₄alkoxy. In some embodiments, n and p are zero.

In some embodiments, the compound is:

embedded image

In some embodiments, R¹is —C(Y)NR^bR^b′. In some embodiments, R¹is halo.

In some embodiments, R²is C₁-C₄alkoxy. In some embodiments, R²is halo. In some embodiments, m is 2 and two R¹are 3,4-dichloro; 3,4-difluoro, 3,5-dichloro; 3,5-difluoro; 3-chloro,4-fluoro; or 3-chloro,5-fluoro. In some embodiments, R²is —C(O)NR^bR^b′ and R³is H. In some embodiments, R^band R^b′ are H. In some embodiments, R^band R^b′ are independently C₁-C₄alkyl or halo-substituted C₁-C₄alkyl. In some embodiments, R^bis methyl and R^b′ is trifluoroethyl. In some embodiments, R¹is C₁-C₄alkoxy or halo-substituted C₁-C₄alkoxy. In some embodiments, n and p are zero.

In some embodiments, the compound is:

embedded image

In some embodiments, the compound is:

embedded image

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, X⁴and X⁵is independently CH or N, provided that at least two of X¹, X², X³, X⁴and X⁵are N;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

R¹is C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl or heterocyclylalkyl, each of which is optionally substituted with 1-5 R⁹; wherein R¹or R⁹is optionally taken together with one of R⁴, R⁵, R⁶or 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 R²and R³is independently hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹¹;

R¹²is —OR^d;

Y is O or S;

q is 1 or 2; and

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;

R¹is C₁-C₈alkyl, aryl or heteroaryl;

each R²and R³is independently hydrogen, C₁-C₈alkyl, aryl, halo, heterocyclylalkyl, —NR^cC(Y)R^c′, —NR^bR^b′ or —OR^d, each of which is optionally substituted with 1-3 R¹¹;

R⁷is hydrogen; and

each R⁹, R¹⁰and R¹¹is independently C₁-C₈alkyl, heterocyclyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR^a, —C(Y)NR^bR^b′, —OR^dor —C(Y)R^e;

Y is O;

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently hydrogen, C₁-C₈alkyl, cyclyl, heterocyclyl, aryl or heteroaryl.

Item 11. The compound according to item 10 represented by general formula (II) or a salt thereof,

wherein:

R¹is C₁-C₈alkyl, phenyl or benzodioxolyl;

each R²and R³is independently hydrogen, C₁-C₈alkyl, phenyl, halo, morholinylalkyl, —NR^cC(Y)R^c′, —NR^bR^b′ or —OR^d;

R⁹is independently C₁-C₈alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR^a, —C(Y)NR^bR^b′, —OR^dor —C(Y)R^e; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently hydrogen, C₁-C₈alkyl, C₃-C₈cycloalkyl, tetrahydropyranyl, phenyl or pyridyl.

Item 12. The compound according to item 10 represented by general formula (II) or a salt thereof,

wherein:

R¹is C₁-C₈alkyl, phenyl or benzodioxolyl;

each R²and R³is independently hydrogen, C₁-C₈alkyl, phenyl, halo, morholinylalkyl, —NR^cC(Y)R^c′, —NR^bR^b′ or —OR^d, each of which is optionally substituted with 1-3 R¹¹;

each R⁹, R¹⁰and R¹¹is independently C₁-C₈alkyl, morpholinyl, tetrahydropyranyl, halo, haloalkyl, haloalkoxy, —CN, —C(O)OR^a, —C(Y)NR^bR^b′, —OR^dor —C(Y)R^e; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently hydrogen, C₁-C₈alkyl, C₃-C₈cycloalkyl, tetrahydropyranyl, phenyl, or pyridyl.

