Compounds for treating spinal muscular atrophy

Abstract

Provided herein are compounds for the treatment of spinal muscular atrophy, compositions thereof, and uses thereof.

Description

[0001] The technology described in this article has not been developed with U.S. government support.

[0002] Cross-references

[0003] This application is a divisional application of Chinese invention patent application No. 201810234432.7, filed February 8, 2013, entitled “Compounds for Treating Spinal Muscular Atrophy.” This application claims the benefit of priority to U.S. Provisional Application Serial No. 61 / 597,523, filed February 10, 2012, the entire contents of which are incorporated herein by reference for all purposes.

[0004] Statement on Joint Research Agreement

[0005] The subject matter disclosed is a joint research agreement in effect on or before the effective filing date of the claimed invention, and the research conducted by or on behalf of one or more parties resulted in the claimed invention;

[0006] the claimed invention was made as a result of activities carried out within the scope of the joint research agreement; and

[0007] The patent application for the claimed invention discloses, or as amended discloses, the names of the parties to the joint research agreement.

[0008] introduction

[0009] Provided herein are compounds, compositions, and uses thereof for treating spinal muscular atrophy. Background Art

[0010] Spinal muscular atrophy (SMA) in its broadest sense describes a class of inherited and acquired central nervous system (CNS) diseases characterized by progressive motor neuron loss in the spinal cord and brainstem, leading to muscle weakness and atrophy. The most common form of SMA is caused by mutations in the survival motor neuron (SMN) gene and manifests over a wide range of severity, affecting infants to adults (Crawford and Pardo, Neurobiol. Dis., 1996, 3:97).

[0011] SMA in infants is the most severe form of this neurodegenerative disorder. Symptoms include muscle weakness, poor muscle tone, a weak voice, a limp or tendency to collapse, difficulty sucking or swallowing, a buildup of secretions in the lungs or throat, difficulty eating, and an increased susceptibility to respiratory infections. The legs tend to be weaker than the arms and developmental milestones, such as lifting the head or sitting up, are not achieved. In general, the earlier these symptoms appear, the shorter the lifespan. Symptoms appear soon after as the motor neuron cells deteriorate. The severe forms of the disease are fatal and there is no known cure for all forms. The course of SMA is directly related to the rate at which the motor neuron cells degenerate and the severity of the resulting weakness. Infants with severe forms of SMA often die from respiratory problems due to weakness of the muscles that support breathing. Children with milder forms of SMA live much longer, although they may require extensive medical support, especially those at the more severe end of the spectrum. The clinical spectrum of SMA symptoms has been divided into the following five groups:

[0012] (a) Type 0 SMA (in utero SMA) is the most severe form of the disease and begins before birth. Typically, the first symptom of type 0 SMA is decreased fetal movement, which is first observed between 30 and 36 weeks of gestation. After birth, these newborns have little movement and have difficulty swallowing and breathing.

[0013] (b) Type 1 SMA (infantile SMA or Werdnig-Hoffmann disease) typically presents between 0 and 6 months of age. This form of SMA is also very severe. Patients are never able to sit and, without ventilatory support, generally die within the first 2 years.

[0014] (c) Type 2 SMA (intermediate SMA) has an age of onset of 7-18 months. Patients are able to sit independently but never stand or walk independently. The prognosis of this group depends mainly on the degree of respiratory involvement.

[0015] (d) Type 3 SMA (juvenile SMA or Kugelberg-Welander disease) is usually diagnosed after 18 months of age. Individuals with Type 3 SMA are able to walk independently at some point during the course of the disease but often become wheelchair-bound during adolescence or adulthood.

[0016] (e) Type 4 SMA (adult-onset SMA). Weakness usually begins in the tongue, hands, or feet in late adolescence and then spreads to other areas of the body. Adult SMA progresses much more slowly and has little or no effect on life expectancy.

[0017] The SMN gene has been located by linkage analysis of a complex region in chromosome 5q. In humans, this region contains a 500,000 base pair (kb) inverted duplication, resulting in two nearly identical copies of the SMN gene. SMA is caused by inactivating mutations or deletions of the telomeric gene copies (SMN1) in both chromosomes, leading to loss of SMN1 gene function. However, all patients retain the centromeric gene copy (SMN2), and the copy number of the SMN2 gene in SMA patients is generally inversely correlated with disease severity; that is, patients with less severe SMA have more SMN2 copies. However, SMN2 cannot completely offset the loss of SMN1 function because a translationally silent C to T mutation in exon 7 causes alternative splicing of exon 7. Therefore, the majority of transcripts are produced by SMN2 lacking exon 7 (SMN2Δ7) and encode a truncated Smn protein that has reduced function and is rapidly degraded.

[0018] Smn proteins are thought to play a role in RNA processing and metabolism, with well-characterized functions mediating the assembly of specific types of RNA-protein complexes (called snRNPs). Smn may have other functions in motor neurons, however, its role in preventing selective degeneration of motor neurons is less certain.

[0019] In most cases, SMA is diagnosed based on clinical symptoms and the absence of all copies of exon 7 in the SMN1 gene, as determined by genetic testing. However, in approximately 5% of cases, SMA is caused by mutations other than deletion of the entire SMN1 gene or deletion of all exon 7 in the SMN1 gene, some of which are known and others of which are not. In such cases, other tests such as electromyography (EMG) or muscle biopsy may be indicated when SMN1 gene testing is not feasible or when SMN1 gene sequencing does not reveal any abnormalities.

[0020] Medical care for people with SMA is currently limited to supportive therapies, including respiratory, nutritional, and rehabilitation care; there are no known medications that address the underlying cause of the disease. Current treatment for SMA consists of preventing and managing the secondary effects of chronic motor unit loss. The primary management issue in type 1 SMA is the prevention and early treatment of lung problems, which are the main cause of death in most cases. Although some infants with SMA grow into adults, the life expectancy for those with type 1 SMA is less than two years.

[0021] Several mouse models of SMA have been studied. In particular, the SMNΔ7 model (Le et al., Hum. Mol. Genet., 2005, 14:845) carries multiple copies of both the SMN2 gene and the SMN2Δ7 cDNA and recapitulates many phenotypic features of type 1 SMA. The SMNΔ7 model can be used to study SMN2 expression and assess motor function and survival. The C / C-allele mouse model (Jackson Laboratory strain No.: 008714) provides a less severe model of SMA disease, with reduced levels of both full-length SMN2 (SMN2 FL) mRNA and SMN protein. The C / C-allele mouse phenotype possesses both the SMN2 gene and an alternatively spliced ​​hybrid mSmn1-SMN2 gene, but does not exhibit overt muscle weakness. The C / C-allele mouse model is used for SMN2 expression studies.

[0022] As our understanding of the genetic basis and pathophysiology of SMA has improved, several therapeutic strategies have been investigated, but none have proven successful in the clinic.

[0023] Gene replacement of SMN1 using viral delivery vectors and the use of differentiated SMN1 + / + Both cell replacement with stem cells have demonstrated efficacy in animal models of SMA. More research is needed to determine safety and immune responses before these approaches can be used in humans and to address the need to start treatment in the neonatal period.

[0024] Correction of alternative splicing of SMN2 in cultured cells has also been achieved using synthetic nucleotides as therapeutic agents: (i) antisense oligonucleotides that target sequence elements in the SMN2 pre-mRNA and shift the outcome of the splicing reaction toward the production of full-length SMN2 mRNA (Passini et al., Sci. Transl. Med., 2011, 3:72ra18; and Hua et al., Nature, 2011, 478:123) and (ii) anti-splicing RNA molecules that provide a fully functional RNA sequence that replaces the mutant fragment during splicing and produces full-length SMN1 mRNA (Coady and Lorson, J Neurosci., 2010, 30:126).

[0025] Other approaches under investigation include finding drugs that increase Smn levels, enhance the function of residual Smn, or compensate for Smn loss. Aminoglycosides have been shown to enhance the expression of stabilized Smn protein produced by SMN2Δ7 mRNA by promoting translational readthrough of abnormal stop codons, but have poor central nervous system penetration and are toxic after repeated doses. Chemotherapeutic agents, such as aclarubicin, have been shown to increase Smn protein in cell culture; however, the toxicity of these drugs prevents their long-term use in SMA patients. Certain drugs under clinical investigation for the treatment of SMA include transcriptional inhibitors, such as histone deacetylase ("HDAC") inhibitors (e.g., butyrate, valproic acid, and hydroxyurea), and mRNA stabilizers (RG3039, an mRNA decapping inhibitor obtained from Repligen), which aim to increase the amount of total RNA transcribed from the SMN2 gene. However, the use of HDAC inhibitors or mRNA stabilizers does not address the root cause of SMA and may cause a comprehensive enhancement of transcription and gene expression, posing potential safety concerns to humans.

[0026] In an alternative approach, neuroprotective agents such as olesoxime have been selected for investigation. Rather than aiming to enhance the production of functional Smn for the treatment of SMA, such strategies are being investigated to protect Smn-deficient motor neurons from neurodegeneration.

[0027] A system designed to identify compounds that enhance the inclusion of SMN exon 7 into RNA transcribed from the SMN2 gene, and certain benzoxazole and benzisoxazole compounds identified thereby, are described in International Application PCT / US2009 / 003238, filed May 27, 2009 (published as International Publication No. WO 2009 / 151546 and U.S. Publication No. US 2011 / 0086833). A system designed to identify compounds that enhance the production of stable Smn protein from SMN2Δ7 mRNA, and certain isoindolinone compounds identified thereby, are described in International Application PCT / US2009 / 004625, filed August 13, 2009 (published as International Publication No. WO 2010 / 019236 and U.S. Publication No. US 2011 / 0172284). Each of the foregoing documents is incorporated herein in its entirety for all purposes.

[0028] All other documents mentioned herein are incorporated by reference into this application as if fully set forth herein.

[0029] Despite progress in understanding the genetic basis and pathophysiology of SMA, there remains a need to identify compounds that can modify the course of spinal muscular atrophy, one of the most devastating childhood neurological diseases. Summary of the Invention

[0031] In one aspect, provided herein are compounds of formula (I):

[0032]

[0033] or a form thereof, wherein w1, w2, w3, w4, w5, w6, and w7 are as defined herein. In one embodiment, provided herein is a pharmaceutical composition comprising a compound of formula (I) or a form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. In a specific embodiment, provided herein is a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, for use in treating spinal muscular atrophy (SMA).

[0034] SMA is caused by the selective degeneration of Smn-deficient motor neurons due to deletion or mutation of the SMN1 gene. Although human subjects retain some copies of the SMN2 gene, the small amount of functional Smn protein expressed by SMN2 cannot fully compensate for the loss of Smn expressed from the SMN1 gene. The compounds, compositions thereof, and uses described herein are based, in part, on the applicant's discovery that compounds of Formula (I) enhance the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 minigene. The minigene duplicates exon 7 of SMN2 via an alternative splicing reaction, which results in the omission of exon 7 from a large fraction of SMN2 transcripts. Therefore, compounds of Formula (I) or forms thereof can be used to modulate the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene. The applicant has also discovered that compounds of Formula (I) enhance the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 minigene. Therefore, compounds of Formula (I) or forms thereof can be used to modulate the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene.

[0035] In one specific embodiment, provided herein are compounds of Formula (I), or forms thereof, that are useful for modulating the inclusion of exon 7 of SMN2 into the mRNA transcribed from the SMN2 gene. In another specific embodiment, provided herein are compounds of Formula (I), or forms thereof, that are useful for modulating the inclusion of exon 7 of SMN1 into the mRNA transcribed from the SMN1 gene. In yet another embodiment, provided herein are compounds of Formula (I), or forms thereof, that are useful for modulating the inclusion of exon 7 of SMN1 and SMN2 into the mRNA transcribed from the SMN1 and SMN2 genes, respectively.

[0036] In another aspect, provided herein is the use of a compound of formula (I) or a form thereof for treating SMA. In one embodiment, provided herein is a method for treating SMA in a human subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. The compound of formula (I) or a form thereof is preferably administered to the human subject as a pharmaceutical composition. In another embodiment, provided herein is the use of a compound of formula (I) for treating SMA, wherein the compound enhances the inclusion of exon 7 of SMN2 into the mRNA transcribed from the SMN2 gene. Without being limited by theory, the compound of formula (I) enhances the inclusion of exon 7 of SMN2 into the mRNA transcribed from the SMN2 gene and increases the level of Smn protein produced by the SMN2 gene and, therefore, can be used to treat SMA in a human subject in need thereof.

[0037] In another aspect, provided herein are primers and / or probes described in the Biological Examples below (e.g., SMN primers, such as SEQ ID NOs. 1, 7, 8, 11, or 13, and / or SEQ ID NOs. 2, 9, or 12, and / or SMN probes, such as SEQ ID NOs. 3 or 10), and uses of those primers and / or probes. In one embodiment, provided herein are isolated nucleotide sequences comprising SEQ ID NOs. 1, 2, 3, 7, 8, 9, 10, 11, 12, or 13. In another embodiment, provided herein are isolated nucleotide sequences consisting essentially of SEQ ID NOs. 1, 2, 3, 7, 8, 9, 10, 11, 12, or 13. In another embodiment, provided herein are isolated nucleotide sequences consisting of SEQ ID NOs. 1, 2, 3, 7, 8, 9, 10, 11, 12, or 13.

[0038] In certain embodiments, the amount of mRNA transcribed from the SMN1 and / or SMN2 genes that does not include exon 7 of SMN1 and / or SMN2 can be used as a biomarker for SMA, such as those disclosed herein. In other embodiments, the amount of mRNA transcribed from the SMN1 and / or SMN2 genes that includes exon 7 of SMN1 and / or SMN2 can be used as a biomarker for patients treated with a compound, such as those disclosed herein. In one specific embodiment, the patient is an SMA patient. In another specific embodiment, the patient is not an SMA patient.

[0039] In certain embodiments, the amount of mRNA transcribed from the SMN1 and / or SMN2 genes and including exon 7 of SMN1 and / or SMN2, and the amount of mRNA transcribed from the SMN1 and / or SMN2 genes and excluding exon 7 of SMN1 and / or SMN2, can be used as biomarkers for patients treated with a compound, such as those disclosed herein. In one embodiment, the patient is a patient with SMA. In another embodiment, the patient is not a patient with SMA.

[0040] According to these embodiments, the SMN primers and / or SMN probes described below can be used in assays, such as PCR (e.g., qPCR), rolling circle amplification, and RT-PCR (e.g., end-point RT-PCR and / or RT-qPCR) to evaluate and / or quantify the amount of mRNA transcribed from the SMN1 gene and / or SMN2 gene and including or excluding exon 7 of SMN1 and / or SMN2.

[0041] In a specific embodiment, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NO. 1, 7, 8, 11, or 13 and / or SEQ ID NO. 2, 9, or 12, and / or SMN probes such as SEQ ID NO. 3 or 10) are used in an assay, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, Northern blot, or Southern blot (e.g., such as the assays described in the Biological Examples below), to determine whether a compound (e.g., a compound of Formula (I) or a form thereof) enhances the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene.

[0042] In a specific embodiment, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NO. 1, 7, 8, 11, or 13 and / or SEQ ID NO. 2, 9, or 12, and / or SMN probes such as SEQ ID NO. 3 or 10) are used in an assay, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, Northern blot, or Southern blot (e.g., such as the assays described in the Biological Examples below), to determine whether a compound (e.g., a compound of Formula (I) or a form thereof) enhances the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene.

[0043] In a specific embodiment, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NO. 1, 7, 8, 11, or 13 and / or SEQ ID NO. 2, 9, or 12, and / or SMN probes such as SEQ ID NO. 3 or 10) are used in an assay, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, Northern blot, or Southern blot (e.g., such as the assays described in the Biological Examples below), to determine whether a compound (e.g., a compound of Formula (I) or a form thereof) enhances the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 genes.

[0044] In another embodiment, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NOs. 1, 7, 8, 11, or 13 and / or SEQ ID NOs. 2, 9, or 12, and / or SMN probes such as SEQ ID NOs. 3 or 10) are used in an assay, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, Northern blot, or Southern blot (e.g., such as the assays described in the Biological Examples below), to monitor the amount of mRNA transcribed from the SMN2 gene and including exon 7 of SMN2 in a patient sample. In one specific embodiment, the patient is a patient with SMA. In another specific embodiment, the patient is not a patient with SMA.

[0045] In another embodiment, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NOs. 1, 7, 8, 11, or 13 and / or SEQ ID NOs. 2, 9, or 12, and / or SMN probes such as SEQ ID NOs. 3 or 10) are used in an assay, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, Northern blot, or Southern blot (e.g., such as the assays described in the Biological Examples below), to monitor the amount of mRNA transcribed from the SMN1 gene and including exon 7 of SMN1 in a patient sample. In one specific embodiment, the patient is a patient with SMA. In another specific embodiment, the patient is not a patient with SMA.

[0046] In another embodiment, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NOs. 1, 7, 8, 11, or 13 and / or SEQ ID NOs. 2, 9, or 12, and / or SMN probes such as SEQ ID NOs. 3 or 10) are used in an assay, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, Northern blot, or Southern blot (e.g., such as the assays described in the Biological Examples below), to monitor the amount of mRNA transcribed from the SMN1 and / or SMN2 gene and including exon 7 of SMN1 and / or SMN2 in a patient sample. In one specific embodiment, the patient is a patient with SMA. In another specific embodiment, the patient is not a patient with SMA.

[0047] In another embodiment, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NOs. 1, 7, 8, 11, or 13 and / or SEQ ID NOs. 2, 9, or 12, and / or SMN probes such as SEQ ID NOs. 3 or 10) are used in assays, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, Northern blot, or Southern blot (e.g., such as the assays described in the Biological Examples below), to monitor a patient's response to a compound (e.g., a compound of Formula (I) or a form thereof). In one embodiment, the patient is a patient with SMA. In another embodiment, the patient is not a patient with SMA.

[0048] In another embodiment, provided herein is an assay for determining whether a compound (e.g., a compound of Formula (I) disclosed herein) enhances inclusion of exon 7 of SMN2 into mRNA transcribed from an SMN2 gene, comprising (a) subjecting mRNA transcribed from an SMN2 minigene described herein or in International Application PCT US2009 / 004625 filed August 13, 2009 (published as International Publication No. WO 2010 / 019236) or U.S. Publication No. US2011 / 0172284 to amplification of the SMN2 gene, together with components useful for, e.g., RT-PCR, RT-qPCR, PCR, end-point RT-PCR, qPCR, or rolling circle amplification, in the presence of a compound (e.g., a compound of Formula (I) disclosed herein), to amplification of the SMN2 gene with primers described herein (e.g., SEQ ID NO: 100). 1 and / or 2); and (b) detecting the amount of mRNA transcribed from the minigene and including exon 7 of SMN2, wherein (1) an increase in the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the absence of the compound indicates that the compound enhances inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene; and (2) no change or no substantial change in the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the absence of the compound indicates that the compound does not enhance inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene.

[0049] In another embodiment, provided herein is an assay for determining whether a compound (e.g., a compound of Formula (I) disclosed herein) enhances inclusion of exon 7 of SMN1 into mRNA transcribed from an SMN1 gene, comprising (a) subjecting mRNA transcribed from an SMN1 minigene described herein or in International Application PCT US2009 / 004625 filed August 13, 2009 (published as International Publication No. WO 2010 / 019236) or U.S. Publication No. US2011 / 0172284 to amplification of the SMN1 gene, and (b) allowing mRNA transcribed from an SMN1 minigene described herein or in International Application PCT US2009 / 004625 filed August 13, 2009 (published as International Publication No. WO 2010 / 019236) or U.S. Publication No. US2011 / 0172284 to amplification of the SMN1 gene, together with components useful for, e.g., RT-PCR, RT-qPCR, PCR, end-point RT-PCR, qPCR, or rolling circle amplification, to amplification of the SMN1 gene, in the presence of a compound (e.g., a compound of Formula (I) disclosed herein), and (c) allowing mRNA transcribed from an SMN1 minigene described herein or in International Application PCT US2009 / 004625 filed August 13, 2009 (published as International Publication No. WO 2010 / 019236) and U.S. Publication No. US2011 / 0172284 to amplification of the SMN1 gene, and (d) allowing mRNA transcribed from an SMN1 minigene described herein or in International Application PCT US2009 / 004625 filed August 13, 2009 (published as International Publication No. WO 1 and / or 2); and (b) detecting the amount of mRNA transcribed from the minigene and including exon 7 of SMN1, wherein (1) an increase in the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the absence of the compound indicates that the compound enhances inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene; and (2) no change or no substantial change in the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the absence of the compound indicates that the compound does not enhance inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene.

[0050] In another embodiment, provided herein is a method for determining whether a compound (e.g., a compound of Formula (I) disclosed herein) enhances inclusion of exon 7 of SMN2 into mRNA transcribed from an SMN2 gene, comprising (a) subjecting mRNA transcribed from an SMN2 minigene described herein or in International Application PCT US2009 / 004625 filed August 13, 2009 (published as International Publication No. WO 2010 / 019236) or U.S. Publication No. US2011 / 0172284 to amplification of the SMN2 protein, and (b) combining mRNA with a probe described herein (e.g., SEQ ID NO: 100) in the presence of a compound (e.g., a compound of Formula (I) disclosed herein) and a probe described herein (e.g., SEQ ID NO: 100) with components useful for, for example, RT-PCR, RT-qPCR, PCR, end-point RT-PCR, qPCR, or rolling circle amplification, and, where applicable, Northern or Southern blotting. 3 and / or 10); and (b) detecting the amount of mRNA transcribed from the minigene and including exon 7 of SMN2, wherein (1) an increase in the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the absence of the compound indicates that the compound enhances inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene; and (2) no change or no substantial change in the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the absence of the compound indicates that the compound does not enhance inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene.

[0051] In another embodiment, provided herein is a method for determining whether a compound (e.g., a compound of Formula (I) disclosed herein) enhances inclusion of exon 7 of SMN1 into mRNA transcribed from an SMN1 gene, comprising (a) subjecting mRNA transcribed from an SMN1 minigene described herein or in International Application PCT US2009 / 004625 filed August 13, 2009 (published as International Publication No. WO 2010 / 019236) or U.S. Publication No. US2011 / 0172284 to amplification of the SMN1 protein, and (b) combining mRNA with a probe described herein (e.g., SEQ ID NO: 100) in the presence of a compound (e.g., a compound of Formula (I) disclosed herein) and a probe described herein (e.g., SEQ ID NO: 100) with components useful for, e.g., RT-PCR, RT-qPCR, PCR, end-point RT-PCR, qPCR, or rolling circle amplification, and, where applicable, Northern or Southern blotting. 3 and / or 10); and (b) detecting the amount of mRNA transcribed from the minigene and including exon 7 of SMN1, wherein (1) an increase in the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the absence of the compound indicates that the compound enhances inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene; and (2) no change or no substantial change in the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the absence of the compound indicates that the compound does not enhance inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene.

[0052] In another embodiment, provided herein is a method for determining whether a compound (e.g., a compound of Formula (I) disclosed herein) enhances inclusion of exon 7 of SMN2 into mRNA transcribed from an SMN2 gene, comprising (a) subjecting mRNA transcribed from an SMN2 minigene described herein or in International Application PCT US2009 / 004625 filed August 11, 2009 (published as International Publication No. WO 202 / 019216) or U.S. Publication No. US2011 / 0172284 to amplification of the SMN2 protein, and (b) combining mRNA with primers (e.g., SEQ ID NOs. 1 or 2) and / or probes (e.g., SEQ ID NOs. 1 or 2) described herein in the presence of a compound (e.g., a compound of Formula (I) disclosed herein) and using a primer (e.g., SEQ ID NOs. 1 or 2) and / or a probe (e.g., SEQ ID NOs. 2 or 3) as described herein. NO. 3 and / or 10); and (b) detecting the amount of mRNA transcribed from the minigene and including exon 7 of SMN2, wherein (1) an increase in the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the absence of the compound indicates that the compound enhances inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene; and (2) no change or no substantial change in the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN2 in the absence of the compound indicates that the compound does not enhance inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene.

[0053] In another embodiment, provided herein is a method for determining whether a compound (e.g., a compound of Formula (I) disclosed herein) enhances inclusion of exon 7 of SMN1 into mRNA transcribed from an SMN1 gene, comprising (a) subjecting mRNA transcribed from an SMN1 minigene described herein or in International Application PCT US2009 / 004625 filed August 11, 2009 (published as International Publication No. WO 202 / 019216) or U.S. Publication No. US2011 / 0172284 to amplification of the SMN1 gene, and (b) combining mRNA with primers (e.g., SEQ ID NO. 1 or 2) and / or probes (e.g., SEQ ID NO. 3) described herein in the presence of a compound (e.g., a compound of Formula (I) disclosed herein) and with components useful for, for example, RT-PCR, RT-qPCR, PCR, end-point RT-PCR, qPCR, or rolling circle amplification, and, where applicable, Northern or Southern blotting; NO. 3 and / or 10); and (b) detecting the amount of mRNA transcribed from the minigene and including exon 7 of SMN1, wherein (1) an increase in the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the absence of the compound indicates that the compound enhances inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene; and (2) no change or no substantial change in the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the presence of the compound relative to the amount of mRNA transcribed from the minigene and including exon 7 of SMN1 in the absence of the compound indicates that the compound does not enhance inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene.

[0054] In another aspect, provided herein are kits comprising the primers and / or probes described in the biological examples below (e.g., SMN primers, such as SEQ ID NO. 1, 7, 8, 11 or 13 and / or SEQ ID NO. 2, 9 or 12, and / or SMN probes such as SEQ ID NO. 3 or 10) and their uses. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1, mentioned in Biological Example 1, is a schematic diagram of an SMN2-A minigene construct that produces two alternatively spliced ​​mRNA transcripts: a full-length mRNA containing exon 7 and a Δ7 mRNA lacking exon 7. The adenine nucleotide inserted into exon 7 of SMN2-A after nucleic acid residue 48 is represented by the letter "A." Alternatively, the nucleotide can be selected from cytosine or thymine. Due to the insertion of a nucleotide (A, C, or T) after nucleic acid residue 48, the full-length mRNA does not contain a stop codon in the SMN open reading frame, while the Δ7 mRNA has a stop codon in exon 8, indicated by the word "Stop."

[0057] FIG2 , mentioned in Biological Example 1, provides the DNA sequence of the minigene from the SMN2-A minigene construct SEQ ID NO. 21 ( Figure 2a ).like Figure 2b As shown, the following subsequences can be found:

[0058] 1-70:5'UTR(deg);

[0059] 71-79: Exon 6: start codon and BamHI site (atgggatcc);

[0060] 80-190: exon 6;

[0061] 191-5959: intron 6;

[0062] 5960-6014: Exon 7 with an adenine nucleotide "A" insertion (position 6008);

[0063] 6015-6458: intron 7;

[0064] 6459-6481: part of exon 8;

[0065] 6482-8146: BamHI site (sequence at the 5' end), luciferase coding sequence starting from codon 2 (no start codon), NotI site (sequence at the 3' end), TAA stop codon; and

[0066] 8147-8266:3'UTR(deg).

[0067] To generate the SMN1 variant of the minigene, site-directed mutagenesis was used to convert the sixth nucleotide (thymine residue) of exon 7 of the SMN2-A minigene construct to a cytosine. Thus, similar to the SMN2-A minigene construct, the SMN1 minigene construct had a single adenine residue inserted after nucleic acid residue 48 of exon 7. The SMN1 minigene construct was designated SMN1-A. Similarly, the nucleotide inserted after nucleic acid residue 48 of exon 7 in the SMN1 minigene construct can also alternatively be selected from cytosine or thymine.

[0068] FIG3 , referred to in Biological Example 2, shows that the Figure 3a ) and compound 170 ( Figure 3b Correction of alternative splicing of the SMN2 minigene in cells treated with dapoxetine (dapoxetine) for 24 hours. Full-length SMN2 minigene mRNA levels were quantified using reverse transcription-quantitative PCR (RT-qPCR). Full-length SMN2 minigene mRNA levels in compound-treated samples were normalized to those in vehicle-treated samples and plotted as a function of compound concentration.

[0069] FIG4, referred to in Biological Example 3, shows that the Figure 4a ) and compound 170 ( Figure 4b Correction of SMN2 alternative splicing in SMA Type 1 patient fibroblasts treated with dapoxetine (dapoxetine) for 24 hours. Full-length and Δ7 SMN2 mRNA levels were quantified using RT-qPCR. Full-length and Δ7 SMN2 mRNA levels in compound-treated samples were normalized to those in vehicle-treated samples and plotted as a function of compound concentration.

[0070] FIG5, referred to in Biological Example 4, shows that the Figure 5a ) and compound 170 ( Figure 5b Correction of SMN2 alternative splicing in fibroblasts from patients with type 1 SMA treated with RT-PCR for 25 hours. Full-length and Δ7 SMN2 mRNAs were amplified using reverse transcription-endpoint PCR (RT-PCR), and PCR products were separated by agarose gel electrophoresis. The top and bottom bands correspond to full-length and Δ7 SMN2 mRNAs, respectively. The intensity of each band is proportional to the amount of RNA present in the sample.

[0071] FIG6 , referred to in Biological Example 5, shows that the compound 6 ( Figure 6a ) and compound 170 ( Figure 6bTreatment with 5-mg dapoxetine (DDS) for 10 days (twice daily, BID) corrected SMN2 alternative splicing in the brain and muscle tissues of the C / C-allele SMA mouse model. Full-length and Δ7 SMN2 mRNA levels were quantified using RT-qPCR, with the combined amount of full-length and Δ7 SMN2 mRNA set to 1, and the fractional amounts of full-length and Δ7 SMN2 were calculated.

[0072] FIG7 , referred to in Biological Example 6, shows that the compound 6 ( Figure 7a ) and compound 170 ( Figure 7b Treatment with 50 mg / mL of 50 mg / mL (BID) for 10 days (BID) corrects SMN2 alternative splicing (in the SMN2 gene and the Smn1-SMN2 gene of hybrid mice) in the brain and muscle tissues of the C / C-allele SMA mouse model. Full-length and Δ7 SMN2 mRNAs were amplified using reverse RT-PCR. PCR products were separated by agarose gel electrophoresis. The top and bottom bands correspond to full-length and Δ7 SMN2 mRNAs, respectively. The intensity of each band is proportional to the amount of RNA present in the sample.

