Fused pyrimidine compounds as KCC2 regulator

Abstract

To provide novel compounds which activate KCC2 and are therefore useful in treating neuropathy.SOLUTION: The invention concerns compounds of Formula (I) or pharmaceutically acceptable salts thereof; process for their preparation; pharmaceutical compositions containing them and their use in treating KCC2 mediated diseases.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention generally relates to fused aminopyrimidine compounds and their pharmaceutically acceptable salts.These compounds and their pharmaceutically acceptable salts selectively regulate KCC2, and therefore the present invention also relates to the use of such compounds and their salts for treating or preventing KCC2-mediated diseases, including neuropathies.The present invention further relates to pharmaceutical compositions containing such compounds and salts; methods for producing such compounds and salts; and methods for treating KCC2-mediated diseases, including neuropathies, using such compounds and salts. [Background technology]

[0002] KCC2 is an electroneutral membrane transporter encoded by the SLC12A5 gene and plays an important role in inhibitory neurotransmission. KCC2 transports K across the neuronal membrane. + and Cl - It couples the efflux of ions and maintains a low intracellular chloride concentration. Low intracellular chloride levels are essential for GABA A It is essential for receptor-mediated signaling, and ligand-dependent Cl release is required to hyperpolarize the neuronal membrane, resulting in inhibition of action potential firing. - It is similarly dependent on the influx of ions.

[0003] GABA ASignal transduction is the major inhibitory neurotransmitter mechanism in the adult brain, and as such, KCC2 has an important role in normal neurodevelopment and in a variety of neurological disorders. Decreased KCC2 activity has been implicated in conditions involving neuronal hyperexcitability, such as epilepsy (Galanopoulou et al., Epilepsia 2007;48:14-18; Huberfield et al., The Journal of Neuroscience (2007) 27, 9866-9873), neuropathic pain (Price et al., Curr Top Med Chem 2005;5:547-555), Rett syndrome (Tang et al., 2019, Translational Medicine, 11(503)), autism (Tyzio et al., Science 343, 675-679; Merner et al., Frontiers in cellular neuroscience 9, 2015), psychiatric disorders, spinal cord injury (Boulenguez et al., Nature Medicine 2010, 16, 302-307), and ALS (Fuchs et al., Journal of Neuropathology & Experimental Neurology, Volume 11, 2019). 69, Issue 10, October 2010, Pages 1057-1070).

[0004] Increasing the expression level or activity of KCC2 is a therapeutic approach for treating diseases related to neuronal hyperexcitation. KCC2 is preferentially expressed in neuronal cells, making it an ideal drug target for neurological disorders.

[0005] Genetic knockdown of KCC2 in mice results in network hyperexcitability and spontaneous seizure activity (Hubner et al, Neuron 2001:30:515-524; Woo et al, Hippocampus 2002; 12:258-268).

[0006] Mutations in the KCC2 gene have been found in human patients with epilepsy (Duy et al, Front Cell Neurosci. 2019; 13: 515), strengthening the link between KCC2 dysfunction and epilepsy and suggesting Cl - This study supports the approach of KCC2 activation as a means to increase release and restore GABA inhibition, treating disorders such as refractory epilepsy and status epilepticus.

[0007] Status epilepticus can be caused by neurological substances (de Araujo Furtado et al, 2012, NeuroToxicology, 33(6), 1476-1490), and activation of KCC2 is a potential therapeutic option.

[0008] Recently, it has been shown that enhancing KCC2 activity by genetic modification of the regulatory sites for KCC2 activity is sufficient to limit the onset and severity of epilepsy in mice (Moore et al, Proc Natl Acad Sci USA. 2018 Oct 2; 115(40): 10166-10171).

[0009] KCC2 activity is regulated by phosphorylation at numerous regulatory sites, including T1007 by STK39 and OSR1 (Cordshagen et al, Journal of Biological Chemistry 2018, 293, 16984-16993). KCC2 cell surface expression is controlled by phosphorylation of S940.

[0010] Direct regulation of KCC2 through interaction with small molecules has been reported. Delpire et al. describe an assay for identifying small molecule inhibitors of KCC2 (Proc Natl Acad Sci USA. 2009 Mar 31; 106(13): 5383-5388), and Zhang et al. describe an assay used to identify positive regulators of KCC2 (Journal of Biomolecular Screening 15(2): 2010).

[0011] There is a need for novel compounds that activate KCC2 and are thereby useful in the treatment of neurological disorders. Summary of the Invention

[0012] Briefly, the present invention relates in part to a compound of formula (I): [ka] [During the ceremony, R 1 is C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy;C 2-6 Alkenyloxy;C 2-6 Alkynyloxy;C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thiophenyl; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3, and said aryl and heteroaryl are selected from -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein said -C 1-3 Alkyl, -C1-8 Alkoxy and -C 2-8 Alkynyloxy is -F, -CF3, -NHC(O)OC 1-6 optionally substituted with 1, 2, or 3 substituents selected from alkyl, or two substituents which together with the connecting carbon form diazirinyl; R 2 is -C optionally substituted with 1, 2, or 3 substituents selected from -H; -halo; and -F and -CF 1-3 alkyl; A is [ka] and [ka] or an N-oxide thereof; R 3 is -H;-C 1-6 Alkyl;-C 2-6 Alkenyl;-C 2-6 Alkynyl; C 3-7 cycloalkyl; and 5- or 6-membered heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is selected from -F, -CF3, -F, -CF3, -C(O)NR 8 R 9 and -NR 8 R 9 -C optionally substituted with one or two substituents selected from 1-3 optionally substituted with 1, 2, or 3 groups selected from alkyl; R 4a and R 4b are each independently —C optionally substituted with 1, 2, or 3 substituents selected from —H and —F and —CF 1-3 alkyl; R 4c and R 4dare each independently —C optionally substituted with 1, 2, or 3 substituents selected from —H and —F and —CF 1-3 alkyl, or R 4c and R 4d together with the carbon to which they are attached represent a carbonyl; R 5a , R 5b , R 5c and R 5d are each independently —C optionally substituted with 1, 2, or 3 substituents selected from —H and —F and —CF 1-3 alkyl; R 6 is -C optionally substituted with 1, 2 or 3 substituents selected from -H; -halo; -NH2; -CN; -F and -CF3; 1-3 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9 -C(O)OH; and -NHC(O)-C 1-3 alkyl; R 7 is NR 10 R 11 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, or three substituents selected from -CN; -F, -CF3, and -OH. 1-6 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl;-C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl; C 3-5or said heterocycloalkyl may be optionally substituted with two substituents on the same ring carbon, which together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic heterocycloalkyl; wherein R 7 is morpholinyl and R 1 When is unsubstituted phenyl, R 2 is - not H; R 8 and R 9 are each independently -H and -C 1-6 alkyl; R 10 Ha-C 1-6 is alkyl; R 11 -F and -C 1-3 -C optionally substituted with 1 or 2 substituents selected from alkoxy 1-6 Alkyl; and -(CH2) n R 12 Selected from; R 12 is a 5- or 6-membered heteroaryl, a 3- to 5-membered cycloalkyl, or a 3- to 6-membered heterocycloalkyl; m is 0 or 1; n is 1, 2, or 3. or a pharmaceutically acceptable salt thereof.

[0013] This invention also relates, in part, to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable diluent or carrier.

[0014] This invention also pertains, in part, to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

[0015] This invention also pertains, in part, to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurological disorder.

[0016] This invention also pertains, in part, to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a neurological disorder.

[0017] This invention also relates, in part, to a method for treating neurological disorders in a warm-blooded animal comprising administering to the animal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0018] Further aspects of the present invention will be apparent to those skilled in the art upon reading this specification.

[0019] Detailed Description of the Invention Many embodiments are described throughout this specification and will be apparent to those skilled in the art, and this specification should not be understood as limiting any particular embodiment described herein.

[0020] In one embodiment, formula (I): [ka] [During the ceremony, R 1 is C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy;C 2-6 Alkenyloxy;C 2-6 Alkynyloxy;C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thiophenyl; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; and wherein said aryl and heteroaryl are selected from -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8alkynyloxy, wherein said -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy includes -F, -CF3 and -NHC(O)OC 1-6 optionally substituted with 1, 2, or 3 substituents selected from alkyl, or two substituents which together with the attaching carbon atom form diazirinyl; R 2 is -C optionally substituted with 1, 2, or 3 substituents selected from -H; -halo; and -F and -CF 1-3 is alkyl; A is [ka] and [ka] or an N-oxide thereof; R 3 is -H;-C 1-6 Alkyl;-C 2-6 Alkenyl;-C 2-6 Alkynyl;-C 3-7 cycloalkyl; and 5- or 6-membered heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is selected from -F, -CF3, and -F, -CF3, -C(O)NR 8 R 9 and -NR 8 R 9 -C optionally substituted with one or two substituents selected from 1-3 optionally substituted with 1, 2, or 3 groups selected from alkyl; R 4a and R 4b are each independently —C optionally substituted with 1, 2, or 3 substituents selected from —H and —F and —CF 1-3 alkyl; R 4c and R 4d are each independently —C optionally substituted with 1, 2, or 3 substituents selected from hydrogen and —F and —CF 1-3 alkyl; or R 4c and R 4d together with the carbon to which they are attached represent a carbonyl; R 5a , R 5b , R 5c and R 5d are each independently —C optionally substituted with 1, 2, or 3 substituents selected from —H and —F and —CF 1-3 alkyl; R 6 is -C optionally substituted with 1, 2 or 3 substituents selected from -H; -halo; -NH2; -CN; -F and -CF3; 1-3 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9 -C(O)OH; and -NHC(O)-C 1-3 alkyl; R 7 is -NR 10 R 11 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, or three substituents selected from -CN; -F, -CF3, and -OH. 1-6 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl;-C 1-3 Alkylene-NHC(O)OC 1-6alkyl; and C 3-5 cycloalkyl; or heterocycloalkyl may be optionally substituted with two substituents on the same ring carbon, which together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic heterocycloalkyl; where R 7 is morpholinyl and R 1 When is unsubstituted phenyl, R 2 is - not H; R 8 and R 9 are each independently -H and -C 1-6 alkyl; R 10 Ha-C 1-6 is alkyl; R 11 -F and -C 1-3 -C optionally substituted with 1 or 2 substituents selected from alkoxy 1-6 Alkyl; and -(CH2) n R 12 Selected from; R 12 is a 5- or 6-membered heteroaryl, a 3- to 5-membered cycloalkyl, or a 3- to 6-membered heterocycloalkyl; m is 0 or 1; n is 1, 2, or 3. or a pharmaceutically acceptable salt thereof.

[0021] In the present description, unless otherwise specified, the term "alkyl" includes both straight and branched chain alkyl groups. p-q The prefix C in alkyl and other terms p-q (where p and q are integers) indicates the range of carbon atoms present in the group, e.g., C 1-3 Alkyl includes C1 alkyl (methyl), C2 alkyl (ethyl) and C3 alkyl (propyl as n-propyl and isopropyl).

[0022] The term “C p-q "Alkoxy" is -OCp-q -C alkyl group and O atom present in the alkyl chain p-q Contains alkyl groups, for example, -CH2-O-CH3.

[0023] The term “C p-q "Alkenyl" includes both straight and branched chain alkyl groups containing at least two carbon atoms and at least one carbon-carbon double bond.

[0024] The term “C p-q "Alkenyloxy" is -OC p-q -C where the alkenyl group and O atom are present in the alkenyl chain p-q Contains alkenyl groups.

[0025] The term “C p-q "Alkynyl" includes both straight and branched chain alkyl groups containing at least two carbon atoms and at least one carbon-carbon triple bond.

[0026] The term “C p-q "Alkynyloxy" is -OC p-q -C where alkynyl group and O atom are present in the alkynyl chain p-q Contains alkynyl groups.

[0027] C p-q Cycloalkyl refers to a cyclic non-aromatic group of p to q carbon atoms and no heteroatoms. For example, a 3- to 7-membered cycloalkyl refers to a ring containing 3 to 7 carbon atoms. 3-7 Cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0028] Aryl is a 6-10 membered monocyclic or bicyclic aromatic ring containing no heteroatoms. Aryl includes phenyl.

[0029] Heterocycloalkyl is a monocyclic saturated or partially unsaturated non-aromatic ring having, for example, 3 to 7 members, for example, 3 to 6 members, 5 to 7 members, for example, 5 or 6 members, in which at least one ring member and up to four ring members, particularly 1, 2, or 3 ring members, of the ring are heteroatoms selected from N, O, and S, and the remaining atoms are carbon atoms, in a stable combination known to those skilled in the art. The nitrogen and sulfur atoms of the heterocycloalkyl ring may optionally be oxidized. Suitable heterocycloalkyl rings include morpholinyl, thiazolidinyl, homomorpholine, tetrahydropyranyl, pyrrolyl, thiomorpholinyl, and tetrahydrofuranyl. In certain embodiments, R 7 When R is heterocycloalkyl, it may be substituted with two substituents on the same ring carbon, which, together with the carbon to which they are attached, form a 5- to 7-membered heterocycloalkyl ring, thereby forming a spirocyclic ring system. For example, in some embodiments, R 7 is morpholinyl, which, together with two substituents on the same ring carbon, forms a tetrahydropyran.

[0030] Heteroaryl is a polyunsaturated monocyclic 5- or 6-membered aromatic ring containing at least one and up to three heteroatoms, particularly one or two heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon atoms. The nitrogen and sulfur atoms of the heteroaryl ring may optionally be oxidized. Suitable heteroaryl rings include pyridinyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazinyl, oxazolyl, thiophenyl, and thiazolyl.

[0031] The term "halo" refers to fluorine, chlorine or bromine.

[0032] The use of the dashed bond "---" in ring A of formula (I) represents the fusion of a pyrimidine ring.

[0033] When the term "optionally" is used, it is intended that the subsequently described feature may or may not occur. As such, use of the term "optionally" includes instances where the feature is present and instances where the feature is not present. For example, a group "optionally substituted with 1, 2, or 3 -F substituents" includes groups with and without -F substituents.

[0034] The term "substituted" means that one or more hydrogens (e.g., one or two hydrogens, or one hydrogen) in the specified group are replaced with the indicated substituents (e.g., one, two, or three substituents, or one or two substituents, or one substituent), provided that any atom bearing a substituent maintains an allowed valence. Substituent combinations encompass only stable compounds and stable synthetic intermediates. "Stable" means that the relevant compound or intermediate is sufficiently robust to be isolated and has utility as a synthetic intermediate or an agent with potential therapeutic utility. If a group is not described as "substituted" or "optionally substituted," it should be considered unsubstituted (i.e., none of the hydrogens in the specified group are replaced).

[0035] The term "pharmaceutically acceptable" is used to specify that an object (e.g., a salt, dosage form, or excipient) is appropriate for use in patients. A list of examples of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.H. Stahl and C.G. Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.

[0036] Suitable pharmaceutically acceptable salts of compounds of formula (I) are, for example, salts formed in the human or animal body after administration of a compound of formula (I) to said body.

[0037] Further embodiments provide any of the embodiments defined herein (e.g., embodiments of claim 1), except that Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, One or more specific embodiments (e.g., one, two, or three specific embodiments) selected from the group consisting of 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, and 114 are individually disclaimed.

[0038] The following embodiments of Moiety A may be applied to the description of compounds of Formula (I) provided herein: A is: [ka] and [ka] or an N-oxide thereof.

[0039] In certain embodiments, A is [ka] is.

[0040] In certain embodiments, A is [ka] is.

[0041] In certain embodiments, A is [ka] is.

[0042] In certain embodiments, A is [ka] is.

[0043] In certain embodiments, A is [ka] is.

[0044] In some embodiments, a compound of formula (II): [ka] [In the formula, R 1 , R 2 , R 3 , R 4a , R 4b and R 7 is as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, R 1 , R 2 , R 3 , R 4a , R 4b and R 7 is as defined for formula (I), and R 7 When is morpholinyl: R 1 is C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy;C 2-6 Alkenyloxy;C 2-6 Alkynyloxy;C 3-7Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thiophenyl; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; heteroaryl is selected from -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein said -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy is -F, -CF3, -NHC(O)OC 1-6 aryl is optionally substituted by one, two or three substituents selected from alkyl, or two substituents which together with the carbon atoms to which they are attached form diazirinyl; aryl is optionally substituted by one, two or three substituents selected from -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein the —C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy is -F, -CF3, -NHC(O)OC 1-6 optionally substituted with one, two, or three substituents selected from alkyl, or two substituents which together with the carbon atom to which they are attached form diazirinyl; R 2 is optionally substituted with 1, 2, or 3 substituents selected from -H; -halo; and -F and -CF 1-3 alkyl; or R 1 is C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6Alkoxy;C 2-6 Alkenyloxy;C 2-6 Alkynyloxy;C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thiophenyl; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; heteroaryl is selected from -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein said -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy is -F, -CF3, -NHC(O)OC 1-6 optionally substituted with one, two, or three substituents selected from alkyl, or two substituents which together with the carbon atom to which they are attached form diazirinyl; R 2 is -C optionally substituted with 1, 2 or 3 substituents selected from -halo, -F and -CF 1-3 selected from alkyl The present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0046] In one embodiment: R 1 But -C 2-6 Alkyl;-C 2-6 Alkoxy;C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8phenyl optionally substituted with 1 or 2 substituents selected from alkynyloxy, wherein said -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy is -F, -CF3, -NHC(O)OC 1-6 alkyl or two substituents which, together with the attached carbon atom, form diazirinyl; -O-phenyl optionally substituted with one or two halo substituents; -O-CH2-phenyl; and thiophenyl; wherein said -C 2-6 Alkyl and -C 2-6 The alkoxy may be optionally substituted with 1, 2, or 3 substituents selected from -F and -CF3; R 2 is selected from -H, -F and -CH3; R 3 But -C 2-4 Alkynyl and optionally -NR 8 R 9 may be substituted with -C 1-3 alkyl; R 4a and R 4b are both -H; R 7 Ga-NR 10 R 11 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, or three substituents selected from -CN; -F, -CF3, and -OH. 1-3 Alkyl;-C 1-3 Alkoxy;Cyclopropyl;-C(O)OH;-C 1-3 Alkylene-NHC(O)C 1-6 Alkyl;-C 1-3 Alkylene-NHC(O)OC 1-6alkyl; or heterocycloalkyl may be optionally substituted with two substituents on the same ring carbon, which, together with the carbon atom to which they are attached, form a 6-membered monocyclic heterocycloalkyl; R 8 and R 9 However, each independently, -C 1-6 alkyl; R 10 Ga-C 1-3 alkyl; R 11 But -F and -C 1-3 -C optionally substituted with 1 or 2 substituents selected from alkoxy 1-3 Alkyl; and -(CH2) n R 12 Selected from; R 12 is selected from 5- or 6-membered heteroaryl, 3- to 5-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; n is 1 or 2 The present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0047] In one embodiment: R 1 But -C 2-6 Alkyl;-C 2-6 Alkoxy;C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 phenyl substituted with one or two substituents selected from alkynyloxy, wherein said -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy is -F, -CF3, -NHC(O)OC 1-6alkyl or two substituents which, together with the attached carbon atom, form diazirinyl; -O-phenyl optionally substituted with one or two halo substituents; -O-CH2-phenyl; and thiophenyl; wherein said -C 2-6 Alkyl and -C 2-6 Alkoxy may be optionally substituted with 1, 2, or 3 substituents selected from -F and -CF3; R 2 is selected from -H, -F and -CH3; or R 1 But -C 2-6 Alkyl;-C 2-6 Alkoxy;C 3-7 Cycloalkyl; -OC 3-7 cycloalkyl; unsubstituted phenyl; -O-phenyl optionally substituted with one or two -halo substituents; -O-CH2-phenyl; and thiophenyl; wherein said -C 2-6 Alkyl and -C 2-6 Alkoxy may be optionally substituted with 1, 2, or 3 substituents selected from -F and -CF3; R 2 is selected from -F and -CH3; R 3 But -C 2-4 Alkynyl and optionally -NR 8 R 9 may be substituted with -C 1-3 alkyl; R 4a and R 4b are both -H; R 7 But, -NR 10 R 11 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein said heterocycloalkyl and heteroaryl are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, and -OH. 1-3 Alkyl;-C 1-3 Alkoxy;Cyclopropyl;-C(O)OH;-C1-3 Alkylene-NHC(O)C 1-6 Alkyl;-C 1-3 Alkylene-NHC(O)OC 1-6 alkyl; or heterocycloalkyl may be optionally substituted with two substituents on the same ring carbon, which, together with the carbon atom to which they are attached, form a 6-membered monocyclic heterocycloalkyl; R 8 and R 9 However, each independently, -C 1-6 alkyl; R 10 But -C 1-3 alkyl; R 11 But -F and -C 1-3 -C optionally substituted with 1 or 2 substituents selected from alkoxy 1-3 Alkyl; and -(CH2) n R 12 Selected from; R 12 is selected from 5- or 6-membered heteroaryl, 3- to 5-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; n is 1 or 2 10. The compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0048] In some embodiments, a compound of formula (III): [ka] [In the formula, R 1 , R 2 , R 5a , R 5b , R 5c , R 5d and R 7 is as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment: R1 But C 3-7 Cycloalkyl and C 6-10 aryl, wherein said aryl is optionally selected from -C 2-8 substituted with an alkoxy substituent, wherein said alkoxy is optionally substituted with one or two -CF3 substituents; R 2 is -H; R 5a , R 5b , R 5c and R 5d are -H, respectively; R 7 But, -NR 10 R 11 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, or three substituents selected from -CN; -F, -CF3, and -OH. 1-6 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl;-C 1-3 Alkylene-NHC(O)OC 1-6 alkyl; and C 3-5 cycloalkyl; or heterocycloalkyl may be optionally substituted with two substituents on the same ring carbon, which together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic heterocycloalkyl; where R 7 is morpholinyl and R 1 When is unsubstituted phenyl, R 2 is not -H The present invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein:

