PYRAZOLO AND TRIAZOLOPYRIDINE DERIVATIVES AS MUSCARINIC M4 RECEPTOR POSITIVE ALLOSTERIC MODULATORS (M4 PAMs)

Abstract

The present invention relates to pyrazolo and triazolopyridine derivatives of formula (I), or an isotopic form, a stereoisomer, or pharmaceutically acceptable salt thereof as muscarinic M4 receptor positive allosteric modulators (M4 PAMs). The present invention also relates to chemical synthesis, pharmaceutical compositions comprising such compounds, and use of such compounds in the treatment of psychiatric and / or neurological disorders.

Description

[0001] FIELD OF INVENTION

[0002] The present invention relates to pyrazolo and triazolopyridine derivatives of formula (I), or their isotopic forms, stereoisomers, or pharmaceutically acceptable salts thereof as muscarinic M4 receptor positive allosteric modulators (M4 PAMs). The present invention also describes methods of making such compounds, pharmaceutical compositions comprising such compounds, and their potential use in treating psychiatric and / or neurological disorders.

[0003] BACKGROUND OF THE INVENTION

[0004] Currently, the available pharmacological treatments for psychiatric and / or neurological disorders such as schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression have shown modest improvement with dose-limiting side effects leading to non-compliance and a partial response.

[0005] Targeting muscarinic acetylcholine receptors (mAChRs) is a promising approach for treating psychiatric and / or neurological disorders, as it provides new and improved pharmacological options. mAChRs, which are G-protein-coupled receptors (GPCRs), are widely expressed throughout the body. Five subtypes termed Ml through M5 that respond to the endogenous neurotransmitter acetylcholine (ACh) have been identified till date. They play key role in regulating the activity of many important functions of the central and peripheral nervous system. The Ml, M3, and M5 receptor subtypes usually couple to the G proteins Gq / Gll, whereas the M2 and M4 receptor subtypes primarily couple to Gi / Go proteins (Wess et al., 1996, Crit Rev Neurobiol.;10(1):69-99; Langmead et al, 2008, Pharmacol Ther.;117(2):232-243).

[0006] The M4 mAChR subtype is of major therapeutic interest due to its expression in regions of the brain that are rich in dopamine and dopamine receptors, where it regulates dopaminergic neurons implicated in cognition, schizophrenia, psychosis, and addiction (Kentaro et al., 2018, Chem. Pharm. Bull. 66(1), 37–44; Daniel et al., 2019, Drug Discov Today;24(12):2307-2314).

[0007] Xanomeline, a Ml / M4-pref erring mAChR agonist, has shown to significantly reduce the behavioral symptoms in patients with Alzheimer’s disease (Bodick et al., 1997, Arch Neurol.;54(4):465-73) although gastrointestinal side effects led to a high drop-out rate in clinical trials. In a separate study, Xanomeline was shown to be efficacious against positive and negative symptoms of schizophrenia (Shekhar et al., 2008, Am JPsychiatry; 165(8): 1033 -9). Xanomeline has shown antipsychotic-like activity in various preclinical behavioral models (Mirza et al,. 2003, CNS Drug Rev.;9(2): 159-86). Subsequent studies indicated that the antipsychotic -like effects of Xanomeline were absent in M4-K0 mice Woolley et al,. 2009 Eur J Pharmacol;603(l-3):147-9). There is a high degree of conservation between muscarinic receptor subtypes at their orthosteric acetylcholine ligand binding sites which makes it difficult to identify a muscarinic subtype selective agonist. To circumvent this issue of selectivity and safety with the agonists, an alternative approach consists of developing selective muscarinic M4 receptor positive allosteric modulators (PAMs) that act at the less conserved allosteric binding sites.

[0008] In this connection, a number of muscarinic M4 receptor PAMs have been described in the literature indicating cognitive enhancement and antipsychotic -like activity. For example, VU0467154 demonstrated antipsychotic-like activity, in rodent assays predictive of antipsychotic effects (Gould et al., 2018, Neuropharmacology; 128:492-502). In addition, muscarinic M4 receptor PAMs have demonstrated procognitive benefits in rodent models of learning and memory (Bubser et al., 2014 ACS Chem Neurosci.;5(10):920-42).

[0009] WO2023 / 141511A1 discloses 5,6,7,8-Tetrahydro-l,6-naphthyridine compounds substituted in the 6-position with pyrimido[l,2-b]pyridazin-4-one, which are PAMs of the muscarinic receptor M4 for treating a neurological and / or psychiatric disorders.

[0010] WO2022 / 015988A1 discloses analogues of 6-(4-((2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)oxy)piperidin-l-yl)-[l,2,4]triazolo[4,3-b]pyridazine, i.e. 7-(4-((phenyl or pyridin-3-yl)oxy)piperidin-l-yl)-4H-pyrimido[l,2- b]pyridazin-4-one derivatives, which are PAMs of the muscarinic acetylcholine receptor M4 for treating a neurological and / or psychiatric disorders.

[0011] WO2018118736A1 discloses 6,5-fused hetero arylpiperidine ether compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor with the following Markush structure and selected examples reported therein.

[0012] R2R3

[0013]

[0014] Markush structure

[0015]

[0016] Example 2 Example 80

[0017] WO2018 / 118734A1, WO2018 / 118735A1, and WO2018 / 118736A1 disclose heteroarylpiperidine ether compounds, which are allosteric modulators of the M4 muscarinic acetylcholine receptors used in the potential treatment or prevention of neurological and psychiatric disorders.

[0018] WO2017 / 112719A1 discloses 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-onecompounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor for the treatment or prevention of neurological and psychiatric disorders.

[0019] WO2023 / 064584A1, WO2023 / 064585A1, and WO2023 / 064587A1 discloses 7,8-dihydro-5H-l,6-naphthyridine derivatives as PAMs of the muscarinic acetylcholine receptor M4 for treating neurological and psychiatric disorders.

[0020] WO2024220641A1 discloses 1,6-naphthyridine derivatives as positive allosteric modulators of the muscarinic acetylcholine receptor m4 useful for the treatment of neurological and psychiatric disorders with the following Markush structure and selected examples reported therein.

[0021] Markush Structure

[0022]

[0023] Other Patent publications WO2018 / 002760, WO2018 / 234953, WO2021 / 099527, WO2023 / 064584, and US20180028501 disclose compounds that are muscarinic M4 receptor PAMs. While several muscarinic M4 receptor PAMs have been disclosed in the literature till date, no muscarinic M4 receptor PAM compound is launched in the market for the treatment of M4-mediated disease or disorders such as schizophrenia, Alzheimer’s disease, psychosis, Parkinson’s disease, pain, addiction and Huntington’s disease. Therefore, there remains an unmet need for developing novel and more effective muscarinic M4 receptor PAMs for treatment of disorders that are affected by the muscarinic M4 receptors.

[0024] Literature suggests that compounds that acts on Muscarinic M2 receptor mediate cholinergic side effects such as bradycardia and hypotension (Grauer et al., 2020 Brain Research; 1737:146814; Sundaram et al., 1989 Brain research, 477(1-2), 358-362; Mirza et al., 2003 CNS drug reviews, 9(2), 159-186). Additionally there exists a similarity in allosteric binding pocket for muscarinic acetylcholine receptors, M4 as well as M2, which pose key challenges in development of M4 PAM with subtype selectivity against M2 receptors (Bioorganic & Medicinal Chemistry Letters, vol. 27, no. 13, July 2017, pp. 2990- 2995; Butler et al., 2024 Journal of medicinal chemistry, 67(13), 10831-10847; Croy et al., 2014 Molecular pharmacology, 86(1), 106-115).

[0025] The present invention discloses novel compounds that are muscarinic M4 receptor PAMs with desirable profile. The compounds of this invention have potent affinity at muscarinic M4, selectivity over muscarinic subtype receptors like Ml, M2, M3 and M5, acceptable pharmacokinetic properties, good brain penetration, receptor occupancy and efficacy in animal models.

[0026] SUMMARY OF THE INVENTION

[0027] In first aspect, the present invention relates to a compound of formula (I), or an isotopic form, or a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0028] / / N

[0029] o

[0030] ?X2

[0031]

[0032] wherein,Xi is C or N, provided that when Xi is N then Ri is absent;

[0033] X2 is C or N, provided that when X2 is N then R2 is absent;

[0034] Ri is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -Ci-C4alkoxyalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, 3 to 7 membered cycloalkyl, 6 to 12 membered aryl, 4 to 12 membered heterocyclic ring, -(Ci-C4)alkyl-aryl, -(Ci-C4)alkyl-heteroaryl or 5 to 12 membered heteroaryl, wherein the cycloalkyl, aryl, heterocyclic or heteroaryl ring are optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxy alkyl, -OCi-C4alkyl, and -OCi-C4haloalkyl;

[0035] R2 is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxy alkyl, -OCi-C4alkyl, or -OCi-C4haloalkyl;

[0036] Alternatively, when Xi and X2 is C, then Ri and R2 together with the carbon atoms to which they are attached form a 3 to 7 membered cycloalkyl, 6 to 12 membered aryl or 4 to 12 membered heterocyclic, wherein the cycloalkyl, aryl and heterocyclic ring are optionally substituted with one to four substituents independently selected from the group consisting of hydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, and -Ci-C4alkoxyalkyl;

[0037] R3 and R4a are each independently is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxyalkyl, -OCi-C4alkyl, or -OCi-C4haloalkyl; Alternatively R3 and R4a together with the carbon atoms to which they are attached from a 3 to 7 membered cycloalkyl, 6 to 12 membered aryl or 4 to 12 membered heterocyclic ring, wherein the cycloalkyl, aryl and heterocyclic ring is optionally substituted with one to four substituents independently selected from the group consisting of hydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, and -Ci-C4alkoxyalkyl;

[0038] R8

[0039] A is selected from

[0040]

[0041] represents point of attachment;

[0042] R4 at each occurrence is independently selected from hydrogen, deuterium, halogen, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, or -OCi-C4alkyl;

[0043]

[0044] Re and R7 are each independently selected from hydrogen, halogen, cyano, -OH, -NH2, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, -OCi-C4alkoxyalkyl, or -NHCi-C4alkyl;

[0045] Alternatively Re and R7 together with the carbon atoms to which they are attached form a 4 to 12 membered heterocyclic ring, or 5 to 12 membered heteroaryl ring, wherein the heteroaryl, and heterocyclic ring is optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -Cs-Cycycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, and -Ci-C4alkoxyalkyl;

[0046] X is N or C;

[0047] m is 0, 1 or 2;

[0048] Rs is hydrogen, halogen, -Ci-C4alkyl, or -OCi-C4alkyl;

[0049] R9 is hydrogen, halogen, G1, -Ci-C4alkyl, or -Ci-C4haloalkyl;

[0050] Rio is hydrogen, halogen, -Ci. C4alkyl, or -OCi. C4alkyl;

[0051] Gi at each occurrence is independently selected from a 5 to 12 membered heteroaryl, 6 to 12 membered aryl, 4 to 12 membered heterocyclic, or 3 to 7 membered cycloalkyl ring, wherein Gi is optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, halogen, cyano, oxo, -Ci-C4alkyl, and -Ci-C4haloalkyl.

[0052] In another aspect, the invention provides a process for the preparation of the compound of formula (I), or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0053] In another aspect, the invention provides a compound of formula (I), or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof for use as muscarinic M4 receptor positive allosteric modulator.

[0054] In another aspect, the invention provides a compound of formula (I), or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof, for the treatment of psychiatric and / or neurological disorders.

[0055] In another aspect, the invention provides a method of treating muscarinic M4 receptor mediated disease or disorders comprising administering to a patient in need thereofa therapeutically effective amount of the compound of formula (I), or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0056] In another aspect, the invention provides a pharmaceutical composition comprising the compound of formula (I), or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0057] DETAILED DESCRIPTION OF THE INVENTION

[0058] Disclosed herein are muscarinic M4 receptor PAMs, methods of making such compounds, pharmaceutical compositions comprising such compounds, and method of treating muscarinic M4 receptor mediated diseases or disorders such as psychiatric and / or neurological disorders.

[0059] Definitions

[0060] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The following definitions apply throughout the specification and claims. In the event that multiple interpretations exist, the definitions provided herein shall prevail. All publications, patents, and patent applications referenced herein are incorporated by reference in their entirety unless otherwise indicate.

[0061] The term, “-Ci-C4alkyl” as used herein refers to branched or linear chain aliphatic hydrocarbon containing from one to four carbon atoms. Examples of -Ci-C4alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0062] The term, “-Ci-C4haloalkyl” as used herein refers to -Ci-C4alkyl as defined above wherein one or more hydrogen of the same or different carbon atoms is substituted with halogen atom. Examples of the -Ci-C4haloalkyl include, but are not limited to, fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoroethyl and trifluoromethyl.

[0063] The term, “-C3-C7cycloalkyl” or “3 to 7 membered cycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon ring containing from three to seven carbon atoms. Examples of -Cs-Cycycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0064] The term, “-Ci-C4alkoxyalkyl” as used herein refers to -Ci-C4alkyl as defined above in which one or more hydrogen atoms of the same or different carbon atoms are substitutedwith an -0Ci-C4alkyl group. Examples of -Ci-C4alkoxy alkyl group include, but are not limited to, methoxymethyl, ethoxymethyl propoxymethyl and butoxymethyl.

[0065] The term, “-OCi-C4alkyl” as used herein refers to -Ci-C4alkyl as defined above, attached to the parent molecular moiety through an oxygen atom. Examples of the -OCi-C4alkyl include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy and butoxy.

[0066] The term, “-NHCi-C4alkyl” as used herein refers to -Ci-C4alkyl as defined above, attached to the parent molecular moiety through an nitrogen atom. Examples of the -NHCi-C4alkyl include, but are not limited to, methylamine, ethylamine, propoylamine, and butylamine.

[0067] The term “-(Ci-C4)alkyl-aryl” as used herein refers to -Ci-C4alkyl as defined above is attached to an aryl ring. Examples of -(Ci-C4)alkyl-aryl include, but are not limited to benzyl, phenethyl, phenylpropyl and phenylbutyl.

[0068] The term “-(Ci-C4)alkyl-heteroaryl” as used herein refers to a -C1-C4 alkyl group, as defined above, attached to a heteroaryl ring. A heteroaryl ring is an aromatic ring containing one to six carbon atoms in which at least one carbon atom is substituted with a heteroatom independently selected from oxygen, nitrogen, or sulphur. Non-limiting examples of -(Ci-C4)alkyl-heteroaryl include, but are not limited to the following rings z=\ N^ / -RI N-^ZRI

[0069] TT,+.,.

[0070]

[0071] N N; The terms m and Ri herein refers to ‘m’ and Ri as defined above in the Markush.

[0072] The term “-OCi-C4haloalkyl” as used herein refers to -Ci-C4haloalkyl as defined above that is bonded to the parent molecular moiety through an oxygen atom. Examples of the -OCi-C4haloalkyl include, but are not limited to, -OCH2F, -OCHF2, and -OCF3.

[0073] The term, “halogen” as used herein refers to fluorine, chlorine, bromine or iodine. Preferably, halogen is fluorine, chlorine or bromine.

[0074] The phrase “4 to 12 membered heterocyclic ring” as used herein refers to monocyclic or bicyclic ring system having from 4 to 12 ring atoms, in which at least one ring atom is heteroatom independently selected from oxygen, nitrogen, or sulphur, and the remaining ring atoms are carbon. The heterocyclic ring may be saturated, partially unsaturated, or aromatic, and may be unsubstituted or substituted with one or more substituents as described herein. Non-limiting examples of 4 to 12 membered heterocyclic ring include azetidinyl, thietanyl, oxetanyl, 1,2-diazetidinyl, tetrahydrofuranyl, 1,2-oxathiolanyl, 1,2-dioxanyl, IH-pyrazolyl, 1 -methyl- IH-pyrazolyl, IH-pyrrolyl, 1 -methyl- IH-pyrrolyl, oxazolyl, isoxazolyl, 2-methyloxazolyl, thiazolyl, IH-imidazolyl, 1,4-dioxanyl, 1,3-dioxanyl, oxolanyl, thiolanyl, oxanyl, thianyl, oxepanyl, azocanyl, thiocanyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, piperazinyl and 4,5,6,7-tetrahydro-pyrazolo[l,5-a]pyrimidine.

[0075] The phrase “5 to 12 membered heteroaryl” as used herein refers to an aromatic heterocyclic ring system containing 5 to 12 ring atoms, including both mono- and bicyclic ring systems, wherein at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from oxygen, nitrogen, or sulfur, or at least two carbon atoms of one or both of the rings are replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. Non-limiting examples of 5- to 12- membered heteroaryl include 6-membered ring substituents such as pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl; 5-membered heteroaryls such as triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5- oxadiazolyl, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thienyl, thiadiazolyl, isothiazolyl, and pyrazolyl; 6 / 5-membered fused ring substituents such as indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, furanopyridinyl, purinyl, imidazopyridinyl, imidazopyrim idinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl (e.g., [l,2,4]triazolo[l,5-a]pyridin-2-yl), and anthranilyl; and 6 / 6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromanyl, and 1,4-benzoxazinyl.

[0076] The phrase “6 to 12 membered aryl” as used herein include but not limited to an allcarbon monocyclic or fused polycyclic aromatic ring system having a conjugated 7t-electron system containing from 6 to 12 carbon atoms. Examples of 6 to 12 membered aryl include but are not limited to phenyl or naphthyl.

[0077] The phrase, “isotopic form” as used herein refers to the compound of formula (I), wherein one or more atoms of the compound of formula (I) are substituted by their respective isotopes. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as H (deuterium Q 11 1 Q 1 1 Q 1 C or D) and H (tritium or T), carbon such as C, C and C, nitrogen such as N and N,

[0078] 15 17 18 36 18 oxygen such as O, O and O, chlorine such as Cl, fluorine such as F, iodine such as I, I, I and I and sulphur such as S. Substitution with heavier isotopes, for example, replacing one or more key carbon-hydrogen bonds with carbon-deuterium bond may show certain therapeutic advanatges, resulting from longer metabolism cycles (e.g.,increases in vivo half life or reduced dosage requirements), improved safety or greater effectiveness and hence may be preferred in certain circumstances.

[0079] Representative examples of isotopic forms of the compounds of formula (I) can include, without limitation, deuterated compounds of formula (I). The term "deuterated" as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom. For example, the compounds of formula (I) can include in the definitions of one or more of its various variables, wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deuterated-cycloalkyl, deuterated-heterocyclyl, deuterated-aryl, deuterated-heteroaryl and the like. The term "deuterated-alkyl" refers to an -Ci-C4alkyl group as defined above, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. That is, in a deuterated alkyl group, at least one carbon atom is bound to a deuterium. In a deuterated alkyl group, it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium. Analogously, the term "deuterated" and the terms deuterated-heterocyclyl, deuterated-heteroaryl, deuterated-cycloalkyl, deuterated-aryl, deuterated-alkoxy each refer to the corresponding chemical moiety wherein at least one carbon is bound to a deuterium.

[0080] The term, “stereoisomer” as used herein refers to isomers of the compound of formula (I) that differ in the arrangement of their atoms in space. Compounds disclosed herein may exist as a single stereoisomer, racemates and / or mixtures of enantiomers and / or diastereomers. All such pure stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention.

[0081] The phrase, “pharmaceutically acceptable salt” as used herein refers to a salt of the active compound i.e. the compound of formula (I), and is prepared by reaction with the appropriate acid or base, depending on the particular substituents found on the compounds described herein.

[0082] The phrase, "therapeutically effective amount" as used herein refers to an amount of a compound of the present invention that (i) treats the particular disease, condition or disorder, (ii) eliminates one or more symptoms of the particular disease, condition or disorder, and / or (iii) delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.

[0083] The phrase “M4 receptor positive allosteric modulators (PAMs)” as used herein refers to a ligand which interacts with an allosteric site of a receptor to augment the responseproduced by the endogenous ligand at the orthosteric binding site. The compounds of the invention are allosteric modulators of the M4 muscarinic acetylcholine receptor, including as positive allosteric modulators of the M4 muscarinic acetylcholine receptor and silent allosteric modulators of the M4 muscarinic acetylcholine receptor.

[0084] The term, “patient” as used herein refers to an animal. Preferably the term “patient” refers to a mammal. The term mammal includes mice, rats, dogs, rabbits, pigs, monkeys, horses, guinea pigs and humans. More preferably the patient is human.

[0085] Embodiments

[0086] The present invention relates to compounds encompassed by formula (I), as described herein. Without limitation, preferred aspects and elements of the invention are discussed below in the form of the following embodiments.

[0087] In one embodiment, the present invention relates to the compound of formula (I), or an isotopic form, or a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0088] / / N

[0089] -Xi 1

[0090] . X,

[0091]

[0092] wherein,

[0093] Xi is C or N, provided that when Xi is N then Ri is absent;

[0094] X2 is C or N, provided that when X2 is N then R2 is absent;

[0095] Ri is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -Ci-C4alkoxyalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, 3 to 7 membered cycloalkyl, 6 to 12 membered aryl, 4 to 12 membered heterocyclic ring, -(Ci-C4)alkyl-aryl, -(Ci-C4)alkyl-heteroaryl or 5 to 12 membered heteroaryl, wherein the cycloalkyl, aryl, heterocyclic or heteroaryl ring are optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxy alkyl, -OCi-C4alkyl, and -OCi-C4haloalkyl;

[0096] R2 is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxy alkyl, -OCi-C4alkyl, or -OCi-C4haloalkyl;

[0097] Alternatively, when Xi and X2 is C, then Ri and R2 together with the carbon atoms to which they are attached form a 3 to 7 membered cycloalkyl, 6 to 12 membered aryl or 4 to 12 membered heterocyclic, wherein the cycloalkyl, aryl or heterocyclic ring is optionally substituted with one to four substituents independently selected from the group consisting ofhydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, and -Ci-C4alkoxyalkyl;

[0098] R3and R4aare each independently is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxyalkyl, -OCi-C4alkyl, or -OCi-C4haloalkyl; Alternatively R3and R4atogether with the carbon atoms to which they are attached from a 3 to 7 membered cycloalkyl, 6 to 12 membered aryl or 4 to 12 membered heterocyclic ring, wherein the cycloalkyl, aryl and heterocyclic ring are optionally substituted with one to four substituents independently selected from the group consisting of hydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, and -Ci-C4alkoxyalkyl;

[0099] A is selected from

[0100]

[0101] “*rwv'” represents point of attachment;

[0102] R4 at each occurrence is independently selected from hydrogen, deuterium, halogen, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, or -OCi-C4alkyl;

[0103] R

[0104]

[0105] 5is

[0106] Re and R7are each independently selected from hydrogen, halogen, cyano, -OH, -NH2, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, -OCi-C4alkoxyalkyl, -NHCi-C4alkyl; or

[0107] Alternatively Re and R7together with the carbon atoms to which they are attached form a 4 to 12 membered heterocyclic, or 5 to 12 membered heteroaryl ring, wherein the heteroaryl and heterocyclic ring is optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, and -Ci-C4alkoxy alkyl;

[0108] X is N or C;

[0109] m is 0, 1 or 2;

[0110] Rs is hydrogen, halogen, -C1-C4alkyl, or -OC1-C4alkyl;

[0111] R9 is hydrogen, halogen, G1, -C1-C4alkyl, or -C1-C4haloalkyl;

[0112] R10 is hydrogen, halogen, -C1-C4alkyl, or -OC1-C4alkyl;Gi at each occurrence is independently selected from a 5 to 12 membered heteroaryl, 6 to 12 membered aryl, 4 to 12 membered heterocyclic, or 3 to 7 membered cycloalkyl ring, wherein Gi is optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, halogen, cyano, oxo, -Ci-C4alkyl, or -Ci-C4haloalkyl;

[0113] In another embodiment, the present invention relates to method of treating or preventing diseases or disorders mediated by muscarinic M4 receptors, comprising administering to a patient a therapeutically effective amount of a compound having the structure of formula (I), or an isotopic form, or a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0114]

[0115] wherein,

[0116] Xi is C or N, provided that when Xi is N then Ri is absent;

[0117] X2 is C or N, provided that when X2 is N then R2 is absent;

[0118] Ri is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -Ci-C4alkoxyalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, 3 to 7 membered cycloalkyl, 6 to 12 membered aryl, 4 to 12 membered heterocyclic, -(Ci-C4)alkyl-aryl, -(Ci-C4)alkyl-heteroaryl or 5 to 12 membered heteroaryl, wherein the cycloalkyl, aryl, heterocyclic or heteroaryl ring are optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxyalkyl, -OCi-C4alkyl, and -OCi-C4haloalkyl;

[0119] R2 is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxy alkyl, -OCi-C4alkyl, or -OCi-C4haloalkyl;

[0120] Alternatively, when Xi and X2 is C, then Ri and R2 together with the carbon atoms to which they are attached form a 3 to 7 membered cycloalkyl, 6 to 12 membered aryl or 4 to 12 membered heterocyclic ring, wherein the cycloalkyl, aryl or heterocyclic ring are optionally substituted with one to four substituents independently selected from the group consisting of hydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, and -Ci-C4alkoxyalkyl;

[0121] R3 and R4a are each independently is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxyalkyl, -OCi-C4alkyl, or -OCi-C4haloalkyl;Alternatively R3 and R4atogether with the carbon atoms to which they are attached from a 3 to 7 membered cycloalkyl, 6 to 12 membered aryl or 4 to 12 membered heterocyclic ring, wherein the cycloalkyl, aryl and heterocyclic ring is optionally substituted with one to four substituents independently selected from the group consisting of hydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi- C4haloalkyl, and -Ci-C4alkoxyalkyl;

[0122] \ TR5

[0123] A is selected from

[0124]

[0125] (R4)m

[0126] “i / vvv'” represents point of attachment;

[0127] R4 at each occurrence is independently selected from hydrogen, deuterium, halogen, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, or -OCi-C4alkyl;

[0128]

[0129] Re and R7 are each independently selected from hydrogen, halogen, cyano, -OH, -NH2, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, -OCi-C4alkoxyalkyl, -NHCi-C4alkyl; or