[0073] FIG8 , mentioned in Biological Example 7, shows that compound 6 ( Figure 8a ) and compound 170 ( Figure 8b ) showed a dose-dependent increase in Smn protein expression in SMA type 1 human fibroblasts treated with β-actin for 48 h.

[0074] FIG9 , mentioned in Biological Example 8, shows that compound 6 ( Figure 9a ) and compound 170 ( Figure 9b ) increased nuclear plaque counts (gems) in SMA Type 1 patient fibroblasts treated with α-glucose phosphate (GLP-1) for 48 hours. Plaques were counted using fluorescence microscopy. The number of plaques in compound-treated samples was normalized to that in vehicle-treated samples and plotted as a function of compound concentration.

[0075] Figure 10 , mentioned in Biological Example 9, shows that compound 6 ( Figure 10 ) Increased Smn protein expression in motor neurons generated from iPS cells derived from SMA Type 1 patient fibroblasts treated for 72 hours (black circles). Smn protein levels were quantified using Smn immunostaining and confocal fluorescence microscopy. Smn protein levels in compound-treated samples were normalized to those in vehicle-treated samples and plotted as a function of compound concentration.

[0076] FIG11 , referred to in Biological Example 11, shows that the effect of 100 mg / kg of compound 6 ( Figure 11a, n=10) and 10 mg / kg of compound 170 ( Figure 11b , n=5) treated with 10 days (BID) of C / C-allele SMA mouse model increased Smn protein expression in brain, spinal cord and muscle tissues. The p value of ANOVA in each figure is represented by three asterisks (***) representing p<0.001.

[0077] Figure 12, referred to in Biological Example 12, shows the effect of Compound 6 (brain, Figure 12a ;spinal cord, Figure 12b ;muscle, Figure 12c ; and skin, Figure 12d , n=6 to 9) and compound 170 (brain, Figure 12e ;spinal cord, Figure 12f ;muscle, Figure 12g Treatment with 5-naphthol (n=7) for 7 days (once daily, QD) resulted in a dose-dependent increase in Smn protein expression in tissues of the neonatal Δ7SMA mouse model. The ANOVA p-values ​​in each figure are represented by a single asterisk (*) for p<0.05, two asterisks (**) for p<0.01, and three asterisks (***) for p<0.001.

[0078] FIG13 , referred to in Biological Example 13, shows that compound 6 ( Figure 13a ) until postnatal day (PND) 59 and compound 170 ( Figure 13b ) treatment until PND 92 caused body weight differences in the newborn Δ7SMA mouse model.

[0079] FIG14 , referred to in Biological Example 14, shows that compound 6 ( Figure 14a ) and compound 170 ( Figure 14b ) treatment resulted in improved righting reflex in the neonatal Δ7SMA mouse model.

[0080] FIG15 , referred to in Biological Example 15, shows that compound 6 ( Figure 15a ) and compound 170 ( Figure 15b ) treatment resulted in improved survival rate in the neonatal Δ7SMA mouse model.

[0081] FIG16 , referred to in Biological Example 15, shows the effects of Compound 6 on the mitochondrial growth factor receptor (MGR) of mice treated with Compound 6 up to PND 156 (P<0.001), relative to vehicle-treated mice and age-matched heterozygous mice, respectively. Figure 16a ) and treated with compound 170 until PND 185 ( Figure 16b ) caused increased Smn protein expression in the brain, spinal cord, and muscle tissues of the Δ7SMA mouse model.

[0082] FIG17 , referred to in Biological Example 16, shows that compound 6 ( Figure 17a ) and compound 170 ( Figure 17b ) treatment for 7 hours in HEK293H human cells showed a dose-dependent increase in SMN1 minigene FL mRNA and a dose-dependent decrease in SMN1 minigene Δ7 mRNA. Full-length and Δ7 SMN1 minigene mRNAs were amplified using RT-PCR, and the resulting PCR products were separated by agarose gel electrophoresis. The top and bottom bands correspond to full-length and Δ7 SMN1 minigene mRNAs, respectively. The intensity of each band is proportional to the amount of RNA present in the sample. Detailed description

[0084] Provided herein are compounds of formula (I):

[0085]

[0086] or a form thereof in which:

[0087] w1 and w5 are CR independently a or N;

[0088] w2 is CR b or N;

[0089] w3, w4 and w7 are independently C-R1, C-R2, CR a or N;

[0090] w6 is C-R1, C-R2, CR c or N;

[0091] wherein one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that,

[0092] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[0093] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[0094] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N;

[0095] or

[0096] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c or N;

[0097] and

[0098] wherein any one, two or three of w1, w2, w3, w4, w5, w6 and w7 may optionally be N;

[0099] R1 is C 1-8 Alkyl, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, (C 1-8 Alkoxy-C 1-8 alkyl) 2-amino, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, amino-C 1-8 Alkyl-amino, (amino-C 1-8 alkyl) 2-amino, (amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, [(C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino, amino-C 1-8 Alkoxy, C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8alkyl)2-amino-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, amino-C 2-8 Alkenyl, C 1-8 Alkyl-amino-C 2-8 Alkenyl, (C 1-8 alkyl)2-amino-C 2-8 Alkenyl, amino-C 2-8 Alkynyl, C 1-8 Alkyl-amino-C 2-8 Alkynyl, (C 1-8 alkyl)2-amino-C 2-8 Alkynyl, halo-C 1-8 Alkyl-amino, (halo-C 1-8 alkyl)2-amino, (halogenated-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkoxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8Alkyl-amino-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl-amino, [(hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino, [(hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl](C 1-8 alkyl)amino, heterocyclyl, heterocyclyl-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2-amino, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heterocyclic-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 Cycloalkyl, aryl-C 1-8 Alkyl-amino, (aryl-C 1-8 alkyl) 2-amino, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (aryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heteroaryl, heteroaryl-C 1-8 Alkyl, heteroaryl-C1-8 Alkoxy, heteroaryl-amino, heteroaryl-C 1-8 Alkyl-amino, (heteroaryl-C 1-8 alkyl)2-amino, (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heteroaryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl;

[0100] In each case, the heterocyclic group, C 3-14 Cycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three R3 substituents and optionally with 1 additional R4 substituent; or

[0101] wherein, optionally, each case of heterocyclyl, C 3-14 Cycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, three, or four R3 substituents;

[0102] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;

[0103] wherein each occurrence of aryl, heterocyclyl and heteroaryl is optionally substituted by one, two or three R6 substituents and optionally by one further R7 substituent;

[0104] R a is independently selected at each occurrence from hydrogen, halogen or C 1-8 alkyl;

[0105] R b For hydrogen, halogen, C 1-8 Alkyl or C 1-8 alkoxy;

[0106] R c is hydrogen, halogen or C 1-8 alkyl;

[0107] R3 is independently selected from cyano, halogen, hydroxy, oxo, C 1-8 Alkyl, halo-C 1-8 Alkyl, C 1-8 Alkyl-carbonyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl, C1-8 Alkoxy-carbonyl, amino, C 1-8 Alkyl-amino, (C 1-8 alkyl) 2-amino, amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, amino-C 1-8 Alkyl-amino, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, [(C 1-8 alkyl)2-amino-C 1-8 alkyl]2-amino, (C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 alkyl)amino, [(C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 Alkyl)amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, (C 1-8 Alkoxy-C 1-8 alkyl) 2-amino, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 Alkyl)amino, C 1-8 Alkyl-carbonyl-amino, C 1-8 Alkoxy-carbonyl-amino, hydroxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkoxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl) 2-amino or (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino;

[0108] R4 is C 3-14 Cycloalkyl, C 3-14 Cycloalkyl-C 1-8 Alkyl, C 3-14 Cycloalkyl-amino, aryl-C 1-8 Alkyl, aryl-C 1-8 Alkoxy-carbonyl, aryl-sulfonyloxy-C 1-8 Alkyl, heterocyclyl or heterocyclyl-C 1-8Alkyl; wherein each occurrence of C 3-14 Cycloalkyl, aryl and heterocyclyl are optionally substituted with one, two or three R5 substituents;

[0109] R5 is independently selected from halogen, hydroxy, cyano, nitro, C 1-8 Alkyl, halo-C 1-8 Alkyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino or C 1-8 alkyl-thio;

[0110] R6 is independently selected from halogen, hydroxy, cyano, nitro, C 1-8 Alkyl, C 2-8 Alkenyl, halo-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino or C 1-8 Alkyl-thio; and

[0111] R7 is C 3-14 Cycloalkyl, C 3-14 Cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl. DETAILED DESCRIPTION

[0112] In one embodiment of the compound of formula (I), w1 is CR a .

[0113] In another embodiment of the compounds of formula (I), w1 is N.

[0114] In one embodiment of the compound of formula (I), w2 is CR b .

[0115] In another embodiment of the compounds of formula (I), w2 is N.

[0116] In one embodiment of the compound of formula (I), w3 is CR a .

[0117] In another embodiment of the compounds of formula (I), w3 is N.

[0118] In one embodiment of the compound of formula (I), w4 is CR a .

[0119] In another embodiment of the compounds of Formula (I), w4 is N.

[0120] In one embodiment of the compound of formula (I), w5 is CR a .

[0121] In another embodiment of the compounds of Formula (I), w5 is N.

[0122] In one embodiment of the compound of formula (I), w6 is CR c .

[0123] In another embodiment of the compounds of Formula (I), w6 is N.

[0124] In one embodiment of the compound of formula (I), w7 is CR a .

[0125] In another embodiment of the compounds of Formula (I), w7 is N.

[0126] In one embodiment of the compounds of formula (I), w3 is C-R1 and w6 is C-R2.

[0127] In another embodiment of the compounds of Formula (I), w3 is C-R2 and w6 is C-R1.

[0128] In one embodiment of the compounds of formula (I), w4 is C-R1 and w7 is C-R2.

[0129] In another embodiment of the compounds of Formula (I), w4 is C-R2 and w7 is C-R1.

[0130] In one embodiment of the compound of formula (I), w3 is C-R1, w6 is C-R2 and w1, w4, w5 and w7 are independently CR a or N and w2 is CR b or N.

[0131] In another embodiment of the compounds of formula (I), w3 is C-R2, w6 is C-R1 and w1, w4, w5 and w7 are independently CR a or N and w2 is CR b or N.

[0132] In one embodiment of the compound of formula (I), w4 is C-R1, w7 is C-R2, w1, w3 and w5 are independently CR aor N, w2 is CR b or N, and w6 is CR c or N.

[0133] In another embodiment of the compound of formula (I), w4 is C-R2, w7 is C-R1, w1, w3 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c or N.

[0134] In one embodiment of the compound of formula (I), w1 and w2 are N.

[0135] In one embodiment of the compound of formula (I), w1 and w3 are N.

[0136] In one embodiment of the compound of formula (I), w1 and w4 are N.

[0137] In one embodiment of the compound of formula (I), w1 and w5 are N.

[0138] In one embodiment of the compound of formula (I), w1 and w6 are N.

[0139] In one embodiment of the compound of formula (I), w1 and w7 are N.

[0140] In one embodiment of the compound of formula (I),

[0141] R1 is C 1-8 Alkyl, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, (C 1-8 Alkoxy-C 1-8 alkyl) 2-amino, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, amino-C 1-8 Alkyl-amino, (amino-C 1-8 alkyl) 2-amino, (amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, [(C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino, amino-C 1-8 Alkoxy, C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8 alkyl)2-amino-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 Alkoxy, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, amino-C 2-8 Alkenyl, C 1-8 Alkyl-amino-C 2-8 Alkenyl, (C 1-8 alkyl)2-amino-C 2-8 Alkenyl, amino-C 2-8 Alkynyl, C 1-8 Alkyl-amino-C 2-8 Alkynyl, (C 1-8 alkyl)2-amino-C 2-8 Alkynyl, halo-C 1-8 Alkyl-amino, (halo-C 1-8 alkyl)2-amino, (halogenated-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl, hydroxy-C 1-8Alkoxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl-amino, [(hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino, [(hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl](C 1-8 alkyl)amino, heterocyclyl, heterocyclyl-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2-amino, (heterocyclyl-C 1-8 Alkyl)(C 1-8alkyl)amino, heterocyclic-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 Cycloalkyl, aryl-C 1-8 Alkyl-amino, (aryl-C 1-8 alkyl) 2-amino, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (aryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heteroaryl, heteroaryl-C 1-8 Alkyl, heteroaryl-C 1-8 Alkoxy, heteroaryl-amino, heteroaryl-C 1-8 Alkyl-amino, (heteroaryl-C 1-8 alkyl)2-amino, (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heteroaryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; wherein each case of heterocyclyl, C 3-14 Cycloalkyl, aryl, and heteroaryl groups are optionally substituted with R3 and R4 substituents.

[0142] In another embodiment of the compounds of formula (I),

[0143] R1 is amino, (C 1-8 Alkyl) 2-amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, (C 1-8 Alkoxy-C 1-8 alkyl) 2-amino, amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, amino-C 1-8 Alkyl-amino, (amino-C 1-8 alkyl) 2-amino, (amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, [(C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino, amino-C 1-8 Alkoxy, C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8 alkyl)2-amino-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 Alkoxy, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, amino-C 2-8 Alkenyl, C 1-8 Alkyl-amino-C 2-8 Alkenyl, (C 1-8 alkyl)2-amino-C 2-8 Alkenyl, amino-C 2-8 Alkynyl, C 1-8 Alkyl-amino-C2-8 Alkynyl, (C 1-8 alkyl)2-amino-C 2-8 Alkynyl, halo-C 1-8 Alkyl-amino, (halo-C 1-8 alkyl)2-amino, (halogenated-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkoxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl-amino, [(hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino, [(hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl](C 1-8 alkyl)amino, heterocyclyl, heterocyclyl-C1-8 Alkyl, heterocyclyl-C 1-8 Alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2-amino, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heterocyclic-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 Cycloalkyl, aryl-C 1-8 Alkyl-amino, (aryl-C 1-8 alkyl) 2-amino, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (aryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heteroaryl, heteroaryl-C 1-8 Alkyl, heteroaryl-C 1-8 Alkoxy, heteroaryl-C 1-8 Alkyl-amino, (heteroaryl-C 1-8 alkyl)2-amino, (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heteroaryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; wherein each case of heterocyclyl, C 3-14 Cycloalkyl, aryl, and heteroaryl groups are optionally substituted with R3 and R4 substituents.

[0144] In another embodiment of the compounds of formula (I),

[0145] R1 is C 1-8 Alkyl, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, (C 1-8 Alkoxy-C 1-8 alkyl) 2-amino, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, amino-C 1-8 Alkyl-amino, (amino-C 1-8 alkyl) 2-amino, (amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, [(C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino, amino-C 1-8 Alkoxy, C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8 alkyl)2-amino-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 Alkoxy, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, amino-C 2-8 Alkenyl, C 1-8 Alkyl-amino-C 2-8 Alkenyl, (C 1-8 alkyl)2-amino-C 2-8 Alkenyl, amino-C 2-8 Alkynyl, C 1-8 Alkyl-amino-C 2-8 Alkynyl, (C 1-8 alkyl)2-amino-C 2-8 Alkynyl, halo-C 1-8 Alkyl-amino, (halo-C 1-8 alkyl)2-amino, (halogenated-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkoxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, (hydroxy-C1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl-amino, [(hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino or [(hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl](C 1-8 alkyl)amino.

[0146] In another embodiment of the compounds of formula (I),

[0147] R1 is a heterocyclic group, a heterocyclic group-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2-amino, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heterocyclic-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 Cycloalkyl, aryl-C 1-8 Alkyl-amino, (aryl-C 1-8 alkyl) 2-amino, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (aryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heteroaryl, heteroaryl-C 1-8 Alkyl, heteroaryl-C 1-8Alkoxy, heteroaryl-amino, heteroaryl-C 1-8 Alkyl-amino, (heteroaryl-C 1-8 alkyl)2-amino, (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heteroaryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; wherein each case of heterocyclyl, C 3-14 Cycloalkyl, aryl, and heteroaryl groups are optionally substituted with R3 and R4 substituents.

[0148] In another embodiment of the compounds of formula (I),

[0149] R1 is a heterocyclic group, a heterocyclic group-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2-amino, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heterocyclic-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl or heterocyclyl-carbonyl-oxy; wherein each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

[0150] In another embodiment of the compounds of Formula (I), R1 is heterocyclyl, optionally substituted with R3 and R4 substituents.

[0151] In another embodiment of the compound of formula (I), R1 is C 3-14 Cycloalkyl, optionally substituted with R3 and R4 substituents.

[0152] In another embodiment of the compounds of formula (I),

[0153] R1 is aryl-C1-8 Alkyl-amino, (aryl-C 1-8 alkyl) 2-amino, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (aryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 wherein each instance of aryl is optionally substituted with R3 and R4 substituents.

[0154] In another embodiment of the compound of formula (I), R1 is aryl-C 1-8 Alkyl-amino, optionally substituted with R3 and R4 substituents.

[0155] In another embodiment of the compounds of formula (I),

[0156] R1 is heteroaryl, heteroaryl-C 1-8 Alkyl, heteroaryl-C 1-8 Alkoxy, heteroaryl-amino, heteroaryl-C 1-8 Alkyl-amino, (heteroaryl-C 1-8 alkyl)2-amino, (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heteroaryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; wherein each case of heterocyclyl, C 3-14 Cycloalkyl, aryl, and heteroaryl groups are optionally substituted with R3 and R4 substituents.

[0157] In another embodiment of the compounds of Formula (I), R1 is heteroaryl, optionally substituted with R3 and R4 substituents.

[0158] In one embodiment of the compound of formula (I),

[0159] R1 is a heterocyclic group selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)- Hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydro Pyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1 H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.1.0]hexyl Heterobicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl , 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or 6,9-diazaspiro[4.5]decyl; wherein each instance of heterocyclyl is optionally substituted by R3 and R4 substituents.

[0160] In another embodiment of the compounds of formula (I),

[0161] R1 is a heterocyclic group selected from azetidin-1-yl, tetrahydrofuran-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperidin-4-yl, piperazin-1-yl, 1,4-diazepan-1-yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-4-yl, hexahydropyrrolo[3,4-b]pyrrole-1( 2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl )-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl, octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7a S)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazine -2(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazin-2-yl, 3-aza Bicyclo[3.1.0]hex-3-yl, 8-azabicyclo[3.2.1]oct-3-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-3-yl, 8-azabicyclo[3.2.1]oct-2-en-3-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl, 9-azabicyclo[3. 3.1]non-3-yl, (1R,5S)-9-azabicyclo[3.3.1]non-3-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, (1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.2]oct-2-yl, 3,8-diazabicyclo[3.2 .1]oct-3-yl, (1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl, 1,4-diazabicyclo[3.2.2]non-4-yl, azaspiro[3.3]hept-2-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2,7-diazaspiro[3.5]non-7-yl, 5,8-diazaspiro[3.5]non-8-yl, 2,7-diazaspiro[4.4]non-2-yl or 6,9-diazaspiro[4.5]dec-9-yl; wherein the heterocyclyl in each case is optionally substituted by R3 and R4 substituents.

[0162] In another embodiment of the compounds of formula (I),

[0163] R1 is a substituted heterocyclic group selected from 4-methyl-1,4-diazepan-1-yl, (3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aS,6aS)-5-methylhexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3, 4-c]pyrrol-2(1H)-yl, (3aR,6aS)-5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aR,7aR)-1-ethyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aR,7aR)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6 -yl, (4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7aS)-1-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-8a-methyloctahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (1R,5S,6s)-6-(dimethylamino)- 3-azabicyclo[3.1.0]hexan-3-yl, (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl, 9-methyl-9-azabicyclo[3.3.1]nonan-3-yl, (3-exo)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl, (1R,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl, (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl or (1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl.

[0164] In one embodiment of the compound of formula (I), R1 is heterocyclyl-C 1-8 alkyl, wherein the heterocyclyl group is selected from morpholinyl, piperidinyl, piperazinyl, imidazolyl or pyrrolidinyl; and wherein each instance of the heterocyclyl group is optionally substituted with R3 and R4 substituents.

[0165] In another embodiment of the compound of formula (I), R1 is heterocyclyl-C 1-8 alkyl selected from morpholin-4-yl-methyl, morpholin-4-yl-ethyl, morpholin-4-yl-propyl, piperidin-1-yl-methyl, piperazin-1-yl-methyl, piperazin-1-yl-ethyl, piperazin-1-yl-propyl, piperazin-1-yl-butyl, imidazol-1-yl-methyl, imidazol-1-yl-ethyl, imidazol-1-yl-propyl, imidazol-1-yl-butyl, pyrrolidin-1-yl-methyl, pyrrolidin-1-yl-ethyl, pyrrolidin-1-yl-propyl or pyrrolidin-1-yl-butyl; wherein each instance of heterocyclyl is optionally substituted with R and R substituents.

[0166] In one embodiment of the compound of formula (I), R1 is heterocyclyl-C 1-8 Alkoxy, wherein the heterocyclyl group is selected from pyrrolidinyl, piperidinyl or morpholinyl; and wherein each instance of the heterocyclyl group is optionally substituted with R3 and R4 substituents.

[0167] In another embodiment of the compound of formula (I), R1 is heterocyclyl-C 1-8 Alkoxy is selected from pyrrolidin-2-yl-methoxy, pyrrolidin-2-yl-ethoxy, pyrrolidin-1-yl-methoxy, pyrrolidin-1-yl-ethoxy, piperidin-1-yl-methoxy, piperidin-1-yl-ethoxy, morpholin-4-yl-methoxy or morpholin-4-yl-ethoxy; wherein each instance of heterocyclyl is optionally substituted by R3 and R4 substituents.

[0168] In one embodiment of the compounds of Formula (I), R1 is heterocyclyl-amino, wherein the heterocyclyl group is selected from azetidinyl, pyrrolidinyl, piperidinyl, 9-azabicyclo[3.3.1]nonyl or (1R,5S)-9-azabicyclo[3.3.1]nonyl; and wherein each instance of the heterocyclyl group is optionally substituted with R3 and R4 substituents.

[0169] In another embodiment of the compounds of formula (I), R1 is a heterocyclyl-amino group selected from azetidin-3-yl-amino, pyrrolidin-3-yl-amino, piperidin-4-yl-amino, 9-azabicyclo[3.3.1]non-3-yl-amino, (1R,5S)-9-azabicyclo[3.3.1]non-3-yl-amino, 9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino, (3-exo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino or (1R,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino; wherein each instance of the heterocyclyl group is optionally substituted with R3 and R4 substituents.

[0170] In one embodiment of the compound of formula (I), R1 is (heterocyclyl)(C 1-8 alkyl)amino, wherein the heterocyclyl is selected from pyrrolidinyl or piperidinyl; and wherein each instance of the heterocyclyl is optionally substituted with R3 and R4 substituents.

[0171] In another embodiment of the compound of formula (I), R1 is (heterocyclyl)(C 1-8 wherein the heterocyclyl group in each instance is optionally substituted with R3 and R4 substituents.

[0172] In one embodiment of the compound of formula (I), R1 is heterocyclyl-amino-C 1-8 alkyl, wherein the heterocyclyl is selected from tetrahydrofuranyl; and wherein each instance of the heterocyclyl is optionally substituted with R3 and R4 substituents.

[0173] In another embodiment of the compound of formula (I), R1 is heterocyclyl-amino-C 1-8 Alkyl is selected from 3-(tetrahydrofuran-3-yl-amino)propyl; wherein each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

[0174] In one embodiment of the compound of formula (I), R1 is heterocyclyl-C 1-8 Alkyl-amino-C 1-8 alkyl, wherein the heterocyclyl group is selected from tetrahydrofuranyl, thienyl or pyridinyl; and wherein each instance of the heterocyclyl group is optionally substituted with R3 and R4 substituents.

[0175] In another embodiment of the compound of formula (I), R1 is heterocyclyl-C 1-8 Alkyl-amino-C 1-8Alkyl is selected from 3-[(tetrahydrofuran-2-ylmethyl)amino]propyl, 3-[(thiophen-3-ylmethyl)amino]propyl, 3-[(pyridin-2-ylmethyl)amino]propyl or 3-[(pyridin-4-ylmethyl)amino]propyl; wherein each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

[0176] In one embodiment of the compounds of formula (I), R1 is heterocyclyl-oxy, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and wherein each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

[0177] In another embodiment of the compounds of formula (I), R1 is heterocyclyl-oxy selected from pyrrolidin-3-yl-oxy or piperidin-4-yl-oxy; wherein each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

[0178] In one embodiment of the compounds of formula (I), R1 is heterocyclyl-carbonyl, wherein the heterocyclyl group is selected from piperazinyl; and wherein each instance of the heterocyclyl group is optionally substituted with R3 and R4 substituents.

[0179] In another embodiment of the compounds of Formula (I), R1 is a heterocyclyl-carbonyl selected from piperazin-1-yl-carbonyl; wherein each instance of the heterocyclyl is optionally substituted with R3 and R4 substituents.

[0180] In one embodiment of the compounds of formula (I), R1 is heterocyclyl-carbonyl-oxy, wherein heterocyclyl is selected from piperazinyl; and wherein each instance of heterocyclyl is optionally substituted with R3 and R4 substituents.

[0181] In another embodiment of the compounds of formula (I), R1 is a heterocyclyl-carbonyl-oxy group selected from piperazin-1-yl-carbonyl-oxy; wherein each instance of the heterocyclyl group is optionally substituted with R3 and R4 substituents.

[0182] In one embodiment of the compound of formula (I), R1 is C 3-14 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl or cycloheptyl; wherein each occurrence of C 3-14 The cycloalkyl group is optionally substituted with R3 and R4 substituents.

[0183] In another embodiment of the compound of formula (I), R1 is C 3-8 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl or cycloheptyl; wherein each occurrence of C 3-14 The cycloalkyl group is optionally substituted with R3 and R4 substituents.

[0184] In one embodiment of the compound of formula (I), R1 is aryl-C 1-8 Alkyl-amino-C 1-8 alkyl, wherein the aryl group is selected from phenyl; and wherein each instance of the aryl group is optionally substituted with R3 and R4 substituents.

[0185] In another embodiment of the compound of formula (I), R1 is aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl is selected from 3-(benzylamino)propyl; wherein each instance of aryl is optionally substituted with R3 and R4 substituents.

[0186] In one embodiment of the compounds of Formula (I), R1 is heteroaryl, wherein heteroaryl is selected from pyridinyl; and wherein each instance of heteroaryl is optionally substituted with R3 and R4 substituents.

[0187] In another embodiment of the compounds of Formula (I), R1 is heteroaryl selected from pyridin-4-yl; wherein each instance of heteroaryl is optionally substituted with R3 and R4 substituents.

[0188] In one embodiment of the compound of formula (I), R1 is heteroaryl-C 1-8 Alkyl, wherein heteroaryl, is selected from 1H-imidazolyl; and wherein each instance of heteroaryl is optionally substituted with R3 and R4 substituents.

[0189] In another embodiment of the compounds of formula (I), R1 is heteroaryl-C 1-8 Alkyl is selected from 1H-imidazol-1-yl-methyl; wherein each instance of heteroaryl is optionally substituted with R3 and R4 substituents.

[0190] In one embodiment of the compound of formula (I), R1 is (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, wherein heteroaryl is selected from pyridinyl; and wherein each instance of heteroaryl is optionally substituted with R3 and R4 substituents.

[0191] In another embodiment of the compounds of formula (I), R1 is (heteroaryl-C 1-8 Alkyl)(C 1-8 wherein each instance of heteroaryl is optionally substituted with R3 and R4 substituents.

[0192] In one embodiment of the compound of formula (I), R1 is heteroaryl-C 1-8 Alkyl-amino-C 1-8alkyl, wherein the heteroaryl is selected from thienyl or pyridinyl; and wherein each instance of the heteroaryl is optionally substituted with R3 and R4 substituents.

[0193] In another embodiment of the compounds of formula (I), R1 is heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl selected from thien-3-yl-methyl-amino-propyl, pyridin-2-yl-methyl-amino-propyl, pyridin-3-yl-methyl-amino-propyl or pyridin-4-yl-methyl-amino-propyl; wherein each instance of heteroaryl is optionally substituted with R3 and R4 substituents.

[0194] In one embodiment of the compound of formula (I), R3 is selected from cyano, halogen, hydroxy, oxo, C 1-8 Alkyl, halo-C 1-8 Alkyl, C 1-8 Alkyl-carbonyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl, C 1-8 Alkoxy-carbonyl, amino, C 1-8 Alkyl-amino, (C 1-8 alkyl) 2-amino, amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, amino-C 1-8 Alkyl-amino, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, C 1-8 Alkyl-carbonyl-amino, C 1-8 Alkoxy-carbonyl-amino, hydroxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkoxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl) 2-amino or (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino.

[0195] In another embodiment of the compound of formula (I), R3 is selected from cyano, halogen, hydroxy, oxo, C 1-8Alkyl, halo-C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl, C 1-8 Alkoxy-carbonyl, amino, C 1-8 Alkyl-amino, (C 1-8 alkyl) 2-amino, amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, C 1-8 Alkoxy-carbonyl-amino, hydroxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkoxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl) 2-amino or (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino.

[0196] In one embodiment of the compound of formula (I), R3 is C 1-8 Alkyl is selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

[0197] In another embodiment of the compound of formula (I), R3 is C 1-8 Alkyl is selected from ethyl, propyl, isopropyl or tert-butyl.

[0198] In one embodiment of the compound of formula (I), R3 is halo-C 1-8 Alkyl is selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein halogen is selected from fluorine, chlorine, bromine or iodine.

[0199] In another embodiment of the compound of formula (I), R3 is halo-C 1-8 Alkyl is selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, trihalo-propyl or dihalo-propyl; wherein halogen is selected from fluorine, chlorine, bromine or iodine.

[0200] In one embodiment of the compound of formula (I), R3 is hydroxy-C 1-8Alkyl is selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

[0201] In another embodiment of the compound of formula (I), R3 is hydroxy-C 1-8 Alkyl is selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

[0202] In one embodiment of the compound of formula (I), R3 is C 1-8 Alkoxy is selected from methoxy, ethoxy, propoxy or isopropoxy.

