Substituted benzoxazole and benzofuran compounds as PDE7 inhibitors

Abstract

Substituted benzoxazole and benzofuran chemical entities of formula (I): #imgabs0# wherein V, W, X, Y, Z and m have any of the values described herein, and compositions comprising such chemical entities; methods for preparing them; and their use in various methods, including metabolic and reaction kinetics studies; detection and imaging techniques; radiotherapy; and the treatment of one or more conditions, including neurological conditions, cognitive disorders, immune conditions and inflammatory conditions, as well as other conditions and diseases involving PDE7 or cyclic nucleotide signaling.

Description

[0001] Background

[0002] Field

[0003] The present disclosure relates to certain substituted benzoxazole and benzofuran compounds and related chemical entities; compositions containing them; methods for their preparation; and their use in various methods and therapies, including enhancing neuroplasticity, and treating neurological disorders, cognitive impairments, allergic disorders, immunological disorders, inflammatory disorders, and other conditions and diseases involving PDE7 or cyclic nucleotide signaling.

[0004] Description of Related Art

[0005] Cyclic nucleotides, adenosine, and guanosine 3',5'-cyclic monophosphates (cAMP and cGMP) are ubiquitous second messengers in cell signaling cascades activated by multiple transduction pathways (such as those triggered by neurotransmitters and hormones). See, e.g., Kelly and Brandon, 2009, Prog. Brain Res. 179, 67 - 73; Schmidt, 2010, Curr. Top. Med. Chem. 10, 222 - 230. Once generated, cAMP and cGMP transmit their signals through various effector molecules, such as cAMP-dependent protein kinase (PKA), cGMP-dependent protein kinase (PKG), and other proteins. In turn, these effectors regulate other targets in downstream cascades, such as enzymes and transcription factors, ultimately leading to cellular changes that affect many physiological processes, including neuronal plasticity, muscle contraction, sensory transduction, cell division, and inflammation.

[0006] Cyclic nucleotide levels are tightly regulated, including by the action of phosphodiesterases (PDEs), a superfamily of intracellular enzymes that hydrolyze cAMP and cGMP to their inactive non-cyclic forms, 5'-AMP and 5'-GMP. See, e.g., Bender and Beavo, 2006, Pharmacol. Rev. 58, 488–520. Based on structural, biochemical, and pharmacological properties, mammalian PDEs can be classified into 11 families, PDE1–11. Some are cAMP-selective hydrolyzing enzymes (PDE4, 7, and 8), some are cGMP-selective hydrolyzing enzymes (PDE5, 6, and 9), and some hydrolyze both cAMP and cGMP (PDE1, 2, 3, 10, and 11). By regulating cAMP and cGMP levels, PDEs play a key role in modulating the cyclic nucleotide cascade, and due to their diverse tissue distributions and functional properties, PDEs have emerged as attractive targets for treating various diseases and disorders. See, e.g., Keravis and Lugnier, 2001, Br. J. Pharmacol. 165, 1288–1305. For example, alterations in cyclic nucleotide concentrations can affect biochemical and physiological processes related to cognitive function (Kelly and Brandon, 2009, Prog. Brain Res. 179, 67–73; Schmidt, 2010, Curr. Top. Med. Chem. 10, 222–230; Perez-Gonzalez et al., 2013, Neurobiol. Aging 34, 2133–2145; Lipina et al., / 2013, Neuropharmacology 64, 295–214; Morales-Garcia et al., 2016, Stem Cells 35, 458–472).

[0007] The PDE7 family specifically hydrolyzes cAMP, is insensitive to rolipram (a specific inhibitor of the cAMP PDE4 family), and includes two genes, PDE7A and PDE7B, which give rise to multiple isoforms and show overlapping but distinct expression patterns throughout the body. See, e.g., Jankowska et al., 2017, Curr. Med. Chem. 24, 1–28. In the brain, PDE7 is expressed in neurons and non-neuronal cells, and elevated levels are observed in multiple regions, including the hippocampus, cerebral cortex, basal ganglia, midbrain, and temporal lobe. Outside the brain, PDE7 is expressed in many regions, including skeletal muscle, heart, kidney, pancreas, lung, and bronchus, as well as the immune system, where PDE7 is found in lymphocytes and is elevated in activated T cells.

[0008] These expression patterns implicate PDE7 in many biological processes. PDE7 inhibition can mitigate the inflammatory response after various injuries in vivo and in vitro, suggesting therapeutic approaches for CNS and peripheral disorders, including neurodegenerative, traumatic, and immune disorders. Additionally, by regulating cAMP levels, PDE7 can modulate cognitive processes, such as potential memory formation processes, which involve cAMP activation of PKA, which in turn can phosphorylate the cAMP response element-binding protein (CREB). Phosphorylated CREB is an activated transcription factor that binds to specific DNA loci and initiates transcription of multiple genes involved in neuronal plasticity and memory formation.

[0009] These and other studies have highlighted the interest in PDE7 as a target for treating multiple disorders and modulating physiological processes such as cognition. There is an urgent need for PDE7 inhibitors with desired pharmacological and therapeutic properties, such as effective potency, exposure, selectivity, and safety. The present invention addresses these and other needs in the art by disclosing substituted benzoxazole and benzofuran chemical entities as potent, selective, and well-tolerated PDE7 inhibitors.

[0010] Overview

[0011] The present disclosure relates to substituted benzoxazole and benzofuran chemical entities, compositions thereof, methods for their preparation, and their use in various methods, including the treatment of neurological and peripheral disorders associated with phosphodiesterase 7 (PDE7).

[0012] Some embodiments provide chemical entities of formula (I), more specifically, compounds of formula (I) or pharmaceutically acceptable salts of compounds of formula (I):

[0013]

[0014] wherein V, W, X, Y, Z, and m have any of the values described herein.

[0015] In some embodiments, the chemical entity of formula (I) is a chemical entity of formula (Ia), or more specifically, a compound of formula (Ia) or a pharmaceutically acceptable salt of a compound of formula (Ia):

[0016] wherein W, X, Y, and Z have any of the values described herein.

[0017] In some embodiments, the chemical entity of formula (I) is a chemical entity of formula (Ib), or more specifically, a compound of formula (Ib) or a pharmaceutically acceptable salt of a compound of formula (Ib):

[0018] where W, L 1 , L 2 , X, Y, and Z can each have any value described herein.

[0019] Some embodiments provide chemical entities of general formula (II), or more specifically, compounds of general formula (II) or pharmaceutically acceptable salts of compounds of general formula (II):

[0020]

[0021] where V, W, Y, and Z can each have any value described herein.

[0022] In some embodiments, the chemical entity of general formula (II) is a chemical entity of general formula (IIa) or general formula (IIb), or more specifically, a compound of general formula (IIa) or general formula (IIb) or a pharmaceutically acceptable salt of a compound of general formula (IIa) or general formula (IIb):

[0023]

[0024] where W and Y can each have any value described herein.

[0025] Some embodiments provide chemical entities of general formula (III), or more specifically, compounds of general formula (III) or pharmaceutically acceptable salts of compounds of general formula (III):

[0026]

[0027] where V, W, Y, and Z can each have any value described herein.

[0028] In some embodiments, the chemical entity of general formula (III) is a chemical entity of general formula (IIIa) or general formula (IIIb), or more specifically, a compound of general formula (IIIa) or general formula (IIIb) or a pharmaceutically acceptable salt of a compound of general formula (IIIa) or general formula (IIIb):

[0029]

[0030] where W and Y can each have any value described herein.

[0031] In certain embodiments, the chemical entity is selected from any of the substances described or exemplified herein, more specifically, a compound or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the chemical entities and compositions comprising such entities are used in a number of diverse methods as described herein. In some embodiments, the methods include metabolic and reaction kinetics studies, detection and imaging techniques, and radiological procedures. In some embodiments, the methods include inhibiting PDE7, treating PDE7-mediated disorders, enhancing neuronal plasticity, conferring neuroprotection, and reducing inflammation. In some embodiments, the methods include treating neurological disorders, particularly CNS disorders, and more specifically, include mental disorders and psychiatric conditions, cognitive disorders, movement disorders, and neurodegenerative disorders. In some embodiments, the methods relate to treating peripheral disorders, including infectious diseases, hematological disorders, cardiovascular diseases, gastrointestinal disorders, skin disorders, immune and inflammatory disorders, and fertility disorders.

[0033] In some embodiments, the chemical entities and compositions comprising these entities are used as enhancers to improve the efficiency of cognitive and motor training, including during post-stroke rehabilitation or traumatic brain injury (TBI) rehabilitation; to improve the efficiency of non-human animal training regimens.

[0034] The present disclosure also relates to general and specific embodiments defined by the appended independent and dependent claims, respectively, which are incorporated herein by reference. Other embodiments, features, and advantages of the present disclosure will be apparent from the following detailed description and by practice of the exemplary embodiments.

[0035] Detailed Description

[0036] The embodiments may be more fully understood by reference to the following description, which includes examples. All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, unless otherwise defined. Although methods and materials similar or equivalent to those described herein may be used to practice or test the embodiments, suitable methods and materials are described herein. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0037] For the sake of brevity, all disclosures, including patent applications, patents, and other citations mentioned herein, are incorporated herein by reference in their entirety. However, the citation of any such disclosure should not be construed as an admission that it is prior art to the embodiments.

[0038] Terms and Definitions

[0039] The use of headings and subheadings provided in parts of this specification is for convenience of reference only and does not limit the various embodiments herein, which are interpreted by reference to the entire specification.

[0040] Overview

[0041] As used herein, the terms "about" or "approximately" mean within an acceptable range of a particular value as determined by one of ordinary skill in the art, and can depend in part on how the value is measured or determined, e.g., the limitations of the measurement system or technique. For example, "about" can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% or less on either side of a given value. To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It should be understood that whether or not the term "about" is explicitly used, each quantity given herein is meant to be the actual given value, and also means an approximation of the given value that would be reasonably inferred based on ordinary skill in the art, including equivalents and approximations due to experimental and / or measurement conditions for the given value. Accordingly, for any embodiment of the invention where a numerical value begins with "about" or "approximately", this disclosure includes embodiments where the exact value is described. Conversely, for any embodiment of the invention where a numerical value does not begin with "about" or "approximately", this disclosure includes embodiments where the numerical value begins with "about" or "approximately".

[0042] As used herein, unless otherwise expressly stated, the terms "a", "an", and "the" are to be construed to mean both the singular and the plural. Thus, "a", "an", and "the" (and their grammatical variations where appropriate) refer to one or more. In addition, although the items, elements, or components of this embodiment may be described or claimed in the singular, the plural is included within their scope unless expressly limited to the singular.

[0043] The terms "comprising" and "including" are used in their open, non-limiting sense herein. Unless otherwise expressly stated, other terms and phrases used in this document and their variations are to be construed as open-ended as opposed to limiting. As an example of the foregoing, the term "example" is used to provide exemplary instances of the item being discussed, rather than an exhaustive or limiting listing thereof; adjectives such as "common", "normal", "known", and terms of similar import are not to be construed as limiting the item to the given time period or to items available as of a given time, but rather are to be read to cover common or normal techniques available or known at any time, present or future. Similarly, if this document refers to techniques that one of ordinary skill in the art would be aware of or would know, such techniques cover those that the skilled person is aware of or knows at any time, present or future.

[0044] As will be apparent to one of ordinary skill in the art upon reading this document, the illustrated embodiments and their various alternatives can be practiced without being limited to the illustrated examples.

[0045] Chemical Terms

[0046] The term "alkyl" refers to a fully saturated aliphatic hydrocarbon group (i.e., containing no double or triple bonds). The alkyl moiety can be a straight-chain or branched-chain alkyl having 1 to 12 carbon atoms in the chain. Examples of alkyl include, but are not limited to, methyl (Me, which can also be structurally described by the symbol ), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, and isohexyl. The alkyl can be optionally substituted with one or more substituents, including but not limited to hydroxy, alkoxy, thioalkoxy, amino, aminoalkyl, and cyano.

[0047] The term "alkenyl" refers to an unsaturated acyclic aliphatic moiety having at least one carbon-carbon double bond. Unless otherwise specified, the term alkenyl includes all possible geometric isomers, including the E and Z isomers of the alkenyl moiety. Examples of alkenyl include vinyl, propenyl, butenyl, 1,4-butadienyl, etc.

[0048] The term "alkynyl" refers to an optionally substituted unsaturated acyclic aliphatic moiety having at least one carbon-carbon triple bond. Examples of alkynyl include ethynyl, propynyl, butynyl, etc.

[0049] The term "haloalkyl" refers to a straight-chain or branched-chain alkyl having 1 to 12 carbon atoms in the chain in which one or more hydrogens are replaced by halogen. Examples of haloalkyl include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, and -CH2CF2CF3.

[0050] The term "alkoxy" includes a straight-chain or branched-chain alkyl having an oxygen atom that connects the alkyl to the rest of the molecule. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and pentyloxy. "Aminoalkyl", "thioalkyl", and "sulfonylalkyl" are similar to alkoxy, replacing the terminal oxygen atom of alkoxy with NH (or NR), S, and SO2, respectively, where R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 5-, 6-, 9-, or 10-membered heteroaryl, and 5-10 membered heterocycloalkyl, as defined herein

[0051] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogens are replaced by a halogen. Examples of haloalkoxy groups include, but are not limited to, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCH2CH2Cl, -OCH2CF2CF3, and -OCH(CH3)CHF2.

[0052] The term "amino" refers to the -NH2 group.

[0053] The term "cyano" refers to the group -CN.

[0054] The term "aryl" refers to a monocyclic, or fused polycyclic or spiro polycyclic, aromatic carbocyclic ring (having a ring structure in which all ring atoms are carbon) (the carbon atoms in the aryl group are sp2 hybridized) having 3 to 15 ring atoms in each ring. Exemplary instances of aryl groups include the following moieties:

[0055] and so on.

[0056] The term "phenyl" denotes the following moiety:

[0057] The term "aryloxy" refers to a group having the formula -O-R, where R is an aryl group.

[0058] The term "cycloalkyl" refers to a fully saturated or partially saturated carbocyclic ring having 3 to 15 ring atoms in each carbon ring, such as a monocyclic, fused polycyclic, bridged monocyclic, bridged polycyclic, spiro or spiro polycyclic carbocyclic ring. If the term cycloalkyl is defined by a specific characteristic, such as monocyclic, fused polycyclic, bridged polycyclic, spiro, and spiro polycyclic, then the term cycloalkyl refers only to the carbocyclic ring so characterized. Exemplary instances of cycloalkyl groups include the following entities in the form of appropriately bonded moieties:

[0059]

[0060] "Heterocycloalkyl" refers to a fully saturated or partially saturated monocyclic, or fused polycyclic, bridged polycyclic or spiro polycyclic ring structure and having at least one heteroatom selected from nitrogen, oxygen, and sulfur in the ring skeleton. The heterocycloalkyl group can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom can be present in a non-aromatic ring or an aromatic ring in the ring system. The heterocycloalkyl group can have 3 to 20 ring members (i.e., the number of atoms making up the ring skeleton, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heterocycloalkyl" in which no numerical range is specified. The heterocycloalkyl group can be designated as "3-15 membered heterocycloalkyl", "4-10 membered heterocycloalkyl", "3-15 membered C 2-14 heterocycloalkyl", "5-9 membered C 4-8 heterocycloalkyl", "5-10 membered C 4-9 heterocycloalkyl", "5 membered C3-4 "heterocyclic hydrocarbyl", "6-membered C 4-5 heterocyclic hydrocarbyl, "7-membered C 5-6 "heterocyclic hydrocarbyl" or similar nomenclature. The heterocyclic hydrocarbyl can be a 5- to 10-membered ring or ring system containing 1 to 4 heteroatoms, each heteroatom independently selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocyclic hydrocarbyl can be a monocyclic five-membered ring containing 1 to 3 heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. The heterocyclic hydrocarbyl can be a monocyclic six-membered ring containing 1 to 3 heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. The heterocyclic hydrocarbyl can be a bicyclic 9-membered ring containing 1 to 3 heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. The heterocyclic hydrocarbyl can be a bicyclic ten-membered ring containing 1 to 3 heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. The heterocyclic hydrocarbyl can be optionally substituted. Exemplary unsubstituted heterocyclic hydrocarbyl entities in the form of suitable bonding moieties include:

[0061]

[0062] Exemplary carbon or thioxo-substituted heterocyclic hydrocarbyl entities in the form of suitable bonding moieties include:

[0063]

[0064] The term "heteroaryl" refers to an aromatic monocyclic, fused-ring, or fused polycyclic ring or ring system having one or more heteroatoms selected from nitrogen, oxygen, and sulfur in the ring skeleton. When the heteroaryl is a ring system, each ring in the ring system is fully unsaturated. The heteroaryl can have 5 to 18 ring members (i.e., the number of atoms making up the ring skeleton, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heteroaryl" where no numerical range is specified. In some embodiments, the heteroaryl has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl can be designated as "5- to 9-membered heteroaryl", "5- to 10-membered heteroaryl", "5- to 9-membered C 4-8 heteroaryl", "5- to 10-membered C 4-9 heteroaryl" or similar nomenclature. The heteroaryl can be a 5- to 10-membered ring or ring system containing 1 to 4 heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. The heteroaryl can be a monocyclic five-membered ring containing one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. The heteroaryl can be a monocyclic six-membered ring containing one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. The heteroaryl can be a bicyclic nine-membered ring containing one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. The heteroaryl can be a bicyclic ten-membered ring containing one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl can be a tautomer of a heterocyclic hydrocarbyl, where the heteroaryl is the predominant form under equilibrium conditions. Exemplary instances of the heteroaryl include the following entities, in the form of suitable bonding moieties:

[0065]

[0066] Those skilled in the art should recognize that the species of aryl, cycloalkyl, heterocycloalkyl, and heteroaryl listed or exemplified above are not exhaustive, and additional species within the scope of these defined terms can also be selected.

[0067] The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo" represents chloro, fluoro, bromo, or iodo.

[0068] The term "heteroatom" as used herein refers to, for example, O (oxygen), S (sulfur), or N (nitrogen).

[0069] "Optional" and "optionally" mean that the subsequent described event or circumstance may or may not occur, and this description includes instances where the event or circumstance occurs and instances or circumstances where the event or circumstance does not occur. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined below. Those skilled in the art will understand that for any group containing one or more substituents, these groups are not intended to introduce any substitutions or substitution patterns that are spatially infeasible, synthetically unfeasible, and / or inherently unstable.

[0070] The term "substituted" means that a particular group or moiety bears one or more substituents. Substituents are derived from an unsubstituted parent group in which one or more hydrogen atoms are exchanged with another atom or group, or are derived from an unsubstituted parent group in which one or more atoms or groups are added to carbon, nitrogen, or sulfur. When the term "substituted" is used to describe a structural system, unless otherwise specified, the substitution means occurring at any valence-allowed position in the system. The term "unsubstituted" means that the designated group bears no substituents.

[0071] Any chemical formula given herein is intended to represent a compound by a structural formula and certain variations or forms. Specifically, compounds of any chemical formula given herein may have asymmetric centers and thus exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, as well as their mixtures, are considered to be within the scope of the chemical formula. Therefore, any chemical formula given herein is intended to represent racemates, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and their mixtures. In addition, certain structures can exist in the form of geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers.

[0072] As used herein, "tautomer" refers to the migration of a proton between adjacent single and double bonds. The tautomerization process is reversible. The compounds described herein may undergo any possible tautomerization, which is within the physical characteristics of the compounds. The following are exemplary tautomerizations that may occur in the compounds described herein:

[0073]

[0074] The use of the symbol and means the same spatial arrangement of the chemical structures shown herein. Similarly, the use of the symbol and means the same spatial arrangement of the chemical structures shown herein.

[0075] The term "chiral" refers to a molecule that has the property that its mirror image partner is non - superimposable.

[0076] "Stereoisomers" are compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups.

[0077] "Diastereomers" are stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectroscopic properties, and reactivity. A mixture of diastereomers can be separated by high - resolution analytical procedures, such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral HPLC column.

[0078] "Enantiomers" refer to two stereoisomers of a compound that are non - superimposable mirror images of each other. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in a chemical reaction or process without stereoselectivity or stereospecificity.

[0079] The stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to denote the sign of rotation of plane-polarized light by the compound, (-) or l indicating that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory.

[0080] A "racemic mixture" or "racemate" is an equimolar (or 50:50) mixture of two enantiomeric substances and has no optical activity. A racemic mixture can occur in the absence of stereoselectivity or stereospecificity in a chemical reaction or process.

[0081] Wherever a substituent is described as a diyl (i.e., having two points of attachment to the remainder of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise specified. Thus, for example, a substituent described as –AE– or includes cases where the substituent is oriented such that A is attached at the leftmost point of attachment of the molecule and A is attached at the rightmost point of attachment of the molecule.

[0082] Chemical Entities

[0083] As used herein, the term "chemical entity" collectively refers to a compound and all of its pharmaceutically acceptable forms, including its pharmaceutically acceptable salts, chelates, solvates, conformational isomers, crystal forms / polymorphs, tautomers, prodrugs, metabolites, and mixtures. In some embodiments, the chemical entity is selected from a compound and its pharmaceutically acceptable salts.

[0084] Chelates

[0085] The term "chelate" refers to a chemical entity formed by coordination of a compound with a metal ion at two (or more) points.

[0086] Solvates

[0087] In addition, any chemical formula given herein is also intended to mean hydrates and solvates of the compounds herein, as well as mixtures thereof, even if these forms are not explicitly listed. Some embodiments provide solvates of the compounds of general formula (I), (II) or (III), and the use of such solvates in the methods described herein. Certain compounds of general formula (I), (II) or (III) or pharmaceutically acceptable salts of the compounds of general formula (I), (II) or (III) may be obtained in solvate form. In some embodiments, the solvent is water and the solvate is a hydrate.

[0088] More particularly, solvates include those formed by the interaction or complexation of the compounds of the embodiments with one or more solvents, either in solution or as a solid or crystalline form. These solvent molecules are those commonly used in the pharmaceutical field and are known to be harmless to the recipient, such as water, ethanol, ethylene glycol, etc. Other solvents may be used as intermediate solvates in the preparation of more desirable solvates, such as methanol, methyl tert-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butynediol, etc. Hydrates include molecules of a compound associated with one or more water molecules.

[0089] Conformational Isomers and Crystal Forms / Polymorphs

[0090] Some embodiments provide conformational isomers and crystal forms of the compounds of general formula (I), (II) or (III), and their use in the methods of the present disclosure. Conformational isomers are structures that are conformationally isomeric.

[0091] Conformational isomerism is a molecular phenomenon in which molecules have the same structural formula but different atomic conformations (conformational isomers) with respect to rotatable bonds.

[0092] Polymorphs are solid materials of a specific chemical formula that can exist in more than one form, where each form is different from the others. In certain embodiments, the compounds of general formula (I), (II) or (III) are obtained in crystal form. In addition, certain crystal forms of the compounds of general formula (I), (II) or (III) or pharmaceutically acceptable salts of the compounds of general formula (I), (II) or (III) may be obtained in the form of co-crystals. In other embodiments, the compounds of general formula (I), (II) or (III) may be obtained in one of a plurality of polymorphs, a mixture of crystal forms, a polymorph or an amorphous form.

[0093] Compounds

[0094] As used herein, "compound" means any of the following: (a) the actual recited form of such compound; and (b) any form of such compound in the medium in which the compound is considered at the time of naming. For example, a reference herein to a compound of the formula R-COOH, for example, includes a reference to any of R-COOH(s), R-COOH(sol), and R-COO-(sol). In such instances, R-COOH(s) refers to the solid compound, as it may be, for example, in a tablet or some other solid pharmaceutical composition or formulation; R-COOH(sol) refers to the undissociated form of the compound in a solvent; and R-COO-(sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether the dissociated form is derived from R-COOH, its salts, or any other entity that dissociates to give R-COO- in the medium under consideration.

[0095] In another example, an expression such as "exposing an entity to a compound of the formula R-COOH" means exposure of such entity to one or more forms of the compound R-COOH present in the medium in which such exposure takes place. In yet another example, an expression such as "reacting an entity with a compound of the formula R-COOH" means reacting (a) such entity in one or more of its chemically related forms present in the medium in which such reaction takes place, with (b) one or more chemically related forms of the compound R-COOH present in the medium in which such reaction takes place. In this regard, if such entity is, for example, in an aqueous environment, it is understood that the compound R-COOH is in the same such medium, and thus the entity is exposed to species such as R-COOH(aq) and / or R-COO-(aq), where the subscript "(aq)" represents "aqueous solution" in its conventional meaning in chemistry and biochemistry. The carboxylic acid functional group has been chosen in these naming examples; however, such choice is not intended to be limiting, but is for illustration only. It is understood that similar examples can be provided for other functional groups, including but not limited to hydroxyl, basic nitrogen members (such as those in amines), and any other groups that interact or transform in a medium containing the compound in a known manner. Such interactions and transformations include but are not limited to dissociation, association, tautomerization, solvation including hydration, protonation, and deprotonation. No further examples are provided herein in this regard, as any person of ordinary skill in the art is aware of these interactions and transformations in a given medium.

[0096] When referring to any general formula given herein, the selection of a particular subset from the list of possible species of a designated variable is not intended to define the same species selection for that variable as it appears elsewhere. In other words, if a variable appears more than once, then, unless otherwise stated, the selection of species from the designated list is independent of the selection of species of the same variable elsewhere in the general formula.

[0097] Salt

[0098] Embodiments include pharmaceutically acceptable salts of the compounds represented by general formula (I), (II) or (III), and methods of using these salts.

[0099] "Pharmaceutically acceptable salts" means salts of the free acids or bases of the compounds represented by general formula (I), (II) or (III), which salts are non-toxic, biologically tolerable or otherwise biologically suitable for administration to an individual. See generally G.S. Paulekuhn et al., 2007, J. Med. Chem. 50, 6665 - 6672; Berge et al., 1977, J. Pharm. Sci. 66, 1 - 19; Stahl and Wermuth (eds), Pharmaceutical Salts: Properties, Selection, and Use: 2nd Revised Edition, Wiley - VCS, Zurich, Switzerland (2011). Examples of pharmaceutically acceptable salts are salts that are pharmacologically effective and suitable for contact with patient tissues without producing undue toxicity, irritation or allergic response. The compounds of general formula (I), (II) or (III) may have groups that are sufficiently acidic, groups that are sufficiently basic or both types of functional groups, and thus react with a variety of inorganic or organic bases, as well as inorganic and organic acids to form pharmaceutically acceptable base salts and react with inorganic and organic acids to form pharmaceutically acceptable salts.

[0100] Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, borate, nitrate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne - 1,4 - dioate, hexyne - 1,6 - dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ - hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene - 1 - sulfonate, naphthalene - 2 - sulfonate, benzenesulfonate, mesylate and mandelate.

[0101] When the compounds of formula (I), (II) or (III) contain basic nitrogen, the desired pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid or an organic acid: said inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc.; said organic acids such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosyl acids (such as glucuronic acid or galacturonic acid), α-hydroxy acids (such as mandelic acid, citric acid or tartaric acid), amino acids (such as aspartic acid, glutaric acid or glutamic acid), aromatic acids (such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid), sulfonic acids (such as laurylsulfonic acid, p-toluenesulfonic acid or methanesulfonic acid or ethanesulfonic acid), any compatible mixture of acids such as those given by way of example herein, and any other acids and their mixtures regarded as equivalents or acceptable substitutes according to the ordinary skill in the art.

[0102] When the compounds of formula (I), (II) or (III) are acids, such as carboxylic acids or sulfonic acids, the desired pharmaceutically acceptable salts can be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as amines (primary, secondary or tertiary), alkali metal hydroxides, alkaline earth metal hydroxides, any compatible mixture of bases such as those given by way of example herein, and any other bases and their mixtures regarded as equivalents or acceptable substitutes according to the ordinary skill in the art. Exemplary examples of suitable salts include organic salts derived from: amino acids, such as N-methyl-O-glucosamine, lysine, choline, glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary and tertiary amines, and cyclic amines, such as tromethamine, benzylamine, pyrrolidine, piperidine, morpholine and piperazine; and inorganic salts derived from: sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0103] Prodrugs

[0104] Some embodiments provide prodrugs of the compounds of formula (I), (II) or (III), and the use of such pharmaceutically acceptable prodrugs in the methods of the present disclosure, particularly in therapeutic methods.

[0105] The term "prodrug" is a precursor of a designated compound that is initially inactive or partially inactive and that produces the compound in vivo after administration to an individual by a chemical or physiological process (such as solvolysis or enzymatic cleavage) or under physiological conditions (e.g., the prodrug is converted to the pharmacologically active compound of formula (I), (II) or (III) at physiological pH).

[0106] "Pharmaceutically acceptable prodrug" refers to a prodrug that is preferably non-toxic, biologically tolerable and otherwise biologically suitable for administration to an individual. Prodrugs are generally useful because in certain cases they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration while the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Exemplary procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0107] Exemplary prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues covalently linked to the free amino, hydroxyl or carboxylic acid group of a compound of formula (I), (II) or (III) via an amide bond or an ester bond. Examples of amino acid residues include the twenty naturally occurring amino acids, usually represented by three-letter symbols, as well as 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.

[0108] Prodrugs can be determined using conventional techniques known or available in the art (e.g., Bundgard (ed.), 1985, Design of prodrugs, Elsevier; Krogsgaard-Larsen et al. (eds.), 1991, Design and Application of Prodrugs, Harwood Academic Publishers). Prodrugs can be generated, for example, by derivatizing the free carboxyl group of a structure of formula (I), (II) or (III) into an amide or an alkyl ester. Examples of amides include those derived from ammonia, C 1-6 alkyl primary amines and those amides of di(C 1-6 alkyl) secondary amines. Secondary amines include five- or six-membered heterocyclic hydrocarbon or heteroaryl ring moieties. Examples of amides include those derived from ammonia, C 1-3 alkyl primary amines and those of di(C 1-2 alkyl)amines. Examples of esters of the present invention include C 1-6 alkyl, C 1-6 cycloalkyl, phenyl and phenyl(C 1-6(alkyl) esters. Preferred esters include methyl esters. Prodrugs can also be prepared by derivatizing free hydroxyl groups with groups including hemisuccinate esters, phosphate esters, dimethylaminoacetate esters, and phosphonyloxymethyloxycarbonyl by following procedures outlined in, for example, Fleisher et al., 1996, Adv. Drug Delivery Rev. 19, 115 - 130.

[0109] Carbamate derivatives of hydroxyl and amino groups can also produce prodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxyl groups can also provide prodrugs. Derivatization of hydroxyl groups to (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl group can be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functional groups, or the acyl group is an amino acid ester as described above, can also be used to produce prodrugs. This type of prodrug can be prepared as described in Robinson et al., 1996, J. Med. Chem. 39, 10 - 18. Free amines can also be derivatized to amides, sulfonamides, or phosphoramides. All of these prodrug moieties can be introduced into groups including ether, amine, and carboxylic acid functional groups.

[0110] Tautomers

[0111] Some embodiments provide tautomers of the compounds of formula (I), (II), or (III) as further defined herein, which can also be used in the methods of the present disclosure.

[0112] Metabolites

[0113] Some embodiments provide pharmaceutically active metabolites of the compounds of formula (I), (II), or (III), which can also be used in the methods of the present disclosure. "Pharmaceutically active metabolite" refers to a pharmacologically active product of the metabolism in vivo of a compound of formula (I), (II), or (III) or its salt. Preferably, the metabolite is in an isolated form in vitro.

[0114] Active metabolites of the compounds can be determined using conventional techniques known or available in the art. For example, isolated metabolites can be produced in enzymatic and synthetic ways (e.g., Bertolini et al., 1997, J. Med. Chem. 40, 2011 - 2016; Shan et al., 1997, J. Pharm. Sci. 86, 765 - 767; Bagshawe, 1995, Drug Dev. Res. 34, 220 - 230; and Bodor, 1984, Adv Drug Res. 13, 224 - 231).

[0115] Isotopes

[0116] Isotopes can be present in the compounds described herein. Each chemical element present in the compounds described hereinbelow or above may include any isotope of that element. Any chemical formula given herein is also intended to represent both the unlabeled form and the isotopically labeled form of the compound. An isotopically labeled compound has the structure described by the chemical formula given herein, but one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present embodiment include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl and 125 I.

[0117] Combinations

[0118] As used in the term "composition" in a pharmaceutical composition, it is intended to cover a product containing an active ingredient and an inert ingredient (a pharmaceutically acceptable excipient) constituting a carrier, as well as any product directly or indirectly produced by the combination, complexation, or aggregation of any two or more of said ingredients, or any product produced by the dissociation of one or more of said ingredients, or any product produced by other types of reactions or interactions of one or more of said ingredients. Thus, the pharmaceutical compositions of the present embodiment cover any composition made by mixing a compound of general formula (I), (II), or (III) and a pharmaceutically acceptable excipient.

[0119] The term "pharmaceutically acceptable" as used in connection with the compositions of the present disclosure refers to such molecular entities and other ingredients of the compositions that are physiologically tolerable and generally do not produce adverse reactions when administered to an animal (e.g., a human). The term "pharmaceutically acceptable" may also mean approved by a federal regulatory agency or a state government or listed in the United States Pharmacopeia or other recognized pharmacopeias for animals (e.g., mammals), and more particularly for humans.

[0120] "Pharmaceutically acceptable excipient" refers to a substance that is added to a pharmaceutical composition or otherwise used as a vehicle, carrier or diluent to facilitate the administration of a medicament and is compatible therewith, non-toxic, biologically tolerable and otherwise biologically suitable for administration to an individual, such as an inert substance. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy, 21 st Ed., Lippincott Williams & Wilkins (2005).

[0121] The term "carrier" refers to an adjuvant, vehicle or excipient administered together with a compound. In a preferred embodiment, the carrier is a solid carrier. Suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy, 21 st Ed., Lippincott Williams & Wilkins (2005).

[0122] As used herein, the term "dosage form" is the form in which a dose is administered to an individual or patient. A drug is usually administered as part of a formulation that includes non-medical agents. The dosage form has unique physical and pharmaceutical properties. For example, the dosage form can be solid, liquid or gaseous. "Dosage form" can include, for example, capsules, tablets, cachets, gelatin capsules (capsule-shaped tablets), syrups, liquid compositions, powders, concentrated powders, concentrated powders mixed with liquids, chewable forms, swallowable forms, soluble forms, effervescent agents, granule forms, and oral liquid solutions. In a specific embodiment, the dosage form is a solid dosage form, more specifically, including tablets or capsules.

[0123] As used herein, the term "inert" refers to any inactive ingredient of the composition. The definition of "inactive ingredient" as used herein follows that defined by the US Food and Drug Administration as in 21 C.F.R. 201.3(b)(8), which is any component of a drug product other than the active ingredient.

[0124] As used herein, "suitable for oral administration" refers to a sterile pharmaceutical product produced under Good Manufacturing Practice (GMP) and prepared and presented in such a way that the composition is unlikely to cause any adverse or harmful effects when administered orally to an individual. Unless otherwise stated, all compositions disclosed herein are suitable for oral administration.

[0125] Methods and Uses

[0126] As used herein, the term "condition" may be used interchangeably with "disease" or "disorder". For example, a CNS condition also means a CNS disease or a CNS disorder.

[0127] As used herein, the term "cognitive impairment" may be used interchangeably with "cognitive dysfunction" or "cognitive deficit", and all are considered to cover the same therapeutic indications.

[0128] The term "treatment" covers treatment methods for an individual disease state and includes: (i) specifically, preventing the occurrence of a disease state when an individual is predisposed to the disease state but has not been diagnosed with the disease state; (ii) inhibiting the disease state, such as preventing its progression or delaying its onset; and (iii) alleviating the disease state, such as causing the disease state to subside until a desired endpoint is reached. Treatment also includes improving the symptoms of a disease (e.g., reducing pain, discomfort or deficit), where such improvement may directly affect the disease (e.g., affecting the cause, spread or manifestation of the disease) or not directly affect the disease.