[0130] Alternatively Re and R7together with the carbon atoms to which they are attached form a 4 to 12 membered heterocyclic, or 5 to 12 membered heteroaryl ring, wherein the heterocyclic ring is optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, and -Ci-C4alkoxyalkyl; X is N or C;

[0131] m is 0, 1 or 2;

[0132] R8 is hydrogen, halogen, -C1-C4alkyl, or -OC1-C4alkyl;

[0133] R9 is hydrogen, halogen, G1, -C1-C4alkyl, or -C1-C4haloalkyl;

[0134] R10 is hydrogen, halogen, -C1-C4alkyl, or -OC1-C4alkyl;

[0135] G1 at each occurrence is independently selected from 5 to 12 membered heteroaryl, 6 to 12 membered aryl, 4 to 12 membered heterocyclic, or 3 to 7 membered cycloalkyl ring, wherein G1 is optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, halogen, cyano, oxo, -C1-C4alkyl, and -C1-C4haloalkyl;In another embodiment, the present invention relates to the compound of formula (I), or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0136]

[0137] In another embodiment, the present invention relates to the compound of formula (I), or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0138]

[0139] In another embodiment, the present invention relates to the compound of formula (I), or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0140]

[0141] In certain embodiments, Re is selected from hydrogen, halogen, cyano, -OH, -NH2, - Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, -OCi- C4alkoxyalkyl, or -NHCi-C4alkyl;

[0142] In certain embodiments, R7 is selected from hydrogen, halogen, cyano, -OH, -NH2, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, -OCi-C4alkoxyalkyl, or -NHCi-C4alkyl;

[0143] R3

[0144] Ri-Xi \ I5

[0145] In another embodiment, the ring

[0146]

[0147] R2 is selected from,

[0148]

[0149] In another embodiment, the ring

[0150]

[0151] is selected from,

[0152]

[0153]

[0154] In another embodiment, the present invention relates to the compound of formula (I) or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof is selected from:

[0155] 5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2,6-dimethyl-pyrazolo[l,5-a] pyrimidine;

[0156] 3-[l-(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-piperidin-4-yloxy]-benzonitrile;

[0157] 5-[4-(4-Methoxy-phenoxy)-piperidin-l-yl]-2,6-dimethyl-pyrazolo[l,5-a]pyrimidine;

[0158] 5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-2,6-dimethyl-pyrazolo[l,5-a]pyrimidine; 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2,6-dimethyl-pyrazolo[l,5-a] pyrimidine;

[0159] 5-[4-(Benzo[l,3]dioxol-5-yloxy)-piperidin-l-yl]-2,6-dimethyl-pyrazolo[l,5-a]pyrimidine; 5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-6-methyl-pyrazolo[l,5-a]pyrimidine;

[0160] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-pyrazolo[l,5-a] pyrimidine;

[0161] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-3,6-dimethyl-pyrazolo[l,5-a] pyrimidine;

[0162] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2,6,7-trimethyl-pyrazolo[l,5-a] pyrimidine;

[0163] 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2,6,7-trimethyl-pyrazolo[l,5-a] pyrimidine;

[0164] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-3,6,7-trimethyl-pyrazolo[l,5-a] pyrimidine;

[0165] 3-Chloro-6-(2,6-dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro-[ 1,6] naphthyridine;6-(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-3-pyrrolidin-l-yl-5,6,7,8-tetrahydro- [ 1,6]naphthyridine;

[0166] 3-Bromo-6-(2,6-dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;

[0167] 6-(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-3-methyl-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;

[0168] 6-(6-Methyl-pyrazolo[l,5-a]pyrimidin-5-yl)-3-pyrrolidin-l-yl-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;

[0169] 6-(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-3-(2-methyl-6,7-dihydro-5H-pyrazolo[l,5-a] pyrimidin-4- yl)- 5,6,7,8-tetrahydro-[1,6]naphthyridine;

[0170] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-7,8-dihydro-6H-cyclopenta[e] [ 1,2,4] triazolo [ 1, 5 - a] pyrimidine;

[0171] 5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a] pyrimidine;

[0172] 5-[4-(4-Methoxy-phenoxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a]pyrimidine; 3-[l-(6-Methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-piperidin-4-yloxy]-benzonitrile;

[0173] 5-[4-(3-Methoxy-phenoxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a]pyrimidine; 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a] pyrimidine;

[0174] 5-[4-(Benzo[l,3]dioxol-5-yloxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a]pyrimidine; 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a] pyrimidine;

[0175] 5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-6,7-dimethyl-[l,2,4]triazolo[l,5-a] pyrimidine;

[0176] 5-[4-(4-Methoxy-phenoxy)-piperidin-l-yl]-6,7-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidine; 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6,7-dimethyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0177] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6,7,8,9-tetrahydro- [ 1, 2, 4] triazolo [ 1,5-a]quinazoline;

[0178] 5-[4-(4-Methoxy-phenoxy)-piperidin-l-yl]-2,6-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidine; 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2,6-dimethyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-2,6-dimethyl-[l,2,4]triazolo[l,5-a] pyrimidine;

[0179] 3-[l-(2,6-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-piperidin-4-yloxy]-benzonitrile; 5-[4-(3-Methoxy-phenoxy)-piperidin-l-yl]-2,6-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidine; 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2,6-dimethyl-[l,2,4]triazolo[l,5-a] pyrimidine;

[0180] 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2,6,7-trimethyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0181] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2,6,7-trimethyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0182] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2-ethyl-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0183] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2-isopropyl-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0184] 2-Cyclopropyl-5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0185] 2-Cyclobutyl-5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0186] 2-Cyclopentyl-5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0187] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-2-(tetrahydro-furan- 3-yl)-[l,2,4]triazolo[l,5-a]pyrimidine;

[0188] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-2-(tetrahydro-pyran- 4-yl)-[l,2,4]triazolo[l,5-a]pyrimidine;

[0189] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-2-phenyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0190] 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-6-methyl-2-phenyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0191] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-2-pyridin-3-yl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0192] 2-Benzyl-5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-2-pyridin-2-ylmethyl- [ 1,2,4] triazolo [ 1,5 - a] pyrimidine;

[0193] 3-Bromo-6-(6-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;

[0194] 3-Methyl-6-(6-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;

[0195] 3-( l-Methyl-lH-pyrazol-4-yl)-6-(6-methyl-[ 1,2, 4]triazolo[l,5-a]pyrimidin-5-yl)-5, 6,7,8-tetrahydro-[ 1,6]naphthyridine;

[0196] 6-(6-Methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-3-pyrrolidin-l-yl-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;

[0197] 3-(6,7-Dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-6-(6-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine;

[0198] 3-(2-Methyl-6,7 -dihydro-5H-pyrazolo[ 1,5 -a]pyrimidin-4-yl)-6-(6-methyl- [ 1,2,4] triazolo[ 1,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine;

[0199] 3-Bromo-6-(6,7-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;

[0200] 6-(6,7-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-3-pyrrolidin-l-yl-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;

[0201] 3-Bromo-6-(2,6-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;

[0202] 6-(2,6-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-3-methyl-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;

[0203] 3-(6,7-Dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-6-(2,6-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine;

[0204] 6-(2,6-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-3-(2-methyl-6,7-dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine;

[0205] 3-Bromo-6-(2-isopropyl-6-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro-[ 1,6] naphthyridine;

[0206] 3-Bromo-6-(6-methyl-2-pyridin-3-yl-[ 1,2, 4]triazolo[l, 5-a]pyrimidin-5-yl)-5, 6,7,8-tetrahydro-[ 1,6]naphthyridine;

[0207] 6-(2-Benzyl-6-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-3-bromo-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;3-Bromo-6-(6-methyl-2-pyridin-2-ylmethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro-[ 1,6]naphthyridine;

[0208] 6-Methyl-5-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-[l,2,4]triazolo[l,5-a] pyrimidine;

[0209] 2,6-Dimethyl-5-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-[l,2,4]triazolo[l,5-a] pyrimidine;

[0210] 2-Ethyl-6-methyl-5-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;

[0211] 2-[4-(4-Methoxy-phenoxy)-piperidin- 1-yl] -3 -methyl -pyrimido[ 1,2-b]indazole;

[0212] 3-[l-(3-Methyl-pyrimido[l,2-b]indazol-2-yl)-piperidin-4-yloxy]-benzonitrile;

[0213] 2-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-3-methyl-pyrimido[l,2-b]indazole;

[0214] 2-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-3-methyl-pyrimido[l,2-b]indazole;

[0215] 2-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-3-methyl-pyrimido[l,2-b]indazole;

[0216] 2-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-3,7-dimethyl-pyrimido[l,2-b]indazole; 2-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-3,7-dimethyl-pyrimido[l,2-b]indazole;

[0217] 6-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-7-methyl-l,5,8a,9-tetraaza-fluorene; 6-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-7-methyl-l,5,8a,9-tetraaza-fluorene;

[0218] 6-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-7-methyl-l,5,8a,9-tetraaza-fluorene;

[0219] 6-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2,7-dimethyl- 1,5, 8a, 9-tetraaza-fluorene;

[0220] 6-[4-(4-Methoxy-phenoxy)-piperidin-l-yl] -2, 7-dimethyl- 1,5, 8a, 9-tetraaza- fluorene;

[0221] 3-Methyl-2-[3-(2-methyl-6,7-dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-7,8-dihydro-5H- [ 1,6]naphthyridin-6-yl]-pyrimido[ 1,2-b]indazole;

[0222] 2-(3-Bromo-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-3, 7 -dimethyl -pyrimido[l,2-b]indazole; 2-[3-(6,7-Dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-7,8-dihydro-5H-[l,6]naphthyridin-6-yl] -3,7 -dimethyl -pyrimido [ 1,2-b] indazole;

[0223] 6-(3-Bromo-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-7-methyl- 1,5, 8a, 9-tetraaza- fluorene; 7-Methyl-6-(3-methyl-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-l,5,8a,9-tetraaza-fluorene;6-(3-Bromo-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-2, 7 -dimethyl- 1,5, 8a, 9-tetraaza-fluorene;

[0224] 2,7-Dimethyl-6-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-l,5,8a,9-tetraaza-fluorene;

[0225] 6-(2-Ethyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2,7-dimethyl-l,5,8a,9-tetraaza-fluorene;

[0226] 6-(2-Isopropyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2,7-dimethyl-l,5,8a,9-tetraaza-fluorene;

[0227] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-[l,2,4]triazolo[l,5-a]quinazoline;

[0228] 5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-[l,2,4]triazolo[l,5-a]quinazoline;

[0229] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2-methyl-[l,2,4]triazolo[l,5-a]quinazoline;

[0230] 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2-methyl-[l,2,4]triazolo[l,5-a]quinazoline;

[0231] 5-[3-(6,7-Dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-7,8-dihydro-5H-[l,6]naphthyridin-6-yl] - [ 1,2,4] triazolo [ 1,5 -a] quinazoline;

[0232] 5-(3-Methyl-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-[l,2,4]triazolo[l,5-a]quinazoline; 5-(3-Bromo-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-2-methyl-[l,2,4]triazolo[l,5-a] quinazoline;

[0233] 2-Methyl-5-(3-methyl-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-[l,2,4]triazolo[l,5-a] quinazoline;

[0234] 2-Methyl-5-[3-(l-methyl-lH-pyrazol-4-yl)-7,8-dihydro-5H-[l,6]naphthyridin-6-yl]- [ 1, 2, 4] triazolo [ 1,5 -a] quinazoline;

[0235] 2-Methyl-5-[3-(2-methyl-6,7-dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-7,8-dihydro-5H-[l,6]naphthyridin-6-yl]-[l,2,4]triazolo[l,5-a]quinazoline;

[0236] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2-methoxy-[l,2,4]triazolo[l,5-a] quinazoline;

[0237] 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2-methoxy-[l,2,4]triazolo[l,5-a] quinazoline;

[0238] 2-Methoxy-5-(3-methyl-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-[l,2,4]triazolo[l,5-a] quinazoline;2-Methyl-5-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-[l,2,4]triazolo[l,5-a]quinazoline;

[0239] 5-(2-Ethyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-methyl-[l,2,4]triazolo[l,5-a]quinazoline;

[0240] 5-(2-Isopropyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-methyl-[l,2,4]triazolo[l,5-a]quinazoline;

[0241] 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-tetrazolo[l,5-a]quinazoline; 5-[4-(1,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-tetrazolo[1,5-a]quinazoline;

[0242] 5-(3-Bromo-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-tetrazolo[l,5-a]quinazoline; and 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-tetrazolo[l,5-a]pyrimidine.

[0243] Experimental procedure

[0244] The below scheme depicts a general process for the preparation of the compound of formula (I), wherein Xi, X2, Ri, R2, R3, R4, Ria, Rs, Rs, R9, Rio, m and A are as defined above. Further, Z is selected from the group consisting of chloro, bromo, mesylate, triflate, tosylate and others.

[0245] Scheme:

[0246] (ROm Formula-2

[0247]

[0248] Formula-4

[0249] Preparation of the compound of formula (I)

[0250] A compound of formula- 1 and formula-2 or formula-3 or formula-4 were mixed in solvent selected from water, ethanol, butanol or DMSO, preferably in water with KF (potassium fluoride) or CsF (caesium fluoride) preferably with KF, in the presence or absence of basesuch as K2CO3, EtsN, DIPEA preferably K2CO3 and heated at 100 - 120 °C for 8 to 24 h. After completion of the reaction, the reaction mass cooled to RT, extracted with solvents such as DCM or EtOAc and volatiles were removed under reduced pressure. The crude product can be purified either by trituration with some solvent such as hexanes or ether or other similar solvents or mixture of solvents or can be purified by silica-gel column chromatography to obtain the compound of formula (I).

[0251] Preparation of pharmaceutically acceptable salts of the compound of formula (I)

[0252] The compound of formula (I) can optionally be converted into its pharmaceutically acceptable salt by reaction with the appropriate acid or base. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. The salts are formed with inorganic acids e.g., hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, or organic acids e.g., oxalic, succinic, maleic, acetic, citric, malic, tartaric, benzoic, p-toluic, p-toluenesulfonic, benzenesulfonic, methanesulfonic or naphthalene sulfonic acid.

[0253] Preparation of stereoisomers of the compound of formula (I)

[0254] The stereoisomers of the compounds of formula (I) may be prepared by one or more conventional ways presented below:

[0255] a. One or more of the reagents may be used in their optically active form.

[0256] b. Optically pure catalyst or chiral ligands along with metal catalyst may be employed in the reduction process. The metal catalyst may be rhodium, ruthenium, indium and the like. The chiral ligands may preferably be chiral phosphines.

[0257] c. The mixture of stereoisomers may be resolved by conventional methods such as forming diastereomeric salts with chiral acids, chiral amines, chiral amino alcohols or chiral amino acids. The resulting mixture of diastereomers may then be separated by methods such as fractional crystallization, chromatography and the like, which is followed by an additional step of isolating the optically active product from the resolved material salt.

[0258] d. The mixture of stereoisomers may be resolved by conventional methods such as microbial resolution, resolving the diastereomeric salts formed with chiral acids or chiral bases. Chiral acids that can be employed may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids and the like. Chiral bases that can beemployed may be cinchona alkaloids, brucine or a basic amino acid such as lysine, arginine and the like.

[0259] In another embodiment, the suitable pharmaceutically acceptable salt includes acetate, hydrochloride, hydrobromide, oxalate, fumarate, tartrate, maleate, benzoate, mesylate and succinate.

[0260] In another embodiment of the present invention, the compound of formula (I) or an isotopic form, a stereoisomer or a pharmaceutically acceptable salt thereof, for use as muscarinic M4 receptor positive allosteric modulators (PAMs).

[0261] In another embodiment of the present invention, the compound of formula (I) or an isotopic form, a stereoisomer or a pharmaceutically acceptable salt thereof, for use in the manufacture of medicament for treating or preventing diseases or disorders mediated by muscarinic M4 receptors.

[0262] In another embodiment, the present invention relates to a method of treating or preventing diseases or disorders mediated by muscarinic M4 receptors in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of the compound of formula (I) or an isotopic form, a stereoisomer or a pharmaceutically acceptable salt thereof.

[0263] In another embodiment, the present invention relates to a method of treating or preventing diseases or disorders mediated by muscarinic M4 receptors, wherein the diseases or disorders are selected from psychiatric disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

[0264] In another embodiment, the present invention relates to a compound of formula (I), or an isotopic form, or a stereoisomer or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or disorders selected from psychiatric disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

[0265] In another embodiment, the present invention relates to use of the compound of formula (I), or an isotopic form, a stereoisomer or a pharmaceutically acceptable salt thereof, for the treatment of diseases or disorders selected from psychiatric disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

[0266] In another embodiment, the present invention relates to use of the compound of formula (I), or an isotopic form, a stereoisomer or a pharmaceutically acceptable salt thereof, in the manufacture of medicament in an amount sufficient to treat or reduce a symptom of a neurological, psychiatric or cognitive disorders.In some embodiments the neurological or psychiatric disorder involves a psychosis or psychotic symptoms.

[0267] In some embodiments, the neurological, psychiatric or cognitive disorders can be an Alzheimer’s disease (AD), schizophrenia, psychosis, Parkinson’s disease (PD), depression, bipolar disorder, Huntington’s disease, cognitive dysfunction in Alzheimer’s disease, Attention deficit hyperactivity disorder (ADHD), pain disorder, or drug addiction.

[0268] In some embodiments, the neurological, psychiatric or cognitive disorder are associated with an M4 receptor activity or is M4 receptor mediated.

[0269] In another embodiment, the present invention comprises a pharmaceutical composition comprising the compound of formula (I), or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients, for use in the treatment of disease or disorder mediated by muscarinic M4 receptors, wherein said disease or disorder is selected from psychiatric disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

[0270] In another embodiment, the present invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise the compound of formula (I), or an isotopic form, a stereoisomer or a pharmaceutically acceptable salt thereof, of the invention presented with a pharmaceutically acceptable carrier. The carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, pills, tablets, coated tablets, capsules, powder, granules, pellets, patches, implants, films, liquids, semi-solids, gels, aerosols, emulsions, elixirs and the like.

[0271] The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and compositions, for example, may be administered orally, rectally, parenterally, intra-ocular, intra-nasal or topically.

[0272] The dose of the active compounds can vary depending on factors such as age and weight of patient, nature and severity of the disease to be treated and other factors. Therefore, any reference regarding therapeutically effective amounts of the compounds of general formula (I), stereoisomers and pharmaceutically acceptable salts thereof refer to the aforementioned factors.

[0273] The following abbreviations are used hereinAch Acetylcholine

[0274] CDCl3Deuterated chloroform

[0275] Cs2CO3Cesium carbonate

[0276] CsF Cesium fluoride

[0277] DCM Dichloromethane

[0278] DIPEA Diisopropylethylamine

[0279] DMAP 4-(Dimethylamino)pyridine

[0280] DMF N, N -Dimethyl formamide

[0281] DMSO Dimethylsulfoxide

[0282] Emax Maximal effect or receptor activity

[0283] EC50Half maximal effective concentration

[0284] EtOAc Ethyl Acetate

[0285] Et3N Triethylamine

[0286] g Gram

[0287] h Hour(s)

[0288] hM4 PAM human muscarinic M4 Positive Allosteric Modulator K2CO3Potassium carbonate

[0289] KF Potassium Fluoride

[0290] KOlBu Potassium tert-butoxide

[0291] MeOH Methanol

[0292] mL Millilitre

[0293] mmol Millimole

[0294] NaHCO3Sodium bicarbonate

[0295] Na2SO4Sodium sulphate

[0296] POC13Phosphoryl chloride

[0297] ppm Parts per million

[0298] RT Room Temperature

[0299] TLC Thin Layer Chromatography

[0300] mAChR Muscarinic acetylcholine receptor

[0301] EXAMPLES

[0302] The compounds of the present invention were prepared according to the following experimental procedures, using appropriate materials and conditions. The followingexamples are provided by way of illustration only but not to limit the scope of the present invention.

[0303] Preparation of Intermediates:

[0304] Intermediate- 1: 2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin-5-ol

[0305]

[0306] Intermediate-1

[0307] To a stirred solution of 5-Methyl-2H-pyrazol-3-ylamine (0.50 g, 5.74 mmol) in DMF (8.0 mL), were added CS2CO3 (2.8 g, 8.6 mmol) and 3-ethoxy-2-methyl-acrylic acid ethyl ester (1.36 g, 8.60 mmol) sequentially at RT. The reaction mixture was heated to 120 °C for 10 hours (h) until completion of the reaction. The reaction mass was cooled to RT, solvent DMF was removed under reduced pressure and the crude product was diluted with water, extracted multiple times with DCM and combined organic layer was dried over anhydrous Na₂SO₄ and the solvent was removed under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography using 2 - 10 % gradient mixture of MeOH in DCM to obtain the title compound. Yield: 0.43 g (46 %).1H - NMR (400 MHz, DMSO-d6): 5 11.95 (s, 1H), 8.29 (s, 1H), 5.60 (s, 1H), 2.19 (s, 3H), 1.90 (s, 3H), Mass (m / z); 164.0 (M+H)+.

[0308] The starting materials, the substituted aminopyrazoles or aminotriazols as used in the above reaction were either procured commercially or prepared using the procedures reported in Molecules 2011, 16, 8083-8097; doi:10.3390 / molecules 16098083.

[0309] The below intermediates-2 to 19 were prepared by following the intermediate- 1 experimental procedure given above with some non-critical variations.

[0310] Intermediate Chemical structure and

[0311] Characterization Data No. IUPAC Name

[0312] ’H - NMR (400 MHz, CDCI3): 5 10.22 (bs, 1H), 8.06 (s, 1H), 7.67 (d, J = 2 2.4Hz, 1H), 5.89 (d, J = 2.4Hz, 1H),

[0313] 6-Methyl-pyrazolo[l,5- 2.12 (s, 3H); Mass (m / z); 149.9 a]pyrimidin-5-ol (M+H)+.

[0314] ’H - NMR (400 MHz, DMSO-d6): 5 3 8.00 (s, 1H), 7.60 (s, 1H), 5.57 (bs,

[0315] 1H), 1.83 (s, 3H); Mass (m / z); 149.0 6-Methyl-[l,2,4]triazolo[l,5- (M-H)+.

[0316]

[0317] a]pyrimidin-5-ol

[0318] ’H - NMR (400 MHz, DMS0-d6): 5 12.89 (s, 1H), 8.47 (s, 1H), 2.27 (s, 2,6-Dimethyl- 3H), 1.93 (s, 3H); Mass (m / z); 164.9 [ 1,2,4]triazolo[ 1,5-a]pyrimidin- (M+H)+.

[0319] 5-ol

[0320] HO^N^N ’H - NMR (400 MHz, DMSO-d6): 5 12.87 Xk^A (bs, 1H), 7.86 (s, 1H), 2.49-2.46 (m, 2H),

[0321] 1.79 (s, 3H), 1.18 (t, 3H); Mass (m / z); 2-Ethyl-6-methyl- 179.0 (M+H)+.

[0322] [ 1,2,4] tri azo Io 11,5-a]pyrimidin-5- ol

[0323] 1H - NMR (400 MHz, DMSO-d6): 5 12.88 (bs, 1H), 8.49 (s, 1H) 3.01-2.92 (m, 1H), 2.89 (s, 3H) 1.25 (d, J = 6.8Hz, 6H); Mass 2-Isopropyl-6-methyl- (m / z); 193.0 (M+H)+.

[0324] [ 1,2,4] tri azo Io 11,5-a]pyrimidin-5- ol

[0325] HO^N^ AJ

[0326] 1H - NMR (400 MHz, DMSO-d6): 5 12.84 (bs, 1H), 8.41 (s, 1H) 2.10-1.94 (m, 1H), 1.93 (s, 3H), 0.99-0.93 (m, 2H), 0.87-0.82 2-Cyclopropyl-6-methyl- (m, 2H); Mass (m / z); 191.0 (M+H)+.

[0327] [ 1,2,4] triazolof 1,5-a]pyrimidin-5- ol

[0328] 1H - NMR (400 MHz, DMSO-d6): 5 12.90HX TH > (bs, 1H), 8.45 (s, 1H) 3.55-3.50 (m, 1H),

[0329] 2.30-2.24 (m, 4H), 2.07-1.97 (m, 1H), 1.94 2-Cyclobutyl-6-methyl- (s, 3H), 1.92-1.85 (m, 1H); Mass (m / z);

[0330] [ 1,2,4] triazolof 1,5-a]pyrimidin-5- 205.1 (M+H)+.

[0331] ol

[0332] 1H - NMR (400 MHz, DMSO-d6): 5 12.87 (bs, 1H), 8.46 (s, 1H) 3.15-3.07 (m, 1H), X X 2.01-1.95 (m, 2H), 1.93 (s, 3H), 1.85-1.58

[0333] (m, 6H); Mass (m / z); 219.0 (M+H)+.

[0334]

[0335] 2-Cyclopentyl-6-methyl-[ 1,2,4] triazolo[ 1,5-a]pyrimidin-5- ol

[0336] 1H - NMR (400 MHz, DMSO-d6): 8 12.95 X xK?

[0337] (bs, 1H), 8.56 (s, 1H) 4.04-3.98 (m, 1H), 3.87-3.73 (m, 4H), 2.28-2.10 (m, 2H), 1.94 6-Methyl-2-(tetrahydro-furan-3- (s, 3H); Mass (m / z); 220.9 (M+H)+. yl)- [ 1,2,4] triazolo[ 1,5- a]pyrimidin-5-ol

[0338] 1H - NMR (400 MHz, DMSO-d6): 8 12.93 (bs, 1H), 8.50 (s, 1H) 3.91-3.86 (m, 2H), 3.47-3.41 (m, 2H), 2.98-2.90 (m, 1H), 1.93 (s, 3H), 1.90-1.84 (m, 2H), 1.76-1.66 (m, 2H); Mass (m / z); 234.9 (M+H)+.