[0050] In one embodiment: R 1 But C3-7 Cycloalkyl and C 6-10 aryl, wherein said aryl is optionally selected from -C 2-8 substituted with an alkoxy substituent, wherein said alkoxy is optionally substituted with one or two -CF3 substituents; R 2 is -H; R 5a , R 5b , R 5c and R 5d are -H, respectively; R 7 is selected from 5- to 7-membered monocyclic heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl, wherein said heterocycloalkyl and heteroaryl are optionally substituted with 1, 2, or 3 substituents selected from -F and -OH; 1-3 alkyl; and cyclopropyl. The present invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein:

[0051] In some embodiments, a compound of formula (IV): [ka] [In the formula, R 1 , R 2 , R 6 and R 7 is as defined for formula (I). or an N-oxide or a pharmaceutically acceptable salt thereof.

[0052] In one embodiment: R 1 is optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 3-7 cycloalkyl; R 2is optionally substituted with 1, 2, or 3 substituents selected from -H; -halo; and -F and -CF 1-3 alkyl; R 6 is optionally substituted with 1, 2 or 3 substituents selected from -H; -halo; -NH2; -CN; -F and -CF3; 1-3 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9 -C(O)OH; and -NHC(O)-C 1-3 alkyl; R 7 But, -NR 10 R 11 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, or three substituents selected from -CN; -F, -CF3, and -OH. 1-6 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl;-C 1-3 Alkylene-NHC(O)OC 1-6 alkyl; and C 3-5 cycloalkyl; or heterocycloalkyl may be optionally substituted with two substituents on the same ring carbon, which, together with the carbon atom to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl; R 8 and R 9 each independently represents -H and -C 1-6 alkyl; R 10 But -C1-6 is alkyl; R 11 But -F and -C 1-3 -C optionally substituted with 1 or 2 substituents selected from alkoxy 1-6 Alkyl; and -(CH2) n R 12 Selected from; R 12 is a 5- or 6-membered heteroaryl, a 3- to 5-membered cycloalkyl, or a 3- to 6-membered heterocycloalkyl; n is 1, 2, or 3 The present invention provides a compound of formula (IV) or an N-oxide or pharmaceutically acceptable salt thereof, wherein:

[0053] In one embodiment: R 1 is optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 3-7 cycloalkyl; R 2 is -H; R 6 is optionally substituted with 1, 2 or 3 substituents selected from -H; -halo; -NH2; -CN; -F and -CF3; 1-3 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9 -C(O)OH; and -NHC(O)-C 1-3 alkyl; R 7 is optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; 1-6 alkyl; and C 3-5 cycloalkyl; 5-7 membered monocyclic heterocycloalkyl optionally substituted with 1, 2, or 3 groups; R 8and R 9 each independently represents -H and -C 1-6 selected from alkyl The present invention provides a compound of formula (IV) or an N-oxide or pharmaceutically acceptable salt thereof, wherein:

[0054] Part R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 5 , R 6a , R 6b , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 The following embodiments of m and n may be applied alone or in combination to the description of compounds of formula (I) provided herein: 1 , R 2 , R 3 , R 4a , R 4b , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 The following embodiments of m and n may be applied alone or in combination to the description of compounds of formula (II) provided herein: 1 , R 2 , R 5a , R 5b , R 5c , R 5d , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 The following embodiments of m and n may be applied alone or in combination to the description of compounds of formula (III) provided herein: 1 , R 2 , R 6 , R 7 , R 8, R 9 , R 10 , R 11 , R 12 The following embodiments of m and n may be applied alone or in combination to the description of compounds of formula (IV) provided herein.

[0055] R 1 is C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy;C 2-6 Alkenyloxy;C 2-6 Alkynyloxy;C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thiophenyl; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3, and wherein said aryl and heteroaryl are selected from -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein said -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy includes -F, -CF3 and -NHC(O)OC 1-6 It may be optionally substituted with 1, 2 or 3 substituents selected from alkyl, or two substituents which together with the connecting carbon atom form diazirinyl.

[0056] In some embodiments, R 1 is C 2-6 Alkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 2-6 Alkoxy;C2-6 Alkenyloxy;C 2-6 Alkynyloxy;C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 aryl; 6-membered heteroaryl; and thiophenyl; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3, and wherein said -O-(CH2) m -C 6-10 Aryl and heteroaryl include -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein said -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy includes -F, -CF3 and -NHC(O)OC 1-6 optionally substituted with 1, 2 or 3 substituents selected from alkyl, or two substituents which together with the carbon atom to which they are attached form diazirinyl; C 6-10 Aryl is -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein the —C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy includes -F, -CF3 and -NHC(O)OC 1-6 It may be optionally substituted with 1, 2 or 3 substituents selected from alkyl, or two substituents which together with the connecting carbon atom form diazirinyl.

[0057] In some embodiments, R 1 is C 2-6Alkyl; C 2-6 Alkoxy;C 3-7 Cycloalkyl; -OC 3-7 Cycloalkyl; C 6-10 Aryl; -O-(CH2) m -C 6-10 wherein said alkyl, alkoxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3, and wherein said aryl is selected from -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein said -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy includes -F, -CF3 and -NHC(O)OC 1-6 It may be optionally substituted with 1, 2 or 3 substituents selected from alkyl, or two substituents which together with the connecting carbon atom form diazirinyl.

[0058] In some embodiments, R 1 is a C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 2-6 Alkyl; C 2-4 Alkoxy;C 4-6 Cycloalkyl; -OC 4-6 Cycloalkyl; Phenyl; -O-(CH2) m -phenyl; and thiophenyl; wherein said phenyl is selected from -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein said -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy includes -F, -CF3 and -NHC(O)OC 1-6It may be optionally substituted with 1, 2 or 3 substituents selected from alkyl, or two substituents which together with the connecting carbon atom form diazirinyl.

[0059] In some embodiments, R 1 is a C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 2-6 Alkyl; C 2-4 Alkoxy;C 4-6 Cycloalkyl; -OC 4-6 Cycloalkyl; Phenyl; -O-(CH2) m -phenyl; and thiophenyl; wherein said O—(CH2) m -phenyl, -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein said -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy includes -F, -CF3 and -NHC(O)OC 1-6 phenyl is optionally substituted by one, two or three substituents selected from alkyl, or two substituents which together with the carbon atom to which they are attached form diazirinyl; phenyl is optionally substituted by one, two or three substituents selected from -halo, -C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 alkynyloxy, wherein the —C 1-3 Alkyl, -C 1-8 Alkoxy and -C 2-8 Alkynyloxy includes -F, -CF3 and -NHC(O)OC 1-6 It may be optionally substituted with 1, 2 or 3 substituents selected from alkyl, or two substituents which together with the connecting carbon atom form diazirinyl.

[0060] In some embodiments, R 1is selected from -CFCF; propyl; butyl; pentyl; propoxy; cyclobutyl; cyclohexyl; -O-cyclopentyl; thiophenyl; phenyl; -O-phenyl; -O-CH-phenyl; wherein said phenyl is optionally substituted by one or two substituents selected from -F, -Cl, -CH, -O-(CH)C≡CH, -O-(CH), -O-(CH)C(N=N)(CH)C≡CH, -O-(CH)NHC(O)OC(CH), -O-CHC≡CH, -O-(CH)CF and -O-(CH).

[0061] In some embodiments, R 1 is a phenyl substituted by one or two substituents selected from -CF2CF3; propyl; butyl; pentyl; propoxy; cyclobutyl; cyclohexyl; -O-cyclopentyl; thiophenyl; -F, -Cl, -CH3, -O-(CH2)5C≡CH, -O-(CH2)7, -O-(CH2)2C(N=N)(CH2)2C≡CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C≡CH, -O-(CH2)5CF3 and -O-(CH2)7. -O-phenyl; -O-CH-phenyl; wherein said -O-phenyl and -O-CH-phenyl are optionally substituted by one or two substituents selected from -F, -Cl, -CH, -O-(CH)C≡CH, -O-(CH), -O-(CH)C(N=N)(CH)C≡CH, -O-(CH)NHC(O)OC(CH), -O-CHC≡CH, -O-(CH)CF and -O-(CH).

[0062] In some embodiments, R 1 is cyclohexyl. In another embodiment, R 1 is phenyl substituted with -F, -Cl, -CH, -O-(CH)C≡CH, -O-(CH), -O-(CH)C(N=N)(CH)C≡CH, -O-(CH)NHC(O)OC(CH), -O-CHC≡CH, -O-(CH)CF, and -O-(CH).1 is phenyl.

[0063] R 2 is —C optionally substituted with 1, 2, or 3 substituents selected from —H, -halo, and F and —CF 1-3 In some embodiments, R 2 is —H. In another embodiment, R 2 is -halo. In some embodiments, R 2 is -F. In another embodiment, R 2 Ha-C 1-3 In some embodiments, R 2 is methyl.

[0064] R 3 is -H;-C 1-6 Alkyl;-C 2-6 Alkenyl;-C 2-6 Alkynyl;-C 3-7 cycloalkyl; and 5- or 6-membered heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is selected from -F, -CF3, -C(O)NR 8 R 9 and -NR 8 R 9 -C optionally substituted with 1, 2 or 3 substituents selected from 1-3 It may be substituted with 1, 2 or 3 groups, for example 1 or 2 groups, selected from alkyl.

[0065] In some embodiments, R 3 is -H;-C 2-4 Alkynyl; -C(O)NR 8 R 9 or -NR 8 R 9 -C optionally substituted with 1-3 alkyl; and C 1-3 is selected from 5- or 6-membered heterocycloalkyl optionally substituted with alkyl.

[0066] In some embodiments, R 3 is -H;-C 2-4 Alkynyl; optionally —C(O)NR 8 R 9 or -NR 8 R 9 may be substituted with -C 1-3 alkyl; and optionally C 1-3 The heterocycloalkyl is selected from 5- or 6-membered nitrogen-containing heterocycloalkyl optionally substituted with alkyl.

[0067] In some embodiments, R 3 is -H;-C 2-4 Alkynyl; optionally —C(O)NR 8 R 9 or -NR 8 R 9 may be substituted with -C 1-3 alkyl; and optionally C 1-3 piperidinyl optionally substituted with alkyl.

[0068] In some embodiments, R 3 is selected from methyl, ethyl, i-propyl, —(CH)N(CH), —(CH)N(CH), —CHC≡CH, —CHC(O)N(CH), and N-methylpiperidine. 3 is selected from ethyl, i-propyl, —(CH2)2N(CH3)2, —(CH2)3N(CH3)2, —CH2C≡CH, —CH2C(O)N(CH3)2 and N-methylpiperidine.

[0069] In some embodiments, R 3 -C 2-4 Alkynyl and optionally -NR 8 R 9 may be substituted with -C 1-3 alkyl.

[0070] In some embodiments, R 3is selected from ethyl, i-propyl, —(CH2)2N(CH3)2, —(CH2)3N(CH3)2 and —CH2C≡CH.

[0071] In some embodiments, R 3 is i-propyl.

[0072] R 4a and R 4b are each independently —C optionally substituted with 1, 2, or 3 substituents selected from —H and —F and —CF 1-3 In some embodiments, R 4a is methyl and R 4b is —H. In some embodiments, R 4a and R 4b are both -H.

[0073] R 4c and R 4d are each independently a C optionally substituted with 1, 2, or 3 substituents selected from -F and -CF 1-3 alkyl; or R 4c and R 4d together with the carbon to which they are attached represent a carbonyl. 4c and R 4d together with the carbon to which they are attached represent a carbonyl. 4c and R 4d are each independently a C optionally substituted with 1, 2, or 3 substituents selected from -H and -F and -CF 1-3 In another embodiment, R 4c and R 4d are both -H or together with the carbon to which they are attached represent a carbonyl. 4c and R 4d are both -H.

[0074] R 5a , R5b , R 5c and R 5d are each independently —C optionally substituted with 1, 2, or 3 substituents selected from —H and —F and —CF 1-3 In some embodiments, R 5a , R 5b , R 5c and R 5d are each independently —C optionally substituted with 1, 2, or 3 substituents selected from —H and —F and —CF 1-3 In some embodiments, R 5a , R 5b , R 5c and R 5d are each independently -H and -C 1-3 In some embodiments, R 5a is methyl and R 5b , R 5c and R 5d Each is —H. In some embodiments, R 5a , R 5b and R 5c are -H, and R 5d is methyl. In some embodiments, R 5a , R 5b , R 5c and R 5d Each represents -H.

[0075] R 6 is -C optionally substituted with 1, 2 or 3 substituents selected from -H; -halo; -NH2; -CN; -F and -CF3; 1-3 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OC 1-3 Alkyl; -C(O)NR 8 R 9 -C(O)OH; and -NHC(O)-C 1-3 In some embodiments, R 6is selected from -H; -Br; -NH2; -CN; methoxy; ethyl; -C(O)OCH3; -C(O)NH2; -C(O)OH; and -NHC(O)CH3.

[0076] R 7 is -NR 10 R 11 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, or three substituents selected from -CN; -F, -CF3, and -OH. 1-6 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl;-C 1-3 Alkylene-NHC(O)OC 1-6 alkyl; and C 3-5 A heterocycloalkyl may be optionally substituted with one, two, or three (e.g., one or two) groups selected from a cycloalkyl; or a heterocycloalkyl may be optionally substituted with two substituents on the same ring carbon that, together with the carbon to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl.

[0077] In some embodiments, R 7 is NR 10 R 11 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl, and 3,4-dihydro-2H-pyranyl; 5- or 6-membered monocyclic heteroaryl selected from pyridinyl, dihydropyranyl, imidazolyl, oxazolyl, imidazolyl, and thiazolyl; wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, or three substituents selected from -CN; -F, -CF3, and -OH. 1-6alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl;-C 1-3 Alkylene-NHC(O)OC 1-6 alkyl; and C 3-5 A heterocycloalkyl may be optionally substituted with one, two, or three (e.g., one or two) groups selected from a cycloalkyl; or a heterocycloalkyl may be optionally substituted with two substituents on the same ring carbon, which, together with the carbon atom to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl.

[0078] In some embodiments, R 7 is NR 10 R 11 a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl, and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridinyl, dihydropyranyl, imidazolyl, oxazolyl, imidazolyl, and thiazolyl; wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, or three (e.g., one or two) groups selected from -CN, methyl, ethyl, propyl, cyclopropyl, methoxy, -CHCF, -CHOH, -CHCHOH, -C(O)OH, -(CH)NHC(O)CH, and -CHNHC(O)OC(CH); or said heterocycloalkyl is optionally substituted with two substituents on the same ring carbon that, together with the carbon atom to which they are attached, form a 6-membered monocyclic heterocycloalkyl.

[0079] In some embodiments, R 7 is NR 10 R 11 Selected from R 10 is selected from methyl, ethyl or propyl; R 11are ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -(CH2) p R 12 a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl, and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridinyl, dihydropyranyl, imidazolyl, oxazolyl, imidazolyl, and thiazolyl; wherein said heterocycloalkyl and heteroaryl are optionally substituted with one or two groups selected from -CN, methyl, ethyl, propyl, cyclopropyl, methoxy, -CH-CF, -CHOH, -CHCHOH, -C(O)OH, -(CH)NHC(O)CH, and -CHNHC(O)OC(CH); or a heterocycloalkyl is optionally substituted with two substituents on the same ring carbon that, together with the carbon atom to which they are attached, form tetrahydropyranyl.

[0080] In some embodiments, R 7 is NR 10 R 11 wherein R is selected from 10 is selected from methyl, ethyl, or propyl; 11 are ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -(CH2) n R 12 is selected from.

[0081] In some embodiments, R 7 is NR 10 R 11 wherein R is selected from 10 is selected from methyl, ethyl, or propyl; 11 are ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -(CH2) n R 12 n is 1 or 2; R 12is selected from isoxazolyl, oxadiazolyl, cyclopropyl, pyrazinyl, tetrahydrofuranyl and pyridinyl.

[0082] In some embodiments, R 7 is -CN; -C optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; 1-6 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OH; -C 1-3 Alkylene-NHC(O)C 1-6 Alkyl;-C 1-3 Alkylene-NHC(O)OC 1-6 Alkyl and C 3-5 a 5- to 7-membered monocyclic heterocycloalkyl optionally substituted with 1, 2, or 3 (e.g., 1 or 2) groups selected from cycloalkyl; or a heterocycloalkyl optionally substituted with two substituents on the same ring carbon that, together with the carbon atom to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl.

[0083] In some embodiments, R 7 is a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl, and 3,4-dihydro-2H-pyranyl, wherein said heterocycloalkyl is optionally substituted with one, two, or three substituents selected from -CN; -F, -CF3, and -OH; 1-6 alkyl; -C optionally substituted with 1, 2 or 3 substituents selected from -F and -CF 1-3 Alkoxy; -C(O)OH; -CH2NHC(O)CH3; -CH2NHC(O)OC(CH3)3; and C 3-5A cycloalkyl may be optionally substituted with one or two groups selected from: a cycloalkyl; or a heterocycloalkyl may be optionally substituted with two substituents on the same ring carbon, which, together with the carbon atom to which they are attached, form a 6-membered monocyclic heterocycloalkyl.

[0084] In some embodiments, R 7 is selected from a 5- to 7-membered monocyclic heterocycloalkyl optionally substituted with one or two substituents selected from methyl, ethyl, propyl, cyclopropyl, —CHCHOH, —CHOH, —C(O)OH, —CHCF, and —CHNHC(O)OC(CH); or a heterocycloalkyl optionally substituted with two substituents on the same ring carbon that, together with the carbon atom to which they are attached, form a tetrahydropyran.