[0129] As used in this disclosure, the term "effective amount" may be used interchangeably with "therapeutically effective amount" and means the amount or dose at which a compound or composition effectively treats a specific disease, disorder or condition disclosed herein, and thus "treatment" includes producing a desired preventive, inhibitory, alleviating or improving effect. In the treatment method according to the embodiments, an "effective amount" of at least one compound according to the embodiments is administered to an individual (e.g., a mammal). "Effective amount" also means the amount or dose at which a compound or composition effectively modulates PDE7 activity or a related signaling pathway. The "effective amount" will vary depending on the compound, the disease, the type of desired treatment and its severity, as well as age, body weight, etc.

[0130] As used herein, the term "PDE7" refers to all translation products encoded by transcripts of either or both of two genes, PDE7A and PDE7B. The amino acid and nucleotide sequences encoding PDE7 of various species are known to those skilled in the art and can be found, for example, in GenBank (GeneBank) under accession numbers AB057409, U77880, AB038040, L12052, AK035385, AY007702.

[0131] The term "animal" may be used interchangeably with "individual" and may be a vertebrate, particularly a mammal, more particularly a human, and in the context of clinical trials or screening or activity experiments includes laboratory animals or patients. Thus, as can be readily understood by those of ordinary skill in the art, the compositions and methods of the present embodiments are particularly suitable for administration to any vertebrate, particularly a mammal, more particularly a human.

[0132] As used herein, "control animal" or "normal animal" is an animal of the same species as the animal trained under conditions sufficient to induce transcription-dependent memory formation in the animal and otherwise comparable (e.g., similar age, sex).

[0133] "Enhance" means the ability to strengthen, increase, improve a biochemical or physiological action or effect or make it greater or better relative to normal conditions. For example, enhancing long-term memory formation means the ability to strengthen or increase the long-term memory formation of an animal relative to (or "compared to") the normal long-term memory formation of the animal or a control. Thus, long-term memory can be acquired more rapidly or retained better. Enhancing the performance of a cognitive task means the ability to strengthen or improve the performance of an animal on a specific cognitive task relative to the normal performance of the animal or a control on that cognitive task.

[0134] As used herein, the terms "training regimen" or "training" refer to "cognitive training" or "exercise training".

[0135] Reference will now be made to the embodiments of the present disclosure, examples of which are explained and described by way of the appended examples. Although certain embodiments are described herein, it should be understood that the embodiments are not intended to limit the scope of the invention. On the contrary, the present disclosure is intended to cover alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the appended claims.

[0136] Chemical Entities

[0137] Some embodiments provide certain substituted benzoxazole and benzofuran chemical entities, which can be used, for example, as inhibitors of PDE7 enzyme activity.

[0138] In some embodiments, the chemical entities include the compounds disclosed herein and their pharmaceutically acceptable chelates, solvates, conformational isomers, crystal forms / polymorphs, salts, tautomers, and mixtures. In some embodiments, the chemical entities include the compounds disclosed herein and their pharmaceutically acceptable salts.

[0139] General Formula (I)

[0140] Some embodiments provide chemical entities of general formula (I), or more specifically, compounds of general formula (I) or pharmaceutically acceptable salts of compounds of general formula (I):

[0141] Wherein,

[0142] X is -CH or -N;

[0143] Y is selected from: -H, halogen, and -C 1-4 alkyl;

[0144] Each Z is independently selected from: -H, halogen, and -C 1-4 alkyl;

[0145] V is selected from: a bond, -(CH2) m -, -(CH2) m O(CH2) n -, -(CH2) m O(CH2) n C(O)-, -(CH2) m N[(CH2) n R 1A -, -(CH2) m C(O)O-, -(CH2) m C(O)-, -(CH2) m C(O)N[(CH2) n R 1A -, -L 1 -L 2 -, -L 1 -L 2 -L 3 -, -L 1 -L 2 -L 3 -L 4 - and -L 1 -L 5 ;

[0146] Each m is independently 0, 1, 2, or 3;

[0147] Each n is independently 0, 1, 2, or 3;

[0148] L 1 is -C(O)(CH2) m -, -[C(R 1A )2] m - or -(CH2) m -;

[0149] L 2 is -N[(CH2) n R 1A or -N((CH2) n R 1A )(CH2) p -;

[0150] L 3 is selected from: -(CH2) m -C 3-7 cycloalkyl, -[C((CH2) n R 1B )2] m [C((CH2) nR 1C )2] n -, -[N[(CH2) m R 1A (CH2) n -, -[(CH2) m N((CH2) n R 1A )(CH2) p -, -[(CH2) m C(O)N((CH2) n R 1B )(CH2) p -, -(CH2) m C(O)-, -[C(R 1A )2] m - and -[(CH2) p O]-;

[0151] L 4 is selected from: -(CH2) m C(O)-, -(CH2) m O-, -C 1-6 alkyl, -C 3-7 cycloalkyl, heteroaryl, aryl, 3-10 membered heterocycloalkyl, and -CH(OH)-, wherein the -C 1-6 alkyl, -C 3-7 cycloalkyl, heteroaryl, aryl, and 3-10 membered heterocycloalkyl are each optionally substituted with one to four R 2A groups;

[0152] L 5 is selected from: -C(O)(CH2) m N[(CH2) n R 1B -, -C(O)(CH2) m -, -CH(OH)-, and -(CH2) m C(O)O-;

[0153] Each p is independently 0, 1, 2, or 3;

[0154] Each R 1A is independently selected from: -H, -OH, -CN, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-7 cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, -C 1-6 haloalkyl, and -C 1-6 alkoxy, wherein the -C 3-7 cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, -C1-6 Haloalkyl and -C 1-6 Each alkoxy group is supported by one to four R 2A Optional substitution;

[0155] Each R 1B Independently selected from: -H, -OH, -CN, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 Cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl and -C 1-6 Alkoxy, the -C 3-7 Cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, -C 1-6 Haloalkyl and -C 3-7 The cyclic hydrocarbon groups are each supported by one to four R 2A Optional substitution;

[0156] Each R 1C Independently selected from: -H, -OH, -CN, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-7 Cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, -C 1-6 Haloalkyl and -C 1-6 Alkoxy, the -C 3-7 Cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, -C 1-6 Haloalkyl and -C 1-6 Each alkoxy group is supported by one to four R 2A Optional substitution;

[0157] W is selected from: -H, halogen, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, aryl, heteroaryl, 3-15 membered heterocyclic hydrocarbon, -C 3-7 Cyclic hydrocarbon, -SO2C 1-6 Alkyl, -(CH2) m R 1A 、-(CH2) m N(R 1B )2、-(CH2) m O(CH2) n R 1A 、-(CH2) m S(CH2) n R 1A 、-(CH2)m C(O)C 1-6 alkyl, -(CH2) m C(O)heterocyclic hydrocarbyl, -(CH2) m C(O)OH, -(CH2) m C(O)OC 1-6 alkyl, -(CH2) m C(O)NH2, -(CH2) m C(O)N(C 1-4 alkyl)2 and -(CH2) m C(O)NH(C 1-4 alkyl), said aryl, heteroaryl, 3-15 membered heterocyclic hydrocarbyl and -C 3-7 cyclic hydrocarbyl are each optionally substituted by one to five R 3A optionally;

[0158] each R 2A independently selected from: halogen, -CN, =O, -OH, -SO2C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, aryl, heteroaryl, 3-15 membered heterocyclic hydrocarbyl, -C 3-7 cyclic hydrocarbyl, -(CH2) m N(C 1-4 alkyl)2, -OCH2(CH2) m R 2AA 、-CH2(CH2) m R 2AA 、-C 1-6 alkyl-OH, -C 1-6 haloalkyl OH, -C 1-6 haloalkyl -C 3-7 cyclic hydrocarbyl, -C 3-7 cyclic hydrocarbyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C(CH3)3, -OC 3-7 cyclic hydrocarbyl, -C(O)C 1-6 alkyl, -C(O)aryl, -C(O)heterocyclic hydrocarbyl, -C(O)OC 1-6 alkyl, -C(O)R 2AA 、-NHC(O)R 2AA 、-C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cyclic hydrocarbyl, -C(CH3)2OH, -N(R 2AA)2, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -CH2CF2C 3-7 cycloalkyl group, where the aryl group, heteroaryl group, 3 - 15 - membered heterocycloalkyl group, and -C 3-7 cycloalkyl group are each optionally substituted with one to five substituents, and each of the substituents is independently selected from: -CN, =O, -OH, -SO2C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, aryl, heteroaryl, 3 - 15 - membered heterocycloalkyl, -C 3-7 cycloalkyl, -N(C 1-4 alkyl)2, -NH(C 1-4 alkyl), -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C(CH3)3, -OC 3-7 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)aryl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl and -C(CH3)2OH;

[0159] Each R 3A is independently selected from: halogen, -CN, =O, -OH, -SO2C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, aryl, heteroaryl, 3 - 15 - membered heterocycloalkyl, -C 3-7 cycloalkyl, -(CH2) m N(C 1-4 alkyl)2, -OCH2(CH2) m R 3AA 、-CH2(CH2) m R 3AA 、-C 1-6 alkyl - OH, -C 1-6 haloalkyl OH, -C 1-6 haloalkyl - C 3-7 cycloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C(CH3)3, -OC 3-7 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)aryl, -C(O)heterocycloalkyl, -C(O)OC1-6 alkyl, -C(O)R 3AA , -NHC(O)R 3AA , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -N(R 3AA )2, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -CH2CF2C 3-7 cycloalkyl, wherein the aryl, heteroaryl, 3- to 15-membered heterocycloalkyl and -C 3-7 cycloalkyl are each optionally substituted with one to five substituents, and the substituents are each independently selected from: -CN, =O, -OH, -SO2C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, aryl, heteroaryl, 3- to 15-membered heterocycloalkyl, -C 3-7 cycloalkyl, -N(C 1-4 alkyl)2, -NH(C 1-4 alkyl), -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C(CH3)3, -OC 3-7 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)aryl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl and -C(CH3)2OH;

[0160] Each R 2AA is independently selected from: -H, -OH, -SO2C 1-6 alkyl, -halogen, -CN, -C 1-6 alkoxy, -C 1-6 haloalkyl, -N(C 1-4 alkyl)2, -NH(C 1-4 alkyl), -NH2, aryl, heteroaryl, 3- to 15-membered heterocycloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-7 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)N(C 1-4(alkyl)2 and -C(O)aryl; and

[0161] Each R 3AA is independently selected from: -H, -OH, -SO2C 1-6 alkyl, halogen, -CN, -C 1-6 alkoxy, -C 1-6 haloalkyl, -N(C 1-4 alkyl)2, -NH(C 1-4 alkyl), -NH2, aryl, heteroaryl, 3-15 membered heterocyclic hydrocarbyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-7 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)heterocyclic hydrocarbyl, -C(O)OC 1-6 alkyl, -C(O)N(C 1-4 alkyl)2 and -C(O)aryl.

[0162] In some embodiments, V is selected from: a bond, -(CH2) m -, -(CH2) m O(CH2) n -, -(CH2) m O(CH2) n C(O)-, -C(O)O-, -C(O)-, -(CH2) m C(O)O- and -(CH2) m C(O)-; and m is 1, 2 or 3.

[0163] In some embodiments, V is selected from:

[0164] -C(O)(CH2) m N[(CH2) n R 1A )[C(R 1B )2] m [C(R 1C )2] n -, -[C(R 1A )2] m N[(CH2) n R 1A )[C(R 1B )2] m [C(R 1C )2] n - and -[(CH2) m N((CH2) n R 1A )(CH2) p )[C(R 1B )2]m [C(R 1C )2] n -.

[0165] In some embodiments, V is selected from

[0166] -C(O)(CH2) m N((CH2) n R 1A )(CH2) p [N[(CH2) m R 1A ](CH2) n ]-、-[C(R 1A )2] m N((CH2) n R 1A )(CH2) p [N[(CH2) m R 1A ](CH2) n ]- and -[(CH2) m N((CH2) n R 1A )(CH2) p [N[(CH2) m R 1A ](CH2) n ]-.

[0167] In some embodiments, V is selected from:

[0168] -C(O)(CH2) m N[(CH2) n R 1A ][(CH2) m N((CH2) n R 1A )(CH2) p ]-、-[C(R 1A )2] m N[(CH2) n R 1A ][(CH2) m N((CH2) n R 1A )(CH2) p ]- and -[(CH2) m N((CH2) n R 1A )(CH2) p ][(CH2) m N((CH2) n R 1A )(CH2)p -.

[0169] In some embodiments, V is selected from:

[0170] -C(O)(CH2) m N[(CH2) n R 1A (CH2) p O-, -[C(R 1A )2] m N[(CH2) n R 1A [(CH2) p O]- and -[(CH2) m N((CH2) n R 1A )(CH2) p [(CH2) p O]-.

[0171] In some embodiments, V is selected from:

[0172] -C(O)(CH2) m N[(CH2) n R 1A [N[(CH2) m R 1A (CH2) n CH(OH)-, -[C(R 1A )2] m N[(CH2) n R 1A [N[(CH2) m R 1A (CH2) n CH(OH)-, -[(CH2) m N((CH2) n R 1A )(CH2) p [N[(CH2) m R a (CH2) n CH(OH)-, -C(O)(CH2) m N[(CH2) n R 1A [(CH2) m N((CH2) n R 1A )(CH2) p CH(OH)-, -[C(R 1A )2] m N[(CH2) n R1A [(CH2) m N((CH2) n R 1A )(CH2) p CH(OH)-, -[(CH2) m N((CH2) n R 1A )(CH2) p [(CH2) m N((CH2) n R 1A )(CH2) p CH(OH)-, -C(O)(CH2) m N[(CH2) n R 1A [(CH2) p O]CH(OH)-, -[C(R 1A 2] m N[(CH2) n R 1A [(CH2) p O]CH(OH)- and -[(CH2) m N((CH2) n R 1A )(CH2) p [(CH2) p O]CH(OH)-.

[0173] In some embodiments, V is selected from: -CH2-, -C(O)-, -C(O)O-, -CH2C(O)-, -CH2OCH2- and -CH2C(O)O-.

[0174] In some embodiments, V is selected from:

[0175] -C(O)(CH2) m N[(CH2) n R 1A CH2CF2CH(OH)-, -C(O)(CH2) m N[(CH2) n R 1A CH2CH(OH)CH2-,-C(O)(CH2) m N[(CH2) n R 1A CH2CH2CH(OH)-, -C(O)(CH2) m N[(CH2) n R 1A CH2CH(OH)-, -C(O)(CH2) mN[(CH2) n R 1A ][(CH2) m C(O)]-、-(CH2) m N[(CH2) n R 1A ][(CH2) n N((CH2) n R 1A )(CH2) n ]-、-(CH2) m N[(CH2) n R 1A ](CH2) n (CF2) n - and -(CH2) m N[(CH2) n R 1A ](CH2) n (CF2) n CH(OH)-.

[0176] In some embodiments, V is selected from:

[0177] -C(O)N[(CH2) n R 1A ]CH2CF2CH(OH)-、-C(O)N[(CH2) n R 1A ]CH2CH(OH)CH2-、-C(O)N[(CH2) n R 1A ]CH2CH2CH(OH)-、-C(O)N[(CH2) n R 1A ]CH2CH(OH)-、-C(O)N[(CH2) n R 1A ][(CH2) m C(O)]-、-CH2N[(CH2) n R 1A ][(CH2) n N((CH2) n R 1A )(CH2) n ]-、-CH2N[(CH2) n R 1A ](CH2) n (CF2) n - and -CH2N[(CH2) n R 1A ](CH2) n (CF2) n CH(OH)-.

[0178] In some embodiments, V is selected from: -CH2-, -CH2C(O)-, -CH2OCH2-, and -CH2C(O)O-.

[0179] In some embodiments, V is selected from: -CH2-, -C(O)NR 1A -, -C(O)NR 1A CH2-, -C(O)NR 1A CH2CF2CH2-, -N[CH2CH2R 1A CH2CH2-, -C(O)NR 1A CH2CH2NR 1A CH2-, -CH2NR 1A CH2-, -CH2NR 1A CH2CH2-, -CH2NR 1A CH2CF2-, -C(O)-, -CH2NR 1A -, -CH2NR 1A CH(CH3)-, -CH2NR 1A CH2CH(OH)-, -CH2NR 1A CH2C(O)-, -CH2NR 1A CH2CH2C(O)-, -CH2NR 1A CH(CH3)C(O)-, -CH2NR 1A CH2CH2O-, -C(O)NR 1A CH2CH2-, -C(O)NR 1A C(CH3)2CH2-, -C(O)N[CH2R 1A CH2CH2-, -C(O)N[CH2R 1A CH2-, -C(O)NR 1A CH2C(CH3)2-, -C(O)NR 1A CH2CH2CH2-, -CH2OCH2C(O)-, -C(O)NR 1A CH2CH2CH2CH2-, -C(O)NR 1A CH(R 1A )CH2-, -C(O)NR 1A CH2CH2O-, -C(O)NR 1A CH2CH(OH)CH2-, -C(O)NR 1A CH2CH2CH(OH)-, -C(O)NR 1A CH2CH2C(O)-, -C(O)NR 1ACH2CH(OH)-、-C(O)NR 1A [CH2C(O)O]-, -CH2OCH2CH2C(O)-, -C(O)NR 1A CH2CH2C(O)NR 1A CH2-、-CH2NR 1A [(CH2) n N((CH2) n R 1A )(CH2) n ]-、-CH2NR 1A CH2CH2CH2-、-CH2N[CH2R 1A )]CH2CH2-、-C(O)NR 1A CH2CF2-、-C(O)NR 1A CH2C(O)-、-C(O)NR 1A CH(CH2OH)CH2-、-C(O)N[CH2R 1A ]CH2CH2CH2-、-C(O)N[CH2R 1A ]CH2CH2O-、-CH2NR 1A CH2CH2CH2NR 1A -、-CH2NR 1A C(CH3)2CH2CH2O-、-CH2NR 1A CH2C(O)O-、-CH2NR 1A CH2CH2NR 1A C(O)- and -CH2NR 1A (CH2) m (CF2) n CH(OH)-.

[0180] In certain embodiments, the chemical entity of formula (I) is a chemical entity of formula (Ia), more specifically, a compound of formula (Ia) or a pharmaceutically acceptable salt of a compound of formula (Ia):

[0181] wherein W, X, Y, and Z have any of the values described herein.

[0182] In certain embodiments of the chemical entity of formula (Ia), W is selected from: -H, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, aryl, heteroaryl, heterocyclic hydrocarbon, -C 3-7 Cycloalkyl, -(CH2) m R 1A 、-(CH2) m N(R 1B )2、-(CH2)m O(CH2) n R 1A 、 -(CH2) m S(CH2) n R 1A 、 -CH2C(O)C 1-6 alkyl, -C(O)C 1-6 alkyl, -C(O)heterocycloalkyl, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NH(C 1-4 alkyl) and -C(O)N(C 1-4 alkyl)2, wherein the aryl, heteroaryl, 3- to 15-membered heterocycloalkyl and -C 3-7 cycloalkyl are each optionally substituted with one to three R 3A ; and

[0183] each R 1A is independently selected from: -H, -OH, -CN, halogen, -C 3-7 cycloalkyl, aryl, heteroaryl, 3- to 15-membered heterocycloalkyl, -C 1-6 haloalkyl and -C 1-6 alkoxy, wherein the -C 3-7 cycloalkyl, aryl, heteroaryl, 3- to 15-membered heterocycloalkyl, -C 1-6 haloalkyl and -C 1-6 alkoxy are each optionally substituted with one to three R 2A .

[0184] In certain embodiments, the chemical entity of formula (I) is a chemical entity of formula (Ib), more specifically, a compound of formula (Ib) or a pharmaceutically acceptable salt of a compound of formula (Ib):

[0185] wherein W, X, Y, Z, L 2 and L 1 have any of the values described herein.

[0186] In certain embodiments of the chemical entity of formula (Ib),

[0187] L 1 is -C(O)(CH2) m -, -[C(R 1A )2] m - or -(CH2) m -;

[0188] L 2 is -N[(CH2) n R 1A - or -N((CH2)n R 1A )(CH2) p -;

[0189] W is selected from: -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, aryl, heteroaryl, 3-15 membered heterocyclic hydrocarbon, -C 3-7 Cycloalkyl, -(CH2) m R 1A 、-(CH2) m N(R 1B )2、-(CH2) m O(CH2) n R 1A 、-(CH2) m S(CH2) n R 1A 、-C(O)C 1-6 Alkyl, -C(O)heterocyclic hydrocarbon, -(CH2) m C(O)OC 1-6 Alkyl and -C(O)N(C 1-4 alkyl) 2, the aryl, heteroaryl, 3-15 membered heterocyclic hydrocarbon group and -C 3-7 The cyclic hydrocarbon groups are each supported by one to three R 3A optionally substituted; and

[0190] Each R 1A Independently selected from: -H, -OH, -CN, halogen, -C 3-7 Cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, -C 1-6 Haloalkyl and -C 1-6 Alkoxy, the -C 3-7 Cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl and -C 1-6 Each haloalkyl group is replaced by one to three R 2A Optional substitution;

[0191] Each R 3A Independently selected from: halogen, -CN, =O, -OH, -SO2C 1-6 Alkyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkyl, aryl, heteroaryl, 3-15 membered heterocyclic hydrocarbon, -C 3-7 Cycloalkyl, -(CH2) m N(C 1-4 Alkyl)2, -OCH2(CH2) m R 3AA 、-CH2(CH2) m R3AA 、 -C 1-6 alkyl - OH, -C 1-6 haloalkyl OH, -C 1-6 haloalkyl - C 3-7 cycloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C(CH3)3, -OC 3-7 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)aryl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)R 3AA 、 -NHC(O)R 3AA 、 -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -N(R 3AA )2, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -CH2CF2C 3-7 cycloalkyl, wherein the aryl, heteroaryl, 3 - 15 - membered heterocycloalkyl and -C 3-7 cycloalkyl are each optionally substituted with one to five substituents, and the substituents are each independently selected from: -CN, =O, halogen, -OH, -SO2C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, aryl, heteroaryl, 3 - 15 - membered heterocycloalkyl, -C 3-7 cycloalkyl, -N(C 1-4 alkyl)2, -NH(C 1-4 alkyl), -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C(CH3)3, -OC 3-7 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)aryl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl and -C(CH3)2OH; and

[0192] each R 3AA is independently selected from: -H, -OH, -SO2C 1-6 alkyl, halogen, -CN, -C 1-6 alkoxy, -C1-6 haloalkyl, -N(C 1-4 alkyl)2, -NH(C 1-4 alkyl), -NH2, aryl, heteroaryl, 3- to 15-membered heterocycloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-7 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)N(C 1-4 alkyl)2 and -C(O)aryl.

[0193] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0194] Each R 3A is independently selected from: halogen, -CN, =O, -OH, -SO2C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, aryl, heteroaryl, 4- to 12-membered heterocycloalkyl, -C 3-7 cycloalkyl, -OCH2(CH2) m R 3AA , -CH2(CH2) m R 3AA , -C(O)C 1-6 alkyl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)R 3AA , -NHC(O)R 3AA , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl)2 and -N(R 3AA )2, wherein the aryl, heteroaryl, 4- to 12-membered heterocycloalkyl and -C 3-7 cycloalkyl are each optionally substituted with one to five substituents, and the substituents are each independently selected from: -CN, -OH and -C 1-6 alkoxy; and

[0195] Each R 3AA is independently selected from: -H, -OH, -N(C 1-4 alkyl)2, -NH2, heteroaryl, -C 3-7 cycloalkyl- and -C(O)OC 1-6 alkyl.

[0196] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0197] Each R 3A is independently selected from: halogen, -CN, -OH, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 haloalkyl, aryl, heteroaryl, 4-12 membered heterocyclic hydrocarbon group, -C 3-7 cyclic hydrocarbon group, -C(O)NH(C 1-4 alkyl) and -C(O)N(C 1-4 alkyl)2, wherein the aryl, heteroaryl, 4-12 membered heterocyclic hydrocarbon group and -C 3-7 cyclic hydrocarbon group are each optionally substituted with one to five substituents, and the substituents are each independently selected from: -CN, -OH and -C 1-6 alkoxy.

[0198] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0199] W, R 1B , R 1C , R 3A and R 3AA in at least one is a 4-12 membered C 3-11 heterocyclic hydrocarbon group or a 5-10 membered C 4-9 heteroaryl.

[0200] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0201] W, R 1B , R 1C , R 3A and R 3AA in at least one is a 4-12 membered C 3-11 heterocyclic hydrocarbon group.

[0202] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein: Y is chlorine.

[0203] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein: each Z is H or fluorine.

[0204] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein: each Z is H.

[0205] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein: W is selected from: azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, piperazinyl, piperidinyl, oxetanyl, pyrrolidinyl, morpholinyl, pyrazolyl, triazolyl, furanyl, thiazolyl, pyridinyl, phenyl, thienyl, imidazolyl, 1,3-oxazolyl, 1,2-oxazolyl, pyrrolyl, 2-oxa-8-azaspiro[4.5]dec-8-yl, 7-oxa-2-azaspiro[3.5]non-2-yl, 1-oxa-8-azaspiro[4.5]dec-8-yl, 5',6'-dihydro-4'H-spiro[piperidine-4,7'-thieno[2,3-c]pyridine], cyclopentyl, 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine]-1-yl, 3,4-dihydrospiro[2-benzopyran-1,4'-piperidine]-1'-yl, 3-azabicyclo[4.1.0]hept-3-yl, 2-oxa-6-azaspiro[2.5]oct-6-yl, 2-oxa-6-azaspiro[2.5]oct-6-yl, 6-azaspiro[2.5]oct-6-yl, 6-azaspiro[3.5]non-6-yl, 6-oxa-9-azaspiro[4.5]dec-9-yl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2,3-dihydro-1-benzofuranyl, 1,3-dihydro-2-benzofuranyl, bicyclo[1.1.1]pent-1-yl, azepanyl, octahydropyrrolo[3,4-c]pyrrol-2-yl, octahydropyrrolo[1,2-a]piperazin-2-yl, 3,4-dihydrospiro[1-benzopyran-2,3'-pyrrolidinyl, 2,9-diazaspiro[5.5]undecanyl, 2,3-dihydro-1,4-benzodioxinyl, 3-azabicyclo[3.1.0]hexyl, 3-oxabicyclo[3.1.0]hex-6-yl, 2H,3H,4H,5H-pyrido[3,2-f][1,4]oxazepinyl, 5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl, 5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl, 1,3-benzodioxazol-2-yl, bicyclo[3.1.0]hex-3-yl, 2H-1,3-benzodioxolyl, 2,3-dihydro-1H-indol-1-yl, 5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 1,4-diazepan-1-yl, oxepanyl, pyrimidinyl, each optionally substituted with one to three R 3A Optionally substituted.

[0206] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein: Each R 1A Is independently -H, -OH, fluoro or methyl.

[0207] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein: each R 1B is independently -H, -OH, fluoro or methyl.

[0208] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein: each R 1C is independently -H, -OH, fluoro or methyl.

[0209] General Formulas (II) and (III)

[0210] Some embodiments provide chemical entities of general formula (II), or more specifically, compounds of general formula (II) or pharmaceutically acceptable salts of compounds of general formula (II):

[0211] wherein: V, W, Y and Z have any of the values described herein.

[0212] Some embodiments provide chemical entities of general formula (III), or more specifically, compounds of general formula (III) or pharmaceutically acceptable salts of compounds of general formula (III):

[0213] wherein: V, W, Y and Z have any of the values described herein.

[0214] In some embodiments of general formula (II) or (III),

[0215] Y is selected from: -H, -F, -Cl, -Br and -C 1-4 alkyl;

[0216] Z is selected from: -H, -F and -C 1-4 alkyl;

[0217] V is selected from: a bond, -CH2-, -C(O)- and -NR a -, where R a is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl or -CH2CH2OC 1-6 alkyl; and

[0218] W is selected from: -H, halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC1-4 alkyl, -C 3-7 cycloalkyl, said -C 3-7 cycloalkyl is optionally substituted by one or more -halogens or -C 1-6 alkyl, -C 1-6 aryl, -C 1-6 heteroaryl, said aryl or heteroaryl is optionally substituted, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -O-piperidinyl, optionally substituted heterocycloalkyl and -N(R b )2,

[0219] wherein each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c and -(CH2) n -R d ,

[0220] wherein R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridinyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH�3 or -SO2CH3,

[0221] wherein Rd -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with up to 4 substituents, said substituents being independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, morpholine, phenyl or benzyl,

[0222] where n is 0, 1, 2 or 3;

[0223] Alternatively, optionally, two R b together form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, optionally containing up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), said 4- to 15-membered monocyclic, bicyclic or tricyclic ring being optionally substituted with one to 4 R b1 where each R b1 is independently selected from -halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole, and -C(O)phenyl.

[0224] In some embodiments of the compound of formula (II) or (III), W is -N(R b )2,

[0225] where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c and -(CH2) n -R d ,

[0226] where R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O phenyl, -O pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3,

[0227] wherein R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7 halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, benzodioxin, benzodioxole, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine or benzimidazole, and the R d is optionally substituted with up to 4 substituents, and the substituents are each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, phenyl or benzyl, where n is 0, 1, 2 or 3;

[0228] Alternatively, optionally, two Rs bTogether form a single ring, double ring or triple ring, the rings being selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-5-azabicyclo[2.2.1]heptane, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, -2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-7'-thieno[2,3-c]pyridine]), each optionally substituted by up to 4 substituents, the substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0229] In certain embodiments, the chemical entity of formula (II) is a chemical entity of formula (IIa), or more specifically, a compound of formula (IIa) or a pharmaceutically acceptable salt of a compound of formula (IIa): Wherein:

[0230] W and Y have any of the values described herein.

[0231] In certain embodiments, the chemical entity of formula (II) is a chemical entity of formula (IIb), or more specifically, a compound of formula (IIb) or a pharmaceutically acceptable salt of a compound of formula (IIb): Wherein:

[0232] W and Y have any of the values described herein.

[0233] In some embodiments of the chemical entity of formula (IIa) or (IIb),

[0234] Y is selected from: -H, -F, -Cl, -Br and -CH3; and

[0235] W is -N(R b )2,

[0236] where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl OH, -C 1-6 haloalkyl, -C 1-6 haloalkyl OH, -C 1-6 haloalkyl -C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7Cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c and -(CH2) n -R d ,

[0237] wherein R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3,

[0238] wherein R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with up to 4 substituents, said substituents being independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, morpholine, phenyl or benzyl,

[0239] wherein n is 0, 1, 2 or 3;

[0240] Alternatively, optionally, two R b together form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, said ring optionally containing up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), said 4- to 15-membered monocyclic, bicyclic or tricyclic ring being optionally substituted with up to 4 substituents, said substituents being independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6Alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 Alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 Alkyl, -CH2CH2OC 1-6 Haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 Alkyl, -OCH2-C 3-7 Cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 Alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0241] In certain embodiments, the chemical entity of formula (III) is a chemical entity of formula (IIIa), or more specifically, a compound of formula (IIIa) or a pharmaceutically acceptable salt of a compound of formula (IIIa):

[0242] Wherein:

[0243] W and Y have any of the values described herein.

[0244] In some embodiments of the chemical entity of formula (IIIa),

[0245] Y is selected from: -H, -F, -Cl, -Br and -CH3; and

[0246] W is -N(R b )2,

[0247] Where each R b is independently selected from: -H, -C 1-6 Alkyl, -C 1-6 Alkyl-OH, -C 1-6 Haloalkyl, -C 1-6 HaloalkylOH, -C 1-6 Haloalkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c and -(CH2) n -R d ,

[0248] wherein R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3,

[0249] wherein R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with up to 4 substituents, said substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, phenyl or benzyl,

[0250] where n is 0, 1, 2 or 3;

[0251] Alternatively, optionally, two R bTogether form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, said ring optionally containing up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), said 4- to 15-membered monocyclic, bicyclic or tricyclic ring being optionally substituted with up to 4 substituents, said substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0252] In certain embodiments, the chemical entity of formula (III) is the chemical entity of formula (IIIb), or more specifically, a compound of formula (IIIb) or a pharmaceutically acceptable salt of a compound of formula (IIIb):

[0253] wherein: W and Y have any of the values described herein.

[0254] In some embodiments of the chemical entity of formula (IIIb),

[0255] Y is selected from: -H, -F, -Cl, -Br and -CH3; and

[0256] W is -C 1-6 aryl, -C 1-6The heteroaryl, said aryl or heteroaryl is optionally substituted, or -N(R b )2,

[0257] wherein each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c and -(CH2) n -R d ,

[0258] wherein R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C[[ID=*]] 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3,

[0259] wherein R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted by up to 4 substituents, said substituents being independently selected from: halogen, -C 1-6 [[ID=6*]]alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, phenyl or benzyl,

[0260] wherein n is 0, 1, 2 or 3;

[0261] Alternatively, optionally, two Rs b together form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, which ring optionally contains up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), and the 4- to 15-membered monocyclic, bicyclic or tricyclic ring is optionally substituted with up to 4 substituents, each substituent independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0262] In some embodiments of the chemical entity of general formula (II), (III), (IIa), (IIb), (IIIa) or (IIIb), W is selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-5-azabicyclo[2.2.1]heptane, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidin]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-7'-thieno[2,3-c]pyridine], each optionally substituted with up to 4 substituents, said substituents being independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0263] In some embodiments of the chemical entities of general formula (II), (III), (IIa), (IIb), (IIIa) or (IIIb), W is -halogen, -C 1-6 alkyl, -C 1-6 haloalkyl or -C 3-7 cycloalkyl; said -C 3-7 cycloalkyl is optionally substituted with one or more halogens or -C 1-6 alkyl.

[0264] In some embodiments of the chemical entities of general formula (II), (III), (IIa), (IIb), (IIIa) or (IIIb), W is halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC 1-4 alkyl, -C 3-7 cycloalkyl, said -C 3-7 cycloalkyl is optionally substituted with one or more halogens or -C 1-6 alkyl, -C 1-6 aryl, -C 1-6 heteroaryl, said aryl or heteroaryl is optionally substituted, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -O-piperidinyl and -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7Cycloalkyl, -C 3-7 Cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 Cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 Alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 Alkyl, -CH2C(O)N(C 1-4 Alkyl)2, -CH2CH(OH)C 3-7 Cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 Alkyl)2, -CH2CF2C 3-7 Cycloalkyl, -CH2CH2-R c (wherein R c is -C 2-6 Alkynyl, -C 3-7 Cycloalkyl, -OH, -O-C F 1-6 Alkyl, -OC(CH3)2, -O-C 1-6 Haloalkyl, -O-phenyl, -O-pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3) and -(CH2) n -R d (wherein R d is -C 3-7 Cycloalkyl, -C 3-7 Haloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with up to 4 substituents, said substituents being independently selected from: -halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-7 Cycloalkyl, -OH, -OC 1-6 Alkyl, -O-C 1-6 Haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, phenyl or benzyl, where n is 0, 1, 2 or 3); or, alternatively, two R b together form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, said ring optionally containing up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), said 4- to 15-membered monocyclic, bicyclic or tricyclic ring being optionally substituted with up to 4 substituents, said substituents being independently selected from: halogen, -C 1-6 Alkyl, -C 1-6Halogenoalkyl, -C 1-6 Halogenoalkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl, -bicyclo[2.2.1]heptane, -C 1-6 Alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 Alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 Alkyl, -CH2CH2OC 1-6 Halogenoalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 Alkyl, -OCH2-C 3-7 Cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 Alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0265] In some embodiments of the chemical entities of general formula (II), (III), (IIa), (IIb), (IIIa) or (IIIb), W is selected from: halogen, -C 1-6 Alkyl, -C 1-6 Halogenoalkyl, -CH2OC 1-5 Alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 Alkyl, -C(O)C 3-7 Cycloalkyl, -C(O)OC 1-4 Alkyl, -C 3-7 Cycloalkyl, said C 3-7 Cycloalkyl is optionally substituted with one or more halogens or -C 1-6 Alkyl, -C 1-6 Aryl, -C 1-6 Heteroaryl, said aryl or heteroaryl is optionally substituted, -OH, -OC 1-6 Alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -Opiperidinyl and -N(R b )2, where each R bIndependently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)piperidine, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c (wherein R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O phenyl, -O pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3) and -(CH2) n -R d (wherein R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7 halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, benzodioxin, benzodioxole, phenyl, benzyl, -CH2CH2 phenyl, -CH2CH2CH2 phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine or benzimidazole, said R dOptionally substituted with up to 4 substituents, each of which is independently selected from: -F, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, morpholine, pyrrolidone, hydroxypiperidine, phenyl, benzyl, imidazole or pyridine, where n is 0, 1, 2 or 3); or, alternatively, two R b together form a monocyclic, bicyclic or tricyclic ring selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-5-azabicyclo[2.2.1]heptane, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-7'-thieno[2,3-c]pyridine], and the 4- to 15-membered monocyclic, bicyclic or tricyclic ring is optionally substituted with up to 4 substituents, each of which is independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6Alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 Alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 Alkyl, -CH2CH2OC 1-6 Haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 Alkyl, -OCH2-C 3-7 Cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 Alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0266] In some embodiments of the chemical entities of general formula (II), (III), (IIa), (IIb), (IIIa) or (IIIb), W is -N(R b )2, where two R bTogether form a monocyclic, bicyclic or tricyclic ring, the rings being selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-5-azabicyclo[2.2.1]heptane, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-7'-thieno[2,3-c]pyridine], the monocyclic, bicyclic or tricyclic ring being optionally substituted with up to 4 substituents, the substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, -thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0267] In some embodiments of the chemical entities of general formula (II), (III), (IIa), (IIb), (IIIa) or (IIIb), W is selected from: -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl and -CH2CH2OCH3.