[0203] In one embodiment of the compound of formula (I), R3 is halo-C 1-8 Alkoxy is selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein halogen is selected from fluorine, chlorine, bromine or iodine.

[0204] In one embodiment of the compound of formula (I), R3 is C 1-8 Alkoxy-carbonyl-amino is selected from methoxy-carbonyl-amino, ethoxy-carbonyl-amino, propoxy-carbonyl-amino, isopropoxy-carbonyl-amino, tert-butoxy-carbonyl-amino.

[0205] In one embodiment of the compound of formula (I), R4 is C 3-14 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein each occurrence of C 3-14 The cycloalkyl group is optionally substituted with an R5 substituent.

[0206] In another embodiment of the compound of formula (I), R4 is C 3-8 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein each occurrence of C 3-8 The cycloalkyl group is optionally substituted with an R5 substituent.

[0207] In one embodiment of the compound of formula (I), R4 is C 3-14 Cycloalkyl-C 1-8 Alkyl, where C 3-14 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and wherein each occurrence of C 3-14 The cycloalkyl group is optionally substituted with an R5 substituent.

[0208] In another embodiment of the compound of formula (I), R4 is C 3-8 Cycloalkyl-C 1-8 Alkyl, where C3-8 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and wherein each occurrence of C 3-8 The cycloalkyl group is optionally substituted with an R5 substituent.

[0209] In one embodiment of the compound of formula (I), R4 is C 3-14 Cycloalkyl-amino, wherein C 3-14 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and wherein each occurrence of C 3-14 The cycloalkyl group is optionally substituted with an R5 substituent.

[0210] In another embodiment of the compound of formula (I), R4 is C 3-8 Cycloalkyl-amino, wherein C 3-8 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and wherein each occurrence of C 3-8 The cycloalkyl group is optionally substituted with an R5 substituent.

[0211] In one embodiment of the compound of formula (I), R4 is aryl-C 1-8 Alkyl, aryl-C 1-8 Alkoxy-carbonyl or aryl-sulfonyloxy-C 1-8 alkyl, wherein the aryl group is selected from phenyl; and wherein each instance of the aryl group is optionally substituted with an R5 substituent.

[0212] In another embodiment of the compounds of formula (I), R4 is aryl-C 1-8 Alkyl or aryl-C 1-8 Alkoxy-carbonyl, in which each occurrence of aryl is optionally substituted by an R5 substituent.

[0213] In one embodiment of the compound of formula (I), R4 is heterocyclyl selected from oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxanyl or morpholinyl, wherein each instance of heterocyclyl is optionally substituted with an R5 substituent.

[0214] In another embodiment of the compounds of formula (I), R4 is a heterocyclyl selected from oxetan-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 1,3-dioxan-5-yl or morpholin-4-yl, wherein each instance of the heterocyclyl is optionally substituted with an R5 substituent.

[0215] In one embodiment of the compound of formula (I), R4 is heterocyclyl-C 1-8 alkyl, wherein each instance of heterocyclyl is selected from pyrrolidinyl or piperidinyl; and wherein each instance of heterocyclyl is optionally substituted with an R5 substituent.

[0216] In another embodiment of the compound of formula (I), R4 is heterocyclyl-C 1-8 Alkyl, selected from pyrrolidin-1-yl-C 1-8 Alkyl or piperidin-1-yl-C 1-8 Alkyl, wherein each instance of heterocyclyl is optionally substituted by an R5 substituent.

[0217] In one embodiment of the compound of formula (I), R5 is selected from halogen, hydroxy, cyano, nitro, halo-C 1-8 Alkyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino or C 1-8 Alkyl-thio; wherein halogen or halo is selected from fluorine, chlorine, bromine or iodine.

[0218] In one embodiment of the compound of formula (I), R5 is hydroxy.

[0219] In one embodiment of the compound of formula (I), R5 is C 1-8 Alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.

[0220] In another embodiment of the compound of formula (I), R5 is C 1-8 Alkyl is selected from ethyl, propyl, isopropyl or tert-butyl.

[0221] In one embodiment of the compound of formula (I), R5 is halo-C 1-8 Alkyl is selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein halogen is selected from fluorine, chlorine, bromine or iodine.

[0222] In one embodiment of the compound of formula (I), R5 is C 1-8 Alkoxy is selected from methoxy, ethoxy, propoxy or isopropoxy.

[0223] In one embodiment of the compound of formula (I), R5 is halo-C 1-8 Alkoxy is selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein halogen is selected from fluorine, chlorine, bromine or iodine.

[0224] In one embodiment of the compound of formula (I), R2 is aryl selected from phenyl optionally substituted with R6 and R7 substituents.

[0225] In one embodiment of the compounds of formula (I), R2 is aryl-amino, wherein aryl is selected from phenyl; and wherein each instance of aryl is optionally substituted with R6 and R7 substituents.

[0226] In another embodiment of the compounds of formula (I), R2 is aryl-amino, selected from phenyl-amino; wherein each instance of aryl is optionally substituted with R6 and R7 substituents.

[0227] In one embodiment of the compounds of formula (I), R2 is aryl-amino-carbonyl, wherein aryl is selected from phenyl; and wherein each instance of aryl is optionally substituted with R6 and R7 substituents.

[0228] In another embodiment of the compounds of formula (I), R2 is aryl-amino-carbonyl selected from phenyl-amino-carbonyl; wherein each instance of aryl is optionally substituted with R6 and R7 substituents.

[0229] In one embodiment of the compound of formula (I),

[0230] R2 is a heterocyclyl selected from 1,2,3,6-tetrahydropyridyl, 1,3-benzodioxolyl or 2,3-dihydro-1,4-benzodioxinyl; wherein each instance of the heterocyclyl is optionally substituted with R6 and R7 substituents.

[0231] In another embodiment of the compounds of formula (I), R2 is a heterocyclyl selected from 1,2,3,6-tetrahydropyridin-4-yl, 1,3-benzodioxol-5-yl or 2,3-dihydro-1,4-benzodioxin-6-yl; wherein the heterocyclyl in each instance is optionally substituted with R6 and R7 substituents.

[0232] In one embodiment of the compound of formula (I), R2 is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl , 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; wherein each instance of heteroaryl is optionally substituted with R6 and R7 substituents.

[0233] In another embodiment of the compound of formula (I), R2 is heteroaryl selected from thiophene-2-yl, thiophene-3-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1,3-thiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H -indazol-5-yl, 2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl, benzofuran-5-yl, benzothiophen-2-yl, benzothiophen-3-yl, 1H-benzimidazol-2-yl, 1H-benzimidazol-6-yl, 1,3-benzooxazol-2-yl, 1,3-benzooxazol-5-yl, 1,3-benzooxazol-6-yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 9H-purin-8-yl, furo[3,2-b]pyridin-2-yl, furo[3,2-c]pyridin-3-yl -2-yl, furo[2,3-c]pyridin-2-yl, thieno[3,2-c]pyridin-2-yl, thieno[2,3-d]pyrimidin-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl, pyrrolo[1,2-a]pyrimidin-7-yl, pyrrolo[1,2-a]pyrazin-7-yl, pyrrolo[1,2-b]pyridazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyrazin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-2-yl, [1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[2,1-b][1,3]thiazol-6-yl, imidazo[2,1-b][1,3,4]thiadiazol-6-yl, [1,3]oxazolo[4,5-b]pyridin-2-yl or quinoxalin-2-yl; wherein each instance of heteroaryl is optionally substituted by R6 and R7 substituents.

[0234] In another embodiment of the compound of formula (I), R2 is a substituted heteroaryl selected from 4-methylthiophene-2-yl, 1-methyl-1H-pyrazol-3-yl, 4-methyl-1H-pyrazol-3-yl, 1-phenyl-1H-pyrazol-3-yl, 1-phenyl-1H-imidazol-4-yl, 2-methyl-1-(pyridin-2-yl)-1H-imidazol-4-yl, 4-methyl-1,3-thiazol-2-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl, 4-phenyl-1,3-thiazol-2-yl, 5-phenyl-1,2,4-oxadiazol-3-yl, 3-fluoropyridin-4-yl, 6-fluoropyridin-2-yl, 2-chloropyridin-4-yl, 4-chloropyridin-3-yl, 5-chloropyridin-2-yl. , 6-methylpyridin-3-yl, 2-(trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 2-methoxypyridin-4-yl, 4-methoxypyridin-3-yl, 6-methoxypyridin-2-yl, 2-ethoxypyridin-3-yl, 6-ethoxypyridin-2-yl, 6-(propan-2-yloxy)pyridin-2-yl, 6-(dimethylamino)pyridin-3-yl, 6-(methylsulfanyl)pyridin-2-yl, 6-(cyclobutyloxy)pyridin-2-yl, 6-(pyrrolidin-1-yl)pyridin-2-yl, 2-methylpyrimidin-4-yl, 2-(propan-2-yl)pyrimidin-4-yl, 2-cyclopropylpyrimidin-4-yl, 1-methyl-1 H-indol-3-yl, 2-methyl-2H-indole-5-yl, 2-methyl-1-benzofuran-5-yl, 1-methyl-1H-benzimidazol-2-yl, 4-methyl-1H-benzimidazol-2-yl, 5-fluoro-1H-benzimidazol-2-yl, 4-fluoro-1,3-benzoxazol-2-yl, 5-fluoro-1,3-benzoxazol-2-yl, 4-chloro-1,3-benzoxazol-2-yl, 4-iodo-1,3-benzoxazol-2-yl, 2-methyl-1,3-benzoxazol-6-yl, 4-methyl-1,3-benzoxazol-2-yl, 4-(trifluoromethyl)-1,3-benzoxazol-2-yl, 7-(trifluoromethyl)-1,3-benzoxazol-2-yl, 2-methyl-1,3-benzoxazol-6-yl, thiazol-2-yl, 2-methyl-1,3-benzothiazol-5-yl, 2-methyl-1,3-benzothiazol-6-yl, 4-chloro-1,3-benzothiazol-2-yl, 7-chloro-1,3-benzothiazol-2-yl, 4-(trifluoromethyl)-1,3-benzothiazol-2-yl, 5-methylfuro[3,2-b]pyridin-2-yl, 4,6-dimethylfuro[3,2-c]pyridin-2-yl, 5,7-dimethylfuro[2,3-c]pyridin-2-yl, 4,6-dimethylthieno[3,2-c]pyridin-2-yl, 2,4-dimethylthieno[2,3-d]pyrimidin-6-yl, 1-methylpyrrolo[1,2-a]pyrazin-7-yl, 3-methylpyrrolo[1,2-a]pyrazin-7-yl, 1,3-dimethylpyrrolo[1,2-a]pyrazin-7-yl, 2-methylpyrrolo[1,2-b]pyridazin-2-yl, 4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl, 5-methylpyrazolo[1,5-a]pyridin-2-yl, 4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl, 2-chloroimidazo[2,1-b][1,3]thiazol-6-yl, 2-methylimidazo[2,1-b][1,3]thiazol-6-yl, 3-methylimidazo[2,1-b][1,3]thiazol-6-yl, 2-ethylimidazo[2,1-b][1,3]thiazol-6-yl, 2-methylimidazo[2,1-b][1,3 ,4]thiadiazol-6-yl, 6-cyanoimidazo[1,2-a]pyridin-2-yl (also known as 2-imidazo[1,2-a]pyridine-6-carbonitrile), 6-fluoroimidazo[1,2-a]pyridin-2-yl, 8-fluoroimidazo[1,2-a]pyridin-2-yl, 6,8-difluoroimidazo[1,2-a]pyridin-2-yl, 7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl, 8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl, 6-chloroimidazo[1,2-a]pyridin-2-yl, 7-chloroimidazo[1,2-a]pyridin-2-yl, 8-chloroimidazo[1,2-a]pyridin-2-yl, 8-bromoimidazo[1,2-a]pyridin-2-yl , 2-methylimidazo[1,2-a]pyridin-2-yl, 5-methylimidazo[1,2-a]pyridin-2-yl, 6-methylimidazo[1,2-a]pyridin-2-yl, 7-methylimidazo[1,2-a]pyridin-2-yl, 8-methylimidazo[1,2-a]pyridin-2-yl, 7-ethylimidazo[1,2-a]pyridin-2-yl, 8-ethylimidazo[1,2-a]pyridin-2-yl, 6,8-dimethylimidazo[1,2-a]pyridin-2-yl, 8-ethyl-6-methylimidazo[1,2-a]pyridin-2-yl, 7-methoxyimidazo[1,2-a]pyridin-2-yl, 8-methoxyimidazo[1,2-a]pyridin-2-yl, 6-fluoro-8 2-Methylimidazo[1,2-a]pyridin-2-yl, 8-fluoro-6-methylimidazo[1,2-a]pyridin-2-yl, 8-chloro-6-methylimidazo[1,2-a]pyridin-2-yl, 6-methyl-8-nitroimidazo[1,2-a]pyridin-2-yl, 8-cyclopropylimidazo[1,2-a]pyridin-2-yl, 2-methylimidazo[1,2-a]pyridin-6-yl, 2-ethylimidazo[1,2-a]pyridin-6-yl, 2,3-dimethylimidazo[1,2-a]pyridin-6-yl, 2,8-dimethylimidazo[1,2-a]pyridin-6-yl, 2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl, 8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl, 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl, 6-fluoroimidazo[1,2-a]pyrimidin-2-yl, 6-chloroimidazo[1,2-a]pyrimidin-2-yl, 6-methylimidazo[1,2-a]pyrimidin-2-yl, 7-methylimidazo[1,2-a]pyrimidin-2-yl, 2-methylimidazo[1,2-a]pyrimidin-6-yl, 6-methylimidazo[1,2-b]pyridazin-2-yl, 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl, 6-methylimidazo[1,2-a ]pyrazin-2-yl, 8-methylimidazo[1,2-a]pyrazin-2-yl, 6,8-dimethylimidazo[1,2-a]pyrazin-2-yl, 6-chloro-8-methylimidazo[1,2-a]pyrazin-2-yl, 6-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyrazin-2-yl, 8-(methylsulfanyl)imidazo[1,2-a]pyrazin-2-yl, 2-methylimidazo[2,1-b][1,3]thiazol-6-yl, 3-methylimidazo[2,1-b][1,3]thiazol-6-yl or 2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl.

[0235] In another embodiment of the compounds of formula (I),

[0236] R2 is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl; wherein each instance of heteroaryl is optionally substituted with R6 and R7 substituents.

[0237] In another embodiment of the compounds of formula (I),

[0238] R2 is a heteroaryl group selected from furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-b]pyridinyl, pyrazolo[1,5-d ... [1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; wherein each instance of heteroaryl is optionally substituted by R6 and R7 substituents.

[0239] In one embodiment of the compounds of formula (I), R2 is heteroaryl-amino, wherein heteroaryl is selected from pyridinyl or pyrimidinyl; and wherein each instance of heteroaryl is optionally substituted with R6 and R7 substituents.

[0240] In another embodiment of the compounds of formula (I), R2 is heteroaryl-amino selected from pyridin-2-yl-amino, pyridin-3-yl-amino or pyrimidin-2-yl-amino; wherein each instance of heteroaryl is optionally substituted with R6 and R7 substituents.

[0241] In one embodiment of the compound of formula (I), R6 is selected from halogen, hydroxy, cyano, nitro, C 1-8 Alkyl, halo-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl, (C 1-8 Alkyl) 2-amino or C 1-8 Alkyl-thio; wherein halogen or halo is selected from fluorine, chlorine, bromine or iodine.

[0242] In one embodiment of the compound of formula (I), R6 is C 1-8 Alkyl is selected from methyl, ethyl, propyl, isopropyl or tert-butyl.

[0243] In another embodiment of the compound of formula (I), R6 is C 1-8 Alkyl is selected from ethyl, propyl, isopropyl or tert-butyl.

[0244] In one embodiment of the compound of formula (I), R6 is C 2-8 Alkenyl is selected from vinylallyl or buta-1,3-dienyl.

[0245] In another embodiment of the compound of formula (I), R6 is C 2-8 Alkenyl is selected from vinyl or allyl.

[0246] In one embodiment of the compound of formula (I), R6 is halo-C 1-8 Alkyl is selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein halogen is selected from fluorine, chlorine, bromine or iodine.

[0247] In one embodiment of the compound of formula (I), R6 is hydroxy-C 1-8 Alkyl is selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

[0248] In another embodiment of the compound of formula (I), R6 is hydroxy-C 1-8 Alkyl is selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.

[0249] In one embodiment of the compound of formula (I), R6 is C 1-8 Alkoxy is selected from methoxy, ethoxy, propoxy or isopropoxy.

[0250] In one embodiment of the compound of formula (I), R6 is halo-C 1-8 Alkoxy is selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein halogen is selected from fluorine, chlorine, bromine or iodine.

[0251] In one embodiment of the compound of formula (I), R7 is C 3-14 Cycloalkyl, C 3-14 Cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl; wherein C 3-14 wherein cycloalkyl is selected from cyclopropyl or cyclobutoxy; wherein aryl is selected from phenyl; wherein heterocyclyl is selected from oxetanyl, pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl; and wherein heteroaryl is selected from thienyl or pyridinyl.

[0252] In another embodiment of the compound of formula (I), R7 is C 3-14 Cycloalkyl or C 3-14Cycloalkyl-oxy, wherein each occurrence of C 3-14 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0253] In another embodiment of the compound of formula (I), R7 is C 3-8 Cycloalkyl or C 3-8 Cycloalkyl-oxy, wherein each occurrence of C 3-8 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0254] In one embodiment of the compound of formula (I), R7 is aryl selected from phenyl.

[0255] In one embodiment of the compound of formula (I), R7 is a heterocyclyl selected from oxetanyl, pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl.

[0256] In another embodiment of the compound of formula (I), R7 is a heterocyclyl selected from oxetan-3-yl, pyrrolidin-1-yl or 1,2,3,6-tetrahydropyridin-4-yl.

[0257] In one embodiment of the compound of formula (I), R7 is heteroaryl selected from thienyl or pyridinyl.

[0258] In another embodiment of the compounds of formula (I), R7 is heteroaryl selected from pyridinyl.

[0259] In one embodiment of the compound of formula (I), R7 is heteroaryl selected from thien-2-yl or pyridin-2-yl.

[0260] In another embodiment of the compounds of formula (I), R7 is heteroaryl selected from pyridin-2-yl.

[0261] In one embodiment of the compound of formula (I), R c Selected from hydrogen or C 1-8 alkyl.

[0262] In another embodiment of the compounds of formula (I),

[0263] R1 is a heterocyclic group, a heterocyclic group-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2-amino, (heterocyclyl-C 1-8 Alkyl)(C 1-8alkyl)amino, heterocyclic-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 Cycloalkyl, aryl-C 1-8 Alkyl-amino, (aryl-C 1-8 alkyl) 2-amino, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (aryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heteroaryl, heteroaryl-C 1-8 Alkyl, heteroaryl-C 1-8 Alkoxy, heteroaryl-amino, heteroaryl-C 1-8 Alkyl-amino, (heteroaryl-C 1-8 alkyl)2-amino, (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heteroaryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; wherein each case of heterocyclyl, C 3-14 Cycloalkyl, aryl, and heteroaryl groups are optionally substituted with R3 and R4 substituents; and

[0264] wherein the heterocyclic group is selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, 6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl [1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R, [3.3.1]nonyl, (5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or 6,9-diazaspiro[4.5]decyl.

[0265] In another embodiment of the compounds of formula (I),

[0266] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;

[0267] wherein aryl is phenyl;

[0268] wherein the heterocyclic group is selected from 1,2,3,6-tetrahydropyridyl, 1,3-benzodioxolyl or 2,3-dihydro-1,4-benzodioxinyl;

[0269] wherein heteroaryl is selected from the group consisting of thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; and wherein each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with R6 and R7 substituents.

[0270] In another embodiment of the compounds of formula (I),

[0271] R1 is a heterocyclic group, a heterocyclic group-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2-amino, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heterocyclic-C 1-8Alkyl-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 Cycloalkyl, aryl-C 1-8 Alkyl-amino, (aryl-C 1-8 alkyl) 2-amino, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (aryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heteroaryl, heteroaryl-C 1-8 Alkyl, heteroaryl-C 1-8 Alkoxy, heteroaryl-amino, heteroaryl-C 1-8 Alkyl-amino, (heteroaryl-C 1-8 alkyl)2-amino, (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heteroaryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl;

[0272] wherein the heterocyclic group is selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl -hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl Pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo [3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl or 6,9-diazaspiro[4.5]decyl; and wherein each occurrence of heterocyclyl, C 3-14Cycloalkyl, aryl, and heteroaryl groups are optionally substituted with R3 and R4 substituents; and

[0273] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;

[0274] wherein the heterocyclic group is selected from 1,2,3,6-tetrahydropyridin-4-yl, 1,3-benzodioxol-5-yl or 2,3-dihydro-1,4-benzodioxin-6-yl;

[0275] wherein the heteroaryl group is selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, 1H-indolyl, 2H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3- c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl or quinoxalinyl; and wherein each instance of heterocyclyl and heteroaryl is optionally substituted by R6 and R7 substituents.

[0276] In another embodiment of the compounds of formula (I),

[0277] R1 is C 1-8 Alkyl, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, (C 1-8 Alkoxy-C 1-8 alkyl) 2-amino, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, amino-C 1-8 Alkyl, C 1-8Alkyl-amino-C 1-8 Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, amino-C 1-8 Alkyl-amino, (amino-C 1-8 alkyl) 2-amino, (amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, [(C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino, amino-C 1-8 Alkoxy, C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8 alkyl)2-amino-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 Alkoxy, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, amino-C 2-8 Alkenyl, C 1-8 Alkyl-amino-C 2-8 Alkenyl, (C 1-8 alkyl)2-amino-C 2-8 Alkenyl, amino-C 2-8 Alkynyl, C1-8 Alkyl-amino-C 2-8 Alkynyl, (C 1-8 alkyl)2-amino-C 2-8 Alkynyl, halo-C 1-8 Alkyl-amino, (halo-C 1-8 alkyl)2-amino, (halogenated-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkoxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl-amino, [(hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino or [(hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl](C 1-8alkyl)amino group; and

[0278] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino, wherein each instance of aryl, heterocyclyl and heteroaryl is optionally substituted by R6 and R7 substituents.

[0279] In another embodiment of the compounds of formula (I),

[0280] R1 is a heterocyclic group, a heterocyclic group-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2-amino, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heterocyclic-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 Cycloalkyl, aryl-C 1-8 Alkyl-amino, (aryl-C 1-8 alkyl) 2-amino, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (aryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heteroaryl, heteroaryl-C 1-8 Alkyl, heteroaryl-C 1-8 Alkoxy, heteroaryl-amino, heteroaryl-C 1-8 Alkyl-amino, (heteroaryl-C 1-8 alkyl)2-amino, (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heteroaryl-C 1-8alkyl)2-amino-C 1-8 Alkyl or (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; wherein each case of heterocyclyl, C 3-14 Cycloalkyl, aryl and heteroaryl are optionally substituted with R3 and R4 substituents; and

[0281] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino, wherein each instance of aryl, heterocyclyl and heteroaryl is optionally substituted by R6 and R7 substituents.

[0282] In another embodiment of the compounds of formula (I),

[0283] R1 is a heterocyclic group, a heterocyclic group-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2-amino, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heterocyclic-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl or heterocyclyl-carbonyl-oxy; wherein each instance of heterocyclyl is optionally substituted with R3 and R4 substituents; and

[0284] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino, wherein each instance of aryl, heterocyclyl and heteroaryl is optionally substituted by R6 and R7 substituents.

[0285] In another embodiment of the compounds of formula (I),

[0286] R1 is heterocyclyl, optionally substituted with R3 and R4 substituents; and

[0287] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino, wherein each instance of aryl, heterocyclyl and heteroaryl is optionally substituted by R6 and R7 substituents.

[0288] In another embodiment of the compounds of formula (I),

[0289] R1 is C 3-14 The cycloalkyl group is optionally substituted with R3 and R4 substituents; and

[0290] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino, wherein each instance of aryl, heterocyclyl and heteroaryl is optionally substituted by R6 and R7 substituents.

[0291] In another embodiment of the compounds of formula (I),

[0292] R1 is aryl-C 1-8 Alkyl-amino, (aryl-C 1-8 alkyl) 2-amino, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (aryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; wherein each instance of aryl is optionally substituted with R3 and R4 substituents; and

[0293] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino, wherein each instance of aryl, heterocyclyl and heteroaryl is optionally substituted by R6 and R7 substituents.

[0294] In another embodiment of the compounds of formula (I),

[0295] R1 is aryl-C 1-8 Alkyl-amino, optionally substituted with R3 and R4 substituents; and

[0296] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino, wherein each instance of aryl, heterocyclyl and heteroaryl is optionally substituted by R6 and R7 substituents.

[0297] In another embodiment of the compounds of formula (I),

[0298] R1 is heteroaryl, heteroaryl-C 1-8 Alkyl, heteroaryl-C 1-8 Alkoxy, heteroaryl-amino, heteroaryl-C 1-8 Alkyl-amino, (heteroaryl-C 1-8alkyl)2-amino, (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heteroaryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl; wherein each case of heterocyclyl, C 3-14 Cycloalkyl, aryl, and heteroaryl groups are optionally substituted with R3 and R4 substituents; and

[0299] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino, wherein each instance of aryl, heterocyclyl and heteroaryl is optionally substituted by R6 and R7 substituents.

[0300] In another embodiment of the compounds of formula (I),

[0301] R1 is heteroaryl, optionally substituted with R3 and R4 substituents; and

[0302] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino, wherein each instance of aryl, heterocyclyl and heteroaryl is optionally substituted by R6 and R7 substituents.

[0303] One embodiment of the compound of formula (I) is a compound selected from the group consisting of formula (II)-(II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), or formula (XIV):

[0304]

[0305] or its form.

[0306] In one embodiment of the compound of formula (I), w3 is C-R1, w6 is C-R2, w1, w4, w5 and w7 are independently CR a or N and w2 is CR b or N.

[0307] In another embodiment of the compound of formula (I), w3 is C-R2, w6 is C-R1, w1, w4, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0308] In another embodiment of the compound of formula (I), w4 is C-R1, w7 is C-R2, w1, w3 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0309] In another embodiment of the compound of formula (I), w4 is C-R2, w7 is C-R1, w1, w3 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0310] In one embodiment of the compound of formula (II), w3 is C-R1, w6 is C-R2, w4, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0311] In another embodiment of the compound of formula (II), w3 is C-R2, w6 is C-R1, w4, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0312] In another embodiment of the compound of formula (II), w4 is C-R1, w7 is C-R2, w3 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0313] In another embodiment of the compound of formula (II), w4 is C-R2, w7 is C-R1, w3 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0314] In one embodiment of the compound of formula (III), w3 is C-R1, w6 is C-R2 and w1, w4, w5 and w7 are independently CR a is N.

[0315] In another embodiment of the compound of formula (III), w3 is C-R2, w6 is C-R1 and w1, w4, w5 and w7 are independently CR a is N.

[0316] In another embodiment of the compound of formula (III), w4 is C-R1, w7 is C-R2, w1, w3 and w5 are independently CR a or N and w6 is CR c is N.

[0317] In another embodiment of the compound of formula (III), w4 is C-R2, w7 is C-R1, w1, w3 and w5 are independently CR a or N and w6 is CR c is N. , w1 and

[0318] In one embodiment of the compound of formula (IV), w4 is C-R1, w7 is C-R2, w1 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0319] In another embodiment of the compound of formula (IV), w4 is C-R2, w7 is C-R1, w1 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0320] In one embodiment of the compound of formula (V), w3 is C-R1, w6 is C-R2, w1, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0321] In another embodiment of the compound of formula (V), w3 is C-R2, w6 is C-R1, w1, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0322] In one embodiment of the compound of formula (VI), w3 is C-R1, w6 is C-R2, w1, w4 and w7 are independently CR a or N and w2 is CR b is N.

[0323] In another embodiment of the compound of formula (VI), w3 is C-R2, w6 is C-R1, w1, w4 and w7 are independently CR a or N and w2 is CR b is N.

[0324] In another embodiment of the compound of formula (VI), w4 is C-R1, w7 is C-R2, w1 and w3 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0325] In another embodiment of the compound of formula (VI), w4 is C-R2, w7 is C-R1, w1 and w3 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0326] In another embodiment of the compound of formula (VII), w4 is C-R1, w7 is C-R2, w1, w3 and w5 are CR a or N and w2 is CR b is N.

[0327] In another embodiment of the compound of formula (VII), w4 is C-R2, w7 is C-R1, w1, w3 and w5 are CR a or N and w2 is CR b is N.

[0328] In another embodiment of the compound of formula (VIII), w3 is C-R1, w6 is C-R2, w1, w4 and w5 are CR a or N and w2 is CR b is N.

[0329] In another embodiment of the compound of formula (VIII), w3 is C-R2, w6 is C-R1, w1, w4 and w5 are CR a or N and w2 is CR b is N.

[0330] In one embodiment of the compound of formula (IX), w3 is C-R1, w6 is C-R2, w4 and w7 are independently CR a or N and w2 is CR b is N.

[0331] In another embodiment of the compound of formula (IX), w3 is C-R2, w6 is C-R1, w4 and w7 are independently CR a or N and w2 is CR b is N.

[0332] In another embodiment of the compound of formula (IX), w4 is C-R1, w7 is C-R2, and w2 is CRb or N, w3 is CR a or N and w6 is CR c is N.

[0333] In another embodiment of the compound of formula (IX), w4 is C-R2, w7 is C-R1, and w2 is CR b or N, w3 is CR a or N and w6 is CR c is N.

[0334] In one embodiment of the compound of formula (X), w3 is C-R1, w6 is C-R2, and w2 is CR b or N and w5 and w7 are independently CR a is N.

[0335] In another embodiment of the compound of formula (X), w3 is C-R2, w6 is C-R1, and w2 is CR b or N and w5 and w7 are independently CR a is N.

[0336] In one embodiment of the compound of formula (XI), w4 is C-R1, w7 is C-R2, and w2 is CR b or N, w5 is CR a or N and w6 is CR c is N.