[0085] In some embodiments, R 7 is morpholinyl optionally substituted with one or two substituents selected from methyl, ethyl, propyl, cyclopropyl, —CHCHOH, —CHOH, —C(O)OH, —CHCF, and —CHNHC(O)OC(CH); or is optionally substituted with two substituents on the same ring carbon that, together with the carbon atom to which they are attached, form a tetrahydropyran (i.e., R 7 becomes a spirocyclic group).

[0086] In some embodiments, R 7 is 2-methylmorpholin-4-yl.

[0087] R 8 -H and -C 1-6 In some embodiments, R 8 -H and -C 1-3 In some embodiments, R 8 is —H. In some embodiments, R 8 Ha-C 1-3In some embodiments, R 8 is methyl.

[0088] R 9 -H and -C 1-6 In some embodiments, R 9 -H and -C 1-3 In some embodiments, R 9 is —H. In some embodiments, R 9 Ha-C 1-3 In some embodiments, R 9 is methyl.

[0089] R 10 Ha-C 1-6 In some embodiments, R 10 Ha-C 1-3 In some embodiments, R 10 is methyl. In another embodiment, R 10 is ethyl. In another embodiment, R 10 is propyl.

[0090] R 11 -F and -C 1-3 -C optionally substituted with 1 or 2 substituents selected from alkoxy 1-6 Alkyl; or -(CH2) n R 12 In some embodiments, R 11 is —C optionally substituted with 1 or 2 substituents selected from —F and ethoxy; 1-6 In some embodiments, R 11 are ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -(CH2) n R 12 In some embodiments, R 11 is -(CH2) n R 12 are selected.

[0091] R 12 is selected from 5- or 6-membered heteroaryl, 3- to 5-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl. 12 is selected from isoxazolyl, oxadiazolyl, cyclopropyl, pyrazinyl, tetrahydrofuranyl and pyridinyl.

[0092] m is 0 or 1. In some embodiments, m is 0. In other embodiments, m is 1.

[0093] n is 1, 2, or 3. In some embodiments, n is 1 or 2. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3.

[0094] In certain embodiments, the compound of Formula (I) is selected from the following compounds and pharmaceutically acceptable salts thereof: 2-(Diethylamino)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-2-(1,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-2-(thiomorpholin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2S)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3-methylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-methylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-((2R)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-((2S)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(2,2,2-trifluoroethyl)morpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; tert-Butyl {[(2R)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl]methyl}carbamate; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(propan-2-yl)morpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(1,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(2-ethoxyethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-ethylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(1,2-oxazol-3-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(1,2,4-oxadiazol-3-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1,4-oxazepan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1,9-dioxa-4-azaspiro[5.5]undecan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(3-methoxypyrrolidin-1-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[2-(2-hydroxyethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(dipropylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(cyclopropylmethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[2-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[3-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(pyrazin-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(diethylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(oxolan-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(2,2-difluoroethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(pyridin-2-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; (3S)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholine-3-carboxylic acid; N-[2-(4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl)ethyl]acetamide; 6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}pyridine-2-carbonitrile; 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-methoxypyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-methylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1-methyl-1H-pyrazol-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1,3-oxazol-5-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(1,3-thiazol-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(4-fluorophenoxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-4-({4'-[(hept-6-yn-1-yl)oxy][1,1'-biphenyl]-4-yl}amino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-4-{[4'-(heptyloxy)[1,1'-biphenyl]-4-yl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4'-{2-[3-(but-3-yn-1-yl)-3H-diazilen-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(2-cyclopropyl-morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-4-[(4-pentylphenyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(butan-2-yl)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(benzyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-({4-[(propan-2-yl)oxy]phenyl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclobutylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(cyclopentyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(2,2,2-trifluoroethyl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; tert-Butyl {2-[(4'-{[2-(2-cyclopropylmorpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[1,1'-biphenyl]-4-yl)oxy]ethyl}carbamate; 6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; tert-Butyl {2-[(4'-{[2-(morpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[1,1'-biphenyl]-4-yl)oxy]ethyl}carbamate; 4-[(4'-{2-[3-(but-3-yn-1-yl)-3H-diazilen-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(morpholin-4-yl)-6-(propan-2-yl)-4-({4'-[(prop-2-yn-1-yl)oxy][1,1'-biphenyl]-4-yl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclobutylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclobutylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(morpholin-4-yl)-4-{[4-(propan-2-yl)phenyl]amino}-6-(prop-2-yn-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(oxan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1H-imidazol-1-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2'-methyl[1,1'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4'-{2-[3-(but-3-yn-1-yl)-3H-diazilen-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2-fluoro[1,1'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(morpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(2-fluoro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-tert-butylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(2-methyl[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4'-chloro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; N-(4-cyclobutylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholin-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; 2-(2-cyclopropylmorpholin-4-yl)-N-[4'-(heptyloxy)[1,1'-biphenyl]-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; 2-[(2R)-2-methylmorpholin-4-yl]-N-{4'-[(6,6,6-trifluorohexyl)oxy][1,1'-biphenyl]-4-yl}-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-(2-methylpyridin-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine; 6-Bromo-N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-8-oxo-8lambda~5~-pyrido[2,3-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine; 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carbonitrile; Methyl 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxylate; 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxylic acid; 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxamide; 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)pyrido[2,3-d]pyrimidine-6-carboxamide; N-(4-cyclohexylphenyl)-6-methoxy-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine; N-{4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-6-yl}acetamide; N-4-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-4,6-diamine; N-(4-cyclohexylphenyl)-2-(morpholin-4-yl)-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine; 2-{4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl}-N,N-dimethylacetamide; N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholin-4-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine; 2-(morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-3-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one.

[0095] When the term "optionally" is used, it is intended that the subsequent feature may or may not occur. As such, use of the term "optionally" includes instances where the feature is present as well as instances where the feature is not present. For example, a group "optionally substituted with one methoxy group" includes groups with and without a methoxy substituent.

[0096] The term "substituted" means that one or more hydrogens (e.g., one or two hydrogens, or one hydrogen) in the specified group are replaced with the indicated substituents (e.g., one or two substituents, or one substituent), provided that any atom bearing a substituent maintains an allowed valence. Substituent combinations encompass only stable compounds and stable synthetic intermediates. "Stable" means that the relevant compound or intermediate is sufficiently robust to be isolated and has utility as a synthetic intermediate or an agent with potential therapeutic utility. If a group is not described as "substituted" or "optionally substituted," it should be considered unsubstituted (i.e., none of the hydrogens in the specified group are replaced).

[0097] The term "pharmaceutically acceptable" is used to specify that an object (e.g., a salt, dosage form, diluent, or carrier) is appropriate for use in patients. A list of examples of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.H. Stahl and C.G. Wermuth, editors, Weinheim / Zurich:Wiley-VCH / VHCA, 2002.

[0098] Suitable pharmaceutically acceptable salts of compounds of formula (I) are, for example, acid addition salts, which can be formed by contacting the compounds of formula (I) with a suitable inorganic or organic acid under conditions known to those skilled in the art.

[0099] The compounds described herein can form base addition salts. The base addition salts of the compounds of formula (I) can be formed by contacting the compounds with a suitable inorganic or organic base under conditions known to those skilled in the art.

[0100] In certain embodiments, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

[0101] In certain embodiments, a compound of Formula (I) is provided:

[0102] In certain embodiments, pharmaceutically acceptable salts of compounds of Formula (I) are provided.

[0103] The compounds and salts described herein can exist in solvate form and non-solvate form.For example, solvate form can be hydrate form, such as hemihydrate, monohydrate, dihydrate, trihydrate or their alternative amounts.The present invention particularly encompasses all such solvate and non-solvate forms of the compound of formula (I), to the extent that such form has KCC2 regulating activity, for example, as measured by the test described herein.

[0104] The atoms of the compounds and salts described herein may exist as their isotopes. All compounds of formula (I) in which an atom is substituted with one or more of its isotopes (e.g., where one or more carbon atoms are substituted with one or more of its isotopes) are also included. 11 C or 13 C carbon isotope or one or more hydrogen atoms 2 H or 3 H isotope or one or more nitrogen atoms 15 N isotope or one or more oxygen atoms 17 O or 18 0 isotope) of compounds of formula (I).

[0105] The compounds of the present invention may exist in one or more geometric, optical, enantiomeric, and diastereomeric forms, including, but not limited to, cis and trans forms, E and Z forms, and R, S, and meso forms. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate, such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g., chromatographic and recrystallization techniques). Where appropriate, such isomers can be prepared by the application or adaptation of known methods. In some embodiments, a single stereoisomer is obtained, for example, by isolation from an isomeric mixture (e.g., a racemate) using chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained, for example, by direct synthesis from chiral starting materials.

[0106] In some embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, which is a single optical isomer in enantiomeric excess (% ee) of ≧95%, ≧98%, or ≧99%. In some embodiments, the single optical isomer is present in enantiomeric excess (% ee) of ≧99%.

[0107] In certain embodiments, there is provided an N-oxide of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0108] R 7 Ga-NR 10 R 11 (i.e., R 7 is attached through an aliphatic N atom) can be represented, for example, by the formula (V): [ka] [In the formula, R 1 , R 2 and A is as defined in any of the embodiments described herein. or a salt thereof with an amine. The reaction is conveniently carried out in a suitable solvent at a suitable temperature, for example, with diisopropylethylamine in dimethyl sulfoxide at a temperature of 20-100°C, or with TsOH in butanol at 80°C.

[0109] R 7 is attached through a carbon atom, the compound of formula (I) can be converted into a compound of formula (V) by the addition of a boronic acid or R 7 is as defined in any of the embodiments described herein, and each R is the same or different and represents -H, an aliphatic chain, or two R groups form a ring with the boron and two oxygen atoms. The reaction is conveniently carried out in the presence of a palladium catalyst and a solvent using a suitable base at a suitable temperature, for example, cesium carbonate or sodium carbonate in aqueous dioxane and a palladium catalyst such as Pd(PPh3)4 at a temperature in the range of 80-100°C. [ka]

[0110] R 7 is bonded through an aromatic N atom, the compound of formula (I) can be converted into a compound of formula (V) by the reaction of R 7 for example, by reacting the anion of imidazole, generated by treatment with a suitable base (for example), sodium hydride, in a suitable solvent (for example, dimethylformamide), with a compound of formula (V).

[0111] Compounds of formula (V) can be prepared by reacting a compound of formula (VII), wherein A is as defined in any of the embodiments described herein, or a salt thereof, with R 1 and R 2or a salt thereof. [ka]

[0112] Compounds of formula (I) can also be prepared by reacting compounds of formula (VIII) with amines R 7 and reacting with a compound of formula (VII) in one pot. The reaction is conveniently carried out in the presence of a base (e.g., isopropylethylamine), in a suitable solvent (e.g., dimethyl sulfoxide), at a suitable temperature (e.g., 20 to 100°C).

[0113] Compounds of formula (VII) can be prepared, for example, from compounds of formula (IX). Suitable conditions for this transformation are heating in POCl3 in the presence of an amine such as diethylphenylamine at a temperature of about 80°C. [ka]

[0114] The compound of formula (IX) can be prepared, for example, by reacting the compound of formula (X) with propan-2-amine and formaldehyde in a suitable solvent (e.g., ethanol) at a suitable temperature (e.g., 0 to 80°C). [ka]

[0115] R 5a and R 5b are both H, the compound of formula (I) also has 1 , R 2 and R 7or a salt thereof, with an appropriate amine, such as N,N-dimethylpropane-1,3-diamine. Suitable conditions for this reaction are a solution of HCl in ethanol in a sealed tube at a temperature of about 190° C. [ka]

[0116] It is understood that some of the various ring substituents in the compounds of the present invention can be introduced by standard aromatic substitution reactions before or immediately after the above method, or can be formed by conventional functional group modification, and such are included in the embodiments of the method of the present invention.For example, a compound of formula (I) can be converted into another compound of formula (I) by conventional functional group modification.Such reactions and modifications include, for example, the introduction of substituents by aromatic substitution reactions, CH activation reactions, reduction of substituents, alkylation of substituents, and oxidation of substituents.Reagents and reaction conditions for such methods are known in the field of chemistry.A specific example of an aromatic substitution reaction includes the introduction of a halogen group.

[0117] It is also understood that in some of the above reactions it may be necessary / desirable to protect any sensitive groups in the compounds. The cases where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups can be used in accordance with standard practice (for a description, see TW Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if a reactant contains amino, carboxy, or hydroxy, it may be desirable to protect that group in some of the above reactions.

[0118] The compounds of formula (I), formula (II), formula (III) and formula (IV) and the intermediates used to prepare them may be prepared in a similar manner as shown in the Examples section.

[0119] Compounds may be further selected based on additional biological or physical properties that can be measured by techniques known in the art and used to evaluate or select compounds for therapeutic or prophylactic applications.

[0120] As a result of the KCC2 activating activity of the compounds of formula (I) and their pharmaceutically acceptable salts, they are believed to be useful in the therapy, e.g., treatment of diseases or medical conditions mediated at least in part by KCC2, including epilepsy, pain, autism spectrum disorders, cognitive disorders, anxiety disorders, and neurological disorders such as amyotrophic lateral sclerosis.

[0121] Certain compounds described herein may be selective for other targets, including P2X3.

[0122] The term "treatment" is intended to have its ordinary meaning of addressing a disease in order to alleviate one, some, or all of the symptoms of the disease or to correct or compensate for the underlying pathology. The term "treatment" also includes "prophylaxis" unless otherwise indicated. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

[0123] The term "prevention" has its ordinary meaning and is intended to include primary prevention, to prevent the onset of disease, and secondary prevention, once the disease has already developed, to provide temporary or permanent protection to a patient from exacerbation or worsening of the disease, or the onset of new symptoms associated with the disease.

[0124] The term "treatment" is used synonymously with "therapy." The analogous term "treating" can be understood as "applying therapy," as "therapy" is defined herein.

[0125] In certain embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0126] In certain embodiments, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.

[0127] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating a disease mediated by KCC2. In some embodiments, the disease mediated by KCC2 is a neurological disorder.

[0128] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating epilepsy. In some embodiments, the epilepsy is selected from the group consisting of refractory epilepsy, status epilepticus, benzodiazepine (e.g., lorazepam or diazepam)-resistant status epilepticus, status epilepticus caused by a neurotransmitter or an organophosphorus compound (e.g., soman), Dravet syndrome, Lennox-Gastaut syndrome, Doze syndrome, Jeavons syndrome, and myoclonic absence epilepsy.

[0129] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is provided for use in treating pain.In some embodiments, the pain is selected from the group consisting of widespread pain, local pain, nociceptive pain, central pain, central and peripheral neuropathic pain, diabetic neuropathic pain, central and peripheral neuropathic pain, central and peripheral neuralgia, lower back pain, postoperative pain, visceral pain, pelvic pain, analgesia, anesthetic pain, burning pain, dysesthesia, fibromyalgia, hyperalgesia, hyperesthesia, hyperalgesia, ischemic pain, sciatica, burn-induced pain, pain associated with multiple sclerosis, pain associated with arthritis, pain associated with pancreatitis, pain associated with psoriasis, pain associated with fibromyalgia, pain associated with IBS and pain associated with cancer.

[0130] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating autism spectrum disorder.In some embodiments, the autism spectrum disorder is selected from autism, Asperger's syndrome, childhood disintegrative disorder and Rett syndrome.

[0131] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating cognitive disorders. In some embodiments, the cognitive disorders are selected from the group consisting of amnesia, dementia, and delirium.

[0132] In certain embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of an anxiety disorder.

[0133] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a motor neuron disease. In one embodiment, the motor neuron disease is amyotrophic lateral sclerosis.

[0134] In certain embodiments, there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease or disorder mediated by KCC2. In certain embodiments, the disease or disorder mediated by KCC2 is epilepsy. In another embodiment, the disease or disorder mediated by KCC2 is pain. In another embodiment, the disease or disorder mediated by KCC2 is autism spectrum disorder. In another embodiment, the disease or disorder mediated by KCC2 is cognitive impairment. In another embodiment, the disease or disorder mediated by KCC2 is anxiety disorder. In another embodiment, the disease or disorder mediated by KCC2 is amyotrophic lateral sclerosis.

[0135] The term "therapeutically effective amount" refers to a compound of Formula (I) according to any of the embodiments described herein that is effective to provide "therapy" in a subject or to "treat" a disease or disorder in a subject. In the case of neurological disorders, a therapeutically effective amount may result in some observable or measurable change in the subject as described above in the definitions of "therapy," "treatment," and "prevention." As will be recognized by those skilled in the art, the effective amount may vary depending on the route of administration, the use of excipients, and the use in combination with other agents. For example, when a combination therapy is used, the amount of a compound of Formula (I) or a pharmaceutically acceptable salt described herein and the amount of another pharmaceutically active agent, when combined, are jointly effective to treat the disorder in the target animal patient. In this context, the combined amounts, if any, in a "therapeutically effective amount" are sufficient, when combined, to reduce the symptoms of the disease or disorder responsive to activation of KCC2. Typically, such amounts can be determined by one of ordinary skill in the art by starting from the dosage ranges set forth herein for the compounds of formula (I) or pharmaceutically acceptable salts thereof and approved or other published dosage ranges for other pharmaceutically active compounds.

[0136] A "subject" includes, for example, a human.

[0137] In certain embodiments, provided is a method for treating a neurological disease or disorder selected from epilepsy, pain, autism spectrum disorder, cognitive impairment, anxiety disorder, and amyotrophic lateral sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, there is provided a method for treating epilepsy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, there is provided a method for treating pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, provided is a method for treating autism spectrum disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0140] In certain embodiments, there is provided a method for treating cognitive impairment in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0141] In certain embodiments, provided are methods for treating an anxiety disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments, provided is a method for treating amyotrophic lateral sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0143] In any embodiment where epilepsy is referred to in a general sense, the epilepsy may be selected from the group consisting of refractory epilepsy, status epilepticus, benzodiazepine (e.g., lorazepam or diazepam) resistant status epilepticus, status epilepticus caused by a neurotransmitter or an organophosphate compound (e.g., soman), Dravet syndrome, Lennox-Gastaut syndrome, Dawes syndrome, Jeavons syndrome, and myoclonic absence epilepsy.

[0144] In any embodiment where epilepsy is referred to in a general sense, the following embodiments may apply.

[0145] In some embodiments, the epilepsy is intractable epilepsy.

[0146] In some embodiments, the epilepsy is status epilepticus.

[0147] In some embodiments, the epilepsy is benzodiazepine (e.g., lorazepam or diazepam) resistant status epilepticus.

[0148] In some embodiments, the epilepsy is status epilepticus caused by a neurotransmitter or an organophosphorus compound (eg, soman).

[0149] In some embodiments, the epilepsy is Dravet syndrome.

[0150] In one embodiment, the epilepsy is Lennox-Gastaut syndrome.

[0151] In some embodiments, the epilepsy is Doze syndrome.

[0152] In some embodiments, the epilepsy is Jeavons syndrome.

[0153] In some embodiments, the epilepsy is myoclonic absence epilepsy.

[0154] In any embodiment where pain is referred to in a general sense, the pain may be selected from widespread pain, regional pain, nociceptive pain, central pain, central and peripheral neuropathic pain, diabetic neuropathic pain, central and peripheral neuropathic pain, central and peripheral neuralgia, low back pain, postoperative pain, visceral pain, pelvic pain, analgesia, anesthetic pain, burning pain, dysesthesia, fibromyalgia, hyperalgesia, hyperesthesia, hyperalgesia, ischemic pain, sciatica, burn-induced pain, pain associated with multiple sclerosis, pain associated with arthritis, pain associated with pancreatitis, pain associated with psoriasis, pain associated with fibromyalgia, pain associated with IBS, and pain associated with cancer.