[0268] In some embodiments of the chemical entities of general formula (II) or (III), where V is a bond and W is halogen, -C 1-6 alkyl, -C 1-6 haloalkyl or -C 3-7 cycloalkyl, the -C 3-7 cycloalkyl is optionally substituted with one or more halogens or -C 1-6 alkyl.

[0269] In some embodiments of the chemical entities of general formula (II) or (III), where V is -CH2- and W is selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC 1-4 alkyl, -C 3-7 cycloalkyl, the -C 3-7 cycloalkyl is optionally substituted with one or more halogens or -C 1-6 alkyl, -C 1-6 aryl, -C 1-6 heteroaryl, the aryl or heteroaryl is optionally substituted, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -Opiperidinyl and -N(R b )2, where each R bIndependently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkyl OH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH₂-alkenyl, -CH₂-alkynyl, -CH₂C 3-7 cycloalkyl, -CH₂C(O)C(CH₃)₃, -CH₂C(O)C 1-6 alkyl, -CH₂C(O)heterocycloalkyl, -CH₂C(O)OC 1-6 alkyl, -CH₂C(O)N(C 1-4 alkyl)₂, -CH₂CH(OH)C 3-7 cycloalkyl, -C(CH₃)₂OH, -C(CH₃)₂CH₂OCH₃, -CH(CH₃)C(O)N(C 1-4 alkyl)₂, -CH₂CF₂C 3-7 cycloalkyl, -CH₂CH₂-R c wherein R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH₃)₂, -O-C 1-6 haloalkyl, -O phenyl, -O pyridyl, -CH₂N(CH₃)₂, -C(O)NHCH₃, -C(O)N(CH₃)₂, -CN, -NHCH₃, -N(CH₃)₂, -NHC(O)CH₃ or -SO₂CH₃, -(CH₂) n -R d wherein R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, heterocycloalkyl, aryl and heteroaryl, each optionally substituted by up to 4 substituents, said substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH₂OH, -CH₂OCH₃, -CH₂OCH₂CH₃, heteroaryl, heterocycloalkyl, morpholine, phenyl, -CN, -N(CH₃)₂, -N(CH₃)benzyl, heterocycloalkyl, aryl or heteroaryl, where n is 0, 1, 2 or 3; or, alternatively, two R bTogether form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, which ring optionally contains up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), and the 4- to 15-membered monocyclic, bicyclic or tricyclic ring is optionally substituted with up to 4 substituents, each substituent independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0270] In some embodiments of the chemical entity of formula (II) or (III), W is selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC 1-4 alkyl, -C 3-7 cycloalkyl, the -C 3-7 cycloalkyl is optionally substituted with one or more halogens or -C 1-6 alkyl, optionally substituted -C 1-6 aryl, optionally substituted -C 1-6Heteroaryl, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -O-piperidinyl, and -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)piperidine, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c (where R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3, or -SO2CH3) and -(CH2) n -R d (where R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7Halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, indoline, benzodioxin, benzodioxolene, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine, benzimidazole, said R d is optionally substituted by up to 4 substituents, each of said substituents being independently selected from: -F, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN or -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, morpholine, phenyl, pyrrolidone, hydroxypiperidine, benzyl, imidazole or pyridine, where n is 0, 1, 2 or 3); or, alternatively, two R bTogether form a monocyclic, bicyclic or tricyclic ring, the rings being selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-5-azabicyclo[2.2.1]heptane, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-7'-thieno[2,3-c]pyridine], the monocyclic, bicyclic or tricyclic ring being optionally substituted with up to 4 substituents, the substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0271] In some embodiments of the chemical entity of formula (II) or (III), W is -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)piperidine, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c (where R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O phenyl, -O pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3) and -(CH2) n -R d (where R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, benzodioxin, benzodioxole, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine or benzimidazole, said R d is optionally substituted with up to 4 substituents, each of said substituents independently selected from: -F, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, morpholine, pyrrolidone, hydroxypiperidine, phenyl, benzyl, imidazole or pyridine, where n is 0, 1, 2 or 3).

[0272] In some embodiments of the chemical entity of formula (II) or (III), W is N(R b )2, where two R bTogether form a monocyclic, bicyclic or tricyclic ring, and the rings are selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-5-azabicyclo[2.2.1]heptane, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, -diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-7'-thieno[2,3-c]pyridine], and the monocyclic, bicyclic or tricyclic ring is optionally substituted with up to 4 substituents, and each substituent is independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0273] In some embodiments of the chemical entity of formula (II) or (III), W is selected from: -halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC 1-4 alkyl, -C 3-7 cycloalkyl, the -C 3-7 cycloalkyl is optionally substituted with one or more -halogen or -C 1-6 alkyl and is optionally substituted, optionally substituted -C 1-6 aryl, optionally substituted -C 1-6 heteroaryl, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -Opiperidinyl and -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4(alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c , where R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3 and -(CH2) n -R d , where R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, heterocycloalkyl, aryl and heteroaryl, each optionally substituted by up to 4 substituents, said substituents being independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN or -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, phenyl or benzyl, where n is 0, 1, 2 or 3; or, alternatively, two R b together form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, said ring optionally containing up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), said 4- to 15-membered monocyclic, bicyclic or tricyclic ring being optionally substituted by up to 4 substituents, said substituents being independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0274] In some embodiments of the compounds of Formulas (II), (IIa), (IIb), (III), (IIIa) and (IIIb),

[0275] Y is selected from: -H, -F, -Cl, -Br and -CH3;

[0276] Z is selected from: -H, -F and -CH3;

[0277] m is 0, 1 or 2;

[0278] V is -CH2- or -C(O)-; and

[0279] W is -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-Rc (where R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3) and -(CH2) n -R d (where R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7 halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, benzodioxin, benzodioxole, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine, benzimidazole, and the R d is optionally substituted with up to 4 substituents, each of which is independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, phenyl or benzyl, where n is 0, 1, 2 or 3); or, alternatively, two R bTogether form a single ring, a double ring or a triple ring, and the rings are selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-5-azabicyclo[2.2.1]heptane, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-7'-thieno[2,3-c]pyridine]), and the single ring, double ring or triple ring is optionally substituted with up to 4 substituents, and the substituents are each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl;

[0280] In some embodiments of the compounds of general formulas (II), (IIa), (IIb), (III), (IIIc) and (IIId),

[0281] Y is a member selected from: -H, -F, -Cl, -Br and -CH3;

[0282] Z is a member selected from: -H, -F and -CH3;

[0283] m is 0, 1 or 2;

[0284] V is -CH2- or -C(O)-; and

[0285] W is -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c (where R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -Ophenyl, -Opyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3) and -(CH2) n -R d (wherein R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7 halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, benzodioxin, benzodioxole, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine or benzimidazole, and the R d is optionally substituted with up to 4 substituents, each of the substituents being independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, phenyl or benzyl, where n is 0, 1, 2 or 3).

[0286] In some embodiments of the compounds of Formulas (II), (IIa), (IIb), (III), (IIIa) and (IIIb),

[0287] Y is selected from: -H, -F, -Cl, -Br and -CH3;

[0288] Z is selected from: -H, -F and -CH3;

[0289] m is 0, 1 or 2;

[0290] V is -CH2- or -C(O)-; and

[0291] W is -N(R b )2, where the two R bTogether form a single ring, a double ring or a triple ring, the rings being selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-5-azabicyclo[2.2.1]heptane, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-7'-thieno[2,3-c]pyridine], the single ring, double ring or triple ring being optionally substituted by up to 4 substituents, the substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -bicyclo[2.2.1]heptane, -C 1-6 alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0292] In certain embodiments, X is -CH.

[0293] In certain embodiments, X is -N.

[0294] In certain embodiments of the compounds of formula (II), (IIa), (IIb), (III), (IIIa) and (IIIb), Y is -F, -Cl or -Br.

[0295] In certain embodiments, Y is -H or -CH3.

[0296] In certain embodiments, Z is -H.

[0297] In certain embodiments, Z is -F or -CH3.

[0298] In certain embodiments, m is 1.

[0299] In certain embodiments, V is -CH2-.

[0300] In certain embodiments, V is -C(O)-.

[0301] In certain embodiments, W is -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c (wherein R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -Ophenyl, -Opyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3) and -(CH2) n -R d (wherein R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with up to 4 substituents, said substituents being independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, heteroaryl, heterocycloalkyl, phenyl or benzyl, where n is 0, 1, 2 or 3); or, alternatively, two R b together form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, said ring optionally containing up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), said 4- to 15-membered monocyclic, bicyclic or tricyclic ring being optionally substituted with up to 4 substituents, said substituents being independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, bicyclo[2.2.1]heptane, -C 1-6 [[ID=----]]alkyl-OH, -C(CH3)2OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6Haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 Alkyl, -OCH2-C 3-7 Cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 Alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

[0302] Some embodiments provide one or more of the compounds of Examples 1 - 583 and all pharmaceutically acceptable forms thereof, including pharmaceutically acceptable chelates, solvates, conformational isomers, crystal forms / polymorphs, salts, prodrugs, and pharmaceutically active metabolites. Some embodiments provide one or more of the compounds of Examples 1 - 583 and pharmaceutically acceptable salts thereof. Some embodiments provide one or more of the compounds of Examples 1 - 583.

[0303] Isotope-Labeled Compounds

[0304] The compounds of the present disclosure (and all forms of such compounds) may contain any isotope in which one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. For example, the isotopes may be isotopes of carbon, chlorine, fluorine, hydrogen, iodine, nitrogen, oxygen, phosphorus, sulfur, and technetium, including 11 C, 13 C, 14 C, 36 Cl, 18 F, 2 H, 3 H, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S and 99m Tc.

[0305] The disclosed compounds of the present invention containing the isotopes mentioned above or other isotopes of other atoms (and all forms of these compounds, such as pharmaceutically acceptable salts) are within the scope of the present invention. The isotopically labeled compounds of this embodiment can be used in drug and substrate tissue distribution and target occupancy analysis. For example, as further described herein, isotopically labeled compounds can be particularly used in SPECT (single photon emission computed tomography) and PET (positron emission tomography). In addition, isotopically labeled compounds can be used to improve the absorption, distribution, metabolism, and / or excretion (ADME) properties of drugs. For example, replacing one or more hydrogen atoms with deuterium ( 2 H) can alter the metabolism of the drug and improve the metabolic profile by reducing in vivo metabolic clearance, prolonging the half-life, reducing C max or reducing the level of potentially toxic metabolites.

[0306] Combinations

[0307] In some embodiments, the chemical entities disclosed herein, more particularly the compounds and their pharmaceutically acceptable salts, are used alone or in combination with one or more additional active ingredients to formulate pharmaceutical compositions.

[0308] In some embodiments, the pharmaceutical composition may comprise: (a) an effective amount of at least one chemical entity disclosed herein; (b) a pharmaceutically acceptable carrier.

[0309] In some embodiments, the pharmaceutical composition comprises a compound or a pharmaceutically acceptable salt thereof of any of the embodiments and examples disclosed herein; and a pharmaceutically acceptable carrier. In a specific embodiment, the pharmaceutical composition comprises a compound or a pharmaceutically acceptable salt thereof of any one of Examples 1-583; and a pharmaceutically acceptable carrier.

[0310] Formulations and Administration

[0311] Numerous standard references are available that describe procedures for preparing various formulations suitable for administration of the compounds according to the described embodiments. Examples of potential formulations and preparations include, for example, Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (latest edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors), latest edition, published by Marcel Dekker, Inc., and Remington's Pharmaceutical Sciences (Osol editor), 1980, 1553 - 1593.

[0312] Any suitable route of administration can be employed to provide an effective dose of the compounds of the present embodiments to an animal, particularly a human. For example, oral, rectal, topical, parenteral, ophthalmic, pulmonary, nasal, etc. can be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc.

[0313] Suitable carriers, diluents, and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific carrier, diluent, or excipient used will depend on the manner and purpose of applying the compounds of the present embodiments. Solvents are typically selected based on solvents that are generally recognized as safe (GRAS) for administration to animals. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (such as PEG400, PEG300), etc. and mixtures thereof. Formulations may also contain one or more of buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide an aesthetic presentation of the drug (i.e., the compounds of the present embodiments or their pharmaceutical compositions) or to assist in the manufacture of the drug product (i.e., the pharmaceutical).

[0314] Formulations can be prepared using conventional dissolution and mixing procedures. For example, in the presence of one or more of the above excipients, most of the drug substance (i.e., the compounds of the present embodiments or stable forms of the compound (such as complexes with cyclodextrin derivatives or other known complexing agents)) is dissolved in a suitable solvent. The compounds of the present embodiments are typically formulated into pharmaceutical dosage forms to provide a drug with easy control and appropriate dosage.

[0315] The pharmaceutical composition (or formulation) applied can be packaged in various ways, depending on the method of administering the drug. Generally, the dispensing article includes a container having the pharmaceutical formulation stored in a suitable form. Suitable containers are known to those skilled in the art and include, for example, bottles (plastic and glass bottles), sachets, ampoules, plastic bags, metal cylinders, and other materials. The container may also include tamper-resistant fittings to prevent accidental contact with the contents of the package. In addition, a label describing the contents of the container is placed on the container. The label may also include appropriate warnings.

[0316] Dosage Forms

[0317] The compounds of the present invention can be administered systemically, such as orally, in combination with a pharmaceutically acceptable vehicle (such as an inert diluent or an absorbable edible carrier). Thus, in some embodiments, the chemical entities of this embodiment are suitable for oral administration. It can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into the food of the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, lozenges, troches, capsules, elixirs, suspensions, syrups, wafers, etc. Such compositions and formulations should contain at least 0.1% of the active compound. Of course, the percentages of such compositions and formulations can vary and can suitably be 1% to 65% or 2% to 60% of the weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions should be such that an effective dosage level will be obtained.

[0318] Tablets, lozenges, pills, capsules, etc. may also contain the following: binders such as tragacanth, gum arabic, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweetening agents such as sucrose, fructose, lactose, or aspartame; or flavoring agents such as peppermint, wintergreen oil, or cherry flavoring. When the unit dosage form is a capsule, in addition to materials of the above types, it may also contain a liquid carrier such as a vegetable oil or polyethylene glycol. Various other materials may be present in the form of coatings or otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar, etc. Syrups or elixirs may contain the active compound, sucrose or fructose as a sweetening agent, methylparaben and propylparaben as preservatives, dyes, and flavoring agents such as cherry or orange flavoring. Of course, any material used in the preparation of any unit dosage form, when in the amounts employed, should be pharmaceutically acceptable and substantially non-toxic. In addition, the active compound can be incorporated into sustained-release formulations and devices.

[0319] The active compounds can also be administered by infusion or injection, intravenously or peritoneally. Solutions of the active compounds or their salts can be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0320] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient, which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, and are optionally encapsulated in liposomes. In all cases, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or a liquid dispersion medium, which includes, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycols, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. For example, appropriate fluidity can be maintained by forming liposomes, by maintaining the required particle size in the case of a dispersion, or by using surfactants. The action of microorganisms can be prevented by various antibacterial or antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it will be preferable to include isotonic agents, such as sugars, buffers, or sodium chloride. The absorption of injectable compositions can be prolonged by using compositions of agents that delay absorption, such as aluminum monostearate and gelatin.

[0321] Sterile injectable solutions are usually prepared by incorporating the required amount of the active compound into a suitable solvent that, according to need, contains any number of the other ingredients enumerated above, and then filtering the solution sterilize. In the case where sterile powders are used for the preparation of sterile injectable solutions, the commonly used methods of preparation are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional required ingredients that were present in a previously sterile-filtered solution.

[0322] For topical administration, the compounds of the present invention can be applied in pure form, i.e., when they are liquids. However, it is generally desirable to administer them in the form of a composition or formulation to the skin, which is combined with a dermatologically acceptable carrier, and the carrier can be solid or liquid.

[0323] Useful solid carriers include finely divided solids, such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols, or diols, or water-alcohol / diol blends, in which the compounds of the present invention are optionally dissolved or dispersed at an effective concentration with the aid of a non-toxic surfactant. Adjuvants, such as fragrances and additional antimicrobial agents, can be added to optimize the properties for a given use. The resulting liquid composition can be applied from absorbent pads useful for impregnating bandages and other dressings, or can be sprayed onto the affected area using a pump or an aerosol sprayer.

[0324] Thickeners and liquid carriers can also be used to form spreadable pastes, gels, ointments, soaps, etc. for direct application to the skin of the user. The thickeners are, for example, synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified minerals.

[0325] Doses

[0326] The useful doses of the chemical entities and compounds (active agents) of the present disclosure can be determined by comparing their in vitro activities with their in vivo activities in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known in the art. The useful doses of the active agents can be determined by comparing their in vitro activities with their in vivo activities in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known in the art (e.g., U.S. Patent No. 4,938,949).

[0327] The effective amount or dose of the active agent of the present invention can be determined by conventional methods such as modeling, dose escalation studies, or clinical trials, and by considering the following conventional factors: for example, the mode or route of administration or drug delivery; the pharmacokinetics of the agent; the severity and course of the disease, disorder or condition; the individual's prior or ongoing therapy; the individual's health status and response to the drug, concomitant drug therapy, and the judgment of the treating physician. Exemplary doses can be 0.0001 mg of active agent per day to 200 mg of active agent per day, 0.001 mg / day to 200 mg / day, 0.05 mg / day to 100 mg / day, 0.1 mg / day to 10 mg / day, 1 mg / day to 200 mg / day, or 5 mg / day to 50 mg / day.

[0328] In some embodiments, the desired dose can be presented in unit dosage forms; for example, a composition containing 0.01 mg to 1000 mg, 0.1 mg to 200 mg, 0.5 mg to 100 mg, or 1 mg to 50 mg of active ingredient per unit dosage form.

[0329] In other embodiments, the desired dose can be presented in sub-doses administered at appropriate intervals, for example, 2, 3, 4, or more sub-doses per day. (e.g., BID, TID, QID). The sub-doses themselves can be further divided into multiple administrations at different times, for example, according to the compositions and methods of the present invention.

[0330] Methods and Uses

[0331] Uses of Isotope-Labeled Compounds

[0332] In some embodiments, the present disclosure provides methods of using the isotopically labeled compounds and chemical entities of the invention in the following: (i) metabolic studies (using, for example, 14 C), reaction kinetics studies (using, for example, 2 H or 3 H); (ii) detection or imaging techniques [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)], including drug or substrate tissue distribution analysis; or (iii) radioactive treatment of patients.

[0333] Isotopically labeled compounds and chemical entities of the present disclosure can generally be prepared by performing the procedures disclosed in the schemes or examples and preparations described below, by substituting unlabeled reagents with readily available isotopically labeled reagents. Compounds labeled with 18 F or 11 C can be particularly preferably used for PET, and 123 I-labeled compounds can be particularly preferably used for SPECT studies. Further substitution of compounds of general formula (I) with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages due to stronger metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[0334] Therapeutic Methods

[0335] General

[0336] The chemical entities and compositions of the present disclosure can be used in a variety of therapeutic methods (or for preparing drugs for such methods), which include administering the chemical entities or compositions herein to an individual in need. In certain aspects, the chemical entity is a compound of general formula (I) or a pharmaceutically acceptable salt thereof. As further described herein, such therapeutic methods can be directed to a wide range of indications, including cognitive or motor deficits associated with neurological disorders, neurodegenerative disorders, immune disorders, and inflammatory disorders, as well as many peripheral disorders.

[0337] In some embodiments, the chemical entities and compositions herein are used in a method of inhibiting PDE7 activity, which includes exposing PDE7 to an effective amount of a chemical entity or composition of any of the embodiments disclosed herein. In some embodiments, PDE7 is in an animal, more specifically in a human individual.

[0338] In some embodiments, the chemical entities and compositions herein can be used in methods for treating an individual having or diagnosed with a disorder mediated by PDE7 activity, including administering to an individual in need thereof an effective amount of a chemical entity or composition of any embodiment herein. In one aspect, the individual is diagnosed with a disorder mediated by PDE7 activity. In another aspect, the individual has a disorder mediated by PDE7 activity.

[0339] In some embodiments, the chemical entities and compositions herein can be used in methods for enhancing neuronal plasticity, which is a fundamental property of the brain that can be impaired in many CNS disorders and enhanced in healthy animals. Without being limited by mechanism, such chemical entities can enhance the function of the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) pathway in cells and regulate the transcription of multiple genes involved in synaptic plasticity (see, e.g., Tully et al., 2003, Nat. Rev. Drug Discov. 2, 267-277; Alberini, 2009, Physiol. Rev. 89, 121-145). Thus, in some embodiments, the present disclosure provides methods for enhancing neuronal plasticity, which include administering to an individual in need thereof an effective amount of a chemical entity or composition of any embodiment herein. In a specific embodiment, the chemical entities of the present disclosure can be used in methods for enhancing cognitive or motor function, including administering to an individual in need thereof an effective amount of a chemical entity of any embodiment disclosed herein.

[0340] In some embodiments, the chemical entities and compositions herein are used as neuroprotective agents. Thus, the present disclosure provides methods for conferring neuroprotection, which include administering to an individual in need thereof an effective amount of a chemical entity of formula (I).

[0341] In some embodiments, the chemical entities and compositions herein are used as anti-inflammatory agents, including for treating neurological and peripheral disorders. Thus, the present disclosure provides methods for treating or reducing inflammation, which include administering to an individual in need thereof an effective amount of a chemical entity of formula (I).

[0342] In some embodiments, the chemical entities and compositions are used as "agents" (or "enhancers") to increase the efficiency of a training regimen that promotes functional reorganization in a targeted "region" (or "function") in the brain.

[0343] In some embodiments, the chemical entities and compositions are used in combination with other therapies or with other active agents, as further described herein.

[0344] Neurological Disorders

[0345] In some embodiments, the present disclosure provides methods of treating neurological disorders, which include administering to an individual in need thereof a chemical entity or composition described herein.

[0346] In some embodiments, the methods target nerve damage (“neural deficits”) associated with neurological disorders, including cognitive impairment (“cognitive deficits”) or motor impairment (“motor deficits”) related to (“attributable to”) the pathology of a neurological disorder.

[0347] Cognitive impairment can manifest as deficits in, for example, attention (e.g., sustained attention, divided attention, selective attention, processing speed); executive function (e.g., planning, decision-making, and working memory); memory (e.g., immediate memory; recent memory, including free recall, cued recall, and recognition memory; and long-term memory, which can be divided into explicit memory (declarative memory), such as episodic memory, semantic memory, and autobiographical memory, and implicit memory (procedural memory)); expressive language, including naming, word recall, fluency, grammar, and syntax; comprehension of speech or writing (such as aphasia); sensorimotor function (e.g., including abilities under visual perception, visual construction, sensorimotor praxis, and gnosis); and social cognition (e.g., emotion recognition, theory of mind). In certain embodiments, the cognitive deficit is a memory deficit, more particularly a long-term memory deficit.

[0348] Motor impairment can manifest as, for example, weakness or paralysis, upper and lower limb deficits, balance or coordination problems, gross motor skill impairment, and fine motor skill deficits.

[0349] A neurological disorder (or condition or disease) is any disorder of the body's nervous system. Neurological disorders can be classified according to the main site affected, the main type of dysfunction involved, and the main type of cause. The broadest division is between disorders of the central nervous system (CNS) (including the nerves in the brain and spinal cord) and disorders of the peripheral nervous system (PNS) (including the nerves outside the brain and spinal cord).

[0350] Many CNS disorders are amenable to treatment with chemical entities and compositions, including those discussed herein. The terms "neurodevelopmental disorders", "schizophrenia spectrum and other psychotic disorders", "bipolar disorder and related disorders", "depressive disorders", "anxiety disorders", "obsessive-compulsive and related disorders", "dissociative disorders", "disruptive, impulse-control, and conduct disorders", "trauma- and stressor-related disorders", "feeding and eating disorders", "sleep-wake disorders", "sexual dysfunctions", "substance-related and addictive disorders", "personality disorders", "neurodegenerative disorders", "neurocognitive disorders", "delirium", "dementia", "age-related cognitive decline", and "trauma" encompass the diagnoses and classifications of these CNS conditions and disorders (and related CNS conditions and disorders) as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; 5th Edition, 2013, American Psychiatric Association). Those skilled in the art will recognize that there are alternative naming and classification systems for these CNS disorders that have evolved with medical and scientific progress. Accordingly, these terms in this paragraph are intended to include similar diseases described in other diagnostic sources.

[0351] Mental disorders and psychiatric conditions:

[0352] In certain embodiments, the chemical entities and compositions herein can be used to treat mental disorders or psychiatric conditions, particularly cognitive impairments associated with the pathology of such conditions. Mental disorders and psychiatric conditions are well known in the art and include, but are not limited to, one or more of the following:

[0353] · Neurodevelopmental disorders (or "developmental" disorders), such as intellectual disability disorders (e.g., Rubinstein-Taybi syndrome, Down syndrome); communication disorders; autism spectrum disorder; attention-deficit / hyperactivity disorder; specific learning, language, or reading (e.g., dyslexia) disorders; motor disorders; fetal alcohol spectrum disorder (FASD); and other neurodevelopmental disorders;

[0354] · Schizophrenia spectrum and other psychotic disorders, such as schizophrenia, schizotypal (personality) disorder, delusional disorder, brief psychotic disorder, schizoaffective disorder, substance / medication-induced psychotic disorder, psychotic disorder due to another medical condition, catatonia, catatonia associated with another mental disorder (catatonia specifier), catatonic disorder due to another medical condition, unspecified catatonia, schizophreniform disorder, and other schizophrenia spectrum and psychotic disorders;

[0355] · Bipolar disorder and related disorders, such as bipolar I disorder and bipolar II disorder, cyclothymic disorder, and other bipolar disorders and related conditions;

[0356] · Depression, such as major depressive disorder, persistent depressive disorder (dysthymia), major depressive episodes of mild, moderate or severe type, depressive episodes with melancholic features, depressive episodes with catatonic features, seasonal depression (seasonal affective disorder), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, mood disorder due to a general medical condition, and other depressive disorders;

[0357] · Anxiety disorders, such as specific phobia, agoraphobia, social anxiety disorder (social phobia), panic attack, panic disorder, acute stress disorder, generalized anxiety disorder, posttraumatic stress disorder (PTSD), and other anxiety disorders;

[0358] · Obsessive-compulsive and related disorders, such as obsessive-compulsive disorder (OCD), body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), excoriation (skin-picking) disorder, substance / medication-induced obsessive-compulsive and related disorders, obsessive-compulsive and related disorders due to another medical condition, other specified obsessive-compulsive and related disorders, and unspecified obsessive-compulsive and related disorders (e.g., body-focused repetitive behavior disorder, obsessive jealousy), and other obsessive-compulsive and related disorders;

[0359] · Dissociative disorders, such as dissociative identity disorder, dissociative amnesia, depersonalization / derealization disorder, dissociative subtype (in combination with other disorders), and other dissociative disorders;

[0360] · Disruptive, impulse-control, and conduct disorders, such as conduct disorder, antisocial personality disorder, pyromania, kleptomania, and other disruptive, impulse-control, and conduct disorders;

[0361] · Trauma- and stressor-related disorders, such as reactive attachment disorder, disinhibited social engagement disorder, posttraumatic stress disorder, acute stress disorder, adjustment disorder, and other trauma- and stressor-related disorders;

[0362] · Feeding and eating disorders, such as pica, rumination disorder, avoidant / restrictive food intake disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, and other feeding and eating disorders;

[0363] · Sleep-wake disorders, such as insomnia disorder, hypersomnolence disorder, narcolepsy, breathing-related sleep disorders, sleep apnea, circadian rhythm sleep-wake disorders, non-rapid eye movement (NREM) sleep arousal disorders, nightmare disorder, rapid eye movement (REM) sleep behavior disorder, restless legs syndrome, and substance / medication-induced sleep disorders, parasomnias, and other sleep-wake disorders;

[0364] · Sexual disorders, such as arousal disorders, desire disorders, functional disorders, substance- and medication-induced sexual dysfunctions, impotence, and other sexual disorders;

[0365] · Substance-related disorders and addictive conditions, such as those involving alcohol, drugs, stimulants, opioids, tobacco, and non-substance-related addictive conditions; and other substance-related disorders and addictive conditions; and

[0366] · Personality disorders, such as antisocial personality disorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizotypal personality disorder, schizoid personality disorder, personality change due to another medical condition, and other personality disorders;

[0367] · Somatic symptoms and related disorders, such as somatic symptom disorder, illness anxiety disorder (hypochondriasis), factitious disorder, factitious disorder imposed on another, pain disorder, conversion disorder, and other somatic symptoms and related disorders.

[0368] Schizophrenia:

[0369] In certain embodiments, the mental disorder or psychiatric condition is a schizophrenia spectrum disorder or a psychotic disorder, particularly schizophrenia. Schizophrenia is a debilitating neurological disorder characterized by a combination of symptoms that may include negative, positive, or cognitive symptoms. Negative symptoms may include affective flattening (lack or decrease in emotional responsiveness), alogia (lack or decrease in speech), avolition (lack or decrease in motivation), anhedonia (inability to experience pleasure from activities that are normally found to be pleasurable), and asociality (lack of motivation to engage in social interactions or preference for solitary activities). Positive symptoms include paranoia, hallucinations, and delusions. Cognitive symptoms may include impairments in functions such as attention, memory, reasoning, and processing speed. See, e.g., Keefe and Harvey, 2012, Handb. Exp. Pharmacol. 213, 11-23. PDE7 inhibitors have been shown to improve various cognitive functions associated with schizophrenia, such as deficits in working memory, short-term memory, spatial memory, and cued memory. (E.g., Lipan et al., 2013, Neuropharmacology. 64, 205-214).

[0370] Accordingly, the present invention provides a method for treating schizophrenia, which comprises administering to an individual in need an effective amount of a chemical entity or composition herein. In some embodiments, the treatment is directed to the positive symptoms of schizophrenia. In some embodiments, the treatment is directed to the negative symptoms of schizophrenia. In some embodiments, the treatment is directed to cognitive impairment associated with schizophrenia (CIAS). In some embodiments, the treatment further comprises a cognitive training program.

[0371] Addictive disorders:

[0372] In specific embodiments, the present disclosure provides a method for treating addictive disorders, which comprises administering to an individual in need an effective amount of a chemical entity or composition herein. On the one hand, the individual is addicted to an addictive agent selected from alcohol, nicotine, cannabis, cannabis derivatives, opioid receptor agonists (such as morphine, methadone, fentanyl, sufentanil or heroin), benzodiazepines, barbiturates, and psychostimulants such as cocaine or amphetamine. On the other hand, the addiction is associated with obsessive-compulsive disorder. On the other hand, the disorder is associated with primary impulse control disorders, such as binge eating, pathological gambling, porn addiction, sexual addiction, compulsive consumption, anorexia nervosa, bulimia nervosa, kleptomania, pyromania, trichotillomania, compulsive overexercise or compulsive overwork.

[0373] Cognitive disorders:

[0374] In specific embodiments, the present disclosure provides a method for treating cognitive disorders, more specifically, a method for treating nerve damage associated with the disorder, which comprises administering to an individual in need a chemical entity or composition as described herein. "Cognitive disorder" (or "neurocognitive disorder") is a disorder whose main clinical feature is impaired cognitive function, that is, a disease in which there is no primary cognitive defect since birth or very early life, and thus represents a decline from a previously achieved functional level. Such disorders include one or more of the following:

[0375] · Delirium, such as substance intoxication (or withdrawal) delirium, drug-induced delirium, and other forms of delirium;

[0376] · Dementia and other cognitive impairments caused by acquired diseases (such as HIV infection) or infectious encephalopathies; or dementia and other cognitive impairments caused by neurodegenerative or progressive neurological diseases, such as Alzheimer's disease, Parkinson's disease (especially Parkinson's disease dementia (PDD)), Huntington's disease, Lewy body disease, Pick's disease, prion diseases (such as Creutzfeldt-Jakob disease), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), frontotemporal lobar degeneration (FTLD), and corticobasal ganglionic degeneration; dementia caused by vascular diseases ("vascular diseases"); autoimmune disorders; and other dementias and neurodegenerative diseases.

[0377] · Age-related cognitive decline, including age-associated memory impairment (AAMI), also known as age-related memory disorder (AMI) (see, e.g., Crook et al., 1986, Devel. Neuropsychol. 2, 261-276); and cognitive decline affecting patients in the early stages of cognitive decline, such as mild cognitive impairment (MCI) (see, e.g., Arnáiz and Almkvist, 2003, Acta Neurol. Scand. Suppl. 179, 34–41);

[0378] · Trauma-dependent functional loss, including vascular diseases such as stroke (such as ischemic stroke or hemorrhagic stroke) or ischemia; infarction, including cerebral infarction and myocardial infarction; microvascular or macrovascular diseases caused by diabetes or joint sclerosis; traumatic brain injury (TBI), such as brain trauma, including subdural hematoma and brain tumors; head trauma (closed and penetrating); head injury; tumors, such as nervous system cancers, including brain tumors affecting the thalamus or temporal lobe; hypoxia, viral, fungal or bacterial infections (such as encephalitis or meningitis); excitotoxicity; and seizures; and

[0379] · Chemotherapy-induced cognitive impairment, such as post-chemotherapy cognitive impairment (PCCI); chemotherapy-induced cognitive dysfunction or impairment; chemo brain; or chemo fog.

[0380] Such cognitive disorders may include neurological damage in addition to cognitive impairment. For example, trauma-dependent functional losses such as stroke, traumatic brain injury, head trauma, and head injury may include damage to multiple neurological functions, such as motor function.

[0381] Age-related cognitive decline:

[0382] In a specific embodiment, the cognitive disorder is age-related cognitive decline.

[0383] On the one hand, age-related cognitive decline is age-associated memory impairment (AAMI). AAMI is the decline of various cognitive abilities (especially memory ability) associated with normal aging. For example, individuals with AAMI show a decreased ability to encode new memories of events or facts and a decline in working memory (Hedden and Gabrieli, 2004, Nat. Rev. Neurosci. 5, 87-96). In addition, compared with age-matched control groups, individuals with AAMI seem to be impaired in executive function tests related to frontal lobe function. These and other studies suggest that frontal lobe dysfunction plays an important role in memory loss in the elderly. (Nilsson, 2003, Acta Scand. Suppl. 179, 7-13). Generally speaking, the diagnosis of AAMI can identify people who prove memory loss subjectively and objectively but whose cognitive decline is not impaired enough to be confirmed as a diagnosis of dementia. For example, the NIH working group established multiple criteria for the diagnosis of AAMI in people aged 50 or older, including the presence of subjective memory decline, objective evidence of memory loss, evidence of sufficient intellectual function, and the absence of dementia (or other diseases affecting memory) (Crook et al., 1986, Devel. Neuropsychol. 2, 261-276). Compared with individuals who do not meet the AAMI criteria, individuals with AAMI are three times more likely to develop dementia (Goldman and Morris, 2002, Alzheimer Dis. Assoc. Disord. 75, 72-79).