[0337] In another embodiment of the compound of formula (XI), w4 is C-R2, w7 is C-R1, and w2 is CR b or N, w5 is CR a or N and w6 is CR c is N.

[0338] In one embodiment of the compound of formula (XII), w3 is C-R1, w6 is C-R2 and w4, w5 and w7 are independently CR a is N.

[0339] In another embodiment of the compound of formula (XII), w3 is C-R2, w6 is C-R1 and w4, w5 and w7 are independently CR a is N.

[0340] In another embodiment of the compound of formula (XII), w4 is C-R1, w7 is C-R2, w3 and w5 are independently CR a or N and w6 is CR c is N.

[0341] In another embodiment of the compound of formula (XII), w4 is C-R2, w7 is C-R1, w3 and w5 are independently CR a or N and w6 is CR c is N.

[0342] In one embodiment of the compound of formula (XIII), w3 is C-R1, w6 is C-R2, and w2 is CR b or N and w4 and w5 are independently CR a is N.

[0343] In another embodiment of the compound of formula (XIII), w3 is C-R2, w6 is C-R1, and w2 is CR b or N and w4 and w5 are independently CR a is N.

[0344] In one embodiment of the compound of formula (XIV), w4 is C-R1, w7 is C-R2, and w2 is CR b or N and w3 and w5 are independently CR a is N.

[0345] In another embodiment of the compound of formula (XIV), w4 is C-R2, w7 is C-R1, and w2 is CR b or N and w3 and w5 are independently CR a is N.

[0346] Another embodiment of the compound of formula (I) is selected from the following compounds: formula (II), formula (III), formula (IX), formula (XI) or formula (XII):

[0347]

[0348] or its form.

[0349] Another embodiment of the compound of formula (I) is the compound of formula (II):

[0350]

[0351] or its form.

[0352] Another embodiment of the compound of formula (I) is the compound of formula (III):

[0353]

[0354] or its form.

[0355] Another embodiment of the compound of formula (I) is the compound of formula (IV):

[0356]

[0357] or its form.

[0358] Another embodiment of the compound of formula (I) is the compound of formula (V):

[0359]

[0360] or its form.

[0361] Another embodiment of the compound of formula (I) is the compound of formula (VI):

[0362]

[0363] or its form.

[0364] Another embodiment of the compound of formula (I) is the compound of formula (VII):

[0365]

[0366] or its form.

[0367] Another embodiment of the compound of formula (I) is the compound of formula (VIII):

[0368]

[0369] or its form.

[0370] Another embodiment of the compound of formula (I) is the compound of formula (IX):

[0371]

[0372] or its form.

[0373] Another embodiment of the compound of formula (I) is a compound of formula (X):

[0374]

[0375] or its form.

[0376] Another embodiment of the compound of formula (I) is the compound of formula (XI):

[0377]

[0378] or its form.

[0379] Another embodiment of the compound of formula (I) is the compound of formula (XII):

[0380]

[0381] or its form.

[0382] Another embodiment of the compound of formula (I) is the compound of formula (XIII):

[0383]

[0384] or its form.

[0385] Another embodiment of the compound of formula (I) is the compound of formula (XIV):

[0386]

[0387] or its form.

[0388] One embodiment of the compound of Formula (I)-(Ia)-(IIa)-(IIIa)-(IVa)-(Va)-(VIIIa)-(VIIIa)-(IXa)-(Xa)-(XIa)-(XIIa)-(XIIIa)-(XIVa)-(XIVa)-(VIIIa)-(IXa)-(Xa)-(XIa)-(XIIa)-(XIIIa)-(XIVa)-(XIVa)-(XIVa)

[0389]

[0390]

[0391] or its form.

[0392] In one embodiment of the compounds of formula (Ia), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[0393] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[0394] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[0395] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[0396] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[0397] In one embodiment of the compound of formula (IIa), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[0398] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[0399] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[0400] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[0401] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[0402] In one embodiment of the compound of formula (IIIa), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[0403] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[0404] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[0405] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[0406] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[0407] In one embodiment of the compound of formula (IVa), one of w4 and w7 is C-R1 and the other is C-R2, provided that when w4 is C-R1, then w7 is C-R2; or, when w4 is C-R2, then w7 is C-R1.

[0408] In one embodiment of the compound of formula (Va), one of w3 and w6 is C-R1 and the other is C-R2, provided that when w3 is C-R1, then w6 is C-R2; or, when w3 is C-R2, then w6 is C-R1.

[0409] In one embodiment of the compound of formula (VIa), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[0410] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[0411] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[0412] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[0413] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[0414] In one embodiment of the compound of formula (VIIa), one of w4 and w7 is C-R1 and the other is C-R2, provided that when w4 is C-R1, then w7 is C-R2; or, when w4 is C-R2, then w7 is C-R1.

[0415] In one embodiment of the compound of formula (VIIIa), one of w3 and w6 is C-R1 and the other is C-R2, provided that when w3 is C-R1, then w6 is C-R2; or, when w3 is C-R2, then w6 is C-R1.

[0416] In one embodiment of the compound of formula (IXa), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[0417] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CRa or N; or

[0418] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[0419] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[0420] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[0421] In one embodiment of the compound of formula (Xa), one of w3 and w6 is C-R1 and the other is C-R2, provided that when w3 is C-R1, then w6 is C-R2; or, when w3 is C-R2, then w6 is C-R1.

[0422] In one embodiment of the compound of formula (XIa), one of w4 and w7 is C-R1 and the other is C-R2, provided that when w4 is C-R1, then w7 is C-R2; or, when w4 is C-R2, then w7 is C-R1.

[0423] In one embodiment of the compound of formula (XIIa), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[0424] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[0425] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[0426] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[0427] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[0428] In one embodiment of the compound of formula (XIIIa), one of w3 and w6 is C-R1 and the other is C-R2, provided that when w3 is C-R1, then w6 is C-R2; or, when w3 is C-R2, then w6 is C-R1.

[0429] In one embodiment of the compound of formula (XIVa), one of w4 and w7 is C-R1 and the other is C-R2, provided that when w4 is C-R1, then w7 is C-R2; or, when w4 is C-R2, then w7 is C-R1.

[0430] One embodiment of the compound of Formula (I), Formula (II), Formula (III), Formula (IX), Formula (XI) or Formula (XII) is a compound selected from the following: Formula (Ia), Formula (IIa), Formula (IIIa), Formula (IXa), Formula (XIa) or Formula (XIIa):

[0431]

[0432] or its form.

[0433] Another embodiment of the compound of formula (I) is the compound of formula (Ia):

[0434]

[0435] or its form.

[0436] Another embodiment of the compound of formula (II) is the compound of formula (IIa):

[0437]

[0438] or its form.

[0439] Another embodiment of the compound of formula (III) is the compound of formula (IIIa):

[0440]

[0441] or its form.

[0442] Another embodiment of the compound of formula (IV) is the compound of formula (IVa):

[0443]

[0444] or its form.

[0445] Another embodiment of the compound of formula (V) is the compound of formula (Va):

[0446]

[0447] or its form.

[0448] Another embodiment of the compound of formula (VI) is the compound of formula (VIa):

[0449]

[0450] or its form.

[0451] Another embodiment of the compound of formula (VII) is the compound of formula (VIIa):

[0452]

[0453] or its form.

[0454] Another embodiment of the compound of formula (VIII) is the compound of formula (VIIIa):

[0455]

[0456] or its form.

[0457] Another embodiment of the compound of formula (IX) is the compound of formula (IXa):

[0458]

[0459] or its form.

[0460] Another embodiment of the compound of formula (X) is the compound of formula (Xa):

[0461]

[0462] or its form.

[0463] Another embodiment of the compound of formula (XI) is the compound of formula (XIa):

[0464]

[0465] or its form.

[0466] Another embodiment of the compound of formula (XII) is the compound of formula (XIIa):

[0467]

[0468] or its form.

[0469] Another embodiment of the compound of formula (XIII) is the compound of formula (XIIIa):

[0470]

[0471] or its form.

[0472] Another embodiment of the compound of formula (XIV) is the compound of formula (XIVa):

[0473]

[0474] or its form.

[0475] One embodiment of the compound of formula (Ia) is a compound of formula (Ia1), formula (Ia2), formula (Ia3) or formula (Ia4):

[0476]

[0477]

[0478] or its form.

[0479] One embodiment of the compound of formula (IIa) is a compound of formula (IIa1), formula (IIa2), formula (IIa3) or formula (IIa4):

[0480]

[0481] or its form.

[0482] One embodiment of the compound of formula (IIIa) is a compound of formula (IIIa1), formula (IIIa2), formula (IIIa3) or formula (IIIa4):

[0483]

[0484] or its form.

[0485] One embodiment of the compound of formula (IVa) includes compounds of formula (IVa1) or formula (IVa2):

[0486]

[0487] or its form.

[0488] One embodiment of the compound of formula (Va) is a compound of formula (Va1) or formula (Va2):

[0489]

[0490] or its form.

[0491] One embodiment of the compound of formula (VIa) is a compound of formula (VIa1), formula (VIa2), formula (VIa3) or formula (VIa4):

[0492]

[0493] or its form.

[0494] One embodiment of the compound of formula (VIIa) includes compounds of formula (VIIa1) or formula (VIIa2):

[0495]

[0496] or its form.

[0497] One embodiment of the compound of formula (VIIIa) is a compound of formula (VIIIa1) or formula (VIIIa2):

[0498]

[0499] or its form.

[0500] One embodiment of the compound of formula (IXa) is a compound of formula (IXa1), formula (IXa2), formula (IXa3) or formula (IXa4):

[0501]

[0502] or its form.

[0503] One embodiment of the compound of formula (Xa) is a compound of formula (Xa1) or formula (Xa2):

[0504]

[0505] or its form.

[0506] One embodiment of the compound of formula (XIa) is a compound of formula (XIa1) or formula (XIa2):

[0507]

[0508] or its form.

[0509] One embodiment of the compound of formula (XIIa) is a compound of formula (XIIa1), formula (XIIa2), formula (XIIa3) or formula (XIIa4):

[0510]

[0511] or its form.

[0512] One embodiment of the compound of formula (XIIIa) is a compound of formula (XIIIa1) or formula (XIIIa2):

[0513]

[0514] or its form.

[0515] One embodiment of the compound of formula (XIVa) is a compound of formula (XIVa1) or formula (XIVa2):

[0516]

[0517] or its form.

[0518] One embodiment of the compound of formula (1a) is the compound of formula (Ia1):

[0519]

[0520] or its form.

[0521] One embodiment of the compound of formula (1a) is the compound of formula (Ia2):

[0522]

[0523] or its form.

[0524] One embodiment of the compound of formula (1a) is a compound of formula (Ia3):

[0525]

[0526] or its form.

[0527] One embodiment of the compound of formula (1a) is a compound of formula (Ia4):

[0528]

[0529] or its form.

[0530] One embodiment of the compound of formula (IIa) is a compound of formula (IIa1):

[0531]

[0532] or its form.

[0533] One embodiment of the compound of formula (IIa) is a compound of formula (IIa2):

[0534]

[0535] or its form.

[0536] One embodiment of the compound of formula (IIa) is a compound of formula (IIa3):

[0537]

[0538] or its form.

[0539] One embodiment of the compound of formula (IIa) is a compound of formula (IIa4):

[0540]

[0541] or its form.

[0542] One embodiment of the compound of formula (IIIa) is a compound of formula (IIIa1):

[0543]

[0544] or its form.

[0545] One embodiment of the compound of formula (IIIa) is a compound of formula (IIIa2):

[0546]

[0547] or its form.

[0548] One embodiment of the compound of formula (IIIa) is a compound of formula (IIIa3):

[0549]

[0550] or its form.

[0551] One embodiment of the compound of formula (IIIa) is a compound of formula (IIIa4):

[0552]

[0553] or its form.

[0554] One embodiment of the compound of formula (IVa) is a compound of formula (IVa1):

[0555]

[0556] or its form.

[0557] One embodiment of the compound of formula (IVa) is a compound of formula (IVa2):

[0558]

[0559] or its form.

[0560] One embodiment of the compound of formula (Va) is a compound of formula (Va1):

[0561]

[0562] or its form.

[0563] One embodiment of the compound of formula (Va) is a compound of formula (Va2):

[0564]

[0565] or its form.

[0566] One embodiment of the compound of formula (VIa) is a compound of formula (VIa1):

[0567]

[0568] or its form.

[0569] One embodiment of the compound of formula (VIa) is a compound of formula (VIa2):

[0570]

[0571] or its form.

[0572] One embodiment of the compound of formula (VIa) is a compound of formula (VIa3):

[0573]

[0574] or its form.

[0575] One embodiment of the compound of formula (VIa) is a compound of formula (VIa4):

[0576]

[0577] or its form.

[0578] One embodiment of the compound of formula (VIIa) is a compound of formula (VIIa1):

[0579]

[0580] or its form.

[0581] One embodiment of the compound of formula (VIIa) is a compound of formula (VIIa2):

[0582]

[0583] or its form.

[0584] One embodiment of the compound of formula (VIIIa) is a compound of formula (VIIIa1):

[0585]

[0586] or its form.

[0587] One embodiment of the compound of formula (VIIIa) is a compound of formula (VIIIa2):

[0588]

[0589] or its form.

[0590] One embodiment of the compound of formula (IXa) is a compound of formula (IXa1):

[0591]

[0592] or its form.

[0593] One embodiment of the compound of formula (IXa) is a compound of formula (IXa2):

[0594]

[0595] or its form.

[0596] One embodiment of the compound of formula (IXa) is a compound of formula (IXa3):

[0597]

[0598] or its form.

[0599] One embodiment of the compound of formula (IXa) is a compound of formula (IXa4):

[0600]

[0601] or its form.

[0602] One embodiment of the compound of formula (Xa) is a compound of formula (Xa1):

[0603]

[0604] or its form.

[0605] One embodiment of the compound of formula (Xa) is a compound of formula (Xa2):

[0606]

[0607] or its form.

[0608] One embodiment of the compound of formula (XIa) is a compound of formula (XIa1):

[0609]

[0610] or its form.

[0611] One embodiment of the compound of formula (XIa) is a compound of formula (XIa2):

[0612]

[0613] or its form.

[0614] One embodiment of the compound of formula (XIIa) is a compound of formula (XIIa1):

[0615]

[0616] or its form.

[0617] One embodiment of the compound of formula (XIIa) is a compound of formula (XIIa2):

[0618]

[0619] or its form.

[0620] One embodiment of the compound of formula (XIIa) is a compound of formula (XIIa3):

[0621]

[0622] or its form.

[0623] One embodiment of the compound of formula (XIIa) is a compound of formula (XIIa4):

[0624]

[0625] or its form.

[0626] One embodiment of the compound of formula (XIIIa) is a compound of formula (XIIIa1):

[0627]

[0628] or its form.

[0629] One embodiment of the compound of formula (XIIIa) is a compound of formula (XIIIa2):

[0630]

[0631] or its form.

[0632] One embodiment of the compound of formula (XIVa) is a compound of formula (XIVa1):

[0633]

[0634] or its form.

[0635] One embodiment of the compound of formula (XIVa) is a compound of formula (XIVa2):

[0636]

[0637] or its form.

[0638] In one embodiment of the compound of formula (I), the compound is selected from:

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689] or its form.

[0690] the term

[0691] Unless specifically defined otherwise, those of ordinary skill in the art will understand that the chemical terms used above and throughout the specification herein have the meanings specified below.

[0692] As used herein, the term "C 1-8 "Alkyl" generally refers to a saturated hydrocarbon group having 1 to 8 carbon atoms in a straight or branched configuration, including, but not limited to, methyl, ethyl, n-propyl (also known as propyl or propanyl), isopropyl, n-butyl (also known as butyl or butanyl), isobutyl, sec-butyl, tert-butyl, n-pentyl (also known as pentyl or pentylalkyl), n-hexyl (also known as hexyl or hexyl), n-heptyl (also known as heptyl or heptyl), n-octyl, and the like. In certain embodiments, C 1-8 Alkyl groups include but are not limited to C 1-6 Alkyl, C 1-4 Alkyl, etc. C 1-8 Alkyl groups are optionally substituted with substituent species as described herein (where permitted by available valences).

[0693] As used herein, the term "C 2-8 "Alkenyl" generally refers to partially unsaturated hydrocarbon groups having 2 to 8 carbon atoms in a straight-chain or branched configuration and one or more carbon-carbon double bonds, including, but not limited to, ethenyl (also known as vinyl), allyl, propenyl, etc. In certain embodiments, C 2-8 Alkenyl groups include, but are not limited to, C 2-6 Alkenyl, C 2-4 Alkenyl, etc. C2-8 Alkenyl groups are optionally substituted with substituent species as described herein (as permitted by available valences).

[0694] As used herein, the term "C 2-8 "Alkynyl" generally refers to partially unsaturated hydrocarbon groups having 2 to 8 carbon atoms in a straight-chain or branched configuration and one or more carbon-carbon triple bonds, including, but not limited to, ethynyl, propynyl, butynyl, etc. In certain embodiments, C 2-8 Alkynyl groups include, but are not limited to, C 2-6 Alkynyl, C 2-4 Alkynyl, etc. C 2-8 Alkynyl groups are optionally substituted with substituent species as described herein, as permitted by available valences.

[0695] As used herein, the term "C 1-8 "Alkoxy" generally refers to a saturated hydrocarbon group having 1 to 8 carbon atoms in a straight or branched chain configuration, having the formula: -OC 1-8 Alkyl, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, etc. In certain embodiments, C 1-8 Alkoxy groups include, but are not limited to, C 1-6 Alkoxy, C 1-4 Alkoxy, etc. C 1-8 Alkoxy groups are optionally substituted with substituent species as described herein (where available valences permit).

[0696] As used herein, the term "C 3-14 "Cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthyl, etc. In certain embodiments, C 3-14 Cycloalkyl groups include, but are not limited to, C 3-8 Cycloalkyl, C 5-8 Cycloalkyl, C 3-10 Cycloalkyl, etc. 3-14 Cycloalkyl groups are optionally substituted with substituent species as described herein (as permitted by available valences).

[0697] As used herein, the term "aryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure group, including but not limited to phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. Aryl groups are optionally substituted with substituents as described herein (when available valences permit).

[0698] As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure group in which one or more carbon atom ring members have been replaced by one or more heteroatoms (e.g., O, S or N atoms) where structural stability permits, including but not limited to furanyl (furyl), thienyl (also known as thiophenyl), pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 1H-pyrazolyl, imidazolyl, 1H-imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl (e.g., 1H-1,2,3-triazolyl, etc.), oxadiazolyl, 1H-1,2,3-triazolyl, etc. (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc.), thiadiazolyl, tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), pyridyl (also known as pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, 1H-indolyl, indazolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothiophenyl (also known as benzothiophenyl), benzimidazolyl, 1H-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl (also known as 1,3-benzooxazolyl) l)), purinyl, 9H-purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl, 1,4-naphthyridinyl, acridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, pyrrolo[1,2 [1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, and the like. Heteroaryl groups are optionally substituted on carbon or nitrogen atom ring members with substituent species as described herein, as permitted by available valences.

[0699] As used herein, the term "heterocyclyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure group in which one or more carbon atom ring members have been replaced by heteroatoms such as O, S or N atoms where structural stability permits, including but not limited to oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H- ... pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl (also known as benzo[d][1,3]dioxolyl), 1,4-benzodioxanyl, 2,3-dihydro-1,4-benzodioxinyl (also known as 2,3-dihydrobenzo[b][1,4]dioxinyl), hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol- (1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS) -hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl , (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (8aR)-hexahydropyrrolo[ 1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl Azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl, and the like. Heterocyclyl groups are optionally substituted on carbon or nitrogen atom ring members with substituent species as described herein, as permitted by available valences.

[0700] As used herein, the term "C 1-8 Alkoxy-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-OC 1-8 alkyl.

[0701] As used herein, the term "C 1-8 Alkoxy-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-OC 1-8 alkyl.

[0702] As used herein, the term "(C 1-8 Alkoxy-C 1-8 "alkyl)2-amino" refers to a group of the formula: -N(C 1-8 Alkyl-OC 1-8 Alkyl)2.

[0703] As used herein, the term "C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-NH-C 1-8 Alkyl-OC 1-8 alkyl.

[0704] As used herein, the term "(C 1-8 Alkoxy-C1-8 alkyl)2-amino-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-N(C 1-8 Alkyl-OC 1-8 Alkyl)2.

[0705] As used herein, the term "(C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-N(C 1-8 Alkyl)(C 1-8 Alkyl-OC 1-8 alkyl).

[0706] As used herein, the term "C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-NH-C 1-8 Alkyl-OC 1-8 alkyl.

[0707] As used herein, the term "(C 1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8 Alkyl-OC 1-8 Alkyl)2.

[0708] As used herein, the term "(C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8 Alkyl)(C 1-8 Alkyl-OC 1-8 alkyl).

[0709] As used herein, the term "C 1-8 "Alkoxy-carbonyl" refers to a radical of the formula: -C(O)-OC 1-8 alkyl.

[0710] As used herein, the term "C 1-8 Alkoxy-carbonyl-C 2-8 "Alkenyl" refers to a radical of the formula: -C 2-8 Alkenyl-C(O)-OC1-8 alkyl.

[0711] As used herein, the term "C 1-8 "Alkoxy-carbonyl-amino" refers to a radical of the formula: -NH-C(O)-OC 1-8 alkyl.

[0712] As used herein, the term "C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 alkyl.

[0713] As used herein, the term "(C 1-8 "alkyl)2-amino" refers to a group of the formula: -N(C 1-8 Alkyl)2.

[0714] As used herein, the term "C 1-8 Alkyl-amino-C 2-8 "Alkenyl" refers to a radical of the formula: -C 2-8 Alkenyl-NH-C 1-8 alkyl.

[0715] As used herein, the term "(C 1-8 alkyl)2-amino-C 2-8 "Alkenyl" refers to a radical of the formula: -C 2-8 Alkenyl-N(C 1-8 Alkyl)2.

[0716] As used herein, the term "C 1-8 Alkyl-amino-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-NH-C 1-8 alkyl.

[0717] As used herein, the term "(C 1-8 alkyl)2-amino-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-N(C 1-8 Alkyl)2.

[0718] As used herein, the term "C 1-8 Alkyl-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-NH-C 1-8 alkyl.

[0719] As used herein, the term "(C 1-8 alkyl)2-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8Alkyl)2.

[0720] As used herein, the term "C 1-8 Alkyl-amino-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-NH-C 1-8 alkyl.

[0721] As used herein, the term "(C 1-8 alkyl)2-amino-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-N(C 1-8 Alkyl)2.

[0722] As used herein, the term "(C 1-8 Alkyl-amino-C 1-8 "alkyl)2-amino" refers to a group of the formula: -N(C 1-8 Alkyl-NH-C 1-8 Alkyl)2.

[0723] As used herein, the term "[(C 1-8 alkyl)2-amino-C 1-8 "alkyl]2-amino" refers to a group of the formula: -N[C 1-8 Alkyl-N(C 1-8 Alkyl)2]2.

[0724] As used herein, the term "(C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 Alkyl)(C 1-8 Alkyl-NH-C 1-8 alkyl).

[0725] As used herein, the term "[(C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 Alkyl)[C 1-8 Alkyl-N(C 1-8 alkyl)2].

[0726] As used herein, the term "C 1-8 Alkyl-amino-C 2-8 "Alkynyl" refers to a group of the formula: -C 2-8 Alkynyl-NH-C 1-8 alkyl.

[0727] As used herein, the term "(C1-8 alkyl)2-amino-C 2-8 "Alkynyl" refers to a group of the formula: -C 2-8 Alkynyl-N(C 1-8 Alkyl)2.

[0728] As used herein, the term "C 1-8 "Alkyl-carbonyl" refers to a radical of the formula: -C(O)-C 1-8 alkyl.

[0729] As used herein, the term "C 1-8 "Alkyl-carbonyl-amino" refers to a radical of the formula: -NH-C(O)-C 1-8 alkyl.

[0730] As used herein, the term "C 1-8 "Alkyl-thio" refers to a radical of the formula: -SC 1-8 alkyl.

[0731] As used herein, the term "amino-C 2-8 "Alkenyl" refers to a radical of the formula: -C 2-8 Alkenyl-NH2.

[0732] As used herein, the term "amino-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-NH2.

[0733] As used herein, the term "amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-NH2.

[0734] As used herein, the term "amino-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-NH2.

[0735] As used herein, the term "(amino-C 1-8 "alkyl)2-amino" refers to a group of the formula: -N(C 1-8 Alkyl-NH2)2.

[0736] As used herein, the term "(amino-C 1-8 Alkyl)(C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 Alkyl)(C 1-8 Alkyl-NH2).

[0737] As used herein, the term "amino-C 2-8 "Alkynyl" refers to a group of the formula: -C 2-8 Alkynyl-NH2.

[0738] As used herein, the term "aryl-C 1-8 "Alkoxy-carbonyl" refers to a radical of the formula: -C(O)-OC 1-8 Alkyl-aryl.

[0739] As used herein, the term "aryl-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-aryl.

[0740] As used herein, the term "aryl-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-aryl.

[0741] As used herein, the term "(aryl-C 1-8 "alkyl)2-amino" refers to a group of the formula: -N(C 1-8 Alkyl-aryl)2.

[0742] As used herein, the term "(aryl-C 1-8 Alkyl)(C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 Alkyl)(C 1-8 alkyl-aryl).

[0743] As used herein, the term "aryl-C 1-8 Alkyl-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-NH-C 1-8 Alkyl-aryl.

[0744] As used herein, the term "(aryl-C 1-8 alkyl)2-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8 Alkyl-aryl)2.

[0745] As used herein, the term "(aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8 Alkyl)(C 1-8 alkyl-aryl).

[0746] As used herein, the term "aryl-amino" refers to a radical of the formula: -NH-aryl.

[0747] As used herein, the term "aryl-amino-carbonyl" refers to a radical of the formula: -C(O)-NH-aryl.

[0748] As used herein, the term "aryl-sulfonyloxy-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-O-SO2-aryl.

[0749] As used herein, the term "benzoyloxy-carbonyl" refers to a radical of the formula: -C(O)O-CH2-phenyl.

[0750] As used herein, the term "C 3-14 Cycloalkyl-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-C 3-14 Cycloalkyl.

[0751] As used herein, the term "C 3-14 "Cycloalkyl-amino" refers to a radical of the formula: -NH-C 3-14 Cycloalkyl.

[0752] As used herein, the term "C 3-14 "Cycloalkyl-oxy" refers to a radical of the formula: -OC 3-14 Cycloalkyl.

[0753]

[0046] As used herein, the term "halo" or "halogen" generally refers to a halogen atom radical, including fluorine, chlorine, bromine, and iodine.

[0754] As used herein, the term "halo-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-halide, where C 1-8 The alkyl group is partially or fully substituted (where available valences permit) with one or more halogen atoms.

[0755] As used herein, the term "halo-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-halide, where C 1-8 The alkyl group is partially or fully substituted (where available valences permit) with one or more halogen atoms.

[0756] As used herein, the term "halo-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-halide.

[0757] As used herein, the term "(halo-C 1-8 Alkyl)(C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8Alkyl)(C 1-8 alkyl-halide).

[0758] As used herein, the term "(halo-C 1-8 "alkyl)2-amino" refers to a group of the formula: -N(C 1-8 Alkyl-halide)2.

[0759] As used herein, the term "heteroaryl-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-heteroaryl.

[0760] As used herein, the term "heteroaryl-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-heteroaryl.

[0761] As used herein, the term "heteroaryl-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-heteroaryl.

[0762] As used herein, the term "(heteroaryl-C 1-8 "alkyl)2-amino" refers to a group of the formula: -N(C 1-8 alkyl-heteroaryl)2.

[0763] As used herein, the term "(heteroaryl-C 1-8 Alkyl)(C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 Alkyl)(C 1-8 alkyl-heteroaryl).

[0764] As used herein, the term "heteroaryl-C 1-8 Alkyl-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-NH-C 1-8 Alkyl-heteroaryl.

[0765] As used herein, the term "(heteroaryl-C 1-8 alkyl)2-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8 alkyl-heteroaryl)2.

[0766] As used herein, the term "(heteroaryl-C 1-8 Alkyl (C 1-8 alkyl)amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8 Alkyl)(C1-8 alkyl-heteroaryl).

[0767] As used herein, the term "heteroaryl-amino" refers to a radical of the formula: -NH-heteroaryl.

[0768] As used herein, the term "heterocyclyl-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-heterocyclyl.

[0769] As used herein, the term "heterocyclyl-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-heterocyclyl.

[0770] As used herein, the term "heterocyclyl-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-heterocyclyl.

[0771] As used herein, the term "(heterocyclyl-C 1-8 "alkyl)2-amino" refers to a group of the formula: -N(C 1-8 Alkyl-heterocyclyl)2.

[0772] As used herein, the term "(heterocyclyl-C 1-8 Alkyl)(C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 Alkyl)(C 1-8 alkyl-heterocyclyl).

[0773] As used herein, the term "heterocyclyl-C 1-8 Alkyl-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-NH-C 1-8 Alkyl-heterocyclyl.

[0774] As used herein, the term "(heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8 Alkyl-heterocyclyl)2.

[0775] As used herein, the term "(heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8 Alkyl)(C 1-8 alkyl-heterocyclyl).

[0776] As used herein, the term "heterocyclyl-amino" refers to a radical of the formula: -NH-heterocyclyl.

[0777] As used herein, the term "(heterocyclyl)(C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 alkyl)(heterocyclic group).

[0778] As used herein, the term "heterocyclyl-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-NH-heterocyclyl.

[0779] As used herein, the term "heterocyclyl-carbonyl" refers to a radical of the formula: -C(O)-heterocyclyl.

[0780] As used herein, the term "heterocyclyl-carbonyl-oxy" refers to a radical of the formula: -OC(O)-heterocyclyl.

[0781] As used herein, the term "heterocyclyl-oxy" refers to a radical of the formula: -O-heterocyclyl.

[0782] As used herein, the term "hydroxy" refers to a group of the formula: -OH.

[0783] As used herein, the term "hydroxy-C 1-8 Alkoxy-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-OC 1-8 Alkyl-OH.