[0155] In any embodiment where pain is referred to in a general sense, the following embodiments may apply.

[0156] In some embodiments, the pain is widespread pain.

[0157] In some embodiments, the pain is localized pain.

[0158] In some embodiments, the pain is nociceptive pain.

[0159] In some embodiments, the pain is central pain.

[0160] In some embodiments, the pain is central and peripheral neuropathic pain.

[0161] In some embodiments, the pain is diabetic neuropathic pain.

[0162] In some embodiments, the pain is central and peripheral neuropathic pain.

[0163] In some embodiments, the pain is central and peripheral neuralgia.

[0164] In some embodiments, the pain is low back pain.

[0165] In some embodiments, the pain is post-operative pain.

[0166] In some embodiments, the pain is visceral pain.

[0167] In some embodiments, the pain is pelvic pain.

[0168] In some embodiments, the pain is dysphagia.

[0169] In some embodiments, the pain is anesthetic pain.

[0170] In some embodiments, the pain is burning pain.

[0171] In some embodiments, the pain is paresthesia.

[0172] In some embodiments, the pain is fibromyalgia.

[0173] In some embodiments, the pain is hyperalgesia.

[0174] In some embodiments, the pain is hyperesthesia.

[0175] In some embodiments, the pain is hyperalgesia.

[0176] In some embodiments, the pain is ischemic pain.

[0177] In some embodiments, the pain is sciatica.

[0178] In some embodiments, the pain is burn-induced pain.

[0179] In some embodiments, the pain is pain associated with multiple sclerosis.

[0180] In some embodiments, the pain is pain associated with arthritis.

[0181] In some embodiments, the pain is pain associated with pancreatitis.

[0182] In some embodiments, the pain is pain associated with psoriasis.

[0183] In some embodiments, the pain is pain associated with fibromyalgia.

[0184] In some embodiments, the pain is pain associated with IBS.

[0185] In some embodiments, the pain is cancer-related pain.

[0186] In any embodiment where an autism spectrum disorder is referred to in a general sense, said autism spectrum disorder may be selected from the group consisting of autism, Asperger's syndrome, childhood disintegrative disorder, and Rett syndrome.

[0187] In any embodiment where autism spectrum disorder is referred to in a general sense, the following embodiments may apply.

[0188] In some embodiments, the autism spectrum disorder is autism.

[0189] In some embodiments, the autism spectrum disorder is Asperger's syndrome.

[0190] In some embodiments, the autism spectrum disorder is childhood disintegrative disorder.

[0191] In some embodiments, the autism spectrum disorder is Rett syndrome.

[0192] In any embodiment where cognitive disorders are referred to in a general sense, said cognitive disorders may be selected from the group consisting of amnesia, dementia and delirium.

[0193] In any embodiment, when anxiety disorders are referred to in a general sense, the anxiety disorder may be selected from the group consisting of generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder.

[0194] In any embodiment where motor neuron disease is referred to in a general sense, the motor neuron disease may be amyotrophic lateral sclerosis.

[0195] The compounds of formula (I) and their pharmaceutically acceptable salts may be administered as pharmaceutical compositions containing one or more pharmaceutically acceptable excipients.

[0196] Thus, in certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0197] The excipient selected for inclusion in specific compositions depends on factors such as mode of administration and the form of the composition provided.Suitable pharmaceutically acceptable excipients are known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, Rowe, Ray C; Sheskey, Paul J; Quinn, Marian, eds.Pharmaceutically acceptable excipients can function as, for example, adjuvants, diluents, carriers, stabilizers, flavoring agents, coloring agents, fillers, binders, disintegrants, lubricants, glidants, thickeners and coating agents.Those skilled in the art will understand that certain pharmaceutically acceptable excipients can provide multiple functions and can provide alternative functions depending on the amount of excipient present in the composition and the other excipients present in the composition.

[0198] The pharmaceutical compositions may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by insufflation (e.g., as finely divided powders), or parenteral administration (e.g., as sterile aqueous or oily solutions or suspensions for intravenous, subcutaneous, or intramuscular administration), or as suppositories for rectal administration. The compositions may be obtained by conventional pharmaceutical methods known in the art. Thus, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0199] The compound of formula (I) is usually administered in an amount of 2.5 to 5000 mg / m 2It is administered to warm-blooded animals at a unit dose in the range of about 0.05-100 mg / kg of animal body area, which typically provides a therapeutically effective amount. Unit dosage forms such as tablets or capsules typically contain, for example, 0.1-250 mg of active ingredient. The daily dose will necessarily vary depending on the subject being treated, the particular route of administration, any co-administered treatments, and the severity of the disease being treated.

[0200] The pharmaceutical compositions described herein, which comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, are believed to be useful in therapy.

[0201] Thus, in certain embodiments, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in therapy.

[0202] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating a disease or condition in which activation of KCC2 is beneficial.

[0203] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating epilepsy.

[0204] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating epilepsy in which activation of KCC2 is beneficial.

[0205] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating refractory epilepsy, status epilepticus, benzodiazepine (e.g., lorazepam or diazepam) resistant status epilepticus, status epilepticus caused by a neurotransmitter or an organophosphorus compound (e.g., soman), Dravet syndrome, Lennox-Gastaut syndrome, Dawes syndrome, Jeavons syndrome, or myoclonic absence epilepsy.

[0206] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating pain.

[0207] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating pain in which activation of KCC2 is beneficial.

[0208] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of widespread pain, regional pain, nociceptive pain, central pain, central and peripheral neuropathic pain, diabetic neuropathic pain, central and peripheral neuropathic pain, central and peripheral neuralgia, low back pain, postoperative pain, visceral pain, pelvic pain, analgesia, anesthetic pain, burning pain, dysesthesia, fibromyalgia, hyperalgesia, hyperesthesia, hyperalgesia, ischemic pain, sciatica, burn-induced pain, pain associated with multiple sclerosis, pain associated with arthritis, pain associated with pancreatitis, pain associated with psoriasis, pain associated with IBS, or pain associated with cancer.

[0209] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating an autism spectrum disorder.

[0210] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating an autism spectrum disorder in which activation of KCC2 is beneficial.

[0211] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating autism, Asperger's syndrome, childhood disintegrative disorder, or Rett syndrome.

[0212] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating cognitive impairment.

[0213] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating a cognitive disorder in which activation of KCC2 is beneficial.

[0214] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating amnesia, dementia, or delirium.

[0215] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of an anxiety disorder.

[0216] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of an anxiety disorder in which activation of KCC2 is beneficial.

[0217] In certain embodiments, a pharmaceutical composition is provided for use in treating generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, or post-traumatic stress disorder.

[0218] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating amyotrophic lateral sclerosis.

[0219] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of amyotrophic lateral sclerosis in which activation of KCC2 is beneficial.

[0220] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in treating amyotrophic lateral sclerosis. [Example]

[0221] Various embodiments of the present invention are illustrated by the following examples, which should not be construed as limiting the invention.

[0222] General Experimental Methods Unless otherwise indicated: (i) all syntheses are carried out at ambient temperature, i.e., in the range of 17-25°C, under an atmosphere of an inert gas such as nitrogen, unless otherwise specified; (ii) evaporation is carried out in vacuo, by rotary evaporation, or by using a Genevac apparatus or a Biotage v10 evaporator, and workup is carried out after removing residual solids by filtration; (iii) flash column chromatography is performed manually or automatically using an Isco CombiFlash Companion system or a similar system on Merck Kieselgel silica (Art. 9385), or on reversed-phase silica (Fluka silica gel 90 C18), or on Silicycle cartridges (40-63 μm silica, 4-330 g weight), or on Grace resolv cartridges (4-120 g), or on RediSep Rf 1.5 Flash columns, or on RediSep Rf Fast Gold Flash columns (150-415 g weight), or on RediSep Rf Gold C18 reversed-phase columns (20-40 μm silica); (iv) Preparative HPLC Conditions A: Xselect CSH OBD column 30 × 150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient elution; detection at 254 / 220 nm. Preparative HPLC condition B: XBridge Prep OBD C18 column 30 × 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient elution; detection at 254 / 220 nm. Preparative HPLC Condition C: XBridge Prep OBD C18 column 30 × 150 mm, 5 μm; Mobile phase A: water (0.05% NH3·H2O), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient elution; Detection at 254 / 220 nm. Preparative HPLC Condition D: XBridge Prep OBD C18 column 30 x 150 mm, 5 μm; Mobile phase A: water (10 mL NH4HCO3), Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient elution; Detection at 254 / 220 nm. (v) if present, the yield need not be the maximum obtainable; (vi) 1H NMR spectra were obtained at 25°C using a Bruker 300 MHz, 400 MHz, or 500 MHz spectrometer unless otherwise noted; chemical shifts are expressed in parts per million (ppm, δ units) and are referenced to the residual H isotopic isomers of the solvent (CHCl: 7.24 ppm; CHDCl: 5.32 ppm; CDS(=O)CDH: 2.49 ppm). Coupling constants are given in hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and brs (broad singlet). (vii) In general, the final compounds of Formula (I) were characterized by liquid chromatography (LCMS or UPLC) followed by mass spectrometry; typically, reverse-phase C18 silica was used at a rate of 1 mL / min, with detection by electrospray mass spectrometry and UV absorbance recording in the wavelength range of 220-320 nm. UPLC analysis was performed on CSH C18 reverse-phase silica using a Waters XSelect CSH C18 column with dimensions of 2.1 x 50 mm and a particle size of 1.7 microns. Gradient analysis was performed using mixtures of decreasing polarity, e.g., water (containing 0.1% formic acid or 0.1% ammonia) as solvent A and acetonitrile as solvent B, as eluents. A typical 2-minute UPLC analysis method utilizes a 1.3-minute solvent gradient from a 97:3 mixture of solvents A and B, respectively, to a 3:97 mixture of solvents A and B, respectively, at approximately 1 mL per minute. Unless otherwise noted, the reported molecular ion is [M+H]. + for molecules with multiple isotopic patterns (Br, Cl, etc.), the reported value is that obtained for the lowest isotopic mass unless otherwise stated; (viii) If the reaction refers to the use of microwaves, one of the following microwave reactors is used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smithcreator or CEM Explorer; (ix) the purity of intermediates was assessed by thin layer graphic analysis, mass spectrometry, LCMS, UPLC / MS, HPLC and / or NMR analysis; (x) Where compounds exist in single stereoisomers, it is understood that the absolute stereochemistry has not been determined and that reference to each separate isomer equally includes reference to the alternative stereoisomers and to the racemate; (xi) The following abbreviations are used: [Table 1]

[0223] Synthesis of intermediates Intermediate 1: 2,4-Dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] Intermediate 1, Step 1: 2,4-Dihydroxy-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] At 0°C, propan-2-amine (136 mL, 1601.57 mmol) was added dropwise to a solution of 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (50 g, 320.31 mmol) and formaldehyde solution (120 mL, 1601.57 mmol) in ethanol (800 mL). The resulting solution was stirred at 80°C for 16 hours. The reaction mixture was cooled in an ice bath, and the white solid was collected by filtration and washed with ethanol to give the crude intermediate as a solid (45 g). To the above crude intermediate (45 g), 2-methoxyethanol (250 mL) and 12 N HCl (25 mL, 822.86 mmol) were added. The reaction mixture was refluxed for 16 hours, cooled in an ice bath, and the solid was collected by filtration and washed with ethanol to give 2,4-dihydroxy-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a solid (35.0 g, 52.2%).1 H NMR (400MHz, DMSO-d6) δ 11.81(s, 1H), 11.26(s, 1H), 4.27(p, J=6.7Hz, 1H), 4.14(s, 2H), 1.20(d, J=6.7Hz, 6H).

[0224] Intermediate 1, Step 2: 2,4-Dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] N,N-Diethylaniline (67.1 mL, 418.25 mmol) was added to a solution of 2,4-dihydroxy-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (35 g, 167.30 mmol) in POCl3 (300 mL) at 0 °C. The resulting solution was stirred at 80 °C for 2.5 h, then concentrated under reduced pressure and azeotroped with toluene to completely remove phosphorus oxychloride. The residue was poured onto crushed ice, and the pH of the mixture was adjusted to pH 6 with 30% NH4OH at 0 °C and extracted with EtOAc (3 × 400 mL). The organic layers were combined and washed with brine (200 mL). The organic layers were dried over Na2SO4, filtered, and evaporated to give a dark oil. The crude product was purified by flash silica chromatography with an elution gradient of 25–30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a white solid (23.40 g, 56.8%). 1 H NMR (400MHz, DMSO-d6) δ 4.58 (s, 2H), 4.45 (p, J=6.7Hz, 1H), 1.27 (d, J=6.8Hz, 6H). ES+ m / z [M+H] + :246, HPLC t R =0.92 minutes (99.0%).

[0225] Intermediate 2: 2,4-Dichloro-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] Using the method described for Intermediate 1, 2,4-dichloro-6-ethyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one was prepared. 1 H NMR (300MHz, CD3OD) δ 1.31 (t, J=7.3, 7.3Hz, 3H), 3.73 (q, J=7.3, 7.3, 7.3Hz, 2H), 4.63 (s, 2H). ES+ m / z [M+H] + :232, HPLC t R =1.10 minutes (99.0%).

[0226] Intermediate 3: 2-chloro-4-((4-cyclohexylphenyl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (5.0 g, 20.32 mmol) and 4-cyclohexylaniline (3.56 g, 20.32 mmol) in tBuOH (100 mL) was added DIEA (3.55 mL, 20.32 mmol) at room temperature. The resulting solution was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature. The precipitate was collected by filtration, washed with water (100 mL) and EtO (50 mL), and dried in vacuo to give 2-chloro-4-((4-cyclohexylphenyl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a white solid (7.00 g, 90%), which was used without further purification. 1 H NMR (400MHz, DMSO)δ 1.25(m, 8H), 1.32-1.47(m, 4H), 1.72(d, J=12.7Hz, 1H), 1.81(d, J=9.6Hz, 4H), 4. 37(s, 2H), 4.36-4.47(m, 1H), 7.23-7.31(m, 2H), 7.56-7.62(m, 2H), 9.93(s, 1H). ES+ m / z [M+H] + :385, HPLC tR =1.32 minutes (98.0%).

[0227] Intermediate 4: 2-chloro-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] Using the method described for Intermediate 3, 2-chloro-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one was prepared. 1 H NMR (400MHz, DMSO) δ 1.22(d, J=6.8Hz, 6H), 1.25(d, J=6.7Hz, 6H), 2.82-2.97(m, 1H), 4.36(s, 2) H), 4.36-4.47(m, 1H), 7.25-7.32(m, 2H), 7.56-7.63(m, 2H), 9.94(s, 1H). ES+ m / z [M+H] + :345, HPLC t R =0.98 minutes (84.3%).

[0228] Intermediate 5: 4'-(hept-6-yn-1-yloxy)-[1,1'-biphenyl]-4-amine [ka] Intermediate 5, Step 1: tert-butyl (4'-hydroxy-[1,1'-biphenyl]-4-yl)carbamate [ka] Di-tert-butyl dicarbonate (0.860 g, 3.94 mmol) was added to a solution of 4'-amino-[1,1'-biphenyl]-4-ol (0.73 g, 3.94 mmol) and DIEA (2.065 mL, 11.82 mmol) in DMF (10 mL) under nitrogen at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and diluted with DCM (50 mL), then washed sequentially with water (3 × 50 mL) and saturated brine (50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0–20% MeOH in DCM. Pure fractions were evaporated to dryness to give tert-butyl (4'-hydroxy-[1,1'-biphenyl]-4-yl)carbamate as a yellow solid (0.462 g, 41.1%). 1 H NMR (300MHz, DMSO) δ 1.46(s, 9H), 6.74-6.83(m, 2H), 7.36-7.51(m, 6H), 9.35(s, 1H), 9.44(s, 1H). E.S. + m / z [M-tBu] + :230, HPLC t R =1.33 minutes (97.0%).

[0229] Intermediate 5, Step 2: tert-butyl (4'-(hept-6-yn-1-yloxy)-[1,1'-biphenyl]-4-yl)carbamate [ka] To a solution of tert-butyl (4'-hydroxy-[1,1'-biphenyl]-4-yl)carbamate (200 mg, 0.70 mmol) and K2CO3 (194 mg, 1.40 mmol) in DMF (2 mL) was added hept-6-yn-1-yl methanesulfonate (160 mg, 0.84 mmol). The resulting mixture was stirred at 60 °C for 14 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and evaporated to give a yellow liquid. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 30% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to give tert-butyl (4'-(hept-6-yn-1-yloxy)-[1,1'-biphenyl]-4-yl)carbamate as a yellow solid (300 mg, 113%). 1 H NMR (300MHz, DMSO)δ 1.47(s, 9H), 1.45-1.55(m, 4H), 1.68-1.74(m, 3H), 2.14-2.22(m, 1H), 2.75(t, J=2. 7Hz, 1H), 3.97(t, J=6.4Hz, 2H), 6.91-7.01(m, 2H), 7.45-7.56(m, 6H), 9.37(s, 1H). E.S. + m / z [M-tBu] + :324, HPLC t R =1.56 minutes (97.0%).

[0230] Intermediate 5, Step 3: 4'-(hept-6-yn-1-yloxy)-[1,1'-biphenyl]-4-amine [ka] To a solution of HCl in 1,4-dioxane (10 mL) was added tert-butyl (4'-(hept-6-yn-1-yloxy)-[1,1'-biphenyl]-4-yl)carbamate (300 mg, 0.79 mmol). The resulting mixture was stirred at room temperature for 2 hours. The solid was dried in vacuo to give 4'-(hept-6-yn-1-yloxy)-[1,1'-biphenyl]-4-amine as a yellow solid (290 mg, 116%). ES+ m / z [M+H] + :280, HPLC tR =1.17 minutes (95.4%).

[0231] Intermediate 6: 4'-(heptyloxy)-[1,1'-biphenyl]-4-amine [ka] Intermediate 6, Step 1: 1-Bromo-4-(heptyloxy)benzene [ka] To a solution of 1-bromoheptane (2 g, 11.17 mmol) and K2CO3 (1.543 g, 11.17 mmol) in MeCN (30 mL) was added 4-bromophenol (1.932 g, 11.17 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 10% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to give 1-bromo-4-(heptyloxy)benzene (2.80 g, 92%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 0.89-0.97(m, 3H), 1.27-1.37(m, 4H), 1.33-1.42(m, 2H), 1.39-1.51(m, 2H), 1 .74-1.85(m, 2H), 3.94(t, J=6.6Hz, 2H), 6.76-6.83(m, 2H), 7.34-7.43(m, 2H).

[0232] Intermediate 6, Step 2: 4'-(heptyloxy)-[1,1'-biphenyl]-4-amine [ka] To a solution of 1-bromo-4-(heptyloxy)benzene (1 g, 3.69 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.808 g, 3.69 mmol), and KCO (1.529 g, 11.06 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added Pd(PPh) (0.426 g, 0.37 mmol) under nitrogen at room temperature. The resulting mixture was stirred at 90 °C for 16 h. The crude product was purified by flash silica chromatography with an elution gradient of 0–20% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to give 4'-(heptyloxy)-[1,1'-biphenyl]-4-amine as a yellow solid (0.302 g, 28.9%). 1 H NMR (300MHz, DMSO)δ 0.80-0.88(m, 2H), 1.24-1.30(m, 8H), 1.62-1.77(m, 3H), 3.94(t, J=6.5Hz, 2H), 5.10(s, 2H) , 6.58(d, J=8.5Hz, 2H), 6.90(d, J=8.8Hz, 2H), 7.25(d, J=8.5Hz, 2H), 7.40(d, J=8.8Hz, 2H). E.S. + m / z [M+H] + :284, HPLC t R =1.18 minutes (97.2%).