[0339] 6-Methyl-2-(tetrahydro-pyran-4- yl)- [ 1,2,4] triazolo[ 1,5- a]pyrimidin-5-ol

[0340] 1H - NMR (400 MHz, DMSO-d6): 8 13.10 (bs, 1H), 8.62 (s, 1H), 8.03 (dd, J = 2.0, ox

[0341] 8.0Hz, 2H), 7.52-7.45 (m, 3H), 1.98 (s, 6-Methyl-2-phenyl- 3H); Mass (m / z); 225.0 (M-H)+.

[0342] [ 1,2,4] triazolo[ 1,5-a]pyrimidin-5- ol

[0343] z=N

[0344] 1H - NMR (400 MHz, DMSO-d6): 8 13.20 x x o

[0345] (bs, 1H), 9.18 (s, 1H), 8.68-8.66 (m, 2H), 8.34-8.32 (m, 1H), 7.56-7.53 (m, 1H), 2.49 6-Methyl-2-pyridin-3-yl- (s, 3H); Mass (m / z); 227.8 (M+H)+.

[0346] [ 1,2,4] triazolo[ 1,5-a]pyrimidin-5- ol

[0347] 1H - NMR (400 MHz, DMSO-d6): 8 12.89 (bs, 1H), 8.48 (s, 1H), 7.32-7.28 (m, 4H), 7.25-7.19 (m, 1H), 3.97 (s, 2H), 1.93 (s, 2-Benzyl-6-methyl- 3H); Mass (m / z); 241.1 (M+H)+.

[0348] [ 1,2,4] triazolo[ 1,5-a]pyrimidin-5- ol

[0349] 1H - NMR (400 MHz, DMSO-d6): 8 12.92 (bs, 1H), 8.51 (s, 1H), 8.47 (d, J = 4.8Hz, 1H), 7.75 (t, 1H), 7.35 (d, J = 7.6Hz, 1H), 7.26 (dd, 7 = 7.6, 4.8Hz, 1H), 4.13 (s, 2H), 1.93 (s, 3H); Mass (m / z); 242.0 (M+H)+.

[0350]

[0351] 6-Methyl-2-pyridin-2-ylmethyl- [ 1,2,4] tri azo Io 11,5-a]pyrimidin-5- ol

[0352] ’H - NMR (400 MHz, CDCl3): δ 13.23 (bs, 1H), 8.35 (d, J = 1.2Hz, 1H), 7.77 (d, J = 8.8Hz, 1H), 7.62 (d, J = 8.8Hz, 16

[0353] 1H), 7.42 (t, 1H), 7.09 (t, 1H), 2.28 (s, 3 -Methyl-pyrimido [1,2- 3H); Mass (m / z); 198.1 (M-H)+.

[0354] b]indazol-2-ol

[0355] ’H - NMR (400 MHz, DMSO-d6): δ 13.22 (bs, 1H), 8.78 (s, 1H), 7.73 (d, J = 8.4Hz, 1H), 7.11 (d, J = 6.4Hz, 1H), 17

[0356] 6.88 (dd, J = 6.8, 8.4Hz, 1H), 2.46 (s, 3,7 -Dimethyl-pyrimido [1,2- 3H), 2.07 (s, 3H); Mass (m / z); 211.8 b]indazol-2-ol (M-H)+.

[0357] ’H - NMR (400 MHz, DMSO-d6): δ 13.41 (bs, 1H), 8.79 (s, 1H), 8.65 (d, J 18 = 2.4Hz, 1H), 8.32 (d, J = 8.0Hz, 1H),

[0358] 7 -Methyl- 1,5,8a,9-tetraaza- 7.04 (dd, J = 4.0, 8.0Hz, 1H), 2.09 (s, fluoren-6-ol 3H); Mass (m / z); 199.0 (M-H)+.' HO } — ’H - NMR (400 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.15 (s, 1H), 7.89 (d, J = 19 8.0Hz, 1H), 6.53 (d, J = 8.0Hz, 1H),

[0359] 2,7-Dimethyl-l,5,8a,9-tetraaza- 2.44 (s, 3H), 1.92 (s, 3H); Mass (m / z);

[0360] 215.1 (M+H)+.

[0361]

[0362] fluoren-6-ol

[0363] Intermediate-20: 6,7-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-ol

[0364]

[0365] Intermediate-20

[0366] To the stirred solution of 3-methyl-4H-[l,2,4]triazole (0.50 g, 5.94 mmol) in absolute ethanol (2.3 mL), ethyl 2-methyl-3 -oxo-butyrate (0.86 g, 5.95 mmol) and sodium ethoxide solution (21% w / v, 2.3 mL) were added sequentially at RT. The reaction mixture was heated to 90 °C for 8 h until completion of the reaction. The reaction mass was cooled to RT, volatiles were removed under reduced pressure and the crude product was diluted with water, extracted multiple times with EtOAc and combined organic layer was dried overanhydrous Na₂SO₄ and the solvent was removed under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography using 2 - 10 % gradient mixture of MeOH in DCM to obtain the title compound. Yield: 0.4 g (41 %).1H - NMR (400 MHz, CDCl3): δ 11.93 (bs, 1H), 8.04 (s, 1H), 2.47 (s, 3H), 2.16 (s, 3H); Mass (m / z); 163.0 (M-H)+.

[0367] The below intermediates 21 to 25 were prepared by following the intermediate -20 experimental procedure with some non-critical variations.

[0368] Chemical structure and IUPAC

[0369] Intermediate Characterization Data Name

[0370] ’H - NMR (400 MHz, DMSO-d6): δ 11.91 (bs, 1H), 2.31 (s, 3H), 2.29

[0371] (s, 3H), 1.94 (s, 3H); Mass (m / z); 2,6,7-Trimethyl-[l,2,4]triazolo[l,5- 177.2 (M-H)+.

[0372] a]pyrimidin-5-ol

[0373] HO^. N^^

[0374] ’H - NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1H), 5.84 (s, 1H), 2.26 22

[0375] (d, J = 3.2Hz, 6H), 1.93 (s, 3H); 2,6,7-Trimethyl-pyrazolo[l,5- Mass (m / z); 176.2 (M-H)+. a]pyrimidin-5-ol

[0376] HO^N- V

[0377] ’H - NMR (400 MHz, DMSO-d6): δ 11.91 (bs, 1H), 7.38 (s, 1H), 2.20

[0378] (s, 3H), 2.06 (s, 3H), 1.98 (s, 3H); 3,6,7-Trimethyl-pyrazolo[l,5- Mass (m / z); 177.9 (M+H)+.

[0379] a]pyrimidin-5-ol

[0380] HOx^NN

[0381] ’H - NMR (400 MHz, DMSO-d6): / A A

[0382] 511.89 (bs, 1H), 7.13 (s, 1H), 2.23 24

[0383] 7,8-Dihydro-6H- (t, 2H), 1.87 (t, 2H), 1.61-1.45 (m, cyclopenta[e] [ 1,2,4] triazolo[ 1,5- 2H); Mass (m / z); 175.2 (M-H)+. a]pyrimidin-5-ol

[0384] HO^N^N ’H - NMR (400 MHz, DMSO-d6): XT?

[0385] 25 5 11.90 (bs, 1H), 7.78 (s, 1H), 2.69

[0386] (t, 2H), 2.45 (t, 2H), 1.77-1.73 (m, 6,7,8,9-Tetrahydro- 4H); Mass (m / z); 189.1 (M-H)+.

[0387]

[0388] [ 1,2,4] triazolo [ 1,5 -a] quinazolin-5-ol

[0389]

[0390] The intermediate 26 to intermediate 28 have been prepared by following the procedures as described in Synthetic communications, 2015, 45, 2426 and J. Heterocyclic Chem., 2011, 48, 656.

[0391] Chemical structure and IUPAC

[0392] Intermediate Characterization Data Name

[0393] o

[0394] ’H - NMR (400 MHz, CDCl3): δ 8.42, (d, J = 9.2Hz, 1H), 8.14 (d, J 26 = 8Hz, 1H), 8.11 (s, 1H), 7.91- 7.87 (t, 1H), 7.58-7.54 (t, 1H), N= /

[0395] 4H-[l,2,4]Triazolo[l,5- Mass (m / z); 185.0 (M-H)+.

[0396] a] quinazolin- 5 -one

[0397] 0 ’H - NMR (400 MHz, CDCl3): δ 8.18

[0398] 27 / =\ (d, J = 8.8, 1H), 7.95 (d, 7 = 8,

[0399] <\ / )— N A 1H), 7.93 (t, 1H), 7.55 (t, 1H),

[0400] 2.32 (s, 3H), Mass (m / z); 201.0 2-Methyl-4H- [ 1,2,4]triazolo[ 1,5 - (M+H)+.

[0401] a] quinazolin- 5 -one

[0402] O ’H - NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.8, 1H), 7.92-7.88 (t, / =\ )=N 1H), 7.84 (d, J = 8.4, 1H), 7.51 (t, 28

[0403] 1H), 3.98 (s, 3H); Mass (m / z); " N^OCH3

[0404] 216.9 (M+H)+.

[0405] 2-Methoxy-4H- [ 1,2,4]triazolo[ 1,5- a] quinazolin- 5 -one

[0406]

[0407] The below intermediates 29 and 30 have been prepared by following the procedures as described in US4085213A application.

[0408] Chemical structure and IUPAC

[0409] Intermediate Characterization Data Name

[0410] O

[0411] ’H - NMR (400 MHz, DMSO-d6): δ 13.45 (bs, 1H), 8.25 (d, J =

[0412] N=N 8,2Hz, 2H), 8.04 (t, 1H), 7.74 (t, 4H-Tetrazolo [ 1,5-a] quinazolin-5- 1H). Mass (m / z); 187.9 (M+H)+.

[0413] one

[0414]

[0415] ’H - NMR (400 MHz, CDCl3): 5

[0416] 8.33 (s, 1H), 2.21 (s, 3H). Mass (m / z); 150.0 (M+H)+.

[0417] 6-Methyl-4H-tetrazolo[ 1,5 - a]pyrimidin-5-one

[0418]

[0419] Intermediate-31: 5-Chloro-2,6-dimethyl-pyrazolo[l,5-a]pyrimidine

[0420]

[0421] Intermediate- 1 Intermediate-31

[0422] The stirred solution of 2,6-dimethyl-pyrazolo[l,5-a]pyrimidin-5-ol (0.20 g, 1.23 mmol, intermediate- 1) in POCI3 (2.5 mL), gradually heated to 100 °C for 4 h until completion of the reaction. The reaction mass was cooled to RT, volatiles were removed under reduced pressure. The crude product was basified with aqueous NaHCO3, extracted multiple times with EtOAc and the combined organic layer was dried over anhydrous Na2SO4and the solvent was removed under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography using 10 - 20 % gradient mixture of EtOAc in hexanes to obtain the title compound. Yield: 0.18 g (81 %). ’H - NMR (400 MHz, CDCl3): 5 ’H - NMR (400 MHz, CDCI3): 5 8.36 (s, 1H), 6.35 (s, 1H), 2.48 (s, 3H), 2.35 (s, 3H); Mass (m / z); 182.1 (M+H)+.

[0423] The below intermediates 32 to 61 were prepared by following the intermediate 31 experimental procedure with some non-critical variations.

[0424] Intermediate Chemical structure and IUPAC

[0425] Characterization Data No. Name

[0426] 1H - NMR (400 MHz, CDCl3): δ 8.50 32 (s, 1H), 8.06 (d, J = 2.0Hz, 1H), 6.58

[0427] (d, J = 1.6Hz, 1H), 2.41 (s, 3H); 5-Chloro-6-methyl-pyrazolo[l,5- Mass (m / z); 167.8, 169.5 (M+H)+. a]pyrimidine

[0428] 1H - NMR (400 MHz, CDCl3): δ 8.67 33 (s, 1H), 8.44 (s, 1H), 2.48 (s, 3H);

[0429] 'XX

[0430] Mass (m / z); 169.2 (M+H)+.

[0431] 5-Chloro-6-methyl-

[0432]

[0433] [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0434] 1H - NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 2.60 (s, 3H), 2.44 (s, 3H); 5-Chloro-2,6-dimethyl- Mass (m / z); 183.0, 185.0 (M+H)+.

[0435] [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0436] 1H - NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 2.98-2.92 (m, 2H), 2.44 (s, 3H), 1.43 (t, 3H); Mass (m / z); 197.0, 5-Chloro-2-ethyl-6-methyl- 199.0 (M+H)+.

[0437] [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0438] 1H - NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 3.28-3.21 (m, 1H), 2.43 (s,

[0439] 3H), 1.43 (d, J = 6.8Hz, 6H); Mass 5-Chloro-2-isopropyl-6-methyl- (m / z); 211.0, 213.1 (M+H)+.

[0440] [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0441] 1H - NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 2.42 (s, 3H), 2.22-2.15 (m, 1H), 1.22-1.17 (m, 2H), 1.15-1.08 5-Chloro-2-cyclopropyl-6- (m, 2H); Mass (m / z); 209.0, 211.0 methyl-[ 1,2,4] triazolo[ 1,5- (M+H)+.

[0442] a]pyrimidine

[0443] 1H - NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 3.85-3.76 (m, 1H), 2.57-2.38 (m, 4H), 2.43 (s, 3H), 2.18-1.98 (m, -Chloro-2-cyclobutyl-6-methyl- 2H); Mass (m / z); 223.0, 225.0 [ 1,2,4]triazolo[ 1,5-a]pyrimidine (M+H)+.

[0444] 1H - NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 3.41-3.32 (m, 1H), 2.43 (s, w 3H), 2.19-2.09 (m, 2H), 2.13-1.93

[0445] (m, 2H), 1.90-1.80 (m, 2H), 1.77- -Chloro-2-cyclopentyl-6-methyl- 1.66 (m, 2H); Mass (m / z); 236.9, [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0446] 238.9 (M+H)+.

[0447] 1H - NMR (400 MHz, CDCl3): δ 8.56 (s, 1H), 4.26-4.20 (m, 1H), 4.10-4.02 X rK? (m, 2H), 4.0-3.95 (m, 1H), 3.78-3.71 -Chloro-6-methyl-2-(tetrahydro- (m, 1H), 2.50-2.40 (m, 2H), 2.44 (s, furan-3 -yl)- [ 1,2,4] triazolo [1,5- 3H); Mass (m / z); 238.9, 241.0

[0448] (M+H)+.

[0449]

[0450] a]pyrimidine1H - NMR (400 MHz, CDCl3): 58.56

[0451] (s, 1H), 4.10-4.04 (m, 2H), 3.62-3.53 (m, 2H), 3.24-3.14 (m, 1H), 2.44 (s, -Chloro-6-methyl-2-(tetrahydro- 3H), 2.10-1.98 (m, 4H); Mass (m / z); pyran-4-yl)-[l,2,4]triazolo[l,5- 252.9, 254.9 (M+H)+.

[0452] a]pyrimidine

[0453] cXr^1H - NMR (400 MHz, CDCl3): δ 8.64

[0454] (s, 1H), 8.31-8.28 (m, 2H), 7.51-7.47 (m, 3H), 2.47 (s, 3H); Mass (m / z); 5-Chloro-6-methyl-2-phenyl- 245.0, 247.0 (M+H)+.

[0455] [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0456] ’H - NMR (400 MHz, CDCl3): δ 9.51 (s, 1H), 8.73-8.72 (m, 1H), 8.67 (s, 1H), 8.57-8.54 (m, 1H), 7.46-7.42 5-Chloro-6-methyl-2-pyridin-3- (m, 1H), 2.49 (s, 3H); Mass (m / z);

[0457] yl- [ 1,2,4] triazolo [1,5- 246.0, 248.0 (M+H)+.

[0458] a]pyrimidine

[0459] 1H - NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 7.40 (d, J = 7.6Hz, 2H), 7.33- b 7.28 (m, 2H), 7.25-7.20 (m, 1H), 4.25

[0460] (s, 2H), 2.42 (s, 3H); Mass (m / z); 2-Benzyl-5-chloro-6-methyl- 259.0, 261.0 (M+H)+.

[0461] [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0462] C^N N

[0463] ’H - NMR (400 MHz, CDCl3): δ 8.58-8.54 (m, 2H), 7.66 (t, 1H), 7.40 (d, J = 8.0Hz, 1H), 7.18 (dd, J = 4.8, 7.2Hz, 1H), 4.47 (s, 2H), 2.43 (s, 5-Chloro-6-methyl-2-pyridin-2- 3H); Mass (m / z); 260.0, 262.0 ylmethyl- [ 1,2,4] triazolo [1,5- (M+H)+.

[0464] a]pyrimidine

[0465] ’H - NMR (400 MHz, CDCl3): δ 6.41 (s, 1H), 2.58 (s, 3H), 2.53 (s, 3H), 2.40 (s, 3H); Mass (m / z); 195.5 5-Chloro-2,6,7-trimethyl- (M+H)+.

[0466]

[0467] pyrazolo[ 1,5-a]pyrimidineCIX ^ X^ N;

[0468] 1H - NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 2.73 (s, 3H), 2.49 (s, 3H);

[0469] Mass (m / z); 182.5 (M+H)+.

[0470] 5-Chloro-6,7-dimethyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0471] 1H - NMR (400 MHz, CDCl3): δ 2.69 (s, 3H), 2.64 (s, 3H), 2.45 (s, 3H); Mass (m / z); 197.1 (M+H)+.

[0472] 5-Chloro-2,6,7-trimethyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0473] Ci^N. V1H - NMR (400 MHz, CDCl3): δ 8.40

[0474] (s, 1H), 7.89 (s, 1H), 2.36 (s, 3H), 2.33 (s, 3H); Mass (m / z); 181.9, 5-Chloro-3,6-dimethyl- 183.1 (M+H)+.

[0475] pyrazolo[ 1,5-a]pyrimidine

[0476] 1H - NMR (400 MHz, CDCl3): δ 7.93 (s, 1H), 2.61 (s, 3H), 2.42 (s, 3H), ^^jXN'N

[0477] 2.36 (s, 3H); Mass (m / z); 196.3, 5-Chloro-3,6,7-trimethyl- 198.0 (M+H)+.

[0478] pyrazolo[ 1,5-a]pyrimidine

[0479] C1X^NX^N

[0480] 1H - NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 3.30-3.10 (m, 2H), 2.45-2.25 (m, 2H), 1.70-1.55 (m, 2H); Mass 5-Chloro-7,8-dihydro-6H- (m / z); 194.9 (M+H)+. cyclopenta[e] [ 1,2,4] triazolo [1,5- a]pyrimidine

[0481] 1H - NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 3.12 (t, 2H), 2.94 (t, 2H),

[0482] 2.00-1.93 (m, 4H); Mass (m / z); 208.7 5-Chloro-6,7,8,9-tetrahydro- (M+H)+.

[0483] [ 1,2, 4] triazolo [ 1,5-a]quinazoline

[0484] Cl1H - NMR (400 MHz, CDCl3): 58.54 \=N

[0485] (s, 1H), 8.42, (d, J = 8.8, 1H), 8.40 / =\

[0486] <\ / )— N J (d, J = 8.8, 1H), 8.10 (t, 1H), 7.77 (t, v— 'J NT 1H), (m / z); 205.1 (M+H)+.

[0487]

[0488] 5-Chloro- [ 1,2,4] triazolo [1,5-a]quinazoline

[0489] Cl

[0490] \=N1H - NMR (400 MHz, CDCl3): δ 8.42 (d, J = 8.8, 1H), 8.39 (d, J = 9.6, <\ / )— N J 1H), 8.05 ((t, 1H), 7.71 (t, 1H), 2.67 v—

[0491] 5-Chloro-2-methyl- (s, 3H), Mass (m / z); 219.1 (M+H)+.

[0492] [ 1,2,4]triazolo[ 1,5-a]quinazoline

[0493] Cl

[0494] 5=N ’H - NMR (400 MHz, CDCl3): δ 8.34-8.32 (m, 2H), 8.04 (t, 1H), 7.68 z>— N J

[0495] " N^OCH3(t, 1H), 4.19 (s, 3H); Mass (m / z); 5-Chloro-2-methoxy- 234.8 (M+H)+.

[0496] [ 1,2,4]triazolo[ 1,5-a]quinazoline

[0497] ’H - NMR (400 MHz, CDCl3): δ 8.80 (d, J = 2.0Hz, 1H), 8.27 (d, J = ( / N c 8.4Hz, 1H), 7.82 (d, J = 8.4Hz, 1H),

[0498] 7.64-7.60 (m, 1H), 7.33-7.30 (m, -Chloro-3-methyl-pyrimido[ 1,2- 1H), 2.54 (s, 3H); Mass (m / z); 217.9, b] indazole

[0499] 219.9 (M+H)+.

[0500] ’H - NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 8.35 (d, J = 8.4Hz, 1H), 7.40

[0501] (d, J = 6.8Hz, 1H), 7.23 (dd, J = 6.8, 8.4Hz, 1H), 2.71 (s, 3H), 2.53 (s, 2-Chloro-3,7 -dimethyl - 3H); Mass (m / z); 231.9, 234.0 pyrimido [ 1,2-b] indazole

[0502] (M+H)+.

[0503] 1H - NMR (400 MHz, CDCl3): δ 8.96 (dd, J= 1.6, 4.4Hz, 1H), 8.91 (s, 1H), / N O 8.61 (d, J = 8.4Hz, 1H), 7.29 (t, 1H), 6-Chloro-7 -methyl- 1,5, 8a, 9- 2.59 (s, 3H); Mass (m / z); 218.7, tetraaza-fluorene 221.3 (M+H)+.

[0504] ’H - NMR (400 MHz, CDCl3): δ 8.87

[0505] (s, 1H), 8.45-8.43 (d, J = 8.0Hz, 1H), T T?--N

[0506] >^N'N 7.16-7.14 (d, J = 8.0Hz, 1H), 2.78 (s,

[0507] 3H), 2.54 (s, 3H); Mass (m / z); 233.0 6-Chloro-2,7 -dimethyl- 1, 5,8a, 9- (M+H)+.

[0508] tetraaza-fluorene

[0509]

[0510] Cl

[0511] ’H - NMR (400 MHZ, CDCl3): 5 8.70 nrS (d, J = 8.4Hz, 1H), 8.52 (d, J 60

[0512] XN= 8.4, 1H), 8.23 (t, 1H), 7.95 (t, 1H). N=N Mass (m / z); 205.7, 207.9 (M+H)+. 5 -Chloro-tetrazolo [1,5- a]quinazoline

[0513] Cl

[0514] ’H - NMR (400 MHZ, CDCl3): 5 8.36 61 Vi (s, 1H), 2.32 (s, 3H). Mass (m / z);

[0515] NXN

[0516] N=N 169.8, 171.8 (M+H)+.

[0517] 5-Chloro-6-methyl-tetrazolo[ 1,5- a]pyrimidine

[0518]

[0519] Intermediate-62: 3-Bromo-5,6,7,8-tetrahydro-[l,6]naphthyridine hydrochloride

[0520]

[0521] Step-4 Step-5 Intermediate-62

[0522] Step-1: Synthesis of 3,5-Dinitro-lH-pyridin-2-one:

[0523] To the stirred concentrated sulphuric acid (52.0 mL), cooled to 0 °C, potassium nitrate (18.6 g, 184.2 mmol) was added over a period of 0.5 h. The 2 -hydroxypyridine (5.0 g, 52.6 mmol) then added at once. The reaction temperature then slowly raised to 60 °C and stirred at this temperature for 4 h. The reaction mass was cooled to RT, transferred to crushed ice over a period of 0.5 h and extracted multiple times with EtOAc. The combined organic layer washed once with brine solution, dried over anhydrous Na2SO4and the solvent removed under reduced pressure to obtain above titled compound (5.8 g) in 59% yield. H - NMR (400 MHz, DMSO): 5 13.92 (bs, 1H), 9.06 (d, J = 2.8 Hz, 1H), 8.99 (d, J = 3.2 Hz, 1H); Mass (m / z): 184.1 (M-H)+

[0524] Step-2: Synthesis of l-Methyl-3,5-dinitro-lH-pyridin-2-one:To the stirred solution of step-1 compound (24.0 g, 129.7 mmol) in DMF (72.0 mL) cooled to 0 °C was added potassium carbonate (35.8 g, 259.4 mmol) followed by methyl iodide (18.4 g, 129.7 mmol) over a period of 0.5 h. The reaction temperature was gradually raised to RT. After 2 h at RT the reaction mass was subjected to vacuum distillation below 50 °C to remove solvent DMF. The residue thus obtained was triturated with solvent ether to obtain l-methyl-3,5-dinitro-lH-pyridin-2-one (24.0 g) in 93% yield. H - NMR (400 MHz, DMSO-d6): 5 9.60 (d, J =3.2Hz, 1H), 9.024 (d, J = 3.2Hz, 1H), 3.68 (s, 3H); Mass (m / z); 199.6 (M+H)+.