[0784] As used herein, the term "hydroxy-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-OH, where C 1-8 The alkyl group is partially or fully substituted (where available valences permit) with one or more hydroxy groups.

[0785] As used herein, the term "hydroxy-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-OH.

[0786] As used herein, the term "(hydroxy-C 1-8 "alkyl)2-amino" refers to a group of the formula: -N(C 1-8 Alkyl-OH)2.

[0787] As used herein, the term "(hydroxy-C 1-8 Alkyl)(C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 Alkyl)(C1-8 alkyl-OH).

[0788] As used herein, the term "hydroxy-C 1-8 Alkyl-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-NH-C 1-8 Alkyl-OH.

[0789] As used herein, the term "(hydroxy-C 1-8 alkyl)2-amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8 Alkyl-OH)2.

[0790] As used herein, the term "(hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 "Alkyl" refers to a group of the formula: -C 1-8 Alkyl-N(C 1-8 Alkyl)(C 1-8 alkyl-OH).

[0791] As used herein, the term "hydroxy-C 1-8 Alkyl-amino-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-NH-C 1-8 Alkyl-OH.

[0792] As used herein, the term "(hydroxy-C 1-8 alkyl)2-amino-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-N(C 1-8 Alkyl-OH)2.

[0793] As used herein, the term "(hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 "Alkoxy" refers to a group of the formula: -OC 1-8 Alkyl-N(C 1-8 Alkyl)(C 1-8 alkyl-OH).

[0794] As used herein, the term "hydroxy-C 1-8 Alkyl-amino-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-NH-C 1-8 Alkyl-OH.

[0795] As used herein, the term "(hydroxy-C 1-8 Alkyl-amino-C 1-8 "alkyl)2-amino" refers to a group of the formula: -N(C 1-8 Alkyl-NH-C 1-8 Alkyl-OH)2.

[0796] As used herein, the term "(hydroxy-C 1-8 alkyl)2-amino-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-N(C 1-8 Alkyl-OH)2.

[0797] As used herein, the term "(hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 Alkyl)(C 1-8 Alkyl-NH-C 1-8 alkyl-OH).

[0798] As used herein, the term "[(hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 Alkyl)[C 1-8 Alkyl-N(C 1-8 alkyl-OH)2]

[0799] As used herein, the term "(hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 "Alkyl-amino" refers to a radical of the formula: -NH-C 1-8 Alkyl-N(C 1-8 Alkyl, C 1-8 alkyl-OH).

[0800] As used herein, the term "[(hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl](C 1-8 "alkyl)amino" refers to a group of the formula: -N(C 1-8 Alkyl)[C 1-8 Alkyl-N(C 1-8 Alkyl)(C 1-8 alkyl-OH)].

[0801] As used herein, the term "substituent" refers to a positional variable located on an atom of a core molecule that is attached to a designated atomic position, replacing one or more hydrogen atoms on the designated atom, provided that the attached atoms do not exceed the available valences or shared valences, such that the substitution results in a stable compound. Therefore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. It should also be noted that any carbon and heteroatom that appears unsaturated at the valence levels described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the valences described or shown.

[0802] For purposes of this specification, where one or more substituent variables of a compound of Formula (I) encompass functionality incorporated into a compound of Formula (I), each functional group occurring at any position in the disclosed compounds may be independently selected and independently and / or optionally substituted as desired.

[0803] As used herein, the term "independently selected" or "independently selected" refers to a functional variable in a list of substituents that can be attached to the structure of the core molecule, wherein the substitution pattern at each occurrence is independent of the pattern at any other occurrence. Further, it should be understood that the use of general substituents on the core structures of the compounds provided herein includes replacing the general substituent with a specific substituent included within a specific class, for example, an aryl group can be independently replaced with a phenyl or naphthalenyl (also known as naphthyl), etc., such that the resulting compound is intended to be included within the scope of the compounds described herein.

[0804] As used herein, the term "each occurrence" is used when applied to phrases such as "aryl, aryl-C 1-8 Alkyl, heterocyclyl and heterocyclyl-C 1-8 alkyl, wherein each occurrence of aryl and heterocyclyl is optionally substituted with one or two substituents, is intended to include the aryl and heterocyclyl rings and the aryl-C 1-8 Alkyl and heterocyclyl-C 1-8 The aryl and heterocyclyl portions of the alkyl group are optionally and independently substituted.

[0805] As used herein, the term "optionally substituted" means that the specified substituent variables, groups, radicals or moieties represent a range of species and can be independently selected as needed to replace one or more hydrogen atoms on the specified attached atom on the core molecule.

[0806] The term "stable compound" or "stable structure" as used herein refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and preparation thereof to serve as an efficacious therapeutic agent.

[0807] Compound names provided herein were obtained using the ACD Labs Index Name software and / or ChemDraw Ultra software is provided. When a compound name described herein is inconsistent with a drawn structure, the structure shown is used rather than the name for purposes of defining the specified compound. The nomenclature of substituent groups defined herein may differ slightly from the chemical name from which they are derived, and one skilled in the art will recognize that the definitions of substituent groups are intended to include groups as appearing in the chemical name.

[0808] Unless otherwise indicated herein, the term "SMN" refers to the human SMN1 gene, DNA or RNA, and / or the human SMN2 gene, DNA or RNA. In one embodiment, the term "SMN1" refers to the human SMN1 gene, DNA or RNA. In another embodiment, the term "SMN2" refers to the human SMN2 gene, DNA or RNA.

[0809] The nucleic acid sequences of human SMN1 and SMN2 genes are known in the art. For the nucleic acid sequence of human SMN1, see, for example, GenBank accession numbers DQ894095, NM-000344, NM-022874, and BC062723. For the nucleic acid sequence of human SMN2, see, for example, NM-022875, NM-022876, NM-022877, NM-017411, DQ894734 (Life Technologies, Inc. (formerly Invitrogen), Carlsbad, Calif.), BC000908, BC070242, CR595484, CR598529, CR609539, U21914, and BC015308.

[0810] The SMN1 gene can be found on the forward strand (from approximately nucleotides 70,220,768 to approximately nucleotides 70,249,769) of human chromosome 5. The approximate locations of exons 6, 7, and 8 and introns 6 and 7 of SMN1 on human chromosome 5 are as follows:

[0811] 70,241,893 to 70,242,003 exon 6;

[0812] 70,242,004 to 70,247,767 intron 6;

[0813] 70,247,768 to 70,247,821 exon 7;

[0814] 70,247,822 to 70,248,265 intron 7; and

[0815] 70,248,266 to 70,248,839 exon 8.

[0816] The SMN2 gene can be found on the plus strand of human chromosome 5 (approximately nucleotides 69,345,350 to approximately nucleotides 69,374,349).

[0817] The approximate locations of exons 6, 7, and 8 and introns 6 and 7 of SMN2 on human chromosome 5 are as follows:

[0818] 69,366,468 to 69,366,578 exon 6;

[0819] 69,366,579 to 69,372,347 intron 6;

[0820] 69,372,348 to 69,372,401 exon 7;

[0821] 69,372,402 to 69,372,845 intron 7; and

[0822] 69,372,846 to 69,373,419 exon 8.

[0823] In specific embodiments, the nucleotide sequences described for exons 6, 7, and 8 and introns 6 and 7 of SMN1 are used in the SMN1 minigene nucleic acid constructs described herein. In other specific embodiments, the nucleotide sequences for exons 6, 7, and 8 and introns 6 and 7 of SMN2 described in the examples provided above are used in the SMN2 minigene nucleic acid constructs described herein.

[0824] Unless otherwise indicated herein, the term "Smn" or "Smn protein" refers to the human Smn protein comprising the amino acid residues encoded by exons 1 to 7 of the SMN1 gene and / or SMN2 gene. In one embodiment, the Smn protein is stable and functional in vitro and / or in vivo, as assessed using methods known to those skilled in the art. In another embodiment, the Smn protein is the full-length protein encoded by the human SMN1 gene and / or SMN2 gene. In another embodiment, the Smn protein has the amino acid sequence found in GenBank Accession Nos. NP_000335, AAC50473.1, AAA66242.1, or NP_059107.

[0825] Unless otherwise indicated herein, the term "enhancing the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene" and similar terms, as used herein, refers to the inclusion of the entire, intact, non-truncated sequence of exon 7 of SMN2 into mature mRNA transcribed from the SMN2 gene in vitro and / or in vivo (i.e., resulting in production of full-length SMN2 mRNA), as assessed by methods known to those skilled in the art, resulting in increased levels of Smn protein produced by the SMN2 gene in vitro and / or in vivo, as assessed by methods known to those skilled in the art; or, resulting in increased expression of a stable and functional Smn protein produced by the SMN2 gene in vitro and / or in vivo, as assessed by methods known to those skilled in the art; or, resulting in increased expression of a fusion protein encoded by a minigene in vitro and / or in vivo, as assessed by methods known to those skilled in the art; or, resulting in increased expression of a Smn protein produced by the SMN2 gene in a subject in need thereof (e.g., an animal model of SMA or a human patient or SMA patient).

[0826] Unless otherwise indicated herein, the term "enhancing the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene" and similar terms, as used herein, refers to the inclusion of the entire, intact, non-truncated sequence of exon 7 of SMN1 into mature mRNA transcribed from the SMN1 gene in vitro and / or in vivo (i.e., resulting in production of full-length SMN1 mRNA), as assessed by methods known to those skilled in the art, resulting in increased levels of Smn protein produced from the SMN1 gene in vitro and / or in vivo, as assessed by methods known to those skilled in the art; or, resulting in increased expression of a stable and functional Smn protein produced from the SMN1 gene in vitro and / or in vivo, as assessed by methods known to those skilled in the art; or, resulting in increased expression of a fusion protein encoded by a minigene in vitro and / or in vivo, as assessed by methods known to those skilled in the art; or, resulting in increased expression of a Smn protein produced from the SMN1 gene in a subject in need thereof (e.g., an animal model of SMA or a human patient or SMA patient).

[0827] The term "substantially altered" as used herein in the context of the amount of an mRNA means that the amount of the mRNA does not change by more than a statistically significant amount, e.g., a p-value less than a value selected from 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, 0.0001, 0.00005, or 0.00001.

[0828] As used herein, the terms "subject" and "patient" are used interchangeably to refer to an animal or any living organism that has the sense and power of voluntary movement and requires oxygen and organic food for its existence. Non-limiting examples include humans, equines, members of the porcine, bovine, murine, murine, canine, and feline species. In certain embodiments, the subject is a mammal or a warm-blooded vertebrate. In certain embodiments, the subject is a non-human animal. In specific embodiments, the subject is a human. In one specific embodiment, the subject is a human SMA patient.

[0829] As used herein, the term "elderly" refers to a person 65 years of age or older.

[0830] As used herein, the term "adult" refers to a person 18 years of age or older.

[0831] As used herein, the term "child" refers to a human between 1 and 18 years of age.

[0832] As used herein, the term "infant" refers to a human from newborn to 1 year old.

[0833] As used herein, the term "toddler" refers to a human between 1 and 3 years old.

[0834] Compound form

[0835] As used herein, the terms "compound of formula (Ia)", "compound of formula (Ia1)", "compound of formula (Ia2)", "compound of formula (Ia3)", "compound of formula (Ia4)", "compound of formula (II)", "compound of formula (IIa)", "compound of formula (IIa1)", "compound of formula (IIa2)", "compound of formula (IIa3)", "compound of formula (IIa4)", "compound of formula (III)", "compound of formula (IIIa)", "compound of formula (IIIa1)", "compound of formula (IIIa2)", "compound of formula (IIIa3)", "compound of formula (IIIa4)" are used interchangeably. compound of formula (VI), "compound of formula (VIa), "compound of formula (VIa1), "compound of formula (VIa2)", "compound of formula (VIa3)", "compound of formula (VIa4)", "compound of formula (VII)", "compound of formula (VIIa)", "compound of formula (VIIa1)", "compound of formula (VIIa2)", "compound of formula (VIIa3)", "compound of formula (VIa4)", "compound of formula (VIIa)", "compound of formula (VIIa1)", "compound of formula (VIIa2)", "compound of formula (VIIa3)", "compound of formula (VIa4)", "compound of formula (VIIa)", "compound of formula (VIIa1)", "compound of formula (VIIa2)" )", "compound of formula (VIII)", "compound of formula (VIIIa)", "compound of formula (VIIIa1)", "compound of formula (VIIIa2)", "compound of formula (IX)", "compound of formula (IXa)", "compound of formula (IXa1)", "compound of formula (IXa2)", "compound of formula (IXa3)", "compound of formula (IXa4)", "compound of formula (X)", "compound of formula (Xa)", "compound of formula (Xa1)", "compound of formula (Xa2)", "compound of formula (XI)", "compound of formula (XIa)", "compound of formula (XIa1)", “Compound of formula (XIa2)”, “Compound of formula (XII)”, “Compound of formula (XIIa)”, “Compound of formula (XIIa1)”, “Compound of formula (XIIa2)”, “Compound of formula (XIIa3)”, “Compound of formula (XIIa4)”, “Compound of formula (XIII)”, “Compound of formula (XIIIa)”, “Compound of formula (XIIIa1)”, “Compound of formula (XIIIa2)”, “Compound of formula (XIV)”, “Compound of formula (XIVa)”, “Compound of formula (XIVa1)” and “Compound of formula (XIVa2)” each refer to a compound of formula (I) or a subtype thereof.

[0836] In certain embodiments, other than repeated embodiments of different subclasses of compounds of Formula (I), the term "compound of Formula (I) or a form thereof" is used to refer inclusively, separately or collectively, to a compound of Formula (Ia) or a form thereof, a compound of Formula (Ia1) or a form thereof, a compound of Formula (Ia2) or a form thereof, a compound of Formula (Ia3) or a form thereof, a compound of Formula (Ia4) or a form thereof, a compound of Formula (II) or a form thereof, a compound of Formula (IIa) or a form thereof, a compound of Formula (IIa) or a form thereof, a compound of Formula (IIa1) or a form thereof, a compound of Formula (IIa2) or a form thereof, a compound of Formula (IIa3) or a form thereof, a compound of Formula (IIa4) or a form thereof, a compound of Formula (III) or a form thereof, a compound of Formula (IIIa) or a form thereof, ), a compound or a form thereof of formula (IIIa1), a compound or a form thereof of formula (IIIa2), a compound or a form thereof of formula (IIIa3), a compound or a form thereof of formula (IIIa4), a compound or a form thereof of formula (IV), a compound or a form thereof of formula (IVa), a compound or a form thereof of formula (IVa1), a compound or a form thereof of formula (IVa2), a compound or a form thereof of formula (V), a compound or a form thereof of formula (Va), a compound or a form thereof of formula (Va1), a compound or a form thereof of formula (Va2), a compound or a form thereof of formula (VI), a compound or a form thereof of formula (VIa), a compound or a form thereof of formula (VIa1), a compound or a form thereof of formula (VIa2), a compound or a form thereof, a compound or a form thereof of formula (VIa3), a compound or a form thereof of formula (VIa4), a compound or a form thereof of formula (VII), a compound or a form thereof of formula (VIIa), a compound or a form thereof of formula (VIIa1), a compound or a form thereof of formula (VIIa2), a compound or a form thereof of formula (VIII), a compound or a form thereof of formula (VIIIa), a compound or a form thereof of formula (VIIIa1), a compound or a form thereof of formula (VIIIa2), a compound or a form thereof of formula (IX), a compound or a form thereof of formula (IXa), a compound or a form thereof of formula (IXa1), a compound or a form thereof of formula (IXa2), a compound or a form thereof of formula (IXa3) , a compound of formula (IXa4) or a form thereof, a compound of formula (X) or a form thereof, a compound of formula (Xa) or a form thereof, a compound of formula (Xa1) or a form thereof, a compound of formula (Xa2) or a form thereof, a compound of formula (XI) or a form thereof, a compound of formula (XIa) or a form thereof, a compound of formula (XIa1) or a form thereof, a compound of formula (XIa2) or a form thereof, a compound of formula (XII) or a form thereof, a compound of formula (XIIa) or a form thereof, a compound of formula (XIIa1) or a form thereof, a compound of formula (XIIa2) or a form thereof, a compound of formula (XIIa3) or a form thereof, a compound of formula (XIIa4) or a form thereof, a compound of formula (XIII) or a form thereof,A compound of formula (XIIIa) or a form thereof, a compound of formula (XIIIa1) or a form thereof, a compound of formula (XIIIa2) or a form thereof, a compound of formula (XIV) or a form thereof, a compound of formula (XIVa) or a form thereof, a compound of formula (XIVa1) or a form thereof, or a compound of formula (XIVa2) or a form thereof.

[0837] Thus, embodiments of and references to "compounds of Formula (I)" are meant to include compounds of Formula (Ia), (Ia1), (Ia2), (Ia3), (Ia4), (II), (IIa), (IIa1), (IIa2), (IIa3), (IIa4), (III), (IIIa), (IIIa1), (IIIa2), (IIIa3), (IIIa4), (IV), (IVa), (IVa1), (IVa2), (V), (Va), (Va1), (Va2), (VI), (VIa), (VIa1), (VIa2), (VIa3), (VIa4), (VII), (VIIIa), (IVa1), (IVa2), (IVa3), (VIa4), (VII), (IVa2), (IVa3), (VIa4), (VIIa5), (VIIa6), (VIIa7), (VIIa8), (VIIa9), (VIIa1), (VIIa2), (VIIa3), (VIIa4), (VIIa1), (VIIa2), (VIIa3), (VIIa4), (VIIa5), (VIIa6), (VIIa7), (VIIa8), (VIIa9), (VIIa1), (IVa2), (IVa3), (VIIa4), (VIIa1), (IVa2), (IVa3), (VIIa4), (VIIa5), (VIIa6), (VIIa7), (VIIa1), (IVa2), (IVa3), (VIIa4), (VIIa7), (VIIa1), (IVa2), (IVa3), (VIIa4), (VIIa5), (VIIa6), (VIIa7), (VIIa8), (VIIa9), (VIIa1), (IVa2), (IVa3), (VIIa4), (VIIa1), (IVa2), (IVa3), (VIIa4), (VIIa5), (VIIa6), (VIIa7), (VIIa1), (IVa2), (IVa3), (VIIa4), (VIIa7), (VIIa1), ( VIIa), Formula (VIIa1), Formula (VIIa2), Formula (VIII), Formula (VIIIa), Formula (VIIIa1), Formula (VIIIa2), Formula (IX), Formula (IXa), Formula (IXa1), Formula (IXa2), Formula (IXa3), Formula (IXa4), Formula (X), Formula (Xa), Formula (Xa1), Formula (Xa2), Formula (XI), Formula (XIa), Formula (XIa1), Formula (XIa2), Formula (XII), Formula (XIIa), Formula (XIIa1), Formula (XIIa2), Formula (XIIa3), Formula (XIIa4), Formula (XIII), Formula (XIIIa), Formula (XIIIa1), Formula (XIIIa2), Formula (XIV), Formula (XIVa), Formula (XIVa1) and Formula (XIVa2).

[0838] The term "form" as used herein refers to a compound of formula (I) selected from a free acid, free base, salt, isotopomer, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

[0839] In certain embodiments described herein, the compound of Formula (I) is in a form selected from a salt, isotopomer, stereoisomer, racemate, enantiomer, diastereomer, or tautomer thereof.

[0840] In certain embodiments described herein, the compound of Formula (I) is in a form selected from the free acid, isotopomer, stereoisomer, racemate, enantiomer, diastereomer, or tautomer thereof.

[0841] In certain embodiments described herein, the compound of Formula (I) is in a form selected from its free base, isotopomer, stereoisomer, racemate, enantiomer, diastereomer, or tautomer.

[0842] In certain embodiments described herein, the compound of Formula (I) is in the form of a free acid, a free base, or a salt thereof.

[0843] In certain embodiments described herein, the compound of Formula (I) is in the form of its isotopologues.

[0844] In certain embodiments described herein, the compounds of Formula (I) are in the form of stereoisomers, racemates, enantiomers, or diastereomers thereof.

[0845] In certain embodiments described herein, the compounds of Formula (I) are in the form of their tautomers.

[0846] In certain embodiments described herein, the compound of Formula (I) is in a pharmaceutically acceptable form.

[0847] In certain embodiments described herein, the compound of Formula (I) or a form thereof is used in isolation.

[0848] The term "isolated" as used herein refers to the physical state of a compound of Formula (I) or a form thereof after isolation and / or purification from a synthetic process (e.g., from a reaction mixture) or natural source, or a combination thereof, to a purity sufficient to be characterized by standard analytical techniques described herein or well-known to those skilled in the art, according to one or more separation or purification methods described herein or well-known to those skilled in the art (e.g., chromatography, recrystallization, etc.).

[0849] As used herein, the term "protected" refers to a functional group on a compound of formula (I) that is in a modified form to prevent undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups are recognizable to those skilled in the art with reference to standard textbooks such as TW Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0850] Also contemplated herein are prodrugs of the compounds of formula (I) or forms thereof.

[0851] As used herein, the term "prodrug" refers to a functional group on a compound of formula (I) that is in a form that is converted in vivo to produce an active or more active compound of formula (I) or a form thereof (e.g., serving as an active or inactive drug precursor). The conversion can occur by different mechanisms (e.g., metabolic and / or non-metabolic chemical processes), such as, for example, by hydrolysis and / or metabolism in the blood, liver, and / or other organs and tissues. A discussion of prodrug uses is provided in VJ. Stella, et.al., "Biotechnology: Pharmaceutical Aspects, Prodrugs: Challenges and Rewards," American Association of Pharmaceutical Scientists and Springer Press, 2007.

[0852] In one example, when the compound of formula (I) or its form comprises a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing the hydrogen atom of an acid group with a functional group such as an alkyl group. In another example, when the compound of formula (I) or its form comprises an alcohol functional group, the prodrug may be formed by replacing the hydrogen atom of an alcohol group with a functional group such as an alkyl group or a substituted carbonyl group. In another example, when the compound of formula (I) or its form comprises an amine functional group, the prodrug may be formed by replacing one or more amine hydrogen atoms of a functional group such as an alkyl group or a substituted carbonyl group. In another example, when the compound of formula (I) or its form comprises a hydrogen substituent, the prodrug may be formed by replacing one or more hydrogen atoms with an alkyl substituent.

[0853] The pharmaceutically acceptable prodrugs of a compound of formula (I) or its form include those compounds substituted with one or more of the following groups: carboxylate, sulfonate, -amino acid ester, phosphonate, monophosphate, diphosphate or triphosphate or alkyl substituents (when appropriate). As described herein, it will be understood by those of ordinary skill in the art that one or more such substituents can be used to provide a compound of formula (I) or its form as a prodrug.

[0854] The compound of formula (I) can form salts that are expected to be included in the scope of this specification. Unless otherwise stated, reference to a compound of formula (I) herein is understood to include reference to its salt. As used herein, the term "salt" refers to an acidic salt formed with an inorganic acid and / or an organic acid, and a basic salt formed with an inorganic base and / or an organic base. In addition, when the compound of formula (I) simultaneously contains a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, a zwitterion ("inner salt") can be formed and is included in the term "salt" as used herein.

[0855] As used herein, the term "pharmaceutically acceptable salts" refers to those salts of the compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and possess biological activity, although other salts are also useful. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) with an amount (e.g., an equivalent or stoichiometric amount) of an acid or base in a medium (e.g., a medium in which the salt is precipitated or an aqueous medium), followed by freeze-drying.

[0856] Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in the compounds described herein. Embodiments of acid addition salts include, but are not limited to, acetate, diacetate, acid phosphate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisate, gluconate, glucaronate, glutamate, hydrobromide, hydrochloride, dihydrochloride, trihydrochloride, hydroiodide, isonicotinate, lactate, maleate, methanesulfonate, naphthenate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, trifluoroacetic acid salt, and the like. One or more embodiments of acid addition salts include chloride, hydrochloride, dihydrochloride, trihydrochloride, acetate, diacetate, trifluoroacetate, trifluoroacetic acid salt, etc. More specific embodiments include chloride, hydrochloride, dihydrochloride, trifluoroacetate, trifluoroacetic acid salt, etc.

[0857] In addition, acids generally considered suitable for forming pharmaceutically useful salts from basic drug compounds are discussed, for example, in P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (see Food & Drug Administration website, Washington, DC). The contents of these are incorporated herein by reference.

[0858] Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. Certain compounds described herein may also form pharmaceutically acceptable salts with organic bases (e.g., organic amines such as, but not limited to, dicyclohexylamine, tert-butylamine, and the like), and with various amino acids (e.g., but not limited to, arginine, lysine, and the like). Basic nitrogen-containing groups may be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long chain halides (e.g., decyl, lauryl, and octadecanoyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0859] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the description herein and all such acid salts and base salts are considered equivalent to the free forms of the corresponding compounds for the purposes described herein.

[0860] The compounds of Formula I and forms thereof may further exist in tautomeric forms. All such tautomeric forms are contemplated herein as part of the present description.

[0861] The compounds of formula (I) may contain asymmetric or chiral centers and, therefore, may exist in different stereoisomeric forms. The present description is intended to include all stereoisomeric forms of the compounds of formula (I) as well as mixtures thereof, including racemic mixtures.

[0862] The compounds of formula (I) described herein may include one or more chiral centers and may therefore exist as racemic mixtures (R / S) or substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when there is one chiral center). In one embodiment, the compounds of formula (I) described herein are (S) isomers and may exist as enantiomerically pure compositions comprising substantially only (S) isomers. In another embodiment, the compounds of formula (I) described herein are (R) isomers and may exist as enantiomerically pure compositions comprising substantially only (R) isomers. As will be appreciated by those skilled in the art, when there are more than one chiral center, the compounds of formula (I) described herein may also include moieties described as (R,R), (R,S), (S,R) or (S,S) isomers, as defined according to the IUPAC Nomenclature Recommendations.

[0863] As used herein, the term "substantially pure" refers to a compound consisting essentially of a single isomer in an amount greater than or equal to 90%, greater than or equal to 92%, greater than or equal to 95%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 100%.

[0864] In one aspect, the compound of Formula (I) is a substantially pure (S) enantiomer present in an amount greater than or equal to 90%, greater than or equal to 92%, greater than or equal to 95%, greater than or equal to 98%, greater than or equal to 99%, or equal to 100%.

[0865] In one aspect, the compound of Formula (I) is a substantially pure (R) enantiomer present in an amount greater than or equal to 90%, greater than or equal to 92%, greater than or equal to 95%, greater than or equal to 98%, greater than or equal to 99%, or equal to 100%.

[0866] As used herein, a "racemate" is any mixture of isometric forms that is not "enantiomerically pure," including, for example and without limitation, mixtures in the following ratios: about 50 / 50, about 60 / 40, about 70 / 30, about 80 / 20, about 85 / 15, or about 90 / 10.

[0867] In addition, the present description encompasses all geometric isomers and positional isomers. For example, if a compound of formula (I) incorporates a double bond or a fused ring, both the cis- and trans- forms, as well as mixtures, are encompassed within the scope of the present description.

[0868] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by using chiral HPLC columns or other chromatographic methods known to those skilled in the art.

[0869] Enantiomers may be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Furthermore, some of the compounds of formula (I) may be atropisomers (e.g., substituted diaryls) and are considered part of this description.

[0870] All stereoisomeric forms (e.g., geometric isomers, optical isomers, positional isomers, etc.) of the compounds of the present invention (including salts, solvates, esters, and prodrugs and converted prodrugs thereof) that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may even exist in the absence of asymmetric carbons), rotational isomers, atropisomers, diastereomeric forms, and regioisomeric forms are contemplated to be within the scope of this specification. For example, if a compound of formula (I) incorporates a double bond or a fused ring, the cis- and trans- forms, as well as mixtures thereof, are encompassed within the scope of this specification. Furthermore, for example, all keto-enol and imine-enamine tautomeric forms of the compounds are encompassed within this specification. Individual stereoisomers of compounds of formula (I) described herein may, for example, be substantially free of other isomers or exist as racemic mixtures, as described above.

[0871] The use of the terms "salt," "prodrug," and "inverted prodrug" are intended to apply equally to all contemplated isotopomers, stereoisomers, racemates, or tautomers of the compounds of the invention.

[0872] The term "isotopologue" refers to an isotopically-enriched compound that is identical to a compound recited herein, but where one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as H, N, and N, respectively. 2 、H 3 、C 13 、C 14 、N 15 , O 18 , O 17 、P 31 、P32 、S 35 、F 18 、Cl 35 and Cl 36 , each of which is within the scope of this description.

[0873] Certain isotopically-enriched compounds described herein (e.g., with H 3 and C 14 those labeled) for use in compound and / or substrate tissue distribution assays. Tritiated (i.e., H 3 ) and carbon-14 (i.e., C 14 ) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes, such as deuterium (i.e., "deuterium-enriched"), may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and, therefore, may be preferred in some circumstances. Isotopically-enriched compounds of Formula (I) can generally be prepared using methods known to those of ordinary skill in the art by substituting an appropriate isotopically-enriched reagent for a non-isotopically-enriched reagent.

[0874] When a compound is deuterium-enriched, the ratio of deuterium to hydrogen on the deuterated atoms of the molecule substantially exceeds the naturally occurring ratio of deuterium to hydrogen.

[0875] The embodiments described herein may include isotopologues of the compounds of Formula (I), wherein the isotopologues are substituted with one or more deuterium atoms in place of one or more hydrogen atoms at one or more atomic members of the compounds of Formula (I).

[0876] One embodiment described herein may include compounds of Formula (I) and forms thereof, wherein a carbon atom may have from 1 to 3 hydrogen atoms optionally replaced with deuterium.

[0877] One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to encompass both solvated and unsolvated forms.

[0878] As used herein, the term "solvate" refers to a physical association of a compound described herein with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

[0879] One or more compounds described herein may optionally be converted into solvates. The preparation of solvates is generally known. A typical, non-limiting method comprises dissolving the compound in a desired amount of a desired solvent (organic solvent or water or a mixture thereof) at a temperature above ambient temperature and cooling the solution at a rate sufficient to form crystals, followed by separation by standard methods. Analytical techniques, such as infrared spectroscopy, show the presence of solvent (or water) in crystals of solvates (or hydrates).