[0233] Intermediate 7: 4'-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)-[1,1'-biphenyl]-4-amine [ka] Intermediate 7, Step 1: tert-butyl (4'-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)-[1,1'-biphenyl]-4-yl)carbamate [ka] To a solution of tert-butyl (4'-hydroxy-[1,1'-biphenyl]-4-yl)carbamate (414 mg, 1.45 mmol) and K2CO3 (334 mg, 2.42 mmol) in DMF (2 mL) was added 3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-diazirine (300 mg, 1.21 mmol). The resulting mixture was stirred at room temperature for 14 h. The reaction mixture was diluted with water. The aqueous layers were combined and extracted with EtOAc (3 x 50 mL). The solvent was removed under reduced pressure to give the crude product. The crude product was purified by flash silica chromatography, eluting with a gradient of 0 to 9.8% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to give tert-butyl (4'-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)-[1,1'-biphenyl]-4-yl)carbamate as a yellow solid (110 mg, 22%). 1 H NMR (400MHz, DMSO)δ 1.49(s, 9H), 1.68(t, J=7.4Hz, 2H), 1.90(t, J=6.1Hz, 2H), 2.03-2.09(m, 2H), 2.85(t, J=2.6Hz, 1H ), 3.86(t, J=6.1Hz, 2H), 6.94-7.02(m, 2H), 7.49-7.53(m, 4H), 7.56(d, J=2.9Hz, 2H), 9.40(s, 1H). E.S. + m / z [M-tBu] + :350, HPLC t R =1.17 minutes (89.1%).

[0234] Intermediate 7, Step 2: 4'-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)-[1,1'-biphenyl]-4-amine [ka] To a 4M HCl / dioxane solution (2 mL) was added tert-butyl (4'-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)-[1,1'-biphenyl]-4-yl)carbamate (110 mg, 0.27 mmol). The resulting mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give the crude product 4'-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)-[1,1'-biphenyl]-4-amine as a white solid (100 mg, 121%). 1 H NMR (400MHz, DMSO)δ 1.68(t, J=7.4Hz, 2H), 1.91(t, J=6.1Hz, 2H), 2.01-2.10(m, 2H), 2.86(t, J=2.7Hz, 1H), 3.87(t, J =6.0Hz, 2H), 6.99-7.06(m, 2H), 7.33(d, J=3.7Hz, 2H), 7.59-7.62(m, 2H), 7.67(d, J=2.1Hz, 2H). ES+ m / z [M+H] + :306, HPLC t R = 1.16 min (58.2%). The product was used without further purification.

[0235] Intermediate 8: tert-butyl (2-((4'-amino-[1,1'-biphenyl]-4-yl)oxy)ethyl)carbamate [ka] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.77 g, 12.65 mmol), tert-butyl (2-(4-bromophenoxy)ethyl)carbamate (4 g, 12.65 mmol), and CsCO (8.24 g, 25.30 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was added Pd(PPh) (0.731 g, 0.63 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 80 °C for 16 h. The crude product was purified by flash silica chromatography with an elution gradient of 40–55% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to give tert-butyl (2-((4'-amino-[1,1'-biphenyl]-4-yl)oxy)ethyl)carbamate as a yellow solid (3.57 g, 86%). 1 H NMR (400MHz, DMSO)δ 1.40(s, 9H), 3.31(p, J=5.2, 5.8Hz, 2H), 3.97(t, J=5.9Hz, 2H), 5.12(s, 2H), 6.58-6.68 (m, 2H), 6.89-6.97(m, 2H), 7.00(t, J=5.7Hz, 1H), 7.23-7.34(m, 2H), 7.40-7.48(m, 2H). ES+ m / z [M+H] + :329, HPLC t R =1.08 minutes (95.0%).

[0236] Intermediate 9: 2-chloro-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (1 g, 4.06 mmol) and DIEA (1.419 mL, 8.13 mmol) in DMSO (10 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.890 g, 4.06 mmol) at 25 °C and stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over NaSO and filtered to give a yellow residue. The crude product was purified by flash silica chromatography using an elution gradient of 0 to 5% MeOH in DCM. Pure fractions were concentrated to dryness to give 2-chloro-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a yellow solid (1.070 g, 61%). 1 H NMR (400MHz, CDCl3)δ 1.24(d, J=6.7Hz, 6H), 1.37(s, 12H), 4.25(s, 2H), 4.63(p, J=6.8Hz, 1H), 7.61(d, J=8.0Hz, 2H), 7.85(d, J=8.1Hz, 2H), 7.97(s, 1H). ES+ m / z [M+H] + :429, HPLC t R =1.38 minutes (71%).

[0237] Intermediate 10: 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] Pd(PPh) (256 mg, 0.22 mmol) was added to a solution of 2-chloro-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (950 mg, 2.22 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (698 mg, 3.32 mmol), and NaCO (470 mg, 4.43 mmol) in 1,4-dioxane (10 mL) and water (2 mL) at room temperature under nitrogen. The resulting mixture was stirred at 80 °C for 3 hours. The solvent was removed by distillation in vacuo. The crude product was purified by flash silica chromatography, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were concentrated to dryness to give 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a yellow solid (650 mg, 61.6%). 1 H NMR (400MHz, CDCl3)δ 1.29(s, 12H), 1.38(s, 6H), 2.77(s, 2H), 3.78(t, J=5.4Hz, 1H), 3.94(t, J=5.5Hz, 2H), 4.22(q, J=2.8 Hz, 1H), 4.42(d, J=3.0Hz, 2H), 4.63-4.77(m, 1H), 6.55(s, 1H), 7.55-7.60(m, 2H), 7.82-7.89(m, 2H). ES+ m / z [M+H] + :477, HPLC t R =1.21 minutes (76.4%).

[0238] Intermediate 11: 6-Isopropyl-2-morpholino-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (1 g, 4.06 mmol) and DIEA (1.419 mL, 8.13 mmol) in DMSO (6 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.890 g, 4.06 mmol) at 25 °C. After stirring at room temperature for 16 h, morpholine (0.708 g, 8.13 mmol) was added. The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated to give a yellow residue. The crude product was purified by flash silica chromatography using an elution gradient of 0 to 8% MeOH in DCM. Pure fractions were concentrated to dryness to give 6-isopropyl-2-morpholino-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a yellow solid (1.477 g, 76%). 1 H NMR(400MHz, DMSO)δ 1.24(d, J=6.7Hz, 6H), 1.29(s, 12H), 3.64-3.70(m, 9H), 4.29(s, 2H), 7.63-7.70(m, 2H), 7.74-7.81(m, 2H), 9.41(s, 1H).ES+ m / z [M+H] + :480, HPLC t R =1.30 minutes (70.9%).

[0239] Intermediate 12: 1-Bromo-4-(prop-2-yn-1-yloxy)benzene [ka] To a solution of 4-bromophenol (1.0 g, 5.78 mmol) and K2CO3 (1.598 g, 11.56 mmol) in DMF (10 mL) was added 3-bromoprop-1-yne (0.825 g, 6.94 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layers were combined and washed with water (2 × 50 mL) and brine (50 mL). The organic layers were dried over Na2SO4, filtered, and evaporated. The crude product was purified by flash silica chromatography with an elution gradient of 0–6% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to give 1-bromo-4-(prop-2-yn-1-yloxy)benzene as a colorless oil (0.598 g, 49.0%). 1 H NMR (400MHz, CDCl3) δ 2.55(t, J=2.4Hz, 1H), 4.70(d, J=2.4Hz, 2H), 6.85-6.93(m, 2H), 7.38-7.47(m, 2H).

[0240] Intermediate 13: 3-(2-(4-bromophenoxy)ethyl)-3-(but-3-yn-1-yl)-3H-diazirine [ka] To a solution of K2CO3 (531 mg, 3.85 mmol) and 4-bromophenol (244 mg, 1.41 mmol) in MeCN (3 mL) was added 3-(but-3-yn-1-yl)-3-(iodoethyl)-3H-diazirine (300 mg, 1.28 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was filtered through Celite. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a gradient of 0 to 10% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to afford 3-(2-(4-bromophenoxy)ethyl)-3-(but-3-yn-1-yl)-3H-diazirine as a brown oil (100 mg, 26.6%). 1H NMR (300MHz, CDCl3)δ 1.75(t, J=7.4Hz, 2H), 1.91(t, J=6.2Hz, 2H), 2.01(t, J=2.6Hz, 1H), 2.05- 2.13(m, 2H), 3.81(t, J=6.2Hz, 2H), 6.74-6.86(m, 2H), 7.34-7.45(m, 2H). ES+ m / z [M+H] + :No mass, HPLC R =1.30 minutes (99.0%).

[0241] Intermediate 14: tert-butyl (2-(4-bromophenoxy)ethyl)carbamate [ka] To a solution of 4-bromophenol (2.5 g, 14.45 mmol) and tert-butyl (2-bromoethyl)carbamate (3.89 g, 17.34 mmol) in DMF (30 mL) at room temperature was added K2CO3 (3.00 g, 21.68 mmol). The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3 × 50 mL). The organic layers were combined and washed with water (2 × 100 mL). The organic layers were dried over Na2SO4, filtered, and evaporated to give a colorless oil. The crude product was purified by flash silica chromatography with an elution gradient of 0–30% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to give tert-butyl (2-(4-bromophenoxy)ethyl)carbamate as a white solid. 1 H NMR (400MHz, CDCl3)δ 1.47(s, 9H), 3.54(q, J=5.3Hz, 2H), 4.00(t, J=5.2Hz, 2H), 4.98(s, 1H), 6.72-6.83(m, 2H), 7.37-7.41(m, 2H). ES+ m / z [M-tBu] + :260, HPLC t R =1.46 minutes (92%).

[0242] Intermediate 15(R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)furo[3,4-d]pyrimidin-7(5H)-one [ka] To a solution of 2,4-dichlorofuro[3,4-d]pyrimidin-7(5H)-one (234 mg, 1.14 mmol) and 4-cyclohexylaniline (200 mg, 1.14 mmol) in DMSO (2 mL) was added DIEA (0.598 mL, 3.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. To the above mixture was added (R)-2-methylmorpholine (115 mg, 1.14 mmol). The resulting mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered and evaporated with water and ethyl acetate to give (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)furo[3,4-d]pyrimidin-7(5H)-one as a yellow solid (412 mg, 88%). 1 H NMR (400MHz, DMSO)δ 1.16(d, J=6.1Hz, 3H), 1.31-1.46(m, 5H), 1.77-1.82(m, 5H), 2.60-2.71(m, 1H), 2.99(t, J=11.4Hz, 1H), 3.43-3.55(m, 3H), 3 .91(d, J=10.8Hz, 1H), 4.40(dd, J=13.2, 30.2Hz, 2H), 5.23(s, 2H), 7.23(d, J=8.3Hz, 2H), 7.62(d, J=8.2Hz, 2H), 9.53(s, 1H). ES+ m / z [M+H] + :409, HPLC t R =1.50 minutes (81.4%).

[0243] Intermediate 16: (R)-4-((4-cyclobutylphenyl)amino)-2-(2-methylmorpholino)furo[3,4-d]pyrimidin-7(5H)-one [ka] Using a method similar to that described for intermediate 15, (R)-4-((4-cyclobutylphenyl)amino)-2-(2-methylmorpholino)furo[3,4-d]pyrimidin-7(5H)-one was prepared from 2,4-dichlorofuro[3,4-d]pyrimidin-7(5H)-one. 1 H NMR (400 MHz, DMSO) δ 1.16(d, J=6.2Hz, 3H), 1.75-1.87(m, 1H), 1.88-2.04(m, 1H), 2.01-2.16(m , 2H), 2.22-2.34(m, 2H), 2.65(dd, J=10.4, 13.1Hz, 1H), 2.92-3.04(m, 1H) , 3.47-3.51(m, 3H), 3.86-3.94(m, 1H), 4.36(d, J=13.1Hz, 1H), (d, J=13.1 Hz, H), 5.22(s, 2H), 7.22-7.27(m, 2H), 7.63(d, J=8.4Hz, 2H), 9.53(s, 1H). ES+ m / z [M+H] + :381, HPLC t R =1.58 minutes (90.7%).

[0244] Intermediate 17: 4-((4-isopropylphenyl)amino)-2-morpholinofuro[3,4-d]pyrimidin-7(5H)-one [ka] Using a method similar to that described for intermediate 15, 4-((4-isopropylphenyl)amino)-2-morpholinofuro[3,4-d]pyrimidin-7(5H)-one was prepared. 1 H NMR (400MHz, DMSO)δ 1.21(d, J=6.9Hz, 6H), 2.88(p, J=6.9Hz, 1H), 3.63-3.75(m, 8H), 5.23(s, 2H), 7.21-7.29(m, 2H), 7.61-7.67(m, 2H), 9.51(s, 1H) ES+ m / z [M+H] + :355, HPLC t R =1.46 minutes (97.3%).

[0245] Synthesis of Example Compounds Example 1: 2-(diethylamino)-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of diethylamine (63.6 mg, 0.87 mmol) and 2-chloro-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.29 mmol) in DMSO (5 mL) was added DIEA (0.152 mL, 0.87 mmol). The resulting mixture was stirred at 100 °C for 4 hours. The crude product was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to give 2-(diethylamino)-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a white solid (70.0 mg, 63%). 1 H NMR (400MHz, DMSO) δ 1.14(t, J=6.9Hz, 6H), 1.22(m, 12H), 2.79-2.92(m, 1H), 3.60(q, J=7.0Hz, 4 H), 4.24(s, 2H), 4.36-4.48(m, 1H), 7.20(d, 2H), 7.75(d, 2H), 9.03(s, 1H). m / z(ES+), [M+H] + :382;HPLC t R= 1.73 minutes.

[0246] Example 2: 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 2-chloro-4-((4-cyclohexylphenyl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.26 mmol) and DIEA (0.091 mL, 0.52 mmol) in DMSO (2 mL) was added 2-cyclopropylmorpholine (49.6 mg, 0.39 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The crude product was purified by preparative HPLC condition D. Fractions containing the desired compound were evaporated to dryness to give 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a white solid (60.0 mg, 48.6%). 1 H NMR (400MHz, DMSO) δ 0.22-0.37(m, 2H), 0.44-0.55(m, 2H), 0.84-0.96(m, 1H), 1.23(d, J=6.8Hz, 7H), 1.30- 1.47(m, 4H), 1.75(dd, J=35.9, 10.9Hz, 5H), 2.47(s, 1H), 2.70-2.86(m, 2H), 2.98(td, J =12.5, 11.8, 3.4Hz, 1H), 3.40(td, 1H), 3.90(dd, 1H), 4.25(s, 2H), 4.33(d, J=13.1Hz, 1H), 4.37-4.47(m, 1H), 4.52(d, J=12.5Hz, 1H), 7.19(d, 2H), 7.63(d, 2H), 9.19(s, 1H). m / z(ES+), [M+H] + :476;HPLC t R =2.37 minutes (99.8%).

[0247] The enantiomers of 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one were separated using preparative chiral HPLC: Column: (R,R)WHELK-01, 5 / 100 Kromasil, 2.11 cm × 25 cm (5 μm); Mobile phase A: Hex (8 mM NH3·MeOH), Mobile phase B: EtOH; Flow rate: 20 mL / min; 20 min at 40% B; Detection at 254 / 220 nm; Isomer 1, tR 1=13.818 min; isomer 2, t R 2=16.895 min. Data for Isomer 1 (Example 15) and Isomer 2 (Example 14) are shown in Table 1.

[0248] The example compounds in Table 1 were prepared from intermediates 3 and 4 in a manner similar to that of Examples 1 and 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12]

[0249] Example 40: 6-Isopropyl-4-((4-isopropylphenyl)amino)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 2-chloro-6-isopropyl-4-((4-isopropylphenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (200 mg, 0.58 mmol), pyridin-4-ylboronic acid (86 mg, 0.70 mmol), and CsCO (378 mg, 1.16 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added Pd(PPh) (67.0 mg, 0.06 mmol) at room temperature under nitrogen. The resulting solution was stirred at 100 °C for 3 h. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography using an elution gradient of 3–5% DCM in MeOH. Pure fractions were concentrated to dryness to give the product as a yellow solid. The crude product was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to give 6-isopropyl-4-((4-isopropylphenyl)amino)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a white solid (100 mg, 44.5%). 1 H NMR (400MHz, DMSO)δ 1.27(dd, J=15.8, 6.8Hz, 12H), 2.85-2.99(m, 1H), 4.44-4.53(m, 3H), 7.34(dd, 2H), 7.81(dd, 2H), 8.23(dd, 2H), 8.77(dd, 2H), 9.70(s, 1H). m / z(ES+), [M+H] + :388;HPLC t R =1.358 minutes (98.8%).

[0250] Example 41: 4-(4-((4-cyclohexylphenyl)amino)-6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)picolinonitrile [ka] To a solution of CsCO (169 mg, 0.52 mmol), 2-chloro-4-((4-cyclohexylphenyl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.26 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (90 mg, 0.39 mmol) in 1,4-dioxane (2 mL) and water (0.400 mL) was added Pd(PPh) (30.0 mg, 0.03 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 100 °C for 6 h. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography using an elution gradient of 0 to 5% MeOH in DCM. Pure fractions were concentrated to dryness to give 4-(4-((4-cyclohexylphenyl)amino)-6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)picolinonitrile as crude product. The crude product was purified by preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to give 4-(4-((4-cyclohexylphenyl)amino)-6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)picolinonitrile as a yellow solid (20.10 mg, 17%). 1 H NMR (400MHz, DMSO)δ 1.29(d, J=6.7Hz, 7H), 1.36-1.51(m, 4H), 1.73(d, J=11.9Hz, 1H), 1.83(s, 4H), 4.42-4.54(m, 3H), 7.31(d, J =8.1Hz, 2H), 7.74(d, J=8.1Hz, 2H), 8.49(d, J=5.7Hz, 1H), 8.62(s, 1H), 8.95(d, J=5.1Hz, 1H), 9.80(s, 1H). m / z(ES+)[M+H] + :453;HPLC t R =2.976 minutes (99.3%).

[0251] The example compounds in Table 2 were prepared from Intermediates 3 and 4 and the appropriate boronic ester or boronic acid according to the methods of Examples 40 and 41. [Table 3-1] [Table 3-2] [Table 3-3]

[0252] Example 51: (R)-4-((4-(4-fluorophenoxy)phenyl)amino)-6-isopropyl-2-(2-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.41 mmol) and DIEA (0.213 mL, 1.22 mmol) in DMSO (2 mL) was added 4-(4-fluorophenoxy)aniline (83 mg, 0.41 mmol) at room temperature. The resulting mixture was stirred at 40° C. for 16 hours. To the reaction mixture was added (R)-2-methylmorpholine (41.1 mg, 0.41 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 16 hours. The crude product was purified using preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to give (R)-4-((4-(4-fluorophenoxy)phenyl)amino)-6-isopropyl-2-(2-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a yellow solid. 1H NMR (400MHz, DMSO)δ 1.15(d, J=6.2Hz, 3H), 1.24(d, J=6.7Hz, 6H), 2.61(dd, J=13.1, 10.4Hz, 1H), 2.88-3.00(m, 1H), 3.44-3.54(m, 2H), 3.89(d, J =9.3Hz, 1H), 4.26(s, 2H), 4.31-4.46(m, 3H), 6.99-7.11(m, 4H), 7.18-7.29(m, 2H), 7.74(dd, J=9.2, 3.0Hz, 2H), 9.30(s, 1H). m / z(ES+), [M+H] + :478;HPLC t R =1.946 minutes (98%).