Item 13. The compound according to Item 12 represented by general formula (II) or a salt thereof, wherein:

R²is C₁-C₈alkyl, phenyl, halo, morholinylalkyl, —NR^cC(Y)R^c′, —NR^bR^b′ or —OR^d, each of which is optionally substituted with 1-3 R¹¹;

R³is hydrogen;

R⁹is halo, haloalkoxy, —CN, —C(O)OR^aor —C(Y)NR^bR^b′; and

R¹¹is C₁-C₈alkyl, morpholinyl, tetrahydropyranyl, halo, —CN, —OR^dor —C(Y)R^e;

Item 14. The compound according to item 11 or 13 represented by general formula (II) or a salt thereof, wherein:

R²is C₁-C₈alkyl, phenyl, halo, morholinylalkyl, —NR^cC(Y)R^c′, —NR^bR^b′ or —OR^d;

R³is hydrogen; and

R⁹is halo, haloalkoxy, —CN, —C(O)OR^aor —C(Y)NR^bR^b′.

In some embodiments, A is CH. In some embodiments, A is N.

In some embodiments, L is NR⁷. In some embodiments, R⁷is H.

In some embodiments, R¹is aryl (e.g., phenyl).

In some embodiments, R¹is phenyl substituted with 1 R⁹. In some embodiments, R¹is phenyl substituted with 1 R⁹in the ortho position. In some embodiments, R¹is phenyl substituted with 1 R⁹in the meta position. In some embodiments, R⁹is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy). In some embodiments, R⁹is —CN. In some embodiments, R⁹is —C(O)OR^a. In some embodiments, R^ais hydrogen. In some embodiments, R⁹is —C(Y)NR^bR^b′. In some embodiments, Y is O. In some embodiments, R^band R^b′ are both hydrogen. In some embodiments, R¹is:

embedded image

In some embodiments, one of R^band R^b′ is hydrogen and the other is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R¹is phenyl substituted with 2 R⁹. In some embodiments, each R⁹is independently halo (e.g., each R⁹is fluoro or each R⁹is chloro). In some embodiments, one R⁹is fluoro and the other is chloro. In some embodiments, one R⁹is halo (e.g., chloro) and the other is haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy).

In some embodiments, 2 R⁹are 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, R¹is selected from:

embedded image

In some embodiments, R¹is aralkyl (e.g., benzyl). In some embodiments, R¹is aralkyl substituted with 2 R⁹(e.g., benzyl substituted with 2 R⁹). In some embodiments, 2 R⁹substituents are on the phenyl ring. In some embodiments, each R⁹is independently halo (e.g., each R⁹is chloro).

In some embodiments, R¹is alkyl (e.g., methyl).

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, R²is C₁-C₈alkyl (e.g., methyl). In some embodiments, R²is C₁-C₈alkyl substituted with 1 R¹¹(e.g., methyl substituted with 1 R¹¹). In some embodiments, R¹¹is heterocyclyl (e.g., morpholino).

In some embodiments, R²is aryl (e.g., phenyl). In some embodiments, R²is phenyl substituted with 1 R¹¹. In some embodiments, R¹¹is —CN. In some embodiments, R¹¹is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, R¹¹is halo.

In some embodiments, R²is halo (e.g., fluoro, chloro, bromo or iodo).

In some embodiments, R²is —NR^cC(Y)R^c′. In some embodiments, R^cis hydrogen. In some embodiments, Y is O. In some embodiments, R^c′ is alkyl (e.g., methyl). In some embodiments, R^c′ is aryl (e.g., phenyl). In some embodiments, R^c′ is phenyl substituted with 1 R⁸. In some embodiments, R⁸is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, R^c′ is heteroaryl. In some embodiments, R^c′ is furanyl. In some embodiments, R^c′ is pyridyl. In some embodiments, R^c′ is pyridyl substituted with 1 R⁸. In some embodiments, R⁸is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, R^c′ is cyclyl (e.g., cyclohexyl). In some embodiments, R^c′ is cyclohexyl substituted with 1 R⁸. In some embodiments, R⁸is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, R^c′ is heterocyclyl (e.g., tetrahydropyranyl).