[0525] Step-3: Synthesis of 3-Nitro-7,8-dihydro-5H-[l,6]naphthyridine-6-carboxylic acid tertbutyl ester:

[0526] To the stirred methanolic ammonia solution (7M, 100.0 mL), step-2 compound (10.0 g, 50.3 mmol) followed by N-Boc-piperidone (10.0 g, 50.3 mmol) was added at RT. The reaction temperature was gradually raised and was stirred at reflux temperature for 12 h. The volatiles were removed under reduced pressure and crude product was purified by silica gel column to obtain above titled compound (9.5 g) as yellow solid in 67% yield. H - NMR (400 MHz, CDCl3): 5 9.25 (s, 1H), 8.23 (s, 1H), 4.71 (s, 2H), 3.81-3.78 (m, 2H), 3.13-3.10 (m, 2H), 1.49 (s, 9H); Mass (m / z); 280.0 (M+H)+

[0527] Step-4: 3-Amino-7,8-dihydro-5H-[l,6]naphthyridine-6-carboxylic acid tert-butyl ester:

[0528] To the stirred solution of intermediate step-3 compound (10.0 g, 35.8 mmol) in methanol (143.0 mL) at RT, Pd / C (5% w / w, 2.0 g) was added. The reaction mass was stirred under hydrogen atmosphere for 5 h. Once the reaction was completed then the reaction mass was filtered to remove Pd / C, volatiles were evaporated to obtain above titled compound (8.2 g) as gummy liquid in 91% yield. ’H - NMR (400 MHz, CDCI3): 57.93 (s, 1H), 6.73 (s, 1H), 4.49 (s, 2H), 3.73-3.70 (m, 2H), 3.64 (s, 2H), 2.89-2.86 (m, 2H), 1.49 ( s, 9H ) Mass (m / z); 249.8 (M+H)+

[0529] Step-5: Synthesis of 3-Bromo-7,8-dihydro-5H-[l,6]naphthyridine-6-carboxylic acid tert-butyl ester:

[0530] To the stirred solution of intermediate step-4 compound (10.0 g, 40.2 mmol) in acetonitrile (143.0 mL) at RT, CuBr (12.5 g, 56.2 mmol) followed by tert-butylnitrite (4.96 g, 48.2 mmol) was added. After stirring for 6 h at RT, the reaction mass was diluted with water and extracted multiple times with chloroform. The combined organic layer was dried over anhydrous Na₂SO₄ and the solvent was removed under reduced pressure. The crude mass was purified by silica gel column chromatography to obtain above titled compound (8.2 g) asbrown colour solid in 65% yield. ’H - NMR (400 MHz, CDCl3): 5 8.47 (s, 1H), 7.56 ( s, 1H ), 4.57 (s, 2H ), 3.75-3.70 (m, 2H), 2.96-2.93 (m, 2H ), 1.49 (s, 9H ); Mass (m / z); 313.0 (M+H)+

[0531] Step-6: Synthesis of 3-Bromo-5,6,7,8-tetrahydro-[l,6]naphthyridine hydrochloride: To the stirred solution of step-5 compound (0.2 g, 0.64 mmol) in IPA (2.6 mL) at RT, dry HC1 in IPA (2.6 mL, 7.8 mmol) was added. After stirring for 6 h at RT, the volatiles were removed under reduced pressure. The crude mass was purified by trituration with solvent ether several times to obtain above titled compound (0.13 g) as brown colour solid in 94% yield. ’H - NMR (400 MHz, DMSO-d6): 59.45 (bs, 2H), 8.59 (s, 1H), 8.00 (s, 1H), 4.31 (s, 2H), 3.47 (t, 2H), 3.0 (t, 2H); Mass (m / z); 212.6, 214.4 (M+H)+.

[0532] Intermediate-63: 3-Methyl-5,6,7,8-tetrahydro-[l,6]naphthyridine hydrochloride

[0533]

[0534] Step-5 compound Step-1 Intermediate-63 of Intermediate-62

[0535] Step-1: Synthesis of 3-Methyl-7,8-dihydro-5H-[l,6]naphthyridine-6-carboxylic acid tert-butyl ester:

[0536] To the stirred solution of 3-Bromo-7,8-dihydro-5H-[l,6]naphthyridine-6-carboxylic acid tert-butyl ester (step-5 compound of intermediate-62, 2.0 g, 6.4 mmol) and methylboronic acid (0.38 g, 6.4 mmol) in 1,4-dioxan (25.0 mL) at RT, water (6.4 mL) followed by K2CO3 (2.65 g, 19.2 mmol) were added. After degasifying for 10 minutes, Pd(dppf)C12 (0.23 g, 0.32 mmol ) was added. The reaction mass was then refluxed for 16 h. The reaction mass was cooled to RT, diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude mass was purified by silica gel column chromatography to obtain above titled compound (0.75 g) in 94% yield. ’H - NMR (400 MHz, CDCI3): 5 8.28 (s, 1H), 7.22 (s, 1H ), 4.55 (s, 2H ), 3.74-3.71 (m, 2H), 2.97-2.94 (m, 2H ), 2.30 (s, 3H), 1.49 (s,9H) Mass (m / z); 250.0 (M+H)+

[0537] Step-2: Synthesis of 3-Methyl-5,6,7,8-tetrahydro-[l,6]naphthyridine hydrochloride: To the stirred solution of step-1 compound (0.75 g, 3.0 mmol) in IPA (12.0 mL) at RT, a solution of dry HC1 in IPA (3M, 12.0 mL) was added. After stirring at RT for 1 h, the volatiles were removed under reduced pressure to obtain above titled compound (0.48 g) asbrown colour solid in 86% yield. ’H - NMR (400 MHz, DMSO-d6): 5 10.00 (bs, 2H), 8.62 (s, 1H), 8.09 (s, 1H), 4.37 (s, 2H), 3.48 (t, 2H), 3.31-3.28 (m, 2H), 2.40 (s, 3H); Mass (m / z); 148.8 (M+H)+

[0538] Intermediate-64: 3-(6,7-Dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine hydrochloride

[0539]

[0540] Sep-5 compound „1

[0541] of intermediate-62

[0542]

[0543] Intermediate-64 Step-1: Synthesis of 3-(6,7-dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-7,8-dihydro-5H-[l,6]naphthyridine-6-carboxylic acid tert-butyl ester:

[0544] To the stirred solution of 3-Bromo-7,8-dihydro-5H-[l,6]naphthyridine-6-carboxylic acid tert-butyl ester (step-5 compound of intermediate-62, 0.5 g, 1.6 mmol) and 4, 5,6,7-tetrahydro-pyrazolo[l,5-a]pyrimidine (0.2 g, 1.6 mmol) in toluene (6.0 mL) at RT, NaOtBu (0.46 g, 4.8 mmol) was added. After degasifying for 10 minutes, Pd(dba)3(0.07 g, 0.08 mmol) was added. The reaction mass was then refluxed for 6 h. The reaction mass was cooled to RT diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na₂SO₄ and the solvent was removed under reduced pressure. The crude mass was purified by silica gel column chromatography to obtain above titled compound (0.48 g) in 84% yield. ’H - NMR (400 MHz, CDCl3): 5 8.42 (d, J=2.4Hz, 1H ), 7.33 (d, J=2.4Hz, 1H ), 7.30 (d, J=2.0Hz, 1H ), 5.58 (d, J=2.0Hz, 1H), 4.57 (s, 2H), 4.28-4.21 (m, 2H), 3.77-3.74 (m, 2H), 3.69-3.66 (m, 2H), 2.98-2.95 (m, 2H), 2.35- 2.29 (m, 2H ), 1.49 (s, 9H ); Mass (m / z); 355.7 (M+H)+

[0545] Step-2: Synthesis of 3-(6,7-dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-5, 6,7,8-tetrahydro-[l,6]naphthyridine hydrochloride:

[0546] To the stirred solution of step-1 compound (0.48 g, 1.3 mmol) in IPA (5.4 mL) at RT a solution of dry HC1 in IPA (3M, 5.4 mL) was added. After stirring at RT for 1.0, the volatiles were removed under reduced pressure to obtain above titled compound (0.32 g) as brown colour solid in 81% yield. ’H - NMR (400 MHz, DMSO-d6): 5 10.08 (bs, 2H), 8.60 (s, 1H), 8.05 (s, 1H), 7.58 (s,lH), 6.00 (s, 1H), 4.44 (s, 2H), 4.21-4.18 (m, 2H), 3.81-3.77 (t, 2H), 3.46-3.41 (t, 2H), 3.24 (t, 2H), 2.26-2.23 (m, 2H); Mass (m / z); 256.2 (M+H)+.The below intermediates 65 to 71 were prepared by following the procedure described in WO2018112843A1 using suitable starting materials with some non-critical variations.

[0547] Intermediate No. Structure and IUPAC Name

[0548] 65 HO °U OCH HC13

[0549] 4-(4-Methoxy-phenoxy)-piperidine hydrochloride

[0550] 66 HO Y

[0551] mN!

[0552] °cH3

[0553] 2-Methoxy-5-(piperidin-4-yloxy)-pyridine hydrochloride

[0554] xr o

[0555] 67

[0556] HC1OCH3

[0557] 4-(3-Methoxy-phenoxy)-piperidine hydrochloride

[0558] 68. O HC1X I

[0559] F

[0560] 4-(3-Fluoro-phenoxy)-piperidine hydrochloride

[0561] .o x

[0562] 69

[0563] HC1 l.N

[0564] 3-(Piperidin-4-yloxy)-benzonitrile hydrochloride

[0565] ' T T 1 >

[0566] 70 HC1

[0567] 4- ( 1, 3 -Dihydro -isobenzofuran- 5 - yloxy ) -piperidine hydrochloride

[0568] 71. O HC1"" C0

[0569] 4- (2, 3 -Dihydro -benzo [ 1,4] dioxin- 6-yloxy) -piperidine hydrochloride

[0570]

[0571] Intermediate-72: 2-Methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine, hydrochloride

[0572]

[0573] HCl

[0574] Intermediate-72

[0575] Step-1: Preparation of 2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester

[0576] To the stirred solution of 3 -bromo-4-oxo-piperidine- 1 -carboxylic acid tert-butyl ester (500 mg, 1.79 mmol), in ethanol (9.0 mL), thioacetamide (134.8 mg, 1.79 mmol) was added. The reaction mass was heated to reflux for 16 h. The volatiles were removed under reduced pressure to obtain a crude mass which was purified by column chromatography to obtain the titled compound (127 mg). ’H - NMR (400 MHz, CDCl3): 4.57 (s, 2H) 3.73-3.70 (t, 2H), 2.90-2.83 (t, 2H), 2.66 (s, 3H), 1.48 (s, 9H); Mass (m / z); 254.8 (M+H)+.

[0577] Step-2: Preparation of 2-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine hydrochloride

[0578] To the stirred solution of 2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (127 mg, 0.5 mmol), in isopropanol (2.0 mL), a solution of dry HCl in isopropanol (3M, 2.0 mL) was added. The reaction mass was stirred for 16 h. The volatiles were removed and the residue was triturated with ether to obtain the titled compound (100.0 mg). ’H - NMR (400 MHz, DMSO-d6): 9.47 (bs, 2H), 4.32 (s, 2H) 3.44-3.41 (t, 2H), 2.95- 2.92 (t, 2H), 2.62 (s, 3H); Mass (m / z); 155.0 (M+H)+.

[0579] The below intermediates 73 to 78 were prepared by following the experimental procedure described for preparation of intermediate-72, with some non-critical variations using suitable starting materials.

[0580] Intermediate

[0581] Structure Characterization Data No.

[0582] O 1 ’H - NMR (400 MHz, CDCl3): 5 73 4.58 (s, 2H), 3.73-3.70 (t, 2H),

[0583] 3.01-2.95 (q, 2H), 2.84 (t, 2H), 1.48 (s, 9H), 1.38-1.34 (t, 3H);

[0584]

[0585] 2-Ethyl-6,7 -dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic Mass (m / z); 269.0 (M+H)+.

[0586] acid tert-butyl ester

[0587] MSJOH’H - NMR (400 MHz, DMSO): 5

[0588] 9.50 (bs, 2H), 4.33 (s, 2H), 4.39-NHC1

[0589] 4.33 (t, 2H), 3.42-3.37 (t, 2H), 2-Ethyl-4,5,6,7-tetrahydro- 2.99-2.92 (q, 2H), 1.28-1.25 (t, thiazolo[5,4-c]pyridine 3H); Mass (m / z); 169.0 (M+H)+.

[0590] hydrochloride

[0591] O 1 ’H - NMR (400 MHz, CDCl3): 5

[0592] 4.59 (s, 2H), 3.73-3.72 (t, 2H), KOA° 3.29-3.22 (m, 1H), 2.84 (t, 2H), 2-Isopropyl-6,7-dihydro-4H- 1.48 (s, 9H), 1.38-1.36 (d, 6H); thiazolo[5,4-c]pyridine-5-carboxylic Mass (m / z); 283.0 (M+H)+.

[0593] acid tert-butyl ester

[0594] ’H - NMR (400 MHz, DMSO): 5 HO19.70 (bs, 2H), 4.33 (s, 2H), 3.80- HCl

[0595] 3.74 (m, 1H), 3.40 (t, 2H), 2.97- 2-Isopropyl-4,5,6,7-tetrahydro- 2.94 (t, 2H), 1.31-1.29 (d, 6H);

[0596] thiazolo[5,4-c]pyridine Mass (m / z); 183.0 (M+H)+.

[0597] hydrochloride

[0598] ’H - NMR (400 MHz, CDCl3): 501 9.10 (d, J = 1.6Hz, 1H), 8.64-8.63

[0599] (dd, J =1.6Hz, 4.8Hz, 1H), 8.19-N= / 8.17 (d,7=8.0 Hz, 1H), 7.39-7.35

[0600] (dd, J=4.8Hz,5.6Hz, 1H), 4.70 (s, 2-Pyridin-3-yl-6,7-dihydro-4H- thiazolo[5,4-c]pyridine-5-carboxylic 2H), 3.79-3.78 (t, 2H), 2.96 (t, acid tert-butyl ester 2H), 1.49 (s, 9H); Mass (m / z);

[0601] 318.0 (M+H)+.

[0602] ’H - NMR (400 MHz, DMSO): 5 9.54 (bs, 2H), 9.13 (7 = 2.0Hz, 1H) N=y / 8.72-8.70 (dd, 7 = 1.6Hz, 5.2 Hz,

[0603] HCl 1H), 8.35-8.33 (d, 7 = 7.6Hz, 1H),

[0604] 7.62-7.59 (dd, 7 = 4.8Hz, 7.6 Hz, 2-Pyridin-3-yl-4,5,6,7-tetrahydro- thiazolo[5,4-c]pyridine 1H), 4.48 (s, 2H), 3.51-3.50 (t, hydrochloride 2H), 3.11-3.08 (t, 2H); Mass (m / z); 218.0 (M+H)+.

[0605]

[0606] Example-1: 5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2,6-dimethyl- pyrazolo[l,5 -a] pyrimidine

[0607]

[0608] To a stirred solution of 5-chloro-2,6-dimethyl-pyrazolo[l,5-a]pyrimidine (0.08 g, 0.44 mmol, intermediate-31) and 4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidine hydrochloride (0.12 g, 0.44 mmol, intermediate-71) in water (4.4 mL), at RT, was added potassium carbonate (0.06 g, 0.45 mmol) followed by potassium fluoride (0.13 g, 2.21 mmol). The reaction mixture was gradually heated to 100 °C and the reaction mixture was stirred for 8 h upon which the TLC reveals completion of the reaction. The reaction mixture was cooled to RT, diluted with DCM, and the two layers were separated. The organic layer was dried over anhydrous Na₂SO₄ and the volatiles were removed under reduced pressure. The resulting crude mass was purified by silica gel column chromatography using 2 - 5 % gradient mixture of MeOH in DCM to obtain the title compound. Yield: 0.1 g (60 %); H - NMR (400 MHz, CDCl3): 5 8.13 (s, 1H), 6.78 (d, J = 8.8Hz, 1H), 6.50 (d, J = 2.8Hz, 1H), 6.47-6.44 (dd, J = 2.8Hz, 2.8Hz, 1H), 6.07 (s, 1H), 4.38-4.34 (m, 1H), 4.26-4.20 (m, 4H), 3.60-3.54 (m, 2H), 3.18-3.12 (m, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 2.11-2.04 (m, 2H), 1.94- 1.89 (m, 2H); Mass (m / z); 380.8 (M+H)+.

[0609] The below examples 2 to 110 were prepared by following the experimental procedure given for preparation of example- 1, with some non-critical variations using suitable starting materials and intermediates.

[0610] Example

[0611] Chemical structure and IUPAC Name Characterization data No.

[0612] ’H - NMR (400 MHz, CDCI3): 5 8.15 (s, 1H), 8.21 (s, 1H), 7.42-7.37 (m, 1H), 7.29-7.24 (m, 1H), 7.20-7.15 (m, 2 1H), 6.08 (s, 1H), 4.60-4.50 (m, 1H),

[0613] 3.61-3.53 (m, 2H), 3.28-3.18 (m, 2H), 3 - [ 1 - (2, 6-Dimethyl-pyrazolo [1,5- a]pyrimidin-5-yl)-piperidin-4-yloxy]- 2.42 (s, 3H), 2.26 (s, 3H), 2.18-2.10

[0614] (m, 2H), 2.02-1.92 (m, 2H); Mass benzonitrile

[0615] (m / z); 348.0 (M+H)+.

[0616]

[0617] ’H - NMR (400 MHz, CDCl3): 58.13

[0618] (s, 1H), 6.91-6.88 (dd, J = 2.4Hz, H3CO 2.4Hz, 2H), 6.86-6.82 (dd, J = 2.4Hz,

[0619] , / %XN'N 2.4Hz, 2H), 6.07 (s, 1H), 4.41-6.36

[0620] (m, 1H), 3.78 (s, 3H), 3.61-3.55 (m, 5 - [4-(4-Methoxy-phenoxy)-piperidin- 1 - 2H), 3.19-3.13 (m, 2H), 2.41 (s, 3H), yl]-2,6-dimethyl-pyrazolo[l,5- 2.25 (s, 3H), 2.13-2.06 (m, 2H), 1.96- a] pyrimidine 1.88 (m, 2H); Mass (m / z); 352.8

[0621] (M+H)+.

[0622] ’H - NMR (400 MHz, CDCI3): 58.14 (s, 1H), 7.87 (d, J = 2.8Hz, 1H), 7.26 (s, 1H), 6.71 (d, J = 8.8Hz, 1H), 6.07 (s, 1H), 4.38-4.37 (m, 1H), 3.90 (s, 3H), 3.61-3.55 (m, 2H), 3.19-3.13 (m, 5-[4-(6-Methoxy-pyridin-3-yloxy)- 2H), 2.42 (s, 3H), 2.26 (s, 3H), 2.13- piperidin- 1 -yl] -2,6-dimethyl-pyrazolo[ 1,5- 2.08 (m, 2H), 1.95-1.91 (m, 2H); a] pyrimidine

[0623] Mass (m / z); 354.0 (M+H)+.

[0624] ’H - NMR (400 MHz, CDCl3): 58.14 (s, 1H), 7.15 (d, J= 8.4Hz, 1H), 6.87- of ]| | [ 1

[0625] 6.84 (dd, J = 2.0Hz, 2.4Hz, 1H ), 6.82 / XN'N (s, 1H), 6.07 (s, 1H), 5.07 (d, J =

[0626] 4.0Hz, 4H), 4.52-4.48 (m, 1H), 3.61- 5- [4-( 1,3 -Dihydro-isobenzofuran-5- 3.55 (m, 2H), 3.22-3.16 (m, 2H), 2.42 yloxy)-piperidin-l-yl]-2,6-dimethyl- (s, 3H), 2.26 (s, 3H), 2.14-2.08 (m, pyrazolo[ 1,5-a]pyrimidine 2H), 1.99-1.92 (m, 2H); Mass (m / z);

[0627] 365.1 (M+H)+.

[0628] ’H - NMR (400 MHz, CDCl3): 58.13 (s, 1H), 6.72 (d, J = 8.4Hz, 1H), 6.54 (d, J = 2.4Hz, 1H), 6.41-6.38 (dd, J = AN-?- 2.4Hz, 2.4Hz, 1H), 6.07 (s, 1H), 5.92

[0629] (s, 2H) 4.36-4.34 (m, 1H), 3.60-3.54 5 - [4-(Benzo [ 1,3 ]dioxol-5-yloxy) - (m, 2H), 3.19-3.13 (m, 2H), 2.41 (s, piperidin- 1 -yl] -2,6-dimethyl-pyrazolo[ 1,5- 3H), 2.25 (s, 3H), 2.11-2.06 (m, 2H), a] pyrimidine 1.93-1.89 (m, 2H); Mass (m / z); 367.1

[0630] (M+H)+.

[0631] 1H - NMR (400 MHz, CDCI3): 58.26 H3CO (s, 1H), 7.89 (d, J = 2.4Hz, 1H), 7.87

[0632]

[0633] / X-N'N (d, J = 2.8Hz, 1H), 7.28 (d, J =8.8Hz, 1H), 6.71 (d, J = 8.8Hz, 1H), 5-[4-(6-Methoxy-pyridin-3-yloxy)- 6.29 (d, J = 2.4Hz, 1H), 4.43-6.36 (m, piperidin- 1 -yl] -6-methyl-pyrazolo [1,5- 1H), 3.90 (s, 3H), 3.65-3.57 (m, 2H), a] pyrimidine 3.23-3.15 (m, 2H), 2.29 (s, 3H), 2.15- 2.07 (m, 2H), 1.99-1.89 (m, 2H); Mass (m / z); 339.5 (M+H)+.

[0634] 1H - NMR (400 MHz, CDCl3): 5 8.25 (s, 1H), 7.88 (d, J = 2.0Hz, 1H), 6.79 (d, J = 8.8Hz, 1H), 6.50 (d, J = oa°oYV,

[0635] 2.8Hz, 1H), 6.48-6.45 (dd, J= 2.8Hz, 2.8Hz, 1H), 6.29 (d, J = 0.8Hz, 1H), 4.38-4.35 (m, 1H), 4.26-4.20 (m, 4H), 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 3.62-3.56 (m, 2H), 3.21-3.15 (m, 2H), yloxy)-piperidin- 1 -yl] -6-methyl- 2.28 (s, 3H), 2.12-2.07 (m, 2H), 1.96- pyrazolo [ 1,5-a]pyrimidine

[0636] 1.90 (m, 2H); Mass (m / z); 367.2 (M+H)+.

[0637] ’H - NMR (400 MHz, CDCl3): 5 8.17 (s, 1H), 7.72 (s, 1H), 6.79 (d, J = 8.8Hz, 1H), 6.51 (d, J = 2.8Hz, 1H), 6.48 (dd, J = 2.8, 8.8Hz, 1H), 4.39- 4.35 (m, 1H), 4.26-4.20 (m, 4H), 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 3.63-3.57 (m, 2H), 3.22-3.16 (m, 2H), yloxy)-piperidin- 1 -yl] -3,6-dimethyl- 2.26 (s, 3H), 2.24 (s, 3H), 2.12-2.07 pyrazolo[ 1,5-a]pyrimidine

[0638] (m, 2H), 1.96-1.90 (m, 2H); Mass (m / z); 380.9 (M+H)+.

[0639] ’H - NMR (400 MHz, CDCI3): 5 6.80 (d, J = 8.4Hz, 1H), 6.54 (d, J = Ca°pVrv

[0640] 2.8Hz, 1H), 6.51-6.48 (dd, J = 2.8Hz, 2.8Hz, 1H), 6.22 (s, 1H), 4.45-4.39 (m, 1H), 4.27-4.21 (m, 4H), 3.56 (s, 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 4H), 2.48 (s, 3H), 2.45 (s, 3H), 2.24 yloxy)-piperidin-l-yl]-2,6,7-trimethyl- (s, 3H), 2.21-2.16 (m, 2H), 1.99-1.91 pyrazolo[ 1,5-a]pyrimidine

[0641] (m, 2H); Mass (m / z); 395.0 (M+H)+.

[0642] ’H - NMR (400 MHz, CDCl3): 57.16 °f ] T T i

[0643] (d, J = 8.0Hz, 1H), 6.91-6.88 (dd, J = 2.4Hz, 1H), 6.86 (s, 1H), 6.22 (s, 1H), 5.08 (d, J = 5.6Hz, 4H), 4.58-4.54 (m, 5- [4-( 1,3 -Dihydro-isobenzofuran-5- 1H), 3.58 (s, 4H), 2.49 (s, 3H), 2.45 yloxy)-piperidin-l-yl]-2,6,7-trimethyl- (s, 3H), 2.25 (s, 3H), 2.22-2.19 (m,

[0644]

[0645] pyrazolo[ 1,5-a]pyrimidine 2H), 2.03-1.97 (m, 2H); Mass (m / z);

[0646] 379.2 (M+H)+.

[0647] 1H - NMR (400 MHz, CDCl3): 57.78 (s, 1H), 6.79 (d, J = 8.8Hz, 1H), 6.52 (d, J = 2.8Hz, 1H), 6.50 (dd, J = 2.8, 8.8Hz, 1H), 4.44-4.38 (m, 1H), 4.26- 4.20 (m, 4H), 3.60-3.50 (m, 4H), 2.53 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- (s, 3H), 2.33 (s, 3H), 2.26 (s, 3H), yloxy)-piperidin- 1 -yl] -3,6,7 -trimethyl- 2.19-2.15 (m, 2H), 1.98-1.90 (m, 2H); pyrazolo[ 1,5-a]pyrimidine

[0648] Mass (m / z); 394.7 (M+H)+.

[0649] 1H - NMR (400 MHz, CDCl3): 5 8.42. N.

[0650] cr (s, 1H), 8.19 (s, 1H), 7.46 (s, 1H),

[0651] / ^N~N 6.11 (s, 1H), 4.54 (s, 2H), 3.60 (t,

[0652] 2H), 3.17 (t, 2H), 2.43 (s, 3H), 2.32 3-Chloro-6-(2,6-dimethyl-pyrazolo[l,5- (s, 3H); Mass (m / z); 313.5, 316.0 a] pyrimidin- 5 -yl) -5, 6,7, 8 - tetrahydro - (M+H)+.

[0653] [ 1,6]naphthyridine

[0654] ’H - NMR (400 MHz, CDCI3): 5 8.17 JL (s, 1H), 7.87 (d, J = 2.8Hz, 1H), 6.65

[0655] (d, J = 2.4Hz, 1H), 6.09 (s, 1H), 4.53 (s, 2H), 3.59 (t, 2H), 3.30-3.27 (m, -(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin- 4H), 3.11 (t, 2H), 2.43 (s, 3H), 2.33 -yl) -3 -pyrrolidin- l-yl-5,6,7,8 -tetrahydro - (s, 3H), 2.04-2.01 (m, 4H); Mass [ 1,6]naphthyridine (m / z); (M+H)+. 348.3, 350.0 (M+H)+.

[0656] Zv-z\ 1H - NMR (400 MHz, CDCI3): 5 8.51

[0657] . N. - (s, 1H), 8.19 (s, 1H), 7.64 (s, 1H), Br 6.11 (s, 1H), 4.54 (s, 2H), 3.59 (t,

[0658] 2H), 3.15 (t, 2H), 2.43 (s, 3H), 2.32 (s, 3H); Mass (m / z); 358.0, 360.0 3-Bromo-6-(2,6-dimethyl-pyrazolo[l,5- (M+H)+.