[0253] The example compounds in Table 3 were prepared from Intermediate 1 or 2, which are commercially available or described in the Intermediates section, and the appropriate amine following methods similar to those described above. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6]

[0254] Example 69: tert-butyl (2-((4'-((6-isopropyl-2-morpholino-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-4-yl)oxy)ethyl)carbamate [ka] To a solution of CsCO (136 mg, 0.42 mmol), tert-butyl (2-(4-bromophenoxy)ethyl)carbamate (99 mg, 0.31 mmol), and 6-isopropyl-2-morpholino-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.21 mmol) in dioxane (5 mL) and water (1.000 mL) was added Pd(dppf)Cl (15.26 mg, 0.02 mmol) under air at 25 °C. The resulting mixture was stirred at 100 °C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography using an elution gradient of 0 to 8% MeOH in DCM to give a yellow oil. The oil was purified by preparative HPLC condition C. Fractions containing the desired compound were evaporated to dryness to give tert-butyl (2-((4'-((6-isopropyl-2-morpholino-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)-[1,1'-biphenyl]-4-yl)oxy)ethyl)carbamate as a grey solid (56.5 mg, 46.0%). 1 H NMR (400MHz, DMSO)δ 1.25(d, J=6.8Hz, 6H), 1.40(s, 9H), 3.13(d, J=5.8Hz, 2H), 3.70(dd, J=12.4, 4.4Hz, 8H), 4.00(t, J=5.8Hz, 2H ), 4.30(s, 2H), 4.29-4.43(m, 1H), 6.96-7.09(m, 3H), 7.62(t, J=8.6Hz, 4H), 7.77-7.85(m, 2H), 9.34(s, 1H). m / z(ES+), [M+H] + :589;HPLC t R =1.79 minutes (99.4%).

[0255] The example compounds in Table 4 were prepared from Intermediate 11 and the appropriate bromide according to the method of Example 69. [Table 5]

[0256] Example 72: (R)-4-((4-cyclohexylphenyl)amino)-6-(3-(dimethylamino)propyl)-2-(2-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of N1,N1-dimethylpropane-1,3-diamine (75 mg, 0.73 mmol) and (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)furo[3,4-d]pyrimidin-7(5H)-one (100 mg, 0.24 mmol) in 2-(2-methoxyethoxy)ethanol (2 mL) was added HCl (0.191 mL, 2.20 mmol). The resulting mixture was stirred at 190 °C for 4 h. The reaction mixture was diluted with water (100 mL), extracted with DCM (3 × 200 mL), and washed successively with water (100 mL) and saturated brine (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to give (R)-4-((4-cyclohexylphenyl)amino)-6-(3-(dimethylamino)propyl)-2-(2-methylmorpholino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a yellow solid (21.0 mg, 14%). 1 H NMR (400MHz, DMSO)δ 1.16(d, J=6.2Hz, 3H), 1.23(d, J=10.9Hz, 1H), 1.32-1.47(m, 4H), 1.71(d, J=12.7Hz, 1H), 1. 79(d, J=9.9Hz, 4H), 1.92-2.02(m, 2H), 2.47(s, 1H), 2.53-2.68(m, 1H), 2.78(d, 6H), 2.95(t d, J=12.6, 12.1, 3.4Hz, 1H), 3.01-3.11(m, 2H), 3.42-3.55(m, 2H), 3.61(t, J=12.9Hz, 2H), 3 .90(dd, 1H), 4.33(s, 3H), 4.43(s, 1H), 7.20(d, 2H), 7.63(d, 2H), 9.28(s, 1H), 9.43(s, 1H). m / z(ES+), [M+H]+ :493;HPLC t R= 1.614 minutes (95%).

[0257] The example compounds in Table 5 were prepared using intermediates 15, 16 or 17 in a manner similar to that used in Example 72. [Table 6-1] [Table 6-2]

[0258] Example 78: 4-((4-cyclohexylphenyl)amino)-6-isopropyl-2-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] Palladium on carbon (73.8 mg, 0.07 mmol) was added to a solution of 4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (300 mg, 0.69 mmol) in MeOH (10 mL) under hydrogen at room temperature. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered through Celite. The crude product was purified by preparative HPLC condition C. Fractions containing the desired compound were evaporated to dryness to give 4-((4-cyclohexylphenyl)amino)-6-isopropyl-2-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a white solid. 1H NMR (400MHz, DMSO)δ 1.25(d, J=6.7Hz, 7H), 1.32-1.48(m, 4H), 1.71(d, J=12.6Hz, 1H), 1.75-1.91(m, 8H), 2.46(d, J=10.7Hz, 1H), 2.92-3.04(m, 1H) , 3.40-3.51(m, 2H), 3.90-3.99(m, 2H), 4.35(s, 2H), 4.44(p, J=6.7Hz, 1H), 7.18-7.26(m, 2H), 7.71-7.79(m, 2H), 9.42(s, 1H). E.S. + m / z [M+H] + :435, HPLC t R =1.855 minutes (99.8%).

[0259] Example 79: 4-((4-cyclohexylphenyl)amino)-2-(1H-imidazol-1-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 1H-imidazole (53 mg, 0.78 mmol) and 2-chloro-4-((4-cyclohexylphenyl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (100 mg, 0.26 mmol) in DMF (2 mL) was added NaH (31.2 mg, 0.78 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 14 h. The crude product was purified by preparative HPLC column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3 HO), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient elution with detection at 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give 4-((4-cyclohexylphenyl)amino)-2-(1H-imidazol-1-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a white solid (10.0 mg, 9%). 1H NMR (DMSO-d6, 400MHz)δ 1.28(d, J=6.8Hz, 7H), 1.31-1.51(m, 4H), 1.72(d, J=12.5Hz, 1H), 1.83(d, J=9.0Hz, 4H), 2.51(s, 1H), 4.41-4.52(m, 3H), 7 .13(d, J=1.2Hz, 1H), 7.28-7.36(m, 2H), 7.65-7.72(m, 2H), 7.86(t, J=1.4, 1.4Hz, 1H), 8.47(d, J=1.1Hz, 1H), 9.91(s, 1H). E.S. + m / z [M+H] + :417, HPLC t R =1.655 minutes (99.3%).

[0260] Example 80: 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((2'-methyl-[1,1'-biphenyl]-4-yl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (200 mg, 0.42 mmol), 1-bromo-2-methylbenzene (108 mg, 0.63 mmol), and CsCO (274 mg, 0.84 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added Pd(dppf)Cl (30.7 mg, 0.04 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 100 °C for 2 hours. The solvent was removed by distillation under reduced pressure. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 5% MeOH in DCM. Pure fractions were concentrated to dryness to give a yellow oil. The crude product was purified by preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to give 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((2'-methyl-[1,1'-biphenyl]-4-yl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a white solid (25.0 mg, 13%). 1 H NMR (400MHz, DMSO-d6)δ 1.28(d, J=6.7Hz, 6H), 2.29(s, 3H), 2.62(s, 2H), 3.83(t, J=5.4, 5.4Hz, 2H), 4.32(q, J=2.8, 2.8, 2.8Hz, 2H), 4 .38-4.58(m, 3H), 7.19(d, J=2.8Hz, 1H), 7.20-7.34(m, 4H), 7.34-7.42(m, 2H), 7.90-7.97(m, 2H), 9.59(s, 1H). E.S. + m / z [M+H] + :441, HPLC t R =1.796 minutes (98.6%).

[0261] Example 81: 4-((4'-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)-[1,1'-biphenyl]-4-yl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka]

[0262] Example 81, Step 1: 2-(3,6-Dihydro-2H-pyran-4-yl)-4-((4'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (650 mg, 1.36 mmol), 4-bromophenol (283 mg, 1.64 mmol), and CsCO (889 mg, 2.73 mmol) in 1,4-dioxane (5 mL) and water (1 mL) at room temperature under nitrogen was added Pd(dppf)Cl (100 mg, 0.14 mmol). The resulting mixture was stirred at 100 °C under nitrogen for 2.5 h. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 5% MeOH in DCM. Pure fractions were concentrated to dryness to give 2-(3,6-dihydro-2H-pyran-4-yl)-4-((4'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a yellow solid (210 mg, 35%). 1H NMR (400MHz, DMSO)δ 1.28(d, J=6.7Hz, 6H), 2.62(s, 2H), 3.84(t, J=5.4Hz, 2H), 3.94(s, 2H), 4.33(d, J=2.8Hz, 2H), 4.44(m, 1H), 6.84(d, J=8 .7Hz, 2H), 7.19(d, J=2.7Hz, 1H), 7.49-7.56(m, 2H), 7.62(d, J=8.7Hz, 2H), 7.87-7.93(m, 2H), 9.50(s, 1H), 9.54(s, 1H). E.S. + m / z [M+H] + :443;HPLC t R =1.175 minutes (95.4%).

[0263] Example 81, Step 2: 4-((4'-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)-[1,1'-biphenyl]-4-yl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of K2CO3 (105 mg, 0.76 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4-((4'-hydroxy-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (168 mg, 0.38 mmol) in DMF (2 mL) was added 3-(but-3-yn-1-yl)-3-(2-iodoethyl)-3H-diazirine (188 mg, 0.76 mmol) under air at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 30% EtOAc in petroleum ether. Pure fractions were concentrated to dryness to give the crude product. The crude product was purified by preparative HPLC column: XBridge Shield RP18 OBD column 19 × 250 mm, 10 μm; mobile phase A: water (10 mM ammonium formate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient elution with detection at 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give 4-((4'-(2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethoxy)-[1,1'-biphenyl]-4-yl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one) as a yellow solid (6.2 mg, 2.9%). 1 H NMR (400MHz, MeOD)δ 1.38(d, J=6.7Hz, 6H), 1.73(t, J=7.5Hz, 2H), 1.91(t, J=6.0Hz, 2H), 2.05-2.15(m, 2H), 2.30(t, J=2.7Hz, 1H), 2.73(s, 2H), 3.86-3.96 (m, 4H), 4.34-4.47(m, 4H), 4.53-4.66(m, 1H), 6.98(d, J=8.7Hz, 2H), 7.27(s, 1H), 7.57(dd, J=8.6, 7.0Hz, 4H), 7.87(d, J=8.5Hz, 2H). E.S. + m / z [M+H] + :563, HPLC t R =3.053 minutes (95.9%).

[0264] Example 82: 2-(3,6-dihydro-2H-pyran-4-yl)-4-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] Example 82, Step 1: 2-chloro-4-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 2-fluoro-[1,1'-biphenyl]-4-amine (228 mg, 1.22 mmol) and 2,4-dichloro-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (300 mg, 1.22 mmol) in DMSO (2 mL) was added DIEA (0.426 mL, 2.44 mmol). The resulting mixture was stirred at room temperature for 16 h. The crude product was purified by C18 flash chromatography with an elution gradient of 90–100% MeOH in water (0.1% formic acid). Pure fractions were concentrated to dryness to give 2-chloro-4-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a white solid (150 mg, 31.0%). m / z (ES+), [M+H] + =397; HPLC t R =1.402 minutes.

[0265] Example 82, Step 2: 2-(3,6-Dihydro-2H-pyran-4-yl)-4-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one [ka] To a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (95 mg, 0.45 mmol), 2-chloro-4-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (150 mg, 0.38 mmol), and CsCO (246 mg, 0.76 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added Pd(PPh) (43.7 mg, 0.04 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 80 °C for 3 h. The crude product was purified by flash silica chromatography using an elution gradient of 0 to 5% MeOH in DCM. Pure fractions were concentrated to dryness to give a yellow solid. The crude product was purified by preparative HPLC: XSelect CSH Prep C18 OBD column, 5 μm, 50 mm diameter, 150 mm length, using mixtures of water (containing 0.1% formic acid) and acetonitrile of decreasing polarity as eluents. Fractions containing the desired compound were evaporated to dryness to give 2-(3,6-dihydro-2H-pyran-4-yl)-4-((2-fluoro-[1,1'-biphenyl]-4-yl)amino)-6-isopropyl-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one as a white solid (20.0 mg, 12%). 1 H NMR (400MHz, DMSO)δ 1.28(d, J=6.7Hz, 6H), 2.64(s, 2H), 3.85(t, J=5.4Hz, 2H), 4.34(d, J=3.0Hz, 2H), 4.47(d, J=6.1Hz, 3H), 7.20(s, 1H), 7.34-7.43 (m, 1H), 7.48 (dd, J=8.4, 6.9Hz, 2H), 7.53-7.62 (m, 3H), 7.73 (dd, J=8.6, 2.1Hz, 1H), 8.02 (dd, J=14.0, 2.1Hz, 1H), 9.79 (s, 1H). E.S. + m / z [M+H] + :445, HPLC t R =2.977 minutes (98.6%).

[0266] The example compounds in Table 6 were prepared in the same manner as above. [Table 7-1] [Table 7-2]

[0267] Example 90: (R)—N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine [ka] To a solution of 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine (1 g, 5.24 mmol) and DIEA (2.74 mL, 15.71 mmol) in DMSO (15 mL) was added 4-cyclohexylaniline (0.918 g, 5.24 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 7 h. (R)-2-methylmorpholine (0.635 g, 6.28 mmol) was added to the above mixture and stirred at 100 °C for 16 h. The reaction mixture was purified by flash chromatography on a C18 column using an elution gradient of 10–85% MeCN in water (0.1% FA). Pure fractions were concentrated to dryness to give (R)-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine as a white solid (0.932 g, 45.1%). 1H NMR (400MHz, DMSO)δ 1.13(d, J=6.1Hz, 3H), 1.18-1.25(m, 1H), 1.27-1.44(m, 4H), 1.70(d, J=12.7Hz, 1H), 1.78(d, J =9.7Hz, 4H), 2.42-2.46(m, 1H), 2.57(dd, J=13.0, 10.3Hz, 1H), 2.90(td, J=12.4, 3.5Hz, 1H), 3. 37-3.56(m, 2H), 3.86(dd, J=11.3, 3.2Hz, 1H), 4.30(d, J=13.2Hz, 1H), 4.38(d, J=12.6Hz, 1H), 4 .68(t, J=2.3Hz, 2H), 4.87(t, J=2.4Hz, 2H), 7.12-7.19(m, 2H), 7.52-7.60(m, 2H), 8.76(s, 1H). E.S. + m / z [M+H] + :395, HPLC t R =1.78 minutes (99.6%).

[0268] Example 91: N-(4-cyclobutylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine [ka] A solution of 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine (50 mg, 0.26 mmol) and 4-cyclobutylaniline (38.5 mg, 0.26 mmol) in DMSO (2 mL) was added with DIEA (0.069 mL, 0.39 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 × 25 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude intermediate. To a solution of CsCO (171 mg, 0.52 mmol), (3,6-dihydro-2H-pyran-4-yl)boronic acid (50.2 mg, 0.39 mmol), and the crude intermediate in 1,4-dioxane (2.0 mL) and water (0.4 mL) under nitrogen at 25 °C, Pd(PPh) (30.2 mg, 0.03 mmol) was added. The resulting mixture was stirred at 90 °C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to give N-(4-cyclobutylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine as a yellow solid (40.0 mg, 43.7%). 1 H NMR (400 MHz, DMSO-d) δ 1.75-1.87(m, 1H), 1.88-2.02(m, 1H), 2.02-2.16(m, 2H), 2.28(qt, J=7.8, 2.4Hz, 2H), 2.55(s, 2H), 3.49(p, J=8.8Hz, 1H), 3.80(t, J=5.4Hz, 2 H), 4.29(q, J=2.8Hz, 2H), 4.85(t, J=2.5Hz, 2H), 5.01(t, J=2.5Hz, 2H), 7.06-7.12(m, 1H), 7.17-7.25(m, 2H), 7.65-7.73(m, 2H), 9.03(s, 1H). E.S. + m / z [M+H] + :350, HPLC t R =1.72 minutes (98.4%).

[0269] The examples in Table 5 were prepared in a similar manner to Example 91 and the above examples using the appropriate intermediates. [Table 8-1] [Table 8-2] [Table 8-3]

[0270] Example 99: (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine 8-oxide [ka] To a solution of (R)-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (130 mg, 0.32 mmol) in CHCl3 (3 mL) was added m-CPBA (222 mg, 1.29 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 60 °C for 5 h. The crude product was purified by flash silica chromatography using an elution gradient of 0 to 6% MeOH in DCM. Pure fractions were evaporated to give a yellow liquid. The crude product was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to give (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine 8-oxide as a yellow solid (11.0 mg, 8%). 1H NMR (400MHz, MeOD)δ 1.15-1.39(m, 5H), 1.44-1.57(m, 4H), 1.80(d, J=12.6Hz, 1H), 1.90(d, J=8.3Hz, 4H), 2 .56(s, 1H), 2.76(dd, J=13.4, 10.3Hz, 1H), 3.11(d, J=11.3Hz, 1H), 3.60(s, 2H), 3.97(d , J=11.0Hz, 1H), 4.61(s, 1H), 4.88-5.10(m, 1H), 7.14(dd, J=8.2, 6.3Hz, 1H), 7.28(d, J=8.5Hz, 2H), 7.61(d, J=8.4Hz, 2H), 8.33-8.39(m, 1H), 8.59(dd, J=6.4, 1.3Hz, 1H).ES + m / z [M+H] + :420, HPLC t R =1.73 minutes (99.4%).

[0271] Example 100: (R)—N-(4-cyclohexylphenyl)-6-ethyl-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine [ka] Diethylzinc (0.118 mL, 0.41 mmol) was added to a solution of (R)-6-bromo-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (200 mg, 0.41 mmol) and Pd(dppf)Cl2 (303 mg, 0.41 mmol) in dioxane (2 mL) at room temperature under nitrogen. The resulting solution was stirred at 70 °C for 5 h. The reaction mixture was loaded onto a silica gel column and eluted with 0–10% MeOH in DCM to give the crude product as a yellow solid. The crude product was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to give (R)-N-(4-cyclohexylphenyl)-6-ethyl-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine as a white solid (50.0 mg, 28%). 1H NMR (400MHz, DMSO-d6)δ 1.16(d, J=6.2Hz, 3H), 1.21-1.29(m, 2H), 1.26-1.49(m, 6H), 1.71(d, J=12.4Hz, 1H), 1.81 (d, J=8.8Hz, 4H), 2.43-2.50(m, 1H), 2.60-2.76(m, 3H), 2.92-3.04(m, 1H), 3.43-3.56(m, 2H), 3.90(dd, J=11.5, 3.0Hz, 1H), 4.47(d, J=13.0Hz, 1H), 4.56(d, J=13.1Hz, 1H), 7.21-7 .28(m, 2H), 7.66-7.73(m, 2H), 8.55(d, J=2.4Hz, 1H), 8.64(d, J=2.3Hz, 1H), 9.65(s, 1H). E.S. + m / z [M+H] + :432, HPLC t R =1.70 minutes (99.9%).