In some embodiments, R²is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl or ethyl). In some embodiments, R^dis ethyl substituted with 1 R⁸. In some embodiments, R⁸is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, R²is —OCH₂CH₂OCH₃. In some embodiments, R²is —OCH₂CH₂OCH₂CH₂CH₃. In some embodiments, R²is —OCH₂CH₂OCH₂CH₂OCH₃.

In some embodiments, n is 2.

In some embodiments, one R²is C₁-C₈alkyl (e.g., methyl) and the other is halo (e.g., chloro).

In some embodiments, one R²is —OR^dand the other is halo (e.g., chloro). In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, X¹and X⁴are N and X², X³and X⁵are CH.

In some embodiments, X¹and X³are N and X², X⁴and X⁵are CH.

In some embodiments, X²and X³are N and X¹, X⁴and X⁵are CH.

In some embodiments, X²and X⁴are N and X¹, X³and X⁵are CH.

In some embodiments, the compound is:

embedded image

wherein s is 0, 1, 2, 3 or 4.

In some embodiments, R⁹is —C(O)NH₂, C₁-C₄alkoxy, or substituted C₁-C₄alkoxy. In some embodiments, R⁹is halo.

In some embodiments, the compound is:

embedded image

In some embodiments, R₁is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R₁is heteroaralkyl (e.g., —CH₂-pyridyl). In some embodiments, LR¹is NH(CH₃).

In some embodiments, the compound is:

embedded image

In some embodiments, R₁is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R₁is heteroaralkyl (e.g., —CH₂-pyridyl). In some embodiments, LR¹is NH(CH₃).

In some embodiments, the compound is:

embedded image

In some embodiments, R₁is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R₁is heteroaralkyl (e.g., —CH₂-pyridyl). In some embodiments, LR¹is NH(CH₃).

In some embodiments, the compound is:

embedded image

In some embodiments, R₁is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R₁is heteroaralkyl (e.g., —CH₂-pyridyl). In some embodiments, LR¹is NH(CH₃).

In some embodiments, the compound is:

embedded image

wherein t is 1-3.

In some embodiments, R₁is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, R₁is heteroaralkyl (e.g., —CH₂-pyridyl). In some embodiments, LR¹is NH(CH₃). In some embodiments, R¹¹is independently halo, nitrile, C₁-C₄alkoxy, —C(O)NH₂, hydroxy, or C₁-C₄hydroxyalkyl. In some embodiments, R¹¹is fluoro. In some embodiments, R¹¹is methoxy, ethoxy, or methoxyethoxy ether. In some embodiments, R¹¹is —OCH₂CH₂OCH₃. In some embodiments, R¹¹is —OCH₂CH₂OCH₂CH₂CH₃. In some embodiments, R¹¹is —OCH₂CH₂OCH₂CH₂OCH₃.

In some embodiments, the compound is:

embedded image

wherein t is 1-3.

In some embodiments, R₁is selected from methyl, cyclohexyl, t-butyl, and pyridinyl. In some embodiments, LR¹is NH(CH₃). In some embodiments, R¹¹is independently halo, nitrile, C₁-C₄alkoxy, —C(O)NH₂, hydroxy, or C₁-C₄hydroxyalkyl. In some embodiments, R¹¹is fluoro. In some embodiments, R¹¹is methoxy, ethoxy, or methoxyethoxy ether. In some embodiments, R¹¹is —OCH₂CH₂OCH₃. In some embodiments, R¹¹is —OCH₂CH₂OCH₂CH₂CH₃. In some embodiments, R¹¹is —OCH₂CH₂OCH₂CH₂OCH₃.

In some embodiments, the compound is:

embedded image

wherein t is 1-3.

In some embodiments, the compound is:

embedded image

wherein t is 1-3.