[0659] a] pyrimidin- 5 -yl) -5, 6,7, 8 -tetrahydro - [ 1,6]naphthyridine

[0660] 1H - NMR (400 MHz, CDCI3): 5 8.28 (s, 1H), 8.18 (s, 1H), 7.29 (s, 1H), / ^N'N 6.11 (s, 1H), 4.52 (s, 2H), 3.61 (t,

[0661] 2H), 3.18 (t, 2H), 2.48 (s, 3H), 2.32 -(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin- (s, 6H); Mass (m / z); 294.1 (M+H)+.

[0662]

[0663] 5-yl)-3-methyl-5,6,7,8-tetrahydro-[ 1,6]naphthyridine

[0664] 1H - NMR (400 MHz, CDCl3): 5 8.29 JL -ISL (s, 1H), 7.90 (d, J = 2.0Hz, 1H), 7.87 / A ><■

[0665] ^^N-N (s, 1H), 6.66 (s, 1H), 6.31 (d, J =

[0666] 0.8Hz, 1H), 4.55 (s, 2H), 3.62 (t, 2H), -(6-Methyl-pyrazolo[l,5-a]pyrimidin-5- 3.31-3.27 (m, 4H), 3.14 (t, 2H), 2.36 yl)-3-pyrrolidin-l-yl-5,6,7,8-tetrahydro- (s, 3H), 2.05-2.01 (m, 4H); Mass [ 1,6]naphthyridine (m / z); 335.2 (M+H)+.

[0667] -XX JL _N.. N. _ _1H - NMR (400 MHz, CDCl3): 5 8.42

[0668] (d, J = 2.8Hz, 1H), 8.19 (s, 1H), 7.43LA / Az

[0669] (d, J = 2.8Hz, 1H), 6.11 (s, 1H), 5.43 N=Z

[0670] (s, 1H), 4.55 (s, 2H), 4.17 (t, 2H), 3.69 (t, 2H), 3.62 (t, 2H), 3.19 (t, 2H), -(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin- 2.43 (s, 3H), 2.34 (s, 3H), 2.32-2.28 5-yl)-3-(2-methyl-6,7-dihydro-5H- (m, 2H), 2.17 (s, 3H); Mass (m / z); pyrazolo[l,5-a]pyrimidin-4-yl)-5,6,7,8- 415.2 (M+H)+.

[0671] tetrahydro- [ 1,6] naphthyridine

[0672] 1H - NMR (400 MHz, CDCl3): 5 8.25 CO AVi

[0673] (s, 1H), 6.80 (d, J = 8.8Hz, 1H), 6.52 / yN'N (d, J = 2.8Hz, 1H), 6.49 (dd, J = 2.8,

[0674] 8.8Hz, 1H), 4.50-4.48 (m, 1H), 4.27- 4.21 (m, 4H), 3.92-3.86 (m, 2H), 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 3.74-3.68 (m, 2H), 3.11 (t, 2H), 3.04 yloxy )-piperidin- 1 - yl] -7, 8 -dihydro -6H- (t, 2H), 2.23-2.11 (m, 4H), 2.07-2.03 cyclopenta[e] [ 1,2,4] triazolo[ 1,5- (m, 2H); Mass (m / z); 394.4 (M+H)+. a] pyrimidine

[0675] ’H - NMR (400 MHz, CDCl3): 5 8.31 rr°X (s, 1H), 8.20 (s, 1H), 7.87 (d, J = H3CO 3.2Hz, 1H), 7.25 (s, 1H), 6.72 (d, J =

[0676] XV 8.8Hz, 1H), 4.44-4.42 (m, 1H), 3.90 5-[4-(6-Methoxy-pyridin-3-yloxy)- (s, 3H), 3.81-3.75 (m, 2H), 3.45-3.39 piperidin- 1 -yl] -6-methyl- (m, 2H), 2.35 (s, 3H), 2.14-2.09 (m,

[0677] 2H), 1.98-1.90 (m, 2H); Mass (m / z);

[0678] [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0679] 341.0, 342.1 (M+H)+.

[0680] ’H - NMR (400 MHz, DMSO-d6): δ 8.87 (s, 1H), 8.25 (s, 1H), 6.96 (d, J = 1 AI3CU A T-’^ \ 9.2Hz, 2H), 6.87 (d, J = 9.2Hz, 2H),

[0681] X? 4.56-4.48 (m, 1H), 3.78-3.71 (m, 2H),

[0682]

[0683] 3.70 (s, 3H), 3.36-3.26 (m, 2H), 2.30 - [4-(4-Methoxy-phenoxy)-piperidin-1- (s, 3H), 2.09-2.01 (m, 2H), 1.80-1.70 yl]-6-methyl-[l,2,4]triazolo[l,5- (m, 2H); Mass (m / z); 340.0 (M+H)+.

[0684] a] pyrimidine

[0685] 1H - NMR (400 MHz, CDCl3): δ 8.33 (d, J = 1.2Hz, 1H), 8.21 (s, 1H), 7.42- 7.37 (m, 1H), 7.29-7.24 (m, 1H), 7.20-7.15 (m, 2H), 4.65-4.58 (m, 1H), 3.81-3.73 (m, 2H), 3.53-3.45 (m, 2H), 3-[l-(6-Methyl-[l,2,4]triazolo[l,5- 2.36 (s, 3H), 2.20-2.10 (m, 2H), 2.03- a]pyrimidin-5-yl)-piperidin-4-yloxy]- 1.93 (m, 2H); Mass (m / z); 335.2 benzonitrile

[0686] (M+H)+.

[0687] 1H - NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 8.19 (s, 1H), 7.21 (t, 1H), g 'Xvv

[0688] OCH36.56-6.50 (m, 3H), 4.58-4.55 (m, 1H),

[0689] 3.80 (s, 3H), 3.78-3.74 (m, 2H), 3.49- - [4-(3 -Methoxy-phenoxy)-piperidin- 1 - 3.43 (m, 2H), 2.34 (s, 3H), 2.16-2.09 yl]-6-methyl-[l,2,4]triazolo[l,5- (m, 2H), 2.0-1.93 (m, 2H); Mass a] pyrimidine (m / z); 340.1 (M+H)+.

[0690] ’H - NMR (400 MHz, CDCl3): 5 8.31 o Ii T I ' (s, 1H), 8.19 (s, 1H), 7.15 (d, J =

[0691] 8.4Hz, 1H), 6.87-6.85 (dd, J = 2.0Hz, xx> 2.8Hz, 1H), 6.82 (s, 1H), 5.07 (d, J =

[0692] 4.4Hz, 4H), 4.58-4.54 (m, 1H), 3.80- 5- [4-( 1,3 -Dihydro-isobenzofuran-5- 3.74 (m, 2H), 3.49-3.43 (m, 2H), 2.35 yloxy)-piperidin- 1 -yl] -6-methyl- (s, 3H), 2.16-2.09 (m, 2H), 2.01-1.95 [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0693] (m, 2H); Mass (m / z); 352.1 (M+H)+.

[0694] 1H - NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 8.19(s, 1H), 6.73 (d, J = 8.4Hz, 1H), 6.54 (d, J = 2.0Hz, 1H), 6.41-6.38 (dd, J = 2.4Hz, 2.4Hz, 1H), 5.93 (s, 2H), 4.42-4.39 (m, 1H), 3.79- 5 - [4-(Benzo [ 1,3 ]dioxol-5-yloxy) - 3.73 (m, 2H), 3.46-3.40 (m, 2H), 2.34 piperidin- 1 -yl] -6-methyl- (s, 3H), 2.12-2.06 (m, 2H), 1.96-1.91 [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0695] (m, 2H); Mass (m / z); 354.2 (M+H)+.

[0696] 1H - NMR (400 MHz, CDCl3): 5 8.30 W ry.,.. (s, 1H), 8.19 (s, 1H), 6.79 (d, J =

[0697] 8.4Hz, 1H), 6.50 (d, J = 2.8Hz, 1H),

[0698]

[0699] 6.47-6.44 (dd, J = 2.8Hz, 2.8Hz, 1H), 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 4.43-4.40 (m, 1H), 4.26-4.21 (m, 4H), yloxy)-piperidin- 1 -yl] -6-methyl- 3.79-3.73 (m, 2H), 3.46-3.40 (m, 2H), [ 1,2,4]triazolo[ 1,5-a]pyrimidine 2.34 (s, 3H), 2.12-2.04 (m, 2H), 1.97- 1.89 (m, 2H); Mass (m / z); 367.6 (M+H)+.

[0700] 1H - NMR (400 MHz, CDCl3): 5 8.29 (s, 1H), 7.90 (d, J = 2.8Hz, 1H), 7.30 H3CO — Y VX

[0701] (s, 1H), 6.73 (d, J = 9.2 Hz, 1H), 4.50-4.47 (m, 1H), 3.90 (s, 3H), 3.78- 3.72 (m, 2H), 3.56-3.50 (m, 2H), 2.60 5-[4-(6-Methoxy-pyridin-3-yloxy)- (s, 3H), 2.29 (s, 3H), 2.75-2.17 (m, piperidin- l-yl]-6,7-dimethyl- 2H), 2.06-1.98 (m, 2H); Mass (m / z);

[0702] [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0703] 354.8 (M+H)+.

[0704] 1H - NMR (400 MHz, CDCl3): 5 8.28 (s, 1H), 6.94-6.90 (dd, J = 2.4Hz, 2.4Hz, 2H), 6.86-6.84 (dd, J = 2.4Hz, 2.4Hz, 2H), 4.51-4.49 (m, 1H), 3.78 (s, 3H), 3.77-3.72 (m, 2H), 3.57-3.51 5 - [4-(4-Methoxy-phenoxy)-piperidin- 1 - (m, 2H), 2.60 (s, 3H), 2.29 (s, 3H), yl] -6,7 -dimethyl- [ 1,2,4]triazolo[ 1,5 - 2.21-2.16 (m, 2H), 2.04-1.99 (m, 2H);

[0705] a] pyrimidine Mass (m / z); 353.7 (M+H)+.

[0706] 1H - NMR (400 MHz, CDCl3): 5 8.28 (s, 1H), 6.80 (d, J = 8.8Hz, 1H), 6.53 ca°pYY(d, J = 2.8Hz, 1H), 6.50-6.47 (dd, J =

[0707] 2.8Hz, 2.8Hz, 1H), 4.48-4.46 (m, 1H), 4.26-4.22 (m, 4H), 3.77-3.71 (m, 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 2H), 3.56-3.50 (m, 2H), 2.59 (s, 3H), yloxy)-piperidin- 1 -yl] -6,7 -dimethyl - 2.28 (s, 3H), 2.20-2.15 (m, 2H), 2.04- [ 1,2,4]triazolo[ 1,5-a]pyrimidine 1.97 (m, 2H); Mass (m / z); 381.7

[0708] (M+H)+.

[0709] 1H - NMR (400 MHz, CDCl3): 5 8.27 ca°orY>(s, 1H), 6.80 (d, J = 8.4Hz, 1H), 6.52

[0710] (d, J = 2.4Hz, 1H), 6.50-6.47 (dd, J = 2.8Hz, 2.8Hz, 1H), 4.50-4.45 (m, 1H), 4.27-4.23 (m, 4H), 3.80-3.73 (m, 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 2H), 3.57-3.48 (m, 2H), 3.05 (t, 2H), yloxy)-piperidin-l-yl]-6,7,8,9-tetrahydro- 2.75 (t, 2H), 2.21-2.14 (m, 2H), 2.04- [ 1,2,4]triazolo[ 1,5-a]quinazoline 1.96 (m, 2H), 1.94-1.88 (m, 2H),

[0711]

[0712] 1.88-1.78 (m, 2H); Mass (m / z); 408.1

[0713] (M+H)+.

[0714] ’H - NMR (400 MHz, CDCl3): 5 8.18 H, CO^0" (d, J = 1.2Hz, 1H), 6.90-6.83 (m,

[0715] 4H), 4.45-4.40 (m, 1H), 3.78 (s, 3H), 3.77-3.72 (m, 2H), 3.42-3.36 (m, 2H), - [4-(4-Methoxy-phenoxy)-piperidin- 1 - 2.50 (s, 3H), 2.31 (s, 3H), 2.12-2.04 yl] -2,6-dimethyl- [ 1,2,4]triazolo[ 1,5 - (m, 2H), 1.96-1.89 (m, 2H); Mass a] pyrimidine (m / z); 354.2 (M+H)+.

[0716] ’H - NMR (400 MHz, CDCl3): 5 8.18 (d, J = 0.8Hz, 1H), 6.79 (d, J = 8.8Hz, 1H), 6.50 (d, J = 2.8Hz, 1H), 6.47-6.44 (dd, J = 2.8Hz, 2.8Hz, 1H), 4.42-4.37 (m, 1H), 4.26-4.20 (m, 4H), - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 3.76-3.70 (m, 2H), 3.42-3.36 (m, 2H), yloxy)-piperidin-l-yl]-2,6-dimethyl- 2.50 (s, 3H), 2.30 (s, 3H), 2.11-2.04 [ 1,2,4]triazolo[ 1,5-a]pyrimidine (m, 2H), 1.95-1.90 (m, 2H); Mass (m / z); 382.2 (M+H)+.

[0717] ’H - NMR (400 MHz, CDCl3): 5 8.19 (s, 1H), 7.86 (d, J = 2.8Hz, 1H), 7.24 (d, J = 2.8Hz, 1H), 6.72 (d, J = 9.2Hz, 1H), 4.42-4.40 (m, 1H), 3.90 (s, 3H), 3.78-3.72 (m, 2H), 3.42-3.35 5-[4-(6-Methoxy-pyridin-3-yloxy)- (m, 2H), 2.50 (s, 3H), 2.31 (s, 3H), piperidin- l-yl]-2,6-dimethyl- 2.13-2.08 (m, 2H), 1.96-1.91 (m, 2H);

[0718] [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0719] Mass (m / z); 355.2 (M+H)+.

[0720] ’H - NMR (400 MHz, CDCl3): 5 8.21 (s, 1H), 7.42-7.37 (m, 1H), 7.29-7.24 (m, 1H), 7.20-7.13 (m, 2H), 4.63-4.56 (m, 1H), 3.79-3.69 (m, 2H), 3.49-3.40 -[l-(2,6-Dimethyl-[l,2,4]triazolo[l,5- (m, 2H), 2.51 (s, 3H), 2.32 (s, 3H), a]pyrimidin-5-yl)-piperidin-4-yloxy]- 2.18-2.10 (m, 2H), 2.02-1.92 (m, 2H);

[0721] benzonitrile Mass (m / z); 349.0 (M+H)+.

[0722] ’H - NMR (400 MHz, CDCl3): 5 8.19 u UYV(s, 1H), 7.21 (t, 1H), 6.55-6.49 (m,

[0723] X^N^ 3H), 4.57-4.53 (m, 1H), 3.80 (s, 3H),

[0724] 3.77-3.71 (m, 2H), 3.45-3.39 (m, 2H), - [4-(3 -Methoxy-phenoxy)-piperidin- 1 - 2.50 (s, 3H), 2.31 (s, 3H), 2.15-2.08

[0725]

[0726] yl] -2,6-dimethyl- [ 1,2,4]triazolo[ 1,5 - (m, 2H), 1.99-1.91 (m, 2H); Mass a] pyrimidine (m / z); 354.1 (M+H)+.

[0727] ’H - NMR (400 MHz, CDCl3): 5 8.19 ■oa"n (s, 1H), 7.15 (d, J= 8.4Hz, 1H), 6.87- 6.82 (m, 2H), 5.07 (d, J = 4.4Hz, 4H), xi'r

[0728] 4.57-4.52 (m, 1H), 3.77-3.71 (m, 2H), 5- [4-( 1,3 -Dihydro-isobenzofuran-5- 3.45-3.39 (m, 2H), 2.50 (s, 3H), 2.31 yloxy)-piperidin-l-yl]-2,6-dimethyl- (s, 3H), 2.15-2.08 (m, 2H), 1.99-1.92 [ 1,2,4]triazolo[ 1,5-a]pyrimidine (m, 2H); Mass (m / z); 366.1 (M+H)+.

[0729] ’H - NMR (400 MHz, CDCl3): 57.17 °K Ji T T ' (d, J = 8.4Hz, 1H), 6.90-6.87 (dd, J =

[0730] 2.0Hz, 2.4Hz, 1H), 6.85 (s, 1H), 5.08 (d, J = 4.8Hz, 4H), 4.62-4.58 (m, 1H), 3.73-3.68 (m, 2H), 3.57-3.51 (m, 5- [4-( 1,3 -Dihydro-isobenzofuran-5- 2H), 2.56 (d, J = 6.8Hz, 6H), 2.26 (s, yloxy)-piperidin-l-yl]-2,6,7-trimethyl- 3H), 2.24-2.19 (m, 2H), 2.04-2.00 (m,

[0731] [ 1,2,4]triazolo[ 1,5-a]pyrimidine 2H); Mass (m / z); 380.0 (M+H)+.

[0732] ’H - NMR (400 MHz, CDCl3): 5 6.80 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 2.8Hz, 1H), 6.50-6.47 (dd, J= 3.2Hz, 2.8 Hz, 1H), 4.46-4.45 (m, 1H), 4.27- 4.21 (m, 4H), 3.71-3.66 (m, 2H), 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 3.54-3.48 (m, 2H), 2.55 (d, J = 5.6Hz, yloxy)-piperidin-l-yl]-2,6,7-trimethyl- 6H), 2.25 (s, 3H), 2.20-2.15 (m, 2H),

[0733] [ 1,2,4]triazolo[ 1,5-a]pyrimidine 2.01-1.96 (m, 2H); Mass (m / z); 396.2

[0734] (M+H)+.

[0735] 1H - NMR (400 MHz, CDCl3): 5 8.20 (s, 1H), 6.79 (d, J = 8.8Hz, 1H), 6.49 (d, J = 2.8Hz, 1H), 6.47 (dd, J = 2.8, 8.8Hz, 1H), 4.45-4.36 (m, 1H), 4.28- 4.20 (m, 4H), 3.77-3.70 (m, 2H), 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 3.42-3.36 (m, 2H), 2.88-2.82 (m, 2H), yloxy)-piperidin-l-yl]-2-ethyl-6-methyl- 2.30 (s, 3H), 2.11-2.04 (m, 2H), 1.95- [ 1,2,4]triazolo[ 1,5-a]pyrimidine 1.87 (m, 2H), 1.40 (t, 3H); Mass (m / z); 396.0 (M+H)+.

[0736]

[0737] 1H - NMR (400 MHz, CDCl3): 5 8.20

[0738] (s, 1H), 6.79 (d, J = 8.8Hz, 1H), 6.49 (d, J = 2.8Hz, 1H), 6.47 (dd, J = 3.2, 8.8Hz, 1H), 4.43-4.37 (m, 1H), 4.28- 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 4.20 (m, 4H), 3.79-3.71 (m, 2H), yloxy)-piperidin- 1 -yl] -2-isopropyl-6- 3.43-3.33 (m, 2H), 3.18-3.11 (m, 1H), methyl-[ 1,2,4]triazolo[ 1,5-a]pyrimidine 2.30 (s, 3H), 2.10-2.04 (m, 2H), 1.94- 1.87 (m, 2H), 1.41 (d, J = 7.2Hz, 6H); Mass (m / z); 410.1 (M+H)+.

[0739] ’H - NMR (400 MHz, CDCl3): δ 8.16 (s, 1H), 6.78 (d, J = 8.8Hz, 1H), 6.49 (d, J = 2.8Hz, 1H), 6.46 (dd, J = 2.8, 8.8Hz, 1H), 4.45-4.35 (m, 1H), 4.27- 2-Cyclopropyl-5-[4-(2,3-dihydro- 4.20 (m, 4H), 3.75-3.69 (m, 2H), benzo[ 1,4]dioxin-6-yloxy)-piperidin- 1 - yl] - 3.42-3.34 (m, 2H), 2.29 (s, 3H), 2.11- 6-methyl-[ 1,2,4]triazolo[ 1,5-a]pyrimidine 1.87 (m, 3H), 1.95-1.87 (m, 2H),

[0740] 1.18-1.15 (m, 2H), 1.04-1.00 (m, 2H); Mass (m / z); 408.0 (M+H)+.

[0741] ’H - NMR (400 MHz, CDCl3): 5 8.19 (s, 1H), 6.79 (d, J = 8.4Hz, 1H), 6.49 (d, J = 2.8Hz, 1H), 6.47 (dd, J = 2.8, 8.8Hz, 1H), 4.45-4.39 (m, 1H), 4.28- 2-Cyclobutyl-5-[4-(2,3-dihydro- 4.20 (m, 4H), 3.79-3.68 (m, 3H), benzo[ 1,4]dioxin-6-yloxy)-piperidin- 1 - yl] - 3.42-3.36 (m, 2H), 2.53-2.45 (m, 2H), 6-methyl-[ 1,2,4]triazolo[ 1,5-a]pyrimidine 2.43-2.32 (m, 2H), 2.30 (s, 3H), 2.11- 1.98 (m, 4H), 1.96-1.87 (m, 2H); Mass (m / z); 422.2 (M+H)+.

[0742] ’H - NMR (400 MHz, CDCl3): 5 8.19 c:»-’'oTV^ (s, 1H), 6.79 (d, J = 8.8Hz, 1H), 6.49

[0743] (d, J = 2.8Hz, 1H), 6.47 (dd, J = 3.2, 8.8Hz, 1H), 4.44-4.36 (m, 1H), 4.27- 2-Cyclopentyl-5-[4-(2,3-dihydro- 4.20 (m, 4H), 3.78-3.70 (m, 2H), benzo[ 1,4]dioxin-6-yloxy)-piperidin- 1 - yl] - 3.41-3.34 (m, 2H), 3.30-3.21 (m, 1H), 6-methyl-[ 1,2,4]triazolo[ 1,5-a]pyrimidine 2.30 (s, 3H), 2.15-2.02 (m, 4H), 2.01- 1.80 (m, 6H), 1.72-1.63 (m, 2H); Mass (m / z); 436.0 (M+H)+.

[0744]

[0745] 1H - NMR (400 MHz, CDCl3): 5 8.20

[0746] (s, 1H), 6.79 (d, J = 8.8Hz, 1H), 6.49 (d, J = 2.8Hz, 1H), 6.46 (dd, J = 2.8, 8.8Hz, 1H), 4.42-4.38 (m, 1H), 4.27- 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 4.19 (m, 4H), 4.07-4.01 (m, 2H), yloxy)-piperidin- 1 -yl] -6-methyl-2- 4.00-3.95 (m, 1H), 3.79-3.71 (m, 2H), (tetrahydro -furan-3 - yl) - [ 1,2,4] triazolo [1,5- 3.70-3.61 (m, 1H), 3.47-3.37 (m, 2H), a] pyrimidine 2.49-2.32 (m, 3H), 2.31 (s, 3H), 2.10- 2.06 (m, 2H), 1.95-1.87 (m, 2H); Mass (m / z); 438.0 (M+H)+.

[0747] ’H - NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 6.79 (d, J = 8.8Hz, 1H), 6.49 (d, J = 2.8Hz, 1H), 6.47 (dd, J = 2.8, 8.8Hz, 1H), 4.41-4.39 (m, 1H), 4.26- 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 4.21 (m, 4H), 4.08-4.03 (m, 2H), yloxy)-piperidin- 1 -yl] -6-methyl-2- 3.77-3.60 (m, 1H), 3.58-3.53 (m, 2H), (tetrahydro-pyran-4-yl)- [ 1,2,4] triazolo[ 1,5- 3.43-3.37 (m, 2H), 3.13-3.07 (m, 1H), a] pyrimidine

[0748] 2.31 (s, 3H), 2.10-2.00 (m, 7H), 1.97- 1.85 (m, 2H); Mass (m / z); 452.5 (M+H)+.

[0749] 1H - NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 8.28-8.26 (m, 2H), 7.50-7.41 (m, 3H), 6.79 (d, J = 8.4Hz, 1H), 6.51 (d, J = 2.8Hz, 1H), 6.48 (dd, J = 2.8, 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 8.8Hz, 1H), 4.42-4.40 (m, 1H), 4.30- yloxy)-piperidin-l-yl]-6-methyl-2-phenyl- 4.21 (m, 4H), 3.82-3.75 (m, 2H),

[0750] [ 1,2,4]triazolo[ 1,5-a]pyrimidine 3.48-3.42 (m, 2H), 2.35 (s, 3H), 2.13- 2.04 (m, 2H), 1.97-1.90 (m, 2H); Mass (m / z); 444.0 (M+H)+.

[0751] ’H - NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 8.30-8.26 (m, 2H), 7.49-7.40 (m, 3H), 7.18-7.15 (m, 1H), 6.89-6.78 (m, 2H), 5.13-5.07 (m, 4H), 4.69-4.51 5- [4-( 1,3 -Dihydro-isobenzofuran-5- (m, 1H), 3.87-3.70 (m, 2H), 3.54-3.45 yloxy)-piperidin-l-yl]-6-methyl-2-phenyl- (m, 2H), 2.36 (s, 3H), 2.36-2.11 (m,

[0752] [ 1,2,4]triazolo[ 1,5-a]pyrimidine 2H), 2.01-1.94 (m, 2H), Mass (m / z);

[0753] 428.1 (M+H)+.

[0754]

[0755] 1H - NMR (400 MHz, CDCl3): 59.48

[0756] (s, 1H), 8.68 (d, J = 2.0Hz, 1H), 8.53 (d, J = 8.0Hz, 1H), 8.31 (s, 1H), 7.41 (dd, J = 4.8, 8.0Hz, 1H), 6.80 (d, J = 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4]dioxin-6- 8.4Hz, 1H), 6.51 (d, J = 2.8Hz, 1H), yloxy)-piperidin-l-yl]-6-methyl-2-pyridin- 6.48 (dd, J = 2.8, 8.8Hz, 1H), 4.45- 3 -yl- [ 1,2,4] triazolo [ 1, 5 - a] pyrimidine 4.41 (m, 1H), 4.27-4.21 (m, 4H),

[0757] 3.83-3.77 (m, 2H), 3.51-3.45 (m, 2H), 2.36 (s, 3H), 2.13-2.07 (m, 2H), 1.98- 1.91 (m, 2H), Mass (m / z); 445.1 (M+H)+.