[0272] Example 101: (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carbonitrile [ka] Copper cyanide (111 mg, 1.24 mmol) was added to a solution of (R)-6-bromo-N-(4-cyclohexyl-phenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (200 mg, 0.41 mmol) in DMF (2 mL) at room temperature under nitrogen. The resulting mixture was stirred at 150 °C for 6 h. The reaction mixture was loaded onto a silica gel column and eluted with 0-10% MeOH in DCM to give the crude product as a yellow solid. The crude product was purified by preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to give (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carbonitrile as a yellow solid (80 mg, 45.0%). 1H NMR (400MHz, DMSO)δ 1.07-1.30(m, 4H), 1.30-1.61(m, 4H), 1.72(d, J=12.4Hz, 1H), 1.81(d, J=9. 3Hz, 4H), 2.34-2.52(m, 1H), 2.73-2.87(m, 1H), 3.05-3.17(m, 1H), 3.37-3.6 6(m, 2H), 3.90-3.98(m, 1H), 4.32-4.77(m, 2H), 7.29(d, J=8.6Hz, 2H), 7.67( d, J=8.3Hz, 2H), 9.04(d, J=2.2Hz, 1H), 9.22(d, J=2.3Hz, 1H), 10.07(s, 1H). E.S. + m / z [M+H] + :429, HPLC t R =3.35 minutes (98.3%).

[0273] Example 102: Methyl (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylate [ka] Palladium acetate (0.023 g, 0.10 mmol) was added to a solution of DIEA (1.086 mL, 6.22 mmol), (R)-6-bromo-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (1.0 g, 2.07 mmol) in MeOH (5.0 mL) and toluene (5.00 mL) at room temperature under carbon monoxide (60 atm). The resulting solution was stirred at 100 °C for 36 h. The reaction mixture was purified by flash silica chromatography using an elution gradient of 0 to 5% MeOH in DCM. Pure fractions were concentrated to dryness to give a yellow solid. The crude product was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to give methyl (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylate as a yellow solid (25.0 mg, 42%). 1H NMR (400MHz, DMSO) δ 1.08-1.30(m, 4H), 1.31-1.50(m, 4H), 1.65-1.88(m, 5H), 2.49-2.51(m, 1H), 2.70-2.77(m, 1H), 3.01-3.07(m, 1H), 3.44-3.56(m, 2H) ), 3.92(s, 4H), 4.38-4.79(m, 2H), 7.22-7.29(m, 2H), 7.65-7.74(m, 2H), 9.14(d, J=2.3Hz, 1H), 9.33(d, J=2.3Hz, 1H), 10.14(s, 1H). E.S. + m / z [M+H] + :462, HPLC t R =1.74 minutes (99.8%).

[0274] Example 103: (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylic acid [ka] Methyl (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d] Pyrimidine-6-carboxylate (150 mg, 0.32 mmol) was added to 1 N HCl (2 mL) under nitrogen at room temperature. The resulting solution was stirred at 60° C. for 16 hours. The crude product was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to give (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylic acid as a yellow solid (20.00 mg, 34.4%). 1H NMR (400MHz, DMSO)δ 1.16(d, J=6.2Hz, 3H), 1.22-1.27(m, 1H), 1.34-1.49(m, 4H), 1.64-1.89(m, 5H) ), 2.49-2.51(m, 1H), 2.69-2.74(m, 1H), 3.02-3.10(m, 1H), 3.44-3.54(m, 2H), 3.92(d, J=9.8Hz, 1H), 4.48-4.66(m, 2H), 7.25(d, J=8.5Hz, 2H), 7.67-7.74(m, 2H), 9.13(d, J=2.2Hz, 1H), 9.32(d, J=2.3Hz, 1H), 10.11(s, 1H), 13.16(s, 1H). E.S. + m / z [M+H] + :448, HPLC t R =1.74 minutes (98.1%).

[0275] Example 104: (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxamide [ka] Methyl (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylate (150 mg, 0.32 mmol) was added to a solution of NH in MeOH (4 mL) at room temperature under nitrogen. The resulting solution was stirred at 60 °C for 16 h. The crude reaction product was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to give (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxamide as a yellow solid (20.0 mg, 35%). 1H NMR (400 MHz, DMSO) δ 1.10-1.27(m, 4H), 1.31-1.49(m, 4H), 1.76(dd, J=10.9, 37.6Hz, 5H), 2.3 3-2.50(m, 1H), 2.72(d, J=11.7Hz, 1H), 3.01-3.06(m, 1H), 3.42-3.59(m, 2H), 3.93(s, 1H), 4.53(s, 2H), 7.25(d, J=8.5Hz, 2H), 7.55(s, 1H), 7.71( d, J=8.5Hz, 2H), 8.04(s, 1H), 9.19(dd, J=2.3, 23.8Hz, 2H), 9.98(s, 1H). E.S. + m / z [M+H] + :447, HPLC t R =1.42 minutes (99.5%).

[0276] Example 105: 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxamide [ka] The title compound was synthesized using the method described above for (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxamide. 1 H NMR (300MHz, DMSO)δ 0.28(d, J=20.5Hz, 2H), 0.49(d, J=8.3Hz, 2H), 0.89(s, 1H), 1.30(d, J=47.9Hz, 5H), 1.70(d, J=12.7 Hz, 1H), 1.79(d, J=7.9Hz, 4H), 2.43-2.49(m, 1H), 2.71(s, 1H), 2.85-2.93(m, 1H), 3.02-3.09(m, 1H) , 3.31-3.45(m, 1H), 3.91(d, J=11.4Hz, 1H), 4.48(s, 1H), 4.64(s, 1H), 7.22(d, J=8.4Hz, 2H), 7.52(s , 1H), 7.68(d, J=8.2Hz, 2H), 8.01(s, 1H), 9.13(d, J=2.2Hz, 1H), 9.18(d, J=2.3Hz, 1H), 9.97(s, 1H). E.S. +m / z [M+H] + :473, HPLC t R =1.66 minutes (99.4%).

[0277] Example 106: (R)—N-(4-cyclohexylphenyl)-6-methoxy-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine [ka] Quinolin-6-ol (60.2 mg, 0.41 mmol) was added to a solution of (R)-6-bromo-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (200 mg, 0.41 mmol), copper(I) iodide (3.95 mg, 0.02 mmol), and potassium phosphate tribasic (176 mg, 0.83 mmol) in MeOH (6 mL) at room temperature under argon. The resulting mixture was stirred at 110 °C for 24 h. The reaction mixture was evaporated to dryness. The crude product was purified by flash C18-flash chromatography using an elution gradient of 50–100% MeOH in water (0.1% NH4HCO3). Pure fractions were concentrated to dryness to give a yellow liquid. The resulting yellow liquid was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to give (R)-N-(4-cyclohexylphenyl)-6-methoxy-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine as a yellow solid (10.0 mg, 5.5%). 1H NMR (400MHz, DMSO)δ 1.16(d, J=6.2Hz, 3H), 1.25(d, J=9.7Hz, 1H), 1.31-1.50(m, 4H), 1.72(d, J=12.5Hz, 1H), 1 .81(d, J=8.6Hz, 4H), 2.32-2.49(m, 1H), 2.62(dd, J=13.1, 10.4Hz, 1H), 2.90-3.01(m, 1H), 3.43-3.54(m, 2H), 3.91(s, 4H), 4.43(d, J=13.2Hz, 1H), 4.51(d, J=12.9Hz, 1H), 7.26(d, J =8.6Hz, 2H), 7.65-7.72(m, 2H), 8.24(d, J=3.1Hz, 1H), 8.55(d, J=3.0Hz, 1H), 9.60(s, 1H). E.S. + m / z [M+H] + :434, HPLC t R =1.89 minutes (99.6%).

[0278] Example 107: (R)—N-(4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-6-yl)acetamide [ka] To a solution of CsCO (675 mg, 2.07 mmol), acetamide (184 mg, 3.11 mmol), and (R)-6-bromo-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (500 mg, 1.04 mmol) in 1,4-dioxane (5 mL) was added Brettphos 3rd generation Pd catalyst (96 mg, 0.10 mmol) under nitrogen at room temperature. The resulting mixture was stirred at 100 °C for 5 h. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 10% MeOH in DCM. Pure fractions were concentrated to dryness to give (R)-N-(4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-6-yl)acetamide as a yellow solid (275 mg). The resulting crude product (125 mg) was purified by preparative HPLC using an XBridge Prep OBD C18 column (19 × 250 mm, 5 μm); mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3 HO), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient elution, detection at 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give (R)—N-(4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-6-yl)acetamide as a yellow solid (25 mg, 5%). 1 H NMR (400MHz, DMSO)δ 1.15(d, J=6.2Hz, 3H), 1.20-1.49(m, 5H), 1.76(dd, J=38.0, 10.7Hz, 5H), 2.10(s, 3H), 2.49-2.51(m, 1H), 2.64(dd, J=13.3, 10.4Hz, 1H), 2.91-3.02(m, 1H), 3.48(dd, J=12.0, 9.3Hz, 2H), 3.85-3.93(m, 1H), 4.49(dd, J=33.9, 13.2Hz, 2H), 7.19-7.26(m, 2H), 7.63 -7.71(m, 2H), 8.68(d, J=2.6Hz, 1H), 8.84(d, J=2.7Hz, 1H), 9.76(s, 1H), 10.14(s, 1H). E.S. + m / z [M+H] + :461, HPLC tR =1.59 minutes (97.7%).

[0279] Example 108: (R)-N4-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-4,6-diamine [ka] (R)-N-(4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidin-6-yl)acetamide (100 mg, 0.22 mmol) was added to 1 mL of 1N aqueous HCl at room temperature. The resulting mixture was stirred at 100° C. for 16 hours. The crude product was purified by preparative HPLC condition B. Fractions containing the desired compound were evaporated to dryness to give (R)-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-4,6-diamine as a yellow solid (35.0 mg, 38.5%). 1 H NMR (400MHz, DMSO)δ 1.15(d, J=6.2Hz, 3H), 1.24(s, 1H), 1.30-1.49(m, 4H), 1.71(d, J=12.6Hz, 1H), 1.80(d, J= 9.6Hz, 4H), 2.46-2.51(m, 1H), 2.57(dd, J=13.0, 10.3Hz, 1H), 2.85-2.97(m, 1H), 3.43-3. 56(m, 2H), 3.89(dd, J=11.3, 3.1Hz, 1H), 4.37(d, J=13.0Hz, 1H), 4.46(d, J=12.9Hz, 1H), 5 .25(s, 2H), 7.21(d, J=8.5Hz, 2H), 7.67-7.74(m, 3H), 8.34(d, J=2.8Hz, 1H), 9.42(s, 1H). E.S. + m / z [M+H] + :419, HPLC t R =2.30 minutes (99.8%).

[0280] Example 109: N-(4-cyclohexylphenyl)-6-isopropyl-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine [ka] Under nitrogen, borane-THF complex (3 mL, 3.00 mmol) was added to a solution of 4-((4-cyclohexylphenyl)amino)-6-isopropyl-2-morpholino-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (120 mg, 0.28 mmol) in THF (3 mL). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with MeOH (5 mL), and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC condition A. Fractions containing the desired compound were evaporated to dryness to give N-(4-cyclohexylphenyl)-6-isopropyl-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine formate as a white solid (37.0 mg, 29.8%). 1 H NMR (400MHz, DMSO)δ 1.10(d, J=6.2Hz, 6H), 1.19-1.30(m, 1H), 1.31-1.44(m, 4H), 1.70(d, J=12.8Hz, 1H), 1.78(d, J=10.0Hz, 4H), 2.41-2.46(m, 1H), 2 .72(q, J=6.2Hz, 1H), 3.57-3.69(m, 10H), 3.75(d, J=2.2Hz, 2H), 7.11-7.17(m, 2H), 7.55-7.63(m, 2H), 8.20(s, 1H), 8.56(s, 1H). ES+ m / z [M+H] + :422, HPLC t R =2.30 minutes (98.2%).

[0281] Example 110: (R)—N-(4-cyclohexylphenyl)-6-isopropyl-2-(2-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine [ka] Using the method described for N-(4-cyclohexylphenyl)-6-isopropyl-2-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine, (R)—N-(4-cyclohexylphenyl)-6-isopropyl-2-(2-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine formate was prepared. 1 H NMR (400MHz, DMSO)δ 1.12(dd, J=6.2, 16.1Hz, 9H), 1.19-1.29(m, 1H), 1.35-1.40(m, 4H), 1.70(d, J=12 .8Hz, 1H), 1.78(d, J=9.8Hz, 4H), 2.65-2.76(m, 1H), 2.87(t, J=12.2Hz, 1H), 3.41- 3.56(m, 3H), 3.70(d, J=35.7Hz, 5H), 3.87(d, J=11.3Hz, 1H), 4.32(dd, J=12.9, 32 .2Hz, 2H), 7.14(d, J=8.3Hz, 2H), 7.59(d, J=8.3Hz, 2H), 8.23(s, 1H), 8.56(s, 1H). ES+ m / z [M+H] + :436, HPLC t R =1.47 minutes (99.0%).

[0282] Example 111: 2-{4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl}-N,N-dimethylacetamide [ka] Example 111, Step 1: tert-butyl 2-chloro-4-((4-cyclohexylphenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate [ka] To a solution of DIEA (3.61 mL, 20.68 mmol) and tert-butyl 2,4-dichloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (5 g, 17.23 mmol) in DMSO (25 mL) was added 4-cyclohexylaniline (3.02 g, 17.23 mmol). The resulting mixture was stirred at 65 °C for 16 h. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 20% MeOH in DCM. Pure fractions were concentrated to dryness to give tert-butyl 2-chloro-4-((4-cyclohexylphenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (7.78 g, 105%). 1 H NMR (400MHz, DMSO)δ 1.20-1.26(m, 1H), 1.26-1.41(m, 4H), 1.47(d, J=4.7Hz, 9H), 1.71(d, J=12.9Hz, 1H), 1.80(d, J=9.8Hz, 4H), 2.50-2.51(m, 1H), 4.39-4.49(m, 4H), 7.22(d, J=8.3Hz, 2H), 7.52(t, J=8.1Hz, 2H), 9.49(d, J=12.3Hz, 1H). ES+ m / z [M+H] + :429, HPLC t R =1.71 minutes (96.7%).

[0283] Example 111, Step 2: tert-butyl 4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate [ka] To a solution of CsCO (7.60 g, 23.31 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.69 g, 12.82 mmol), and tert-butyl 2-chloro-4-((4-cyclohexylphenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (5 g, 11.66 mmol) in water (10 mL) and 1,4-dioxane (50 mL) was added Pd(PPh) (1.347 g, 1.17 mmol). The resulting mixture was stirred at 80 °C for 14 h. The reaction mixture was concentrated, diluted with EtOAc (100 mL), and washed successively with water (2 × 100 mL) and saturated brine (75 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography, eluting with a gradient of 0 to 20% MeOH in DCM. Pure fractions were concentrated to dryness to give tert-butyl 4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate as a white solid. ES+ m / z [M+H] + :477, HPLC t R =1.42 minutes (92.7%).

[0284] Example 111, Step 3: N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine [ka] To a solution of HCl in 1,4-dioxane (4 M, 20 mL) was added tert-butyl 4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (6.622 g, 13.89 mmol), and the resulting mixture was stirred at room temperature for 4 hours. The mixture was filtered to give N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine hydrochloride as a white solid (3.69 g, 64%). 1 H NMR (400 MHz, DMSO) δ 1.14-1.29(m, 1H), 1.32-1.43(m, 4H), 1.70(d, J=12.6Hz, 1H), 1.79(d, J=9 .3Hz, 4H), 2.38-2.49(m, 1H), 2.49-2.56(m, 3H), 3.36(s, 1H), 3.78(t, J=5 .5Hz, 2H), 4.27(q, J=2.8Hz, 2H), 4.42(d, J=10.2Hz, 2H), 4.51(s, 2H), 7.0 5(s, 1H), 7.16(d, J=8.2Hz, 2H), 7.65-7.73(m, 2H), 8.96(d, J=7.0Hz, 1H). ES+ m / z [M+H] + :377, HPLC t R =1.18 minutes (95.1%).

[0285] Example 111, Step 4: 2-(4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-N,N-dimethylacetamide [ka] To a solution of N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine (200 mg, 0.53 mmol) and DIEA (0.278 mL, 1.59 mmol) in DMF (2 mL) was added 2-bromo-N,N-dimethylacetamide (88 mg, 0.53 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC: column XBridge Shield RP18 OBD column 19 × 250 mm, 10 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient elution with detection at 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give 2-(4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-N,N-dimethylacetamide formate as a pale yellow solid (13.0 mg, 5%). 1 H NMR (400MHz, DMSO)δ 1.19-1.27(m, 1H), 1.32-1.47(m, 4H), 1.71(d, J=12.6Hz, 1H), 1.79(d, J=9. 8Hz, 4H), 2.49-2.50(m, 2H), 2.85(s, 3H), 3.01(s, 3H), 3.63(s, 2H), 3.80(t , J=5.4Hz, 2H), 3.94(s, 2H), 4.00(d, J=2.7Hz, 2H), 4.28(d, J=3.0Hz, 2H), 7 .04(s, 1H), 7.13-7.20(m, 2H), 7.65-7.72(m, 2H), 8.29(s, 1H), 8.78(s, 1H). ES+ m / z [M+H] + :462, HPLC t R =2.34 minutes (96.0%).

[0286] Example 112: N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine [ka] Example 112, Step 1: tert-butyl 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate [ka] To a solution of tert-butyl 2-chloro-4-((4-cyclohexylphenyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (600 mg, 1.40 mmol) and DIEA (0.489 mL, 2.80 mmol) in DMSO (3 mL) was added 2-cyclopropylmorpholine (178 mg, 1.40 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The crude product was purified by flash C18-flash chromatography with an elution gradient of 80 to 100% MeOH in water (0.1% NH4HCO3). Pure fractions were concentrated to dryness to give tert-butyl 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate as a white solid (625 mg, 86%). 1H NMR (400MHz, MeOD) δ 0.29(dd, J=4.6, 9.6Hz, 1H), 0.35-0.44(m, 1H), 0.49-0.63(m, 2H), 0.84-0.96(m, 1H), 1.31(d, J=7.9Hz, 2H), 1.37-1.50( m, 4H), 1.54(s, 9H), 1.77(d, J=12.7Hz, 1H), 1.87(d, J=8.7Hz, 4H), 2.49(s, 1H), 2.73(ddd, J=2.3, 8.1, 10.4Hz, 1H), 2.83( dd. 9(m, 3H), 4.41(t, J=2.2Hz, 1H), 4.46(d, J=2.2Hz, 1H), 4.51-4.59(m, 1H), 7.15(dd, J=1.9, 8.6Hz, 2H), 7.49-7.56(m, 2H). ES+ m / z [M+H] + :520, HPLC t R =1.79 minutes (97.8%).

[0287] Example 112, Step 2: N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine [ka] To a solution of HCl in 1,4-dioxane (8 mL) was added tert-butyl 4-((4-cyclohexylphenyl)amino)-2-(2-cyclopropylmorpholino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (615 mg, 1.18 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered with EA to give N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine hydrochloride as a yellow solid (510 mg, 103%). 1H NMR (400MHz, DMSO)δ 0.24-0.28(m, 1H), 0.28-0.37(m, 1H), 0.43-0.53(m, 2H), 0.82-0.95(m, 1H), 1.22-1.27(m, 1H), 1. 30-1.47(m, 4H), 1.67-1.75(m, 1H), 1.79(d, J=9.2Hz, 4H), 2.76(t, J=9.7Hz, 1H), 2.90(dd, J=10.4 , 13.1Hz, 1H), 3.07(t, J=12.1Hz, 1H), 3.42(td, J=2.7, 11.6Hz, 1H), 3.57(s, 1H), 3.91(dd, J=3.1, 11.4Hz, 1H), 4.23-4.52(m, 6H), 7.18-7.24(m, 2H), 7.54-7.61(m, 2H), 9.72(s, 1H), 10.14(s, 2H). ES+ m / z [M+H] + :420, HPLC t R =1.14 minutes (99.8%).