[0880] The term "hydrate" as used herein refers to a solvate wherein the solvent molecule is water.

[0881] Polymorphic crystalline forms and amorphous forms of the compounds of Formula (I), as well as salts, solvates, esters, and prodrugs of the compounds of Formula (I), are further contemplated as being within the scope of the compounds described herein.

[0882] Compound Uses

[0883] Described herein are compounds of Formula (I) or forms thereof that enhance the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene. Using the assays described herein (see, Biological Examples section, below), such compounds of Formula (I) or forms thereof have been shown to enhance the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene. Thus, compounds of Formula (I) or forms thereof act as enhancers for the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene.

[0884] Described herein are compounds of Formula (I), or forms thereof, for use in enhancing the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene. Such compounds of Formula (I) can enhance the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene (using an assay utilizing the SMN1 minigene). Thus, compounds of Formula (I), or forms thereof, can be used as enhancers of the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene.

[0885] In one aspect, provided herein are methods for modulating the inclusion of exon 7 of SMN2 into RNA transcribed from the SMN2 gene, comprising contacting a compound of Formula (I) or a form thereof with a human cell. In a specific embodiment, provided herein are methods for modulating the inclusion of exon 7 of SMN2 into RNA transcribed from the SMN2 gene, comprising contacting a compound of Formula (I) or a form thereof with a human cell, wherein the compound of Formula (I) or a form thereof modulates the expression of an SMN2 minigene described herein or in International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833, each of which is incorporated herein by reference in its entirety. In one embodiment, the minigene is a minigene described in the Examples of International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833. In another embodiment, the minigene is a minigene described in Biological Example 1 below. Human cells can be contacted with a compound of Formula (I) or a form thereof in vitro and / or in vivo, for example, in a non-human animal or in a human. In one embodiment, the human cell is from or in a human. In another embodiment, the human cell is from or in a human SMA patient. In another embodiment, the human cell is from or in a human SMA patient, wherein SMA is caused by an inactivating mutation or deletion of the SMN1 gene on two chromosomes, resulting in loss of SMN1 gene function. In another embodiment, the human cell is a human cell from a human SMA patient. In certain embodiments, the human cell is from a cell line such as GM03813, GM00232, GM09677, and / or GM23240 (available from the Coriell Institute). In one embodiment, the compound is a compound of formula (I) or a form thereof.

[0886] In one embodiment, provided herein are methods for regulating the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, comprising contacting a compound of Formula (I) or a form thereof with a human cell. In another embodiment, provided herein are methods for enhancing the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, comprising contacting a compound of Formula (I) or a form thereof with a human cell, wherein the compound of Formula (I) or a form thereof enhances the expression of an SMN2 minigene described herein or in International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833, each of which is incorporated herein by reference in its entirety. In one embodiment, the minigene is a minigene described in the Examples of International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833. In another embodiment, the minigene is a minigene described in Biological Example 1 below. Human cells can be contacted with a compound of Formula (I) or a form thereof in vitro and / or in vivo, for example, in a non-human animal or in a human. In one embodiment, the human cell is from or in a human. In another embodiment, the human cell is from or in a human SMA patient. In another embodiment, the human cell is from or in a human SMA patient, wherein SMA is caused by an inactivating mutation or deletion of the SMN1 gene on two chromosomes, resulting in loss of SMN1 gene function. In another embodiment, the human cell is a human cell from a human SMA patient. In certain embodiments, the human cell is from a cell line such as GM03813, GM00232, GM09677, and / or GM23240 (available from the Coriell Institute). In one embodiment, the compound is a compound of formula (I) or a form thereof.

[0887] In another aspect, provided herein are methods for increasing the inclusion of exon 7 of SMN1 into RNA transcribed from an SMN1 gene, comprising contacting a compound of Formula (I) or a form thereof with a human cell. In one embodiment, provided herein are methods for increasing the inclusion of exon 7 of SMN1 into RNA transcribed from an SMN1 gene, comprising contacting a compound of Formula (I) or a form thereof with a human cell. In another embodiment, provided herein are methods for increasing the inclusion of exon 7 of SMN1 into RNA transcribed from an SMN1 gene, comprising contacting a compound of Formula (I) or a form thereof with a human cell, wherein the compound of Formula (I) or a form thereof increases the expression of an SMN1 minigene described herein or in International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833, each of which is incorporated herein by reference in its entirety. In one embodiment, the minigene is a minigene described in the Examples of International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833. Human cells can be contacted with a compound of Formula (I) or a form thereof in vitro and / or in vivo, for example, in a non-human animal or in a human. In one embodiment, the human cells are from or in a human. In another embodiment, the human cells are from or in a human SMA patient. In one embodiment, the compound is a compound of Formula (I) or a form thereof.

[0888] In one embodiment, provided herein are methods for increasing the inclusion of exon 7 of SMN1 into RNA transcribed from SMN1 and SMN2 genes, comprising contacting a human cell with a compound of Formula (I) or a form thereof. The human cell can be contacted with a compound of Formula (I) or a form thereof in vitro and / or in vivo, for example, in a non-human animal or in a human. In one embodiment, the human cell is from or in a human. In another embodiment, the human cell is from or in a human SMA patient. In one embodiment, the compound is a compound of Formula (I) or a form thereof.

[0889] In another aspect, provided herein is a method for regulating the inclusion of exon 7 of SMN2 into RNA transcribed from the SMN2 gene, comprising administering a compound of Formula (I) or a form thereof to a non-human SMA animal model. In one embodiment, provided herein is a method for regulating the inclusion of exon 7 of SMN2 into RNA transcribed from the SMN2 gene, comprising administering a compound of Formula (I) or a form thereof to a non-human SMA animal model, wherein the compound of Formula (I) or a form thereof enhances expression of an SMN2 minigene described herein or in International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833, the entire contents of which are incorporated herein by reference. In one embodiment, the minigene is a minigene described in the Examples of International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833. In another embodiment, the minigene is a minigene described in Biological Example 1 below. In one embodiment, the compound is a compound of Formula (I) or a form thereof.

[0890] In one embodiment, provided herein is a method for increasing the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, comprising administering a compound of Formula (I) or a form thereof to a non-human SMA animal model. In another embodiment, provided herein is a method for enhancing the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, comprising administering a compound of Formula (I) or a form thereof to a non-human SMA animal model, wherein the compound of Formula (I) or a form thereof enhances expression of an SMN2 minigene described herein or in International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833, the entire contents of which are incorporated herein by reference. In one embodiment, the minigene is a minigene described in the Examples of International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833. In another embodiment, the minigene is a minigene described in Biological Example 1 below. In one embodiment, the compound is a compound of Formula (I) or a form thereof.

[0891] In another aspect, provided herein is a method for enhancing the inclusion of exon 7 of SMN1 into RNA transcribed from the SMN1 gene, comprising administering a compound of Formula (I) or a form thereof to a non-human SMA animal model. In one embodiment, provided herein is a method for enhancing the inclusion of exon 7 of SMN1 into RNA transcribed from the SMN1 gene, comprising administering a compound of Formula (I) or a form thereof to a non-human SMA animal model, wherein the compound of Formula (I) or a form thereof enhances the expression of an SMN1 minigene described herein or in International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833, each of which is incorporated herein by reference in its entirety. In one embodiment, the minigene is a minigene described in the Examples of International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833. In one embodiment, the compound is a compound of Formula (I) or a form thereof.

[0892] In one embodiment, provided herein is a method for enhancing the inclusion of exon 7 of SMN1 into RNA transcribed from SMN1 and SMN2 genes, comprising administering a compound of formula (I) or a form thereof to a non-human SMA animal model. In one embodiment, the compound is a compound of formula (I) or a form thereof.

[0893] In another aspect, provided herein is a method for increasing the amount of Smn protein, comprising contacting a compound of Formula (I) or a form thereof with a human cell. In one embodiment, provided herein is a method for increasing the amount of Smn protein, comprising contacting a compound of Formula (I) with a human cell, wherein the compound of Formula (I) enhances the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene. In another embodiment, provided herein is a method for increasing the amount of Smn protein, comprising contacting a human cell with a compound of Formula (I), wherein the compound of Formula (I) enhances the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 and / or SMN2 genes. The human cell can be contacted with a compound of Formula (I) or a form thereof in vitro and / or in vivo, for example, in a non-human animal or in a human. In one embodiment, the human cell is from or in a human. In another embodiment, the human cell is from or in a human SMA patient. In another specific embodiment, the human cell is from or in a human SMA patient, wherein SMA is caused by an inactivating mutation or deletion of the SMN1 gene on both chromosomes, resulting in loss of SMN1 gene function. In another embodiment, the human cell is a human cell from a human SMA patient. In certain embodiments, the human cell is from a cell line such as GM03813, GM00232, GM09677, and / or GM23240 (available from the Coriell Institute). In one embodiment, the compound is a compound of formula (I) or a form thereof.

[0894] In another aspect, provided herein is a method for increasing the amount of Smn protein, comprising administering a compound of formula (I) or a form thereof to a non-human SMA animal model. In one embodiment, provided herein is a method for increasing the amount of Smn protein, comprising administering a compound of formula (I) to a non-human SMA animal model, wherein the compound of formula (I) enhances the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, for example, in a cell-based or cell-free assay, such as described in the following biological examples. In another embodiment, provided herein is a method for increasing the amount of Smn protein, comprising administering a compound of formula (I) to a non-human SMA animal model, wherein the compound of formula (I) enhances the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 gene, for example, in a cell-based or cell-free assay.

[0895] In one embodiment, the compound of formula (I) enhances the expression of a minigene described herein or in International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833, each of which is incorporated herein by reference in its entirety. In a specific embodiment, the compound of formula (I) enhances the expression of a minigene described herein or in the Examples of International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833. In another specific embodiment, the compound of formula (I) enhances the expression of a minigene described in Biological Example 1 below. In one embodiment, the compound is a compound of formula (I) or a form thereof.

[0896] In one embodiment, provided herein is the use of a compound of Formula (I) or a form thereof in the preparation of a medicament for enhancing the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene. In another embodiment, provided herein is the use of a compound of Formula (I) or a form thereof in the preparation of a medicament for enhancing the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, thereby enhancing Smn protein expression in a human subject in need thereof. In a specific embodiment, a compound of Formula (I) or a form thereof enhances the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene in an assay described herein (see, e.g., the Biological Examples below). In a specific embodiment, the compound is a compound of Formula (I) or a form thereof.

[0897] In one embodiment, provided herein is the use of a compound of Formula (I) or a form thereof in the preparation of a medicament for enhancing the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 genes. In another embodiment, provided herein is the use of a compound of Formula (I) or a form thereof in the preparation of a medicament for enhancing the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 genes, thereby enhancing Smn protein expression in a human subject in need thereof. In a specific embodiment, the compound is a compound of Formula (I) or a form thereof.

[0898] In another aspect, provided herein are methods for enhancing the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of Formula (I) or a form thereof. In one specific embodiment, provided herein are methods for enhancing the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of Formula (I) or a form thereof that enhances the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene as determined in an assay described herein (see, e.g., the Biological Examples below). In specific embodiments, the effective amount of a compound of Formula (I) or a form thereof is administered to the human subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent. In specific embodiments, a compound of Formula (I) or a form thereof enhances the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene in an assay described herein (see, e.g., the Biological Examples below). In one embodiment, the human subject is a human SMA patient. In another embodiment, the human subject is a human SMA patient, wherein SMA is caused by an inactivating mutation or deletion of the SMN1 gene on both chromosomes, resulting in loss of SMN1 gene function. In one embodiment, the compound is a compound of formula (I) or a form thereof.

[0899] In another aspect, provided herein are methods for enhancing the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of Formula (I) or a form thereof. In specific embodiments, the compound of Formula (I) or a form thereof enhances the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene in an assay described in International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833. In specific embodiments, the effective amount of the compound of Formula (I) or a form thereof is administered to the human subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent. In one specific embodiment, the human subject is a human SMA patient. In one embodiment, the compound is a compound of Formula (I) or a form thereof.

[0900] In another aspect, provided herein is a method for enhancing the inclusion of exon 7 of SMN1 and SMN2 into mRNA transcribed from the SMN1 and SMN2 genes in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of Formula (I) or a form thereof. In a specific embodiment, the compound of Formula (I) or a form thereof enhances the inclusion of exon 7 of SMN1 into mRNA transcribed from the SMN1 gene in an assay described in International Publication No. WO 2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833 (see, e.g., the Examples in these publications), the entire contents of each of which are incorporated herein by reference. In a specific embodiment, an effective amount of a compound of Formula (I) or a form thereof is administered to the human subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent. In one specific embodiment, the human subject is a human SMA patient. In another specific embodiment, the human subject is a human SMA patient, wherein SMA is caused by an inactivating mutation or deletion of the SMN1 gene on both chromosomes, resulting in loss of SMN1 gene function. In one embodiment, the compound is a compound of Formula (I) or a form thereof.

[0901] In another aspect, provided herein are methods for increasing the expression of Smn proteins in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of Formula (I) or a form thereof. In one embodiment, provided herein are methods for increasing the expression of Smn proteins in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of Formula (I) or a form thereof that increases the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene. In another embodiment, provided herein are methods for increasing the expression of Smn proteins in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of Formula (I) or a form thereof that increases the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 genes. In a specific embodiment, the effective amount of a compound of Formula (I) or a form thereof is administered to the human subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent. In specific embodiments, a compound of Formula (I) or a form thereof enhances the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 genes in an assay described herein (see, e.g., the Biological Examples below) or in International Publication No. WO 2009 / 151546 or International Patent Application Publication No. WO 2009 / 0086833 (see, e.g., the Examples in these publications), the entire contents of each of which are incorporated herein by reference.

[0902] In one embodiment, the human subject is a human SMA patient. In another embodiment, the human subject is a human SMA patient, wherein SMA is caused by an inactivating mutation or deletion of the teleomeric copies of the SMN1 gene on both chromosomes, resulting in loss of SMN1 gene function. In one embodiment, the compound is a compound of formula (I) or a form thereof.

[0903] In another embodiment, provided herein is a use of a compound of Formula (I) or a form thereof for the preparation of a medicament for increasing the expression of Smn proteins in a human subject in need thereof. In a specific embodiment, the compound of Formula (I) or a form thereof increases the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, as determined in an assay described herein (see, e.g., the Biological Examples below). In another embodiment, the compound of Formula (I) or a form thereof increases the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 genes, as determined in an assay described herein (see, e.g., the Biological Examples below) or in an assay described in International Publication No. WO2009 / 151546 or International Patent Application Publication No. WO2009 / 0086833 (see, e.g., the Examples in these publications), the entire contents of each of which are incorporated herein by reference. In a specific embodiment, the compound is a compound of Formula (I) or a form thereof.

[0904] In another aspect, provided herein are methods for treating spinal muscular atrophy (SMA), comprising administering to a subject an effective amount of a compound of formula (I) or a form thereof. In one embodiment, provided herein is a method for treating SMA in a human subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. In another embodiment, provided herein is a method for treating SMA in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a form thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. In one embodiment, the compound is a compound of formula (I) or a form thereof.

[0905] In another embodiment, provided herein is a method of treating SMA in a human subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), or a form thereof, which enhances the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene. In a specific embodiment, provided herein is a method of treating SMA in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a form thereof, which enhances the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, and a pharmaceutically acceptable carrier, excipient, or diluent. In another specific embodiment, provided herein is a method of treating SMA in a human subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a form thereof, which enhances the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 genes, and a pharmaceutically acceptable carrier, excipient, or diluent. In a specific embodiment, a compound of Formula (I) or a form thereof enhances the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene in an assay described herein (see, e.g., the Biological Examples below). In another embodiment, a compound of Formula (I) or a form thereof enhances the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 gene as determined in an assay described herein (see, e.g., the Biological Examples below) or in an assay described in International Publication No. WO 2009 / 151546 or U.S. Patent Application Publication No. WO 2009 / 0086833 (see, e.g., the Examples therein), the entire contents of each of which are incorporated herein by reference. In a specific embodiment, the compound is a compound of Formula (I) or a form thereof.

[0906] In another embodiment, provided herein is a use of a compound of Formula (I) or a form thereof in the preparation of a medicament for treating SMA in a human subject in need thereof. In a specific embodiment, the compound of Formula (I) or a form thereof enhances the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene as determined in an assay described herein (see, e.g., the Biological Examples below). In another embodiment, the compound of Formula (I) or a form thereof enhances the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 genes as determined in an assay described herein (see, e.g., the Biological Examples below) or in an assay described in International Publication No. WO2009 / 151546 or U.S. Patent Application Publication No. WO2009 / 0086833 (see, e.g., the Examples therein), the entire contents of each of which are incorporated herein by reference. In a specific embodiment, the compound is a compound of Formula (I) or a form thereof.

[0907] In one embodiment of the purposes or methods provided herein, a compound of formula (I) or a form thereof is used in combination with one or more additional agents. A compound of formula (I) or a form thereof may be administered to a subject or contacted with a cell before, simultaneously with, or after administering another agent to the subject or contacting the cell. A compound of formula (I) or a form thereof and another agent may be administered to a subject or contacted with a cell in a single composition or different compositions. In one embodiment, a compound of formula (I) or a form thereof is used in combination with gene replacement of SMN1 (e.g., using a viral delivery vector). In another embodiment, a compound of formula (I) or a form thereof is used in combination with cell replacement using differentiated SMN1+ / + and / or SMN2+ / + stem cells. In another embodiment, a compound of formula (I) or a form thereof is used in combination with cell replacement using differentiated SMN1+ / + stem cells. In another embodiment, a compound of formula (I) or a form thereof is used in combination with cell replacement using differentiated SMN2+ / + stem cells. In another embodiment, a compound of formula (I) or a form thereof is used in combination with aclarubicin. In another specific embodiment, a compound of Formula (I) or a form thereof is used in combination with a transcriptional activator, such as a histone deacetylase ("HDAC") inhibitor (e.g., butyrate, valproic acid, and hydroxyurea) and an mRNA stabilizer (e.g., an mRNA decapping inhibitor available from Repligen).

[0908] In one embodiment, provided herein is the use of a compound of Formula (I), or a form thereof, in combination with supportive therapy, including respiratory, nutritional, or rehabilitative care.

[0909] In some embodiments, treatment of SMA with a compound of formula (I) or a form thereof (alone or in combination with another agent) has a therapeutic effect and / or beneficial effect. In a specific embodiment, treatment of SMA with a compound of formula (I) or a form thereof (alone or in combination with another agent) produces one, two, or more of the following effects: (i) reducing or ameliorating the severity of SMA; (ii) delaying the onset of SMA; (iii) inhibiting the progression of SMA; (iv) reducing hospitalizations in a subject; (v) reducing the length of hospitalization; (vi) improving the survival rate of a subject; (vii) improving the quality of life of a subject; (viii) reducing the number of symptoms associated with SMA; (ix) reducing or ameliorating the severity of symptoms associated with SMA; (x) the duration of symptoms associated with SMA; (xi) preventing the recurrence of symptoms associated with SMA; (xii) inhibiting the development or onset of symptoms of SMA; and / or (xiii) inhibiting the progression of symptoms associated with SMA.

[0910] Symptoms of SMA include muscle weakness, poor muscle tone, inability to shout, inability to cough, limp or tendency to collapse, difficulty sucking or swallowing, difficulty breathing, secretions pooling in the lungs or throat, fisting with sweaty hands, trembling / vibrating tongue, frequent head tilt to one side (even when lying down), legs tending to be weaker than arms, frequent "frog-leg" posture of the legs, difficulty eating, increased susceptibility to respiratory infections, bowel / bladder weakness, below normal weight, inability to sit unsupported, inability to walk, inability to crawl, and hypotonia, areflexia, and multiple congenital contractures (joint bends) related to anterior horn cell loss.

[0911] In one embodiment, treatment of SMA with a compound of (I) or a form thereof (alone or in combination with another agent) produces one, two, or more of the following effects: (i) reduced loss of muscle strength; (ii) increased muscle strength; (iii) reduced muscle atrophy; (iv) reduced loss of motor function; (v) increased motor neurons; (vii) reduced loss of motor neurons; (viii) prevention of degeneration of SMNs lacking motor neurons; (ix) increased motor function; (x) increased lung function; and / or (xi) reduced loss of lung function.

[0912] In another embodiment, treatment of SMA with a compound of (I) or a form thereof (alone or in combination with another agent) results in or helps maintain the functional ability to sit up in a human infant or human toddler. In another embodiment, treatment of SMA with a compound of (I) or a form thereof (alone or in combination with another agent) results in or helps maintain the functional ability to stand up independently in a human infant, human toddler, human child, or adult. In another embodiment, treatment of SMA with a compound of (I) or a form thereof (alone or in combination with another agent) results in or helps maintain the functional ability to walk independently in a human infant, human toddler, human child, or adult. In another embodiment, treatment of SMA with a compound of (I) or a form thereof (alone or in combination with another agent) results in or helps maintain the functional ability to run independently in a human infant, human toddler, human child, or adult. In another embodiment, treatment of SMA with a compound of (I) or a form thereof, alone or in combination with another agent, results in or helps maintain the functional ability to breathe independently in a human infant, toddler, child, or adult. In another embodiment, treatment of SMA with a compound of (I) or a form thereof, alone or in combination with another agent, results in or helps maintain the functional ability to turn over independently during sleep in a human infant, toddler, child, or adult. In another embodiment, treatment of SMA with a compound of (I) or a form thereof, alone or in combination with another agent, results in or helps maintain the functional ability to swallow independently in a human infant, toddler, child, or adult.

[0913] In some embodiments, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NO. 1, 7, 8, 11, or 13 and / or SEQ ID NO. 2, 9, or 12, and / or SMN probes such as SEQ ID NO. 3 or 10) are used in an assay, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, Northern blotting, or Southern blotting, to determine whether a compound of Formula (I) or a form thereof enhances the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the SMN1 and / or SMN2 genes. In certain embodiments, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NO. 1, 7, 8, 11, or 13 and / or SEQ ID NO. 2, 9, or 12, and / or SMN probes such as SEQ ID NO. 3 or 10) are used in assays, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, Northern blotting, or Southern blotting, or as described below as a pharmaceutical or assay kit, to monitor a patient's response to a compound of Formula (I) or a form thereof.

[0914] In one embodiment, the compound of formula (I) is used as described herein:

[0915]

[0916] or a form thereof in which:

[0917] w1 and w5 are CR independently a or N;

[0918] w2 is CR b or N;

[0919] w3, w4 and w7 are independently C-R1, C-R2, CR a or N;

[0920] w6 is C-R1, C-R2, CR c or N;

[0921] wherein one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[0922] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[0923] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR aor N; or

[0924] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[0925] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c or N; and

[0926] Among them, any one, two or three of w1, w2, w3, w4, w5, w6 and w7 can be

[0927] The selected location is N;

[0928] R1 is C 1-8 Alkyl, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, (C 1-8 Alkoxy-C 1-8 alkyl) 2-amino, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, amino-C 1-8 Alkyl-amino, (amino-C 1-8 alkyl) 2-amino, (amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (C 1-8 Alkyl-amino-C 1-8Alkyl)(C 1-8 alkyl)amino, (C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, [(C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino, amino-C 1-8 Alkoxy, C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8 alkyl)2-amino-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl-amino-C 1-8 Alkoxy, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, amino-C 2-8 Alkenyl, C 1-8 Alkyl-amino-C 2-8 Alkenyl, (C 1-8 alkyl)2-amino-C 2-8 Alkenyl, amino-C 2-8 Alkynyl, C 1-8 Alkyl-amino-C 2-8 Alkynyl, (C 1-8 alkyl)2-amino-C 2-8 Alkynyl, halo-C 1-8 Alkyl-amino, (halo-C 1-8 alkyl)2-amino, (halogenated-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkoxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, hydroxy-C1-8 Alkyl-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkoxy, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkoxy, hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, (hydroxy-C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 Alkyl)amino, (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl-amino, [(hydroxy-C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 alkyl)amino, [(hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl](C 1-8 alkyl)amino, heterocyclyl, heterocyclyl-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkoxy, heterocyclyl-amino, (heterocyclyl)(C 1-8 alkyl)amino, heterocyclyl-amino-C 1-8 Alkyl, heterocyclyl-C 1-8 Alkyl-amino, (heterocyclyl-C 1-8 alkyl) 2-amino, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heterocyclic-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (heterocyclyl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, C 3-14 Cycloalkyl, aryl-C 1-8 Alkyl-amino, (aryl-C 1-8 alkyl) 2-amino, (aryl-C 1-8 Alkyl)(C1-8 alkyl)amino, aryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (aryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl, (aryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 Alkyl, heteroaryl, heteroaryl-C 1-8 Alkyl, heteroaryl-C 1-8 Alkoxy, heteroaryl-amino, heteroaryl-C 1-8 Alkyl-amino, (heteroaryl-C 1-8 alkyl)2-amino, (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino, heteroaryl-C 1-8 Alkyl-amino-C 1-8 Alkyl, (heteroaryl-C 1-8 alkyl)2-amino-C 1-8 Alkyl or (heteroaryl-C 1-8 Alkyl)(C 1-8 alkyl)amino-C 1-8 alkyl;

[0929] In each case, the heterocyclic group, C 3-14 Cycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three R3 substituents and optionally with one additional R4 substituent; or

[0930] In each case, the heterocyclic group, C 3-14 Cycloalkyl, aryl, and heteroaryl are optionally substituted with one, two, three, or four R3 substituents;

[0931] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;

[0932] wherein each occurrence of aryl, heterocyclyl and heteroaryl is optionally substituted by one, two or three R6 substituents and optionally by one further R7 substituent;

[0933] R a is independently selected at each occurrence from hydrogen, halogen or C 1-8 alkyl;

[0934] R b For hydrogen, halogen, C 1-8 Alkyl or C 1-8 alkoxy;

[0935] R3 is independently selected from cyano, halogen, hydroxy, oxo, C 1-8Alkyl, halo-C 1-8 Alkyl, C 1-8 Alkyl-carbonyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl, C 1-8 Alkoxy-carbonyl, amino, C 1-8 Alkyl-amino, (C 1-8 alkyl) 2-amino, amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, amino-C 1-8 Alkyl-amino, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (C 1-8 Alkyl-amino-C 1-8 alkyl) 2-amino, (C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, [(C 1-8 alkyl)2-amino-C 1-8 alkyl]2-amino, (C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 alkyl)amino, [(C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 Alkyl)amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, (C 1-8 Alkoxy-C 1-8 alkyl) 2-amino, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 Alkyl)amino, C 1-8 Alkyl-carbonyl-amino, C 1-8 Alkoxy-carbonyl-amino, hydroxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkoxy-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl) 2-amino or (hydroxy-C 1-8 Alkyl)(C 1-8 alkyl)amino;

[0936] R4 is C 3-14 Cycloalkyl, C 3-14 Cycloalkyl-C1-8 Alkyl, C 3-14 Cycloalkyl-amino, aryl-C 1-8 Alkyl, aryl-C 1-8 Alkoxy-carbonyl, aryl-sulfonyloxy-C 1-8 Alkyl, heterocyclyl or heterocyclyl-C 1-8 Alkyl; wherein each occurrence of C 3-14 Cycloalkyl, aryl and heterocyclyl are optionally substituted with one, two or three R5 substituents;

[0937] R5 is independently selected from halogen, hydroxy, cyano, nitro, C 1-8 Alkyl, halo-C 1-8 Alkyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino or C 1-8 alkyl-thio;

[0938] R6 is independently selected from halogen, hydroxy, cyano, nitro, C 1-8 Alkyl, C 2-8 Alkenyl, halo-C 1-8 Alkyl, hydroxy-C 1-8 Alkyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino or C 1-8 Alkyl-thio; and

[0939] R7 is C 3-14 Cycloalkyl, C 3-14 Cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

[0940] An embodiment of the use of a compound of formula (I) is the use of a compound selected from formula (II)-(II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII) or formula (XIV):

[0941]

[0942]

[0943] or its form.

[0944] In one embodiment of the use of the compound of formula (I), w3 is C-R1, w6 is C-R2, w1, w4, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0945] In another embodiment of the use of the compound of formula (I), w3 is C-R2, w6 is C-R1, w1, w4, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0946] In another embodiment of the use of the compound of formula (I), w4 is C-R1, w7 is C-R2, w1, w3 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0947] In another embodiment of the use of the compound of formula (I), w4 is C-R2, w7 is C-R1, w1, w3 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0948] In one embodiment of the use of the compound of formula (II), w3 is C-R1, w6 is C-R2, w4, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0949] In another embodiment of the use of the compound of formula (II), w3 is C-R2, w6 is C-R1, w4, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0950] In another embodiment of the use of the compound of formula (II), w4 is C-R1, w7 is C-R2, w3 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0951] In another embodiment of the use of the compound of formula (II), w4 is C-R2, w7 is C-R1, w3 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0952] In one embodiment of the use of the compound of formula (III), w3 is C-R1, w6 is C-R2 and w1, w4, w5 and w7 are independently CR a is N.

[0953] In another embodiment of the use of the compound of formula (III), w3 is C-R2, w6 is C-R1 and w1, w4, w5 and w7 are independently CR a is N.

[0954] In another embodiment of the use of the compound of formula (III), w4 is C-R1, w7 is C-R2, w1, w3 and w5 are independently CR a or N and w6 is CR c is N.

[0955] In another embodiment of the use of the compound of formula (III), w4 is C-R2, w7 is C-R1, w1, w3 and w5 are independently CR a or N and w6 is CR c is N.

[0956] In one embodiment of the use of the compound of formula (IV), w4 is C-R1, w7 is C-R2, w1 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0957] In another embodiment of the use of the compound of formula (IV), w4 is C-R2, w7 is C-R1, w1 and w5 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0958] In one embodiment of the use of the compound of formula (V), w3 is C-R1, w6 is C-R2, w1, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0959] In another embodiment of the use of the compound of formula (V), w3 is C-R2, w6 is C-R1, w1, w5 and w7 are independently CR a or N and w2 is CR b is N.

[0960] In one embodiment of the use of the compound of formula (VI), w3 is C-R1, w6 is C-R2, w1, w4 and w7 are independently CR a or N and w2 is CR b is N.