[0758] ’H - NMR (400 MHz, CDCl3): 5 8.19 (s, 1H), 7.42 (d, J = 8.4Hz, 2H), 7.30- 7.27 (m, 2H), 7.22-7.18 (m, 1H), 6.78 (d, J = 8.8Hz, 1H), 6.49 (d, J = 2.8Hz, 1H), 6.46 (dd, J = 2.8, 8.8Hz, 2-Benzyl-5-[4-(2,3-dihydro- 1H), 4.43-4.37 (m, 1H), 4.26-4.20 (m, benzo[ 1,4]dioxin-6-yloxy)-piperidin- 1 - yl] - 4H), 4.15 (s, 2H), 3.78-3.69 (m, 2H), 6-methyl-[ 1,2,4] triazolo [ 1,5-a]pyrimidine 3.41-3.35 (m, 2H), 2.29 (s, 3H), 2.09- 2.03 (m, 2H), 1.92-1.89 (m, 2H); Mass (m / z); 458.2 (M+H)+.

[0759] 1H - NMR (400 MHz, CDCl3): δ 8.55 (d, J = 4.8Hz, 1H), 8.22 (s, 1H), 7.64 (t, 1H), 7.41(d, J = 7.6Hz, 1H), 7.15 (dd, J = 5.6Hz, 7.2Hz, 1H), 6.78 (d, J = 8.4Hz, 1H), 6.49 (d, J = 2.8Hz, 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 1H), 6.46 (dd, J = 2.8, 8.4Hz, 1H), yloxy)-piperidin-l-yl]-6-methyl-2-pyridin- 4.41-4.37 (m, 3H), 4.26-4.20 (m, 4H), 2-ylmethyl- [ 1,2,4] triazolo [1,5- 3.76-3.70 (m, 2H), 3.42-3.36 (m, 2H), a] pyrimidine 2.30 (s, 3H), 2.10-2.03 (m, 2H), 1.93- 1.86 (m, 2H); Mass (m / z); 459.0 (M+H)+.

[0760] 1H - NMR (400 MHz, CDCl3): δ 8.52 (d, J = 2.4Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.65 (d, J = 2.4Hz, 1H), 4.74 (s, 2H), 3.80 (t, 2H), 3.20 (t, 2H), 3-Bromo-6-(6-methyl- [ 1,2,4] triazolo[ 1,5- 2.44 (s, 3H); Mass (m / z); 346.2, a] pyrimidin- 5 -yl) -5, 6,7, 8 - tetrahydro - 344.9 (M+H)+.

[0761] [ 1,6]naphthyridine

[0762]

[0763] 1H - NMR (400 MHz, CDCl3): 58.36

[0764] XX? (s, 1H), 8.29 (s, 1H), 8.22 (s, 1H),

[0765] 7.30 (s, 1H), 4.72 (s, 2H), 3.80 (t, 3-Methyl-6-(6-methyl-[l,2,4]triazolo[l,5- 2H), 3.21 (t, 2H), 2.44 (s, 3H), 2.33 a] pyrimidin- 5 -yl) -5, 6,7, 8 - tetrahydro - (s, 3H); Mass (m / z); 281.0 (M+H)+.

[0766] [ 1,6]naphthyridine

[0767] NvX. v1H - NMR (400 MHz, CDCl3): 58.59N> jT T Jz> (s, 1H), 8.37 (s, 1H), 8.22 (s, 1H),

[0768] 7.78 (s, 1H), 7.67 (s, 1H), 7.55 (s, 1H), 4.79 (s, 2H), 3.98 (s, 3H), 3.83 3-(l-Methyl-lH-pyrazol-4-yl)-6-(6- (t, 2H), 3.25 (t, 2H), 2.45 (s, 3H); methyl-[ 1,2,4] triazolo[ 1,5 -a]pyrimidin-5- Mass (m / z); 347.0 (M+H)+.

[0769] yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine

[0770] 1H - NMR (400 MHz, CDCl3): δ 8.33 _ISLN(s, 1H), 8.20 (s, 1H), 7.87 (d, J =

[0771] 2.8Hz, 1H), 6.63 (d, J = 2.4Hz, 1H), 4.72 (s, 2H), 3.79 (t, 2H), 3.31-3.28 6-(6-Methyl- [ 1,2,4] triazolo [1,5- (m, 4H), 3.14 (t, 2H), 2.43 (s, 3H), a]pyrimidin-5-yl)-3-pyrrolidin-l-yl- 2.05-2.02 (m, 4H); Mass (m / z); 336.2 5, 6,7, 8 -tetrahydro - [ 1, 6] naphthyridine (M+H)+.

[0772] 1H - NMR (400 MHz, CDCl3): 58.48 (d, J = 2.4Hz, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 7.41 (d, J = 2.4Hz, 1H), 7.32 N= / (d, J = 2.0Hz, 1H), 5.62 (d, J = 3-(6,7-Dihydro-5H-pyrazolo[l,5- 2.0Hz, 1H), 4.75 (s, 2H), 4.25 (t, 2H), a]pyrimidin-4-yl)-6-(6-methyl- 3.82 (t, 2H), 3.72 (t, 2H), 3.22 (t, 2H), [ 1,2,4]triazolo[ 1,5-a]pyrimidin-5-yl)- 2.45 (s, 3H), 2.35-2.33 (m, 2H); Mass 5, 6,7, 8 -tetrahydro - [ 1, 6] naphthyridine (m / z); 388.2 (M+H)+.

[0773] 1H - NMR (400 MHz, CDCl3): 58.45 (d, J = 2.8Hz, 1H), 8.38 (d, J = XX JX -- / 1.2Hz, 1H), 8.22 (s, 1H), 7.41 (d, J = N= / 2.8Hz, 1H), 5.44 (s, 1H), 4.75 (s, 2H),

[0774] 4.17 (t, 2H), 3.82 (t, 2H), 3.69 (t, 2H), -(2-Methyl-6,7-dihydro-5H-pyrazolo[l,5- 3.21 (t, 2H), 2.45 (s, 3H), 2.34-2.30 a]pyrimidin-4-yl)-6-(6-methyl- (m, 2H), 2.18 (s, 3H); Mass (m / z);

[0775] [ 1,2,4]triazolo[ 1,5-a]pyrimidin-5-yl)- 402.2 (M+H)+.

[0776]

[0777] 5, 6,7, 8 -tetrahydro - [ 1, 6] naphthyridine

[0778] BrXXJ< N

[0779] 1H - NMR (400 MHz, CDCl3): 58.56 / W (s, 1H), 8.29 (s, 1H), 7.58 (s, 1H),

[0780] 4.74 (s, 2H), 3.90 (t, 2H), 3.21 (t, 2H), 2.64 (s, 3H), 2.32 (s, 3H); Mass 3-Bromo-6-(6,7-dimethyl- (m / z); 360.7, 358.5 (M+H)+.

[0781] [ 1,2,4]triazolo[ 1,5-a]pyrimidin-5-yl)- 5, 6,7, 8 -tetrahydro - [ 1, 6] naphthyridine

[0782] 1H - NMR (400 MHz, CDCl3): 58.30. N.. N.N

[0783] (s, 1H), 7.91 (d, J = 2.8Hz, 1H), 6.53 (d, J = 2.4Hz, 1H), 4.73 (s, 2H), 3.91 (t, 2H), 3.31-3.27 (m, 4H), 3.15 (t, 6-(6,7 -Dimethyl- [ 1,2,4]triazolo[ 1,5- 2H), 2.62 (s, 3H), 2.30 (s, 3H), 2.06- a]pyrimidin-5-yl)-3-pyrrolidin-l-yl- 2.01 (m, 4H); Mass (m / z); 350.0 5, 6,7, 8 -tetrahydro - [ 1, 6] naphthyridine (M+H)+.

[0784] r, _ N. M ’H - NMR (400 MHz, CDCl3): 58.51 Br \ _

[0785] (s, 1H), 8.27 (s, 1H), 7.64 (s, 1H), 4.70 (s, 2H), 3.78 (t, 2H), 3.17 (t, 3-Bromo-6-(2,6-dimethyl- 2H), 2.52 (s, 3H), 2.40 (s, 3H); Mass [ 1,2,4]triazolo[ 1,5-a]pyrimidin-5-yl)- (m / z); 359.0, 360.9 (M+H)+.

[0786] 5, 6,7, 8 -tetrahydro - [ 1, 6] naphthyridine

[0787] 1H - NMR (400 MHz, CDCl3): 58.29 (s, 1H), 8.24 (s, 1H), 7.3 l(s, 1H), Xir

[0788] 4.69 (s, 2H), 3.77 (t, 2H), 3.20 (t, 6-(2,6-Dimethyl- [ 1,2,4]triazolo[ 1,5- 2H), 2.52 (s, 3H), 2.40 (s, 3H), 2.33 a]pyrimidin-5-yl)-3-methyl-5,6,7,8- (s, 3H); Mass (m / z); 295.2 (M+H)+. tetrahydro- [ 1,6] naphthyridine

[0789] 1H - NMR (400 MHz, CDCl3): 58.47 Y XTF (d, J = 2.4Hz, 1H), 8.26 (d, J =

[0790] 0.8Hz, 1H), 7.40 (d, J = 2.4Hz, 1H), N= /

[0791] 7.31 (d, J = 2.0Hz, 1H), 5.61 (d, J = 3-(6,7-Dihydro-5H-pyrazolo[l,5- 2.0Hz, 1H), 4.71 (s, 2H), 4.25 (t, 2H), a]pyrimidin-4-yl)-6-(2,6-dimethyl- 3.80 (t, 2H), 3.72 (t, 2H), 3.20 (t, 2H),

[0792]

[0793] [ 1,2,4]triazolo[ 1,5-a]pyrimidin-5-yl)- 2.52 (s, 3H), 2.41 (s, 3H), 2.37-2.31 (m, 2H); Mass (m / z); 402.2 (M+H)+.5,6,7,8-tetrahydro - [ 1, 6] naphthyridine (m, 2H); Mass (m / z); 402.2 (M+H)+.

[0794] . XJL. N.. N.N

[0795] < N V1- _1H - NMR (400 MHz, CDCl3): δ 8.44

[0796] ^N'N' (s, 1H), 8.26 (s, 1H), 7.40 (s, 1H), N= / 5.43 (s, 1H), 4.72 (s, 2H), 4.17 (t,

[0797] 2H), 3.80 (t, 2H), 3.69 (t, 2H), 3.19 (t, 6-(2,6-Dimethyl- [ 1,2,4]triazolo[ 1,5- 2H), 2.52 (s, 3H), 2.41 (s, 3H), 2.32- a]pyrimidin-5-yl)-3-(2-methyl-6,7- 2.30 (m, 2H), 2.17 (s, 3H); Mass dihydro-5H-pyrazolo[ 1,5-a]pyrimidin-4- (m / z); 416.2 (M+H)+.

[0798] yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine

[0799] ’H - NMR (400 MHz, CDCI3): 58.51 (s, 1H), 8.29 (s, 1H), 7.61 (s, 1H), 4.70 (s, 2H), 3.76 (t, 2H), 3.18-3.15 (m, 3H), 2.40 (s, 3H), 1.42 (d, J = 3-Bromo-6-(2-isopropyl-6-methyl- 8.0Hz, 6H), Mass (m / z); 388.7

[0800] (M+H)+.

[0801] [ 1,2,4]triazolo[ 1,5-a]pyrimidin-5-yl)- 5, 6,7, 8 -tetrahydro - [ 1, 6] naphthyridine

[0802] 1H - NMR (400 MHz, CDCl3): δ 9.49 (s, 1H), 8.69 (d, J = 4.8Hz, 1H), 8.53-8.51 (m, 2H), 8.40 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 4.8Hz, 8.0Hz, 3-Bromo-6-(6-methyl-2-pyridin-3-yl- 1H), 4.78(s, 2H), 3.84 (t, 2H), 3.21 (t, [ 1,2,4]triazolo[ 1,5-a]pyrimidin-5-yl)- 2H), 2.46 (s, 3H), Mass (m / z); 422.0 5, 6,7, 8 -tetrahydro - [ 1, 6] naphthyridine (M+H)+.

[0803]

[0804] ’H - NMR (400 MHz, CDCl3): 58.51

[0805] JL. N.. N. M (s, 1H), 8.28 (s, 1H), 7.61 (s, 1H), Br >> \ _

[0806] 7.42 (d, J = 7.2Hz, 2H), 7.31-7.27 (m, ^^N'N \— A

[0807] 2H), 7.23-7.19 (m, 1H), 4.69 (s, 2H), 4.16 (s, 2H), 3.76 (t, 2H), 3.16 (t, 2H), 2.39 (s, 3H), Mass (m / z); 436.8, 6-(2-Benzyl-6-methyl-[ 1,2,4] triazolo[ 1,5- 439.0 (M+H)+.

[0808] a]pyrimidin-5-yl)-3-bromo-5, 6,7,8- tetrahydro- [ 1,6] naphthyridine

[0809] 1H - NMR (400 MHz, CDCl3): δ 8.56 (d, J = 2.0Hz, 1H), 8.51 (d, J = 2.0Hz, 1H), 8.31 (s, 1H), 7.62-7.60 (m, 2H), 7.41 (d, J = 8.0Hz, 1H), 7.16 (dd, J = 1.2Hz, 6.0Hz, 1H), 4.69 (s,

[0810] 2H), 4.38 (s, 2H), 3.77 (t, 2H), 3.16 3-Bromo-6-(6-methyl-2-pyridin-2- (t, 2H), 2.39 (s, 3H), Mass (m / z); ylmethyl-[ 1,2,4]triazolo[ 1,5-a]pyrimidin- 437.9 (M+H)+.

[0811] -yl) -5,6,7, 8-tetrahydro- [ 1,6] naphthyridine

[0812] 1H - NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 8.21(s, 1H), 4.73 (s, 2H), 3.79 (t, 2H), 3.10 (t, 2H), 2.69 (s, 3H), 2.42 (s, 3H), Mass (m / z); 287.0 (M+H)+.

[0813] 6-Methyl-5-(2-methyl-6,7-dihydro-4H- thiazolo[5,4-c]pyridin-5-yl)- [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0814] 1H - NMR (400 MHz, CDCl3): δ 8.24 (s, 1H), 4.69 (s, 2H), 3.76 (t, 2H), 3.08 (t, 2H), 2.68 (s, 3H), 2.51 (s, 3H), 2.39 (s, 3H); Mass (m / z); 300.9 (M+H)+.

[0815] 2,6-Dimethyl-5-(2-methyl-6,7-dihydro- 4H-thiazolo[5,4-c]pyridin-5-yl)-

[0816]

[0817] [ 1,2,4]triazolo[ 1,5-a]pyrimidine1H - NMR (400 MHz, CDCl3): 58.36

[0818] (s, 1H), 4.70 (s, 2H), 3.76 (t, 2H), 3.08 (t, 2H), 2.88-2.83 (m, 2H), 2.68 2-Ethyl-6-methyl-5-(2-methyl-6,7- (s, 3H), 2.38 (s, 3H), 1.41 (t, dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)- 3H): Mass (m / z); 314.9 (M+H)+.

[0819] [ 1,2,4]triazolo[ 1,5-a]pyrimidine

[0820] 1H - NMR (400 MHz, CDCl3): 58.55 (s, 1H), 8.12 (d, J = 8.4Hz, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.51 (t, 1H), 7.14 (t, 1H), 6.94 (d, J = 9.2Hz, 2H), 6.87 P^N'N (d, J = 9.2Hz, 2H), 4.47-4.43 (m, 2- [4-(4-Methoxy-phenoxy)-piperidin- 1 - 1H), 3.79 (s, 3H), 3.76-3.70 (m, 2H), yl] -3-methyl-pyrimido[ 1,2-b]indazole 3.36-3.30 (m, 2H), 2.42 (s, 3H), 2.18- 2.13 (m, 2H), 2.03-1.95 (m, 2H); Mass (m / z); 388.19 (M+H)+

[0821] 1H - NMR (400 MHz, CDCl3): 58.57 (s, 1H), 8.12 (d, J = 8.4Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.52 (t, 1H), 7.42 (t, 1H), 7.21 (s, 1H), 7.18-7.12 (m, 3H), 4.64-4.60 (m, 1H), 3.74-3.68 (m, -[l-(3-Methyl-pyrimido[l,2-b]indazol-2- 2H), 3.42-3.36 (m, 2H), 2.44 (s, 3H), yl)-piperidin-4-yloxy]-benzonitrile 2.23-2.17 (m, 2H), 2.06-2.00 (m, 2H);

[0822] Mass (m / z); 384.2 (M+H)+

[0823] 1H - NMR (400 MHz, CDCl3): 58.56 (d, J = 0.8Hz, 1H), 8.12 (d, J = 8.0Hz, 1H), 7.90 (d, J = 2.4Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.52-7.48 (m, H,«XX VP

[0824] 1H), 7.28 (d, J = 3.2Hz, 1H), 7.15- 7.11 (m, 1H), 6.73 (dd, J = 0.8, 2-[4-(6-Methoxy-pyridin-3-yloxy)- 0.4Hz, 1H), 4.47-4.41 (m, 1H), 3.91 piperidin- 1 - yl] - 3 -methyl-pyrimido [1,2- (s, 3H), 3.75-3.70 (m, 2H), 3.36-3.30 b] indazole

[0825] (m, 2H), 2.43 (s, 3H), 2.21-2.14 (m, 2H), 2.04-1.96 (m, 2H); Mass (m / z);

[0826]

[0827] 390.10 (M+H)+1H - NMR (400 MHz, CDCl3): 58.55

[0828] (d, J = 0.8Hz, 1H), 8.12 (d, J = 8.4Hz, 1H), 7.51 (t, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.14 (t, 1H), 6.80 (d, J = 8.8Hz, 1H), 6.53 (d, J = 2.8Hz, 1H), 2-[4-(2,3-Dihydro-benzo[l,4]dioxin-6- 6.50 (dd, J = 2.8, 2.8Hz, 1H), 4.43- yloxy)-piperidin- 1 -yl] -3 - methyl - 4.42 (m, 1H), 4.27-4.21 (m, 4H), pyrimido [ 1,2-b] indazole 3.73-3.68 (m, 2H), 3.36-3.30 (m, 2H),

[0829] 2.42 (s, 3H); Mass (m / z); 416.18 (M+H)+

[0830] 1H - NMR (400 MHz, CDCl3): δ 8.56 (s, 1H), 8.12 (d, J = 8.0Hz, 1H), 7.70 (d, J = 8.0Hz, 1H), 7.52-7.48 (m, 1H), 7.17 (d, J = 7.6Hz, 1H), 7.13 (d,

[0831] J = 7.2Hz, 1H), 6.90 (d, J = 2.0Hz, 1H), 6.88 (d, J = 2.4Hz, 1H), 5.09 (s, 2- [4-( 1,3 -Dihydro-isobenzofuran-5- 2H), 5.07 (s, 2H), 4.59-4.55 (m, 1H), yloxy)-piperidin- 1 -yl] -3 - methyl - 3.75-3.69 (m, 2H), 3.40-3.34 (m, 2H), pyrimido [ 1,2-b] indazole

[0832] 2.43 (s, 3H), 2.22-2.16 (m, 2H), 2.06- 1.98 (m, 2H); Mass (m / z); 400.19 (M+H)+

[0833] ’H - NMR (400 MHz, CDCl3): δ 8.61 (d, J = 0.8Hz, 1H), 7.96 (d, J = 8.4Hz, 1H), 7.90 (d, J = 2.8Hz, 1H), 7.30-7.27 (m, 2H), 7.07 (dd, J = 6.8, 8.4Hz, 1H), 6.73 (d, J = 8.8, 1H), 4.45-4.43 (m, 1H), 3.91 (s, 3H), 3.75- piperidin- 1 -yl] -3,7 -dimethyl -pyrimido [1,2- 3.69 (m, 2H), 3.36-3.29 (m, 2H), 2.67 b] indazole (s, 3H), 2.42 (s, 3H), 2.20-2.14 (m,

[0834] 2H), 2.03-1.98 (m, 2H); Mass (m / z); 404.1 (M+H)+

[0835] ’H - NMR (400 MHz, CDCl3): δ 8.61 (d, J = 0.8Hz, 1H), 7.96 (d, J = 8.4Hz, 1H), 7.28 (t, 1H), 7.17 (d, J =

[0836] 8.0Hz, 1H), 7.07-7.04 (m, 1H), 6.90- 2- [4-( 1,3 -Dihydro-isobenzofuran-5- 6.88 (dd, J= 2.0, 2.4Hz, 1H), 6.85 (s, yloxy)-piperidin- 1 -yl] -3,7 -dimethyl - 1H), 5.09-5.07 (m, 4H), 4.59-4.54 (m, pyrimido [ 1,2-b] indazole 1H), 3.75-3.69 (m, 2H), 3.39-3.33 (m,

[0837]

[0838] 2H), 2.67 (s, 3H), 2.42 (s, 3H), 2.21-2.15 (m, 2H), 2.06-2.00 (m, 2H);

[0839] Mass (m / z); 415.3 (M+H)+

[0840] ’H - NMR (400 MHz, CDCl3): 5 8.83-8.81 (dd, J = 2.0, 1.6Hz, 1H), 8.65 (s, 1H), 8.45-8.43 (dd, J = 1.6, 1.6Hz, 1H), 7.90-7.89 (d, J = xy’'Ov,..x >

[0841] H3CO N Y rV / 4.42.8Hz, 1H), 7.30-7.29 (d, J =

[0842] P^N'N 2.8Hz, 1H), 7.10-7.06 (dd, J = 4.4,

[0843] 4.0Hz, 1H), 6.74-6.71 (d, J = 9.6Hz.

[0844] 6-[4-(6-Methoxy-pyridin-3-yloxy)- 1H), 4.48-4.44 (m, 1H), 3.91 (s, 3H), piperidin- 1 -yl] -7 -methyl- 1,5, 8a,9-tetraaza- 3.78-3.72 (m, 1H), 3.41-3.35 (m, 2H), fluorene

[0845] 2.43 (s, 3H), 2.19-2.13 (m, 2H), 2.05- 1.98 (m, 2H); Mass (m / z); 391.2 (M+H)+.

[0846] ’H - NMR (400 MHz, CDCl3): 5 8.82 (dd, J = 2.0, 2.0Hz, 1H), 8.63 (s, 1H), 8.45 (dd, J = 2.0, 2.0Hz, 1H), 7.08 JL J L. N.. N. J \ (dd, J = 4.4, 4.4Hz, 1H), 6.80 (d, J = fY T rp

[0847] <z° 8.4Hz, 1H), 6.53 (d, J = 2.8Hz, 1H),

[0848] 6.50 (dd, J = 2.8, 3.2Hz. 1H), 4.46- 6-[4-(2,3-Dihydro-benzo[l,4]dioxin-6- 4.42 (m, 1H), 4.27-4.22 (m, 4H), yloxy)-piperidin- 1 -yl] -7 -methyl- 1,5,8a, 9- 3.76-3.70 (m, 2H), 3.41-3.35 (m, 2H), tetraaza-fluorene 2.44 (s, 3H), 2.17-2.11 (m,2H), 2.03- 1.97 (m, 2H); Mass (m / z); 418.1 (M+H)+.

[0849] ’H - NMR (400 MHz, CDCl3): 5 8.83 (dd, J = 2.0, 1.6Hz, 1H), 8.64 (s, 1H), 8.45 (dd, J = 1.6, 2.0Hz, 1H), 7.17 (d, \ T \ \ >-N J = 8.0Hz, 1H), 7.09 (dd, J = 4.4, O-7X^N'N 4.4Hz, 1H), 6.90 (dd, J = 2.0, 2.0Hz,

[0850] 1H), 6.85 (s, 1H), 5.14 (d, J = 4.4Hz, 6- [4-( 1,3 -Dihydro-isobenzofuran-5- 4H), 4.60-4.58 (m, 1H), 3.77-3.71 (m, yloxy)-piperidin- 1 -yl] -7 -methyl- 1,5,8a, 9- 2H), 3.44-3.38 (m, 2H), 2.45 (s, 3H), tetraaza-fluorene

[0851] 2.20-2.14 (m, 2H), 2.07-2.01 (m, 2H); Mass (m / z); 402.1 (M+H)+.

[0852] 1H - NMR (400 MHz, CDCl3): 5 8.590X^ O (s, 1H), 8.30-8.28 (d, J = 8.0Hz, 1H),

[0853] 6.97-6.78 (d, J = 8.0Hz, 1H), 6.80- 6.78 (d, J = 8Hz, 1H), 6.52 (d, J =

[0854]

[0855] 6-[4-(2,3-Dihydro-benzo[l,4]dioxin-6- 2.8Hz, 1H), 6.49-6.47 ( dd, J = yloxy)-piperidin- 1 -yl] -2,7 -dimethyl - 2.8,2.8Hz, 1H), 4.45-4.41 (m, 4H), 1,5,8a, 9-tetraaza-fluorene 4.27-4.21 (m, 2H), 3.74-3.68 (m, 2H),

[0856] 3.37-3.31 (m, 2H), 2.72 (s, 3H), 2.41 (s, 3H), 2.16-2.10 (m, 2H), 2.01-1.91 (m, 2H); Mass (m / z); 431.8 (M+H)+.

[0857] 1H - NMR (400 MHz, CDCl3): 58.59 (s, 1H), 8.30-8.28 (d, J = 8.0Hz, 1H), 6.97-6.95 (d, J = 8.0Hz, 1H), 6.93- 6.91 ( d, J = 8.0Hz, 2H), 6.86-6.84 (d, J = 8.0Hz, 2H), 4.46-4.45 (m, 1H), 3.76 (s, 3H), 3.76-3.70 (m, 2H), 3.38- 6- [4-(4-Methoxy-phenoxy)-piperidin- 1 - 3.32 (m, 2H), 2.72 (s, 3H), 2.42 (s, yl]-2, 7 -dimethyl- 1,5, 8a, 9-tetraaza-fluorene 3H), 2.17-2.12 (m, 2H), 2.02-1.96 (m,

[0858] 2H); Mass (m / z); 403.9 (M+H)+.