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, X⁴and X⁵is N and the others are CH;

m is 1, 2 or 3;

n is 1, 2, 3 or 4;

R²is aryl or heteroaryl, each of which is optionally substituted with 1-5 R⁹;

R¹³is independently C₁-C₈alkyl, haloalkyl, halo, heterocyclyl, cyclyl, oxo or —C(Y)NR^bR^b′;

Y is O or S;

q is 1 or 2; and

Item 16. The compound according to item 15 represented by general formula (III) or a salt thereof,

wherein:

m is 1;

n is 1;

R²is aryl, heteroaryl or benzofuryl, each of which is optionally substituted with 1-5 R⁹;

each R³or R⁴is independently hydrogen, C₁-C₈alkyl, halo, haloalkyl or —OR^d;

R⁶is hydrogen or C₁-C₈alkyl;

R¹²is independently C₁-C₈alkyl, oxo, halo, haloalkyl, —CN, —C(O)NR^bR^b′ or —C(O)R^eeach of which is optionally substituted with 1-3 R¹³;

R¹³is independently C₁-C₈alkyl, halo or heterocyclyl; and

Item 17. The compound according to Item 16 represented by general formula (III) or a salt thereof,

wherein:

R¹is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, alkoxyalkyl, hydroxyalkyl, imidazolyl, pyridylalkyl, phenylalkyl, oxazolylalkyl, thienylalkyl, thiazolidinyl isoindolyl, —C(O)R^e, dihydroindenyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkylalkyl, piperidyl, morpholinyl, pyrrolidinyl, azetidinyl or piperazinyl, each of which is optionally substituted with 1-3 R⁷;

each R³or R⁴is independently hydrogen, C₁-C₈alkyl, halo, haloalkyl or —OR^d;

R⁶is hydrogen or C₁-C₈alkyl;

Item 18. The compound according to item 16 represented by general formula (III) or a salt thereof,

wherein:

R²is 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 R³or R⁴is independently hydrogen, C₁-C₈alkyl, halo, haloalkyl or —OR^d;

R⁶is hydrogen or C₁-C₈alkyl;

each R⁷and R⁹is independently C₁-C₈alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, oxo, —CN, —NO₂, —C(O)OR^a, —C(O)NR^bR^b′, —NR^b′, —OR^d, —C(O)R^eor —S(O)_qR^f, each of which is optionally substituted with 1-3 R¹²;

R¹²is independently C₁-C₈alkyl, oxo, halo, haloalkyl, —CN, —C(O)NR^bR^b′ or —C(O)R^e, each of which is optionally substituted with 1-3 R¹³;

R¹³is independently C₁-C₈alkyl, halo or pyrrolidinyl; and

Item 19. The compound according to item 18 represented by general formula (III) or a salt thereof,

wherein:

A is N;

R³is hydrogen, C₁-C₈alkyl, halo, haloalkyl, or —OR^d;

R⁴is hydrogen, C₁-C₈alkyl, halo, or —OR^d;

R⁷is C₁-C₈alkyl, phenyl, halo, haloalkyl, oxo, —C(O)OR^a, —C(O)NR^bR^b′ or —OR^deach of which is optionally substituted with 1-3 R¹²;

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₃-C₈cycloalkyl, 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;

R³is hydrogen, C₁-C₈alkyl, halo, haloalkyl, or —OR^d;

R⁴is hydrogen, C₁-C₈alkyl, halo, or —OR^d;

R⁷is C₁-C₈alkyl, phenyl, halo, haloalkyl, oxo, —C(O)OR^a, —C(O)NR^bR^b′ or —OR^d;

R⁹is C₁-C₈alkyl, phenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, —CN, —NO₂, —C(O)NR^bR^b′, —C(O)OR^a, —NR^bR^b′, —OR^d, —C(O)R^eor —S(O)_qR^f; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^eand R^fis independently hydrogen, C₁-C₈alkyl, C₃-C₈cycloalkyl, 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:

R²is phenyl, which is optionally substituted with 1-5 R⁹; and

In some embodiments, R¹is C₁-C₈alkyl, which is optionally substituted with 1-3 R⁷; or when L is NR⁶, R¹and R⁶may 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, R⁶is hydrogen.

In some embodiments, R¹is C₁-C₈alkyl, e.g., methyl, ethyl, C₃alkyl (e.g., n-propyl or isopropyl), C₄alkyl (e.g., n-butyl, isobutyl or tert-butyl), or C₅alkyl (e.g., pentan-3-yl).