[0384] On the other hand, age-related cognitive decline is mild cognitive impairment, which may be diagnosed when an individual's memory drops below the level considered normal for that age group. In other words, MCI is a situation where people are more often faced with memory problems than the average person of their age. Symptoms usually include misplacing items, forgetting events or appointments, and difficulty recalling the words needed (e.g., Arnaiz and Almkvist, Acta Neurol. Scand. Suppl. 2003, 179, 34-41). MCI can represent a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD). Many people experiencing mild cognitive impairment are at high risk of developing Alzheimer's disease. Among people aged 65 and older who are diagnosed with MCI, about 12% develop Alzheimer's disease within one year, and about 40% develop Alzheimer's disease within three years. This is much higher than the proportion in the general population, in which only about 1% of people aged 65 and older develop Alzheimer's disease each year. Therefore, people with MCI are considered to be at increased risk of developing Alzheimer's disease. However, some patients with MCI never progress to AD.

[0385] Accordingly, the present disclosure includes methods of treating age-related cognitive decline, and more particularly, age-related memory impairment or mild cognitive impairment, comprising administering to an individual in need thereof an effective amount of a chemical entity or composition disclosed herein.

[0386] Trauma-dependent functional loss:

[0387] In certain embodiments, the cognitive disorder is trauma-dependent functional loss, particularly stroke or TBI. Accordingly, the present disclosure includes methods of treating trauma-dependent functional loss, particularly stroke or TBI, comprising administering to an individual in need thereof an effective amount of a chemical entity or composition disclosed herein.

[0388] Movement disorders:

[0389] In certain embodiments, the present disclosure provides methods of treating movement disorders and movement conditions, and more specifically, treating movement impairment or movement injury associated with the pathology of such conditions, comprising administering to an individual in need thereof a chemical entity or composition described herein. PDE7B is highly expressed in striatal neurons of the basal ganglia and it appears to regulate dopaminergic neurotransmission. In primary striatal neurons, PDE7B is transcriptionally activated by dopamine receptor stimulation via the cAMP / PKA / CREB pathway. The loss of dopaminergic neurotransmission in the striatum is the leading cause of neurodegenerative diseases that result in movement disorders, such as Parkinson's disease and Huntington's disease. See, e.g., Sasaki et al., 2004, J. Neurochem. 89, 474-483; Morales-Garcia et al., 2014, Neurobiol. Aging. 36, 1160-1173; Banerjee et al., 2012, Bioorg. Med. Chem. Lett. 22, 6286-6291.

[0390] Movement disorders include, but are not limited to: basal ganglia disorders, Parkinson's disease, postencephalitic Parkinson's disease, dopa-responsive dystonia, Hallervorden-Spatz syndrome (HSS), restless legs syndrome, Wilson's disease, Shy-Drager syndrome, periodic limb movement disorder (PLMD), periodic limb movement in sleep (PLMS), Tourette syndrome, restless legs syndrome (RLS); chorea, such as Huntington's chorea; myoclonus (including generalized myoclonus and focal myoclonus); tics (including simple tics, complex tics and symptomatic tics); hyperkinesia, hypokinesia and dyskinesia disorders; drug-induced movement disorders, diseases associated with striatal hypofunction; and other movement disorders and movement conditions.

[0391] In a specific embodiment, the movement disorder is a drug-induced movement disorder. More specifically, the movement disorder is levodopa-induced dyskinesia (LID) or tardive dyskinesia (TD), which represent the most common forms of drug-induced movement disorders. For example, it is believed that the uncontrolled stimulation of hypersensitive dopamine D1 receptors in the direct striatal pathway mediates LID. In addition, the long-term blockade of dopamine D2 receptors in the basal ganglia by dopamine D2 antagonists (e.g., antipsychotics) may produce compensatory hypersensitivity of dopamine receptors and TD. Thus, in a specific embodiment, the present disclosure provides a method for treating LID (or TD), which comprises administering to an individual in need an effective amount of a chemical entity of any of the embodiments disclosed herein.

[0392] In certain embodiments, the movement disorder is a basal ganglia disorder.

[0393] In other embodiments, the movement disorder includes motion sickness and akinetic-rigid syndrome, such as Parkinson's disease or corticobasal degeneration; Tourette syndrome, epilepsy, muscle spasms, and disorders associated with muscle spasms or weakness; movement disorders, including tremors, such as resting tremors, postural tremors, and intention tremors.

[0394] In a specific embodiment, the movement disorder is Parkinson's disease or Huntington's disease, as further discussed herein.

[0395] In some embodiments, the method targets specific movement abnormalities associated with the pathology of a movement disorder or movement condition. Movement abnormalities include, but are not limited to, tremors, resting tremors, rigidity, bradykinesia, and postural reflex insufficiency.

[0396] Neurodegenerative disorders:

[0397] In a specific embodiment, the present disclosure provides a method for treating neurodegenerative disorders, more specifically, a method for treating nerve damage associated with the pathology of neurodegenerative disorders, which comprises administering to an individual in need a chemical entity or composition described herein.

[0398] Neurodegenerative disorders can be caused by primary nervous system diseases or primary nervous system injuries. Chronic neuroinflammation is a hallmark of neurodegenerative disorders, and in animal and cell models, PDE7 inhibition has shown neuroprotective and anti-inflammatory effects, which are expected to be beneficial for treating neuroinflammation and other hallmarks of such disorders.

[0399] Thus, in some embodiments, the method of treatment is directed to neurodegenerative disorders caused by primary nervous system diseases. Such diseases include, but are not limited to, Parkinson's disease, Alzheimer's disease, Huntington's disease, Lewy body disease, Pick's disease, prion diseases (e.g., Creutzfeldt-Jakob disease), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), frontotemporal lobar degeneration (FTLD), and corticobasal degeneration.

[0400] In other embodiments, the method of treatment is directed to neurodegenerative disorders caused by primary nervous system injury. Such primary injuries can include, but are not limited to, stroke, including hemorrhagic stroke and ischemic stroke; traumatic brain injury (TBI), which can include closed head injury and blunt trauma, including trauma caused by participation in sports and penetrating trauma, such as gunshot wounds; spinal cord injury; glaucoma, cerebral ischemia, or injury caused by surgery such as tumor resection.

[0401] Parkinson's disease:

[0402] In a specific embodiment, the present disclosure provides a method of treating Parkinson's disease, which comprises administering to an individual in need thereof a chemical entity or composition described herein. Parkinson's disease (PD), also known as Parkinsonism, idiopathic Parkinsonism, or primary Parkinsonism, is a neurodegenerative disorder of the CNS, and it is estimated that 5 million people worldwide suffer from this disease. It is a slowly progressive neurological condition characterized by tremors, stiffness, slowness of movement (bradykinesia), and impaired balance. PDE7 inhibitors improve motor function in animal models of PD and promote neurogenesis, demonstrating a neuroprotective effect on dopaminergic neurons both in vitro and in vivo, and can act synergistically in combination with L-DOPA. Morales-Garcia et al., 2012, PLoS One. 6, e17240; Morales-Garcia et al., 2014, ACS Chem. Neurosci. 19, 194-204; Morales-Garcia et al., 2015, Neurobiol. Aging. 36, 1160-1173.

[0403] Although Parkinson's disease has been defined by its motor signature, non-motor features such as cognitive impairment and dementia have increasingly been recognized. For example, MCI is common in a significant proportion (estimated range 20%-50%) of PD patients without dementia. Although diagnostic criteria are not entirely consistent, PD patients with MCI (PD-MCI patients) typically exhibit non-amnestic deficits in cognitive domains such as executive function, attention, and visuospatial function. However, the cognitive phenotype of PD-MCI is heterogeneous, and some patients exhibit amnestic deficits. Certain PD-MCI patients may be at high risk of developing dementia. (e.g., Goldman and Litvan, 2011, Minerva Med. 102, 441–459).

[0404] Alzheimer's disease:

[0405] In certain embodiments, the present disclosure provides methods of treating Alzheimer's disease (AD) comprising administering to an animal in need thereof an effective amount of a chemical entity or composition disclosed herein. Alzheimer's disease is a neurodegenerative disorder that involves the progressive loss of memory and other cognitive functions. Although the pathogenesis of AD is not well understood, its etiology is associated with the presence of β-amyloid (or senile) plaques; lack of neurotransmission; neuronal loss, particularly in the cortex and hippocampus; neurofibrillary tangles; and hyperphosphorylation and intracellular deposition of the microtubule-associated protein tau in the form of filaments; intracellular deposition of aggregated tau filaments. The PDE7-mediated pathway that affects cAMP and CREB signaling has been associated with AD etiology. See, e.g., Perez-Torres et al., 2003, Exp. Neurol. 182, 322-334; Perez-Gonzales et al., 2013, Neurobiol. Aging 34, 2133-2145.

[0406] Huntington's disease:

[0407] In specific embodiments, the present disclosure provides methods for treating Huntington's disease (or "Huntington's chorea"), including administering to an individual in need an effective amount of a chemical entity or compound disclosed herein. Huntington's disease has two forms: adult-onset Huntington's disease, which is the most common form and typically begins in individuals aged 30 to 40 years; and early-onset Huntington's disease, which accounts for a minority of cases and begins in childhood or adolescence. Symptoms of Huntington's disease include behavioral changes, abnormal and involuntary movements, and worsening dementia (e.g., Dumas et al., 2013, Front. Biosci. (Schol. Ed) 5, 1-18). Huntington's disease (HD or Huntington's chorea) is a genetic disorder whose pathology includes degeneration of striatal neurons in the basal ganglia responsible for movement and coordination. In response to dopamine receptor agonists acting through the cAMP / PKA / CREB pathway, PDE7 variants are upregulated in striatal neurons. A detailed set of criteria for diagnosing Huntington's disease is set forth in the Diagnostic and Statistical Manual of Mental Disorders ((DSM-5; 5 th th ed., 2013, American Psychiatric Association).

[0408] Multiple sclerosis:

[0409] In specific embodiments, the present disclosure provides methods for treating multiple sclerosis (MS), which include administering to an individual in need an effective amount of a chemical entity or composition disclosed herein. MS is a complex CNS disease associated with demyelination and axonal injury that impairs normal neurotransmission, resulting in deficits in sensory function and motor coordination. The cause of MS is not fully understood but is thought to be an autoimmune disease involving both neuroinflammatory and neurodegenerative components (Kipp et al., 2012, CNS Neurol. Disord. Drug Targets 11, 506-617).

[0410] Because nerves in any part of the brain or spinal cord can be damaged, patients with multiple sclerosis can have different symptoms in many parts of the body. The frequency and severity of symptom attacks can vary and typically alternate with periods of symptom reduction or no symptoms (remission). Muscle symptoms associated with MS include loss of balance; muscle spasms; numbness, tingling, or abnormal sensations in any area; problems moving the arms or legs; difficulty walking; problems with coordination and performing small movements; tremors in one or more arms or legs; and weakness in one or more arms or legs. In animal models of primary progressive multiple sclerosis, PDE7 inhibition has been shown to play a general role in modulating the inflammatory response and reducing symptoms (Mestre et al., 2015, Br. J. Pharmacol. 172, 4277-4290; Redondo et al., 2012, J. Med. Chem. 55, 3274-84; González-García et al., 2013, Brit. J. Pharm. 170, 602-613; Redondo et al., 2012, ACS Chemical Neuroscience 3, 793-803; Medina-Rodríguez etal., 2017, Sci Rep. 7, 43545; Medina-Rodríguez et al., 2013, Cell Mol. Life Sci. 70, 3449-3462).

[0411] Spinal cord injury:

[0412] In certain embodiments, the present disclosure provides methods of treating spinal cord injury (SCI) that include administering to an individual in need an effective amount of a chemical entity or composition disclosed herein. Excessive inflammatory responses play an important role in the secondary injury process, which leads to the continued death of neurons after the primary injury. This neuroinflammatory response is regulated by cAMP levels, highlighting the role of cAMP PDEs, particularly PDE7 expressed on leukocytes and in the brain. See, Paterniti et al., 2011, PLoS One 6, e15937.

[0413] Enhanced Training

[0414] In some embodiments, the chemical entities and compositions of the present disclosure are used as enhancers in methods to improve the efficiency of training regimens for enhancing neurological function or treating nerve damage associated with neurological disorders. Such methods are referred to as "enhanced training," and more specifically, "enhanced cognitive training" in the case of cognitive impairment and "enhanced motor training" in the case of motor impairment. The enhancer can act by shortening the time taken for a method for rehabilitating (or strengthening) cognitive or motor function to produce improved performance or functional gain. Thus, such enhanced training includes specific training regimens for specific brain functions, such as potential declarative memory, performance of fine motor skills, specific motor functions, language acquisition, executive function, etc.; and general administration of the enhancer of the present disclosure.

[0415] Training (or "training regimen") typically requires multiple sessions to achieve the desired benefits, e.g., rehabilitating motor or language deficits following a stroke. This can be costly and time-consuming, thereby deterring individual compliance and achieving real-world benefits that persist over time. The efficiency of such training regimens can be improved by co-administering certain agents (known as enhancers) in combination with the training regimen (see, e.g., U.S. 7,868,015; U.S. 7,947,731; U.S. 2008-0188525). When co-administered with a training regimen (or "training"), the enhancer enhances functional reorganization in the targeted domain (or "function") in the brain.

[0416] Cognitive domains (or functions) that a training regimen can target include, but are not limited to, the following: attention (e.g., sustained attention, divided attention, selective attention, processing speed); executive function (e.g., planning, decision-making, and working memory); learning and memory (e.g., immediate memory; recent memory, including free recall, cued recall, and recognition memory; and long-term memory, which can be divided into explicit memory (declarative memory), such as episodic, semantic, and autobiographical memory, and implicit memory (procedural memory)); language (e.g., expressive language, including naming, word recall, fluency, grammar, and syntax; and receptive language); sensorimotor function (e.g., the abilities involved in visual perception, visual construction, sensorimotor practice, and intuition); and social cognition (e.g., emotion recognition, theory of mind). In a specific embodiment, the cognitive function is learning and memory, and more specifically, long-term memory.

[0417] Motor domains (or functions) that a training regimen can target include, but are not limited to: those functions involved in overall control, coordination, posture, and balance; bilateral coordination; upper and lower limb coordination; muscle strength and agility; movement and activity; motor planning and integration; manual coordination and dexterity; overall and fine motor skills; and eye-hand coordination.

[0418] Training Regimens

[0419] The training program (or "module") includes a cognitive training program and a motor training program. Training programs are well-known in the art and typically include a set of different exercises that can be process-specific or skill-based: see, for example, Kim et al., 2014, J. Phys. Ther. Sci. 26, 1-6; Allen et al., 2012, Parkinson’s Dis. 2012, 1-15; Jaeggi et al., 2011, Proc. Natl. Acad. Sci. USA 108, 10081-10086; Chein et al., 2010, Psychon. Bull. Rev. 17, 193-199; Klingberg, 2010, Trends Cogn. Sci. 14, 317–324; Owen et al., 2010, Nature 465, 775–778; Tsao et al., 2010, J. Pain 11, 1120-1128; Lustig et al., 2009, Neuropsychol. Rev. 19, 504–522; Park and Reuter-Lorenz, 2009, Ann. Rev. Psych. 60, 173-196; Oujamaa et al., 2009, Ann. Phys. Rehabil. Med. 52, 269–293; Frazzitta et al., 2009, Mov. Disord. 8, 1139-1143; Jaeggi et al., 2008, Proc. Natl. Acad. Sci. USA 105, 6829–6833; Volpe et al., 2008, Neurorehabil. NeuralRepair 22, 305-310; Fischer et al., 2007, Top. Stroke Rehab. 14, 1-12; Jonsdottir et al., 2007, Neurorehabil. Neural Repair 21, 191-194; Stewart et al., 2006, J. Neurol. Sci. 244, 89-95; Krakauer, 2006, Curr. Opin. Neurol. 19, 84–90; Belleville et al., 2006, Dement. Geriatr. Cogn. Disord. 22, 486-499; Klingberg et al., 2005, J. Am. Acad. Child. Adolesc.Psychiatry 44,177-186; Dean et al.,2000,Arch.Phys.Med.Rehabil.81,409-417; Whitall et al.,2000,Stroke 31,2390-2395; Hummelsheim and Eickhof,1999,Scand.J.Rehabil.Med.31,250-256; Merzenich et al.,1996,Science 271,77-81; Merzenich et al.,1996,Cold Spring Harb.Symp.Quant.Biol.61,1-8; Rider and Abdulahad,1991,Percept.Mot.Skills 73,219-224.

[0420] Process-specific training focuses on improving specific domains, such as attention, memory, language, executive function, or motor function. Here, the aim of the training is to obtain an overall improvement, that is, a transfer from the trained activities to the untrained activities based on the same cognitive or motor function or domain.

[0421] Skill-based training aims to improve the performance of specific activities or abilities, such as learning a new language, playing a musical instrument, improving memory, or learning fine motor skills. Different exercises in such a program will focus on the core components within one or more domains that form the basis of the skill. For example, a module for increasing memory can include tasks directed at specific domains involved in the memory process, such as the recognition and use of facts, and the acquisition and understanding of explicit knowledge rules.

[0422] In some embodiments, a series of exercises is performed as part of a single training session. In one aspect, the training program includes multiple training sessions, each separated by discrete intervals. In another aspect, the number of training sessions sufficient to improve the performance is reduced relative to the performance produced by the training alone.

[0423] In another aspect, the enhancer is a PDE7 inhibitor, more specifically, a chemical entity of the present disclosure, and is administered in combination with training. The phrase "in combination with" means that the enhancer enhances CREB pathway function during training. In some embodiments, the deficit is a motor deficit. In other embodiments, the deficit is a cognitive deficit. In other embodiments, the deficit may include cognitive and motor deficits. In other aspects, the compound is administered before and during each training session. In one aspect, the individual is human. In some embodiments, the individual is non-human, more specifically, a primate or a canine. In one aspect, the compounds or compositions of the present disclosure can be used as enhancers in combination with any psychotherapy intended to modulate brain cognitive function, thereby enhancing the efficacy of such therapies by reducing the number of sessions required to obtain a benefit.

[0424] Thus, in some embodiments, the present disclosure provides the use of a compound or composition herein in a method of enhancing training to treat a neurological disorder, the method comprising: (a) providing training to an animal in need of treatment for a neurological impairment associated with the neurological disorder under conditions sufficient to produce an improvement in the performance of the neurological function of the animal, wherein the deficit in the neurological function of the animal is associated with the neurological impairment; (b) administering the compound or composition to the animal in conjunction with the training; (c) repeating the providing and administering steps one or more times; and (d) reducing the number of training sessions sufficient to produce the performance improvement relative to the performance improvement produced by training alone. In certain aspects, the enhanced training is enhanced cognitive training. In certain aspects, the neurological impairment is a cognitive impairment. In certain aspects, the neurological impairment is a motor impairment. In certain aspects, the neurological disorder is stroke or traumatic brain injury. In certain aspects, as further described herein, enhanced training is provided to stroke patients during post-stroke rehabilitation.

[0425] Animal skill protocol:

[0426] In some embodiments, the chemical entities of the present invention are used to improve the efficiency of training protocols for cognitive and motor skills in animals. Such enhanced training (enhancer and training) shortens the time required to acquire cognitive or motor skills and / or enhance functions or cognitive abilities that exceed those that may be achieved by training alone in non-human animals.

[0427] In a specific embodiment, the animal is a non-human animal, more specifically, a service animal, and the categories include but are not limited to dogs, miniature horses, and capuchin monkeys. Service animals can participate in public services or private services, and the training programs will be appropriately matched with these goals. For example, the training programs for public services include public order maintenance, search and rescue, and contraband detection, and the training programs for private services include private security, disability assistance, healthcare, psychiatric assistance, and pest control.

[0428] The training program can target a single skill, such as detecting a specific type of contraband through a service animal. In other embodiments, the training program can target a complex skill set, such as potential search and rescue training for service animals; thus, for a complex skill set, the training will include more than one task.

[0429] Therefore, in some embodiments, the present invention provides a method for teaching a non-human animal one or more skills, which includes (a) administering a PDE7 inhibitor to a non-human animal in need thereof; (b) providing training to the animal under conditions sufficient to improve the performance of one or more skills; and (c) repeating steps (a) and (b) one or more times, so that the training amount sufficient to improve the performance is reduced compared to the performance produced by training alone.

[0430] Stroke

[0431] In certain embodiments, the chemical entities and compositions of the present disclosure can be used for treating trauma-dependent functional loss, especially in methods for treating stroke. Stroke is the main cause of severe long-term disability in adults and the second leading cause of death globally (e.g., Go et al., 2014, Circulation 129, e28 - e92). Stroke includes two main types: 1) ischemic stroke (accounting for 85% of all strokes) that occurs when the blood vessels supplying the brain are blocked by thrombosis; 2) hemorrhagic stroke (accounting for 13 - 15% of all strokes) that occurs when the blood vessels in the brain rupture. Stroke care is time-continuous, which includes medical interventions in the acute phase of stroke and subsequent rehabilitation treatments involving the restoration of function in the post-stroke phase of stroke.

[0432] Acute treatment:

[0433] The treatment after a stroke attack directly targets the initial damage caused by ischemic or hemorrhagic stroke. The acute treatment options for ischemic stroke include drug treatment with intravenous administration of recombinant tissue plasminogen activator (r-tPA) for thrombolysis, or the use of endovascular surgery or mechanical thrombectomy to physically remove the thrombus. The acute treatment options for hemorrhagic stroke usually involve endovascular or surgical procedures to physically repair the rupture.

[0434] PDE7 inhibition has been shown to reduce infarct size and behavioral deficits in animal stroke models, and more generally, PDE7 inhibitors can prevent glial activation and neuronal cell death in the neurodegenerative KA model (Redondo et al., 2012, Eur. J. Med. Chem. 47, 175-185; Susin et al., 2012, J. Neurochem. 122, 1193-1202). Accordingly, in some embodiments, the present disclosure provides methods for treating stroke in the acute phase, which include administering to an individual in need thereof a chemical entity or composition disclosed herein. Accordingly, in some embodiments, the individual is a patient with acute stroke, and a PDE7 inhibitor herein is administered to treat neuroinflammatory and neurodegenerative events caused by the primary stroke injury. In one aspect, the stroke is an ischemic stroke. In another aspect, the stroke is a hemorrhagic stroke.

[0435] Post-stroke rehabilitation:

[0436] After the acute phase of stroke (and generally after the patient is medically stable), the focus of stroke treatment shifts to restoring function through rehabilitation. Depending on the severity and location of the stroke, as well as the timing and effectiveness of acute interventions, post-stroke symptoms may persist and may include motor deficits (e.g., hemiplegia, apraxia), speech disorders (e.g., aphasia), visual disturbances (e.g., loss of visual field), emotional and behavioral changes (e.g., depression, anxiety), and mental and cognitive changes (e.g., confusion, apathy, cognitive impairment) (Winstein et al., 2016, Stroke 47, e98-e169). Rehabilitation (also referred to as "stroke rehabilitation" or "post-stroke rehabilitation") targets post-stroke deficits remaining after the initial stroke injury, such as cognitive and motor deficits, with the aim of restoring and recovering neurological function, such as physical, intellectual, psychological, and social function, as much as possible to compensate for permanent tissue loss (e.g., 1995 Clinical Guideline by the Department of Health and Human Services on Post-Stroke Rehabilitation).

[0437] Stroke rehabilitation is typically a comprehensive program coordinated by a team of medical specialists that may include occupational therapy, speech, and physical therapists. The team's physical therapists, for example, may work to maintain and restore the range and strength of movement of affected limbs, thereby maximizing walking mobility, improving manual dexterity, and rehabilitating other motor and sensorimotor functions. Mental health professionals may be involved in treating cognitive skill loss. Rehabilitation services can be provided in a variety of settings, such as rehabilitation hospitals, long-term care facilities, outpatient clinics, or at home.

[0438] Neurological functions affected by stroke (and targetable during rehabilitation) include impairments of cognitive and motor functions. Impairments of cognitive functions can manifest, for example, as deficits in speech comprehension or writing (aphasia); difficulty in clearly speaking words that are understood appropriately (dysphasia); and other cognitive function deficits, such as attention, reasoning, planning, execution, and learning and memory. Impairments of motor functions can manifest, for example, as weakness (hemiparesis) or paralysis (hemiplegia) affecting the entire side or only one side of the body, such as the arm or leg; problems with balance or coordination; deficits in gross motor skills, such as gait and walking speed; deficits in fine motor skills or manual dexterity; and deficits in upper and lower limb functions.

[0439] In the United States, more than 700,000 people have a stroke each year, and two-thirds of them survive and require rehabilitation. Unfortunately, recovery is usually only partial, and many patients still have significant deficits (e.g., Gordon et al., 2004, Stroke 35, 1230 - 1240). For example, after standard rehabilitation, about 30% to 60% of patients are unable to use their paralyzed arm functionally (Gowland, 1982, Physiother. Can. 34, 77 - 84; Kwakkel et al., Age Ageing 25, 479 - 489), and despite extensive rehabilitation efforts, only about 5% - 20% of patients achieve complete functional recovery of the arm (Nakayama et al., 1994, Arch. Phys. Med. Rehabil. 75, 394 - 398).

[0440] As discussed herein, the chemical entities and their compositions of the present disclosure are used as enhancers to improve the efficiency of training regimens for treating neurological impairments, including those caused by traumatic events such as stroke. Thus, in some embodiments, the present disclosure provides a method for treating neurological function deficits during post-stroke rehabilitation, which includes: (a) administering to an individual in need a PDE7 inhibitor disclosed herein during the period when the individual is recovering from a stroke; (b) providing training to the individual under conditions sufficient to improve the manifestation of neurological function (the impairment of which is caused by the deficit); and (c) repeating steps (a) and (b) one or more times.

[0441] In some embodiments, administration can begin during the acute phase. In other embodiments, the PDE7 inhibitor is administered only after the acute phase, i.e., during post-stroke rehabilitation, which may include the subacute and chronic phases. In some embodiments, administration occurs during the acute phase and the post-stroke period. In some embodiments, the PDE7 inhibitor is administered chronically, which means that the PDE7 inhibitor is suitable for long-term use after the end of the acute phase of stroke and the patient is medically stable.

[0442] In other embodiments, the individual is a post-stroke patient, and a PDE7 inhibitor is administered during stroke rehabilitation to treat stroke deficits (or "post-stroke deficits") resulting from impaired neurological function. In some embodiments, the deficit is a motor deficit, including upper or lower limb motor deficits. In other embodiments, the deficit is a cognitive deficit, such as aphasia, apraxia, and mental and cognitive changes, particularly deficits in memory formation, and more specifically, deficits in long-term memory formation. In other embodiments, the deficit can include cognitive and motor deficits. In another aspect, the training includes a series of tasks directed at neurological function. In a particular aspect, the reduction in the amount of training is a reduction in the number of training sessions.

[0443] In another embodiment, the administering step (a) is combined with the training step (b). In one aspect, the individual is a human. In another aspect, the individual has undergone neuronal stem cell manipulation. In other aspects, the compound is administered before and during each training session.

[0444] Traumatic Brain Injury

[0445] In some embodiments, the chemical entity and composition can be used in a method for treating traumatic brain injury (TBI), and in more specific embodiments, for treating motor or cognitive impairment during TBI rehabilitation following an initial trauma.

[0446] TBI, also known as intracranial injury, occurs when the brain is damaged by an external force. TBI can be classified according to severity, mechanism (closed or penetrating head injury), or other characteristics (e.g., occurring in a specific location or a widespread area). TBI can result in physical, cognitive, social, emotional, and behavioral symptoms. Causes include falls, vehicle collisions, gunshot wounds, and explosives. The outcomes range from full recovery to permanent disability or death.

[0447] Similar to stroke care, TBI cases are time-sequential and include acute (or subacute) treatment for the injury itself and subsequent rehabilitation for functional recovery.

[0448] Thus, in some embodiments, the chemical entities and compositions of the present disclosure are used in the acute (or subacute) phase of TBI, during which their administration can treat neuroinflammatory and neurodegenerative events following the primary injury.

[0449] Some embodiments provide for the use of the disclosed PDE7 inhibitors during TBI rehabilitation to treat TBI deficits (or "post-TBI deficits") resulting from impaired neurological function. Some embodiments provide methods of treating neurological deficits during post-TBI rehabilitation, which include: (a) administering a PDE7 inhibitor to an individual in need thereof during the individual's recovery from TBI; (b) providing training to the individual under conditions sufficient to improve the performance of the neurological function (the deficit of which is caused by the deficit); and (c) repeating steps (a) and (b) one or more times, whereby the amount of training sufficient to improve the performance is reduced as compared to the performance produced by training alone.

[0450] In one aspect, the PDE7 inhibitor is a chemical entity of the present disclosure, and more specifically, is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the deficit is a motor deficit. In other embodiments, the deficit is a cognitive deficit, particularly a deficit in memory formation, and more specifically, a deficit in long-term memory formation. In other embodiments, the deficit can include a cognitive deficit and a motor deficit. In another aspect, the training includes a series of tasks directed to the neurological function. In a particular aspect, the reduction in the amount of training is a reduction in the number of training sessions.

[0451] In another embodiment, the administering step (a) is combined with the training step (b). In one aspect, the individual is a human. In another aspect, the individual has undergone neuronal stem cell manipulation. In other aspects, the compound is administered before and during each training session.

[0452] Peripheral Disorders

[0453] In some embodiments, the present disclosure provides methods of treating peripheral disorders (i.e., disorders other than primary neurological disorders), which comprise administering to an individual in need thereof an effective amount of a chemical entity or composition disclosed herein. Peripheral disorders involving PDE7 include a wide range of diseases, based on many biological studies and the expression of PDE7 subtypes in peripheral tissues such as the heart, ovary, pituitary, kidney, liver, small intestine, thymus, skeletal muscle, colon, bladder, uterus, prostate, stomach, adrenal gland, thyroid, as well as T cells, B cells, lung mast cells, and bronchial epithelial cells.See, for example, Michaeli et al., 1993, Biol. Chem. 268, 12925-12932; Gardner et al., 2000, Biochem. Biophys. Res. Commun. 272, 186-192; Hetman et al., 2000, Proc. Natl. Acad. Sci. USA 97, 472-476; Glavas et al., 2001, Proc. Natl. Acad. Sci. USA 98, 6319-6324; Bloom et al., 1996, Proc. Natl. Acad. Sci. USA 93, 14188-14192; Smith et al., 2003, Cell. Mol. Physiol. 284, L279-L289; Smith et al., 2004, Mol. Pharmacol. 66, 1679-1689; Reyes-Irisarri et al., 2005, Neuroscience 132, 1173-1185; Pekkinen et al., 2008, Bone 43, 84-91; Fortin et al., 2009, Respir. Res. 10, 39-49; Goto et al., 2009, Int. Immunopharmacol. 9, 1347-1351; Dong et al., 2010, Biochem. Pharmacol. 79, 321-329; Goto et al., 2010, Eur. J. Pharmacol. 633, 93-97; Johansson et al., 2012, Neurosci. Lett. 525, 1-6; Fang et al., 2013, Leuk. Res. 37, 536-540; Brooks et al., 2014, PLoS One. 9, e107397; Dong et al., 2015, Breast Cancer Res. Treat. 152, 17-28; Yamamoto et al., 2015, International Journal of Oncology, 46, 325-334; Jankowska et al., 2017, Curr. Med. Chem. 24, 1-28.

[0454] In some embodiments, the peripheral disorder is an infectious disease and may include bacterial, fungal, protozoal, and viral infections.

[0455] In some embodiments, the peripheral disorder is cancer or a blood disorder, which may include anemia, myeloproliferative disorders, hemorrhagic disorders, leukopenia, eosinophilic disorders, leukemia, such as chronic lymphocytic leukemia (CLL), lymphoma, such as mantle cell lymphoma, plasma cell disorders, breast cancer, endometrial cancer, and glioblastoma.

[0456] In some embodiments, the peripheral disorder is a cardiovascular disease, which may include congestive heart failure, myocardial infarction, ischemic disease, atrial and ventricular arrhythmias, pulmonary hypertension, hypertensive vascular disease, and atherosclerosis. The peripheral disorder may also include disorders that may have a vascular component, such as migraine.

[0457] In some embodiments, the peripheral disorder is a gastrointestinal disorder, which may include diseases of the esophagus, stomach, duodenum, pancreas, intestine, and liver.

[0458] In some embodiments, the peripheral disorder is a skin disorder, which may include psoriasis, dermatitis, pustulosis, folliculitis, melanoma, and skin cancer.

[0459] In some embodiments, the peripheral disorder is a kidney disease, such as renal failure.

[0460] In some embodiments, the peripheral disorders include inflammatory and immune disorders (which may include autoimmune diseases and allergic diseases). Such immunological or inflammatory disorders include, but are not limited to

[0461] allergic rhinitis; atopic dermatitis (or eczema); dermatitis herpetiformis; celiac disease; skin disorders such as psoriasis; conjunctivitis; myalgic encephalomyelitis (ME); chronic fatigue syndrome (CFS); encephalomyelitis; systemic lupus erythematosus (SLE or lupus); inflammatory bowel disease (IBD); Crohn's disease; ulcerative colitis; arthritic diseases such as rheumatoid arthritis, osteoarthritis, and psoriatic arthritis; respiratory and pulmonary diseases such as bronchial asthma, chronic bronchitis, and chronic obstructive pulmonary disease (COPD); hepatitis; pancreatitis; sepsis; human immunodeficiency virus (HIV) infection; and acquired immunodeficiency syndrome (AIDS).

[0462] In other embodiments, the peripheral disorder is a fertility disorder (e.g., WO0183772) or a bone disorder, such as osteopenia, and more particularly osteoporosis ( et al., 2005, Cell. Mol. Biol. Lett. 10, 305 - 319).

[0463] In some embodiments, the peripheral disorder is associated with inflammation. Increased cAMP levels can promote inflammatory and immune processes, and PDE7 exhibits widespread expression, including in pro-inflammatory and immune cells, and is involved in the activation of T cell proliferation. See, e.g., Li et al., 1999, Science 283, 848-851; Lee et al., 2002, Cell Signal. 14, 277-284; Smith et al., 2003, Am. J. Physiol Lung Cell. Mol. Physiol. 284, L279–L289. Accordingly, the present disclosure provides methods of reducing inflammation, which include administering to an individual in need thereof an effective amount of a chemical entity or composition herein.

[0464] Therapeutic Combinations

[0465] The chemical entities and compositions of the present disclosure can be administered as monotherapy or as part of combination therapy. "Monotherapy" refers to a treatment regimen based on delivering at least a therapeutically effective chemical entity or a composition thereof.

[0466] In combination therapy, one or more chemical entities or compositions of the invention can be co-administered or used in combination with one or more additional agents (or therapies) known in the art. Such administration can be simultaneous, sequential, or staggered.

[0467] In some embodiments, the combination is administered as part of adjuvant (or additional) therapy, wherein in addition to the primary agent, an agent is given to assist or maximize the effectiveness of the primary agent.

[0468] In certain embodiments, the composition is administered to treat schizophrenia, Parkinson's disease, Alzheimer's disease, Huntington's disease, anxiety and depressive disorders, or stroke.

[0469] Exemplary agents for treating schizophrenia include, but are not limited to: clozapine, aripiprazole, brexpiprazole, cariprazine, lurasidone, paliperidone, quetiapine, risperidone, olanzapine, ziprasidone, and iloperidone.

[0470] Exemplary agents for treating Parkinson's disease include, but are not limited to, dopamine preparations, dopamine agonists, or COMT agents (drugs that inhibit catechol-O-methyltransferase activity).

[0471] Exemplary agents for treating Alzheimer's disease include, but are not limited to, donepezil, rivastigmine, galantamine, cannabinol-like cannabinoids, and memantine.

[0472] Exemplary agents for treating Huntington's disease (or other movement disorders) can include, but are not limited to, tetrabenazine and antipsychotics such as haloperidol, chlorpromazine, risperidone, and quetiapine, as well as antiepileptic drugs such as levetiracetam and clonazepam, which may be beneficial for treating chorea or related movement disorders.