[0859] ’H - NMR (400 MHz, CDCl3): 58.61 plAyA)

[0860] (s, 1H), 8.46 (s, 1H), 8.16 (d, J = ''A 8.0Hz, 1H), 7.70 (s, 1H), 7.53 (m, N=Z

[0861] 2H), 7.21 (t, 1H), 5.46 (s, 1H), 4.72 (s, 2H), 4.18 (t, 2H), 3.76-3.63 (m, 3-Methyl-2-[3-(2-methyl-6,7-dihydro-5H- 4H), 3.25 (t, 2H), 2.51 (s, 3H), 2.35- pyrazolo[l,5-a]pyrimidin-4-yl)-7,8- 2.29 (m, 2H), 2.19 (s, 3H); Mass dihydro-5H-[ 1,6]naphthyridin-6-yl] - (m / z); 451.3 (M+H)+

[0862] pyrimido [ 1,2-b] indazole

[0863] 1H - NMR (400 MHz, CDCl3): 58.69 Br JL xsX Y Y J>— \ \ (s, 1H), 8.55 (s, 1H), 8.00 (d, J =

[0864] 8.0Hz, 1H), 7.74 (s, 1H), 7.28-7.27 (m, 1H), 7.11 (t, 1H), 4.71 (s, 2H), 2-(3-Bromo-7,8-dihydro-5H- 3.73 (t, 2H), 3.23 (t, 2H), 2.69 (s, [l,6]naphthyridin-6-yl)-3,7-dimethyl- 3H), 2.50 (s, 3H); Mass (m / z); 407.9, pyrimido [ 1,2-b] indazole 409.8 (M+H)+

[0865] 1H - NMR (400 MHz, CDCl3): 58.67 f TO / ^\ (d, J = 0.8Hz, 1H), 8.48 (d, J = p Y"xk^NAYNzrN'\U\ 2.4Hz, 1H), 7.98 (d, J = 8.4Hz, 1H), N= / 7.49 (d, J = 2.4Hz, 1H), 7.33 (d, J =

[0866] 2.0Hz, 1H), 7.30 (d, J = 6.8Hz, 1H), 2- [3 -(6,7 -Dihydro-5H-pyrazolo [1,5- 7.10-7.06 (m, 1H), 5.64 (d, J = 2.0Hz, a]pyrimidin-4-yl)-7,8-dihydro-5H- 1H), 4.70 (s, 2H), 4.25 (t, 2H), 3.76- [l,6]naphthyridin-6-yl]-3,7-dimethyl- 3.71 (m, 4H), 3.24 (t, 2H), 2.68 (s, pyrimido [ 1,2-b] indazole

[0867]

[0868] 3H), 2.50 (s, 3H), 2.38-2.32 (m, 2H);Mass (m / z); 451.2 (M+H)+

[0869] ’H - NMR (400 MHz, CDCl3): 58.87 JL. N. J / > (t, 1H), 8.72 (s, 1H), 8.56 (s, 1H),

[0870] Y YVN

[0871] 8.50 (d, J = 8.0Hz, 1H), 7.74 (s, 1H), 7.15 (dd, J = 4.4, 4.0Hz, 1H), 4.73 (s, 6-(3-Bromo-7,8-dihydro-5H- 2H), 3.80 (t, 2H), 3.25 (t, 2H), 2.54 [l,6]naphthyridin-6-yl)-7-methyl-l,5,8a,9- (s, 3H); Mass (m / z); 394.7, 397.1 tetraaza-fluorene (M+H)+

[0872] ’H - NMR (400 MHz, CDCl3): 58.84 (dd, J= 1.6, 1.6Hz, 1H), 8.69 (s, 1H), T IAN8.49 (dd, J= 1.6, 2.0Hz, 1H), 8.32 (s,

[0873] 1H), 7.37 (s, 1H), 7.11 (dd, J = 4.4, 7-Methyl-6-(3-methyl-7,8-dihydro-5H- 4.4Hz, 1H), 4.70 (s, 2H), 3.79-3.76 (t, [l,6]naphthyridin-6-yl)-l,5,8a,9-tetraaza- 2H), 3.26-3.23 (t, 2H), 2.52 (s, 3H), fluorene 2.35 (s, 3H); Mass (m / z); 330.8

[0874] (M+H)+

[0875] 1H - NMR (400 MHz, CDCl3): 58.67 f il l Y\—. (d, J = 1.2Hz, 1H), 8.54 (d, J = y O-N 4.0Hz, 1H), 8.33 (d, J = 8.0Hz, 1H), / ^N'N 7.71 (d, J = 4.0Hz, 1H), 7.01 (d, J =

[0876] 8.0Hz, 1H), 4.69 (s, 2H), 3.76-3.70 6-(3-Bromo-7,8-dihydro-5H- (m, 2H), 3.23-3.20 (m, 2H), 2.74 (s, [ 1,6]naphthyridin-6-yl)-2,7 -dimethyl - 3H), 2.50 (s, 3H); Mass (m / z); 411.0 1,5,8a, 9-tetraaza-fluorene (M+H)+.

[0877] 1H - NMR (400 MHz, CDCl3): 58.64 T ’

[0878] (s, 1H), 8.30 (d, J = 8.4Hz, 1H), 6.99 i >-N

[0879] >^N~N (d, J = 8.4Hz, 1H), 4.70 (s, 2H), 3.76- 3.72 (m, 2H), 3.15-3.08 (m, 2H), 2.73 2,7-Dimethyl-6-(2-methyl-6,7-dihydro- (s, 3H), 2.70 (s, 3H), 2.49 (s, 3H); 4H-thiazolo[5,4-c]pyridin-5-yl)-l,5,8a,9- Mass (m / z); 350.9 (M+H)+.

[0880] tetraaza-fluorene

[0881] 1H - NMR (400 MHz, CDCl3): 58.64 (s, 1H), 8.31 (d, J = 8.4Hz, 1H), 6.99 (d, J = 8.4Hz, 1H), 4.72 (s, 2H), 3.76- 3.72 (m, 2H), 3.15-3.08 (m, 2H), 3.05 6-(2-Ethyl-6,7-dihydro-4H-thiazolo[5,4- (q, 2H), 2.72 (s, 3H), 2.47 (s, 3H), c]pyridin-5-yl)-2,7-dimethyl-l,5,8a,9- 1.41-1.38 (t, 3H); Mass (m / z); 364.9

[0882] (M+H)+.

[0883]

[0884] tetraaza-fluorene1H - NMR (400 MHz, CDCl3): 5 8.64 HSX? N N (s, 1H), 8.32 (d, J = 8.4Hz, 1H), 6.99

[0885] I T / / "N(d, J = 8.4Hz, 1H), 4.70 (s, 2H), 3.76- 3.72 (m, 2H), 3.35-3.25 (m, 1H), 6-(2-Isopropyl-6,7-dihydro-4H- 3.25-3.20 (m, 2H), 2.74 (s, 3H), 2.49 thiazolo[5,4-c]pyridin-5-yl)-2,7-dimethyl- (s, 3H), 1.41 (d, J = 6.8Hz, 6H); Mass 1,5,8a, 9-tetraaza-fluorene (m / z); 378.9 (M+H)+.

[0886] 1H - NMR (400 MHz, CDCl3): δ 8.35 (d, J = 8.0Hz, 1H), 8.25 (s, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.86 (t, 1H), 7.52 (t, 1H), 6.80 (d, J = 8.0, 1H), 6.52-6.47 (m, 2H), 4.47-4.45 (m, 1H),

[0887] 4.26-4.20 (m, 4H), 4.03-3.95 (m, 2H), 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 3.70-3.62 (m, 2H), 2.25-2.15 (m, 2H), yloxy)-piperidin- 1 - y 1] - [ 1,2,4] triazolo [1,5- 2.10-2.0 (m, 2H); Mass (m / z); 403.7 a]quinazoline (M+H)+.

[0888] 1H - NMR (400 MHz, CDCl3): 5 8.36 N y > (d, J = 8.0Hz, 1H), 8.26 (s, 1H), 8.03

[0889] L ^N. ^N.N

[0890] H3CO (d, J = 8.0Hz, 1H), 7.89 (d, J =

[0891] 2.4Hz, 1H), 7.87 (t, 1H), 7.53 (t, 1H), X w

[0892] 7.29 (dd, J = 2.4, 8.0Hz, 1H), 6.73 (d, M J = 8.0Hz, 1H), 4.51-4.47 (m, 1H),

[0893] 4.05-3.97 (m, 2H), 3.90 (s, 3H), 3.70- 5-[4-(6-Methoxy-pyridin-3-yloxy)- 3.62 (m, 2H), 2.25-2.17 (m, 2H), piperidin- 1 -yl] - [ 1,2,4] triazolo [1,5- 2.10-2.0 (m, 2H); Mass (m / z); 376.8 a]quinazoline

[0894] (M+H)+.

[0895] 1H - NMR (400 MHz, CDCl3): 5 8.27 (d, J = 8.4, 1H), 8.00 (d, J = 9.2, 1H), X N NN

[0896] 7.84-7.84 (t, 1H), 7.49-7.45 (t, 1H), 6.80 (d, J = 8.4, 1H), 6.52 (d, 1H), 6.49 (d, J = 11.6, 1H), 4.47-4.45 (m, 1H), 4.26-4.21 (m, 4H), 4.00-3.93 (t, 5 - [4-(2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 2H), 3.66-3.60 (t, 2H), 2.57 (s, 3H), yloxy)-piperidin- 1 -yl] -2-methyl- 2.17-2.15 (m, 2H), 2.58-1.99 (m, 2H);

[0897] [ 1,2, 4] triazolo [ 1,5-a]quinazoline

[0898] Mass (m / z); 418.1(M+H)+.

[0899]

[0900] 1H - NMR (400 MHz, CDCl3): 5 8.28

[0901] (d, J = 8.4, 1H), 8.01 (d, J = 7.6, 1H), N NN

[0902] 7.85-7.81 (t, 1H), 7.50-7.45 (t, 1H), 7.16 (d, J-8.4, 1H), 6.89 (d, J = 10.4, 1H), 6.84 (s, 1H), 5.08 (d, J = 5.2, 5- [4-( 1,3 -Dihydro-isobenzofuran-5- 4H), 4.63-4.59 (m, 1H), 4.01-3.94 (m, yloxy)-piperidin- 1 -yl] -2-methyl- 2H), 3.70-3.64 (m, 2H), 2.58 (s, 3H), [ 1,2,4]triazolo[ 1,5-a]quinazoline 2.24-2.17 (m, 2H), 2.09-2,02 (m, 2H);

[0903] Mass (m / z); 402.2 (M+H)+.

[0904] ’H - NMR (400 MHz, CDCl3): δ 8.51 (d, J = 2.8Hz, 1H), 8.40 (d, J = 8.0Hz, 1H), 8.28 (s, 1H), 8.12 (d, J = 8.0Hz, 1H), 7.94 (t, 1H), 7.61 (t, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 5.63 (d, J = 2.4 Hz, 1H), 5-[3-(6,7-Dihydro-5H-pyrazolo[l,5- 4.90 (s, 2H), 4.24 (t, 2H), 4.08 (t, a]pyrimidin-4-yl)-7,8-dihydro-5H- 2H), 3.72 (t, 2H), 3.37 (t, 2H), 2.36- [ 1,6]naphthyridin-6-yl] - [ 1,2,4] triazolo[ 1,5 - 2.33 (m, 2H); Mass (m / z); 424.0 a]quinazoline (M+H)+.

[0905] / ==\

[0906] 1H - NMR (400 MHz, CDCl3): 5 8.39 Z~\ «

[0907] N\N— \N'"N(d, J = 8.4, 1H), 8.32 (s, 1H), 8.27 (s,

[0908] 1H), 8.11 (d, J = 8.4, 1H), 7.93 (t, 1H), 7.60 (t, 1H), 7.34 (s, 1H) 4.88 (s, 2H), 4.07-4.04 (m, 2H), 3.37-3.34 (m, 5-(3 -Methyl-7, 8-dihydro-5H- 2H), 2.35 (s, 3H); Mass (m / z); 317.0 [ 1,6]naphthyridin-6-yl)- [ 1,2,4] triazolo[ 1,5 - (M+H)+.

[0909] a]quinazoline

[0910] Br\

[0911] / =\ N^ / 1H - NMR (400 MHz, CDCl3): 5 8.54 ( ) — \,N—C "

[0912] N— ( N— N"N(s, 1H), 8.33 (d, J = 8.0, 1H), 8.07 (d,

[0913] J = 8.0, 1H), 7.90 (t, 1H), 7.66 (s, 1H), 7.56 (t, 1H) 4.86 (s, 2H), 4.05- 4.02 (m, 2H), 3.33-3.30 (m, 2H), 2.59 5-(3-Bromo-7,8-dihydro-5H- (s, 3H); Mass (m / z); 394.7, 396.7 [ 1,6]naphthyridin-6-yl)-2-methyl- (M+H)+.

[0914] [ 1,2,4]triazolo[ 1,5-a]quinazoline

[0915]

[0916] 7=\N- X ’H - NMR (400 MHz, CDCl3): 5 8.31

[0917] N\N\N^N(s, 1H), 8.31 (d, 7 = 8, 1H), 8.08 (d, J = 8, 1H), 7.89 (t, 1H), 7.55 (t, 1H), 7.32 (s, 1H) 4.84 (s, 2H), 4.05-4.02 (m, 2H), 3.35-3.32 (m, 2H), 2.59 (s, 2-Methyl-5-(3 -methyl-7, 8-dihydro-5H- 3H), 2.34 (s, 3H); Mass (m / z); 331.0 [ 1,6]naphthyridin-6-yl)- [ 1,2,4] triazolo[ 1,5 - (M+H)+.

[0918] a]quinazoline

[0919] \ JLN’H - NMR (400 MHz, CDCl3): 5 8.61

[0920] (s, 1H), 8.32 (d, 7 = 8, 1H), 8.23 (s, 1H) 8.10 (d, 7 = 8, 1H), 7.90 (t, 1H), 7.79 (s, 1H) 7.72 (t, 1H), 7.68 (s, 1H), 4.91 (s, 2H), 4.08-4.05 (m, 2H), 3.98 2-Methyl-5- [3 -( 1 -methyl- 1 H-pyrazol-4- (s, 3H) 3.39-3.36 (m, 2H), 2.59 (s, yl)-7,8-dihydro-5H-[l,6]naphthyridin-6- 3H); Mass (m / z); 397.0 (M+H)+. yl] - [ 1,2,4] triazolo [ 1,5 -a] quinazoline

[0921] N- / 1H - NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.32 (d, J = 9.2, 1H), 8.094 (d, J = 7.6, 1H), 7.90-7.86 (t, 1H), 7.56-7.52 (t, 1H), 7.42 (s, 1H), 4.55 (s, 1H), 5.45 (s, 1H), 4.877 (s, 2H), 4.17 - 4.14 (t, 2H), 4.07-4.05 (t, 2H), 2-Methyl-5-[3-(2-methyl-6,7-dihydro-5H- 3.70 - 3.67 (t, 2H), 3.35-3.32 (t, 2H), pyrazolo[l,5-a]pyrimidin-4-yl)-7,8- 2.59 (s, 3H), 2.34 - 2.29 (m, 2H), 2.18 dihydro-5H-[ 1,6]naphthyridin-6-yl] - (s, 3H), Mass (m / z); 452.1 (M+H)+[ 1,2, 4] triazolo [ 1,5-a] quinazoline

[0922] ’H - NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.8, 1H), 7.98 (d, J = 8.4, 1H), 7.83-7.77 (t, 1H), 7.46-7.41 (t, 1H), 6.80 (d, J = 8.8, 1H), 6.52 (s, 1H), 6.49 (d, J = 11.6, 1H), 4.48-4.46 (m, 1H), 4.27-4.21 (t, 4H), 4.14 (s, 3H), 4.00-3.94 (t, 2H), 3.68-3.62 (t, 2H), 5 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 2.20-2.13 (m, 2H), 2.05-1.98 (m, 2H); yloxy)-piperidin- 1 -yl] -2-methoxy- Mass (m / z); 434 (M+H)+.

[0923] [ 1,2, 4] triazolo [ 1,5-a] quinazoline

[0924]

[0925] 1H - NMR (400 MHz, CDCl3): 5 8.20 °O=\1(d, J = 8.4, 1H), 7.99 (d, J = 7.6, 1H),

[0926] 7.84-7.79 (t, 1H), 7.46-7.42 (t, 1H), o— / N~^

[0927] 7.166 (d, J = 8.4, 1H), 6.89 (d, J = 10, 1H), 6.84 (s, 1H), 5.08 (d, J = 5.6, 4H), 4.62-4.610 (m, 1H), 4.14 (s, 3H) 5- [4-( 1,3 -Dihydro-isobenzofuran-5- 4.01-3.95 (m, 2H), 3.71-3.65 (m, 2H), yloxy)-piperidin- 1 -yl] -2-methoxy- 2.22-2.18 (m, 2H), 2.09-2.04 (m, 2H);

[0928] [ 1,2,4]triazolo[ 1,5-a]quinazoline

[0929] Mass (m / z); 418 (M+H)+.

[0930] / =\1H - NMR (400 MHz, CDCl3): δ 8.33

[0931] (s, 1H), 8.23-8.21 (d, J = 8.4, 1H),N\N— \N^N8.06-8.04 (d, J = 8.4, 1H), 7.87-7.83

[0932] (t, 1H), 7.52-7.49 (t, 1H), 7.31(s, 1H) 4.85 (s, 2H), 4.15 (s, 3H) 4.06-4.03 (t, 2-Methoxy-5-(3-methyl-7,8-dihydro-5H- 2H), 3.36-3.33 (t, 2H), 2.34 (s, 3H);

[0933] [ 1,6]naphthyridin-6-yl)- [ 1,2,4] triazolo[ 1,5 - Mass (m / z); 347.0 (M+H)+.

[0934] a]quinazoline

[0935] Y XA Y1H - NMR (400 MHz, CDCl3): 5 8.30N\N^\N^N( d, J = 8, 1H), 8.05 (d, J = 8, 1H),

[0936] 7.88 (t, 1H), 7.54 (t, 1H), 4.88 (s, 2H), 4.04-4.01 (m, 2H), 3.24-3.21 (m, 2-Methyl-5-(2-methyl-6,7-dihydro-4H- 2H), 2.69 (s, 3H), 2.58 (s, 3H); Mass thiazolo[5,4-c]pyridin-5-yl)- (m / z); 337.0 (M+H)+.

[0937] [ 1,2,4]triazolo[ 1,5-a]quinazoline

[0938] 1H - NMR (400 MHz, CDCl3): 5 8.30 Y YA "

[0939] ( d, J = 8.0, 1H), 8.06 (d, J = 8.0, \N^\N^N1H), 7.88 (t, 1H), 7.54 (t, 1H), 4.89

[0940] (s, 2H), 4.05-4.02 (m, 2H), 3.25-3.23 (m, 2H), 3.04 (q, 2H) 2.58 (s, 3H), 5-(2-Ethyl-6,7-dihydro-4H-thiazolo[5,4- 1.40-1.37 (t, 3H); Mass (m / z); 350.9 c]pyridin-5-yl)-2-methyl- (M+H)+.

[0941] [ 1,2,4]triazolo[ 1,5-a]quinazoline

[0942] ’H - NMR (400 MHz, CDCl3): 5 8.30 (d, J = 8.4, 1H ), 8.06 (d, J = 8.4, 1H), 7.88 (t, 1H), 7.54 (t, 1H), 4.89 (s, 2H), 4.05 (t, 2H), 3.33-3.29 (m, 1H), 3.25-3.23 (m, 2H ), 2.58 (s, 3H), 1.40 (d, 6H); Mass (m / z); 364.6 (M+H)+.

[0943] 5-(2-Isopropyl-6,7-dihydro-4H-

[0944]

[0945] thiazolo[5,4-c]pyridin-5-yl)-2-methyl- [ 1,2,4]triazolo[ 1,5-a]quinazoline

[0946] 1H - NMR (400 MHz, CDCl3): 5 8.53 (d, J = 8.4Hz, 1H), 8.07 (d, J = 8.4Hz, 1H),7.99 (t, 1H), 7.72 (t, 1H), ] 1, N 6.81 (d, J = 8.8Hz, 1H), 6.52 (s, 1H),

[0947] 6.49 (d, J = 8.8Hz, 1H), 4.54-4.51 (m, 1H), 4.27-4.22 (m, 4H), 4.08-4.02 - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- (m, 2H), 3.87-3.82 (m, 2H), 2.17-2.14 yloxy)-piperidin- 1 -yl] -tetrazolo [1,5- (m, 2H), 2.09-2.01(m, 2H). Mass a]quinazoline (m / z); 404.9 (M+H)+.

[0948] 1H - NMR (400 MHz, CDCl3): 5 8.54 o; jT I T i (d, J=8.4Hz, 1H), 8.08 (d, J=8.4Hz,

[0949] 1H), 7.98 (t, 1H), 7.79 (t, 1H), ), 7.26 A N" "N(s, 1H), 6.88 (d, J = 8.4Hz, 1H), 6.81 II IN(d, J =8.4Hz, 1H), 5.17-5.13 (m, 4H),

[0950] 4.76-4.71 (m, 1H), 4.06-4.00 (m, 2H), 5- [4-( 1,3 -Dihydro-isobenzofuran-5- 3.92-3.86 (m, 2H), 2.26-2.19 (m, 2H), yloxy)-piperidin- 1 -yl] -tetrazolo [1,5- 2.12-2.08 (m, 2H). Mass (m / z); 388.9 a]quinazoline (M+H)+.

[0951] Br

[0952] 1H - NMR (400 MHz, CDCl3): 5 8.59 (d, J = 8.4Hz, 1H), 8.57 (s, 1H), 8.15 I ', N (d, J = 8.4Hz, 1H), 8.04 (t, 1H), 7.77 / yX (t, 1H), 7.70 (s, 1H), 4.98 (s, 2H), M 4.19 (t, 2H), 3.38 (t, 2H). Mass (m / z);

[0953] 381.8, 383.7 (M+H)+.

[0954] 5-(3-Bromo-7,8-dihydro-5H- [ 1,6]naphthyridin-6-yl)-tetrazolo[ 1,5- a]quinazoline

[0955] 1H - NMR (400 MHz, CDCl3): 5 8.48 (s, 1H), 6.82 (d, J = 8.8Hz, 1H), 6.52- m u.

[0956] 6.45 (m, 2H), 4.52-4.47 (m, 1H), XX 4.30-4.22 (m, 4H), 3.93-3.85 (m, 2H),

[0957] 3.70-3.62 (m, 2H), 2.43 (s, 3H), 2.17- - [4 - (2, 3 -Dihydro-benzo [ 1,4] dioxin-6- 2.05 (m, 2H), 2.05-1.97 (m, 2H). yloxy)-piperidin- 1 -yl] -6-methyl- Mass (m / z); 368.8 (M+H)+. tetrazolo[ 1,5-a]pyrimidine

[0958]

[0959] Example-111: Determination of allosteric potency EC50 values for Muscarinic M4 receptor

[0960] The compounds were tested for their ability to activate the Muscarinic M4 receptor. A CH0-K1 cell line (Chinese hamster ovary (CHO) KI (ATCC CCL-61) was purchased from ATCC), engineered to stably express recombinant human Muscarinic M4 receptor and pCRE-Luc reporter system was used for cell-based assay. The assay offers a non-radioactive based approach to determine binding of a compound to GPCRs. In this specific assay, the level of intracellular cyclic AMP which is modulated by activation or inhibition of the receptor is measured. The recombinant cells harbor luciferase reporter gene under the control of cyclic AMP response element.

[0961] The above cells were grown in 96 well clear bottom white plates in Hams F12 medium containing 10% fetal bovine serum (FBS, was purchased from ThermoFisher Scientific). Prior to the addition of compounds or standard agonist, cells were serum starved overnight. Increasing concentrations of test compounds were added along with EC20 of acetylcholine and forskolin (1 pM) in Opti-MEM medium to the cells.

[0962] The incubation was continued at 37 °C in CO2 incubator for 4 hours. After removal of medium, cells were lysed using lysis buffer, detection reagent was added and luciferase activity was measured in a Luminometer. The reference agonist (10 pM) in the presence of forskolin (1 pM) stimulated luciferase activity was assigned a value of 100 % while basal luciferase activity i.e. only forskolin (1 pM) in the absence of a reference agonist was assigned a value of 0 %. Rest of the luminescent values obtained for compounds at various doses were calculated with reference to stimulated after correcting for basal luciferase activities. Compound activity (%) vs compound concentration was plotted and dose response curves were analyzed using a 4-parameter logistic fit model of GraphPad Prism software. EC50 values of the compounds were defined as the concentration required in stimulating the luciferase activity by 50 % in presence of EC20 of acetylcholine and the results are provided in table 1 as EC50 and Emax, where Emaxrepresents the maximum response or asymptote of the fitted dose response curve.

[0963] Results

[0964] Table 1: Allosteric potency EC50 values for Muscarinic M4 receptorExample Human M4 PAM Emax Example Human M4 PAM Emax No. EC50(nM) (%) No. EC50(nM) (%) 1 88 107 53 149 91 2 277 121 54 100 88 3 738 59 55 12 90 4 369 105 56 6 98 5 89 109 57 2388 87 6 246 77 58 1204 54 7 964 90 59 42 95 8 99 110 60 30 100 9 154 109 61 6 92 10 276 97 62 6 101 11 1426 75 63 54 92 12 188 89 64 69 87 13 1365 72 65 18 96 14 327 54 66 62 92 15 12 92 67 166 101 16 97 93 68 216 97 17 >10000 30 69 139 94 18 4 91 70 1029 54 19 275 110 71 1180 88 20 1257 80 72 1366 39 21 824 93 73 374 102 22 143 102 74 426 73 23 522 91 75 1177 44 24 54 108 76 261 113 25 145 110 77 443 49 26 38 103 78 33 97

[0965]

[0966] 939 90 79 133 101 550 111 80 32 105 107 111 81 266 106 324 72 82 12 93 102 101 83 301 42 21 96 84 32 100 220 110 85 89 77 114 104 86 139 83 377 100 87 40 95 47 109 88 187 64 335 94 91 122 95 44 101 92 267 101 15 110 93 83 103 30 106 94 133 106 13 95 95 11 84 8 98 96 33 93 15 107 97 30 91 22 104 98 44 83 40 107 99 119 41 47 118 100 7 97 76 121 101 38 111 22 100 102 146 104 22 100 103 39 95 61 98 104 166 57 207 97 105 56 85 42 97 106 71 74

[0967]

[0968] Example-112: Determination of allosteric potency EC50 values for Muscarinic M2 receptor

[0969] The compounds were tested for their ability to activate the Muscarinic M2 receptor. A CH0-K1 cell line (Chinese hamster ovary (CHO) KI (ATCC CCL-61) was purchased from ATCC), engineered to stably express recombinant human Muscarinic M2 receptor and pCRE-Luc reporter system was used for cell-based assay. The assay offers a non-radioactive based approach to determine binding of a compound to GPCRs. In this specific assay, the level of intracellular cyclic AMP which is modulated by activation or inhibition of the receptor is measured. The recombinant cells harbor luciferase reporter gene under the control of cyclic AMP response element.