In some embodiments, R¹is C₁-C₈alkyl substituted with 1-3 R⁷(e.g., C₁-C₈alkyl substituted with 1 R⁷). In some embodiments, R¹is methyl substituted with 1 R⁷. In some embodiments, R⁷is cyclyl (e.g., cyclopropyl). In some embodiments, R⁷is aryl (e.g., phenyl).

In some embodiments, R¹is ethyl substituted with 1 R⁷. In some embodiments, R⁷is aryl (e.g., phenyl). In some embodiments, R⁷is —OR^d. In some embodiments, R^dis aryl (e.g., phenyl).

In some embodiments, R¹is n-propyl substituted with 1 R⁷. In some embodiments, R⁷is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., C₃alkyl, e.g., n-propyl).

In some embodiments, R¹is C₁-C₈alkyl substituted with 3 R⁷. In some embodiments, R¹is ethyl substituted with 3 R⁷. In some embodiments, each R⁷is independently halo (e.g., each R⁷is fluoro). In some embodiments, R¹is 2,2,2-trifluoroethyl.

In some embodiments, R¹is C₂-C₈alkenyl, e.g., C₃alkenyl (e.g., —CH₂—CH═CH₂).

In some embodiments, R¹is C₂-C₈alkynyl, e.g., C₃alkynyl (e.g. —CH₂—C≡CH).

In some embodiments, R¹is cyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl). In some embodiments, the cyclyl group is a bicyclic group (e.g., indanyl).

In some embodiments, R¹is heterocyclyl (e.g., piperidyl). In some embodiments, R¹is piperidyl substituted with 1 R⁷. In some embodiments, R⁷is —C(Y)R^e. In some embodiments, Y is O. In some embodiments, R^eis C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁷is —OR^d.

In some embodiments, R⁶is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R¹and R⁶are taken together with the atoms to which they are attached to form a heterocyclyl ring (e.g. a pyrrolidine ring).

In some embodiments, R¹and R⁶are 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, R¹is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R²is aryl (e.g., phenyl). In some embodiments, R²is unsubstituted phenyl. In some embodiments, R²is phenyl substituted with 1-3 R⁹. In some embodiments, R²is phenyl substituted with 1 R⁹.

In some embodiments. R²is:

embedded image

In some embodiments, R⁹is halo (e.g., fluoro or chloro). In some embodiments, R⁹is —CN. In some embodiments, R⁹is —NO₂. In some embodiments, R⁹is haloalkoxy (e.g., trifluoroethoxy). In some embodiments, R⁹is —NR^bR^b′. In some embodiments, R^band R^b′ are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl).

In some embodiments, R⁹is hydroxyalkyl (e.g., —CH₂OH). In some embodiments, R⁹is alkoxyalkyl (e.g., —CH₂—O—CH₃). In some embodiments, R⁹is —C(O)R^e. In some embodiments, R^eis heterocyclyl (e.g., morpholino). In some embodiments, R⁹is —S(O)_qR^f. In some embodiments, q is 1. In some embodiments, R^fis C₁-C₈alkyl (e.g., methyl.).

In some embodiments, R²is phenyl substituted with 2 R⁹. In some embodiments, each R⁹is independently halo (e.g., each R⁹is fluoro). In some embodiments, each R⁹is independently —OR^d. In some embodiments, each R^dis independently C₁-C₈alkyl (e.g., each R^dis methyl).

In some embodiments, R²is heteroaryl. In some embodiments, R²is a 6-membered heteroaryl. In some embodiments, R²is a 6-membered nitrogen-containing heteroaryl, e.g., pyridyl. In some embodiments, R²is unsubstituted pyridyl.

In some embodiments, R²is pyridyl substituted with 1 R⁹. In some embodiments, R⁹is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl).

In some embodiments, R²is a 5-membered heteroaryl. In some embodiments, R²is 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, R⁴is C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁴is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁴is halo. In some embodiments, R⁴is methoxy. In some embodiments, R^dis C₁-C₈alkyl.