[0473] Exemplary agents for treating anxiety or depression include, but are not limited to, benzodiazepines and other anxiolytics, serotonin reuptake inhibitors (SSRI) such as sertraline, fluoxetine, citalopram, escitalopram, paroxetine, fluvoxamine, and trazodone; serotonin and norepinephrine reuptake inhibitors (SNRIs) such as desvenlafaxine, duloxetine, levomilnacipran, and venlafaxine; tricyclic antidepressants (TCAs) such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine; monoamine oxidase inhibitors (MAOIs) such as isocarboxazid, phenelzine, selegiline, and tranylcypromine; and other classes of drugs such as maprotiline, bupropion, vilazodone, nefazodone, trazodone, vortioxetine, and mirtazapine.

[0474] Exemplary agents for treating stroke include, but are not limited to, thrombolytics (e.g., streptokinase, anisoylated plasminogen-streptokinase activator complex (APSAC), urokinase, single-chain urokinase-plasminogen activator (scu-PA), anti-inflammatory agents, thrombin-like enzymes, tissue plasminogen activator (t-PA); anticoagulants (such as warfarin or heparin); antiplatelet drugs (such as aspirin); glycoprotein IIb / IIIa inhibitors; glycosaminoglycans; coumarins; GCSF; melatonin; apoptosis inhibitors (such as caspase inhibitors), antioxidants (such as NXY-059); neuroprotective agents (such as NMDA receptor antagonists or cannabinoid antagonists).

[0475] The foregoing list of other active agents is meant to be exemplary and not entirely inclusive. Other active agents not included in the above list can be co-administered with the compounds of formula (I), such as those known for treating the peripheral conditions described herein. Additional active agents will be administered according to their approved prescription information, although in some embodiments, the additional active agents can be administered at a lower than usually prescribed dose. Examples

[0476] The present disclosure will be further illustrated by the following non-limiting examples. These examples are understood to be merely exemplary and they should not be construed as limiting the scope of one or more embodiments and the scope defined by the appended claims.

[0477] Preparation Examples

[0478] Exemplary compounds will now be described by reference to the exemplary synthetic schemes for their general preparation hereinafter and the specific examples hereinafter.

[0479] Those skilled in the art will recognize that, to obtain the numerous compounds herein, starting materials can be suitably selected to carry the ultimately desired substituents through reaction schemes (with or without protection as needed) to produce the desired products. Alternatively, at the position of the ultimately desired substituent, it may be necessary or desirable to employ a suitable group which can be carried through the reaction scheme and replaced by the desired substituent as needed. Unless otherwise indicated, variables are as defined above with reference to general formula (I). Reactions can be carried out between -100 °C and the reflux temperature of the solvent. Conventional heating or microwave heating can be used to heat the reactants. Reactions can also be carried out in a sealed pressure vessel above the normal reflux temperature of the solvent.

[0480] Abbreviations

[0481] This specification includes many abbreviations, the meanings of which are listed in the table below:

[0482] Table 1

[0483]

[0484]

[0485]

[0486] Synthesis Schemes

[0487] Scheme A

[0488]

[0489] The substituted 3-hydroxyphenylureas of general formula (III) can be prepared from the corresponding substituted 3-hydroxyphenylanilines and potassium cyanate under acidic conditions known to those skilled in the art. For example, at a temperature from room temperature to 60 °C (sometimes 40 °C), in a solvent such as water, the compound of general formula (II) wherein Y is -H, -F, -Cl, -Br or -C is treated with potassium cyanate in the presence of an acid such as acetic acid. 1-4An alkyl group provides a compound of general formula (III). Subsequently, under conditions known to those skilled in the art, heat treatment is carried out in the presence of Eaton's reagent using cyclohexanone, providing a hydroxy-1'H-spiro[cycloalkane-1,4'-quinazolin]-2'(3'H)-one of general formula (VIII). For example, treating a compound of general formula (III) with a substituted cyclohexanone and Eaton's reagent at a temperature of 40 °C to 100 °C provides a compound of general formula (VIII), where Y is -H, -F, -Cl, -Br or -C 1-4 alkyl group, and Z is -H, -F or -C 1-4 alkyl group, and m is 0, 1 or 2. Subsequently, nitration is carried out using methods known to those skilled in the art, providing a substituted nitrophenol of general formula (IX). For example, nitrating a compound of general formula (VIII) with nitric acid in the presence of an acid such as trifluoroacetic acid, sulfuric acid, etc., provides a compound of general formula (IX), where Y is -H, -F, -Cl, -Br or -C 1-4 alkyl group, and Z is -H, -F or -C 1-4 alkyl group, and m is 0, 1 or 2.

[0490] Alternatively, a similar synthetic route can be adopted starting from the methyl ether of general formula (V) to synthesize a compound of general formula (IX). The substituted 3-methoxyaniline of general formula (V) can be treated with potassium cyanate and acetic acid, and then heat treated with cyclohexanone under the above conditions in the presence of Eaton's reagent to obtain a tricyclic compound of general formula (VII), where Y is -H, -F, -Cl, -Br or -C 1-4 alkyl group, and Z is -H, -F or -C 1-4 alkyl group, and m is 0, 1 or 2. Next, deprotection of the methyl ether and nitration are carried out in either order to provide a nitrophenol of general formula (IX). In one embodiment, deprotection of the methyl ether is first carried out, and then nitration is carried out using nitric acid in the presence of another strong acid such as trifluoroacetic acid or sulfuric acid to provide a nitrophenol compound of general formula (IX). For example, treating a compound of general formula (VII) with HBr (48%) in a solvent (such as dichloromethane, etc.) in the presence of another acid (such as acetic acid) at a temperature close to or at reflux provides a hydroxy-1'H-spiro[cycloalkane-1,4'-quinazolin]-2'(3'H)-one of general formula (VIII). Alternatively, treating a compound of general formula (VII) with boron tribromide in a solvent such as dichloromethane, etc. also provides a hydroxy-1'H-spiro[cycloalkane-1,4'-quinazolin]-2'(3'H)-one of general formula (VIII), where Y is -H, -F, -Cl, -Br or -C 1-4 alkyl group, and Z is -H, -F or -C 1-4alkyl, and m is 0, 1 or 2. As described above, subsequent treatment with nitric acid provides a compound of formula (IX), where Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, and m is 0, 1 or 2. In another embodiment, nitration and subsequent cleavage of the methyl ether are achieved by treating the compound with nitric acid and then adding LiCl in a solvent (such as DMA, etc.) to provide a compound of formula (IX). For example, treating a compound of formula (VII) with nitric acid at a temperature of 0 °C to 10 °C for 1 hour, and then treating with LiCl in a solvent (such as DMA, etc.), heating to a temperature of 40 °C to 80 °C, desirably 70 °C, overnight, provides the nitrophenol of formula (IX).

[0491] Scheme B

[0492]

[0493] According to Scheme B, a compound of formula (XII) can be prepared from a compound of formula (IX) in three or four steps. Under various conditions known to those skilled in the art, reduction of the compound of formula (IX) provides 6'-amino-5'-hydroxy-1'H-spiro[cycloalkane-1,4'-quinazolin]-2'(3'H)-one of formula (X). For example, under acidic conditions, such as in the presence of an acid (such as ammonium chloride), using a reducing agent (such as zinc) in a solvent mixture (such as acetone and water) provides the aminophenol compound of formula (X). In addition, under acidic conditions, such as in the presence of acetic acid-like, using a reducing agent (such as Zn) in a solvent mixture (such as tetrahydrofuran and water or DMA and water, preferably DMA and water) provides the aminophenol compound of formula (X). Alternatively, in the presence of hydrogen, treating the compound of formula (IX) with a catalyst (such as platinum(IV) oxide, etc.) in a solvent (such as tetrahydrofuran, etc.) at room temperature, and then treating with sulfuric acid, gives the hemisulfate of the compound of formula (X), where Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, and m is 0, 1 or 2.

[0494] In the presence of an acid (such as acetic acid), the compound of general formula (X) is treated with methyl 2,2,2-trichloroacetimidate for several hours, and then potassium carbonate is added in a solvent (such as methanol), and the mixture is heated to a temperature of 40 °C to 60 °C (sometimes 50 °C) for several hours to obtain the ester of general formula (XI). Alternatively, in a solvent (such as ethanol), at a temperature of 60 °C to 80 °C, in the presence of an acid (such as p-toluenesulfonic acid), the compound of general formula (X) is treated with methyl 2,2,2-trimethoxyacetate to obtain the ester of general formula (XI). Under basic or acidic conditions, the ester is hydrolyzed to the carboxylic acid. For example, treating the ester of general formula (XI) with lithium hydroxide in a solvent mixture (such as tetrahydrofuran and water) for several hours, with or without heating, provides 2-carboxybenzoxazole of general formula (XII), where Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl and m is 0, 1 or 2.

[0495] Scheme C

[0496]

[0497] The compound of general formula (XIII) is prepared from the compound of general formula (IX) in two steps. Using one of several methods previously described in Scheme B, the nitrophenol of general formula (IX) is reduced to obtain the aminophenol of general formula (X). Then, at a temperature of 60 °C to 80 °C, in a solvent (such as ethanol), the aminophenol of general formula (X) is treated with a chloroacetimidate ester (such as ethyl 2-chloroacetimidate) to provide 2-(chloromethyl)benzoxazole of general formula (XIII), where Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, and m is 0, 1 or 2. Alternatively, at a temperature of 40 °C to 80 °C (sometimes 50 °C), the aminophenol of general formula (X) is treated with 2-chloro-1,1,1-trimethoxyethane in a solvent (such as DMSO, etc.) to provide 2-(chloromethyl)benzoxazole of general formula (XIII).

[0498] Scheme D

[0499]

[0500] According to Scheme D, the benzofuran-2-carboxylic acid compounds of general formula (XVI) can be synthesized from the phenols of general formula (VIII) in three steps. In the presence of an acid (such as TFA), at a temperature of 80 °C to 110 °C (sometimes 100 °C), the phenol of general formula (VIII) is treated with metheneamine, followed by the addition of HCl and water, and further heated at a temperature of 80 °C to 110 °C (sometimes 100 °C), providing the aldehyde of general formula (XIV). Under conditions known to those skilled in the art, in a solvent (such as DMF or DMA, etc.), at a temperature of 80 °C to 140 °C, sometimes 125 °C, in the presence of a base (such as K2CO3 or Cs2CO3, etc.), by further treating with ethyl bromoacetate, the ester of general formula (XV) is formed. In the presence of a base (such as NaOH or LiOH, etc.), in a solvent such as dioxane, at a temperature from room temperature to 60 °C, hydrolysis of the ester intermediate provides the carboxylic acid compound of general formula (XVI), where Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, and m is 0, 1 or 2.

[0501] Using methods known to those skilled in the art, 2-(chloromethyl)benzofuran of general formula (XVIII) is prepared from the ester compound of general formula (XV) in two steps. Under conditions known to those skilled in the art, for example, at a temperature of -78 °C to 0 °C (sometimes -78 °C), in a solvent (such as THF), using a reducing agent (such as LAH, DIBAL, NaBH4, etc.) to reduce the compound of general formula (XV), providing the hydroxymethyl compound of general formula (XVII). Under conditions known to those skilled in the art, for example, at 0 °C (with or without a solvent), using thionyl chloride, etc. for chlorination, and subsequent halogenation provides 2-(chloromethyl)benzofuran of general formula (XVIII), where Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, and m is 0, 1 or 2.

[0502] Scheme E

[0503]

[0504] In the presence of an amine or an alcohol, under conditions known to those skilled in the art, the nucleophilic substitution reaction of the compound of general formula (XIX) provides a 2-substituted methylamine compound of general formula (XX) or a substituted ether compound of general formula (XXI), respectively. For example, at a temperature from room temperature to 40 °C, treating 2-(chloromethyl)benzoxazole of general formula (XIX) with an amine in a solvent such as dichloromethane provides a 2-substituted methylamine compound of general formula (XX), where X is -C or -N, Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, m is 0, 1 or 2 and R 1 and R 2 independently are -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkyl OH, -C 1-6 haloalkyl -C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c or -(CH2) n -R d , or R 1 and R 2 together form a monocyclic, bicyclic or tricyclic ring; n is 0, 1, 2 or 3; R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6 haloalkyl, -O phenyl, -O pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3; and R d is -C 3-7Cycloalkyl, -C 3-7 Halocycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0505] Alternatively, in a solvent (such as DMSO, etc.), at a temperature of 60 °C to 110 °C (sometimes 90 °C), in the presence of a base (such as DIEA, etc.), treating a compound of general formula (XIX) with an amine for several hours provides a 2-substituted methylamine compound of general formula (XX). In addition, in the presence of a base such as K3PO4, etc., treating with an amine or a hydrochloride salt of an amine in a solvent (such as DMA or DMF, etc.) at a temperature of 50 °C to 120 °C (sometimes 80 °C) for several hours also provides a compound of general formula (XX). In another embodiment, in a solvent (such as DMF or DMA), at a temperature from room temperature to 80 °C, in the presence of a base (such as potassium tert-butoxide, etc.), treating 2-(chloromethyl)benzoxazole of general formula (XIX) with an alcohol provides a compound of general formula (XXI), where X is -C or -N, Y is -H, -F, -Cl, -Br or -C 1-4 Alkyl, Z is -H, -F or -C 1-4 Alkyl, R 3 Is -H, -C 1-6 Alkyl, -CH2CH2OCH3, -CH2C(O)N(CH3)2, tetrahydropyranyl or piperidinyl and m is 0, 1 or 2.

[0506] Similarly, under conditions known to those skilled in the art, in the presence of a diester (such as diethyl malonate), the nucleophilic substitution reaction of a compound of general formula (XIX) provides an analogue of general formula (XXII). For example, in the presence of an acid (such as p-toluenesulfonic acid), treating a compound of general formula (XIX) with diethyl malonate at a temperature of 80 °C to 140 °C (sometimes 120 °C) provides an ethyl ester of general formula (XXII), where X is -C or -N, Y is -H, -F, -Cl, -Br or -C 1-4 Alkyl, Z is -H, -F or -C 1-4 Alkyl and m is 0, 1 or 2.

[0507] Scheme F

[0508]

[0509] Using conditions known to those skilled in the art, in the presence of a base, treating a carboxylic acid of general formula (XXIII) with an amine in an amide coupling reaction provides an amide of general formula (XXIV). For example, in the presence of a base such as N,N-diisopropylethylamine, etc., in a solvent such as DMF or DMA, treating a compound of general formula (XXIII) with an amine and a coupling agent (such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, etc.) provides an analogue of general formula (XXIV), where X is -C or -N, Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, m is 0, 1 or 2 and R 4 and R 5 are independently -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C(CH3)3, -CH2C(O)C 1-6 alkyl, -CH2C(O)heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2OH, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CF2C 3-7 cycloalkyl, -CH2CH2-R c or -(CH2) n -R d , or R 4 and R 5 together form a monocyclic, bicyclic or tricyclic ring; n is 0, 1, 2 or 3; R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -OH, -O-C 1-6 alkyl, -OC(CH3)2, -O-C 1-6haloalkyl, -O-phenyl, -O-pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3; R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0510] Alternatively, under conditions known to those skilled in the art, the carboxylic acid compound of formula (XXIII) is converted to an acyl chloride and then treated with an amine to provide the amide of formula (XXIV). For example, treatment of the compound of formula (XXIII) with a chlorinating reagent (such as thionyl chloride or oxalyl chloride, etc.) neat or in a solvent (such as dichloromethane, etc.) provides an acyl chloride intermediate. Subsequently, addition of an amine in a solvent (such as DMF or DMA, etc.) in the presence of a base (such as DIEA, etc.) provides the amide of formula (XXIV).

[0511] Scheme G

[0512]

[0513] According to Scheme G, various benzoxazoles having different substitutions at the 2-position of benzoxazole can be synthesized from the aminophenol compound of formula (X). In one embodiment, a compound of formula (XXV), wherein R 6 is -H, -C 1-6 alkyl, -C 3-7 cycloalkyl or -C 1-6 alkyl-O-C 1-6 alkyl, all being optionally substituted, can be synthesized by treating the compound of formula (X) with the corresponding trimethoxyalkane. For example, in the presence of an acid (such as p-toluenesulfonic acid), with or without a solvent (such as THF, etc.), treating the compound of formula (X) with 1,1,1-trimethoxypropane at a temperature from rt to 100 °C provides the compound of formula (XXV), wherein R 6 is -ethyl, Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, and m is 0, 1 or 2. In a similar manner, at rt, in the presence of an acid (such as p-toluenesulfonic acid), with or without a solvent, treating the compound of formula (X) with 1,1,1-triethoxy-3-methoxypropane provides the compound of formula (XXV), wherein R 6 is -CH2CH2OCH3, Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4An alkyl group, and m is 0, 1 or 2. Other analogs of general formula (XXV), wherein R 6 is -H, -alkyl, -C 3-7 cycloalkyl or -C 1-6 alkyl-O-C 1-6 alkyl, can be synthesized in a similar manner by substituting appropriate starting materials.

[0514] In another embodiment, the ether of general formula (XXVI) is prepared in one step from the compound of general formula (X). At a temperature of 80 °C to 120 °C (sometimes 110 °C), the aminophenol compound of general formula (X) is treated with ethyl 2-alkoxyacetimidate in a solvent (such as ethanol), providing an analog of general formula (XXVI), wherein R 7 is -alkyl or -C 3-7 cycloalkyl, Y is -H, -Cl, -Br or -CH3, Z is -H, -F or -CH3, and m is 0, 1 or 2. For example, treating aminophenol with ethyl 2-methoxyacetimidate in ethanol gives an analog of general formula (XXVI), wherein R 7 is methyl. In addition, cleavage of the methyl ether of general formula (XXVI) provides methanol of general formula (XXVII). For example, treating the methyl ether compound of general formula (XXVI) with boron tribromide can provide the alcohol of general formula (XXVII), wherein Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, and m is 0, 1 or 2.

[0515] Using conditions known to those skilled in the art, the 2-aminobenzoxazole compound of general formula (XXVIII) can be synthesized from an aminophenol compound. Treating the aminophenol compound of general formula (X) with (1H-imidazol-1-yl)(1H-pyrazol-1-yl)methanamine provides the aminobenzoxazole of general formula (XXVIII), wherein Y is -H, -Cl, -Br or -CH3, Z is -H, -F or -CH3, and m is 0, 1 or 2. Acylation of the aminobenzoxazole analog can be accomplished by reacting with an acid anhydride, carboxylic acid or acyl chloride using conditions known to those skilled in the art. For example, treating the aminobenzoxazole compound of general formula (XXVIII) with acetic anhydride in a solvent (such as dichloromethane, etc.) in the presence of a base such as trimethylamine at a temperature from room temperature to 80 °C, preferably 80 °C, provides the compound of general formula (XXIX), wherein R 8 is methyl, Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl and m is 0, 1 or 2. Other analogs of general formula (XXIX) can be synthesized by substituting appropriate starting materials, wherein R 8 is -C1-6 alkyl or -C 3-8 cycloalkyl group. Similarly, under conditions known to those skilled in the art, in the presence of a coupling agent (such as HATU, etc.) and a base (such as DIEA, etc.), in a suitable solvent (such as DMF or DMA), treating the compound of general formula (XXVIII) with a carboxylic acid also provides the compound of general formula (XXIX). In addition, under conditions known to those skilled in the art, in the presence of a base, in a solvent (such as DCM), treating the aminobenzoxazole of general formula (XXVIII) with an acyl chloride also provides the compound of general formula (XXIX).

[0516] In addition, the aminobenzoxazole compound of general formula (XXVIII) can be alkylated using conditions known to those skilled in the art. Under basic conditions, at a temperature from room temperature to 100 °C (sometimes 60 °C), treatment with an alkyl halide (such as alkyl bromide or alkyl chloride) in a solvent (such as DMF, DMA, etc.) provides a monoalkylated or dialkylated compound. For example, at 100 °C, in DMF, in the presence of a base such as cesium carbonate, potassium carbonate, etc., treatment with alkyl bromide provides the compound of general formula (XXX), where R 9 is independently -H, -C 1-6 alkyl, -C 3-7 cycloalkyl group or -C 1-6 alkyl - O - C 1-6 alkyl, Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, and m is 0, 1 or 2.

[0517] Scheme H

[0518]

[0519] According to Scheme H, the compound of general formula (XIV) can be converted into 2 - substituted benzofuran of general formula (XXXI) by O - alkylation followed by cyclization to form a furan ring, where R 10 is an aryl or heteroaryl ring. Under conditions known to those skilled in the art, in a solvent (such as DMF or DMA, etc.), at a temperature from 80 °C to 150 °C (sometimes 135 °C), in the presence of a base (such as K2CO3 or Cs2CO3, etc.), treating the aldehyde of general formula (XIV) with a substituted bromoacetate for several hours provides the benzofuran of general formula (XXXI), where R 10 is an aryl or heteroaryl ring, Y is -H, -F, -Cl, -Br or -C 1-4 alkyl, Z is -H, -F or -C 1-4 alkyl, and m is 0, 1 or 2.

[0520] Examples

[0521] Chemistry:

[0522] Unless otherwise specified, the following experimental and analytical protocols were followed in obtaining the compounds and the corresponding analytical data described in the examples below.

[0523] Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. If a solution was "dry", it was typically dried over a drying agent (e.g., Na2SO4 or MgSO4). If a mixture, solution, and extract were "concentrated", they were typically concentrated under reduced pressure on a rotary evaporator.

[0524] Reactions under microwave irradiation conditions were carried out in a CEM Discover-SP equipped with an Activent microwave reaction device model 909150 or a Biotage initiator model 355302.

[0525] Normal-phase flash column chromatography (FCC) was performed on silica (SiO2) using a packed or pre-packed column, eluting with the specified solvent.

[0526] Mass spectra (m / z) were recorded using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). On a Waters 2695 separation unit, 2487 dual absorbance detector, Micromass ZQ equipped with an ESI probe, or a Waters Acquity with PDA eλ and SQ detectors TM LC / MS was obtained on a Waters Acquity ultra-performance LC (UPLC).

[0527] Analytical LC-MS was performed on a Waters Acquity UPLC-MS instrument equipped with an Acquity UPLC BEH C18 column (1.7 μm, 2.1×50 mm), solvent system A: H2O solution of 0.1% HCOOH and solvent system B: ACN solution of 0.1% HCOOH. The column temperature was 45 °C. All compounds were run using the same elution gradient, i.e., 5% to 95% of solvent B in 0.75 minutes at a flow rate of 1 mL / min.

[0528] On a Waters UPC 2 -MS instrument, analytical SFC-MS was performed, which was equipped with an Acquity UPC 2BEH 2-Ethylpyridine column (1.7 μm, 2.1 × 50 mm), solvent system A: CO2 and solvent system B: MeOH solution of 0.1% NH4OH. The column temperature was 55 °C. All compounds were run using the same elution gradient, i.e., 3% to 35% of solvent B in 0.75 min at a flow rate of 2.5 mL / min.

[0529] Preparative HPLC was carried out on a Shimadzu SIL-10AP system using Waters SunFire TM OBD (5 μm, 30 × 100 mm) C18 column, 15-minute gradient of 10 - 100% aqueous acetonitrile, and 0.05% trifluoroacetic acid was added as a modifier to both phases. The elution curve was monitored by UV at 254 nm and 220 nm.

[0530] Some compounds were purified using a Waters Fractionlynx system equipped with an XBridge PrepC18 OBD column (5 μm, 19 × 50 mm), solvent system: H2O: AcCN and H2O solution of 2% TFA. The specific elution gradient was based on the retention time obtained using analytical UPLC-MS. However, generally, all elution gradients of H2O and ACN were run at a flow rate of 40 mL / min over a run time of 5.9 min. An automated mixing method was used to ensure a concentration of 0.1% TFA throughout each run.

[0531] Some compounds were purified using a Waters Fractionlynx system equipped with an XBridge PrepC18 OBD column (5 μm, 30 × 100 mm), solvent system: H2O: AcCN and H2O solution of 2% TFA. The specific elution gradient was based on the retention time obtained using analytical UPLC-MS. However, generally, all elution gradients of H2O and ACN were run at a flow rate of 60 mL / min over a run time of 9 min. An automated mixing method was used to ensure a concentration of 0.1% TFA throughout each run.

[0532] Preparative SFC-MS was carried out using a Waters Prep100 SFC-MS system equipped with a Viridis 2-Ethylpyridine OBD column (5 μm, 30 × 100 mm), solvent system: CO2: MeOH and MeOH solution of 0.2% NH4OH as a co-solvent. The specific elution gradient was based on using analytical UPC 2The retention times obtained by MS, however, were generally for all elution gradients of CO2 and MeOH at a flow rate of 100 mL / min over a run time of 3.6 minutes with a column temperature of 55 °C. An automated mixing method was used to ensure a concentration of 0.2% NH4OH throughout each run.

[0533] Nuclear magnetic resonance (NMR) spectra were obtained on a Varian 400 MHz or Bruker 400 MHz NMR. Samples were analyzed in tritiated acetone ((CD3)2CO), chloroform (CDCl3), methanol-d4 (CD3OD), or dimethyl sulfoxide-d6 (DMSO-d6). For CDCl3 samples, the 1 residual central resonance peak at 7.26 for 1 H was used for 1 chemical shift assignment of the 1H NMR spectra. For CD3OD, the 1 residual central resonance peak at 3.31 for 1 H was used for chemical shift assignment, and for DMSO-d6, the

[0534] residual central resonance peak at 2.50 ppm for

[0535] Intermediate 1. 8'-Chloro-5'-hydroxy-6'-nitro-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one.

[0536]

[0537] Step 1. (2-Chloro-5-methoxyphenyl)urea. At 30 °C, a solution of potassium cyanate (124 g, 1.52 mol) in water (850 mL) was added to a solution of 2-chloro-5-methoxyaniline (200 g, 1.27 mol) in water (100 mL) and AcOH (800 mL) over 2 h. The reaction mixture was stirred at 40 °C for 1 h and then cooled to rt. The suspension was filtered using a medium frit and washed with water. The resulting solid was dried in a vacuum oven at 60 °C for 48 h to afford the title compound as a solid (240 g, 95%).1 1H NMR (400 MHz, DMSO) δ 8.00 (s, 1H), 7.85 (d, J = 3.0 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.54 (dd, J = 8.8, 3.0 Hz, 1H), 6.42 (s, 2H), 3.71 (s, 3H). [M+H] = 201.1.

[0538] Step 2. 8-Chloro-5-methoxy-spiro[1,3-dihydroquinazolin-4,1'-cyclohexane]-2-one. A solution of (2-chloro-5-methoxyphenyl)urea (155 g, 125 mmol) in Eaton's reagent (2.0 L; methanesulfonic acid solution with 7% w / w P2O5) was heated at 60 °C. Cyclohexanone (160 mL, 155 mmol) was added dropwise over 1 h, and the reaction mixture was heated to 80 °C for 2 h. The solution was then cooled to rt and the mixture was added dropwise to cold water (2.0 L) over 2 h. The suspension was filtered and the aqueous layer was extracted with DCM (2 × 1.0 L). The solid was dissolved in DCM (1.0 L), the combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure. 2-Propanol (1.5 L) was added to the material and the suspension was stirred at 0 °C for 2 h. The resulting solid was collected by filtration, washed with cold 2-propanol (2 × 150 mL) and then dried in a vacuum oven at 50 °C for 18 h to give the title compound as a solid (158 g, 73%). 1 1H NMR (400 MHz, DMSO) δ 7.96 (d, J = 1.0 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.02 (s, 1H), 6.66 (d, J = 9.0 Hz, 1H), 3.80 (s, 3H), 2.42 (td, J = 13.5, 4.5 Hz, 2H), 1.80 (qt, J = 13.6, 3.4 Hz, 2H), 1.60 (t, J = 15.8 Hz, 3H), 1.47 (d, J = 13.5 Hz, 2H), 1.19 (qt, J = 13.1, 3.6 Hz, 1H). [M+H] = 281.2.

[0539] Step 3. 8-Chloro-5-hydroxy-spiro[1,3-dihydroquinazolin-4,1'-cyclohexane]-2-one. At room temperature, 8-chloro-5-methoxy-spiro[1,3-dihydroquinazolin-4,1'-cyclohexane]-2-one (153 g, 545 mmol) was added to a mixture of hydrobromic acid (48%, 1.2 L) and glacial acetic acid (1.5 L). The reaction mixture was heated to reflux and stirred for 94 h. The reaction mixture was cooled to 100 °C, and water (1.2 L) was added dropwise over 2 h. The stirred reaction mixture was cooled in a cold water bath and then in an ice bath to ~5 °C. The resulting solid was filtered, washed with cold water (2 × 200 mL), air-dried for 2 h (~149 g), and then dried in a vacuum oven at 40 °C for 18 h to give the acetic acid solvate (~130 g). Acetone (320 mL) was added to this material, and the suspension was stirred for 5 h (magnetic stirrer). The solid was filtered, washed with cold acetone (120 mL), and then dried in a vacuum oven at 60 °C for 18 h to give the title compound (105 g, 72%). 1 H NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 7.77 (s, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.96 (s, 1H), 6.43 (d, J = 8.8 Hz, 1H), 2.60–2.51 (m, 2H), 1.84–1.71 (m, 2H), 1.60 (d, J = 12.8 Hz, 1H), 1.54 (d, J = 12.6 Hz, 2H), 1.46 (d, J = 13.6 Hz, 2H), 1.23–1.11 (m, 1H). [M+H] = 267.1.

[0540] Step 4. 8'-Chloro-5'-hydroxy-6'-nitro-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. At 0 °C, nitric acid (70%, 9.23 mL, 155 mmol) was added dropwise to a suspension of 8-chloro-5-hydroxyspiro[benzo[d][1,3]oxazin-4,1'-cyclohexane]-2(1H)-one (32.0 g, 119 mmol) in TFA (350 mL) over 60 min. During the addition, the temperature was maintained between 0 °C and 4 °C. The mixture was warmed to 10 °C over 30 min and then cooled to 0 °C. The mixture was slowly poured into ice water (2000 mL), and the suspension was filtered. The solid was washed with water and dried in a vacuum oven at 50 °C for 48 h to give the title compound (33.2 g, 88%). 11H NMR (400 MHz, CDCl3) δ 11.75 (s, 1H), 8.19 (s, 1H), 7.59 (br, 1H), 2.52 (td, J = 13.9, 4.7 Hz, 2H), 2.06–1.99 (m, 2H), 1.99–1.87 (m, 2H), 1.85–1.77 (m, 1H), 1.71–1.61 (m, 2H), 1.38 (tdd, J = 16.9, 10.3, 6.6 Hz, 1H). [M + H2O] = 330.1.

[0541] Alternative route:

[0542] Step 1. 1-(2-Chloro-5-methoxyphenyl)urea. Under nitrogen, deionized water (7 L, 7V), 2-chloro-5-methoxyaniline hydrochloride (1000 g, 5.15 mol), and acetic acid (4 L, 4V) were added to a dry 20 L glass container. The mixture was warmed to 30 °C until the starting materials were completely dissolved. A solution of potassium cyanate (627 g, 7.73 mol) in water (2 L, 2V) was slowly added dropwise to the container over 2 h at a rate sufficient to keep the reaction temperature below 35 °C. After addition, the internal temperature slowly rose to 38 - 40 °C, and then the resulting mixture was heated at 40 °C for 1 h. HPLC analysis showed about 2.4% of the starting material remaining. The reaction mixture was slowly cooled to below 20 °C, stirred for an additional 1 h, and then the resulting solid was collected by filtration and dried in vacuo at 55 °C over the weekend. The title compound was obtained as a white solid powder (943 g, 91%). 1 1H NMR (400 MHz, DMSO) δ 8.00 (s, 1H), 7.85 (d, J = 3.0 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.54 (dd, J = 8.8, 3.0 Hz, 1H), 6.42 (s, 2H), 3.71 (s, 3H). [M + H] = 201.1.

[0543] Step 2. 8'-Chloro-5'-methoxy-6'-nitro-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. 1-(2-Chloro-5-methoxyphenyl)urea (943 g) was placed in Eaton's reagent (12.7 L, 7.00% w / w) and heated to an internal temperature of 70 °C within 1 hour. Then cyclohexanone (691 g, 7.04 mol) was added dropwise via a dropping funnel over ~1 hour while maintaining the internal temperature at 68 - 72 °C, and then the reaction was heated at 70 °C overnight. HPLC analysis showed complete conversion to the unseparated intermediate 8'-chloro-5'-methoxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. The reaction was cooled to 0 - 5 °C within 1.5 hours. Then nitric acid (1013.2 g, 16.08 mol) was placed in an addition funnel and carefully added dropwise while maintaining the internal temperature below 10 °C. The reaction mixture was allowed to slowly warm to 20 °C naturally and stirred overnight. HPLC analysis showed complete conversion to the title compound. Then deionized water (17 L) was added dropwise via a dropping funnel and the internal temperature was maintained at 20 °C and stirred overnight. The product was separated by filtration, the solid was added to the reactor and reslurried in water (10V) for 3 hours. The reaction mixture was filtered and the resulting solid collected by filtration was dried in vacuo at 45 °C over the weekend to give the title compound as a brown powder (1654 g). 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.12 - 7.99 (m, 1H), 7.30 (s, 1H), 3.76 (s, 3H), 2.28 - 2.16 (m, 2H), 1.88 - 1.75 (m, 4H), 1.65 (d, J = 12.0 Hz, 1H), 1.52 (d, J = 13.7 Hz, 2H), 1.30 - 1.17 (m, 1H). [M+H] = 326.2.

[0544] Step 3. 8'-Chloro-5'-hydroxy-6'-nitro-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. Under nitrogen, dimethylacetamide (7.5 L, 4.5 V) and 8'-chloro-5'-methoxy-6'-nitro-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (1654 g, 5.07 mol) were added to a dry 30 L glass vessel, and then lithium chloride (646 g, 15.23 mol) was added. The reaction mixture was heated to an internal temperature of 70 °C within 1 hour and then stirred overnight at this temperature. The completion of the reaction was determined by HPLC, and it was cooled to 25 °C, filtered, and then water (13 L, 8 V) was added dropwise using a dropping funnel while maintaining the internal temperature at 10 °C. After the addition was complete, the reaction was stirred overnight. Brine (1.5 L) was added to the reaction mixture with stirring to assist in the precipitation of the product, and the mixture was stirred overnight at 10 °C. The reaction mixture was filtered, washed with water, and then the solid was directly added back to the reactor and repulped in ethanol (1 V) and acetic acid (2 V) for 1 hour at 20 °C. The suspension was filtered and washed with ethanol to obtain a yellow solid, which was dried overnight in a vacuum oven at 50 °C to give 1280 g of the product (80% yield, 94.0% purity by UPLC). The solid was crushed into a powder and repulped in ethanol (3 V) for 8 hours at 20 °C. The mixture was filtered, washed with ethanol, and a brown solid was obtained, which was dried in vacuo overnight (8 - 10 h) at 50 °C to give the title compound as a pale yellow - brown powder (1060 g). 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (br s, 1H), 11.47 (br s, 1H), 8.96 (s, 1H), 8.11 (s, 1H), 7.44 (s, 1H), 2.60 (dt, J = 4.5, 13.5 Hz, 2H), 1.90 - 1.78 (m, 2H), 1.66 (d, J = 12.2 Hz, 3H), 1.50 (d, J = 13.4 Hz, 2H), 1.27 - 1.15 (m, 1H). [M + H] = 312.2.

[0545] Intermediate 2. 6'-Amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one.

[0546]

[0547] 6'-Amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. Zinc powder (36.6 g, 0.560 mol) was added to a suspension of 8-chloro-5-hydroxy-6-nitrospiro[benzo[d][1,3]oxazine-4,1'-cyclohexane]-2(1H)-one (35.0 g, 0.112 mol) and NH4Cl (59.9 g, 1.10 mol) in acetone (1.0 L) and water (222 mL) over 30 minutes while maintaining the internal temperature between 20 °C and 25 °C using an ice-water bath. The suspension was stirred at rt for 10 minutes and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to ~250 mL and EtOAc (500 mL) was added to the residue. The layers were separated and the aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (18.3 g, 58%). 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 6.66 (s, 1H), 5.92 (br, 2H), 2.42 (td, J = 13.8, 4.6 Hz, 2H), 1.82 (d, J = 13.5 Hz, 2H), 1.76–1.64 (m, 4H), 1.59–1.51 (m, 2H), 1.33–1.21 (m, 1H). [M+H] = 283.2.