[0970] The above cells were grown in 96 well clear bottom white plates in Hams F12 medium containing 10% fetal bovine serum (FBS, was purchased from ThermoFisher Scientific). Prior to the addition of compounds or standard agonist, cells were serum starved overnight. Increasing concentrations of test compounds were added along with EC 20 of acetylcholine and forskolin (1 pM) in Opti-MEM medium to the cells.

[0971] The incubation was continued at 37 °C in CO2 incubator for 4 hours. After removal of medium, cells were lysed using lysis buffer, detection reagent was added and luciferase activity was measured in a Luminometer. The reference agonist (10 pM) in the presence of forskolin (1 pM) stimulated luciferase activity was assigned a value of 100 % while basal luciferase activity i.e. only forskolin (1 pM) in the absence of a reference agonist was assigned a value of 0 %. Rest of the luminescent values obtained for compounds at various doses were calculated with reference to stimulated after correcting for basal luciferase activities. Compound activity (%) vs compound concentration was plotted and dose response curves were analyzed using a 4-parameter logistic fit model of GraphPad Prism software. EC50 values of the compounds were defined as the concentration required in stimulating the luciferase activity by 50 % in presence of EC 20 of acetylcholine and the results are provided in Table-2 as EC 50 and Emax, where Emaxrepresents the maximum response or asymptote of the fitted dose response curve.

[0972] Results

[0973] Table-2: Allosteric potency EC50 values for Muscarinic M2 receptorsHuman Muscarinic M2 receptor

[0974] Example Example

[0975] PAM EC50PAM EC

[0976] No. No.50

[0977] Emax (%) Emax (%) Not

[0978] 1 >10 pM 60 1.6 pM 78% calculable

[0979] Not Not

[0980] 26 >10 pM 24 >10 pM

[0981] calculable calculable 32 1.7 pM 36% 39 3.0 pM 69%

[0982] Not

[0983] 59 >10 pM 67 3.3 pM 86% calculable

[0984] 31 2.1 pM 67% 68 1.5 pM 70%

[0985] Not

[0986] 56 >10 pM

[0987] calculable

[0988]

[0989] Example- 113: Rodent pharmacokinetic study

[0990] Male Wistar rats (250 ± 50 grams) were used as experimental animals. Animals were housed individually in polypropylene cages. Two days prior to study, male Wistar rats were anesthetized with isoflurane for surgical placement of jugular vein catheter. Rats were administered with test compound intraperitoneally at a dose of 3 or 10 mg / kg. Rats received food and water ad libitum during acclimatization, surgical recovery and study.

[0991] Formulation for intraperitoneal (i.p.) administration was prepared using 5 % v / v DMSO + 5 % v / v Solutol HS15 + 90 % v / v Water for injection as vehicle. The dose formulations were prepared freshly on the day of dosing.

[0992] Post dosing, 200 pL of blood sample was collected at 0.08, 0.25, 0.5, 1, 2, 3, 5, 7 and 24 h post-dose through the jugular vein and replenished with an equivalent volume of normal saline. The collected blood sample was transferred into a labeled eppendorf tube containing 10 pL of sodium heparin (1000 lU / mL) as an anticoagulant. Blood was centrifuged at 4,000 revolutions per minute (rpm) for 10 min. Plasma was separated and stored frozen at -80 °C until analysis. The concentrations of the test compounds were quantified in plasma by qualified LC-MS / MS method using a suitable extraction technique. Study samples were analyzed using calibration samples in the batch and quality control samples spread across the batch.Pharmacokinetic parameters Cmax, Tmax, AUCo-t, ti / 2 were calculated using a standard non-compartmental model by using Phoenix WinNonlin 8.5 version Software package. The pharmacokinetic profile of the test compounds is given in Table3 below:

[0993] Table 3: Pharmacokinetic profile of the compounds of the present invention.

[0994] Example Dose Cmax TmaxAUCo-t tl / 2

[0995] No. (mg / kg) (ng / mL) (h) (ng.h / mL) (h)

[0996] 24 3 3420 + 394 0.25 7040 + 1371 1.63 + 0.78

[0997] 26 3 2690 + 208 0.25 2845 + 430 0.98 + 0.05

[0998] 31 3 979 + 296 0.25 644 + 150 0.60 + 0.20

[0999] 32 3 1703 + 161 0.25 976 + 207 0.40 + 0.20

[1000] 40 3 3370 + 570 0.25 2053 + 423 0.68 + 0.19

[1001] 56 3 1160 + 69 0.25 2573 + 258 2.35 + 0.44

[1002] 59 3 3438 + 161 0.25 7088 + 2910 3.09 + 1.19

[1003] 60 3 5288 + 705 0.25 5363 + 1442 2.05 + 1.18

[1004] 67 10 14275 + 1427 0.08 10929 + 2279 0.58 + 0.04

[1005] 68 10 3740 + 1558 0.25 2678 + 1090 0.85 + 0.18

[1006] 91 3 821 + 49 0.25 1029 + 144 1.85 + 0.49

[1007] 92 3 1925 + 421 0.25 2083 + 225 1.13 + 0.23

[1008] 93 3 592 + 67 0.25 562 + 65 0.98 + 0.12

[1009] 94 3 1878 + 544 0.31 3898 + 882 1.83 + 0.3

[1010] 95 3 1425 + 142 0.25 2260 + 339 1.55 + 0.28

[1011]

[1012] 98 10 9353 + 1387 0.17 7983 + 2398 1.21 + 0.73

[1013] 104 10 11000 + 698 0.21 13200 + 1344 0.78 + 0.1

[1014]

[1015] Example-114: Antagonism of amphetamine induced hyperlocomotion

[1016] Male Wistar rats of 230-250 grams weight were used. The body weights of the rats were recorded. Rats were randomized according to their body weights. Animals were brought to the laboratory 1 hour prior to acclimatizing to the laboratory conditions. The open field is a black colored arena of 51 x 51 x 51 cm enclosed by black plastic walls of same dimensions. Rats were habituated to the open field arena for a period of 30 minutes. Animals were administered respective treatments (vehicle or test compounds) based on the brain exposures. After the habituation period, animals were challenged with amphetamine (0.5 mg / kg, s.c.) or vehicle. Then the animals were placed in open field arenas and distance traveled by rats was tracked for 120 minutes using Videomot software. Data was analyzed using GraphPad prism software. The results of the test compounds are given in Table 4 below:

[1017] Table 4: Antipsychotic like activity of the compounds of the present invention

[1018] Percent Reversal

[1019] Example No. Inference

[1020] 10 mg / kg, i.p. 30 mg / kg, i.p.

[1021] 26 71 89 Active

[1022] 32 50 61 Active

[1023] 33 34 96 Active

[1024] 59 36 65 Active

[1025] 91 29 94 Active

[1026] 92 21 91 Active

[1027] 94 79 105 Active

[1028] 98 53 Not evaluated Active

[1029] 104 86 100 Active

[1030]

[1031] Example- 115: Receptor Occupancy Study in Rats

[1032] Male Wistar rats (250 ± 50 grams) were used as experimental animals. Animals were housed individually in polypropylene cages and acclimatized to the experimental condition for 4 days. On the day of the experiment, rats were administered with vehicle (10 mL / Kg) or test compound (3, 10 or 30 mg / Kg) intraperitoneally. At Tmaxof the test compound, all rats were intravenously administered with MK-6884, 3 pg / Kg (tracer), through lateral tail vein. After 5 minutes of tracer administration, rats were killed by cervical dislocation, brain was separated from the skull, splashed with ice cold water, and two brain regions (striatum and cerebellum) were isolated and transferred into respective pre-labelled / weighed micro centrifuge tubes and stored on dry ice or -80 C until processed for tracer extraction and analysis using LC-MS / MS based method. Study samples were analysed for tracer concentrations with calibration samples in the batch and quality control samples spread across the batch.

[1033] Receptor occupancy in striatum was calculated using ratio method based on the change in tracer concentrations post treatment of test compound.

[1034] Table 5: Receptor occupancy of test compounds of the present invention

[1035] Receptor Occupancy (%)

[1036] Example No.

[1037] 30 mg / kg, i.p.

[1038] 26 35.8 + 7.5

[1039] 31 34.5 + 5.2

[1040] 32 59.9 + 8.7

[1041] 33 49.8 + 3.7

[1042] 40 52.7 + 6.1

[1043] 50 43.0 + 4.3

[1044] 51 53.9 + 2.5

[1045] 59 58.4 + 6.8

[1046] 104 33.3 + 4.8

[1047]

[1048] Example-116: Rodent brain penetration study

[1049] Male Wistar rats (260 ± 40 grams) were used as experimental animals. Three animals were housed in each cage. Animals were given water and food ad libitum throughout the experiment and maintained on a 12 h light / dark cycle.

[1050] Brain penetration was determined in a discrete manner. One day prior to study, male Wistar rats were acclimatized and randomly grouped according to their body weight.

[1051] The test compounds were suitably formulated and administered orally at (free base equivalent) 3 or 10 mg / kg. Blood samples were removed via cardiac puncture by using isoflurane anesthesia. The animals were sacrificed to collect brain tissue. Plasma was separated and brain samples were homogenized and stored frozen at -20 °C until analysis. The concentrations of the test compounds in plasma and brain were determined using LC-MS / MS method.

[1052] The test compounds were quantified in plasma and brain homogenate by qualified LC-MS / MS method using a suitable extraction technique in the calibration range of 1-2000 ng / mL. Study samples were analyzed using calibration samples in the batch and quality control samples spread across the batch. The extent of brain to plasma ratio (Cbrain / C plasma) was calculated. The brain to plasma concentration ratio (Cbrain / Cplasma) of the test compounds are given in the Table-6 below:

[1053] Table-6: Brain concentrations to Plasma concentrations ratio of the compounds of the present invention

[1054] Brain concentrations to

[1055] Dose

[1056] Example No. Plasma concentrations ratio (mg / kg)

[1057] (Cbrain / Cplasma)

[1058] 26 3.0 0.61 ± 0.14

[1059] 32 3.0 0.46 ± 0.16

[1060] 40 10.0 0.36 ± 0.04

[1061] 67 10.0 0.40 ± 0.16

[1062] 98 10.0 0.39 ± 0.02

[1063] 104 10.0 0.37 ± 0.09

[1064]

Claims

We Claim:

1. A compound of formula (I), or an isotopic form, or a stereoisomer, or a pharmaceutically acceptable salt thereof,wherein,Xi is C or N, provided that when Xi is N then Ri is absent;X2 is C or N, provided that when X2 is N then R2 is absent;Ri is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxyalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, 3 to 7 membered cycloalkyl, 6 to 12 membered aryl, 4 to 12 membered heterocyclic ring, -(Ci-C4)alkyl-aryl, -(Ci-C4)alkyl-heteroaryl, or 5 to 12 membered heteroaryl, wherein the cycloalkyl, aryl, heterocyclic or heteroaryl ring are optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -Cs-Cvcycloalkyl, -Ci-C4alkoxyalkyl, -OCi-C4alkyl, and -OCi-C4haloalkyl; R2 is selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -Ci-C4alkoxy alkyl, -OCi-C4alkyl, or -OCi-C4haloalkyl;Alternatively, when Xi and X2 is C, then Ri and R2 together with the carbon atoms to which they are attached form a 3 to 7 membered cycloalkyl, 6 to 12 membered aryl or 4 to 12 membered heterocyclic, wherein the cycloalkyl, aryl and heterocyclic ring is optionally substituted with one to four substituents independently selected from the group consisting of hydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, and -Ci-C4alkoxyalkyl;R3 and R4a are each independently selected from hydrogen, halogen, cyano, -Ci-C4alkyl, -Ci-C4haloalkyl, -Cs-Cvcycloalkyl, -Ci-C4alkoxyalkyl, -OCi-C4alkyl, or -OCi-C4haloalkyl;Alternatively R3 and ^atogether with the carbon atoms to which they are attached from a 3 to 7 membered cycloalkyl, 6 to 12 membered aryl or 4 to 12 membered heterocyclic ring, wherein the cycloalkyl, aryl and heterocyclic ring is optionally substituted with one to four substituents independently selected from the group consisting of hydrogen, oxo, deuterium,halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi- C4haloalkyl, and -Ci-C4alkoxyalkyl;R5 NRioA is selected from(R4)m R9OAN' S- vw'” represents point of attachment;R4 at each occurrence is independently selected from hydrogen, deuterium, halogen, -Ci- C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, or -OC1-C4alkyl;Re and R7are each independently selected from hydrogen, halogen, cyano, -OH, -NH2, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, -OCi-C4alkoxyalkyl, -NHCi-C4alkyl; orAlternatively Re and R7together with the carbon atoms to which they are attached form a 5-12 membered heterocyclic or 5 to 12 membered heteroaryl ring, wherein heterocyclic and heteroaryl ring is optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, oxo, deuterium, halogen, cyano, -OH, -Ci-C4alkyl, -Ci-C4haloalkyl, -C3-C7cycloalkyl, -OCi-C4alkyl, -OCi-C4haloalkyl, and -Ci-C4alkoxyalkyl; X is N or C;m is 0, 1 or 2;R8 is hydrogen, halogen, -C1-C4 alkyl, or -OC1-C4 alkyl;R9 is hydrogen, halogen, G1, -C1-C4 alkyl, or -C1-C4 haloalkyl;R10 is hydrogen, halogen, -C1-C4alkyl, or -OC1-C4 alkyl;G1 at each occurrence is independently selected from a 5 to 12 membered heteroaryl, a 6 to 12 membered aryl, a 4 to 12 membered heterocyclic, or a 3 to 7 membered cycloalkyl, wherein G1 is optionally substituted with one to five substituents independently selected from the group consisting of hydrogen, halogen, cyano, oxo, -C1-C4 alkyl, and -C1-C4haloalkyl.

2. The compound of formula (I) or an isotopic form, or a stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the compound is selected from:5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2,6-dimethyl-pyrazolo[l,5-a] pyrimidine;3-[l-(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-piperidin-4-yloxy]-benzonitrile;5-[4-(4-Methoxy-phenoxy)-piperidin-l-yl]-2,6-dimethyl-pyrazolo[l,5-a]pyrimidine;5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-2,6-dimethyl-pyrazolo[l,5-a]pyrimidine; 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2,6-dimethyl-pyrazolo[l,5-a] pyrimidine;5-[4-(Benzo[l,3]dioxol-5-yloxy)-piperidin-l-yl]-2,6-dimethyl-pyrazolo[l,5-a]pyrimidine; 5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-6-methyl-pyrazolo[l,5-a]pyrimidine; 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-pyrazolo[l,5-a] pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-3,6-dimethyl-pyrazolo[l,5-a] pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2,6,7-trimethyl-pyrazolo[l,5-a] pyrimidine;5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2,6,7-trimethyl-pyrazolo[l,5-a] pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-3,6,7-trimethyl-pyrazolo[l,5-a] pyrimidine;3-Chloro-6-(2,6-dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;6-(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-3-pyrrolidin-l-yl-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;3-Bromo-6-(2,6-dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;6-(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-3-methyl-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;6-(6-Methyl-pyrazolo[l,5-a]pyrimidin-5-yl)-3-pyrrolidin-l-yl-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;6-(2,6-Dimethyl-pyrazolo[l,5-a]pyrimidin-5-yl)-3-(2-methyl-6,7-dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-7,8-dihydro-6H-cyclopenta[e] [ 1,2,4] triazolo [ 1, 5 - a] pyrimidine;5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a] pyrimidine;5-[4-(4-Methoxy-phenoxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a]pyrimidine; 3-[l-(6-Methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-piperidin-4-yloxy]-benzonitrile;5-[4-(3-Methoxy-phenoxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a]pyrimidine; 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a] pyrimidine;5-[4-(Benzo[l,3]dioxol-5-yloxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a]pyrimidine; 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-[l,2,4]triazolo[l,5-a] pyrimidine;5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-6,7-dimethyl-[l,2,4]triazolo[l,5-a] pyrimidine;5-[4-(4-Methoxy-phenoxy)-piperidin-l-yl]-6,7-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidine; 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6,7-dimethyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6,7,8,9-tetrahydro- [ 1, 2, 4] triazolo [ 1,5-a]quinazoline;5-[4-(4-Methoxy-phenoxy)-piperidin-l-yl]-2,6-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidine; 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2,6-dimethyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-2,6-dimethyl-[l,2,4]triazolo[l,5-a] pyrimidine;3-[l-(2,6-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-piperidin-4-yloxy]-benzonitrile; 5-[4-(3-Methoxy-phenoxy)-piperidin-l-yl]-2,6-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidine; 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2,6-dimethyl-[l,2,4]triazolo[l,5-a] pyrimidine;5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2,6,7-trimethyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2,6,7-trimethyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2-ethyl-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2-isopropyl-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;2-Cyclopropyl-5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;2-Cyclobutyl-5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;2-Cyclopentyl-5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-2-(tetrahydro-furan- 3-yl)-[l,2,4]triazolo[l,5-a]pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-2-(tetrahydro-pyran- 4-yl)-[l,2,4]triazolo[l,5-a]pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-2-phenyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-6-methyl-2-phenyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-2-pyridin-3-yl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;2-Benzyl-5-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-2-pyridin-2-ylmethyl- [ 1,2,4] triazolo [ 1,5 - a] pyrimidine;3-Bromo-6-(6-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;3-Methyl-6-(6-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;3-( l-Methyl-lH-pyrazol-4-yl)-6-(6-methyl-[ 1,2, 4]triazolo[l,5-a]pyrimidin-5-yl)-5, 6,7,8-tetrahydro-[ 1,6]naphthyridine;6-(6-Methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-3-pyrrolidin-l-yl-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;3-(6,7-Dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-6-(6-methyl-[l,2,4]triazolo[l,5-a] pyrimidin-5 - yl)- 5,6,7,8-tetrahydro-[1,6]naphthyridine;3-(2-Methyl-6,7 -dihydro-5H-pyrazolo[ 1,5 -a]pyrimidin-4-yl)-6-(6-methyl- [ 1,2,4] triazolo[ 1,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine;3-Bromo-6-(6,7-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;6-(6,7-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-3-pyrrolidin-l-yl-5,6,7,8-tetrahydro- [ 1,6]naphthyridine;3-Bromo-6-(2,6-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;6-(2,6-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-3-methyl-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;3-(6,7-Dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-6-(2,6-dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine;6-(2,6-Dimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-3-(2-methyl-6,7-dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-5,6,7,8-tetrahydro-[l,6]naphthyridine;3-Bromo-6-(2-isopropyl-6-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;3-Bromo-6-(6-methyl-2-pyridin-3-yl-[ 1,2, 4]triazolo[l, 5-a]pyrimidin-5-yl)-5, 6,7,8-tetrahydro-[ 1,6]naphthyridine;6-(2-Benzyl-6-methyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-3-bromo-5,6,7,8-tetrahydro- [ 1,6] naphthyridine;3-Bromo-6-(6-methyl-2-pyridin-2-ylmethyl-[l,2,4]triazolo[l,5-a]pyrimidin-5-yl)-5,6,7,8-tetrahydro-[ 1,6]naphthyridine;6-Methyl-5-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-[l,2,4]triazolo[l,5-a] pyrimidine;2,6-Dimethyl-5-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-[l,2,4]triazolo[l,5-a] pyrimidine;2-Ethyl-6-methyl-5-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)- [ 1,2,4]triazolo[ 1,5-a]pyrimidine;2-[4-(4-Methoxy-phenoxy)-piperidin- 1-yl] -3 -methyl -pyrimido[ 1,2-b]indazole;3-[l-(3-Methyl-pyrimido[l,2-b]indazol-2-yl)-piperidin-4-yloxy]-benzonitrile;2-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-3-methyl-pyrimido[l,2-b]indazole;2-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-3-methyl-pyrimido[l,2-b]indazole;2-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-3-methyl-pyrimido[l,2-b]indazole;2-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-3,7-dimethyl-pyrimido[l,2-b]indazole; 2-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-3,7-dimethyl-pyrimido[l,2-b]indazole;6-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-7-methyl-l,5,8a,9-tetraaza-fluorene; 6-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-7-methyl-l,5,8a,9-tetraaza-fluorene;6-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-7-methyl-l,5,8a,9-tetraaza-fluorene;6-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2, 7-dimethyl- 1,5, 8a, 9-tetraaza-fluorene;6-[4-(4-Methoxy-phenoxy)-piperidin-l-yl] -2, 7-dimethyl- 1,5, 8a, 9-tetraaza- fluorene;3-Methyl-2-[3-(2-methyl-6,7-dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-7,8-dihydro-5H- [ 1,6]naphthyridin-6-yl]-pyrimido[ 1,2-b]indazole;2-(3-Bromo-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-3, 7 -dimethyl -pyrimido[l,2-b]indazole; 2-[3-(6,7-Dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-7,8-dihydro-5H-[l,6]naphthyridin-6-yl] -3,7 -dimethyl -pyrimido [ 1,2-b] indazole;6-(3-Bromo-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-7-methyl- 1,5, 8a, 9-tetraaza- fluorene; 7-Methyl-6-(3-methyl-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-l,5,8a,9-tetraaza-fluorene; 6-(3-Bromo-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-2, 7 -dimethyl- 1,5, 8a, 9-tetraaza-fluorene;2, 7-Dimethyl-6-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)- 1,5, 8a, 9-tetraaza-fluorene;6-(2-Ethyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2, 7-dimethyl- 1,5, 8a, 9-tetraaza-fluorene;6-(2-Isopropyl-6, 7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2, 7-dimethyl- 1,5, 8a, 9-tetraaza-fluorene;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-[l,2,4]triazolo[l,5-a]quinazoline;5-[4-(6-Methoxy-pyridin-3-yloxy)-piperidin-l-yl]-[l,2,4]triazolo[l,5-a]quinazoline;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2-methyl-[l,2,4]triazolo[l,5-a]quinazoline;5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2-methyl-[l,2,4]triazolo[l,5-a]quinazoline;5-[3-(6,7-Dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-7,8-dihydro-5H-[l,6]naphthyridin-6-yl] - [ 1,2,4] triazolo [ 1,5 -a] quinazoline;5-(3-Methyl-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-[l,2,4]triazolo[l,5-a]quinazoline; 5-(3-Bromo-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-2-methyl-[l,2,4]triazolo[l,5-a] quinazoline;2-Methyl-5-(3-methyl-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-[l,2,4]triazolo[l,5-a] quinazoline;2-Methyl-5-[3-(l-methyl-lH-pyrazol-4-yl)-7,8-dihydro-5H-[l,6]naphthyridin-6-yl]- [ 1, 2, 4] triazolo [ 1,5 -a] quinazoline;2-Methyl-5-[3-(2-methyl-6,7-dihydro-5H-pyrazolo[l,5-a]pyrimidin-4-yl)-7,8-dihydro-5H- [ 1,6]naphthyridin-6-yl] -[ 1,2,4] triazolo[ 1,5-a]quinazoline;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-2-methoxy-[l,2,4]triazolo[l,5-a] quinazoline;5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-2-methoxy-[l,2,4]triazolo[l,5-a] quinazoline;2-Methoxy-5-(3-methyl-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-[l,2,4]triazolo[l,5-a] quinazoline;2-Methyl-5-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-[l,2,4]triazolo[l,5-a] quinazoline;5-(2-Ethyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-methyl-[l,2,4]triazolo[l,5-a] quinazoline;5-(2-Isopropyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-methyl-[l,2,4]triazolo[l,5-a] quinazoline;5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-tetrazolo[l,5-a]quinazoline; 5-[4-(l,3-Dihydro-isobenzofuran-5-yloxy)-piperidin-l-yl]-tetrazolo[l,5-a]quinazoline; 5-(3-Bromo-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-tetrazolo[l,5-a]quinazoline; and 5-[4-(2,3-Dihydro-benzo[l,4]dioxin-6-yloxy)-piperidin-l-yl]-6-methyl-tetrazolo[l,5-a]pyrimidine.

3. The compound of formula (I), or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in claim 1 or claim 2, for use as a muscarinic M4 receptor positive allosteric modulator (M4 PAMs).

4. A pharmaceutical composition comprising the compound of formula (I), or an isotopic form, or a stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in claim 1 or claim 2 and pharmaceutically acceptable excipients.

5. The pharmaceutical composition as claimed in claim 4, for use in the treatment of disease or disorder mediated by muscarinic M4 receptors, wherein disease or disorder is selected from psychiatric disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

6. A compound of formula (I) or an isotopic form, a stereoisomer, or a pharmaceutically acceptable salt thereof as claimed in claim 1 or claim 2, for use in the treatment of diseases or disorders mediated by muscarinic M4 receptors, wherein disease or disorder is selected from psychiatric disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

7. The compound for use as claimed in claim 6, wherein the psychiatric, neurological or cognitive disorders are selected from Alzheimer’s disease (AD), schizophrenia, psychosis, Parkinson’s disease (PD), depression, bipolar disorders, Huntington’s disease, cognitive dysfunction in Alzheimer’s disease, Attention deficit hyperactivity disorder (ADHD), pain disorder or drug addiction.

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