[0961] In another embodiment of the use of the compound of formula (VI), w3 is C-R2, w6 is C-R1, w1, w4 and w7 are independently CR a or N and w2 is CR b is N.

[0962] In another embodiment of the use of the compound of formula (VI), w4 is C-R1, w7 is C-R2, w1 and w3 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0963] In another embodiment of the use of the compound of formula (VI), w4 is C-R2, w7 is C-R1, w1 and w3 are independently CR a or N, w2 is CR b or N and w6 is CR c is N.

[0964] In another embodiment of the use of the compound of formula (VII), w4 is C-R1, w7 is C-R2, w1, w3 and w5 are CR a or N and w2 is CR b is N.

[0965] In another embodiment of the use of the compound of formula (VII), is C-R2, w7 is C-R1, w1, w3 and w5 are CR a or N and w2 is CR b is N.

[0966] In another embodiment of the use of the compound of formula (VIII), w3 is C-R1, w6 is C-R2, w1, w4 and w5 are CR a or N and w2 is CR b is N.

[0967] In another embodiment of the use of the compound of formula (VIII), w3 is C-R2, w6 is C-R1, w1, w4 and w5 are CR a or N and w2 is CR b is N.

[0968] In one embodiment of the use of the compound of formula (IX), w3 is C-R1, w6 is C-R2, w4 and w7 are independently CR a or N and w2 is CR b is N.

[0969] In another embodiment of the use of the compound of formula (IX), w3 is C-R2, w6 is C-R1, w4 and w7 are independently CR a or N and w2 is CR b is N.

[0970] In another embodiment of the use of the compound of formula (IX), w4 is C-R1, w7 is C-R2, and w2 is CR b or N, w3 is CR a or N and w6 is CR c is N.

[0971] In another embodiment of the use of the compound of formula (IX), w4 is C-R2, w7 is C-R1, and w2 is CR b or N, w3 is CR a or N and w6 is CR c is N.

[0972] In one embodiment of the use of the compound of formula (X), w3 is C-R1, w6 is C-R2, and w2 is CR b or N and w5 and w7 are independently CR a is N.

[0973] In another embodiment of the use of the compound of formula (X), w3 is C-R2, w6 is C-R1, and w2 is CR b or N and w5 and w7 are independently CR a is N.

[0974] In one embodiment of the use of the compound of formula (XI), w4 is C-R1, w7 is C-R2, and w2 is CR b or N, w5 is CR a or N and w6 is CR c is N.

[0975] In another embodiment of the use of the compound of formula (XI), w4 is C-R2, w7 is C-R1, and w2 is CR b or N, w5 is CR a or N and w6 is CR c is N.

[0976] In one embodiment of the use of the compound of formula (XII), w3 is C-R1, w6 is C-R2 and w4, w5 and w7 are independently CR a is N.

[0977] In another embodiment of the use of the compound of formula (XII), w3 is C-R2, w6 is C-R1 and w4, w5 and w7 are independently CR a is N.

[0978] In another embodiment of the use of the compound of formula (XII), w4 is C-R1, w7 is C-R2, w3 and w5 are independently CR a or N and w6 is CR c is N.

[0979] In another embodiment of the use of the compound of formula (XII), w4 is C-R2, w7 is C-R1, w3 and w5 are independently CR a or N and w6 is CR c is N.

[0980] In one embodiment of the use of the compound of formula (XIII), w3 is C-R1, w6 is C-R2, and w2 is CR b or N and w4 and w5 are independently CR a is N.

[0981] In another embodiment of the use of the compound of formula (XIII), w3 is C-R2, w6 is C-R1, and w2 is CR b or N and w4 and w5 are independently CR a is N.

[0982] In one embodiment of the use of the compound of formula (XIV), w4 is C-R1, w7 is C-R2, and w2 is CR b or N and w3 and w5 are independently CR a is N.

[0983] In another embodiment of the use of the compound of formula (XIV), w4 is C-R2, w7 is C-R1, and w2 is CR b or N and w3 and w5 are independently CR a is N.

[0984] Another embodiment of the use of a compound of formula (I) is the use of a compound selected from formula (II), formula (III), formula (IX), formula (XI) or formula (XII), or a form thereof.

[0985]

[0986] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (II) or a form thereof.

[0987]

[0988] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (III) or a form thereof.

[0989]

[0990] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (IV) or a form thereof.

[0991]

[0992] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (V) or a form thereof.

[0993]

[0994] Another embodiment of the use of compounds of formula (I) is the use of compounds of formula (VI):

[0995]

[0996] or its form.

[0997] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (VII) or a form thereof.

[0998]

[0999] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (VIII) or a form thereof.

[1000]

[1001] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (IX) or a form thereof.

[1002]

[1003] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (X) or a form thereof.

[1004]

[1005] Another embodiment of the use of compounds of formula (I) is the use of compounds of formula (XI):

[1006]

[1007] or its form.

[1008] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (XII) or a form thereof.

[1009]

[1010] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (XIII) or a form thereof.

[1011]

[1012] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (XIV) or a form thereof.

[1013]

[1014] An embodiment of the use of a compound of Formula (I)-(Ia)-(IIa)-(IIIa)-(IVa)-(Va)-(VIIIa)-(VIIIa)-(IXa)-(Xa)-(XIa)-(XIIa)-(XIIIa)-(XIVa)-(XIVa)-(Va)-(VIIIa)-(VIIIla)-(IXa)-(Xa)-(XIa)-(XIIa)-(XIIIa)-(XIIIa)-(XIVa)-(XIVa)-(XIVa)

[1015]

[1016]

[1017] In one embodiment of the use of the compound of formula (Ia), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[1018] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[1019] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[1020] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[1021] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[1022] In one embodiment of the use of the compound of formula (IIa), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[1023] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[1024] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[1025] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[1026] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[1027] In one embodiment of the use of the compound of formula (IIIa), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[1028] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[1029] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[1030] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[1031] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CRc is N.

[1032] In one embodiment of the use of the compound of formula (IVa), one of w4 and w7 is C-R1 and the other is C-R2, provided that when w4 is C-R1, then w7 is C-R2; or, when w4 is C-R2, then w7 is C-R1.

[1033] In one embodiment of the use of the compound of formula (Va), one of w3 and w6 is C-R1 and the other is C-R2, provided that when w3 is C-R1, then w6 is C-R2; or, when w3 is C-R2, then w6 is C-R1.

[1034] In one embodiment of the use of the compound of formula (VIa), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[1035] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[1036] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[1037] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[1038] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[1039] In one embodiment of the use of the compound of formula (VIIa), one of w4 and w7 is C-R1 and the other is C-R2, provided that when w4 is C-R1, then w7 is C-R2; or, when w4 is C-R2, then w7 is C-R1.

[1040] In one embodiment of the use of the compound of formula (VIIIa), one of w3 and w6 is C-R1 and the other is C-R2, provided that when w3 is C-R1, then w6 is C-R2; or, when w3 is C-R2, then w6 is C-R1.

[1041] In one embodiment of the use of the compound of formula (IXa), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[1042] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[1043] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[1044] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[1045] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[1046] In one embodiment of the use of the compound of formula (Xa), one of w3 and w6 is C-R1 and the other is C-R2, provided that when w3 is C-R1, then w6 is C-R2; or, when w3 is C-R2, then w6 is C-R1.

[1047] In one embodiment of the use of the compound of formula (XIa), one of w4 and w7 is C-R1 and the other is C-R2, provided that when w4 is C-R1, then w7 is C-R2; or, when w4 is C-R2, then w7 is C-R1.

[1048] In one embodiment of the use of the compound of formula (XIIa), one of w3, w4, w6 and w7 is C-R1 and another of w3, w4, w6 and w7 is C-R2, provided that

[1049] When w3 is C-R1, then w6 is C-R2 and w4 and w7 are independently CR a or N; or

[1050] When w3 is C-R2, then w6 is C-R1 and w4 and w7 are independently CR a or N; or

[1051] When w4 is C-R1, then w7 is C-R2 and w3 is CR a or N and w6 is CR c or N; or

[1052] When w4 is C-R2, then w7 is C-R1 and w3 is CR a or N and w6 is CR c is N.

[1053] In one embodiment of the use of the compound of formula (XIIIa), one of w3 and w6 is C-R1 and the other is C-R2, provided that when w3 is C-R1, then w6 is C-R2; or, when w3 is C-R2, then w6 is C-R1.

[1054] In one embodiment of the use of the compound of formula (XIVa), one of w4 and w7 is C-R1 and the other is C-R2, provided that, when w4 is C-R1, then w7 is C-R2; or, when w4 is C-R2, then w7 is C-R1.

[1055] An embodiment of the use of a compound of Formula (I)-(II), (III), (IX), (XI) or (XII) is the use of a compound selected from Formula (Ia)-(IIa), (IIIa)-(IXa), (XIa) or (XIIa) or a form thereof.

[1056]

[1057] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (Ia) or a form thereof.

[1058]

[1059] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (IIa) or a form thereof.

[1060]

[1061] Another embodiment of the use of a compound of formula (III) is the use of a compound of formula (IIIa) or a form thereof.

[1062]

[1063] Another embodiment of the use of a compound of formula (IV) is the use of a compound of formula (IVa) or a form thereof.

[1064]

[1065] Another embodiment of the use of a compound of formula (V) is the use of a compound of formula (Va) or a form thereof.

[1066]

[1067] Another embodiment of the use of a compound of formula (VI) is the use of a compound of formula (Via) or a form thereof.

[1068]

[1069] Another embodiment of the use of a compound of formula (VII) is the use of a compound of formula (VIIa) or a form thereof.

[1070]

[1071] Another embodiment of the use of a compound of formula (VIII) is the use of a compound of formula (VIIIa):

[1072]

[1073] or its form.

[1074] Another embodiment of the use of a compound of formula (IX) is the use of a compound of formula (IXa) or a form thereof.

[1075]

[1076] Another embodiment of the use of a compound of formula (I) is the use of a compound of formula (Xa) or a form thereof.

[1077]

[1078] Another embodiment of the use of a compound of formula (XI) is the use of a compound of formula (XIa) or a form thereof.

[1079]

[1080] Another embodiment of the use of the compound of formula (XII) is the use of the compound of formula (XIIa) or a form thereof.

[1081]

[1082] Another embodiment of the use of a compound of formula (XIII) is the use of a compound of formula (XIIIa) or a form thereof.

[1083]

[1084] Another embodiment of the use of compounds of formula (XIV) is the use of compounds of formula (XIVa) or forms thereof.

[1085]

[1086] One embodiment of the use of a compound of formula (Ia) is the use of a compound of formula (Ia1), formula (Ia2), formula (Ia3) or formula (Ia4) or a form thereof.

[1087]

[1088] One embodiment of the use of a compound of formula (IIa) is the use of a compound of formula (IIa1), formula (IIa2), formula (IIa3) or formula (IIa4) or a form thereof.

[1089]

[1090]

[1091] One embodiment of the use of a compound of formula (IIIa) is the use of a compound of formula (IIIa1), (IIIa2), (IIIa3) or (IIIa4) or a form thereof.

[1092]

[1093] One embodiment of the use of a compound of formula (IVa) is the use of a compound of formula (IVa1) or formula (IVa2) or a form thereof.

[1094]

[1095] One embodiment of the use of a compound of formula (Va) is the use of a compound of formula (Va1) or formula (Va2) or a form thereof.

[1096]

[1097] One embodiment of the use of a compound of formula (VIa) is the use of a compound of formula (VIa1), formula (VIa2), formula (VIa3) or formula (VIa4) or a form thereof.

[1098]

[1099] One embodiment of the use of a compound of formula (VIIa) is the use of a compound of formula (VIIa1) or formula (VIIa2) or a form thereof.

[1100]

[1101] One embodiment of the use of a compound of formula (VIIIa) is the use of a compound of formula (VIIIa1) or formula (VIIIa2) or a form thereof.

[1102]

[1103] One embodiment of the use of a compound of formula (IXa) is the use of a compound of formula (IXa1), formula (IXa2), formula (IXa3) or formula (IXa4) or a form thereof.

[1104]

[1105]

[1106] One embodiment of the use of a compound of formula (Xa) is the use of a compound of formula (Xa1) or formula (Xa2) or a form thereof.

[1107]

[1108] One embodiment of the use of a compound of formula (XIa) is the use of a compound of formula (XIa1) or formula (XIa2) or a form thereof.

[1109]

[1110] One embodiment of the use of a compound of formula (XIIa) is the use of a compound of formula (XIIa1), formula (XIIa2), formula (XIIa3) or formula (XIIa4) or a form thereof.

[1111]

[1112] One embodiment of the use of a compound of formula (XIIIa) is the use of a compound of formula (XIIIa1) or formula (XIIIa2) or a form thereof.

[1113]

[1114] One embodiment of the compound of formula (XIVa) is the use of a compound of formula (XIVa1) or formula (XIVa2) or a form thereof.

[1115]

[1116] One embodiment of the use of a compound of formula (1a) is the use of a compound of formula (Ia1) or a form thereof.

[1117]

[1118] One embodiment of the use of a compound of formula (1a) is the use of a compound of formula (Ia2) or a form thereof:

[1119]

[1120] One embodiment of the use of a compound of formula (1a) is the use of a compound of formula (Ia3) or a form thereof:

[1121]

[1122] One embodiment of the use of a compound of formula (1a) is the use of a compound of formula (Ia4) or a form thereof.

[1123]

[1124] One embodiment of the use of a compound of formula (IIa) is the use of a compound of formula (IIa1) or a form thereof.

[1125]

[1126] One embodiment of the use of a compound of formula (IIa) is the use of a compound of formula (IIa2) or a form thereof.

[1127]

[1128] One embodiment of the use of a compound of formula (IIa) is the use of a compound of formula (IIa3) or a form thereof.

[1129]

[1130] One embodiment of the use of a compound of formula (IIa) is the use of a compound of formula (IIa4) or a form thereof.

[1131]

[1132] One embodiment of the use of a compound of formula (IIIa) is the use of a compound of formula (IIIa1) or a form thereof.

[1133]

[1134] One embodiment of the use of a compound of formula (IIIa) is the use of a compound of formula (IIIa2) or a form thereof.

[1135]

[1136] One embodiment of the use of a compound of formula (IIIa) is the use of a compound of formula (IIIa3) or a form thereof.

[1137]

[1138] One embodiment of the use of a compound of formula (IIIa) is the use of a compound of formula (IIIa4) or a form thereof.

[1139]

[1140] One embodiment of the use of a compound of formula (IVa) is the use of a compound of formula (IVa1) or a form thereof.

[1141]

[1142] One embodiment of the use of a compound of formula (IVa) is the use of a compound of formula (IVa2) or a form thereof.

[1143]

[1144] One embodiment of the use of a compound of formula (Va) is the use of a compound of formula (Val) or a form thereof.

[1145]

[1146] One embodiment of the use of a compound of formula (Va) is the use of a compound of formula (Va2) or a form thereof.

[1147]

[1148] One embodiment of the use of a compound of formula (VIa) is the use of a compound of formula (VIa1) or a form thereof.

[1149]

[1150] One embodiment of the use of a compound of formula (VIa) is the use of a compound of formula (VIa2) or a form thereof.

[1151]

[1152] One embodiment of the use of a compound of formula (VIa3) is the use of a compound of formula (VIa) or a form thereof.

[1153]

[1154] One embodiment of the use of a compound of formula (VIa) is the use of a compound of formula (VIa4) or a form thereof.

[1155]

[1156] One embodiment of the use of a compound of formula (VIIa) is the use of a compound of formula (VIIa1) or a form thereof.

[1157]

[1158] One embodiment of the use of a compound of formula (VIIa) is the use of a compound of formula (VIIa2) or a form thereof.

[1159]

[1160] One embodiment of the use of a compound of formula (VIIIa) is the use of a compound of formula (VIIIa1) or a form thereof.

[1161]

[1162] One embodiment of the use of a compound of formula (VIIIa) is the use of a compound of formula (VIIIa2) or a form thereof.

[1163]

[1164] One embodiment of the use of a compound of formula (IXa) is the use of a compound of formula (IXa1) or a form thereof.

[1165]

[1166] One embodiment of the use of a compound of formula (IXa) is the use of a compound of formula (IXa2) or a form thereof.

[1167]

[1168] One embodiment of the use of a compound of formula (IXa) is the use of a compound of formula (IXa3) or a form thereof.

[1169]

[1170] One embodiment of the use of a compound of formula (IXa) is the use of a compound of formula (IXa4) or a form thereof.

[1171]

[1172] One embodiment of the use of a compound of formula (Xa) is the use of a compound of formula (Xa1) or a form thereof.

[1173]

[1174] One embodiment of the use of a compound of formula (Xa) is the use of a compound of formula (Xa2) or a form thereof.

[1175]

[1176] One embodiment of the use of a compound of formula (XIa) is the use of a compound of formula (XIa1) or a form thereof.

[1177]

[1178] One embodiment of the use of a compound of formula (XIa) is the use of a compound of formula (XIa2) or a form thereof.

[1179]

[1180] One embodiment of the use of a compound of formula (XIIa) is the use of a compound of formula (XIIa1) or a form thereof.

[1181]

[1182] One embodiment of the use of a compound of formula (XIIa) is the use of a compound of formula (XIIa2) or a form thereof.

[1183]

[1184] One embodiment of the use of a compound of formula (XIIa) is the use of a compound of formula (XIIa3) or a form thereof.

[1185]

[1186] One embodiment of the use of a compound of formula (XIIa) is the use of a compound of formula (XIIa4) or a form thereof.

[1187]

[1188] One embodiment of the use of a compound of formula (XIIIa) is the use of a compound of formula (XIIIa1) or a form thereof.

[1189]

[1190] One embodiment of the use of a compound of formula (XIIIa) is the use of a compound of formula (XIIIa2) or a form thereof.

[1191]

[1192] One embodiment of the use of a compound of formula (XIVa) is the use of a compound of formula (XIVa1) or a form thereof.

[1193]

[1194] One embodiment of the use of a compound of formula (XIVa) is the use of a compound of formula (XIVa2) or a form thereof.

[1195]

[1196] Patient population

[1197] In certain embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a subject suffering from SMA. In other embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a subject susceptible to or susceptible to SMA. In a specific embodiment, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a human subject suffering from SMA, wherein SMA is caused by an inactivating mutation or deletion of the SMN1 gene on both chromosomes, resulting in loss of SMN1 gene function. In some embodiments, prior to administering a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, the human subject is genotyped to determine whether the subject has an inactivating mutation or deletion of the teleomeric copy of the SMN1 gene on both chromosomes, resulting in loss of SMN1 gene function. In certain embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a subject suffering from type 0 SMA. In certain embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a subject suffering from type 1 SMA. In other embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a subject suffering from type 2 SMA. In other embodiments, a compound of Formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a subject suffering from SMA Type 3. In certain embodiments, a compound of Formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a subject suffering from SMA Type 4. In some embodiments, the human subject is an SMA patient.

[1198] In some embodiments, a compound of Formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a subject who would or would benefit from enhanced inclusion of exon 7 of SMN1 and / or SMN2 into the mRNA transcribed from the SMN1 and / or SMN2 gene. In specific embodiments, a compound of Formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a subject who would or would benefit from increased expression of an SMN protein.

[1199] In some embodiments, a compound of Formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a human having an age range of about 0 months to about 6 months of age, about 6 to about 12 months of age, about 6 to about 18 months of age, about 18 to about 36 months of age, about 1 to about 5 years of age, about 5 to about 10 years of age, about 10 to about 15 years of age, about 15 to about 20 years of age, about 20 to about 25 years of age, about 25 to about 30 years of age, about 30 to about 35 years of age, about 35 to about 40 years of age, about 40 to about 45 years of age, about 45 to about 50 years of age, about 50 to about 55 years of age, about 55 to about 60 years of age, about 60 to about 65 years of age, about 65 to about 70 years of age, about 70 to about 75 years of age, about 75 to about 80 years of age, about 80 to about 85 years of age, about 85 to about 90 years of age, about 90 to about 95 years of age, or about 95 to about 100 years of age.

[1200] In certain embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a human infant. In other embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a human toddler. In other embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a human child. In other embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to an adult. In still other embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to an elderly person.

[1201] In certain embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a patient to prevent the onset of SMA in a patient at risk of developing SMA. In other embodiments, an effective amount of a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a patient to prevent the onset of SMA in a patient at risk of developing SMA. In other embodiments, a prophylactically effective amount of a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a patient to prevent the onset of SMA in a patient at risk of developing SMA. In other embodiments, a therapeutically effective amount of a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to a patient to prevent the onset of SMA in a patient at risk of developing SMA.

[1202] In certain embodiments, a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to an SMA patient to treat or improve SMA. In other embodiments, an effective amount of a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to an SMA patient to treat or improve SMA. In other embodiments, a prophylactically effective amount of a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to an SMA patient to prevent the development of SMA. In other embodiments, a therapeutically effective amount of a compound of formula (I) or a form thereof, or a pharmaceutical composition thereof, is administered to an SMA patient to treat or improve SMA.

[1203] In certain embodiments, a compound of formula (I) or a form thereof or a medicament thereof is administered to a subject suffering from SMA. In other embodiments, a compound of formula (I) or a form thereof is administered to a subject susceptible to or susceptible to SMA. In a specific embodiment, a compound of formula (I) or a form thereof or a medicament thereof is administered to a human subject suffering from SMA, wherein SMA is caused by an inactivating mutation or deletion of the SMN1 gene on both chromosomes, resulting in loss of SMN1 gene function. In some embodiments, prior to administering a compound of formula (I) or a form thereof or a medicament thereof, a human subject is genotyped to determine whether the subject has an inactivating mutation or deletion of the teleomeric copy of the SMN1 gene on both chromosomes, resulting in loss of SMN1 gene function. In certain embodiments, a compound of formula (I) or a form thereof or a medicament thereof is administered to a subject suffering from type 0 SMA. In certain embodiments, a compound of formula (I) or a form thereof or a medicament thereof is administered to a subject suffering from type 1 SMA. In other embodiments, a compound of formula (I) or a form thereof or a medicament thereof is administered to a subject suffering from type 2 SMA. In other embodiments, a compound of Formula (I) or a form thereof, or a medicament thereof, is administered to a subject suffering from SMA Type 3. In certain embodiments, a compound of Formula (I) or a form thereof, or a medicament thereof, is administered to a subject suffering from SMA Type 4. In certain embodiments, the human subject is an SMA patient.

[1204] In some embodiments, a compound of Formula (I) or a form thereof, or a medicament thereof, is administered to a subject who would or would benefit from enhanced inclusion of exon 7 of SMN1 and / or SMN2 into the mRNA transcribed from the SMN1 and / or SMN2 gene. In specific embodiments, a compound of Formula (I) or a form thereof, or a medicament thereof, is administered to a subject who would or would benefit from increased expression of an SMN protein.

[1205] In some embodiments, a compound of Formula (I) or a form thereof, or a medicament thereof, is administered to a human having an age range of about 0 to about 6 months of age, about 6 to about 12 months of age, about 6 to about 18 months of age, about 18 to about 36 months of age, about 1 to about 5 years of age, about 5 to about 10 years of age, about 10 to about 15 years of age, about 15 to about 20 years of age, about 20 to about 25 years of age, about 25 to about 30 years of age, about 30 to about 35 years of age, about 35 to about 40 years of age, about 40 to about 45 years of age, about 45 to about 50 years of age, about 50 to about 55 years of age, about 55 to about 60 years of age, about 60 to about 65 years of age, about 65 to about 70 years of age, about 70 to about 75 years of age, about 75 to about 80 years of age, about 80 to about 85 years of age, about 85 to about 90 years of age, about 90 to about 95 years of age, or about 95 to about 100 years of age.

[1206] In certain embodiments, a compound of formula (I) or a form thereof, or a medicament thereof, is administered to a human infant. In other embodiments, a compound of formula (I) or a form thereof, or a medicament thereof, is administered to a human toddler. In other embodiments, a compound of formula (I) or a form thereof, or a medicament thereof, is administered to a human child. In other embodiments, a compound of formula (I) or a form thereof, or a medicament thereof, is administered to an adult. In still other embodiments, a compound of formula (I) or a form thereof, or a medicament thereof, is administered to an elderly person.

[1207] In certain embodiments, a compound of formula (I) or a form thereof or a medicament thereof is administered to a patient to prevent the onset of SMA in a patient at risk of developing SMA. In other embodiments, an effective amount of a compound of formula (I) or a form thereof or a medicament thereof is administered to a patient to prevent the onset of SMA in a patient at risk of developing SMA. In other embodiments, a prophylactically effective amount of a compound of formula (I) or a form thereof or a medicament thereof is administered to a patient to prevent the onset of SMA in a patient at risk of developing SMA. In other embodiments, a therapeutically effective amount of a compound of formula (I) or a form thereof or a medicament thereof is administered to a patient to prevent the onset of SMA in a patient at risk of developing SMA.

[1208] In certain embodiments, a compound of formula (I) or a form thereof or a medicament thereof is administered to an SMA patient to treat or improve SMA. In other embodiments, an effective amount of a compound of formula (I) or a form thereof or a medicament thereof is administered to an SMA patient to treat or improve SMA. In other embodiments, a prophylactically effective amount of a compound of formula (I) or a form thereof or a medicament thereof is administered to an SMA patient to prevent the development of SMA. In other embodiments, a therapeutically effective amount of a compound of formula (I) or a form thereof or a medicament thereof is administered to an SMA patient to treat or improve SMA.

[1209] Administration

[1210] When applied to a patient, the compound of formula (I) or its form is preferably used as a component of a composition, and the composition optionally comprises a pharmaceutically acceptable carrier, excipient or diluent. The composition can be orally administered, or by any other convenient approach, such as infusion or rapid injection, absorbed via epithelium or mucocutaneous lining (e.g., oral mucosa, rectum and intestinal mucosa), and can be used together with other bioactivators. Administration can be systemic or local. Various delivery systems are known, such as encapsulated in liposomes, microgranules, microcapsules, capsules, and can be used to administer the compound.

[1211] Methods of administration include, but are not limited to, parenteral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical administration, particularly to the ear, nose, eye, or skin. The mode of administration is determined by a licensed physician. In most cases, administration will result in release of the compound into the bloodstream. In one embodiment, the compound is administered orally.

[1212] Dosage and dosage form

[1213] The amount of a compound of Formula (I) or a form thereof that will be effective in treating SMA depends on, for example, the route of administration, the type of SMA, the general health of the subject, the race, age, weight and sex of the subject, diet, time of day, and the severity of SMA, and should be decided according to the judgment of the practitioner and the circumstances of each patient or subject.

[1214] In specific embodiments, the term "effective amount," "prophylactically effective amount," or "therapeutically effective amount" in the context of administering a compound of Formula (I) or a form thereof, or a composition thereof, or a pharmaceutical content thereof refers to an amount of the compound of Formula (I) that has a therapeutic effect and / or beneficial effect. In some specific embodiments, the term "effective amount," "prophylactically effective amount," or "therapeutically effective amount" in the context of administering a compound of Formula (I) or a form thereof, or a composition thereof, or a pharmaceutical content thereof, produces one, two, or more of the following effects: (i) reducing or ameliorating the severity of SMA; (ii) delaying the onset of SMA; (iii) inhibiting the progression of SMA; (iv) reducing the number of hospitalizations for a subject; (v) reducing the length of hospitalization; (vi) improving the survival rate of a subject; (vii) improving the quality of life of a subject; (viii) reducing the number of symptoms associated with SMA; (ix) reducing or ameliorating the severity of symptoms associated with SMA; (x) the duration of symptoms associated with SMA; (xi) preventing the recurrence of symptoms associated with SMA; (xii) inhibiting the development or onset of symptoms of SMA; and / or (xiii) inhibiting the progression of symptoms associated with SMA. In some embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to enhance the inclusion of exon 7 of SMN2 into SMN2 mRNA transcribed from the SMN2 gene and to increase the level of Smn protein produced from the SMN2 gene, thereby producing a desired beneficial effect in a subject in need thereof. In some cases, the desired effect can be determined by analyzing or quantifying: (1) the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene; or (2) the level of Smn protein produced from the SMN2 gene. Non-limiting examples of effective amounts of a compound of Formula (I) or a form thereof are described herein.

[1215] For example, an effective amount can be an amount required to treat SMA in a human subject in need thereof, or an amount required to enhance the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene in a human subject in need thereof, or an amount required to increase the level of SMN protein produced by the SMN2 gene in a human subject in need thereof. In a specific embodiment, the human subject is an SMA patient.

[1216] Generally, for patients or subjects weighing from about 1 kg to about 200 kg, an effective amount ranges from about 0.001 mg / kg / day to about 500 mg / kg / day. Typical adult human subjects are expected to have a median weight range of about 70 to about 100 kg.

[1217] Within the scope of this specification, an "effective amount" of a compound of Formula (I) or a form thereof for use in the preparation of a medicament, in the preparation of a pharmaceutical kit, or in a method of treating SMA in a human subject in need thereof is intended to include an amount in the range of about 0.001 mg to about 35,000 mg. In a specific embodiment, the human subject is an SMA patient.

[1218] The compositions described herein are formulated to be administered to a subject via any drug delivery route known in the art. Non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, ocular, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.

[1219] Pharmaceutical composition

[1220] Embodiments described herein include the use of a compound of Formula (I) or a form thereof in a pharmaceutical composition. In one embodiment, described herein is the use of a compound of Formula (I) or a form thereof in a pharmaceutical composition for treating SMA in a human subject in need thereof, comprising administering an effective amount of a compound of Formula (I) or a form thereof in admixture with a pharmaceutically acceptable excipient. In one embodiment, the human subject is an SMA patient.

[1221] The compound of formula (I) or its form can optionally be in the form of a composition comprising the compound or its form and an optional carrier, excipient or diluent. Other embodiments provided herein include pharmaceutical compositions comprising an effective amount of a compound of formula (I) or its form and a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the pharmaceutical composition is suitable for veterinary and / or human administration. The pharmaceutical composition provided herein can be in any form that allows the composition to be administered to a subject.

[1222] In one embodiment and in this context, the term "pharmaceutically acceptable" refers to a carrier, excipient, or diluent that is approved by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, more particularly humans. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, referring to oils of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a particular carrier for intravenous administration of pharmaceutical compositions. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions.