[0548] Alternative route:

[0549] 6'-Amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one hemisulfate. In a 2-L three-necked round-bottom flask equipped with a stir bar, J-KEM internal temperature probe, N2 inlet, and septum, 8'-chloro-5'-hydroxy-6'-nitro-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'-one (40 g, 128 mmol) was placed in tetrahydrofuran (1.20 L) and water (20 mL), then platinum(IV) oxide (583 mg, 2.57 mmol) was added, and the vessel was evacuated and backfilled with N2 (×3). Then the reaction was charged with a hydrogen balloon (1 atm) and stirred vigorously at rt. The reaction was a yellow-brown suspension that slowly turned into a dark green thin suspension solution. After adding H2, the temperature only increased slightly because the internal temperature remained <20 °C. After stirring overnight, LCMS analysis showed ~80% conversion to the desired product (UV 254 nm). The reaction vessel was evacuated and refilled with a new H2 balloon, then stirred. After 5 h, LCMS analysis showed ~90% conversion. Another H2 balloon was added, and the reaction was stirred at rt overnight. Then, the amber suspension was analyzed by LCMS, showing >98% conversion (UV + ELSD) to the desired product. Then the reaction mixture was diluted with DMSO (200 mL), filtered through a tightly packed Celite pad, and rinsed with EtOH (7.5 V, 300 mL). The deep purple filtrate was transferred to a 3-L round-bottom flask under N2, rinsed with EtOH, and sulfuric acid (7.52 mL, 141 mmol) was added. Within a few minutes, a light-colored solid formed. Another portion of EtOH (2.5 V, 100 mL) was added, and the suspension was stirred rapidly at rt for several hours, then cooled in an ice-water bath. The solid was collected by filtration, washed with ethanol (2 × 400 mL), to give a white solid. The solid was dried overnight in a vacuum oven (35 °C) to give the hemisulfate of the title compound as an off-white powder (34.1 g, 78%). 1 H NMR (400 MHz, DMSO-d6) 7.82 (s, 1H), 6.93 (s, 1H), 6.87 (s, 1H), 2.61 - 2.53 (m, 3H), 1.79 (q, J = 13.6 Hz, 2H), 1.67 - 1.54 (m, 3H), 1.48 (d, J = 13.0 Hz, 2H), 1.21 (q, J = 13.1 Hz, 1H). [M + H] = 282.3.

[0550] Intermediate 3. Methyl 5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinaz olin]-2'-carboxylate.

[0551]

[0552] Under rt, methyl 2,2,2-trichloroacetimidate (5.06 mL, 40.9 mmol) was added dropwise to a solution of 6-amino-8-chloro-5-hydroxyspiro[benzo[d][1,3]oxazine-4,1'-cyclohexane]-2(1H)-one (Intermediate 1, 11.0 g, 38.9 mmol) in AcOH (800 mL). The reaction mixture was stirred for 2 h and then water (1.0 L) was added. The resulting solid was filtered, washed with water (400 mL) and dried under reduced pressure. This material was taken in MeOH (1.1 L) and K2CO3 (6.45 g, 46.7 mmol) was added at rt. The mixture was heated to 52 °C, stirred for 2 h and then cooled to rt. The solvent was concentrated to ~300 mL under reduced pressure. Water (700 mL) was added and the aqueous layer was extracted with DCM (3 × 400 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography (silica gel, 100% DCM (2% AcOH) to DCM solution (2% AcOH) of 7% EtOAc). Then the organic solvent containing the product was triturated in a mixture of ether / hexane (100 mL / 600 mL), the resulting solid was filtered, washed with hexane and dried under reduced pressure to give the title compound (Intermediate 3 and Example 1, 2.70 g, 20%). 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.61 (br, 1H), 4.10 (s, 3H), 2.23 (dd, J = 9.2, 3.6 Hz, 3H), 2.03–1.93 (m, 2H), 1.89–1.82 (m, 1H), 1.77–1.70 (m, 2H), 1.51–1.41 (m, 2H). [M+H] = 351.2.

[0553] Intermediate 4. 5'-Chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinaz olin]-2'-carboxylic acid.

[0554]

[0555] To a mixture of methyl 5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]-2'-carboxylate (Intermediate 3, 2.43 g, 6.93 mmol) in THF (71 mL) and water (18 mL) was added LiOH (581 mg, 6.93 mmol). The mixture was stirred at rt for 15 min and then cooled to 0 °C. Water (500 mL) was added and the pH was adjusted to ~3 by addition of concentrated HCl. The resulting suspension was filtered, washed with water (500 mL) and dried under reduced pressure to give the title compound as a solid (Intermediate 4 and Example 2, 1.80 g, collected at 75% purity, 58% yield) 11H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.08 (s, 1H), 2.19 - 2.09 (m, 4H), 1.81 - 1.63 (m, 5H), 1.41–1.33 (m, 1H).

[0556] Intermediate 5. 5'-Chloro-2'-(chloromethyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7' (8'H)-one.

[0557]

[0558] A solution of 6'-amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 1, 2.07 g, 7.35 mmol) and ethyl 2-chloroethanecarboximidate (1.39 g, 8.82 mmol) in ethanol (20.7 mL) was stirred at 80 °C for 1 h and then cooled to room temperature. The reaction mixture was diluted with i-PrOH / DCM (1:3), washed with water and brine, and then concentrated to give the title compound as a dark brown solid (2.32 g, 92.8%). 1 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.39 (m, 1H), 7.84 (s, 1H), 7.47 - 7.38 (m, 1H), 5.07 (s, 2H), 2.25 - 2.10 (m, 2H), 1.88 (br s, 4H), 1.78 - 1.67 (m, 1H), 1.63 - 1.51 (m, 2H), 1.40 - 1.17 (m, 1H). [M+H]=340.1.

[0559] Intermediate 6. 6'-Amino-8'-fluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one.

[0560]

[0561] Step 1. 1-(2-Fluoro-5-methoxyphenyl)urea. 2-Fluoro-5-methoxyaniline (2.32 g, 16.4 mmol) was dissolved in acetic acid (11.6 mL) and water (1.16 mL), and then a solution of potassium cyanate (1.33 g, 16.4 mmol) in water (1 mL) was added dropwise, and the mixture was stirred at rt for 3 h. The reaction mixture was filtered, and the filter cake was washed with water and ether and dried in vacuo to give the title compound as an off-white solid.

[0562] [M+H]=185.1.

[0563] Step 2. 8'-Fluoro-5'-methoxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. 1-(2-Fluoro-5-methoxyphenyl)urea (520 mg, 2.82 mmol) was added to Eaton's reagent (11.2 mL, 7.70% w / w, 5.36 mmol), heated to 60 °C, then cyclohexanone (585 μL, 5.65 mmol) was slowly added. The mixture was warmed to 80 °C with stirring and then held at 80 °C for 2 h. The reaction mixture was then cooled to 0 °C, ice-cold water was added, and the mixture was extracted with DCM. The combined organics were concentrated to give the crude product as a brown solid. [M+H] = 265.0.

[0564] Step 3. 8'-Fluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. Hydrogen bromide (48%, 0.90 mL) was slowly added to a suspension of 8'-fluoro-5'-methoxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (650 mg, 2.46 mmol) in acetic acid (1.50 mL). The mixture was stirred at reflux (∼145 °C) for 4 days. The reaction was cooled to 100 °C and H2O was slowly added. The mixture was cooled to rt and then to 0 °C in an ice bath. Vacuum filtration afforded the title compound as a grey powder, washed with H2O and then dried under vacuum overnight [M+H] = 251.0.

[0565] Step 4. 8'-Fluoro-5'-hydroxy-6'-nitro-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. At 0 °C, nitric acid (180 μL, 4.05 mmol) was added dropwise to a solution of 8'-fluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (450 mg, 1.80 mmol) in sulfuric acid (1.80 mL). After addition, the reaction was warmed to rt and stirred for 1 h, then LCMS indicated that the reaction was complete. Ice was added to the reaction mixture. After the ice had melted, EtOAc was added, the solid was collected by filtration and washed with EtOAc (249 mg). The filtrate was transferred to a separatory funnel, separated into two layers, and the aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over MgSO4, concentrated, and purified by flash chromatography (0% to 50% EtOAc / heptane) to give the title compound as a yellow solid, which was combined with the previously isolated solid (354 mg, 66.7%). [M+H] = 296.0.

[0566] Step 5. 6'-Amino-8'-fluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. 8'-Fluoro-5'-hydroxy-6'-nitro-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (249 mg, 0.84 mmol) was suspended in a mixture of tetrahydrofuran (3.49 mL), water (0.35 mL) and acetic acid (1.49 mL). The solution was cooled to 0 °C and then zinc (221 mg, 3.37 mmol) was added. After addition, the reaction mixture was warmed to room temperature and stirred for 2 h, at which point LC / MS analysis showed that the reaction was complete. The mixture was filtered and the separated solid was washed with EtOAc. The filtrate was transferred to a separatory funnel, extracted with EtOAc, and then the organic layer was washed with water and brine, dried over MgSO4 and concentrated to give the title compound as a dark brown solid, which was combined with the previously separated solid. [M+H] = 266.0.

[0567] Intermediate 7. 2'-(Chloromethyl)-5'-fluoro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7' (8'H)-one.

[0568]

[0569] A solution of 6'-amino-8'-fluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 5, 150 mg, 0.57 mmol) and ethyl 2-chloroacetimidate (107 mg, 0.68 mmol) in ethanol (1.50 mL) was stirred at 80 °C for 1 h and then cooled to room temperature. The solvent was evaporated to give the title compound as a dark brown solid. The crude product was used in the subsequent reaction without further purification.

[0570] [M+H] = 324.0

[0571] Intermediate 8. 2'-(Chloromethyl)-5'-fluoro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7' (8'H)-one.

[0572]

[0573] Intermediate 8 was synthesized in a manner similar to Intermediate 5 using appropriate starting material substitutions.

[0574] [M+H] = 324.0.

[0575] Intermediate 9. 6'-Amino-8'-chloro-4,4-difluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2' (3'H)-one.

[0576]

[0577] Step 1. 1-(2-Chloro-5-hydroxyphenyl)urea. 3-Amino-4-chlorophenol (10.0 g, 69.7 mmol) was dissolved in acetic acid (40.0 mL) and water (10.0 mL), and a solution of potassium cyanate (6.78 g, 83.6 mmol) in water (40.0 mL) was added dropwise. The mixture was stirred at rt for 3 h. The reaction mixture was filtered, and the filter cake was washed with water and a small amount of DCM, and then dried to give the title compound as an off-white solid (8.4 g, 64%). 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (br s, 1H), 7.88 (s, 1H), 7.73 (d, J = 2.7 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.50 - 6.28 (m, 3H). [M+H] = 187.4.

[0578] Step 2. 8'-Chloro-4,4-difluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. 1-(2-Chloro-5-hydroxyphenyl)urea (1.74 g, 9.32 mmol) was added to Eaton’s reagent (a solution of 7.7 wt.% phosphorus pentoxide in methanesulfonic acid, 6.8 mL, 17.7 mmol). The mixture was heated to 60 °C, and then 4,4-difluorocyclohexanone (2.50 g, 18.6 mmol) was added slowly. The mixture was stirred at this temperature for 1 h until the reaction was complete (determined by LC / MS). Then the reaction mixture was cooled to 0 °C, ice was added, and the mixture was extracted with DCM. The combined organic layers were concentrated to give a crude mixture as a brown solid. The crude product was purified by flash chromatography (0% to 40% EtOAc / hexane) to give the title compound as an off-white solid (1.2 g, 42.5%). 1 H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.7 Hz, 2H), 6.43 (d, J = 8.7 Hz, 1H), 6.05 (br s, 1H), 3.02 (dt, J = 5.7, 13.3 Hz, 2H), 2.21 - 2.10 (m, 4H), 1.92 (d, J = 15.3 Hz, 2H).

[0579] Step 3. 8'-Chloro-4,4-difluoro-5'-hydroxy-6'-nitro-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. At 0 °C, nitric acid (2.13 mL, 47.6 mmol) was added dropwise to a solution of 8'-chloro-4,4-difluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (6.40 g, 21.1 mmol) in TFA (44.8 mL). After the addition was complete, the reaction was warmed to rt, stirred for 1 h, then cooled to 5 °C, and water was added dropwise. The reaction mixture was extracted with DCM, washed with water and brine, and then dried over MgSO4 to afford the title compound as a brown solid. [M+H] = 348.1.

[0580] Step 4. 6'-Amino-8'-chloro-4,4-difluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one. At 0 °C, zinc (418 mg, 6.40 mmol) was added to a suspension of 8'-chloro-4,4-difluoro-5'-hydroxy-6'-nitro-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (556 mg, 1.60 mmol) in tetrahydrofuran (7.79 mL), water (0.78 mL) and acetic acid (3.34 mL). After the addition, the reaction mixture was warmed to room temperature and stirred for 2 h, then monitored by LC / MS to determine that the reaction was complete. A mixture of i-PrOH and DCM (1:3) was added to the reaction mixture, the layers were separated, the combined organics were washed with water and brine, dried over MgSO4 and concentrated to afford the title compound as a dark brown solid. 1 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.35 (s, 1H), 6.79 (s, 1H), 2.99 - 2.87 (m, 3H), 2.47 - 2.27 (m, 4H), 1.88 (br s, 2H), 1.67 (d, J = 12.0 Hz, 2H). [M+H] = 318.0.

[0581] Intermediate 10. Methyl 5'-chloro-4,4-difluoro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo [5,4-f]quinazolin]-2'-carboxylate (XXVII and Example 9).

[0582]

[0583] 6'-Amino-8'-chloro-4,4-difluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (1.00 g, 3.15 mmol), 4-methylbenzenesulfonic acid (27.1 mg, 0.16 mmol), and methyl 2,2,2-trimethoxyacetate (4.58 mL, 31.5 mmol) were combined and stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with a mixture of i-PrOH / DCM (1:3), washed with saturated NaHCO3 solution and brine, and then concentrated to give the title compound as a brown solid. The crude product was used in the subsequent reaction without further purification. 1 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.50 (s, 1H), 6.70 (br s, 1H), 4.11 (s, 3H), 2.85 - 2.70 (m, 2H), 2.34 - 1.76 (m, 6H). [M+H]=386.0.

[0584] Intermediate 11. 5'-Chloro-4,4-difluoro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo [5, materia]]

[0585]

[0586] Methyl 5'-chloro-4,4-difluoro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]-2'-carboxylate (1.16 g, 3.00 mmol) and lithium hydroxide (0.22 g, 9.0 mmol) were suspended in tetrahydrofuran (18.5 mL) and water (4.63 mL), and then stirred at room temperature for 0.5 h. Water was added to the reaction mixture, and then the reaction mixture was washed with EtOAc. The aqueous layer was acidified with 2N HCl, extracted with EtOAc (×2), and then the combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the title compound as a dark brown solid (221 mg). [M+H]=372.0.

[0587] Intermediate 12. 5'-Chloro-2'-(chloromethyl)-4,4-difluoro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f] quinazolin]-7'(8'H)-one.

[0588]

[0589] Intermediate 12 was synthesized in a manner similar to Intermediate 5 using appropriate starting material replacements.

[0590] [M+H]=376.4.

[0591] Intermediate 13. 6'-Amino-8'-chloro- 2'(3'H)-one

[0592]

[0593] Intermediate 13 was synthesized from Intermediate 9 by using appropriate raw material substitution. [M+H]=310.1.

[0594] Intermediate 14. Ethyl 5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quin azoline]-2'-carboxylate

[0595]

[0596] Step 1. 8'-Chloro-5'-hydroxy-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-6'-carbaldehyde. To a suspension of 8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazoline]-2'(3'H)-one (35.0 g, 131 mmol) in TFA (140 mL) was added hexamine (20.3 g, 144 mmol) portionwise, and the reaction mixture was heated to 100 °C for 18 h. The mixture was cooled to 0 °C, then water (700 mL) was added, and then concentrated HCl (50 mL) was added. The mixture was heated to 100 °C and stirred vigorously for 45 min. The mixture was cooled to room temperature, the solid was collected by filtration, washed with water (2×300 mL), and then dried in a vacuum oven at 45 °C for 18 h to give the title compound (38 g, 98%). 1 H NMR (400 MHz, CDCl3) δ 12.22 (s, 1H), 9.66 (s, 1H), 7.62 (br, 1H), 7.48 (s, 1H), 6.60 (br, 1H), 2.69 (td, J = 13.6, 4.3 Hz, 2H), 1.86 - 1.76 (m, 3H), 1.76 - 1.66 (m, 2H), 1.65 - 1.51 (m, 2H), 1.42 - 1.29 (m, 1H). [M+H]=295.2.

[0597] Step 2. Ethyl 5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]-2'-carboxylate. Ethyl bromoacetate (19.1 mL, 173 mmol) was added to a mixture of 8'-chloro-5'-hydroxy-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin]-6'-carbaldehyde (30.0 g, 102 mmol) and K2CO3 (49.2 g, 356 mmol) in DMF (1.0 L). The reaction mixture was heated to 100 °C for 30 minutes and then to 125 °C for 90 minutes. The mixture was cooled to room temperature and water (6.0 L) was added. The mixture was cooled to 0 °C and stirred for 1 h. The solid was collected by filtration, washed with water, and then dried in a vacuum oven at 60 °C for 18 hours. The material was dissolved in DCM (1.5 L), silica gel was added, and the solvent was concentrated under reduced pressure. The material was purified by flash chromatography on silica gel (from 100% hexane (containing 2% AcOH) to a hexane solution of 20% EtOAc (containing 2% AcOH)) to give the title compound (20 g, 54%). 1 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.45 (br, 1H), 7.39 (s, 1H), 6.38 (br, 1H), 4.48 - 4.34 (m, 2H), 2.53 (td, J = 13.6, 4.4 Hz, 2H), 1.99 (d, J = 12.4 Hz, 2H), 1.89 - 1.71 (m, 3H), 1.72 - 1.59 (m, 2H), 1.51 - 1.39 (m, 4H). [M+H] = 363.0.

[0598] Intermediate 15. 5'-Chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quin azoline]-2'-carboxylic acid

[0599]

[0600] To a solution of ethyl 5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]-2'-carboxylate (Intermediate 14, 16.0 g, 44.1 mmol) in dioxane (600 mL) was added 1 M NaOH solution (132 mL, 132 mmol). The reaction mixture was heated to 40 °C for 3 h. The mixture was cooled and the solvent was concentrated under reduced pressure. The aqueous phase was extracted with EtOAc and then acidified by dropwise addition of concentrated HCl until a sustained pH of 2 was obtained. The resulting solid was collected by filtration, washed with water, and dried in a vacuum oven at 50 °C for 18 h to give the title compound (14 g, 95%). 11H NMR (400 MHz, DMSO-d6) δ 13.52 (br, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.37 (d, J = 1.4 Hz, 1H), 2.35 (td, J = 13.3, 4.1 Hz, 2H), 1.91–1.77 (m, 4H), 1.70 (d, J = 12.5 Hz, 1H), 1.56 (d, J = 13.3 Hz, 2H), 1.26 (tdd, J = 12.9, 9.2, 3.6 Hz, 1H). [M+H] = 335.0.

[0601] Intermediate 16. 5'-Chloro-2'-(hydroxymethyl)-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]- 7'(8'H)-one

[0602]

[0603] At 0 °C, a solution of LiAlH4 (2 M in THF, 104 mL, 207 mmol) was added dropwise to a solution of ethyl 5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]-2'-carboxylate (Intermediate 14, 37.6 g, 104 mmol) in THF (1.0 L), and the reaction mixture was stirred at room temperature for 2 h. The mixture was cooled to 0 °C, and then the pH was adjusted to 3 by adding 2 M HCl solution. The resulting solid was filtered, washed with water, and dried in a vacuum oven at 55 °C for 24 h to give the title compound (29 g, 87%). 1 1H NMR (400 MHz, DMSO-d6) δ 8.17 (br, 1H), 7.58 (s, 1H), 7.23 br, 1H), 6.65 (s, 1H), 5.46 (t, J = 5.9 Hz, 1H), 4.54 (d, J = 5.9 Hz, 2H), 2.35 (td, J = 13.2, 4.1 Hz, 2H), 1.91-1.73 (m, 4H), 1.68 (d, J = 13.0 Hz, 1H), 1.54 (d, J = 13.7 Hz, 2H), 1.35-1.25 (m, 1H). [M+H] = 321.2.

[0604] Intermediate 17. 5'-Chloro-2'-(chloromethyl)-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]-7' (8'H)-one

[0605]

[0606] At 0 °C, 5'-chloro-2'-(hydroxymethyl)-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazolin]-7'(8'H)-one (29.0 g, 90.4 mmol) was added portionwise to thionyl chloride (500 mL). The reaction mixture was warmed to room temperature, stirred for 2 h, and then concentrated under reduced pressure without heating. The material was purified by flash chromatography on silica gel (hexane (containing 1% AcOH) to hexane solution of 20% EtOAc (containing 1% AcOH), and the resulting material was triturated in hexane (500 mL), filtered and dried under reduced pressure to give the title compound (7.9 g, 26%). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.65 (s, 1H), 7.29 (s, 1H), 6.91 (s, 1H), 4.98 (s, 2H), 2.39 - 2.27 (m, 2H), 1.94 - 1.75 (m, 4H), 1.70 (d, J = 12.6 Hz, 1H), 1.55 (d, J = 14.0 Hz, 2H), 1.28 (dd, J = 14.8, 11.0 Hz, 1H). [M+H] = 339.1.

[0607] Example 1. Methyl 5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quin oline]-2'-carboxylate

[0608]

[0609] The structure of Example 1 is the same as that of Intermediate 3. The synthesis of Example 1 is described for Intermediate 3. 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.61 (br, 1H), 4.10 (s, 3H), 2.23 (dd, J = 9.2, 3.6 Hz, 3H), 2.03 - 1.93 (m, 2H), 1.89 - 1.82 (m, 1H), 1.77 - 1.70 (m, 2H), 1.51 - 1.41 (m, 2H). [M+H] = 351.2.

[0610] Example 2. 5'-Chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quin oline]-2'-carboxylic acid

[0611]

[0612] The structure of Example 2 is the same as that of Intermediate 4. The synthesis of Example 2 is described for Intermediate 4. 1 H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.08 (s, 1H), 2.19 - 2.09 (m, 4H), 1.81 - 1.63 (m, 5H), 1.41 - 1.33 (m, 1H).

[0613] Example 3. 5'-Chloro-2'-(chloromethyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]-7' (8'H)-one

[0614]

[0615] The structure of Example 3 is the same as that of Intermediate 5. The synthesis of Example 3 is described for Intermediate 5. 1 H NMR(400MHz,DMSO-d6)δ8.63 - 8.39(m,1H),7.84(s,1H),7.47 - 7.38(m,1H),5.07(s,2H),2.25 - 2.10(m,2H),1.88(br s,4H),1.78 - 1.67(m,1H),1.63 - 1.51(m,2H),1.40 - 1.17(m,1H).[M + H]=340.1.

[0616] Example 4. 5'-Chloro-2'-(((2-methoxyethyl)amino)methyl)-6'H-spiro[cyclohexane-1,9'-oxazolo [5,4-f]quinazoline]-7'(8'H)-one

[0617]

[0618] To a solution of 5'-chloro-2'-(chloromethyl)-6'H-spiro[cyclohexane-​1,9'-oxazolo[5,4-f]quinazolin]-7'(8'H)-one (Intermediate 5, 250 mg, 0.73 mmol) in dichloromethane (2.50 mL) was added 2-methoxyethylamine (0.32 mL, 3.67 mmol), and the reaction mixture was stirred at rt for 1 hour. The reaction mixture was diluted with MeOH (1 mL), filtered and purified by preparative HPLC (5 - 95% ACN-H2O). The desired fraction was lyophilized to give the title compound as a brown powder. The product was purified again by flash chromatography (0% to 5% MeOH / EtOAc) using an ISCO amine column to give the title compound as an off-white solid (54.2 mg, 19.5%). 1 H NMR(400MHz,CDCl3)δ7.61(s,1H),7.23(s,1H),5.83(s,1H),4.14(s,2H),3.63 - 3.51(m,2H),3.38(s,3H),3.02 - 2.91(m,2H),2.34 - 2.21(m,3H),2.01(d,J=12.8Hz,2H),1.91 - 1.74(m,3H),1.70 - 1.53(m,2H),1.49 - 1.37(m,1H).[M + H]=379.1.

[0619] Example 5. 5'-Chloro-2'-((2-methoxyethoxy)methyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5, 4-f]quinazoline]-7'(8'H)-one

[0620]

[0621] To a suspension of potassium tert-butoxide (19.8 mg, 0.18 mmol) in DMF (0.99 mL) was added 2-methoxyethanol (13.9 μL, 0.18 mmol). The mixture was stirred at room temperature for 10 minutes, and then a solution of 5'-chloro-2'-(chloromethyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7'(8'H)-one (Intermediate 5, 30 mg, 0.09 mmol) in DMF was added. The reaction mixture was stirred at room temperature for 15 minutes and then heated to 80 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with MeOH (1 mL), filtered and purified by preparative HPLC (H2O solution with 5 - 95% ACN). The desired fraction was lyophilized to give the title product as a gray powder (4.0 mg, 12%). 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.80 (s, 1H), 7.39 (s, 1H), 4.78 (s, 2H), 3.75 - 3.68 (m, 2H), 3.57 - 3.48 (m, 2H), 3.25 (s, 3H), 2.26 - 2.11 (m, 2H), 1.85 (d, J = 11.2 Hz, 4H), 1.71 (d, J = 11.4 Hz, 1H), 1.56 (d, J = 15.2 Hz, 2H), 1.27 (d, J = 13.9 Hz, 1H). [M + H] = 380.1.

[0622] Example 6. Ethyl 2-(5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f] quinazoline]-2'-yl)acetate

[0623]

[0624] 5'-Chloro-2'-(chloromethyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7'(8'H)-one (Intermediate 5, 30 mg, 0.11 mmol), p-toluenesulfonic acid (1.83 mg, 0.01 mmol) and diethyl malonate (80.8 μL, 0.53 mmol) were mixed together and then stirred at 120 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with MeOH, filtered and purified by preparative HPLC (aqueous H2O solution with 5 - 95% ACN). The desired fraction was lyophilized to give the title compound as an off-white powder. 11H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.77 (s, 1H), 7.39 (s, 1H), 4.24 - 4.09 (m, 4H), 2.25 - 2.10 (m, 2H), 1.97 - 1.78 (m, 4H), 1.70 (d, J = 12.0 Hz, 1H), 1.54 (d, J = 13.8 Hz, 2H), 1.33 - 1.14 (m, 4H). [M+H] = 378.1.

[0625] Example 7. 5'-Chloro-2'-(4-methoxypiperidine-1-carbonyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4- f]quinazoline]-7'(8'H)-one

[0626]

[0627] To a mixture of 5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]-2'-carboxylic acid (Intermediate 4, 175 mg, 0.52 mmol) and 4-methoxypiperidine (90 mg, 0.78 mmol) in N,N-dimethylformamide (3.50 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (297 mg, 0.78 mmol), followed by N,N-diisopropylethylamine (273 μL, 1.56 mmol). The reaction was stirred at room temperature for 1 hour, then water was added, followed by EtOAc. The layers were separated, the organic layer was washed with brine, dried over MgSO4 and concentrated. Purification by SFC afforded the title compound as an off-white solid (225 mg, 44.8%). 1 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.24 (s, 1H), 5.67 (br s, 1H), 4.28 - 4.18 (m, 1H), 4.03 - 3.89 (m, 2H), 3.80 - 3.71 (m, 1H), 3.59 (tt, J = 3.4, 6.8 Hz, 1H), 3.42 (s, 3H), 2.37 (tt, J = 3.7, 13.3 Hz, 2H), 2.08 - 1.94 (m, 4H), 1.87 - 1.74 (m, 4H), 1.69 - 1.41 (m, 4H). [M+H] = 433.6.

[0628] Example 8. 5'-Fluoro-2'-((3-methoxyazetidin-1-yl)methyl)-6'H-spiro[cyclohexane-1,9'- oxazolo[5,4-f]quinazoline]-7'(8'H)-one

[0629]

[0630] To a solution of 2'-(chloromethyl)-5'-fluoro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7'(8'H)-one (Intermediate 8, 25 mg, 0.08 mmol) in N,N-dimethylformamide (0.45 ml) was added 3-methoxyazetidine (19.1 mg, 0.15 mmol), then triethylamine (38 μL, 0.27 mmol), and the reaction mixture was stirred at 40 °C for 1 h. The crude product was diluted with MeOH, filtered and purified by preparative HPLC (aqueous solution of H2O with 5 - 95% ACN). The desired fraction was lyophilized to give the desired product as the TFA salt. The product was dissolved in EtOAc, washed with saturated NaHCO3 solution, dried over MgSO4, and then concentrated to give the title compound as the free base (7.44 mg, 25.7%). 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 9.5 Hz, 1H), 7.26 (br s, 1H), 5.72 (br s, 1H), 4.23 - 4.09 (m, 1H), 3.95 (s, 2H), 3.87 (dd, J = 6.2, 8.1 Hz, 2H), 3.29 (s, 3H), 3.23 (dd, J = 5.9, 8.1 Hz, 2H), 2.29 (dt, J = 4.1, 13.5 Hz, 2H), 2.02 (br s, 2H), 1.92 - 1.74 (m, 3H), 1.63 (q, J = 13.7 Hz, 2H), 1.47 - 1.34 (m, 1H). [M + H] = 375.1.

[0631] Example 9. Methyl 5'-chloro-4,4-difluoro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo [5,4-f]quinazoline]-2'-carboxylate

[0632]

[0633] 6'-Amino-8'-chloro-4,4-difluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 9, 1.00 g, 3.15 mmol), 4-methylbenzenesulfonic acid (27.1 mg, 0.16 mmol) and methyl 2,2,2-trimethoxyacetate (4.58 mL, 31.5 mmol) were mixed and then stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with i-PrOH / DCM (1:3), washed with saturated NaHCO3 solution and brine, and then concentrated to give the title compound as a brown solid. 11H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.50 (s, 1H), 6.70 (br s, 1H), 4.11 (s, 3H), 2.85 - 2.70 (m, 2H), 2.34 - 1.76 (m, 6H). [M + H]=386.0.

[0634] Example 10. 5'-Chloro-4,4-difluoro-2'-((4-methylpiperazin-1-yl)methyl)-6'H-spiro[cyclohexane-1, 9'-oxazolo[5,4-f]quinazoline]-7'(8'H)-one

[0635]

[0636] To a solution of 5'-chloro-2'-(chloromethyl)-4,4-difluoro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7'(8'H)-one (Intermediate 12, 30 mg, 0.08 mmol) in DMF (0.60 mL, 20 V) was added 1-methylpiperazine (16 mg, 0.16 mmol), and then triethylamine (28 μL, 0.20 mmol). The reaction mixture was stirred at room temperature for 5 h, then diluted with MeOH, filtered and purified by preparative HPLC (5 - 95% ACN - H2O). The desired fractions were lyophilized to give the title compound as the TFA salt (5.3 mg, 10%). 1 1H NMR (400 MHz, DMSO-d6) δ 9.41 (br s, 1H), 8.64 (s, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 4.01 (s, 2H), 3.40 (d, J=13.0 Hz, 4H), 3.19 - 2.99 (m, 5H), 2.79 (br s, 3H), 2.66 - 2.55 (m, 2H), 2.00 (d, J=8.1 Hz, 4H). [M + H]=440.3.

[0637] Example 11. 5'-Chloro-4,4-difluoro-2'-methyl-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinaz oline]-7'(8'H)-one

[0638]

[0639] 6'-Amino-8'-chloro-4,4-difluoro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 9, 30 mg, 0.09 mmol), 4-methylbenzenesulfonic acid (0.81 mg, 0.005 mmol) and 1,1,1-triethoxyethane (0.30 mL, 1.64 mmol, 10 V) were mixed and stirred at 140 °C for 1 h. The reaction mixture was cooled to room temperature. The crude product was diluted with MeOH, filtered and purified by preparative HPLC (5 - 95% ACN - H2O). The desired fraction was lyophilized to give the title compound as a brown solid (1.8 mg, 5.6%). 1 H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.35 (br s, 1H), 6.70 (br s, 1H), 2.77 - 2.64 (m, 5H), 2.28 - 2.09 (m, 6H).

[0640] Example 12. 5-Chloro-2,4',4'-trimethyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline- 9,1'-cyclohexane]-7-one.

[0641]

[0642] 6'-Amino-8'-chloro-5'-hydroxy-4,4-dimethyl-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 13, 70 mg, 0.23 mmol), 4-methylbenzenesulfonic acid (2.0 mg, 0.01 mmol) and 1,1,1-triethoxyethane (0.70 ml, 1.64 mmol, 10 V) were mixed together and then stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature. The crude product was diluted with MeOH, filtered and purified by preparative HPLC (5 - 95% ACN in H2O). The desired fraction was lyophilized to give the title compound as a brown solid (5.5 mg, 7.3%). 1 H NMR (400 MHz, CDCl3) δ 7.62 - 7.58 (m, 1H), 7.33 (br s, 1H), 6.47 (br s, 1H), 2.68 (s, 3H), 2.58 - 2.48 (m, 2H), 1.88 (d, J = 13.6 Hz, 2H), 1.61 (dt, J = 3.4, 14.2 Hz, 2H), 1.48 - 1.40 (m, 2H), 1.15 (s, 3H), 1.08 (s, 3H). [M + H] = 334.1.

[0643] Example 13. 5'-Chloro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]-7'(8'H)-one.

[0644]

[0645] 6'-Amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 2, 32.0 mg, 0.11 mmol), 4-methylbenzenesulfonic acid (0.98 mg, 0.01 mmol) and triethoxymethane (0.32 mL, 1.91 mmol) were mixed and stirred at rt for 1 h. The crude product was diluted with MeOH, filtered and purified by preparative HPLC (5-95% ACN-H2O). The desired fraction was lyophilized to give the title compound as an off-white powder (7.5 mg, 23%). 1 H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.76 (s, 1H), 7.41 (br s, 1H), 6.37 (br s, 1H), 2.34 (dt, J = 4.3, 13.6 Hz, 2H), 2.05 (d, J = 13.1 Hz, 2H), 1.95 - 1.75 (m, 3H), 1.73 - 1.53 (m, 2H), 1.44 (q, J = 13.2 Hz, 1H). [M+H] = 292.0.

[0646] Example 14. 5'-Chloro-2'-methyl-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]-7'(8' H)-one.

[0647]

[0648] 6'-Amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 2, 21.4 mg, 0.08 mmol), 4-methylbenzenesulfonic acid (0.65 mg, 0.004 mmol) and 1,1,1-triethoxyethane (214 μL, 1.17 mmol) were mixed together and then stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature. The crude product was diluted with MeOH, filtered and purified by preparative HPLC (5-95% ACN-H2O). The desired fraction was lyophilized to give the title compound as an off-white powder (3.8 mg, 16.4%). 1 H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.16 (br s, 1H), 5.61 (br s, 1H), 2.67 (s, 3H), 2.30 (dt, J = 4.1, 13.3 Hz, 2H), 2.02 (d, J = 13.2 Hz, 2H), 1.81 (d, J = 17.5 Hz, 3H), 1.56 (br s, 1H), 1.51 - 1.37 (m, 2H). [M+H] = 306.1.

[0649] Example 15. 5'-Chloro-2'-ethyl-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]-7'(8' H)-one.

[0650]

[0651] 6'-Amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 2, 30 mg, 0.11 mmol), 4-methylbenzenesulfonic acid (0.92 mg, 0.01 mmol), and 1,1,1-triethoxypropane (0.30 mL, 1.5 mmol) were mixed and stirred at 100 °C for 30 minutes. The reaction mixture was cooled to room temperature, then diluted with MeOH (1 mL), filtered, and purified by preparative HPLC (5-95% ACN-H2O). The desired fraction was lyophilized to give the title compound as a white powder (4.2 mg, 12%). 1 H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.15 (br s, 1H), 5.59 (br s, 1H), 2.99 (q, J = 7.6 Hz, 2H), 2.38 - 2.23 (m, 2H), 2.02 (d, J = 13.1 Hz, 2H), 1.92 - 1.74 (m, 3H), 1.57 - 1.53 (m, 1H), 1.52 - 1.43 (m, 5H). [M+H] = 320.2.