In some embodiments, the compound has the following structure:

embedded image

wherein one of X¹and X²is N and the other is CH.

In some embodiments, X¹is CH and X²is N. In some embodiments, X¹is N and X²is CH. In some embodiments, the compound has the following structure:

embedded image

In some embodiments, R²is aryl. In some embodiments, R²is heteroaryl. In some embodiments, R¹is C₁-C₈alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

embedded image

In some embodiments, R²is aryl. In some embodiments, R²is heteroaryl. In some embodiments, R¹is C₁-C₈alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

embedded image

In some embodiments, R²is aryl. In some embodiments, R²is heteroaryl. In some embodiments, R¹is C₁-C₈alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

embedded image

wherein R¹is C₁-C₈alkyl, which is optionally substituted with 1-3 R⁷.

In some embodiments, R²is aryl. In some embodiments, R²is heteroaryl. In some embodiments, R¹is C₁-C₈alkyl (e.g., methyl).

In some embodiments, the compound has the following structure:

embedded image

In some embodiments, R²is aryl. In some embodiments, R²is heteroaryl. In some embodiments, R¹is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R²is

embedded image

In some embodiments, the compound has the following structure:

embedded image

In some embodiments, R²is aryl. In some embodiments, R²is heteroaryl. In some embodiments R¹is C₁-C₈alkyl (e.g., methyl). In some embodiments, R²is

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, R¹is hydrogen or C₁-C₈alkyl. In some embodiments, R¹is cyclyl or heterocyclyl. In some embodiments, R¹is aralkyl or heteroaralkyl. In some embodiments, R¹is methyl, cyclohexyl, t-butyl,

embedded image

or In some embodiments, R⁶is hydrogen or C₁-C₈alkyl.

In some embodiments, R⁹is C₁-C₈alkyl, halo, —CN, or —OR^d. In some embodiments, R³is hydrogen.

In some embodiments, the compound has the following structure:

embedded image

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

embedded image

In some embodiments, R⁶is hydrogen or C₁-C₈alkyl. In some embodiments, R⁹is C₁-C₈alkyl, halo, —CN, or —OR^d. In some embodiments, R³is 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, CR⁴or 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 NR⁵or O;

one of X and Z is N and the other is CH;

p is 0, 1, 2, 3 or 4;

R⁵is hydrogen; or when m is not 0, R⁵and 1 R¹may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;

each Y is independently O or S;

q is 1 or 2; and

or a pharmaceutically acceptable derivative or prodrug thereof,

wherein when B is phenyl, two R¹are not taken together to form a pyrazole ring;

when B is phenyl, R²is not

embedded image

and where in the compound is not:

embedded image

In some embodiments, when B is phenyl, R²is not a substituted pyridyl. In some embodiments, when B is phenyl and n=1, R²is not a substituted pyridyl.

In some embodiments, when X is N, B is not 4-pyridyl.

In some embodiments, each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently selected from hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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, CR⁴or 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 NR⁵or O;

one of X and Z is N and the other is CH;

p is 0, 1, 2, 3 or 4;

R⁵is hydrogen; or when m is not 0, R⁵and 1 R¹may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;

each Y is independently O or S;

q is 1 or 2; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently selected from hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, 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 R⁶wherein R^band R^b′, 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 R¹are not taken together to form a pyrazole ring; and

when B is phenyl, R²is not

embedded image

In some embodiments, when B is phenyl, R²is not a substituted pyridyl. In some embodiments, when B is phenyl and n=1, R²is not a substituted pyridyl.