[0288] Example 112, Step 3: N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine [ka] To a solution of N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine hydrochloride (100 mg, 0.22 mmol), 1-methylpiperidin-4-one (74.4 mg, 0.66 mmol), and DIEA (0.115 mL, 0.66 mmol) in DCM (3 mL) was added AcOH (0.126 mL, 2.19 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the above mixture was added sodium triacetoxyborohydride (139 mg, 0.66 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The crude product was dissolved in MeOH (5 mL). The crude product was purified by flash C18-flash chromatography using an elution gradient of 90-100% MeOH in water (0.1% NH4HCO3). Pure fractions were concentrated to dryness to give the product as a white solid. The resulting product was purified by preparative HPLC: Kinetex EVO C18 column 30 x 150, 5 μm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient elution with detection at 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholino)-6-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine as a white solid (32.5 mg, 28.7%). 1H NMR (400MHz, DMSO)δ 0.19-0.37(m, 2H), 0.45-0.52(m, 2H), 0.87(s, 1H), 1.23(s, 1H), 1.27-1.53(m, 6H), 1.63-1 .86(m, 7H), 1.95(t, J=10.9Hz, 2H), 2.15(s, 3H), 2.38(m, 2H), 2.69-2.76(m, 4H), 2.84-2.94 (m, 1H), 3.33-3.43(m, 1H), 3.64(s, 2H), 3.73(s, 2H), 3.87(d, J=11.9Hz, 1H), 4.24(d, J=13. 0Hz, 1H), 4.44(d, J=10.1Hz, 1H), 7.13(d, J=8.4Hz, 2H), 7.57(d, J=8.5Hz, 2H), 8.56(s, 1H). ES+ m / z [M+H] + :517, HPLC t R =1.05 minutes (97.4%).

[0289] Biological assays A thallium transport FLIPR-based assay was used to measure the ability of compounds to activate KCC2. KCC2-dependent thallium transport in KCC2-expressing cells was measured. + KCC2 activity is assessed by measuring influx. The assay protocol was based on that described by Delpire et al. (Proc Natl Acad Sci USA. 2009 Mar 31; 106(13): 5383-5388) and Zhang et al. (Journal of Biomolecular Screening 15(2): 2010).

[0290] Preparation of HEK cells expressing KCC2 KCC2 was synthesized and codon-optimized by GeneArt based on the Uniprot sequence Q9H2X9. The final sequence was subcloned into pcDNA3.1. HEK293 cells were grown in 10-layer cell stacks at 37°C and 5% CO2 in DMEM, 10% fetal bovine serum, and 2 mM glutamine. Cells were detached by removing the medium and washing the cell stacks with 100 ml of PBS. The PBS was removed, 100 ml of 1x TrypLE was added, and the cell stacks were returned to 37°C for 5 minutes. Detached cells were then counted in a Vi cell counter and spun at 1250 rpm for 10 minutes in a Sorval Legend centrifuge. Cells were diluted in Maxcyte electroporation buffer at a 4x final concentration and spun as above. The cell pellet was collected at 1x10 per ml. 8 The cells were resuspended in 1000µg / ml of plasmid DNA and electroporated through programmed HEK293 cells in a Maxcyte Cl 2.2 bag in a Maxcyte STX instrument. Cells were then allowed to recover for 30 minutes, after which 500ml of PBS was added and counted again on a ViCell. Cells were then frozen in 90% complete medium, 10% DMSO in a planar controlled-speed freezer.

[0291] KCC2 thallium assay method Unless otherwise stated, all reagents were dispensed using a Mulitdrop Combi. The composition of FluXOR Invitrogen proprietary buffers is mentioned in the table below.

[0292] HEK293 KCC2 cells were cultured at 3.33 × 10 in complete medium (DMEM, Sigma, D6546, 10% fetal bovine serum and 1% Glutamax). 5Cells were harvested at a density of 1000 cells / mL and seeded in 30 μL per well into a 384-well PDL-coated black clear plate (Corning, 354663). Cells were allowed to settle for 20 minutes and then incubated at 37°C, 5% CO2 for 48 hours. After incubation, the cells were washed three times with HBSS (Sigma, H6648) using a Biotek cell washer, and finally aspirated, leaving a residual volume of 20 μL of HBSS in each well. Then, 20 μL of thallium loading dye was added per well (1 hour, room temperature, protected from light). Five μL of test compound (maximum concentration 100 μM, 1:2 dilution, 12-point curve) was added using a FLIPR TETRA microscope and incubated for 90 minutes at room temperature in the dark. After compound incubation, thallium flux responses are read on a FLIRR TETRA (e.g., 515-575 nm) starting with the FLIRR TETRA dispensing 5 μL of stimulation buffer into each well. Recordings are taken every 1 second for 120 seconds. EC 50 The thallium flow at 120 seconds is used to determine

[0293] Reagents for KCC2 assay: Assay buffer [Table 9]

[0294] Loading buffer [Table 10]

[0295] Compound buffer: Assay buffer containing 1 μL bumetanide per 10 ml.

[0296] stimulation buffer [Table 11]

[0297] Activity of example compounds in the KCC2 thallium assay. All compounds had E > 140% of the DMSO signal. max showed. [Table 12]

Claims

1. The following formula (I): 【Chemistry 1】 [During the ceremony, R １ is C ２－６ Alkyl; C ２－６ Alkenyl; C ２－６ Alkynyl; C ２－６ Alkoxy; C ２－６ Alkenyloxy; C ２－６ Alkynyloxy; C ３－７ Cycloalkyl; —O—C ３－７ Cycloalkyl; C ６－１０ Aryl; —O—(CH ２ ) ｍ -C ６－１０ aryl; 6-membered heteroaryl; and thiophenyl; wherein said alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, and cycloalkyl are selected from the group consisting of -F and -CF ３ wherein said aryl and heteroaryl are optionally substituted with 1, 2 or 3 substituents selected from -halo, -C １－３ Alkyl, -C １－８ Alkoxy and -C ２－８ alkynyloxy, wherein —C １－３ Alkyl, -C １－８ Alkoxy and -C ２－８ Alkynyloxy is —F, —CF ３ and -NHC(O)O-C １－６ optionally substituted with 1, 2, or 3 substituents selected from alkyl, or two substituents which together with the connecting carbon atom form diazirinyl; R ２ -H; -halo; and -F and -CF ３ -C optionally substituted with 1, 2 or 3 substituents selected from １－３ alkyl; A is: 【Chemistry 2】 and 【Transformation 3】 or an N-oxide thereof; R ３ is -H; -C １－６ Alkyl; -C ２－６ Alkenyl; -C ２－６ Alkynyl; -C ３－７ cycloalkyl; and 5- or 6-membered heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is selected from -F, -CF ３ and -F, -CF ３ , —C(O)NR ８ R ９ and -NR ８ R ９ -C optionally substituted with one or two substituents selected from １－３ optionally substituted with 1, 2, or 3 groups selected from alkyl; R ４ａ and R ４ｂ are each independently —H and —F and —CF ３ C optionally substituted with 1, 2 or 3 substituents selected from １－３ alkyl; R ４ｃ and R ４ｄ are each independently —H and —F and —CF ３ -C optionally substituted with 1, 2 or 3 substituents selected from １－３ alkyl; or R ４ｃ and R ４ｄ together with the carbon to which they are attached represent a carbonyl; R ５ａ , R ５ｂ , R ５ｃ and R ５ｄ are each independently —H and —F and —CF ３ -C optionally substituted with 1, 2 or 3 substituents selected from １－３ alkyl; R ６ -H; -halo; -NH ２ -CN; -F and -CF ３ -C optionally substituted with 1, 2 or 3 substituents selected from １－３ Alkyl; —F and —CF ３ one, two or three substituents selected from: —C(O)O—C １－３ -C optionally substituted with alkyl １－３ Alkoxy; —C(O)NR ８ R ９ -C(O)OH; and -NHC(O)-C １－３ alkyl; R ７ is NR １０ R １１ 5- to 7-membered monocyclic heterocycloalkyl; and 5- or 6-membered monocyclic heteroaryl; wherein said heterocycloalkyl and heteroaryl are selected from -CN; -F, -CF ３ and —C optionally substituted with 1, 2, or 3 substituents selected from —OH １－６ Alkyl; —F and —CF ３ -C optionally substituted with 1, 2 or 3 substituents selected from １－３ Alkoxy; -C(O)OH; -C １－３ Alkylene-NHC(O)C １－６ Alkyl; -C １－３ Alkylene-NHC(O)OC １－６ alkyl; and C ３－５ cycloalkyl; or said heterocycloalkyl may be optionally substituted with two substituents on the same ring carbon, which together with the carbon atom to which they are attached form a 5- to 7-membered monocyclic heterocycloalkyl; R ７ is morpholinyl, and R １ When is unsubstituted phenyl, R ２ is - not H; R ８ and R ９ are each independently —H and —C １－６ alkyl; R １０ Ha-C １－６ is alkyl; R １１ is -F and -C １－３ Alkoxy; and -(CH ２ ) ｎ R １２ -C optionally substituted with one or two substituents selected from １－６ alkyl; R １２ is a 5- or 6-membered heteroaryl, a 3- to 5-membered cycloalkyl, or a 3- to 6-membered heterocycloalkyl; m is 0 or 1; n is 1, 2 or 3. Compound.

2. A is 【Chemistry 4】 and R ３ , R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ 2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. A is 【Transformation 5】 and R ５ａ , R ５ｂ , R ５ｃ and R ５ｄ 2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

4. A is 【Transformation 6】 or its N-oxide, and R ６ 2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

5. R １ is C ２－６ Alkyl; C ２－６ Alkoxy; C ３－７ Cycloalkyl; —O—C ３－７ Cycloalkyl; C ６－１０ Aryl; —O—(CH ２ ) ｍ -C ６－１０ aryl; and thiophenyl, wherein said alkyl, alkoxy, and cycloalkyl are selected from —F and —CF ３ wherein said aryl is optionally substituted with 1, 2 or 3 substituents selected from -halo, -C １－３ Alkyl, -C １－８ Alkoxy and -C ２－８ alkynyloxy, wherein the —C １－３ Alkyl, -C １－８ Alkoxy and -C ２－８ Alkynyloxy is —F, —CF ３ and -NHC(O)O-C １－６ 5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2 or 3 substituents selected from alkyl, or two substituents which together with the carbon to which they are attached form diazirinyl.

6. R １ But -CH ２ CF ３ ;-CF ２ CF ３ ; propyl; Butyl; Pentyl; Propoxy; Cyclobutyl; Cyclohexyl; -O-Cyclopentyl; -F, -Cl, -CH ３ , —O—(CH ２ ) ５ C≡CH, -O-(CH ２ ) ７ , —O—(CH ２ ) ２ C(N=N)(CH ２ ) ２ C≡CH, -O-(CH ２ ) ２ NHC(O)OC(CH ３ ) ３ , —O—CH ２ C≡CH, -O-(CH ２ ) ５ CF ３ and -O-(CH ２ ) ７ Phenyl optionally substituted by one or two substituents selected from: -O-phenyl optionally substituted by -F; -O-CH ２ 6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein - is selected from phenyl and thiophenyl.

7. R ２ The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is -H, -F or methyl.

8. R ３ is ethyl, i-propyl, propynyl, -CH ２ C≡CH, -(CH ２ ) ２ N(CH ３ ) ２ , -(CH ２ ) ３ N(CH ３ ) ２ , -CH ２ C(O)N(CH ３ ) ２ or N-methylpiperidine, or a pharmaceutically acceptable salt thereof.

9. R ４ａ and R ４ｂ A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 and 5 to 8, wherein:

10. R ４ｄ and R ４ｃ and together with the carbon atom to which they are attached represent a carbonyl, or a pharmaceutically acceptable salt thereof.

11. R ５ａ , R ５ｂ , R ５ｃ and R ５ｄ A compound of formula (I) according to any one of claims 1, 3 and 5 to 7, or a pharmaceutically acceptable salt thereof, wherein each is -H.

12. R ６ is -H, -Br, -NH ２ , -CN, methoxy, ethyl, -C(O)OCH ３ , —C(O)NH ２ , —C(O)OH and —NHC(O)CH ３ A compound of formula (I) according to any one of claims 1, 4 and 5 to 7, or a pharmaceutically acceptable salt thereof, selected from

13. R ７ is a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl, and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridinyl, dihydropyranyl, imidazolyl, oxazolyl, imidazolyl, and thiazolyl; wherein said heterocycloalkyl and heteroaryl are selected from -CN; -F, -CF ３ and —C optionally substituted with 1, 2, or 3 substituents selected from —OH １－６ Alkyl; —F and —CF ３ -C optionally substituted with 1, 2 or 3 substituents selected from １－３ Alkoxy; -C(O)OH; -C １－３ Alkylene-NHC(O)C １－６ Alkyl; -C １－３ Alkylene-NHC(O)OC １－６ alkyl; and C ３－５ 13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein said cycloalkyl is optionally substituted with one, two, or three groups; or said heterocycloalkyl is optionally substituted with two substituents on the same ring carbon, which, together with the carbon atom to which they are attached, form a 5- to 7-membered monocyclic heterocycloalkyl.

14. R ７ is a 5- to 7-membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl, and 3,4-dihydro-2H-pyranyl; a 5- or 6-membered monocyclic heteroaryl selected from pyridinyl, dihydropyranyl, imidazolyl, oxazolyl, imidazolyl, and thiazolyl; wherein said heterocycloalkyl and heteroaryl are selected from -CN, methyl, ethyl, propyl, cyclopropyl, methoxy, -CH ２ CF ３ , -CH ２ OH, -CH ２ CH ２ OH, -C(O)OH, -(CH ２ ) ２ NHC(O)CH ３ and -CH ２ NHC(O)OC(CH ３ ) ３ or heterocycloalkyl optionally substituted with two substituents on the same ring carbon which, together with the carbon atom to which they are attached, form tetrahydropyranyl. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13.

15. R ７ NR １０ R １１ 13. The compound of formula (I) according to any one of claims 1 to 12, wherein:

16. R ８ and R ９ 16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4-10 and 12-15, wherein are both -H or both are methyl.

17. R １０ 17. The compound of formula (I) according to any one of claims 1 to 12, 15 and 16, or a pharmaceutically acceptable salt thereof, wherein is selected from methyl, ethyl and propyl.

18. R １１ ethyl, -CH ２ CHF ２ , propyl, -(CH ２ ) ２ O(CH ２ ) ２ and -(CH ２ ) ｎ R １２ 18. A compound of formula (I) according to any one of claims 1 to 12 and 15 to 17, or a pharmaceutically acceptable salt thereof, selected from:

19. R １２ 19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 and 15 to 18, wherein is selected from isoxazolyl, oxadiazolyl, cyclopropyl, pyrazinyl, tetrahydrofuranyl and pyridinyl.

20. The compound is of formula (II): 【Transformation 7】 [In the formula, R １ , R ２ , R ３ , R ４ａ , R ４ｂ and R ７ is as defined for formula (I) in claim 1. or a pharmaceutically acceptable salt thereof.

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

21. The compound is of formula (III): 【Transformation 8】 [In the formula, R １ , R ２ , R ５ａ , R ５ｂ , R ５ｃ , R ５ｄ and R ７ is as defined in claim 1. or a pharmaceutically acceptable salt thereof.

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

22. The compound is of formula (IV): 【Chemistry 9】 [In the formula, R １ , R ２ , R ６ and R ７ is as defined in claim 1. or an N-oxide or a pharmaceutically acceptable salt thereof.

23. 2. The compound of formula (I) of claim 1, wherein the compound is selected from the group consisting of: 2-(diethylamino)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-2-(1,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-2-(thiomorpholin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2S)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3-methylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-methylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-((2R)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-((2S)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(2,2,2-trifluoroethyl)morpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; tert-butyl {[(2R)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl]methyl}carbamate; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(propan-2-yl)morpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(1,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(2-ethoxyethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-ethylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(1,2-oxazol-3-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(1,2,4-oxadiazol-3-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1,4-oxazepan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1,9-dioxa-4-azaspiro[5.5]undecan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(3-methoxypyrrolidin-1-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[2-(2-hydroxyethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(dipropylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(cyclopropylmethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[2-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[3-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(pyrazin-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(diethylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(oxolan-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-[(2,2-difluoroethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(pyridin-2-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; (3S)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholine-3-carboxylic acid; N-[2-(4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl)ethyl]acetamide; 6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}pyridine-2-carbonitrile; 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-methoxypyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(2-methylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1-methyl-1H-pyrazol-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1,3-oxazol-5-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(1,3-thiazol-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(4-fluorophenoxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-4-({4'-[(hept-6-yn-1-yl)oxy][1,1'-biphenyl]-4-yl}amino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-4-{[4'-(heptyloxy)[1,1'-biphenyl]-4-yl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4'-{2-[3-(but-3-yn-1-yl)-3H-diazilen-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(2-cyclopropyl-morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-4-[(4-pentylphenyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(butan-2-yl)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(benzyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-({4-[(propan-2-yl)oxy]phenyl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclobutylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-{[4-(cyclopentyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(2,2,2-trifluoroethyl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; tert-butyl {2-[(4'-{[2-(2-cyclopropylmorpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[1,1'-biphenyl]-4-yl)oxy]ethyl}carbamate; 6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; tert-butyl {2-[(4'-{[2-(morpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[1,1'-biphenyl]-4-yl)oxy]ethyl}carbamate; 4-[(4'-{2-[3-(but-3-yn-1-yl)-3H-diazilen-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(morpholin-4-yl)-6-(propan-2-yl)-4-({4'-[(prop-2-yn-1-yl)oxy][1,1'-biphenyl]-4-yl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclobutylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclobutylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(morpholin-4-yl)-4-{[4-(propan-2-yl)phenyl]amino}-6-(prop-2-yn-1-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(oxan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-cyclohexylphenyl)amino]-2-(1H-imidazol-1-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2'-methyl[1,1'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4'-{2-[3-(but-3-yn-1-yl)-3H-diazilen-3-yl]ethoxy}[1,1'-biphenyl]-4-yl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2-fluoro[1,1'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(morpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(2-fluoro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(3',4'-dichloro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 2-(morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4-tert-butylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(2-methyl[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; 4-[(4'-chloro[1,1'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; N-(4-cyclobutylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholin-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; 2-(2-cyclopropylmorpholin-4-yl)-N-[4'-(heptyloxy)[1,1'-biphenyl]-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; 2-[(2R)-2-methylmorpholin-4-yl]-N-{4'-[(6,6,6-trifluorohexyl)oxy][1,1'-biphenyl]-4-yl}-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-(2-methylpyridin-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine; 6-bromo-N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-8-oxo-8lambda-5-pyrido[2,3-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine; 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carbonitrile; Methyl 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxylate; 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxylic acid; 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxamide; 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)pyrido[2,3-d]pyrimidine-6-carboxamide; N-(4-cyclohexylphenyl)-6-methoxy-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine; N-{4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-6-yl}acetamide; N-4-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-4,6-diamine; N-(4-cyclohexylphenyl)-2-(morpholin-4-yl)-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine; N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine; 2-{4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl}-N,N-dimethylacetamide; N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholin-4-yl)-6-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine; 2-(morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one; and 2-(morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-3-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one.

24. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

25. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 23 for use in therapy.

26. A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 23 for use in the treatment of neurological disorders.

27. 27. The compound for use according to claim 26, wherein the neurological disorder is selected from epilepsy, pain, autism spectrum disorder, cognitive impairment, anxiety disorder and amyotrophic lateral sclerosis.

28. 24. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 for the manufacture of a medicament for the treatment of neurological disorders.

29. 24. A method for treating neurological disorders in a warm-blooded animal, which comprises administering to said animal in need thereof a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

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