[0652] Example 16. 5'-Chloro-2'-propyl-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]-7'(8' H)-one.

[0653]

[0654] 6'-Amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 2, 30 mg, 0.11 mmol), 4-methylbenzenesulfonic acid (0.92 mg, 0.01 mmol), and 1,1,1-triethoxybutane (0.30 mL, 1.4 mmol) were mixed and stirred at 100 °C for 0.5 h. The reaction mixture was cooled to room temperature, the crude product was diluted with MeOH (1 mL), filtered, and purified by preparative HPLC (5-95% ACN-H2O). The desired fraction was lyophilized to give the title compound as an off-white powder (7.4 mg, 21%). 11H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.15 (br s, 1H), 5.60 (br s, 1H), 2.93 (t, J = 7.5 Hz, 2H), 2.30 (dt, J = 4.0, 13.5 Hz, 2H), 2.10 - 1.75 (m, 8H), 1.54 - 1.26 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H). [M + H]+ = 334.2.

[0655] Example 17. 5'-Chloro-2'-isopropyl-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]-7' (8'H)-one.

[0656]

[0657] A solution of 6'-amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 2, 30 mg, 0.11 mmol) and methyl 2-methylpropiolimidate (17 mg, 0.13 mmol) in ethanol (300 μL) was stirred at 90 °C for half an hour and then cooled to room temperature. The crude product was diluted with MeOH (1 mL), filtered and purified by preparative HPLC (5 - 95% ACN - H2O). The desired fraction was lyophilized to give the title compound as a white powder (9.1 mg, 26%). 1 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.34 - 7.29 (m, 1H), 6.10 (br s, 1H), 3.27 (td, J = 7.0, 13.9 Hz, 1H), 2.30 (dt, J = 4.1, 13.5 Hz, 2H), 2.04 (d, J = 13.1 Hz, 2H), 1.94 - 1.78 (m, 3H), 1.73 - 1.56 (m, 2H), 1.49 (d, J = 7.0 Hz, 6H), 1.45 - 1.38 (m, 1H). [M + H]+ = 334.2.

[0658] Example 18. 5'-Chloro-2'-cyclopropyl-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]-7' (8'H)-one.

[0659]

[0660] A solution of 6'-amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 2, 32 mg, 0.11 mmol), 4-methylbenzenesulfonic acid (1.9 mg, 0.01 mmol) and (triethoxymethyl)cyclopropane (25 μL, 0.12 mmol) in ethanol (0.32 mL) was stirred at 90 °C for 0.5 h and then cooled to room temperature. The crude product was diluted with DMSO, filtered and purified by preparative HPLC (5 - 95% ACN - H2O). The desired fraction was lyophilized to give the title compound as a white powder (5.1 mg, 14%). 1 H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.33 - 7.29 (m, 1H), 6.18 (br s, 1H), 2.39 - 2.16 (m, 2H), 2.03 (d, J = 13.3 Hz, 2H), 1.94 - 1.74 (m, 3H), 1.71 - 1.56 (m, 2H), 1.41 (q, J = 13.1 Hz, 1H), 1.30 - 1.11 (m, 5H). [M + H] = 332.1.

[0661] Example 19. 5'-Chloro-2'-(methoxymethyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinaz oline]-7'(8'H)-one.

[0662]

[0663] A suspension of 6'-amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 2, 30 mg, 0.11 mmol) and ethyl 2-methoxyacetimidate (24 mg, 0.16 mmol) in ethanol (300 μL) was irradiated in a microwave at 110 °C for 30 min. The crude product was diluted with MeOH (1 mL), filtered and purified by preparative HPLC (5 - 95% ACN - H2O). The desired fraction was lyophilized to give the title compound as a white powder (4.8 mg, 13.2%). 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.24 (br s, 1H), 5.76 (br s, 1H), 4.72 (s, 2H), 3.56 (s, 3H), 2.41 - 2.23 (m, 2H), 2.04 (d, J = 13.3 Hz, 2H), 1.94 - 1.77 (m, 4H), 1.51 - 1.37 (m, 2H). [M + H] = 336.1.

[0664] Example 20. 5'-Chloro-2'-(hydroxymethyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazoline]- 7'(8'H)-one.

[0665]

[0666] 5'-Chloro-2'-(methoxymethyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7'(8'H)-one (34 mg, 0.10 mmol) in a solution of boron tribromide (2.03 mL, 2.03 mmol, 1N) was stirred at room temperature for 1 h. The solvent was evaporated, the crude product was diluted with MeOH, filtered and purified by preparative HPLC (5 - 95% ACN - H2O). The desired fraction was lyophilized to give the title compound as a white powder (13 mg, 40%). 1 H NMR (400 MHz, DMSO - d6) δ 8.4 (s, 1H), 7.77 (s, 1H), 7.37 (s, 1H), 4.68 (s, 2H), 2.30 - 2.14 (m, 2H), 1.96 - 1.79 (m, 4H), 1.75 - 1.42 (m, 4H), 1.36 - 1.17 (m, 1H). [M + H] = 322.1.

[0667] Example 21. 5'-Chloro-2'-(2-methoxyethyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinaz oline]-7'(8'H)-one.

[0668]

[0669] 6'-Amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 2, 60 mg, 0.21 mmol), 4-methylbenzenesulfonic acid (1.8 mg, 0.01 mmol) and 1,1,1-triethoxy-3-methoxypropane (0.51 mL, 2.2 mmol) were mixed and stirred at rt for 1 h. The crude product was diluted with MeOH, filtered and purified by preparative HPLC (5 - 95% ACN - H2O). The desired fraction was lyophilized to give the title compound as an off-white powder (20 mg, 27%). 1 HNMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.21 (br s, 1H), 5.81 (br s, 1H), 3.91 (t, J = 6.5 Hz, 2H), 3.43 (s, 3H), 3.23 (t, J = 6.5 Hz, 2H), 2.30 (dt, J = 4.1, 13.6 Hz, 2H), 2.03 (d, J = 13.4 Hz, 2H), 1.93 - 1.76 (m, 3H), 1.62 (q, J = 14.0 Hz, 2H), 1.42 (q, J = 12.8 Hz, 1H). [M + H] = 350.1.

[0670] Example 22. 5'-Chloro-2'-(2-hydroxyethyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinaz oline]-7'(8'H)-one.

[0671]

[0672] 5'-Chloro-2'-(2-methoxyethyl)-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7'(8'H)-one (15 mg, 0.04 mmol) in 1N boron tribromide (0.42 mL, 0.42 mmol) was stirred at room temperature for 1 h. The solvent was evaporated, the crude was dissolved in MeOH, filtered and purified by preparative HPLC (5-95% ACN-H2O). The desired fraction was lyophilized to give the title compound as a white powder (2.9 mg, 21%). 1 H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.24 (br s, 1H), 5.88 (br s, 1H), 4. (t, J = 5.6 Hz, 2H), 3.20 (t, J = 5.6 Hz, 2H), 2.40 - 2.22 (m, 2H), 2.03 (d, J = 13.6 Hz, 2H), 1.92 - 1.76 (m, 4H), 1.63 (q, J = 13.5 Hz, 2H), 1.50 - (m, 1H). [M+H] = 336.1.

[0673] Example 23. N-(5'-Chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f] quinazolin]-2'-yl)acetamide.

[0674]

[0675] Step 1. 6'-Amino-8'-chloro-5'-hydroxy-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one (Intermediate 2, 300 mg, 1.06 mmol) and bis(1H-imidazol-1-yl)methanimine (309 mg, 1.92 mmol) were dissolved in dry tetrahydrofuran (9.0 mL) and heated at 70 °C for 2 h. The reaction was cooled to room temperature, then the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, filtered, and then the organic layer was concentrated. The crude product was purified by flash chromatography (20% to 10% EtOAc / hexane) to give 2'-amino-5'-chloro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7'(8'H)-one as a light brown solid (139 mg, ). [M+H] = 307.1.

[0676] Step 2. Under rt, to a solution of 2'-amino-5'-chloro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7'(8'H)-one (17 mg, 0.05 mmol) in dichloromethane (336 μL) was added acetic anhydride (26 μL, 0.27 mmol), and then triethylamine (23 μL, 0.16 mmol). The reaction mixture became clear and was then stirred at room temperature for 1 h and then heated to 80 °C for 3 days. Once the reaction was complete, the crude was diluted with MeOH (1 mL), then filtered and purified by preparative HPLC (5 - 95% ACN - H2O). The desired fraction was lyophilized to give the title compound as a white powder (8.8 mg, 46%). 1 H NMR (400 MHz, DMSO - d6) δ 11.64 (s, 1H), 8.33 (s, 1H), 7.58 (s, 1H), 7.32 (s, 1H), 2.25 - 2.13 (m, 5H), 1.94 - 1.77 (m, 4H), 1.70 (d, J = 13.2 Hz, 1H), 1.54 (d, J = 13.3 Hz, 2H), 1.27 (d, J = 13.4 Hz, 1H). [M + H] = 335.1.

[0677] Example 24. 2'-(Bis(2-methoxyethyl)amino)-5'-chloro-6'H-spiro[cyclohexane-1,9'-oxazolo[5, 4-f]quinazoline]-7'(8'H)-one.

[0678]

[0679] To a solution of 2'-amino-5'-chloro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quinazolin]-7'(8'H)-one (20 mg, 0.07 mmol) and cesium carbonate (53 mg, 0.16 mmol) in DMF (400 μL) was added 2-bromoethyl methyl ether (7.4 μL, 0.08 mmol), and the reaction mixture was stirred at room temperature for 1 h and then heated at 60 °C overnight. The reaction mixture was cooled to room temperature, diluted with MeOH (1 mL), filtered and purified by preparative HPLC (5 - 95% ACN - H2O). The fraction containing the desired product was lyophilized to give the title compound as a light brown powder. 11H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 7.03 (s, 1H), 5.56 (s, 1H), 3.84 - 3.74 (m, 4H), 3.71 - 3.62 (m, 4H), 3.38 (s, 6H), 2.30 - 2.14 (m, 2H), 2.02 (d, J = 12.8 Hz, 2H), 1.91 - 1.70 (m, 3H), 1.59 (q, J = 13.8 Hz, 2H), 1.43 - 1.20 (m, 1H). [M + H] = 423.1.

[0680] Example 25. 5'-Chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-oxazolo[5,4-f]quin azoline]-2'-carboxamide.

[0681]

[0682] 6'-Amino - 8'-chloro - 5'-hydroxy - 1'H - spiro[cyclohexane - 1,4'-quinazolin]-2'(3'H)-one (Intermediate 2, 35 mg, 0.12 mmol), 4 - methylbenzenesulfonic acid (1.1 mg, 0.01 mmol) and trimethoxyacetamide (56 mg, 0.37 mmol) were mixed together and stirred at 100 °C for 0.5 h, then the reaction mixture was cooled to room temperature. The crude product was diluted with MeOH, then filtered and purified by preparative HPLC (5 - 95% ACN - H2O). The desired fraction was lyophilized to give the title compound as an off - white powder (4.1 mg, 10%). 1 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.32 (br s, 1H), 7.15 - 6.88 (m, 1H), 6.07 - 5.53 (m, 2H), 2.56 - 2.23 (m, 2H), 2.05 (d, J = 16.4 Hz, 2H), 1.83 (d, J = 12.5 Hz, 4H), 1.71 - 1.38 (m, 2H). [M + H] = 335.1.

[0683] Example 26. 5'-Chloro-2'-(hydroxymethyl)-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]- 7'(8'H)-one.

[0684]

[0685] The structure of Example 26 is the same as that of Intermediate 16. The synthesis of Example 26 is described for Intermediate 16. 11H NMR (400 MHz, DMSO-d6) δ 8.17 (br, 1H), 7.58 (s, 1H), 7.23 (br, 1H), 6.65 (s, 1H), 5.46 (t, J = 5.9 Hz, 1H), 4.54 (d, J = 5.9 Hz, 2H), 2.35 (td, J = 13.2, 4.1 Hz, 2H), 1.91 - 1.73 (m, 4H), 1.68 (d, J = 13.0 Hz, 1H), 1.54 (d, J = 13.7 Hz, 2H), 1.35 - 1.25 (m, 1H). [M+H] = 321.2.

[0686] Example 27. 5'-Chloro-2'-(4-(2-fluoroethyl)piperazine-1-carbonyl)-6'H-spiro[cyclohexane-1,9'-furo [2,3-f]quinazoline]-7'(8'H)-one.

[0687]

[0688] To a mixture of 5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]-2'-carboxylic acid (Intermediate 15, 50 mg, 0.15 mmol) and 1-(2-fluoroethyl)piperazine hydrochloride in DMF (5 mL) was added a solution of N-ethyl-N-isopropylpropan-2-amine (0.08 mL, 0.45 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (HATU, 68 mg, 0.18 mmol) in DMF (1 mL). The vial was sealed and the reaction mixture was stirred at room temperature for 3.5 h. The reaction mixture was diluted with water and EtOAc. The precipitate formed in the biphasic mixture was filtered, washed with H2O and dried in vacuo to give the title compound as a white solid (19 mg, 28%). 1 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.75 (s, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 4.67 - 4.47 (m, 2H), 3.70 (br s, 4H), 2.77 - 2.63 (m, 2H), 2.59 - 2.54 (m, 4H), 2.36 - 2.25 (m, 2H), 1.95 - 1.81 (m, 4H), 1.72 (d, J = 12.7 Hz, 1H), 1.56 (d, J = 14.2 Hz, 2H), 1.35 - 1.22 (m, 1H). [M+H] = 449.0.

[0689] Example 28. N-(2-(Benzyl(methyl)amino)ethyl)-5'-chloro-N-methyl-7'-oxo-7',8'-dihydro- 6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]-2'-carboxamide.

[0690]

[0691] To a suspension of 5'-chloro-7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]-2'-carboxylic acid (Intermediate 15, 34 mg, 0.10 mmol) in N,N-dimethylacetamide (0.1 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (V) (HATU, 0.2 mL of 0.5 M solution in N,N-dimethylacetamide, 0.1 mmol), and then N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.20 mmol) was added. The resulting solution was added to a solution of N 1 -benzyl-N 1 ,N 2 -dimethylethane-1,2-diamine (21 mg, 0.12 mmol) in N,N-dimethylacetamide (0.12 mL), and the sealed reaction was shaken at 270 rpm at room temperature for 16 h. The reaction mixture was diluted with N,N-dimethylacetamide (0.3 mL), filtered, and the filter cake was rinsed with additional N,N-dimethylacetamide (0.1 mL). The filtered crude product solution was purified by preparative HPLC-MS to give the title compound (30 mg, 49%). [M+H] = 495.5.

[0692] Example 29. 5'-Chloro-2'-((4-isopropylpiperazin-1-yl)methyl)-6'H-spiro[cyclohexane-1,9'-furo [2,3-f]quinazoline]-7'(8'H)-one.

[0693]

[0694] To a solution of 5'-chloro-2'-(chloromethyl)-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]-7'(8'H)-one (Intermediate 17, 30 mg, 0.09 mmol) in DMF (5 mL) was added 1-isopropylpiperazine (22 mg, 0.18 mmol), then N,N'-diisopropylethylamine (0.05 mL, 0.27 mmol), and the reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with H2O (15 mL), and then extracted with EtOAc. The combined organic layers were washed with H2O, dried over Na2SO4, and concentrated in vacuo to give the title compound as an off-white solid (22 mg, 58%). 11H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.57 (s, 1H), 7.26 (br s, 1H), 6.64 (s, 1H), 3.69 (s, 3H), 2.44 (br s, 10H), 1.91 - 1.80 (m, 5H), 1.69 (br s, 1H), 1.56 (br s, 2H), 1.32 - 1.25 (m, 1H), 0.94 (d, J = 6.4 Hz, 6H). [M+H] = 431.0.

[0695] Example 30. 5'-Chloro-2'-((((4-isopropyl-4H-1,2,4-triazol-3-yl)methyl)(methyl)amino)meth yl)-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazoline]-7'(8'H)-one.

[0696]

[0697] To a solution of 1-(4-isopropyl-4H-1,2,4-triazol-3-yl)-N-methylmethanamine (30.8 mg, 0.2 mmol) and N-ethyl-N-isopropylpropan-2-amine (52 μL, 0.30 mmol) in N,N-dimethylacetamide (0.2 mL) was added a solution of 5'-chloro-2'-(chloromethyl)-6'H-spiro[cyclohexane-1,9'-furo[2,3-f]quinazolin]-7'(8'H)-one (Intermediate 17, 34 mg, 0.10 mol) in N,N-dimethylacetamide (0.4 mL), and the reaction was shaken at 60 °C. After shaking at 60 °C for 16 h, the reaction mixture was filtered and the filter cake was rinsed with additional N,N-dimethylacetamide (0.2 mL). The filtered crude product solution was purified by preparative SFC-MS to give the title compound (24 mg, 42%). [M+H] = 457.2.

[0698] Examples 31 - 175 were prepared in a manner similar to Example 4 using appropriate starting material replacements.

[0699] Example 31. 5-Chloro-2-[(dimethylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f] quinazoline-9,1'-cyclohexane]-7-one.

[0700]

[0701] 1 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.33 (s, 1H), 5.89 (s, 1H), 4.54 (s, 2H), 3.00 (s, 6H), 2.32 - 2.18 (m, 2H), 2.03 (d, J = 13.3 Hz, 2H), 1.92 - 1.75 (m, 3H), 1.62 (q, J = 13.6 Hz, 2H), 1.51 - 1.36 (m, 1H). [M+H] = 349.3.

[0702] Example 32. 5-Chloro-2-[(4-methylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5, 4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0703]

[0704] 1 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.36 (s, 1H), 6.18 (s, 1H), 3.99 (s, 2H), 3.60 (br s, 2H), 3.18 (br s, 2H), 3.02 (br s, 4H), 2.85 (s, 3H), 2.25 (dt, J = 4.0, 13.4 Hz, 2H), 2.04 (d, J = 13.2 Hz, 2H), 1.92 - 1.75 (m, 3H), 1.65 (q, J = 13.6 Hz, 2H), 1.41 (q, J = 12.8 Hz, 1H). [M+H] = 404.2.

[0705] Example 33. 5-Chloro-2-(morpholin-4-ylmethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinaz oline-9,1'-cyclohexane]-7-one.

[0706]

[0707] 1 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.39 (s, 1H), 6.15 (br s, 1H), 4.37 (s, 2H), 4.04 - 3.92 (m, 4H), 3.29 - 3.18 (m, 4H), 2.25 (dt, J = 4.3, 13.8 Hz, 2H), 2.04 (d, J = 12.6 Hz, 2H), 1.90 - 1.90 (m, 1H), 1.92 - 1.77 (m, 3H), 1.63 (q, J = 13.7 Hz, 2H), 1.51 - 1.32 (m, 1H). [M+H] = 391.2.

[0708] Example 34. 5-Chloro-2-[(4-hydroxypiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5, 4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0709]

[0710] 11H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.91 (s, 1H), 7.44 (s, 1H), 4.79 (br s, 3H), 4.17 - 3.59 (m, 3H), 3.20 - 2.95 (m, 1H), 2.26 - 2.12 (m, 2H), 2.05 - 1.80 (m, 7H), 1.72 (d, J = 13.6 Hz, 2H), 1.56 (d, J = 14.2 Hz, 3H), 1.38 - 1.21 (m, 1H). [M+H] = 405.3.

[0711] Example 35. 5-Chloro-2-[(methylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quin azoline-9,1'-cyclohexane]-7-one.

[0712]

[0713] 1 1H NMR (400 MHz, DMSO-d6) δ 9.39 (br s, 1H), 8.55 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 4.64 (s, 2H), 2.76 (s, 3H), 2.28 - 2.14 (m, 2H), 2.00 - 1.80 (m, 4H), 1.71 (d, J = 11.5 Hz, 1H), 1.56 (d, J = 13.9 Hz, 2H), 1.39 - 1.20 (m, 1H). [M+H] = 335.2.

[0714] Example 36. 5-Chloro-2-[(cyclopropylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f] quinazoline-9,1'-cyclohexane]-7-one.

[0715]

[0716] 1 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.35 (s, 1H), 6.15 (s, 1H), 4.53 (s, 2H), 2.83 (td, J = 3.5, 7.2 Hz, 2H), 2.25 (dt, J = 4.2, 13.2 Hz, 2H), 2.02 (d, J = 13.4 Hz, 2H), 1.95 - 1.72 (m, 3H), 1.64 (q, J = 14.0 Hz, 2H), 1.48 - 1.28 (m, 1H), 1.12 - 0.99 (m, 2H), 0.90 - 0.76 (m, 2H). [M+H] = 361.3.

[0717] Example 37. 5-Chloro-2-(piperazin-1-ylmethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinaz oline-9,1'-cyclohexane]-7-one.

[0718]

[0719] 1 1H NMR (400 MHz, DMSO-d6) δ 8.54 (br s, 1H), 8.47 (d, J = 1.2 Hz, 1H), 7.78 (s, 1H), 7.40 (s, 1H), 4.02 (s, 2H), 3.13 (br s, 4H), 2.86 - 2.76 (m, 4H), 2.26 - 2.11 (m, 2H), 1.96 - 1.81 (m, 4H), 1.71 (d, J = 12.5 Hz, 1H), 1.56 (d, J = 13.1 Hz, 2H), 1.33 - 1.20 (m, 1H). [M+H] = 390.3.

[0720] Example 38. 5-Chloro-2-(pyrrolidin-1-ylmethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quin azoline-9,1'-cyclohexane]-7-one.

[0721]

[0722] 1 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.20 (br s, 1H), 5.73 (br s, 1H), 4.02 (s, 2H), 2.80 (br s, 4H), 2.31 (dt, J = 4.0, 13.5 Hz, 2H), 2.12 - 1.98 (m, 2H), 1.95 - 1.75 (m, 7H), 1.63 (q, J = 13.7 Hz, 2H), 1.51 - 1.33 (m, 1H). [M+H] = 375.2.

[0723] Example 39. 5-Chloro-2-{[(propan-2-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4- f]quinazoline-9,1'-cyclohexane]-7-one.

[0724]

[0725] 1 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.20 (br s, 1H), 5.74 (br s, 1H), 4.12 (s, 2H), 2.98 (td, J = 6.2, 12.4 Hz, 1H), 2.28 (dt, J = 4.3, 13.5 Hz, 2H), 2.03 (d, J = 12.5 Hz, 3H), 1.90 - 1.75 (m, 3H), 1.70 - 1.55 (m, 2H), 1.50 - 1.35 (m, 1H), 1.17 (d, J = 6.2 Hz, 6H). [M+H] = 362.0.

[0726] Example 40. 5-Chloro-2-[(ethylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quin azoline-9,1'-cyclohexane]-7-one.

[0727]

[0728] 1 1H NMR (400 MHz, DMSO-d6) δ 9.42 (br s, 1H), 8.55 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 4.66 (s, 2H), 3.17 (q, J = 7.3 Hz, 2H), 2.30 - 2.13 (m, 2H), 2.00 - 1.80 (m, 4H), 1.72 (d, J = 12.5 Hz, 1H), 1.56 (d, J = 13.1 Hz, 2H), 1.38 - 1.18 (m, 4H). [M+H] = 349.2.

[0729] Example 41. 5-Chloro-2-{[(2-hydroxyethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo [5,4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0730]

[0731] 1 1H NMR (400 MHz, DMSO-d6) δ 9.50 (br s, 2H), 8.53 (s, 1H), 7.88 (s, 1H), 7.42 (s, 1H), 5.30 (br s, 1H), 4.66 (s, 2H), 3.73 (t, J = 5.2 Hz, 2H), 3.23 (t, J = 5.1 Hz, 2H), 2.30 - 2.13 (m, 2H), 1.98 - 1.78 (m, 4H), 1.71 (d, J = 11.6 Hz, 1H), 1.56 (d, J = 12.8 Hz, 2H), 1.32 (d, J = 13.1 Hz, 1H). [M+H] = 365.2.

[0732] Example 42. 5-Chloro-2-[(4,4-difluoropiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo [5,4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0733]

[0734] 1 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.18 (s, 1H), 5.61 (br s, 1H), 3.99 (s, 2H), 2.85 (br s, 4H), 2.37 - 2.21 (m, 2H), 2.17 - 1.95 (m, 4H), 1.92 - 1.76 (m, 4H), 1.71 - 1.53 (m, 3H), 1.47 - 1.32 (m, 1H). [M+H] = 425.1.

[0735] Example 43. 5-Chloro-2-{[(2,2,2-trifluoroethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazo lo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0736]

[0737] 1 1H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 6.96 (s, 1H), 5.50 (s, 1H), 4.82 (br s, 1H), 4.44 (s, 2H), 4.20 (q, J = 9.1 Hz, 2H), 2.38 (dt, J = 4.3, 13.5 Hz, 2H), 1.94 - 1.46 (m, 7H), 1.40 - 1.20 (m, 1H). [M + H] = 403.1.

[0738] Example 44. 5-Chloro-2-{[(2-hydroxyethyl)(methyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxa zolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0739]

[0740] 1 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.18 (br s, 1H), 5.59 (br s, 1H), 4.21 (s, 2H), 3.88 - 3.72 (m, 2H), 3.00 (t, J = 4.6 Hz, 2H), 2.70 (s, 3H), 2.28 (dt, J = 3.9, 13.4 Hz, 2H), 2.04 (d, J = 12.8 Hz, 2H), 1.95 - 1.74 (m, 4H), 1.61 (q, J = 13.7 Hz, 2H), 1.43 (d, J = 13.0 Hz, 1H). [M + H] = 379.1.

[0741] Example 45. 5-Chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3] oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0742]

[0743] 1 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.19 (br s, 1H), 5.66 (br s, 1H), 4.06 (s, 2H), 3.89 (t, J = 12.0 Hz, 4H), 2.27 (dt, J = 4.2, 13.5 Hz, 2H), 2.04 (d, J = 12.7 Hz, 2H), 1.93 - 1.76 (m, 3H), 1.72 - 1.53 (m, 2H), 1.50 - 1.34 (m, 1H). [M + H] = 397.0.

[0744] Example 46. 5-Chloro-2-[(3,3-difluoropyrrolidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazo lo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0745]

[0746] 1 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.19 (s, 1H), 5.64 (br s, 1H), 4.03 (s, 2H), 3.20 (t, J = 13.3 Hz, 2H), 3.02 (t, J = 7.0 Hz, 2H), 2.45 - 2.22 (m, 4H), 2.04 (d, J = 12.5 Hz, 2H), 1.93 - 1.75 (m, 3H), 1.72 - 1.54 (m, 2H), 1.50 - 1.31 (m, 1H). [M+H] = 411.1.

[0747] Example 47. 2-[(4-acetylpiperazin-1-yl)methyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo [5,4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0748]

[0749] 1 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.50 (s, 1H), 6.50 (s, 1H), 4.28 (s, 2H), 3.90 (br s, 2H), 3.75 (t, J = 4.7 Hz, 2H), 3.16 - 3.04 (m, 4H), 2.33 - 2.19 (m, 2H), 2.16 (s, 3H), 2.05 (d, J = 13.1 Hz, 2H), 1.90 (d, J = 12.6 Hz, 1H), 1.85 - 1.76 (m, 2H), 1.66 (q, J = 13.7 Hz, 2H), 1.49 - 1.36 (m, 1H). [M+H] = 432.2.

[0750] Example 48. 5-Chloro-2-[(4-propionylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazo [5,4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0751]

[0752] 1 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.45 (s, 1H), 6.36 (s, 1H), 4.28 (s, 2H), 3.90 (br s, 2H), 3.75 (br s, 2H), 3.09 (d, J = 17.1 Hz, 4H), 2.28 - 2.18 (m, 4H), 2.05 (d, J = 12.8 Hz, 2H), 1.89 (d, J = 13.8 Hz, 1H), 1.85 - 1.75 (m, 2H), 1.65 (q, J = 13.5 Hz, 2H), 1.50 - 1.33 (m, 1H), 1.18 (t, J = 7.4 Hz, 3H). [M+H] = 446.3.

[0753] Example 49. 5-Chloro-2-{2-oxa-8-azaspiro[4.5]dec-8-ylmethyl}-7,8-dihydro-6H-spiro[[1, 3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0754]

[0755] 1 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.46 (s, 1H), 6.26 (s, 1H), 4.58 (s, 2H), 3.93 (t, J = 7.2 Hz, 2H), 3.64 (s, 2H), 2.34 - 2.19 (m, 3H), 2.14 - 1.95 (m, 6H), 1.94 - 1.75 (m, 6H), 1.70 - 1.32 (m, 5H). [M + H]+ = 445.3.

[0756] Example 50. 5-Chloro-2-{[4-(oxetan-3-yl)piperazin-1-yl]methyl}-7,8-dihydro-6H-spiro [[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one.

[0757]

[0758] 1 1H NMR (400 MHz, CDCl3) δ 7.77 - 7.64 (m, 1H), 7.58 - 7.47 (m, 1H), 6.56 (s, 1H), 5.06 -...

Claims

1. Compound of general formula (II): or a pharmaceutically acceptable salt thereof, wherein, Y is selected from: -H, -F, -Cl, -Br, and -C 1-4 alkyl group; Z is selected from: -H, -F and -C 1-4 alkyl; V is selected from: a bond, -CH2-, and -C(O)-; and W is selected from: -H, -halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC 1-4 alkyl, -C 3-7 cycloalkyl, said -C 3-7 cycloalkyl is unsubstituted or substituted by one or more -halogen or -C 1-6 alkyl, -C 1-6 aryl, -C 1-6 heteroaryl, said -C 1-6 aryl or -C 1-6 heteroaryl is unsubstituted, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -O-piperidinyl, unsubstituted 3-15 membered heterocycloalkyl and -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)3- to 15-membered heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2, -CH2CH2-R c and -(CH2) n -R d , wherein R c is -C 2-6 alkynyl, -C 3-7 cycloalkyl, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NHCH3, -N(CH3)2, -NHC(O)CH3 or -SO2CH3, wherein R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3- to 15-membered heterocycloalkyl, C6 aryl or 5- to 10-membered heteroaryl, wherein -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3- to 15-membered heterocycloalkyl, C6 aryl and 5- to 10-membered heteroaryl are each unsubstituted or substituted by up to 4 substituents, and the substituents are each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, 5- to 10-membered heteroaryl, 3- to 15-membered heterocycloalkyl, phenyl or benzyl, where n is 0, 1, 2, or 3; Alternatively, two Rs b together form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, optionally containing up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), said 4- to 15-membered monocyclic, bicyclic or tricyclic ring being unsubstituted or substituted by one to 4 Rs b1 wherein each R b1 is independently selected from halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

2. The compound according to claim 1, which has the structure of general formula (IIa): or a pharmaceutically acceptable salt thereof, wherein, Y is selected from: -H, -F, -Cl, -Br, and -CH3; and W is -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)3- to 15-membered heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , wherein R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3- to 15-membered heterocycloalkyl, C6 aryl or 5- to 10-membered heteroaryl, wherein -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3- to 15-membered heterocycloalkyl, C6 aryl and 5- to 10-membered heteroaryl are unsubstituted or each is substituted by up to 4 substituents, and the substituents are each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, 5- to 10-membered heteroaryl, 3- to 15-membered heterocycloalkyl, phenyl or benzyl, where n is 0, 1, 2, or 3; Alternatively, two Rs b together form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, said 4- to 15-membered monocyclic, bicyclic or tricyclic ring optionally containing up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), said 4- to 15-membered monocyclic, bicyclic or tricyclic ring being unsubstituted or substituted with up to 4 substituents, said substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

3. The compound according to claim 1, which has the structure of general formula (IIb): or a pharmaceutically acceptable salt thereof, wherein, Y is selected from: -H, -F, -Cl, -Br, and -CH3; and W is -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)3- to 15-membered heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , wherein R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3- to 15-membered heterocycloalkyl, C6 aryl or 5- to 10-membered heteroaryl, wherein -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3- to 15-membered heterocycloalkyl, C6 aryl and 5- to 10-membered heteroaryl are each unsubstituted or substituted by up to 4 substituents, and the substituents are each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, 5- to 10-membered heteroaryl, 3- to 15-membered heterocycloalkyl, C6 aryl or benzyl, where n is 0, 1, 2, or 3; Alternatively, two Rs b together form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, which optionally contains up to 3 additional heteroatoms, each independently selected from O (oxygen), N (nitrogen) and S (sulfur), and the 4- to 15-membered monocyclic, bicyclic or tricyclic ring is unsubstituted or substituted with up to 4 substituents, each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein W is selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-7-azaspiro[3.5]nonane, -2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-4,7'-thieno[2,3-c]pyridine], each of which is unsubstituted or substituted with up to 4 substituents, and the substituents are each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein W is halogen, -C 1-6 alkyl, -C 1-6 haloalkyl or -C 3-7 cycloalkyl; said -C 3-7 cycloalkyl is unsubstituted or substituted by one or more halogens or -C 1-6 alkyl.

6. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein W is selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC 1-4 alkyl, -C 3-7 cycloalkyl, said -C 3-7 cycloalkyl is unsubstituted or substituted by one or more halogens or -C 1-6 alkyl, unsubstituted -C 1-6 aryl, unsubstituted -C 1-6 heteroaryl, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -O-piperidinyl and -N(R b )2, wherein each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)3-15 membered heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , wherein R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3-15 membered heterocycloalkyl, C6 aryl or 5-10 membered heteroaryl, wherein -C 3-7 cycloalkyl, -C 3-7 A halogenated cycloalkyl group, a 3- to 15-membered heterocyclic hydrocarbon group, a C6 aryl group, and a 5- to 10-membered heteroaryl group are each unsubstituted or substituted with up to 4 substituents, and each of the substituents is independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, a 5- to 10-membered heteroaryl group, a 3- to 15-membered heterocyclic hydrocarbon group, phenyl or benzyl, where n is 0, 1, 2 or 3; or, two R b together form a 4- to 15-membered monocyclic, bicyclic or tricyclic ring, and the 4- to 15-membered monocyclic, bicyclic or tricyclic ring optionally contains up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), and the 4- to 15-membered monocyclic, bicyclic or tricyclic ring is unsubstituted or substituted with up to 4 substituents, and each of the substituents is independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

7. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein W is selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC 1-4 alkyl, -C 3-7 cycloalkyl, the -C 3-7 cycloalkyl is unsubstituted or substituted by one or more halogens or -C 1-6 alkyl, -C 1-6 aryl, -C 1-6 heteroaryl, the -C 1-6 aryl or -C 1-6 heteroaryl is unsubstituted, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -O-piperidyl and -N(R b )2, wherein each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)piperidine, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , wherein R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7 Halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, benzodioxin, benzodioxole, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine, benzimidazole, said R d is unsubstituted or substituted with up to 4 substituents, each of said substituents being independently selected from: -F, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, 5-10 membered heteroaryl, 3-15 membered heterocycloalkyl, phenyl, pyrrolidone, hydroxypiperidine or benzyl, where n is 0, 1, 2 or 3; or, two R b Together form a single ring, a bicyclic ring or a tricyclic ring, and the single ring, bicyclic ring or tricyclic ring is selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-7'-thieno[2,3-c]pyridine], and the single ring, bicyclic ring or tricyclic ring is unsubstituted or substituted with up to 4 substituents, and each substituent is independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

8. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein W is -N(R b )2, wherein each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)piperidine, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , wherein R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7 halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, benzodioxin, benzodioxole, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine, benzimidazole, and the R d is unsubstituted or substituted with up to 4 substituents, and each of the substituents is independently selected from: -F, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN or -N(CH3)2, -N(CH3)benzyl, 5- to 10-membered heteroaryl, 3- to 15-membered heterocycloalkyl, phenyl, pyrrolidone, hydroxypiperidine or benzyl, where n is 0, 1, 2 or 3.

9. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein W is -N(R b )2, where the two R b together form a monocyclic, bicyclic or tricyclic ring selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-7-azaspiro[3.5]nonane, -2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-4,7'-thieno[2,3-c]pyridine], the monocyclic, bicyclic or tricyclic ring being unsubstituted or substituted with up to 4 substituents, the substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

10. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein W is selected from: -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl and -CH2CH2OCH3.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein V is a bond and W is halogen, -C 1-3 alkyl, -C 1-3 haloalkyl or -C 3-5 cycloalkyl, and the -C 3-5 cycloalkyl is unsubstituted or substituted by one or more halogens or -C 1-3 alkyl.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein V is -CH2- and W is: -N(R b )2, where each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)3- to 15-membered heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , where R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3- to 15-membered heterocycloalkyl, C6 aryl or 5- to 10-membered heteroaryl, where -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3- to 15-membered heterocycloalkyl, C6 aryl and 5- to 10-membered heteroaryl are each unsubstituted or substituted by up to 4 substituents, and each of the substituents is independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, 5- to 10-membered heteroaryl, 3- to 15-membered heterocycloalkyl, phenyl or benzyl, where n is 0, 1, 2 or 3; or, two R b Together form a 4-15-membered monocyclic, bicyclic or tricyclic ring, said 4-15-membered monocyclic, bicyclic or tricyclic ring optionally containing up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), said 4-15-membered monocyclic, bicyclic or tricyclic ring being unsubstituted or substituted with up to 4 substituents, said substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein W is selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC 1-4 alkyl, -C 3-7 cycloalkyl, the -C 3-7 cycloalkyl is unsubstituted or substituted by one or more halogens or -C 1-6 alkyl, unsubstituted -C 1-6 aryl, unsubstituted -C 1-6 heteroaryl, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -O-piperidyl and -N(R b )2, wherein each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)piperidine, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , wherein R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7 halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, benzodioxin, benzodioxole, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine, benzimidazole, said R d is unsubstituted or substituted with up to 4 substituents, each of said substituents independently selected from: -F, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, 5-10-membered heteroaryl, 3-15-membered heterocycloalkyl, pyrrolidone, hydroxypiperidine, phenyl or benzyl, where n is 0, 1, 2 or 3; or, two R b Together form a single ring, double ring or triple ring, said single ring, double ring or triple ring selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidin]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine], 5',6'-dihydro-4'H-spiro[piperidine-4,7'-thieno[2,3-c]pyridine], said single ring, double ring or triple ring is unsubstituted or substituted with up to 4 substituents, said substituents each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole and -C(O)phenyl.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein W is -N(R b )2, wherein each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)piperidine, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , wherein R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7 halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, benzodioxin, benzodioxole, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine, benzimidazole, and the R d is unsubstituted or substituted with up to 4 substituents, and the substituents are each independently selected from: -F, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, 5-10 membered heteroaryl, 3-15 membered heterocyclic hydrocarbon group, pyrrolidone, hydroxypiperidine, phenyl or benzyl, where n is 0, 1, 2 or 3.

15. A compound or a pharmaceutically acceptable salt thereof according to claim 12 or 13, wherein W is -N(R b )2, where the two R b together form a monocyclic, bicyclic or tricyclic ring selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-4,7'-thieno[2,3-c]pyridine], and the monocyclic, bicyclic or tricyclic ring is unsubstituted or substituted with up to 4 substituents, and the substituents are each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC 1-4 alkyl, -C 3-7 cycloalkyl, the -C 3-7 cycloalkyl is unsubstituted or substituted by one or more halogens or -C 1-6 alkyl, unsubstituted -C 1-6 aryl, unsubstituted -C 1-6 heteroaryl, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -O-piperidinyl and -N(R b )2, wherein each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)3-15-membered heterocycloalkyl, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , wherein R d is -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3-15-membered heterocycloalkyl, C6 aryl and 5-10-membered heteroaryl, wherein -C 3-7 cycloalkyl, -C 3-7 halocycloalkyl, 3-15-membered heterocycloalkyl, C6 aryl and 5-10-membered heteroaryl are each unsubstituted or substituted by up to 4 substituents, and the substituents are each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 3-7 cycloalkyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, 5-10 membered heteroaryl, 3-15 membered heterocycloalkyl, phenyl or benzyl, where n is 0, 1, 2 or 3; or, two R b together form a 4-15-membered monocyclic, bicyclic or tricyclic ring, said 4-15-membered monocyclic, bicyclic or tricyclic ring optionally contains up to 3 additional heteroatoms, each heteroatom independently selected from O (oxygen), N (nitrogen) and S (sulfur), said 4-15-membered monocyclic, bicyclic or tricyclic ring is unsubstituted or substituted with up to 4 substituents, said substituents are each independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

17. The compound or a pharmaceutically acceptable salt thereof according to claim 16, wherein W is selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -CH2OC 1-5 alkyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -C(O)C 1-6 alkyl, -C(O)C 3-7 cycloalkyl, -C(O)OC 1-4 alkyl, -C 3-7 cycloalkyl, said -C 3-7 cycloalkyl is unsubstituted or substituted by one or more halogens or -C 1-6 alkyl, unsubstituted -C 1-6 aryl, unsubstituted -C 1-6 heteroaryl, -OH, -OC 1-6 alkyl, -OCH2CH2OCH3, -OCH2C(O)N(CH3)2, -O-tetrahydropyranyl, -O-piperidyl and -N(R b )2, wherein each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)piperidine, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , wherein R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7 Halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, dibenzo-1,4-dioxin, benzodioxole, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine, benzimidazole, said R d is unsubstituted or substituted with up to 4 substituents, each of said substituents being independently selected from: -F, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, 5-10-membered heteroaryl, 3-15-membered heterocycloalkyl, pyrrolidone, hydroxypiperidine, phenyl or benzyl, where n is 0, 1, 2 or 3; or, two R b Together form a single ring, double ring or triple ring, and the single ring, double ring or triple ring is selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidin]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine], 5',6'-dihydro-4'H-spiro[piperidine-4,7'-thieno[2,3-c]pyridine], and the single ring, double ring or triple ring is unsubstituted or substituted with at most 4 substituents, and each substituent is independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole and -C(O)phenyl.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 16, wherein W is -N(R b )2, wherein each R b is independently selected from: -H, -C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 haloalkyl, -C 1-6 haloalkylOH, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -CH2-alkenyl, -CH2-alkynyl, -CH2C 3-7 cycloalkyl, -CH2C(O)C 1-6 alkyl, -CH2C(O)piperidine, -CH2C(O)OC 1-6 alkyl, -CH2C(O)N(C 1-4 alkyl)2, -CH2CH(OH)C 3-7 cycloalkyl, -C(CH3)2CH2OCH3, -CH(CH3)C(O)N(C 1-4 alkyl)2 and -(CH2) n -R d , wherein R d is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, -C 3-7 halocycloalkyl, oxetane, pyrrolidine, pyrrolidone, piperidine, piperidone, tetrahydropyranyl, tetrahydrofuryl, oxepane, morpholine, 3-azabicyclo[3.1.0]hexane, tetrahydrothiophene-1,1-dioxide, tetrahydro-2H-thiopyran-1,1-dioxide, thiomorpholine-1,1-dioxide, 1,3-dihydroisobenzofuran, benzofuran, dihydroindole, benzodioxin, benzodioxole, phenyl, benzyl, -CH2CH2phenyl, -CH2CH2CH2phenyl, furan, pyrrole, pyrazole, imidazole, triazole, isoxazole, oxazole, thiazole, pyridine, pyrimidine, thiophene, pyrrolopyridine, benzimidazole, and the R d is unsubstituted or substituted with up to 4 substituents, and the substituents are each independently selected from: -F, -C 1-6 alkyl, -C 1-6 haloalkyl, cyclopropyl, -OH, -OC 1-6 alkyl, -O-C 1-6 haloalkyl, -O-phenyl, -O-pyridyl, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CN, -N(CH3)2, -N(CH3)benzyl, 5- to 10-membered heteroaryl, 3- to 15-membered heterocyclic hydrocarbon group, pyrrolidone, hydroxypiperidine, phenyl or benzyl, where n is 0, 1, 2 or 3.

19. A compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein W is -N(R b )2, wherein the two R b together form a monocyclic, bicyclic or tricyclic ring selected from: azetidine, pyrrole, pyrrolidine, pyrrolidone, piperazine, piperazinone, piperidine, piperidone, azepane, morpholine, 1-oxa-8-azaspiro[4.5]dec-3-one, 2-oxa-7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]dec-1-one, 6-oxa-9-azaspiro[4.5]decane, 7-oxa-2-azaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, oxaazabicyclo[2.2.1]heptane, thiomorpholine-1,1-dioxide, diazepane, 2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepane, 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one, azaspiro[2.5]octane, azabicyclo[3.1.0]hexane, azabicyclo[4.1.0]heptane, diazaspiro[5.5]undecane, tetrahydroimidazopyrazine, dihydropyrrolopyridine, spiro[chroman-2,3'-pyrrolidine]-4-one, spiro[isochroman-1,4'-piperidine], 6',7'-dihydro-5'H-spiro[piperidine-4,4'-thieno[3,2-c]pyridine] and 5',6'-dihydro-4'H-spiro[piperidine-4,7'-thieno[2,3-c]pyridine], and the monocyclic, bicyclic or tricyclic ring is unsubstituted or substituted with up to 4 substituents, and each substituent is independently selected from: halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 haloalkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl, -C 1-6 alkyl-OH, -CH2OC 1-6 alkyl, -CH2C(O)OCH2CH3, -CH2CH2OC 1-6 alkyl, -CH2CH2OC 1-6 haloalkyl, -CH2CH2C(O)OCH3, -OH, -OC 1-6 alkyl, -OCH2-C 3-7 cycloalkyl, -OCH2CH2OCH3, =O, -CH2N(CH3)2, -CH2CH2N(CH3)2, -C(O)C 1-6 alkyl, -C(O)H, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CN, -NH2, -NHC(O)CH3, -N(CH3)2, -SO2CH3, oxetane, pyrrolidine, morpholine, furan, thiazole, pyridyl, phenyl, thiophene, -CH2imidazole, -CH2furan, -CH2-thiophene, -CH2pyridyl, benzyl, -C(O)-tetrahydrofuran, -C(O)pyrrole or -C(O)phenyl.

20. A compound selected from: Methyl 5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxylate; 5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxylic acid; 5-Chloro-2-(chloromethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2-methoxyethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(2-methoxyethoxy)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; Ethyl 2-{5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}acetate; 5-Chloro-2-(4-methoxypiperidine-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Fluoro-2-[(3-methoxyazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; Methyl 5-chloro-4',4'-difluoro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxylate; 5-Chloro-4',4'-difluoro-2-[(4-methylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-4',4'-difluoro-2-methyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2,4',4'-trimethyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-methyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-ethyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-propyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(propan-2-yl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-cyclopropyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(methoxymethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(hydroxymethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(2-methoxyethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(2-hydroxyethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; N-{5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}acetamide; 2-[Bis(2-methoxyethyl)amino]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[(dimethylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-methylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(morpholin-4-ylmethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-hydroxypiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(methylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(cyclopropylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(piperazin-1-ylmethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(pyrrolidin-1-ylmethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(propan-2-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(ethylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2-hydroxyethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4,4-difluoropiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2,2,2-trifluoroethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2-hydroxyethyl)(methyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3,3-difluoropyrrolidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[(4-acetylpiperazin-1-yl)methyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-propionylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{2-oxa-8-azaspiro[4.5]dec-8-ylmethyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(oxetan-3-yl)piperazin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}amino)-N,N-dimethylacetamide; tert-Butyl 2-[({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}amino)methyl]piperidine-1-carboxylate; 5-Chloro-2-({[(3,5-difluoropyridin-2-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(piperidin-2-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[2-oxo-2-(piperidin-1-yl)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}amino)-N-ethyl-N-methylacetamide; 5-Chloro-2-[(4-methyl-3-oxopiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-ethyl-3-oxopiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(pyridin-2-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(pyrimidin-2-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(5-methoxypyridin-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(2,4-dimethyl-3-oxopiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; Ethyl 1-{5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}piperidine-4-carboxylate; 5-Chloro-2-({1-oxo-2-oxa-8-azaspiro[4.5]dec-8-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[(4-Acetylpiperidin-1-yl)methyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; Methyl 1-{5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}piperidine-4-carboxylate; 5-Chloro-2-({[(5-fluoropyridin-2-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[3-(2-methylpropoxy)azetidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-ethoxypiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(cyclopropylmethoxy)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(propan-2-yloxy)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3-fluoroazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3-methoxyazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[3-(methoxymethyl)azetidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{7-oxa-2-azaspiro[3.5]non-2-ylmethyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-methoxy-4-methylpiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}(methyl)amino)-N,N-dimethylacetamide; 5-Chloro-2-({[(6-methylpyridin-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[methyl(oxan-4-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({methyl[(3-methyloxetan-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(3-fluorooxetan-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(oxan-4-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{2-oxa-7-azaspiro[3.5]non-7-ylmethyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(3-methyloxetan-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[methyl(2,2,2-trifluoroethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(oxetan-3-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-oxopiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(2-methoxyphenyl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(2,4-dimethoxyphenyl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(propan-2-yl)piperazin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3,3,4-trimethylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[2-(hydroxymethyl)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[1-(hydroxymethyl)cyclopentyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(2-methylpiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[2-(2-methylpropyl)morpholin-4-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2-cyclobutyl-2,2-difluoroethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3-ethylmorpholin-4-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2-cyclohexyl-2-hydroxyethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{6-oxa-9-azaspiro[4.5]dec-9-ylmethyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[1-(oxan-2-yl)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(oxan-2-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3-methyl-2-oxobutyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(4,4-difluorocyclohexyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(1r,4r)-4-methoxycyclohexyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3-methoxy-3-methylazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-methoxypiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(dimethylamino)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[3-(hydroxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3R)-3-methoxypiperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3S)-3-methoxypiperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3R)-3-ethoxypyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[2-(dimethylamino)ethyl](methyl)amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 3-({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}(methyl)amino)-N,N-dimethylpropanamide; 5-Chloro-2-({methyl[2-(morpholin-4-yl)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3-methoxypyrrolidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; Methyl 2-({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-2-ylmethyl}(methyl)amino)acetate; 2-[(8aR)-Octahydropyrrolo[1,2-a]piperazin-2-ylmethyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[methyl(oxan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; Methyl 1-{5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-2-ylmethyl}piperidine-3-carboxylate; Methyl 2-({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-2-ylmethyl}amino)acetate; 5-Chloro-2-{[(3S)-3-methoxypyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(oxan-3-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(3R)-3-(methoxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; (3R)-Methyl 1-{5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-2-ylmethyl}piperidine-3-carboxylate; 5-Chloro-2-({[2-(trifluoromethoxy)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-[(4-ethylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}amino)-N,N-diethylacetamide; (2S)-2-({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}amino)-N,N-dimethylpropanamide; (2R)-2-({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}amino)-N,N-dimethylpropanamide; 5-Chloro-2-({[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(oxan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[({3-oxabicyclo[3.1.0]hex-6-yl}amino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(oxepan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(tetrahydrofuran-3-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3,3-difluoro-2-hydroxypropyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5, ​ ​ 5-Chloro-2-({[(3S)-oxan-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(3S)-tetrahydrofuran-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3-methyltetrahydrofuran-3-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(3R)-tetrahydrofuran-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(2-methoxyethoxy)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[(8aS)-Octahydropyrrolo[1,2-a]piperazin-2-ylmethyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; (3R)-Methyl 1-{5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}pyrrolidine-3-carboxylate; 5-Chloro-2-{[4-(2,2-difluoroethyl)piperazin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(3-methyltetrahydrofuran-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(3R)-oxan-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(3R)-tetrahydrofuran-3-ylmethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3-fluoroxan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2,2-difluoro-3-hydroxypropyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2,2-difluorocyclopentyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-({[4-(methoxymethyl)oxan-4-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-({[(3S)-tetrahydrofuran-3-ylmethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-4',4'-difluoro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-4',4'-difluoro-2-({[(3S)-tetrahydrofuran-3-ylmethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(1,3-oxazol-2-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(1,3-oxazol-5-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-({[2-(1,2-oxazol-3-yl)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(1,3-oxazol-4-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-({[(1-methyl-1H-pyrazol-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(1,2-oxazol-5-ylmethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 2-{5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-2-ylmethoxy}-N,N-dimethylacetamide; 5-Chloro-2-[(tetrahydro-2H-pyran-4-yloxy)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(1-methylpiperidin-4-yl)oxy]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexan]-7-one; 5-Chloro-N-[2-(dimethylamino)ethyl]-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-(morpholine-4-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexan]-7-one; 5-Chloro-N,N-dimethyl-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-(4-methylpiperazine-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexan]-7-one; 5-Chloro-N-(2-methoxyethyl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexan]-7-one; 5-Chloro-N-(2-methoxyethyl)-N-methyl-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[(3R)-3-ethoxypyrrolidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexan]-7-one; 2-{1-(5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexan]-2-yl)-N-methylcarbamoyl}-N,N-dimethylacetamide; 3-{1-(5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin-9,1'-cyclohexan]-2-yl)-N-methylcarbamoyl}-N,N-dimethylpropanamide; 5-Chloro-2-[(2S)-2-(methoxymethyl)pyrrolidin-1-ylcarbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; Methyl 2-{1-5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-2-yl-N-methylformamido}acetate; 5-Chloro-N-methyl-N-[2-(methylamino)ethyl]-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-[2-(dimethylamino)ethyl]-N-methyl-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[4-(dimethylamino)piperidin-1-ylcarbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-[4-(2,2,2-trifluoroethyl)piperazin-1-ylcarbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-[4-(2-methoxyethyl)piperazin-1-ylcarbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 2-[(8aR)-Octahydropyrrolo[1,2-a]piperazin-2-ylcarbonyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-N-methyl-N-(oxan-4-yl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-(3-methoxypyrrolidin-1-ylcarbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-[(3R)-3-methoxypiperidin-1-ylcarbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-N-(oxan-3-yl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[(3S)-3-methoxypyrrolidin-1-ylcarbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-[(3R)-3-(methoxymethyl)pyrrolidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3S)-3-(methoxymethyl)pyrrolidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-7-oxo-N-[2-(trifluoromethoxy)ethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[(3R)-3-methoxypyrrolidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(4-ethylpiperazine-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[4-(propan-2-yl)piperazine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[4-(2,2-difluoroethyl)piperazine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[(8aS)-Octahydropyrrolo[1,2-a]piperazine-2-carbonyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(piperazine-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-7-oxo-N-[(3R)-tetrahydrofuran-3-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[4-(2-fluoroethyl)piperazine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-N-(2,2-difluorocyclopentyl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-[4-(methoxymethyl)tetrahydro-2H-pyran-4-yl]-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-(3-fluorooxan-4-yl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-(2,2-difluoro-3-hydroxypropyl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-7-oxo-N-[(3S)-tetrahydrofuran-3-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-7-oxo-N-[(3S)-tetrahydrofuran-3-yl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-7-oxo-N-[(3R)-tetrahydrofuran-3-yl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 2-[(8aS)-Octahydropyrrolo[1,2-a]piperazine-2-carbonyl]-5-chloro-4',4'-difluoro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[(4,4-Difluoropiperidin-1-yl)methyl]-5-fluoro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Fluoro-2-{[(2-methoxyethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-({5-Fluoro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}(methyl)amino)-N,N-dimethylacetamide; 2-({5-Fluoro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}amino)-N,N-dimethylacetamide; 5-Chloro-4',4'-difluoro-2-({[(3S)-oxan-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-4',4'-difluoro-2-({[(3R)-tetrahydrofuran-3-ylmethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-4',4'-difluoro-2-({[(3S)-tetrahydrofuran-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-4',4'-difluoro-2-({[(3R)-oxan-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; and its pharmaceutically acceptable salts.

21. A compound selected from: Methyl 5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxylate; 5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-[2-(dimethylamino)ethyl]-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-(morpholine-4-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxylic acid; 5-Chloro-N,N-dimethyl-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-(4-methylpiperazine-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(4-methoxypiperidine-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-N-(2-methoxyethyl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-N-(2-methoxyethyl)-N-methyl-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-methyl-N-(oxan-4-ylmethyl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[(3R)-3-ethoxypyrrolidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-{1-5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl-N-methylformamido}-N,N-dimethylacetamide; 3-{1-5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl-N-methylformamido}-N,N-dimethylpropanamide; 5-Chloro-2-[(2S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; Methyl 2-{1-5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl-N-methylformamido}acetate; 5-Chloro-N-methyl-N-[2-(methylamino)ethyl]-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-[2-(dimethylamino)ethyl]-N-methyl-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[4-(dimethylamino)piperidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[4-(2-methoxyethyl)piperazine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[(8aR)-Octahydropyrrolo[1,2-a]piperazine-2-carbonyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-N-methyl-N-(oxan-4-yl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-(3-methoxypyrrolidine-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3R)-3-methoxypiperidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-N-(oxan-3-yl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[(3S)-3-methoxypyrrolidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3R)-3-(methoxymethyl)pyrrolidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3S)-3-(methoxymethyl)pyrrolidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-7-oxo-N-[2-(trifluoromethoxy)ethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[(3R)-3-methoxypyrrolidine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(4-ethylpiperazine-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[4-(propan-2-yl)piperazine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[4-(2,2-difluoroethyl)piperazine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[(8aS)-Octahydropyrrolo[1,2-a]piperazine-2-carbonyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(piperazine-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-7-oxo-N-[(3R)-tetrahydrofuran-3-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-[4-(2-fluoroethyl)piperazine-1-carbonyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-N-(2,2-difluorocyclopentyl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-[4-(methoxymethyl)oxan-4-yl]-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-(3-fluorooxan-4-yl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-N-(2,2-difluoro-3-hydroxypropyl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-7-oxo-N-[(3S)-tetrahydrofuran-3-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-7-oxo-N-[(3S)-tetrahydrofuran-3-yl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-7-oxo-N-[(3R)-tetrahydrofuran-3-yl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; Methyl 5-chloro-4',4'-difluoro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxylate; 2-[(8aS)-Octahydropyrrolo[1,2-a]piperazine-2-carbonyl]-5-chloro-4',4'-difluoro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; and pharmaceutically acceptable salts thereof.

22. A compound selected from: 5-Chloro-2-methyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(chloromethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(methoxymethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(hydroxymethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-propyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-ethyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(dimethylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-methylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(morpholin-4-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-hydroxypiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(methylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(cyclopropylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(piperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(pyrrolidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(2-methoxyethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-(2-hydroxyethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2-methoxyethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(propan-2-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(ethylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2-hydroxyethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4,4-difluoropiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2,2,2-trifluoroethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2-hydroxyethyl)(methyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3,3-difluoropyrrolidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[(4-acetylpiperazin-1-yl)methyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-propionylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({2-oxa-8-azaspiro[4.5]dec-8-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(oxetan-3-yl)piperazin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)amino]-N,N-dimethylacetamide; 2-{[({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)amino]methyl}piperidine-1-carboxylic acid tert-butyl ester; 5-Chloro-2-({[(3,5-difluoropyridin-2-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(piperidin-2-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[2-oxo-2-(piperidin-1-yl)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)amino]-N-ethyl-N-methylacetamide; 5-Chloro-2-[(4-methyl-3-oxopiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-ethyl-3-oxopiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(pyridin-2-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(pyrimidin-2-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(5-methoxypyridin-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(2,4-dimethyl-3-oxopiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; Ethyl 1-({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)piperidine-4-carboxylate; 5-Chloro-2-({1-oxo-2-oxa-8-azaspiro[4.5]dec-8-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[(4-acetylpiperidin-1-yl)methyl]-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; Methyl 1-({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)piperidine-4-carboxylate; 5-Chloro-2-({[(5-fluoropyridin-2-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[3-(2-methylpropoxy)azetidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-ethoxypiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(cyclopropylmethoxy)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-hydroxy-4-(trifluoromethyl)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(propan-2-yloxy)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3-fluoroazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3-methoxyazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[3-(methoxymethyl)azetidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({7-oxa-2-azaspiro[3.5]nonan-2-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-methoxy-4-methylpiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({3-oxo-1-oxa-8-azaspiro[4.5]dec-8-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)(methyl)amino]-N,N-dimethylacetamide; 5-Chloro-2-({[(6-methylpyridin-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({methyl[(oxan-4-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({methyl[(3-methyloxetan-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(3-fluorooxetan-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(oxan-4-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({2-oxa-7-azaspiro[3.5]non-7-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(3-methyloxetan-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({2-oxa-5-azabicyclo[2.2.1]hept-5-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[methyl(2,2,2-trifluoroethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(oxetan-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-oxopiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(2-methoxyphenyl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(2,4-dimethoxyphenyl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(propan-2-yl)piperazin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3,3,4-trimethylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[2-(hydroxymethyl)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[1-(hydroxymethyl)cyclopentyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(2-methylpiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[2-(2-methylpropyl)morpholin-4-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2-cyclobutyl-2,2-difluoroethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3-ethylmorpholin-4-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2-cyclohexyl-2-hydroxyethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({6-oxa-9-azaspiro[4.5]dec-9-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[1-(oxan-2-yl)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(oxan-2-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(2-methoxyethoxy)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; Ethyl 2-{5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-2-yl}acetate; 2-[(4,4-Difluoropiperidin-1-yl)methyl]-5-fluoro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Fluoro-2-{[(2-methoxyethyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(3-methyl-2-oxobutyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Fluoro-2-[(3-methoxyazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(4,4-difluorocyclohexyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Chloro-2-({[(1R,4R)-4-methoxycyclohexyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Chloro-2-[(3-methoxy-3-methylazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Chloro-2-[(4-methoxypiperidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[4-(dimethylamino)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazolin]-9,1'-cyclohexan]-7-one; 5-Chloro-2-({5-methyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[3-(hydroxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3R)-3-methoxypiperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3S)-3-methoxypiperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3R)-3-ethoxypyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3R)-3-hydroxypyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[2-(dimethylamino)ethyl](methyl)amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 3-[({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)(methyl)amino]-N,N-dimethylpropanamide; 5-Chloro-2-({methyl[2-(morpholin-4-yl)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(3-methoxypyrrolidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[4-(2,2,2-trifluoroethyl)piperazin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; Methyl 2-[({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)(methyl)amino]acetate; 2-{[(8aR)-Octahydropyrrolo[1,2-a]pyrazin-2-yl]methyl}-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[methyl(oxan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; Methyl 1-({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)piperidine-3-carboxylate; Methyl 2-[({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)amino]acetate; 5-Chloro-2-{[(3S)-3-methoxypyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(oxan-3-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[(3R)-3-(methoxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; (3R)-Methyl 1-({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)piperidine-3-carboxylate; 2-({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methoxy)-N,N-dimethylacetamide; 5-Chloro-2-[(oxan-4-yloxy)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-({[2-(trifluoromethoxy)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(4-ethylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[3-(dimethylamino)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)amino]-N,N-diethylacetamide; (2S)-2-[({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)amino]-N,N-dimethylpropanamide; (2R)-2-[({5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)amino]-N,N-dimethylpropanamide; 5-Chloro-2-({[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(oxan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[({3-oxabicyclo[3.1.0]hexan-6-yl}amino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(oxepan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(tetrahydrofuran-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3,3-difluoro-2-hydroxypropyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(4-cyclopropyloxan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-2-{[(2,6-dimethyloxan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-2-({[(3S)-oxan-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-2-({[(3S)-tetrahydrofuran-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-2-{[(3-methyltetrahydrofuran-3-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-2-({[(3R)-tetrahydrofuran-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-2-{[4-(2-methoxyethoxy)piperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-{[(8aS)-octahydropyrrolo[1,2-a]pyrazin-2-yl]methyl}-5-chloro-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; (3R)-methyl 1-({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)pyrrolidine-3-carboxylate; 5-chloro-2-{[4-(2,2-difluoroethyl)piperazin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-2-({[(3-methyltetrahydrofuran-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-2-({[(3R)-oxan-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-2-[({[(3R)-tetrahydrofuran-3-yl]methyl}amino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-2-{[(3-fluoroxan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2,2-difluoro-3-hydroxypropyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(2,2-difluorocyclopentyl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[4-(methoxymethyl)oxan-4-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[({[(3S)-tetrahydrofuran-3-yl]methyl}amino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-({[(1,3-oxazol-2-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-4',4'-difluoro-2-methyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(1-methylpiperidin-4-yl)oxy]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 2-[({5-Fluoro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)(methyl)amino]-N,N-dimethylacetamide; 2-[({5-Fluoro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-yl}methyl)amino]-N,N-dimethylacetamide; 5-Chloro-4',4'-difluoro-2-{[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-4',4'-difluoro-2-[({[(3S)-tetrahydrofuran-3-yl]methyl}amino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2,4',4'-trimethyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-chloro-4',4'-difluoro-2-({[(3S)-oxan-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-chloro-4',4'-difluoro-2-[(4-methylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-chloro-4',4'-difluoro-2-[({[(3R)-tetrahydrofuran-3-yl]methyl}amino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-chloro-4',4'-difluoro-2-({[(3S)-tetrahydrofuran-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-chloro-4',4'-difluoro-2-({[(3R)-oxan-3-yl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-chloro-2-({[(1,3-oxazol-5-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-chloro-2-({[2-(1,2-oxazol-3-yl)ethyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-chloro-2-({[(1,3-oxazol-4-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-chloro-2-({[(1-methyl-1H-pyrazol-3-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-chloro-2-({[(1,2-oxazol-5-yl)methyl]amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; and its pharmaceutically acceptable salts.

23. A compound selected from: 5-chloro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-chloro-2-[(3-methoxy-3-methylazetidin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[3-(hydroxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-({[2-(dimethylamino)ethyl](methyl)amino}methyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-{[methyl(oxan-4-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; and pharmaceutically acceptable salts thereof.

24. A compound selected from: 5-Chloro-2-(hydroxymethyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-propyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-ethyl-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-[(dimethylamino)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-[(4-methylpiperazin-1-yl)methyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; and pharmaceutically acceptable salts thereof.

25. A compound selected from: 5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxylic acid; 5-Chloro-N,N-dimethyl-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; 5-Chloro-2-(4-methylpiperazin-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-(4-methoxypiperidin-1-carbonyl)-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-N-(2-methoxyethyl)-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-carboxamide; and pharmaceutically acceptable salts thereof.

26. A compound selected from: 5-Chloro-2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one; 5-Chloro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3-(hydroxymethyl)pyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3R)-3-methoxypiperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(3S)-3-methoxypiperidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; and pharmaceutically acceptable salts thereof.

27. A compound selected from: 1-{5-Chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}piperidine-3-carboxylate; Methyl 2-({5-chloro-7-oxo-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-2-ylmethyl}amino)acetate; 5-Chloro-2-{[(3S)-3-methoxypyrrolidin-1-yl]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; 5-Chloro-2-{[(oxan-3-yl)amino]methyl}-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one; and pharmaceutically acceptable salts thereof.

28. A compound which is 5-chloro-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-7,8-dihydro-6H-spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexane]-7-one or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising the compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

30. Use of the compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 29 in the manufacture of a medicament for treating a neurological disorder in an individual.

31. Use according to claim 30, wherein the neurological disorder is a central nervous system disorder.

32. The use according to claim 31, wherein the central nervous system disorder is selected from mental disorders and psychiatric conditions, addictive disorders, cognitive disorders, movement disorders, and neurodegenerative disorders.

33. The use according to claim 32, wherein the mental disorders and psychiatric conditions are selected from schizophrenia spectrum disorders, psychotic disorders, and schizophrenia.

34. The use according to claim 32, wherein the cognitive disorder is selected from age-related cognitive decline and trauma-dependent loss of function.

35. The use according to claim 34, wherein the trauma-dependent loss of function is a stroke.

36. The use according to claim 35, wherein the stroke is an ischemic stroke.

37. The use according to claim 35, wherein the stroke is a hemorrhagic stroke.

38. The use according to claim 35, wherein the individual is a patient with acute or subacute stroke.

39. The use according to claim 35, wherein the individual is a post-stroke patient.

40. The use according to claim 35, wherein the individual is undergoing post-stroke rehabilitation.

41. The use according to claim 34, wherein the age-related cognitive decline is age-related memory impairment or mild cognitive impairment.

42. The use according to claim 32, wherein the movement disorder is selected from basal ganglia disorders, Parkinson's disease, Huntington's disease, attention deficit hyperactivity disorder, hypokinesia, and movement disordering conditions.

43. The use according to claim 42, wherein the movement disorder is Parkinson's disease.

44. The use according to claim 32, wherein the neurodegenerative disorder is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and spinal cord injury.

45. The use according to claim 44, wherein the neurodegenerative disorder is Parkinson's disease.

46. The use of the compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 29, in the preparation of a medicament for treating peripheral disorders.

47. The use according to claim 46, wherein the peripheral disorder is an infectious disease, cancer or blood disease, cardiovascular disease, gastrointestinal disorder, skin disorder, kidney disease, immune or inflammatory disorder, or fertility disorder.

48. The use according to claim 47, wherein the immune or inflammatory disorder is selected from allergic rhinitis; celiac disease; skin disorders; conjunctivitis; chronic fatigue syndrome; encephalomyelitis; systemic lupus erythematosus; inflammatory bowel disease; arthritis diseases; respiratory and lung diseases; hepatitis; pancreatitis; sepsis; human immunodeficiency virus infection; and acquired immunodeficiency syndrome.

49. The use according to claim 47, wherein the immune or inflammatory disorder is atopic dermatitis or dermatitis herpetiformis.

50. The use according to claim 48, wherein the skin disease is psoriasis; the encephalomyelitis is myalgic encephalomyelitis; the inflammatory bowel disease is Crohn's disease or ulcerative colitis; the arthritis disease is rheumatoid arthritis, osteoarthritis or psoriatic arthritis; and / or the respiratory and pulmonary diseases are bronchial asthma, chronic bronchitis or chronic obstructive pulmonary disease.

51. The use according to claim 49, wherein the atopic dermatitis is eczema.

52. Use of a compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 29 in the manufacture of a medicament for the treatment of a disorder comprising an aberrant or dysregulated signaling pathway mediated by PDE7.

53. The use according to claim 52, wherein the PDE7-mediated signaling pathway involves cAMP, cAMP-dependent protein kinase or transcription factor, cAMP response element binding protein.

54. Use of a compound according to claim 28 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 29 in the manufacture of a medicament for the treatment of a neurological disorder in an individual.

55. The use according to claim 54, wherein the neurological disorder is a central nervous system disorder.

56. The use according to claim 55, wherein the central nervous system disorder is selected from mental disorders and psychiatric conditions, addictive disorders, cognitive disorders, movement disorders and neurodegenerative disorders.

57. The use according to claim 56, wherein the mental disorders and psychiatric conditions are selected from schizophrenia spectrum disorders, psychotic disorders and schizophrenia.

58. The use according to claim 56, wherein the cognitive disorders are selected from age-related cognitive decline and trauma-dependent loss of function.

59. Use of a compound according to claim 28 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 29 in the manufacture of a medicament for the treatment of a peripheral disorder.

60. The use according to claim 59, wherein the peripheral disorder is an infectious disease, cancer or blood disease, cardiovascular disease, gastrointestinal disorder, skin disease, kidney disease, immune or inflammatory disorder or fertility disorder.

61. The use according to claim 60, wherein the immune or inflammatory disorder is selected from allergic rhinitis; celiac disease; skin disease; conjunctivitis; chronic fatigue syndrome; encephalomyelitis; systemic lupus erythematosus; inflammatory bowel disease; arthritis disease; respiratory and pulmonary diseases; hepatitis; pancreatitis; sepsis; human immunodeficiency virus infection; and acquired immunodeficiency syndrome.

62. The use according to claim 60, wherein the immune or inflammatory disorder is atopic dermatitis or dermatitis herpetiformis.

63. The use according to claim 61, wherein the skin disease is psoriasis; the encephalomyelitis is myalgic encephalomyelitis; the inflammatory bowel disease is Crohn's disease or ulcerative colitis; the arthritis disease is rheumatoid arthritis, osteoarthritis or psoriatic arthritis; and / or the respiratory and pulmonary diseases are bronchial asthma, chronic bronchitis or chronic obstructive pulmonary disease.

64. The use according to claim 62, wherein the atopic dermatitis is eczema.

65. Use of the compound according to claim 28 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 29 in the manufacture of a medicament for treating a disorder comprising an abnormal or dysregulated signaling pathway mediated by PDE7.

66. The use according to claim 65, wherein the PDE7-mediated signaling pathway involves cAMP, cAMP-dependent protein kinase or transcription factor, cAMP response element binding protein.

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