In one aspect, the invention features a compound of formula (IV):

embedded image

wherein:

A is CH, CR⁴or N;

B is aryl or a 5-membered heteroaryl;

E is aryl or a 5-membered heteroaryl;

L is NR⁵or 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 R²is independently C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^eor —S(O)_qR^f, 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;

R⁴is hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, heteroaralkyl, cyclylalkyl, heterocyclylalkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, silyloxy, silyloxyalkyl, silylalkoxy, silylalkoxyalkyl, —CN, —NO₂, —C(O)OR^a, —C(Y)NR^bR^b′, —NR^cC(Y)R^c′, —NR^bR^b′, —OC(O)NR^bR^b′, —NR^cC(O)OR^c′, —SO₂NR^bR^b′, —NR^cSO₂R^c′, —NR^cC(Y)NR^bR^b′, —OR^d, —SR^d′, —C(Y)R^cor —S(O)_qR^f, each of which may be optionally substituted with 1-3 R⁶;

R⁵is hydrogen; or when m is not 0, R⁵and 1 R¹may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;

Y is O or S;

q is 1 or 2; and

each R^a, R^b, R^b′, R^c, R^c′, R^d, R^d′, R^e, R^e′ and R^fis independently selected from hydrogen, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, acyl, cyclyl, heterocyclyl, aryl, heteroaryl, cyclylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, each of which may be optionally further substituted with 1-3 R⁶wherein R^band R^b′, 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 R¹are not taken together to form a pyrazole ring.

In one aspect, the invention features a compound of formula (IV):

embedded image

wherein:

A is CH, CR⁴or N;

B is aryl or a 5-membered heteroaryl;

E is aryl or a 5-membered heteroaryl;

L is NR⁵or 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;

R⁵is hydrogen; or when m is not 0, R⁵and 1 R¹may be taken together with the atoms to which they are attached to form an optionally substituted heteroaryl or heterocyclyl ring;

Y is O or S;

q is 1 or 2; and

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, R¹is in the ortho position. In some embodiments, R¹is in the meta position. In some embodiments, R¹is in the para position.

In some embodiments, R¹is C₁-C₈alkyl (e.g., methyl or tert-butyl). In some embodiments, R¹is heteroaryl (e.g., oxazolyl, oxadiazolyl or quinazolinyl).

In some embodiments, R¹is heteroaryl substituted with 1-3 R⁶(e.g., 1 R⁶).

In some embodiments, R¹is oxadiazolyl substituted with 1 R⁶. some embodiments, R⁶is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R¹is haloalkoxy substituted with 1 R⁶. In some embodiments, R¹is —O—CF₂—R⁶. In some embodiments, R⁶is —C(Y)NR^bR^b′. In some embodiments, Y is O, R^bis hydrogen and R^b′ is C₁-C₈alkyl (e.g., methyl). In some embodiments, R¹is —O—CF₂—CH₂—R⁶. In some embodiments, R⁶is —OR^d. In some embodiments, R^dis hydrogen. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁶is —NR^bR^b′. In some embodiments, R^band R^b′are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl). In some embodiments, R⁶is heterocyclyl (e.g., morpholino).

In some embodiments, R¹is hydroxyalkyl. In some embodiments, R¹is —CH₂OH.

In some embodiments, R¹is —CN.

In some embodiments, R¹is —NO₂.

In some embodiments, R¹is —C(O)OR^a. In some embodiments, R^ais hydrogen. In some embodiments, R^ais C₁-C₈alkyl (e.g., methyl or ethyl).

In some embodiments, R¹is —NR^cC(Y)R^c′. In some embodiments, one of R^cand R^c′ is hydrogen and the other is C₁-C₈alkyl (e.g., methyl).

In some embodiments, R¹is —OR^d. In some embodiments, R^dis hydrogen. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl or ethyl).

In some embodiments, R¹is —SO₂NR^bR^b′. In some embodiments, R^band R^b′ are both hydrogen.

In some embodiments, R¹is —C(Y)R^e. In some embodiments, Y is O. In some embodiments, R^eis C₁-C₈alkyl (e.g., methyl). In some embodiments, R^eis heterocyclyl (e.g., pyrrolidinyl, piperidinyl or morpholino).