[1223] Typical compositions and dosage forms include one or more excipients. Suitable excipients are well known to those skilled in the art of medicine, and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form is administered to the patient and the specific active ingredient in the dosage form. Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising a compound of formula (I) as described herein or a form thereof. The compositions and single unit dosage forms can take the following forms: solution or syrup (optionally containing flavorings), suspension (optionally containing flavorings), emulsion, tablet (e.g., chewable tablet), pill, capsule, granule, powder (optionally for reconstitution), taste-masking or sustained-release formulations, etc.

[1224] The pharmaceutical compositions provided herein suitable for oral administration can be prepared into independent dosage forms, such as, but not limited to, tablets, caplets, capsules, granules, powders and liquids. Such dosage forms contain predetermined amounts of active ingredients and can be prepared by pharmaceutical methods well known to those skilled in the art.

[1225] Examples of excipients that can be used in the oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.

[1226] biomarkers

[1227] In some embodiments, in certain embodiments, the amount of mRNA transcribed from the SMN1 gene and / or SMN2 gene that does not include exon 7 of SMN1 and / or SMN2 can be used as a biomarker for SMA. In some embodiments, in certain embodiments, the amount of mRNA transcribed from the SMN1 gene and / or SMN2 gene that does not include exon 7 of SMN1 and / or SMN2 can be used as a biomarker for SMA. In other embodiments, the amount of mRNA transcribed from the SMN1 gene and / or SMN2 gene that does not include exon 7 of SMN1 and / or SMN2 can be used as a biomarker for SMA patients treated with, for example, the compounds disclosed herein. In other embodiments, the amount of mRNA transcribed from the SMN1 gene and / or SMN2 gene that does not include exon 7 of SMN1 and / or SMN2 can be used as a biomarker for SMA patients treated with, for example, the compounds disclosed herein. In certain embodiments, changes in the amount of mRNA transcribed from the SMN1 and / or SMN2 genes and including exon 7 of SMN1 and / or SMN2, and corresponding changes in the amount of mRNA transcribed from the SMN1 and / or SMN2 genes and excluding exon 7 of SMN1 and / or SMN2, are biomarkers for patients being treated with, for example, a therapy disclosed herein. In a specific embodiment, the patient is an SMA patient.

[1228] In one embodiment, following administration of a compound (e.g., a compound of Formula (I) disclosed herein), an increase in the amount of mRNA transcribed from the SMN1 and / or SMN2 genes and including exon 7 of SMN1 and / or SMN2 and a corresponding decrease in the amount of mRNA transcribed from the SMN1 and / or SMN2 genes but not including exon 7 of SMN1 and / or SMN2 indicates that the compound is effective in treating SMA. In another embodiment, following administration of a compound (e.g., a compound of Formula (I) disclosed herein), a decrease in the amount of mRNA transcribed from the SMN1 and / or SMN2 genes and including exon 7 of SMN1 and / or SMN2 and a corresponding increase in the amount of mRNA transcribed from the SMN1 and / or SMN2 genes but not including exon 7 of SMN1 and / or SMN2 indicates that the compound is not effective in treating SMA. According to these embodiments, the SMN primers and / or SMN probes described below can be used in assays, such as PCR (e.g., qPCR) and RT-PCR (e.g., RT-qPCR or end-point RT-PCR) to evaluate and / or quantify the amount of mRNA transcribed from the SMN1 gene and / or SMN2 gene and including or excluding exon 7 of SMN1 and / or SMN2.

[1229] In one embodiment, provided herein are SMN primers and / or SMN probes (e.g., forward primers having the nucleotide sequence of SEQ ID NO. 1, 7, 8, 11, or 13; and / or reverse primers having the nucleotide sequence of SEQ ID NO. 9 or 12; and / or SMN probes such as SEQ ID NO. 3 or 10) for amplifying nucleic acids encoding human SMN1 and / or SMN2 or encoded by human SMN1 and / or SMN2. These primers can be used, for example, as primers in RT-PCR (e.g., RT-PCR, end-point RT-PCR, and / or RT-qPCR, as described herein or as known to those skilled in the art), PCR (e.g., qPCR), or rolling circle amplification, and as probes in hybridization assays such as Northern and / or Southern blots. As used in the biological examples herein, end-point RT-PCR is a reverse transcription-polymerase chain reaction performed by performing a predetermined number of amplification cycles (or until the starting material is exhausted), followed by quantification of each DNA product using, for example, gel electrophoresis separation, fluorescent dye staining, fluorescence quantification, and the like.

[1230] SEQ ID NO. 1 hybridizes to a DNA or RNA comprising nucleotides corresponding to nucleotides 22 to 40 of exon 7 of SMN1 and / or SMN2, SEQ ID NO. 2 hybridizes to a DNA or RNA comprising nucleotides corresponding to nucleotides 4 to 26 of the firefly luciferase coding sequence, SEQ ID NO. 7 hybridizes to a nucleic acid sequence (e.g., the sense strand of the DNA) comprising nucleotides corresponding to nucleotides 32 to 54 of exon 7 of SMN1 and / or SMN2 and nucleotides 1 to 4 of exon 8 of SMN1 and / or SMN2, SEQ ID NO. 8 hybridizes to a nucleic acid sequence (e.g., the sense strand of the DNA) comprising nucleotides corresponding sequentially to nucleotides 87 to 111 of exon 7 of SMN1 and / or SMN2 and nucleotides 1 to 3 of exon 8 of SMN1 and / or SMN2, SEQ ID NO. 9 hybridizes to a nucleic acid sequence (e.g., the antisense strand of the DNA or RNA) comprising nucleotides corresponding to nucleotides 39 to 62 of exon 8 of SMN1 and / or SMN2, SEQ ID NO. SEQ ID NO. 11 hybridizes to a nucleic acid sequence comprising nucleotides corresponding to nucleotides 43 to 63 of exon 6 of SMN1 and / or SMN2 (e.g., the sense strand of DNA), SEQ ID NO. 12 hybridizes to a nucleic acid sequence comprising nucleotides corresponding sequentially to nucleotides 51 to 73 of exon 8 of SMN1 and / or SMN2 (e.g., the antisense strand of DNA), and SEQ ID NO. 13 hybridizes to a nucleic acid sequence comprising nucleotides corresponding to nucleotides 22 to 46 of exon 6 of SMN1 and / or SMN2 (e.g., the sense strand of DNA or RNA).

[1231] Thus, oligonucleotides corresponding to SEQ ID NOs. 9, 11, 12, and / or 13 can be used in amplification reactions to amplify nucleotides encoding human SMN1 and / or SMN2 or encoded by human SMN1 and / or SMN2 and lacking exon 7 of human SMN1 and / or SMN2, and to amplify nucleotides encoding human SMN1 and / or SMN2 or encoded by human SMN1 and / or SMN2 and including exon 7 of human SMN1 and / or SMN2. Conversely, an oligonucleotide corresponding to SEQ ID NO. 8 together with a downstream reverse primer (e.g., SEQ ID NO. 9 or 12) can be used to amplify nucleotides encoding human SMN1 and / or SMN2 or encoded by human SMN1 and / or SMN2 and lacking exon 7 of human SMN1 and / or SMN2, and oligonucleotides corresponding to SEQ ID NOs. 1 and 7 together with a downstream reverse primer (e.g., SEQ ID NO. 9 or 12) can be used to amplify nucleotides encoding human SMN1 and / or SMN2 or encoded by human SMN1 and / or SMN2 and including exon 7 of human SMN1 and / or SMN2.

[1232] SEQ ID NO. 3 hybridizes to a nucleic acid sequence (e.g., the sense strand of a DNA) comprising nucleotides corresponding, in sequence, to nucleotides 50 to 54 of exon 7 of human SMN1 and / or SMN2 and nucleotides 1 to 21 of exon 8 of human SMN1 and / or SMN2, and SEQ ID NO. 10 hybridizes to a nucleic acid sequence (e.g., the sense strand of a DNA) comprising nucleotides corresponding to nucleotides 7 to 36 of exon 8 of human SMN1 and / or SMN2. SEQ ID NO. 3 is used as a probe to detect mRNA transcribed from a minigene and including exon 7 of SMN1 and / or SMN2 (described herein or in International Publication No. WO 2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833, the entire contents of each of which are incorporated herein by reference), and to detect mRNA transcribed from human SMN1 and / or SMN2 and including exon 7 of SMN1 and / or SMN2. In addition, SEQ ID NO. 10 is used as a probe to detect mRNA transcribed from a minigene and including or excluding exon 7 of SMN1 and / or SMN2, and to detect mRNA transcribed from human SMN1 and / or SMN2 (described herein or in International Publication No. WO 2009 / 151546 or U.S. Patent Application Publication No. 2011 / 0086833, the entire contents of each of which are incorporated herein by reference).

[1233] In a specific embodiment, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NOs. 1, 7, 11, or 13 and / or SEQ ID NOs. 2, 9, or 12, and / or SMN probes such as SEQ ID NOs. 3 or 10) are used in assays, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, and, where applicable, Northern or Southern blotting (e.g., such as the assays described in the Biological Examples below), to determine whether a compound (e.g., a compound of Formula (I) or a form thereof) enhances the inclusion of exon 7 of SMN1 and / or SMN2 into mRNA transcribed from the smn1 and / or SMN2 genes.

[1234] In another embodiment, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NOs. 1, 7, 11, or 13 and / or SEQ ID NOs. 2, 9, or 12, and / or SMN probes such as SEQ ID NOs. 3 or 10) are used in assays, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, and, where applicable, Northern or Southern blotting (e.g., such as the assays described in the Biological Examples below), to monitor the amount of mRNA transcribed from the SMN1 and / or SMN2 gene and including exon 7 of SMN1 and / or SMN2 in a patient sample. In a specific embodiment, the patient is an SMA patient.

[1235] In another embodiment, the primers and / or probes described in the Biological Examples below (e.g., SMN primers such as SEQ ID NOs. 1, 7, 11, or 13 and / or SEQ ID NOs. 2, 9, or 12, and / or SMN probes such as SEQ ID NOs. 3 or 10) are used in assays, such as RT-PCR, RT-qPCR, end-point RT-PCR, PCR, qPCR, rolling circle amplification, and, where applicable, Northern or Southern blotting (e.g., such as the assays described in the Biological Examples below), to monitor a patient's response to a compound (e.g., a compound of Formula (I) or a form thereof). In a specific embodiment, the patient is a SMA patient.

[1236] Patient-derived samples (e.g., blood samples, PBMCs, or tissue samples such as skin or muscle tissue samples) can be obtained using techniques known to those skilled in the art, and the primers and / or probes described in the Biological Examples below can be used in assays (e.g., PCR, RT-PCR, RT-qPCR, qPCR, end-point RT-PCR, rolling circle amplification, Northern blot, or Southern blot) to determine the amount of mRNA transcribed from the SMN1 and / or SMN2 genes (e.g., the amount of mRNA transcribed from the SMN2 gene that includes exon 7 of SMN2). A patient-derived sample refers to a sample that has been processed and / or manipulated after being obtained from a patient using techniques known to those skilled in the art. For example, a patient-derived sample can be processed using techniques known to those skilled in the art to, for example, extract RNA. A patient-derived sample can be processed to, for example, extract RNA and reverse transcribe the RNA to produce cDNA. In one embodiment, the patient is an SMA patient.

[1237] In one embodiment, provided herein is a method for detecting the amount of mRNA transcribed from the SMN1 and / or SMN2 gene and including exon 7 of SMN1 and / or SMN2, comprising: (a) contacting a patient sample (e.g., a blood sample or tissue sample) or a sample derived from a patient (e.g., a blood sample or tissue sample that has been processed to extract RNA) with a forward SMN primer as described below (e.g., SEQ ID NOs. 1, 7, 11, or 13) and / or a reverse SMN primer as described herein (e.g., SEQ ID NOs. 9 or 12) along with components useful for, for example, RT-PCR (e.g., end-point RT-PCR and / or RT-qPCR), PCR (e.g., qPCR), or rolling circle amplification; and (b) detecting the amount of mRNA transcribed from the SMN1 and / or SMN2 gene and including exon 7 of SMN1 and / or SMN2. In some embodiments, the sample is from or derived from a patient administered a compound, such as a compound of Formula (I) as described herein, or a form thereof. In one embodiment, the patient is a patient with SMA.

[1238] In another specific embodiment, provided herein is a method for detecting the amount of mRNA transcribed from the SMN1 and SMN2 genes, comprising: (a) contacting a patient sample (e.g., a blood sample or tissue sample) or a patient-derived sample (e.g., a blood sample or tissue sample that has been processed to extract RNA) with a forward SMN primer as described below (e.g., SEQ ID NOs. 1, 7, 11, or 13) and / or a reverse SMN primer as described herein (e.g., SEQ ID NOs. 9 or 12) along with components useful for, for example, RT-PCR (e.g., end-point RT-PCR and / or RT-qPCR), PCR (e.g., qPCR), or rolling circle amplification; and (b) detecting the amount of mRNA transcribed from the SMN1 and SMN2 genes. In some embodiments, the sample is from or derived from a patient administered a compound, such as a compound of Formula (I) as described herein, or a form thereof. In one specific embodiment, the patient is a SMA patient.

[1239] The amount of mRNA transcribed from the human SMN1 and SMN2 genes and including exon 7 of SMN1 and SMN2 and the amount of mRNA transcribed from the human SMN1 and SMN2 genes but not including exon 7 of SMN1 and SMN2 can be distinguished from each other by, for example, the sizes of RNA or DNA fragments produced from SMN1 and SMN2 mRNA including exon 7 of SMN1 and SMN2 and from SMN1 and SMN2 mRNA not including exon 7 of SMN1 and SMN2.

[1240] In another specific embodiment, provided herein is a method for detecting the amount of mRNA transcribed from the SMN1 and / or SMN2 gene that does not include exon 7 of SMN1 and / or SMN2, comprising: (a) contacting a patient sample (e.g., a blood sample or tissue sample) or a sample derived from a patient (e.g., a blood sample or tissue sample that has been processed to extract RNA) with a forward SMN primer as described below (e.g., SEQ ID NOs. 8, 11, or 13) and / or a reverse SMN primer as described herein (e.g., SEQ ID NOs. 9 or 12) along with components useful for, for example, RT-PCR (e.g., end-point RT-PCR and / or RT-qPCR), PCR (e.g., qPCR), or rolling circle amplification; and (b) detecting the amount of mRNA transcribed from the SMN1 and / or SMN2 gene that does not include exon 7 of SMN1 and / or SMN2. In some embodiments, the sample is from or derived from a patient administered a compound, such as a compound of Formula (I) as described herein, or a form thereof. In one specific embodiment, the patient is a patient with SMA.

[1241] In another specific embodiment, provided herein is a method for detecting the amount of mRNA transcribed from the SMN1 and / or SMN2 gene and including exon 7 of SMN1 and / or SMN2, comprising: (a) contacting a patient sample (e.g., a blood sample or tissue sample) or a sample derived from a patient (e.g., a blood sample or tissue sample that has been processed to extract RNA) with an SMN probe as described below (e.g., SEQ ID NO. 3 or 10) together with components for, for example, RT-PCR (e.g., end-point RT-PCR and / or RT-qPCR), PCR (e.g., qPCR), or rolling circle amplification, and applicable Northern or Southern blotting; and (b) detecting the amount of mRNA transcribed from the SMN1 and / or SMN2 gene and including exon 7 of SMN1 and / or SMN2. In some embodiments, the sample is from or derived from a patient administered a compound, such as a compound of Formula (I) as described herein, or a form thereof. In one specific embodiment, the patient is a patient with SMA.

[1242] In another specific embodiment, provided herein is a method for detecting the amount of mRNA transcribed from SMN1 and SMN2 genes, comprising: (a) contacting a patient sample (e.g., a blood sample or tissue sample) or a sample derived from a patient (e.g., a blood sample or tissue sample that has been processed to extract RNA) with an SMN probe as described below (e.g., SEQ ID NO. 3 or 10) together with, for example, components for RT-PCR (e.g., end-point RT-PCR and / or RT-qPCR), PCR (e.g., qPCR) or rolling circle amplification, and applicable Northern or Southern blotting; and (b) detecting the amount of mRNA transcribed from the SMN1 and SMN2 genes.

[1243] The amount of mRNA transcribed from the human SMN1 and SMN2 genes and including exon 7 of SMN1 and SMN2 can be distinguished from the amount of mRNA transcribed from the human SMN1 and SMN2 genes and excluding exon 7 of SMN1 and SMN2 by, for example, the size of RNA or DNA fragments generated from SMN1 and SMN2 mRNA including exon 7 of SMN1 and SMN2 and from SMN1 and SMN2 mRNA excluding exon 7 of SMN1 and SMN2. In some embodiments, the sample is from or derived from a patient to whom a compound, such as a compound of Formula (I) as described herein, or a form thereof, is administered. In a specific embodiment, the patient is an SMA patient.

[1244] In another specific embodiment, provided herein is a method for detecting the amount of mRNA transcribed from the SMN1 and / or SMN2 gene and excluding exon 7 of SMN1 and / or SMN2, comprising: (a) contacting a patient sample (e.g., a blood sample or tissue sample) or a sample derived from a patient (e.g., a blood sample or tissue sample that has been processed to extract RNA) with an SMN probe as described below (e.g., SEQ ID NO. 10) together with components useful, for example, for RT-PCR (e.g., end-point RT-PCR and / or RT-qPCR), PCR (e.g., qPCR), rolling circle amplification, or Northern or Southern blotting; and (b) detecting the amount of mRNA transcribed from the SMN1 and / or SMN2 gene and excluding exon 7 of SMN1 and / or SMN2. In some embodiments, the sample is from or derived from a patient administered a compound, such as a compound of Formula (I) described herein, or a form thereof. In one specific embodiment, the patient is a patient with SMA.

[1245] In one embodiment, provided herein is a method for detecting the amount of mRNA transcribed from the SMN1 and / or SMN2 gene and including exon 7 of SMN1 and / or SMN2, comprising: (a) contacting a patient sample (e.g., a blood sample or tissue sample) or a sample derived from a patient (e.g., a blood sample or tissue sample that has been processed to extract RNA) with a forward SMN primer as described below (e.g., SEQ ID NOs. 1, 7, 11, or 13) and / or a reverse SMN primer as described herein (e.g., SEQ ID NOs. 9 or 12) and / or an SMN probe as described herein (e.g., SEQ ID NOs. 3 or 10) together with components useful for, for example, RT-PCR (e.g., end-point RT-PCR and / or RT-qPCR), PCR (e.g., qPCR), or rolling circle amplificatio...

Claims

1. A compound of formula (IIa1) or a form thereof: in: R1 is a heterocyclic group selected from the group consisting of oxirane, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, isoxazolidinyl, isothiazolidinyl, oxazolidinyl, thiazolidinyl, triazolidinyl, oxadiazolidinyl, thiadiazolidinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, benzo[d][1,3]dioxolyl, 1,4-benzodioxanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, ( 3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl )-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c ]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2 -a]pyrazine-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazine-(1H)-yl, Hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl heterobicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, or 6,9-diazaspiro[4.5]decyl;. wherein R1 is optionally substituted with one, two or three R3 substituents and optionally substituted with one additional R4 substituent; or wherein R1 is optionally substituted with one, two, three or four R3 substituents; R2 is phenyl; wherein R2 is optionally substituted with one, two or three R6 substituents and optionally with one additional R7 substituent; R a is independently selected at each occurrence from hydrogen, halogen or C 1-8 alkyl; R b is hydrogen, halogen, C 1-8 Alkyl or C 1-8 Alkoxy; R c is hydrogen, halogen or C 1-8 alkyl; R3 is independently selected from cyano, halogen, hydroxy, oxo, C 1-8 Alkyl, halo-C 1-8 Alkyl, C 1-8 Alkyl-carbonyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl, C 1-8 Alkoxy-carbonyl, amino, C 1-8 Alkyl-amino, (C 1-8 alkyl)2-amino, amino-C 1-8 Alkyl, C 1-8 Alkyl-amino-C 1-8 Alkyl, (C 1-8 alkyl)2-amino-C 1-8 Alkyl, amino-C 1-8 Alkyl-amino, C 1-8 Alkyl-amino-C 1-8 Alkyl-amino, (C 1-8 Alkyl-amino-C 1-8 alkyl)2-amino, (C 1-8 alkyl)2-amino-C 1-8 Alkyl-amino, [(C 1-8 alkyl)2-amino-C 1-8 alkyl]2-amino, (C 1-8 Alkyl-amino-C 1-8 Alkyl)(C 1-8 alkyl)amino, [(C 1-8 alkyl)2-amino-C 1-8 Alkyl](C 1-8 Alkyl)amino, C 1-8 Alkoxy-C 1-8 Alkyl-amino, (C 1-8 Alkoxy-C 1-8 alkyl)2-amino, (C 1-8 Alkoxy-C 1-8 Alkyl)(C 1-8 Alkyl)amino, C 1-8 Alkyl-carbonyl-amino, C 1-8 Alkoxy-carbonyl-amino, hydroxy-C 1-8 Alkyl, Hydroxyl-C 1-8 Alkoxy-C 1-8 Alkyl, Hydroxyl-C 1-8 Alkyl-amino, (hydroxy-C 1-8 alkyl)2-amino or (hydroxy-C 1-8 Alkyl)(C 1-8 Alkyl)amino; R4 is C 3-14 Cycloalkyl, C 3-14 Cycloalkyl-C 1-8 Alkyl, C 3-14 Cycloalkyl-amino, aryl-C 1-8 Alkyl, Aryl-C 1-8 Alkoxy-carbonyl, aryl-sulfonyloxy-C 1-8 Alkyl, heterocyclyl or heterocyclyl-C 1-8 Alkyl; wherein each occurrence of C 3-14 Cycloalkyl, aryl and heterocyclyl are optionally substituted with one, two or three R5 substituents; R5 is independently selected from halogen, hydroxy, cyano, nitro, C 1-8 Alkyl, halo-C 1-8 Alkyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino or C 1-8 Alkyl-thio; R6 is independently selected from halogen, hydroxy, cyano, nitro, C 1-8 Alkyl, C 2-8 Alkenyl, halo-C 1-8 Alkyl, Hydroxyl-C 1-8 Alkyl, C 1-8 Alkoxy, halo-C 1-8 Alkoxy, C 1-8 Alkoxy-C 1-8 Alkyl, amino, C 1-8 Alkyl-amino, (C 1-8 Alkyl) 2-amino or C 1-8 Alkyl-thio; and R7 is C 3-14 Cycloalkyl, C 3-14 Cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.

2. The compound according to claim 1, wherein R1 is a heterocyclic group selected from the group consisting of azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3a R,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, pyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, and 6,9-diazaspiro[4.5]5] Decyl; wherein the heterocyclyl is optionally substituted by one, two or three R3 substituents in each case and optionally substituted by one further R4 substituent. .

3. The compound according to claim 1, wherein The form is selected from the free acid, free base, salt, isotopomer, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

4. The compound according to claim 3, wherein The salt is chloride, hydrobromide, hydrochloride, dihydrochloride, acetate, trifluoroacetate or trifluoroacetate.

5. A method for enhancing the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, comprising contacting a compound of claim 1 with a human cell.

6. The method of claim 5, wherein: The human cells are human cells from human spinal muscular atrophy patients.

7. A method for increasing the amount of Smn protein, comprising contacting the compound of claim 1 with human cells.

8. The method of claim 7, wherein: The human cells are human cells from human spinal muscular atrophy patients.

9. The compound according to claim 1, wherein The compound is selected from: 2-(4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(1,4-diazepan-1-yl)-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(3,3-dimethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, ,4-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(4-ethylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(1,4-diazepan-1-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(4-propylpiperazine-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(3,3-dimethylpiperazin-1-yl)-2-(4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(4-ethylpiperazine-1-yl)-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(1,4-diazepan-1-yl)-2-(3-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-phenyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(3S)-3-methylpiperazin-1-yl]-2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-fluoro-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-chlorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-chlorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(piperazin-1-yl)-2-[3-(trifluoromethyl)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(piperazin-1-yl)-2-[4-(trifluoromethyl)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-Fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-fluoro-7-(piperidin-4-ylamino)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-(dimethylamino)phenyl]-9-fluoro-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-(dimethylamino)phenyl]-9-fluoro-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(2-Fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 3-(3,4-dimethoxyphenyl)-8-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-(dimethylamino)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-(dimethylamino)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[3-(dimethylamino)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[3-(dimethylamino)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-(difluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-(difluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-Fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(2-fluoro-4,5-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(2-fluoro-4,5-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methoxy-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,5-difluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 4-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile 2-[3-Fluoro-5-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-Fluoro-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[2-methoxy-3-(trifluoromethyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,5-difluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(piperazin-1-yl)-2-[3-(trifluoromethoxy)phenyl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-methoxy-3-(trifluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-hydroxy-3-(trifluoromethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-methoxy-3-(trifluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[4-hydroxy-3-(trifluoromethoxy)phenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-Fluoro-4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(2,4-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(2,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[3-(difluoromethoxy)-4-methoxyphenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[3-(difluoromethoxy)-4-hydroxyphenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[3-(difluoromethoxy)-4-methoxyphenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[3-(Difluoromethoxy)-4-hydroxyphenyl]-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,5-difluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-chloro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-chloro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-ethoxy-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-ethoxy-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(2-methylpyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(4-aminopiperidin-1-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-5-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-5-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4,5-dimethoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(4-hydroxypiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-methoxy-3-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 3-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile 2-methoxy-5-[4-oxo-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile 2-(3-fluoro-4-hydroxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-ethoxy-3-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-Fluoro-4-methylphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-Fluoro-4-methylphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(3S)-3-aminopyrrolidin-1-yl]-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(3S)-3-(propan-2-ylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-(4-methyl-1,4-diazepan-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-methoxy-3-nitrophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-[3-fluoro-4-(methylsulfanyl)phenyl]-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-{[2-(methylamino)ethyl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,5-difluoro-4-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,5-difluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[4-(Dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(piperidin-4-ylamino)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-chloro-5-fluorophenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-chloro-5-fluorophenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(4-aminopiperidin-1-yl)-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-Fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)piperidin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-fluoro-3-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-fluoro-3-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-difluoro-5-methoxyphenyl)-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-difluoro-5-methoxyphenyl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(3-fluoro-4-methoxyphenyl)-2-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-(methylamino)pyrrolidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-{4-[(methylamino)methyl]piperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(3S)-3-aminopyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-{[(3R)-1-methylpyrrolidin-3-yl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one, 7-{4-[(dimethylamino)methyl]piperidin-1-yl}-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 3-Fluoro-5-{7-[(3S)-3-methylpiperazin-1-yl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}benzonitrile 3-Fluoro-5-[4-oxo-7-(piperazine-1-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl]benzonitrile 2-(3-fluoro-4-methoxyphenyl)-7-[(3'S,4'S)-4'-hydroxy-1,3'-dipyrrolidin-1'-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-Fluoro-4-methoxyphenyl)-7-{methyl[(3R)-pyrrolidin-3-yl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(1-methylpiperidin-4-yl)oxy]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(3S)-pyrrolidin-3-yloxy]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yloxy)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(1,4-diazepan-1-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-{methyl[(3R)-1-methylpyrrolidin-3-yl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl]-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1,2,5,6-tetrahydropyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-[(3aS,6aS)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-[(3aR,6aS)-5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-Fluoro-4-methoxyphenyl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(3aR,6aS)-5-ethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(3-fluoro-4-methoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-[(4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(2R)-2-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-[(3S)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[4-(dimethylamino)piperidin-1-yl]-2-(3-fluoro-4-methoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-9-methyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[4-(Cyclopropylamino)piperidin-1-yl]-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(3R)-3,4-dimethylpiperazin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)piperidin-1-yl]-9-ethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrimido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(methylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[4-(ethylamino)piperidin-1-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-8-methyl-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[1-(propane-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[4-(methylamino)cyclohex-1-en-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[4-(dimethylamino)cyclohex-1-en-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-{4-[ethyl(methyl)amino]cyclohex-1-en-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-{4-[methyl(propyl)amino]cyclohex-1-en-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(1-cyclobutyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-[1-(oxetane-3-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-[1-(propan-2-yl)-1,2,3,6-tetrahydropyridin-4-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-8-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-8-methyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrimido[1,2-b]pyridazin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one, 2-(3-fluoro-4-methoxyphenyl)-7-(piperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[cis-4-(methylamino)cyclohexyl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-(piperidin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(propylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(propan-2-ylamino)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-methyl-7-[4-(morpholin-4-yl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-{4-[(2-hydroxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-methylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[4-(diethylamino)piperidin-1-yl]-2-(3,4-dimethoxyphenyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-ethyl-7-(1-ethylpiperidin-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-{4-[(2-hydroxyethyl)(methyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-ethyl-7-[(3R)-3-methylpiperazin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-9-ethyl-7-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-{4-[(2-methoxyethyl)amino]piperidin-1-yl}-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-{4-[(dimethylamino)methyl]piperidin-1-yl}-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(3,4-dimethoxyphenyl)-7-[4-(piperidin-1-ylmethyl)piperidin-1-yl]-4H-pyrido[1,2-a]pyrimidin-4-one, 7-(3-aminoprop-1-yn-1-yl 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[3-(Dimethylamino)propyl]-2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-{[2-(dimethylamino)ethyl]amino}-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-{[2-(dimethylamino)ethyl](methyl)amino}-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-{methyl[2-(methylamino)ethyl]amino}-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[2-(Dimethylamino)ethoxy]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 7-[2-(Dimethylamino)ethoxy]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-(piperidin-4-ylmethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[2-(piperidin-1-yl)ethoxy]-4H-pyrido[1,2-a]pyrimidin-4-one, 2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-7-[3-(morpholin-4-yl)propoxy]-4H-pyrido[1,2-a]pyrimidin-4-one, or 7-[3-(dimethylamino)propoxy]-2-(4-ethyl-6-methylpyrazolo[1,5-a]pyrazin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, or a salt, isotope, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.

10. A method for enhancing the inclusion of exon 7 of SMN2 into mRNA transcribed from the SMN2 gene, comprising contacting a compound of claim 9 with a human cell.

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