In some embodiments, R^b′ is C₁-C₈alkyl substituted with 1 R⁶. In some embodiments, R⁶is —OR^d. In some embodiments, R^dis aryl (e.g., phenyl). In some embodiments, R^b′ is C₂-C₈alkenyl, e.g., C₃alkenyl (e.g., —CH₂—CH═CH₂). In some embodiments, R^b′ is C₂-C₈alkynyl, e.g., C₃alkenyl (e.g., —CH₂—C≡CH).

In some embodiments, R^b′ is aryl (e.g., phenyl). In some embodiments, R^b′ is aryl substituted with 1 R⁶(e.g., phenyl substituted with 1 R⁶). In some embodiments, R⁶is haloalkyl (e.g., trifluoromethyl). In some embodiments, R^b′ is cyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl). In some embodiments, R^b′ is cyclyl substituted with 1 R⁶(e.g., cyclopropyl substituted with 1 R⁶or cyclopentyl substituted with 1 R⁶). In some embodiments, R⁶is C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁶is —OR^d. In some embodiments, R^dis aralkyl (e.g., benzyl).

In some embodiments, R^b′ is cyclohexyl substituted with 1 R⁶. In some embodiments, R⁶is —C(O)OR^a. In some embodiments, R^ais C₁-C₈alkyl (e.g., methyl).

In some embodiments, R^b′ is heterocyclyl substituted with 1 R⁶(e.g., piperidinyl substituted with 1 R⁶). In some embodiments, R⁶is —C(O)OR^a. In some embodiments, R^ais C₁-C₈alkyl (e.g., ethyl). In some embodiments, R⁶is —C(Y)R^e. In some embodiments, Y is O. In some embodiments, R^eis C₁-C₈alkyl (e.g., methyl or ethyl).

In some embodiments, R^b′ is aralkyl. In some embodiments, the alkyl is a C₁-C₈alkyl (e.g., C₁, C₂, C₃or C₄alkyl). 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, R^b′ is benzyl. In some embodiments, R^b′ is phenylethyl. In some embodiments, the aryl is substituted with 1 R⁶. In some embodiments, R⁶is C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁶is halo (e.g., fluoro or chloro). In some embodiments, R⁶is haloalkyl (e.g., trifluoromethyl). In some embodiments, R⁶is —OR^d. In some embodiments, R^dis C₁-C₈alkyl (e.g., methyl). In some embodiments, the aryl is substituted with 2 R⁶. In some embodiments, each R⁶is independently —OR^d. In some embodiments, each R^dis independently C₁-C₈alkyl (e.g., each R^dis methyl). In some embodiments, each R⁶is independently halo (e.g., each R⁶is fluoro).

In some embodiments, R^b′ is heteroaralkyl. In some embodiments, the alkyl is a C₁-C₈alkyl (e.g., C₁, C₂or C₃alkyl). 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, R⁶is C₁-C₈alkyl (e.g., methyl). In some embodiments, R⁶is haloalkyl (e.g., trifluoromethyl).

In some embodiments, R^b′ is cyclylalkyl. In some embodiments, the alkyl is a C₁-C₈alkyl (e.g., C₁alkyl). 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, R^b′ is cyclylalkyl substituted with 1 R⁶. In some embodiments, R⁶is aryl (e.g., phenyl).

In some embodiments, R^b′ is heterocyclylalkyl. In some embodiments, the alkyl is a C₁-C₈alkyl (e.g., C₁alkyl). In some embodiments, the heterocyclyl group is tetrahydropyranyl.

In some embodiments, R^b′ is haloalkyl (e.g., fluoroethyl, difluoroethyl, trifluoroethyl or trifluoropropyl).

In some embodiments, R^band R^b′ are each independently C₁-C₈alkyl (e.g., R^band R^b′ are both methyl, both ethyl or both isopropyl).

In some embodiments, R¹and R⁵, together with the atoms to which they are attached, form a heteroaryl ring (e.g., a substituted heteroaryl ring). In some embodiments, R¹and 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, R⁶is halo. In some embodiments, R⁶is at the 6, 7, or 8 position.

In some embodiments, R¹, R⁵, B and L are taken together to form a group selected from: