Substituted furopyrimidine compounds as PDE1 inhibitors

Abstract

Substituted furopyrimidine chemical entities of general formula (I): wherein R a has 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; modulating and treating disorders mediated by PDE1 activity or dopaminergic signaling; treating neurological disorders, CNS disorders, dementia, neurodegenerative diseases, and trauma-dependent loss of function; treating stroke, including cognitive and motor function deficits during stroke rehabilitation; promoting neuroprotection and neurorestoration; enhancing the efficiency of cognitive and motor training, including animal skill training protocols; and treating peripheral disorders, including cardiovascular disorders, renal disorders, hematological disorders, gastrointestinal disorders, liver disorders, cancer, fertility disorders, and metabolic disorders.

Description

[0001] Background

[0002] Field

[0003] The present invention relates to certain substituted furopyrimidine compounds and related chemical entities; compositions containing them; methods for preparing them; and their use in various methods and therapies, including enhancing neuroplasticity, and treating neurological disorders, cognitive impairments, cardiovascular disorders, gastrointestinal disorders, renal disorders, and other conditions and diseases involving PDE1, dopaminergic, or cyclic nucleotide signaling.

[0004] Description of Related Art

[0005] Cyclic nucleotides, adenosine, and guanosine 3',5'-cyclic monophosphates (cAMP and cGMP) are second messengers in cellular signaling cascades activated by a variety of 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 and survival, muscle contraction, sensory transduction, cell division, stress response, and inflammation.

[0006] Cyclic nucleotide levels are tightly regulated, including the action of phosphodiesterases (PDEs), which are 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 divided into 11 families, PDE1–11. Some are cAMP-selective hydrolases (PDE4, 7, and 8), some are cGMP-selective hydrolases (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 become attractive targets for the treatment of 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 associated with 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 PDE1 family, which hydrolyzes both cAMP and cGMP, is distinguished from other PDEs by its requirement for calcium (Ca 2+ ) and calmodulin (CaM) for full activation (Goraya and Cooper, 2005, Cell. Signal. 17, 789-797). Binding of the Ca 2+ -CaM complex at a site near the N-terminus of PDE1 stimulates the hydrolysis of cyclic nucleotides. In intact cells, PDE1 is almost completely activated by Ca 2+It is activated by entering the cell from the extracellular space. Thus, PDE1 is a point of convergence and integration of multiple signaling pathways that regulate multiple downstream targets and cellular events. For a review, see Bender and Beavo, 2006, Pharmacol. Rev. 58, 488–520; Sharma et al., 2006, Int. J. Mol. Med. 18, 95-105.

[0008] The PDE1 family contains three members, encoded by separate genes (Pde1A, PDE1B, and PDE1C), which generate multiple isoforms through alternative splicing and differential transcription. All PDE1 enzymes appear to hydrolyze both cAMP and cGMP, although their respective relative affinities, as well as their relative affinities for calcium and CaM, may differ. For a review, see Bender and Beavo, 2006, Pharmacol. Rev. 58, 488–520. PDE1 isoforms exhibit distinct but overlapping expression patterns throughout the body. In the brain, PDE1 is expressed in many regions, including the striatum, cerebral cortex, frontal lobe, hippocampus, cerebellum, and amygdala. The brain expression pattern of PDE1B is closely related to that of dopamine receptors, suggesting that PDE1 is involved in the regulation of dopamine signaling, a role supported by experiments in PDE1B knockout mice (Reed et al., 2002, J. Neurosci. 22, 5188-5197). Outside the brain, PDE1 is expressed in many regions, including muscle, heart, kidney, pancreas, lung, stomach, and liver. In the cardiovascular system, PDE1 appears to play an important role in organizing cAMP microdomains and mediating hormone specificity in cardiac cells. See Maurice et al., 2003, Mol. Pharm. 64, 533-546.

[0009] This property enables PDE1 to be involved in multiple physiological and pathological processes. Alterations in cyclic nucleotide signaling pathways, including those involving PDE1, are implicated in various disorders of the brain, such as depression, schizophrenia, and cognitive impairment. See, e.g., Keravis and Lugnier, 2012, Br. J. Pharmacol. 165, 1288-1305. For example, inhibiting PDE1 activity in the nervous system can increase cAMP or cGMP levels and thus induce the expression of genes related to neuronal plasticity, neurotrophic factors, and neuroprotective molecules. Similarly, PDE1 enzymes and cyclic nucleotides have been involved in the etiology of vascular disorders, such as hypertension, myocardial infarction, and heart failure, as well as in the development and progression of kidney diseases. See, e.g., Miller et al., 2011, Basic Res. Cardiol. 106, 1023-1039; Miller et al, 2009, Circ. Res. 105, 956-964; Wang et al., 2010, Kidney Int. 77. 129-140; Cheng et al., 2007, Soc. Exp. Biol. Med. 232, 38-51; Dousa, 1999, Kidney Int. 55, 29-62.

[0010] These and other studies have highlighted the interest in PDE1 as a target for treating multiple disorders and regulating physiological processes such as cognition. There is an urgent need for PDE1 inhibitors with the 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 furopyrimidine chemical entities as potent, selective, and well-tolerated PDE1 inhibitors.

[0011] Overview

[0012] The present disclosure relates to substituted furopyrimidine chemical entities; compositions comprising these entities; methods for preparing them; and their use in various methods, including treating neurological and peripheral disorders related to PDE1, as disclosed herein.

[0013] Some embodiments provide chemical entities of formula (I), more specifically, a pharmaceutically acceptable salt of a compound of formula (I) or a compound of formula (I):

[0014]

[0015] wherein R a has any one of the values described herein.

[0016] 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):

[0017]

[0018] wherein L 1 and L 3 each have any of the values described herein.

[0019] 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):

[0020]

[0021] wherein L 1 、L 2 and L 3 each have any of the values described herein.

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

[0023]

[0024] wherein L 2 、L 3 、m and R b each have any of the values described herein.

[0025] In some embodiments, the chemical entity of formula (I) is a chemical entity of formula (Ibb), or more specifically, a compound of formula (Ibb) or a pharmaceutically acceptable salt of a compound of formula (Ibb):

[0026]

[0027] wherein L 2 、L 3 、m、R d and R b each have any of the values described herein.

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

[0029]

[0030] wherein L 4 and L 5 can have any value described herein.

[0031] In some embodiments, the chemical entity of formula (I) is a chemical entity of formula (Icaa) or (Icab), or more specifically, a compound of formula (Icaa) or (Icab) or a pharmaceutically acceptable salt of a compound of formula (Icaa) or (Icab):

[0032]

[0033] wherein L 6 , B 1 , B 2 and p can have any value described herein.

[0034] In some embodiments, the chemical entity of formula (I) is a chemical entity of formula (Icb), or more specifically, a compound of formula (Icb) or a pharmaceutically acceptable salt of a compound of formula (Icb):

[0035]

[0036] wherein L 6 , B 2 , Q and q can have any value described herein.

[0037] In some embodiments, the chemical entity of formula (I) is a chemical entity of formula (Icc), or more specifically, a compound of formula (Icc) or a pharmaceutically acceptable salt of a compound of formula (Icc):

[0038]

[0039] wherein L 6 , B 1 , D 1 , E, G and r can have any value described herein.

[0040] In some embodiments, the chemical entity is selected from any of the substances described or exemplified herein, and more specifically, is a compound or a pharmaceutically acceptable salt thereof.

[0041] 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 PDE1, treating PDE1-mediated disorders, treating disorders characterized by alterations in dopamine signaling, enhancing neuronal plasticity, conferring neuroprotection, and promoting neurogenesis. In some embodiments, the methods include treating neurological disorders, particularly CNS disorders, and more specifically, include psychiatric and psychological disorders, cognitive disorders, movement disorders, and neurodegenerative disorders. In some embodiments, the methods relate to treating peripheral disorders, including cardiovascular disorders, renal disorders, hematological disorders, gastrointestinal disorders, hepatic disorders, fertility disorders, cancer, and metabolic disorders.

[0042] 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 protocols.

[0043] 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.

[0044] Detailed Description

[0045] The invention 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 invention, suitable methods and materials are described herein. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0046] 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 present invention.

[0047] Terms and Definitions

[0048] The use of headings and subheadings provided in portions of this specification is for reference convenience only and does not limit the various embodiments herein, which are interpreted by reference to the entire specification.

[0049] Overview

[0050] 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, such as the limitations of the measurement system or technique. For example, "about" can mean a range up to 20%, up to 10%, up to 5%, or up to 1% or less on either side of a given value. For the sake of more concise description, some 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 reasonably inferred based on ordinary skill in the art, including equivalents and approximations of the given value due to experimental and / or measurement conditions. Thus, for any embodiment of the present invention in which a numerical value begins with "about" or "approximately", this disclosure includes embodiments in which the exact value is described. Conversely, for any embodiment of the present invention in which a numerical value does not begin with "about" or "approximately", this disclosure includes embodiments in which the numerical value begins with "about" or "approximately".

[0051] 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. Further, although the articles, elements, or components of this embodiment may be described or claimed in the singular, the plural is covered within their scope unless expressly limited to the singular.

[0052] The terms "comprising" and "including" are used herein in their open, non-limiting sense. 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 should not be construed to limit the item to items available during a given period of time or available as of a given time, but rather should be interpreted 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 should be aware of or that are known, such techniques cover those that the technician is aware of or that are known at any time, present or future.

[0053] As will be apparent to those 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.

[0054] Chemical Terms

[0055] 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 or branched chain alkyl having 1 to 12 carbon atoms in the chain and more specifically, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbons in the chain. Preferably, the alkyl moiety is -C 1-6 alkyl, and more preferably C 1-4 alkyl. Examples of alkyl include, but are not limited to, methyl (Me, which can also be structurally depicted 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.

[0056] 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, and the like.

[0057] 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, and the like.

[0058] The term "haloalkyl" refers to a straight 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, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, and -CH 2 CF 2 CF 3 .

[0059] The term "alkoxy" includes straight-chain or branched-chain alkyl groups having an oxygen atom that connects the alkyl group to the remainder of the molecule. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and pentyloxy. "Aminoalkyl", "thioalkyl", and "sulfonylalkyl" are similar to alkoxy, and are -NH(or NR), S, and SO 2 replacing the terminal oxygen atom of alkoxy, 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

[0060] 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, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCH 2 CF 3 , -OCH 2 CHF 2 , -OCH 2 CH 2 Cl, -OCH 2 CF 2 CF 3 and -OCH(CH 3 )CHF 2 .

[0061] The term "amino" refers to the -NH 2 group.

[0062] The term "cyano" refers to the group -CN.

[0063] 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 per ring. Exemplary examples of aryl groups include the following moieties:

[0064] etc.

[0065] The term "phenyl" represents the following moiety:

[0066] The term "aryloxy" refers to a group having the formula -O-R, where R is an aryl group.

[0067] The term "cycloalkyl" refers to a fully saturated or partially saturated carbocyclic ring having 3 to 15 ring atoms per carbocyclic ring, such as a monocyclic, fused polycyclic, bridged monocyclic, bridged polycyclic, spirocyclic or spiro polycyclic carbocyclic ring. If the term cycloalkyl is defined by a specific characteristic, such as monocyclic, fused polycyclic, bridged polycyclic, spirocyclic and spiro polycyclic, then the term cycloalkyl refers only to the carbocyclic rings so characterized. Exemplary instances of cycloalkyl include the following entities in the form of suitable bonded moieties:

[0068]

[0069] "Heterocycloalkyl" refers to a monocyclic, or fused polycyclic, bridged polycyclic or spiro polycyclic ring structure that is fully saturated or partially saturated and includes at least one heteroatom selected from nitrogen, oxygen and sulfur in the ring backbone. Heterocycloalkyl can have any degree of saturation, provided that at least one of the rings in the polycyclic ring structure is not aromatic. The heteroatom can be present in a non-aromatic ring or an aromatic ring in the polycyclic structure. Heterocycloalkyl can have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heterocycloalkyl" where no numerical range is specified. Heterocycloalkyl 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 C 3-4 heterocycloalkyl", "6 membered C 4-5 heterocycloalkyl", "7 membered C 5-6 heterocycloalkyl", "bicyclic or tricyclic 9-15 membered C 8-14 heterocycloalkyl", "monocyclic or bicyclic 3-10 membered C 2-9 heterocycloalkyl", "bicyclic 8-10 membered C 4-9 heterocycloalkyl", "bicyclic 8-10 membered C 5-9 heterocycloalkyl", "monocyclic 4-7 membered C 3-6- heterocycloalkyl", "monocyclic 5-6 membered C 3-5-"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:

[0070]

[0071]

[0072] Exemplary carbon or thioxo-substituted heterocyclic hydrocarbyl entities in the form of suitable bonding moieties include:

[0073]

[0074] 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 backbone. When the heteroaryl is a ring system, each ring in the ring system is completely unsaturated. The heteroaryl can have 5 to 18 ring members (i.e., the number of atoms making up the ring backbone, 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", "5- to 6-membered C 3-5 heteroaryl", "6-membered C 4-5 heteroaryl", "5-membered C 3-4"Heteroaryl" or similar nomenclature. A 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. A heteroaryl can be a monocyclic five-membered ring containing one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. A heteroaryl can be a monocyclic six-membered ring containing one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. A heteroaryl can be a bicyclic nine-membered ring containing one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. A 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, a heteroaryl can be a tautomer of a heterocyclic hydrocarbyl group, where the heteroaryl is the predominant form under equilibrium conditions. Exemplary instances of heteroaryls include the following entities, in the form of appropriate bonded moieties:

[0075]

[0076] "Cycloalkyloxy" refers to a fully saturated or partially saturated monocyclic or fused polycyclic, bridged polycyclic, or spiro polycyclic ring structure having at least two carbons and at least one oxygen in the ring skeleton. A cycloalkyloxy can have any degree of saturation provided that at least one of the rings in the polycyclic ring structure is not aromatic. The oxygen can be present in a non-aromatic ring or an aromatic ring in the polycyclic structure. A cycloalkyloxy 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 "cycloalkyloxy" where no numerical range is specified. A cycloalkyloxy group can be designated as "3- to 15-membered cycloalkyloxy", "4- to 10-membered cycloalkyloxy", "3- to 15-membered C 2-14 cycloalkyloxy", "5- to 9-membered C 4-8 cycloalkyloxy", "5- to 10-membered C 4-9 cycloalkyloxy", "5-membered C 3-4 cycloalkyloxy", "6-membered C 4-5 cycloalkyloxy", "7-membered C 5-6 cycloalkyloxy" or similar nomenclature. A cycloalkyloxy can be a 5- to 10-membered ring or ring system that contains one oxygen and the remainder carbons in the ring skeleton. A cycloalkyloxy can be optionally substituted. Exemplary unsubstituted cycloalkyloxy entities include the following, in the form of appropriate bonded moieties:

[0077]

[0078] One of ordinary skill in the art will recognize that the above-listed or exemplified species of aryl, cycloalkyl, heterocyclic hydrocarbyl, and heteroaryl are not exhaustive and that additional species within the scope of these defined terms can also be selected.

[0079] The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo" represents chloro, fluoro, bromo, or iodo.

[0080] As used herein, the term "heteroatom" refers to, for example, O (oxygen), S (sulfur), or N (nitrogen).

[0081] "Optional" and "optionally" mean that the subsequently described event or circumstance may or may not occur, and the 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.

[0082] 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 that it occurs at any position allowed by the valence in the system. The term "unsubstituted" means that the specified group bears no substituents.

[0083] For simplicity, groups that can have more than one point of attachment (i.e., divalent, trivalent, polyvalent) as described herein may be referred to by a common term. For example, the term "C 3-10 cycloalkyl" can be used to describe a cycloalkyl group having from three to ten members (L 3 ), which is monovalent, as in -L 1 -L 3 , where L 3 has one point of attachment, and it can also be divalent (L 2 ), as in -L 1 -L 2 -L 3 , where L 2 has two points of attachment.

[0084] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms have been exchanged with another atom or group. Unless otherwise specified, when a group is considered "substituted", this means that the group is substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7Cycloalkyl group (optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl (optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), 3- to 10-membered heterocycloalkyl group (optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), 3- to 10-membered heterocycloalkyl-C 1 -C 6 -alkyl (optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), aryl group (optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), aryl(C 1 -C 6 )alkyl (optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C6 haloalkoxy (optionally substituted), 5- to 10-membered heteroaryl (substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy (optionally substituted), 5- to 10-membered heteroaryl (C 1 -C 6 ) alkyl (substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy (optionally substituted), halogen, cyano, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy (C 1 -C 6 ) alkyl (i.e., ether), aryloxy (substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy (optionally substituted), C 3 -C 7 cycloalkoxy (substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy (optionally substituted), 3- to 10-membered heterocycloalkyl-oxy (substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy (optionally substituted), 5- to 10-membered heteroaryl-oxy (substituted by halogen, C 1 -C 6Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Haloalkoxy (optionally substituted), C 3 -C 7 -Cycloalkyl-C 1 -C 6 -Alkoxy (substituted by halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Haloalkoxy (optionally substituted), 3- to 10-membered heteroalkyl-C 1 -C 6 -Alkoxy (substituted by halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Haloalkoxy (optionally substituted), aryl (C 1 -C 6 ) alkoxy (substituted by halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Haloalkoxy (optionally substituted), 5- to 10-membered heteroaryl (C 1 -C 6 ) alkoxy (substituted by halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl and C 1 -C 6 Haloalkoxy (optionally substituted), hydrogen sulfide group (mercapto), halogenated (C 1 -C 6 ) alkyl (e.g., -CF 3 ), halogenated (C 1 -C 6 ) alkoxy (e.g., –OCF 3 ), C1 -C 6 alkylthio, arylthio (optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy (optionally substituted), amino, amino(C 1 -C 6 )alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl and oxo(=O). When a group is described as "optionally substituted", the group can be substituted by the above substituents, unless the optional substituents are otherwise specifically determined.

[0085] Any chemical formula given herein is intended to represent compounds by structural formulas 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 general formula compounds and 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.

[0086] 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 can occur in the compounds described herein:

[0087]

[0088] Using the symbols and means the same spatial arrangement of the chemical structures shown herein. Similarly, using the symbols and means the same spatial arrangement of the chemical structures shown herein.

[0089] The compounds described herein exist in various tautomeric forms, and the term "compound" is intended to include all tautomeric forms (tautomers) of the compound.

[0090] The term "chiral" refers to a molecule that has the property that its mirror image partner is non - superimposable.

[0091] "Stereoisomers" are compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups.

[0092] "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.

[0093] "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.

[0094] 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 an optically active compound, 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. A compound prefixed with (+) or d is dextrorotatory.

[0095] 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 a chemical reaction or process without stereoselectivity or stereospecificity.

[0096] Whenever 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, unless otherwise specified, the substituent can be attached in any directional configuration. 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.

[0097] Chemical Entities

[0098] As used herein, the term “chemical entity” collectively refers to compounds and all of their pharmaceutically acceptable forms, including their pharmaceutically acceptable salts, chelates, solvates, conformational isomers, crystal forms / polymorphs, tautomers, prodrugs, metabolites, and mixtures. In some embodiments, the chemical entity is selected from compounds and their pharmaceutically acceptable salts.

[0099] Chelates

[0100] The term “chelate” refers to a chemical entity formed by coordination of a compound with a metal ion at two (or more) points.

[0101] Solvates

[0102] In addition, any chemical formula given herein is also intended to mean the solvates, including hydrates, of the compounds herein, and mixtures thereof, even if these forms are not explicitly listed. Some embodiments provide solvates of the compounds of formula (I), and the use of such solvates in the methods described herein. Certain compounds of formula (I) or pharmaceutically acceptable salts of the compounds of formula (I) may be obtained in solvated form. In some embodiments, the solvent is water and the solvate is a hydrate.

[0103] More particularly, solvates include those formed by the interaction or complexation of the compounds of the invention with one or more solvents, either in solution or as a solid or crystal form. These solvent molecules are those commonly used in the pharmaceutical art and are known to be harmless to the recipient, such as water, ethanol, ethylene glycol, etc. Other solvents can 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 the molecules of the compounds associated with water molecules.

[0104] Conformational Isomers and Crystal Forms / Polymorphs

[0105] Some embodiments provide conformational isomers and crystal forms of the compounds of formula (I), and their use in the methods of the present disclosure. A conformational isomer is a structure that is conformationally isomeric.

[0106] 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.

[0107] Polymorphs refer to solid materials that can exist in more than one form or crystal structure, where each form or crystal structure is different from the others. Thus, a single compound can give rise to multiple polymorphic forms, which have different and distinct physical properties such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, density, flowability, compactibility, and X-ray diffraction peaks. In certain embodiments, the compounds of formula (I) are obtained in crystal forms. Additionally, certain crystal forms of the compounds of formula (I) or pharmaceutically acceptable salts of the compounds of formula (I) can be obtained in the form of co-crystals. In other embodiments, the compounds of formula (I) can be obtained in one of multiple polymorphs, a mixture of crystal forms, a polymorph, or an amorphous form.

[0108] Compounds

[0109] As used herein, "compound" refers to any of the following: (a) the actual recited form of such a compound; and (b) any form of such a compound in the medium in which the compound is considered in naming. For example, a reference herein to a compound such as R-OH includes a reference to any of R-OH(s), R-OH(sol), and R-O-(sol). In such instances, R-OH(s) refers to the solid compound, as it can be, for example, in a tablet or some other solid pharmaceutical composition or formulation; R-OH(sol) refers to the undissociated form of the compound in a solvent; and R-O-(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-OH, its salt, or any other entity that dissociates to give R-O- in the medium under consideration.

[0110] In another instance, a statement such as "modulating the activity of PDE1 or a related signaling pathway" refers to PDE1 being exposed to the form of the compound R-OH present in the medium in which such exposure occurs. In this regard, if such a compound is, for example, in an aqueous environment, it is understood that the compound R-OH is in the same such medium, and thus PDE1 is exposed to the compound when compounds such as R-OH(aq) and / or R-O-(aq) are present in the medium, where the subscript "(aq)" represents "aqueous solution" according to its conventional meaning in chemistry and biochemistry. The hydroxyl functional group has been selected in these illustrative instances; however, such selection is not intended to be limiting, but merely illustrative. It should be understood that similar instances can be provided according to other functional groups, including but not limited to basic nitrogen members (such as those in amines), and any other groups that interact or transform with each other in the medium containing the compound in a known manner. Such interactions and transformations include but are not limited to dissociation, association, tautomerization, solvolysis including hydrolysis, 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.

[0111] When referring to any general formula given herein, the selection of a particular moiety from the list of possible species of a designated variable is not intended to define the same species selection of that variable occurring elsewhere. In other words, if a variable occurs more than once, then unless otherwise stated, the selection of species from the designated list is independent of the species selection of the same variable elsewhere in the general formula.

[0112] Salts

[0113] Embodiments include pharmaceutically acceptable salts of the compounds represented by general formula (I), and methods of using these salts.

[0114] "Pharmaceutically acceptable salts" means salts of the free acids or bases of the compounds represented by formula (I), 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 (2011) Wiley-VCH, Zurich, Switzerland. Examples of pharmaceutically acceptable salts are salts that are pharmacologically effective and suitable for contact with the tissues of a patient without producing undue toxicity, irritation, or allergic response. The compounds of formula (I) 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.

[0115] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, hydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, borates, nitrates, propionates, caprates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, benzenesulfonates, mesylates, and mandelates.

[0116] When the compound of formula (I) contains a 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, glutamic 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 mixtures thereof regarded as equivalents or acceptable substitutes according to the ordinary skill in the art.

[0117] When the compound of formula (I) is an acid, such as a carboxylic acid or a sulfonic acid, 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 mixtures thereof 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.

[0118] Prodrugs

[0119] Some embodiments provide prodrugs of the compound of formula (I), and the use of such pharmaceutically acceptable prodrugs in the methods of the present disclosure, particularly in therapeutic methods.

[0120] The term "prodrug" is a precursor of a designated compound that is initially inactive or partially inactive and that, after administration to an individual, produces the compound in vivo by a chemical or physiological process (such as solvolysis or enzymatic cleavage) or under physiological conditions (for example, the prodrug is converted to the pharmacologically active compound of formula (I) at physiological pH).

[0121] "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 often useful because in some cases they are more readily administered than the parent drug. For example, they may be bioavailable by oral administration while the parent is not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug.

[0122] Prodrugs can be determined using conventional techniques known or available in the art. Prodrugs can be produced, for example, by derivatizing free carboxyl groups, free hydroxyl groups or free amino groups. See, for example, Bundgard (ed.), 1985, Design of prodrugs, Elsevier; Krogsgaard-Larsen et al., (eds.), 1991, Design and Application of Prodrugs, Harwood Academic Publishers; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130; Robinson et al., 1996, J. Med. Chem. 39, 10-18.

[0123] Tautomers

[0124] Some embodiments provide tautomers of the compounds of formula (I) as further defined herein, which may also be used in the methods of the present disclosure.

[0125] Metabolites

[0126] Some embodiments provide pharmaceutically active metabolites of the compounds of formula (I), which may 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) or a salt thereof. Preferably, the metabolite is in an isolated form in vitro.

[0127] The 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).

[0128] Isotopes

[0129] Isotopes can be present in the compounds described herein. Each chemical element present in the compounds described hereinbelow or hereinabove 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. Isotopically labeled compounds have the structure described by the chemical formula given herein, but have one or more atoms replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this 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.

[0130] Combinations

[0131] As used in the context of a pharmaceutical composition, the term "composition" is intended to cover a product comprising an active ingredient (e.g., one or more chemical entities of the present disclosure) and an inert ingredient (a pharmaceutically acceptable excipient) that constitutes a carrier, as well as any product directly or indirectly produced by the combination, complexation, or aggregation of any two or more of these ingredients, or any product produced by the dissociation of one or more of these ingredients, or any product produced by other types of reactions or interactions of one or more of these ingredients. Thus, the pharmaceutical compositions of the present invention cover any composition made by mixing a chemical entity of general formula (I) and a pharmaceutically acceptable excipient.

[0132] The term "pharmaceutically acceptable" as used in connection with the compositions of the present invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and generally produce no 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 use in animals (e.g., mammals), and more particularly in humans.

[0133] "Pharmaceutically acceptable excipient" means a substance that is added to a pharmaceutical composition or otherwise serves as a vehicle, carrier, or diluent to facilitate the administration of the 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).

[0134] "Pharmaceutically acceptable salt" is intended to mean a salt of the free acid or base of a compound represented by formula (I) as previously defined herein. The term "carrier" refers to an excipient, vehicle, or diluent administered together with the compound. In a preferred embodiment of the present invention, 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).

[0135] As used herein, the term "dosage form" is the form in which a dose is administered to an individual or patient. A drug is typically administered as part of a formulation that includes a non-medical agent. 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, caplets, gelatin capsules (capsulants), syrups, liquid compositions, powders, concentrated powders, concentrated powders mixed with liquids, chewable forms, swallowable forms, dissolvable 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.

[0136] 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 U.S. Food and Drug Administration in 21 C.F.R. 201.3(b)(8), which is any component of a drug product other than the active ingredient.

[0137] As used herein, "suitable for oral administration" means 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.

[0138] Methods and Uses

[0139] As used herein, the term "disorder" may be used interchangeably with "disease" or "condition". For example, a CNS disorder also means a CNS disease or a CNS condition.

[0140] 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.

[0141] 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 development (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 deficits), 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. In particular, with respect to a progressive disease state or condition, maintaining the status quo or preventing the progression of symptoms is understood to be the alleviation of such symptoms.

[0142] As used in the present 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, condition, or disorder disclosed herein, and thus "treatment" includes producing a desired preventive, inhibitory, alleviating, or improving effect. In a treatment method according to the present invention, an "effective amount" of at least one compound according to the present invention 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 PDE1 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.

[0143] As used herein, the term "PDE1" refers to all translation products encoded by transcripts of any one or any combination of the three genes PDE1A, PDE1B, and PDE1C. The amino acid and nucleotide sequences encoding PDE1 of various species are known to those skilled in the art and can be found, for example, in GenBank (GeneBank) under accession numbers AJ401610.1, AJ401609.1, and in Fiddock et al., 2002, Cell. Signal. 14, 53 - 60.

[0144] The term "animal" may be interchangeable with "individual" and may be a vertebrate, particularly a mammal, more particularly a human, and includes laboratory animals in the context of clinical trials or screening or activity experiments. Thus, as will be readily understood by one of ordinary skill in the art, the compositions and methods of the present invention are particularly suitable for administration to any vertebrate, particularly a mammal, more particularly a human.

[0145] As used herein, a "control animal" or "normal animal" is an animal of the same species as an animal trained under conditions sufficient to induce transcription-dependent memory formation in the animal and otherwise comparable (e.g., similar age, sex).

[0146] "Enhance" means the ability to strengthen, increase, improve a biochemical or physiological action or effect or make it greater or better relative to the normal situation. 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 quickly 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 the cognitive task.

[0147] As used herein, the terms "training protocol" or "training" refer to "cognitive training" or "exercise training".

[0148] Embodiments of the present invention will now be cited, and examples thereof are explained and described by reference to the accompanying examples. Although certain embodiments are described herein, it should be understood that the embodiments are not intended to limit the scope of the present invention. On the contrary, the present disclosure is intended to cover alternatives, modifications, and equivalents that may be included within the scope of the present invention as defined by the appended claims.

[0149] Chemical Entities

[0150] Some embodiments provide certain substituted furopyrimidine chemical entities that can be used, for example, as inhibitors of PDE1 enzyme activity.

[0151] In some embodiments, the chemical entity includes the compounds disclosed herein and their pharmaceutically acceptable salts, chelates, solvates, conformational isomers, crystal forms / polymorphs, tautomers, prodrugs, metabolites, and mixtures. In some embodiments, the chemical entity includes the compounds disclosed herein and their pharmaceutically acceptable salts.

[0152] Some embodiments provide chemical entities of general formula (I):

[0153] wherein R a has any of the values described herein.

[0154] In some embodiments of the chemical entity of formula (I), R a is -L 1 -L 3 、-L 1 -L 2 -L 3 or -N(L 4 )-L 5 ; L 1 is selected from: -N(R b )-, -N(R b )(C(R b )) 2 )-, -N(R m )(CH b ) 2 ) m O-, -NHNH-, 3- to 15-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 15-membered heterocycloalkyl or 5- to 10-membered heteroaryl is optionally substituted with one to four R 1A , and each R 1A is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl;

[0155] Each m is independently 0, 1, 2, or 3;

[0156] Each R b is independently -H, -OH, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -C 3-7 cycloalkyl, -C2-6 Alkenyl or -C 2-6 alkynyl;

[0157] L 2 selected from: -N(R c )-, -N(R c )(CH 2 ) m -, -O-, -S-, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -CHR c -, -(CH 2 ) m NH-, -(CH 2 ) m O-, -(CH 2 ) m S-, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl and 5- to 10-membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl and 5- to 10-membered heteroaryl are optionally substituted with one to four R 1B , wherein each R 1B is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 , -C 3-7 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl and 5- to 10-membered heteroaryl;

[0158] each R c is independently -H, -C1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -C 3-7 cycloalkyl, -C 2-6 alkenyl or -C 2-6 alkynyl;

[0159] L 3 selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -N(R 1DD ) 2 , -N=S(=O)(CH 3 ) 2 , -NO 2 , -SO 2 CH 3 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C 1-6 alkyl-O-C 1-4 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl and 5- to 10-membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl and 5- to 10-membered heteroaryl are optionally substituted by one to four R 1C , wherein each R 1C is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 、-C 3-7 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl;

[0160] Each R 1DD is independently selected from: -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C 3-7 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl;

[0161] L 4 and L 5 together with the nitrogen to which they are attached form a 3- to 15-membered heterocycloalkyl or 5- to 10-membered heteroaryl ring, which is optionally substituted by one to four R 1D wherein each R 1D is independently selected from: L 6 、=O、-C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl and -COOC 1-6 alkyl; and

[0162] L 6 is selected from: -H, -OH, -CN, -NH 2 、-NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 、-N=S(=O)(CH 3 ) 2 、-NO 2 、-SO 2 CH 3 、halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -C(O)NH 2 、-C 3-10Cycloalkyl, -C 1-6 Alkyl-O-C 1-4 Alkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl, and 5- to 10-membered heteroaryl, wherein said -C 1-6 Alkyl, -C 3-10 Cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl, and 5- to 10-membered heteroaryl are optionally substituted with one to four R 1E s, where each R 1E is independently selected from: halogen, -OH, ═O, -NH 2 , -NHC 1-4 Alkyl, -N(C 1-4 Alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy, -C 1-6 Alkyl-O-C 1-4 Alkyl, -C(O)C 1-6 Alkyl, -COOC 1-6 Alkyl, -C(O)NH 2 , -C 3-7 Cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl.

[0163] In certain embodiments, the chemical entity of formula (I) is the chemical entity of formula (Ia), and more specifically, is a compound of formula (Ia) or a pharmaceutically acceptable salt of a compound of formula (Ia):

[0164] wherein L 1 and L 3 have any of the values described herein.

[0165] In certain embodiments of the chemical entity of formula (Ia),

[0166] L 1 is selected from: -N(R b )-, -N(R b )(CR b 2 ) m -, -N(R b )(CH 2 ) mO−, −NHNH−, 3- to 15-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein the 3- to 15-membered heterocycloalkyl or 5- to 10-membered heteroaryl is optionally substituted with one to four R 1A independently selected from: halogen, -OH, =O, -NH 1A , -NHC 2 alkyl, -N(C 1-4 alkyl) 1-4 , -NO 2 , -SO 2 CH 2 , -CN, -C 3 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-6 alkyl, -C(O)C 1-4 alkyl, -COOC 1-6 alkyl, -C(O)NH 1-6 and -C 2 cycloalkyl;

[0167] Each m is independently 0, 1, 2, or 3;

[0168] Each R independently is -H, -OH, -C b alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-6 alkyl, -C(O)C 1-4 alkyl, -C 1-6 cycloalkyl, -C 3-7 alkenyl or -C 2-6 alkynyl.

[0169] L

[0170] is selected from: -H, -OH, -CN, -NH 3 , -NHC 2 alkyl, -N(C 1-4 alkyl) 1-4 , -N(R 2 1DD ) 2 , -N=S(=O)(CH 3 ) 2 , -NO 2 , -SO 2 CH 3 , halogen, -C 1-6 alkyl, -C 1-6 ​Halogenated alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl - O - C 1-4 Alkyl, -C(O)C 1-6 Alkyl, -C(O)NH 2 、-C 3-10 Cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl, where the -C 1-6 Alkyl, -C 3-10 Cycloalkyl, -C 3-7 Cycloalkoxy, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl are optionally substituted by one to four R 1C Where each R 1C Independently selected from: halogen, -OH, =O, -NH 2 、-NHC 1-4 Alkyl, -N(C 1-4 Alkyl) 2 、-NO 2 、-SO 2 CH 3 、-CN、-C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-6 Alkyl - OH, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy, -C 1-6 Alkyl - O - C 1-4 Alkyl, -C(O)C 1-6 Alkyl, -COOC 1-6 Alkyl, -C(O)NH 2 、-C 3-7 Cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl and 5 - 10 - membered heteroaryl; and

[0170] Each R 1DD Independently selected from: -H, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-6 Alkyl - OH, -C 1-6 Alkyl - O - C 1-4 Alkyl, -C(O)C 1-6 Alkyl, -COOC 1-6 Alkyl, -C 3-7 Cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl and 5 - 10 - membered heteroaryl.

[0171] In certain embodiments, the chemical entity of formula (I) is a chemical entity of formula (Ib), and more specifically, a compound of formula (Ib) or a pharmaceutically acceptable salt of a compound of formula (Ib):

[0172] wherein L 1 、L 2 and L 3 have any of the values described herein.

[0173] In certain embodiments of the chemical entity of formula (Ib),

[0174] L 1 is selected from: -N(R b )-, -N(R b )(CR b 2 ) m -, -N(R b )(CH 2 ) m O-, -NHNH-, a 3- to 15-membered heterocycloalkyl group, and a 5- to 10-membered heteroaryl group, wherein the 3- to 15-membered heterocycloalkyl group or 5- to 10-membered heteroaryl group is optionally substituted with one to four R 1A , where each R 1A is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl;

[0175] Each m is independently 0, 1, 2, or 3;

[0176] Each R b is independently -H, -OH, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -C 3-7 cycloalkyl, -C 2-6 alkenyl or -C 2-6 alkynyl;

[0177] L 2 selected from: -N(R c )-, -N(R c )(CH 2 ) m -, -O-, -S-, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -CHR c -, -(CH 2 ) m NH-, -(CH 2 ) m O-, -(CH 2 ) m S-, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl and 5- to 10-membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl and 5- to 10-membered heteroaryl are optionally substituted with one to four R 1B wherein each R 1B is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 , -C 3-7Cycloalkyl, 3- to 15-membered hetero cycloalkyl, phenyl, benzyl, and 5- to 10-membered heteroaryl;

[0178] Each R c independently is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -C 3-7 cycloalkyl, -C 2-6 alkenyl or -C 2-6 alkynyl;

[0179] L 3 is selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -N(R 1DD ) 2 , -N=S(=O)(CH 3 ) 2 , -NO 2 , -SO 2 CH 3 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C 3-10 cycloalkyl, 3- to 15-membered hetero cycloalkyl, phenyl, benzyl, and 5- to 10-membered heteroaryl, where the -C 1-6 alkyl, -C 3-10 cycloalkyl, -C 3-7 cycloalkoxy, 3- to 15-membered hetero cycloalkyl, phenyl, benzyl, and 5- to 10-membered heteroaryl are optionally substituted by one to four R 1C , where each R 1C independently is selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 , -C 3-7 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl; and

[0180] each R 1DD is independently selected from: -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C 3-7 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl.

[0181] In some embodiments of the chemical entities of general formula (I), (Ia), or (Ib) disclosed herein:

[0182] L 1 is selected from: -N(R b )-, -N(R b )(CR b 2 ) m -, -N(R b )(CH 2 ) m O-, and -NHNH-;

[0183] each m is independently 0, 1, 2, or 3; and

[0184] each R b is independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -C 3-7 cycloalkyl, -C 2-6 alkenyl, or -C 2-6 alkynyl.

[0185] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0186] L 1 is -N(R b )- or -N(R b )-(CR b 2 ) m -;

[0187] Each m is independently 0, 1, 2 or 3; and

[0188] Each R b is independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl or -C 3-7 cycloalkyl.

[0189] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0190] L 1 is -NH- or -NHCH 2 -.

[0191] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0192] L 1 is a 3- to 15-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, optionally substituted by one to four R 1A groups.

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

[0194] L 1Selected from: azetidine, pyrrolidine, 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, imidazolidine, piperidine, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, piperazine, morpholine, 3-azabicyclo[3.1.0]hexane, octahydrocyclopenta[c]pyrrole, octahydrocyclopenta[b]pyrrole, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 5,6,7,8-tetrahydro-1,6-naphthyridine, 5,6,7,8-tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,6-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, isoindoline, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, 5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[1,2-c]pyrimidine, hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole, hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole, decahydroisoquinoline, decahydroquinoline, azepane, diazepane, 8-oxa-3-azabicyclo[3.2.1] Octane, 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine, 3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocin, spiro[indoline-3,3'-piperidine]-2-one, spiro[indoline-3,3'-pyrrolidine]-2-one, 2,3-dihydrospiro[indene-1,2'-morpholine], 3H-spiro[isobenzofuran-1,3'-piperidine], 3H-spiro[isobenzofuran-1,3'-pyrrolidine], spiro[benzo[d][1,3]oxazine-4,4'-piperidine]-2(1H)-one, spiro[indene-1,4'-piperidine], 3H-spiro[benzo[c]thiophene-1,4'-piperidine] and 2,3,4,5-tetrahydro-1H-1,5-methanobenzodiazepine, wherein the 3- to 15-membered heterocyclic hydrocarbon group is substituted with one to four R. 1A Optionally substituted.

[0195] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0196] L 1 Selected from: azetidine, pyrrolidine, piperidine, azepane, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine and 2,3-dihydro-1H-pyrrole.

[0197] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0198] L 1 Selected from: imidazolidine, piperazine, diazepane and morpholine.

[0199] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0200] L 1 Selected from: 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 5,6,7,8-tetrahydro-1,6-naphthyridine, 5,6,7,8-tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,6-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine and isoindoline.

[0201] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0202] L 1 is selected from: 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, octahydropyrrolo[1,2-a]pyrazine, and octahydropyrrolo[1,2-c]pyrimidine.

[0203] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0204] L 1 is selected from: 3-azabicyclo[3.1.0]hexane, octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole, hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole, decahydroisoquinoline, decahydroquinoline, 8-oxa-3-azabicyclo[3.2.1]octane, 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine, 3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine, spiro[indoline-3,3'-piperidine]-2-one, spiro[indoline-3,3'-pyrrolidine]-2-one, 2,3-dihydrospiro[indene-1,2'-morpholine], 3H-spiro[isobenzofuran-1,3'-piperidine], 3H-spiro[isobenzofuran-1,3'-pyrrolidine], spiro[benzo[d][1,3]oxazine-4,4'-piperidine]-2(1H)-one, spiro[indene-1,4'-piperidine], 3H-spiro[benzo[c]thiophene-1,4'-piperidine], and 2,3,4,5-tetrahydro-1H-1,5-methanobenzodiazepine.

[0205] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0206] L 1 is a 5- to 10-membered heteroaryl selected from pyrazole, imidazole, pyrrole, oxazole, thiazole, indole, and indazole, wherein the 5- to 10-membered heteroaryl is optionally substituted with one to four R 1A substituents.

[0207] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0208] L1 is a pyrazole, substituted by one to four R 1A optionally.

[0209] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein: R a is -L 1 -L 3 or -L 1 -L 2 -L 3 and R 1A are independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl.

[0210] In certain embodiments, the chemical entity of general formula (I) is the chemical entity of general formula (Iba), and more specifically, is a compound of general formula (Iba) or a pharmaceutically acceptable salt of a compound of general formula (Iba):

[0211] wherein R b , L 2 , m and L 3 have any of the values described herein.

[0212] In certain embodiments of the chemical entity of general formula (Iba),

[0213] L 2 is -C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl, the -C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted by one to four R 1B , wherein each R 1B is independently selected from: halogen, -OH, =O, -NH2 、 -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 、 -NO 2 、 -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy and -C 1-6 alkyl-O-C 1-4 alkyl;

[0214] R b is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 3-6 cycloalkyl, -C 2-6 alkenyl or -C 2-6 alkynyl;

[0215] L 3 is -H, -OH, -CN, -NH 2 、 -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 、 -NO 2 、 halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkyl-O-C 1-4 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl or 5- to 10-membered heteroaryl, wherein said -C 1-6 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl and 5- to 10-membered heteroaryl are optionally substituted by one to four R 1C 's, where each R 1C is independently selected from: halogen, -OH, =O, -NH 2 、 -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 、 -NO 2 、 -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C1-6 Alkoxy, -C 1-6 Haloalkoxy, -C 1-6 Alkyl - O - C 1-4 alkyl; and

[0216] m is 0, 1 or 2.

[0217] In certain embodiments, the chemical entity of formula (I) is a chemical entity of formula (Ibb), and more specifically, a compound of formula (Ibb) or a pharmaceutically acceptable salt of a compound of formula (Ibb):

[0218] wherein R b , R d , m, L 2 and L 3 have any of the values described herein.

[0219] In certain embodiments of the chemical entity of formula (Ibb),

[0220] L 2 is - C 3-10 cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl or 5 - 10 - membered heteroaryl, said - C 3-10 cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl and 5 - 10 - membered heteroaryl are optionally substituted with one to four R 1B , wherein each R 1B is independently selected from: halogen, - OH, = O, - NH 2 , - NHC 1-4 alkyl, - N(C 1-4 alkyl) 2 , - NO 2 , - CN, - C 1-6 alkyl, - C 1-6 haloalkyl, - C 1-6 alkyl - OH, - C 1-6 alkoxy, - C 1-6 haloalkoxy and - C 1-6 alkyl - O - C 1-4 alkyl;

[0221] L 3 is - H, - OH, - CN, - NH 2 , - NHC 1-4 alkyl, - N(C 1-4 alkyl) 2 , - NO 2 , halogen, - C 1-6 alkyl, - C 1-6 haloalkyl, - C 1-6 alkoxy, - C 1-6Halogenated alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl - O - C 1-4 Alkyl, -C 3-10 Cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl or 5 - 10 - membered heteroaryl, wherein the -C 1-6 Alkyl, -C 3-10 Cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl are each independently substituted with one to four optional substituents R 1C wherein each R 1C is independently selected from: halogen, -OH, ═O, -NH 2 , -NHC 1-4 Alkyl, -N(C 1-4 Alkyl) 2 , -NO 2 , -CN, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-6 Alkyl - OH, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy and -C 1-6 Alkyl - O - C 1-4 Alkyl;

[0222] R b is -H, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-6 Alkyl - OH, -C 3-6 Cycloalkyl, -C 2-6 Alkenyl or -C 2-6 Alkynyl;

[0223] Each R d is independently selected from: -H, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-6 Alkyl - OH, -C 3-6 Cycloalkyl; and

[0224] m is 0, 1 or 2.

[0225] In certain embodiments, the chemical entity of formula (I) is the chemical entity of formula (Ic), and more specifically, is a compound of formula (Ic) or a pharmaceutically acceptable salt of a compound of formula (Ic):

[0226] wherein L 4 and L 5 have any value described herein.

[0227] In certain embodiments of the chemical entity of general formula (Ic),

[0228] L 4 and L 5 together with the nitrogen to which they are attached form a 3- to 15-membered heterocyclic hydrocarbyl or 5- to 10-membered heteroaryl ring, which is optionally substituted by one to four R 1D wherein each R 1D is independently selected from: L 6 、=O、-C 1-6 alkyl-OH、-C 1-6 alkyl-O-C 1-4 alkyl and -COOC 1-6 alkyl; and

[0229] L 6 is selected from: -H、-OH、-CN、-NH 2 、-NHC 1-4 alkyl、-N(C 1-4 alkyl) 2 、-N=S(=O)(CH 3 ) 2 、-NO 2 、-SO 2 CH 3 、halogen、-C 1-6 alkyl、-C 1-6 haloalkyl、-C 1-6 alkoxy、-C 1-6 haloalkoxy、-C 2-6 alkenyl、-C 2-6 alkynyl、-C(O)C 1-6 alkyl、-C(O)NH 2 、-C 3-10 cycloalkyl、-C 1-6 alkyl-O-C 1-4 alkyl、3- to 15-membered heterocyclic hydrocarbyl、phenyl、benzyl and 5- to 10-membered heteroaryl, wherein the -C 1-6 alkyl、-C 3-10 cycloalkyl、-C 3-7 cycloalkoxy、3- to 15-membered heterocyclic hydrocarbyl、phenyl、benzyl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 1E wherein each R 1E is independently selected from: halogen、-OH、=O、-NH 2 、-NHC 1-4 alkyl、-N(C 1-4 alkyl) 2 、-NO 2 、-SO 2 CH 3 、-CN、-C 1-6 alkyl、-C1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 , -C 3-7 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl.

[0230] In certain embodiments, the chemical entity of formula (I) is a chemical entity of formula (Icaa) or (Icab), and more specifically, a compound of formula (Icaa) or (Icab) or a pharmaceutically acceptable salt of a compound of formula (Icaa) or (Icab):

[0231] wherein L 6 , B 1 , B 2 and p have any of the values described herein.

[0232] In certain embodiments of the chemical entity of formula (Icaa) or (Icab),

[0233] L 6 is selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C 3-10 cycloalkyl, -C 1-6 alkyl-O-C 1-4 alkyl, -3- to 15-membered heterocycloalkyl, phenyl, benzyl, and 5- to 10-membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl, and 5- to 10-membered heteroaryl are substituted with one to four R 1EOptionally substituted, wherein each R 1E is independently selected from: halogen, -OH, ═O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl;

[0234] B 1 is CH or C(R 1D );

[0235] B 2 is CH 2 or CH(R 1D );

[0236] R 1D is L 6 , ═O, -C 1-6 alkyl-OH or -C 1-6 alkyl-O-C 1-4 alkyl; and

[0237] p is 0, 1, 2 or 3.

[0238] In certain embodiments, the chemical entity of formula (I) is the chemical entity of formula (Icb), and more specifically, a compound of formula (Icb) or a pharmaceutically acceptable salt of a compound of formula (Icb):

[0239] wherein L 6 , B 2 , Q and q have any value as described herein.

[0240] In certain embodiments of the chemical entity of formula (Icb),

[0241] L 6 is selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C1-4 alkyl 2 、 -NO 2 、 -SO 2 CH 3 、 halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -C(O)NH 2 、 -C 3-10 cycloalkyl, -C 1-6 alkyl - O - C 1-4 alkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl are optionally substituted by one to four R 1E s, where each R 1E is independently selected from: halogen, -OH, =O, -NH 2 、 -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 、 -NO 2 、 -SO 2 CH 3 、 -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl - OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl - O - C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl;

[0242] B 2 is CH 2 or CH(R 1D );

[0243] R 1D is L 6 、 =O, -C 1-6 alkyl - OH or -C 1-6 alkyl - O - C 1-4 alkyl;

[0244] Q is NH, N(R 1D ), or O; and

[0245] each q is 1, 2, or 3.

[0246] In certain embodiments, the chemical entity of formula (I) is a chemical entity of formula (Icc), and more specifically, a compound of formula (Icc) or a pharmaceutically acceptable salt of a compound of formula (Icc):

[0247] wherein L 6 , B 1 , D 1 , E, G, and r have any of the values described herein.

[0248] In certain embodiments of the chemical entity of formula (Icc),

[0249] L 6 is selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -N═S(═O)(CH 3 ), 2 , -NO 2 , -SO 2 CH 3 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C 3-10 cycloalkyl, -C 1-6 alkyl-O-C 1-4 alkyl, 3-15 membered heterocycloalkyl, phenyl, benzyl, and 5-10 membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, phenyl, benzyl, and 5-10 membered heteroaryl are optionally substituted with one to four R 1E , where each R 1E is independently selected from: halogen, -OH, ═O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl;

[0250] Each B 1 , D 1 , E and G is either CH, C(R 1D ), or N, provided that B 1 , D 1 , E and G no more than two are N at the same time;

[0251] Each R 1D is independently selected from: L 6 , =O, -C 1-6 alkyl-OH and -C 1-6 alkyl-O-C 1-4 alkyl; and

[0252] r is 1 or 2.

[0253] In some embodiments of the chemical entities of general formula (Icc) disclosed herein:

[0254] L 6 is selected from: -H, halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy and -C 1-6 haloalkoxy;

[0255] B 1 and E are N;

[0256] D 1 and G are independently CH or C(R 1D );

[0257] And r is 2.

[0258] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0259] L 6 is selected from: -H, halogen, -C 1-6 alkyl, -C1-6 haloalkyl, -C 1-6 alkoxy, and -C 1-6 haloalkoxy;

[0260] D 1 and G are N;

[0261] B 1 and E are independently CH or C(R 1D );

[0262] and r is 2.

[0263] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0264] L 2 is -N(R c )-, -NR c (CH 2 ) m -, -O-, -S-, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 2-5 alkenyl, -C 2-5 alkynyl, -C(O)C 1-4 alkyl, -CHR c -, -(CH 2 ) m NH-, -(CH 2 ) m O-, or -(CH 2 ) m S-, wherein the -C 1-4 alkyl is optionally substituted with one to three R 1B , and each R 1B is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-6 cycloalkyl.

[0265] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0266] L 2 is selected from: -C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl and 5- to 10-membered heteroaryl, wherein said -C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl and 5- to 10-membered heteroaryl are optionally substituted with one to three R 1B substituents.

[0267] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0268] L 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pent-1-yl, adamantyl or 2,3-dihydro-1H-inden-5-yl, each optionally substituted with one to three R 1B substituents.

[0269] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0270] L 2Selected from: azetidine, pyrrolidine, piperidine, azepane, dihydropyrrole, tetrahydropyridine, imidazoline, piperazine, diazepane, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, benzo[d][1,3]dioxole, 2,3-dihydrobenzo[b][1,4]dioxine, tetrahydroquinoline, tetrahydroisoquinoline, quinolin-2(1H)-one, decahydroisoquinoline, decahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3-dihydrobenzo[b][1,4]dioxine, pyrimidinone, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 8-oxa-3-azabicyclo[3.2.1]octane, pyrimidin-4(3H)-one, octahydrocyclopenta[c]pyrrole, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, tetrahydronaphthyridine, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine and isoindoline, each optionally substituted with one to four R 1B Optionally substituted, wherein each R 1B is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-6 cycloalkyl.

[0271] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0272] L 2 Selected from: azetidine, pyrrolidine, piperidine, azepane, imidazoline, piperazine, diazepane, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, benzo[d][1,3]dioxole, 2,3-dihydrobenzo[b][1,4]dioxin, tetrahydroquinoline, tetrahydroisoquinoline, quinolin-2(1H)-one, decahydroisoquinoline, decahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3-dihydrobenzo[b][1,4]dioxin, pyrimidinone, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 8-oxa-3-azabicyclo[3.2.1]octane and pyrimidin-4(3H)-one, each optionally substituted with one to three R 1B optionally, wherein each R 1B is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-6 cycloalkyl.

[0273] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0274] L 2 is phenyl, which is optionally substituted with one to three R 1B optionally.

[0275] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0276] L 2is a 5- to 10-membered heteroaryl selected from: pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole, indole, indazole, benzimidazole, benzoxazole, benzothiazole, [1,2,4]triazolo[4,3-a]pyridine, and imidazo[1,2-a]pyrazine, each optionally substituted with one to three R 1B wherein each R 1B is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-6 cycloalkyl.

[0277] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0278] L 2 is pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole, oxazole, or isoxazole, each optionally substituted with one to three R 1B wherein each R 1B is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-6 cycloalkyl.

[0279] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0280] L 3 is selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -N=S(=O)(CH 3 ) 2 , -NO 2 , -SO 2 CH 3 , -F, -Cl, -Br, -I, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 2-5 alkenyl, -C 2-5 alkynyl, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl and -C(O)NH 2 , wherein the -C 1-4 alkyl is optionally substituted with one to three R 1C .

[0281] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0282] L 3 is selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -F, -Cl, -Br, -I, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkoxy, -C 1-4 haloalkoxy, wherein the -C 1-4 alkyl is optionally substituted with one to three R 1C .

[0283] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0284] L 3 is selected from: -C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl and 5- to 10-membered heteroaryl, wherein said -C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl and 5- to 10-membered heteroaryl is optionally substituted with one to three R 1C substituents.

[0285] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0286] L 3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pent-1-yl, adamantyl or 2,3-dihydro-1H-inden-5-yl, each optionally substituted with one to three R 1C substituents.

[0287] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0288] L 3Selected from: azetidine, pyrrolidine, piperidine, azepane, dihydropyrrole, tetrahydropyridine, imidazoline, piperazine, diazepane, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, benzo[d][1,3]dioxolene, 2,3-dihydrobenzo[b][1,4]dioxin, tetrahydroquinoline, tetrahydroisoquinoline, quinolin-2(1H)-one, decahydroisoquinoline, decahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3-dihydrobenzo[b][1,4]dioxin, pyrimidinone, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 8-oxa-3-azabicyclo[3.2.1]octane, pyrimidin-4(3H)-one, octahydrocyclopenta[c]pyrrole, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, tetrahydronaphthyridine, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine and isoindoline, each optionally substituted with one to three R 1C Optionally substituted, wherein each R 1C Is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 Alkyl, -N(C 1-4 Alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OH, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy, -C 1-6 Alkyl-O-C 1-4 Alkyl, -C(O)C 1-6 Alkyl, -COOC 1-6 Alkyl, -C(O)NH 2 And -C 3-7 Cycloalkyl.

[0289] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0290] L3 Selected from: azetidine, pyrrolidine, piperidine, azepane, imidazoline, piperazine, diazepane, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, benzod[d][1,3]dioxolene, 2,3-dihydrobenzo[b][1,4]dioxin, tetrahydroquinoline, tetrahydroisoquinoline, quinolin-2(1H)-one, decahydroisoquinoline, decahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3-dihydrobenzo[b][1,4]dioxin, pyrimidinone, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 8-oxa-3-azabicyclo[3.2.1]octane and pyrimidin-4(3H)-one, each optionally substituted with one to three R 1C optionally, wherein each R 1C is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl and -C 3-6 cycloalkyl.

[0291] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0292] L 3 is phenyl, which is optionally substituted with one to three R 1C optionally.

[0293] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0294] L 3 is selected from: pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole, indole, indazole, benzimidazole, benzoxazole, benzothiazole, [1,2,4]triazolo[4,3-a]pyridine and imidazo[1,2-a]pyrazine, each optionally substituted with one to four R 1C optionally, wherein each R 1CIndependently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl.

[0295] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0296] L 3 is selected from: pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole, oxazole and isoxazole, each optionally substituted by one to three R 1C wherein each R 1C is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy and -C 3-6 cycloalkyl.

[0297] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0298] L 3 is selected from: pyrrole, pyrazole, imidazole, thiazole, oxazole and isoxazole, each optionally substituted by one to three R 1C wherein each R 1C is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl)2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy and -C 3-6 cycloalkyl.

[0299] In some embodiments of the chemical entities of general formula (I) or (Ic) disclosed herein:

[0300] L 4 and L 5Together with the nitrogen atoms to which they are attached, form azetidine, pyrrolidine, 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, imidazolidine, piperidine, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, piperazine, morpholine, 3-azabicyclo[3.1.0]hexane, octahydrocyclopenta[c]pyrrole, octahydrocyclopenta[b]pyrrole, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 5,6,7,8-tetrahydro-1,6-naphthyridine, 5,6,7,8-tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,6-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, isoindoline, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, 5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[1,2-c]pyrimidine, hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole, hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole, decahydroisoquinoline, decahydroquinoline, azepane, diazepane, 8-oxa-3-azabicyclo[3.2.1) Octane, 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine, 3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine, spiro[indoline-3,3'-piperidine]-2-one, spiro[indoline-3,3'-pyrrolidine]-2-one, 2,3-dihydrospiro[indene-1,2'-morpholine], 3H-spiro[isobenzofuran-1,3'-piperidine], 3H-spiro[isobenzofuran-1,3'-pyrrolidine], spiro[benzo[d][1,3]oxazine-4,4'-piperidine]-2(1H)-one, spiro[indene-1,4'-piperidine], 3H-spiro[benzo[c]thiophene-1,4'-piperidine] or 2,3,4,5-tetrahydro-1H-1,5-methano-1,5-benzodiazepine, each optionally substituted with one to three R 1D Optionally substituted.

[0301] In some embodiments of the chemical entities of formula (I) or (Ic) disclosed herein:

[0302] L 4 and L 5 together with the nitrogen to which they are attached form azetidine, pyrrolidine, piperidine, azepane, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine or 2,3-dihydro-1H-pyrrole, each optionally substituted with one to three R 1D Optionally substituted.

[0303] In some embodiments of the chemical entities of formula (I) or (Ic) disclosed herein:

[0304] L 4 and L 5 together with the nitrogen to which they are attached form imidazolidine, piperazine, diazepane or morpholine, each optionally substituted with one to three R 1D Optionally substituted.

[0305] In some embodiments of the chemical entities of formula (I) or (Ic) disclosed herein:

[0306] L 4 and L 5Together with the nitrogen to which they are attached, form 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 5,6,7,8-tetrahydro-1,6-naphthyridine, 5,6,7,8-tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,6-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine or isoindoline, each optionally substituted by one to three R 1D Optionally substituted.

[0307] In some embodiments of the chemical entities of general formula (I) or (Ic) disclosed herein:

[0308] L 4 And L 5 Together with the nitrogen to which they are attached, form 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, octahydropyrrolo[1,2-a]pyrazine or octahydropyrrolo[1,2-c]pyrimidine, each optionally substituted by one to three R 1D Optionally substituted.

[0309] In some embodiments of the chemical entities of general formula (I) or (Ic) disclosed herein:

[0310] L 4 And L 5Together with the nitrogen to which they are attached, form: 3-azabicyclo[3.1.0]hexane, octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole, hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole, decahydroisoquinoline, decahydroquinoline, 8-oxa-3-azabicyclo[3.2.1]octane, 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine, 3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine, spiro[indoline-3,3'-piperidine]-2-one, spiro[indoline-3,3'-pyrrolidine]-2-one, 2,3-dihydrospiro[indene-1,2'-morpholine], 3H-spiro[isobenzofuran-1,3'-piperidine], 3H-spiro[isobenzofuran-1,3'-pyrrolidine], spiro[benzo[d][1,3]oxazine-4,4'-piperidine]-2(1H)-one, spiro[indene-1,4'-piperidine], 3H-spiro[benzo[c]thiophene-1,4'-piperidine] or 2,3,4,5-tetrahydro-1H-1,5-methanobenzodiazepine, each optionally substituted by one to three R 1D Optionally substituted.

[0311] In some embodiments of the chemical entities of formula (I) or (Ic) disclosed herein:

[0312] L 4 and L 5 Together with the nitrogen to which they are attached, form pyrazole, imidazole, pyrrole, oxazole, thiazole, indole or indazole, each optionally substituted by one to three R 1D Optionally substituted.

[0313] In some embodiments of the chemical entities of formula (I) or (Ic) disclosed herein:

[0314] L 4 and L 5 Together with the nitrogen to which they are attached, form pyrazole, which is optionally substituted by one to three R 1D Optionally substituted.

[0315] In some embodiments of the chemical entities of formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0316] Each R b Independently is -H, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 alkyl-OH, -C 1-3Alkyl-O-C 1-3 Alkyl or -C 3-5 Cycloalkyl.

[0317] In some embodiments of the chemical entities of general formula (I), (Ic), (Icaa), (Icab), (Icb) or (Icc) disclosed herein:

[0318] L 6 Is selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 Alkyl, -N(C 1-4 Alkyl) 2 , -F, -Cl, -Br, -I, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 Alkoxy, -C 1-4 Haloalkoxy, -C(O)C 1-4 Alkyl, -C(O)NH 2 , -C 3-10 Cycloalkyl, -C 1-4 Alkyl-O-C 1-4 Alkyl, 3-10 membered heterocycloalkyl, phenyl, benzyl and 5-10 membered heteroaryl, wherein the -C 1-4 Alkyl, -C 3-10 Cycloalkyl, -C 3-7 Cycloalkoxy, 3-10 membered heterocycloalkyl, phenyl, benzyl and 5-10 membered heteroaryl are optionally substituted with one or more R 1E wherein each R 1E is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 Alkyl, -N(C 1-4 Alkyl) 2 , -NO 2 , -CN, -C 1-4 Alkyl, -C 1-4 Haloalkyl, -C 1-4 Alkyl-OH, -C 1-4 Alkoxy, -C 1-4 Haloalkoxy, -C 1-4 Alkyl-O-C 1-4 Alkyl and -C 3-6 Cycloalkyl.

[0319] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0320] R c is -H, -C 1-4 Alkyl or -C 1-4Halogenated alkyl

[0321] In some embodiments of the chemical entities of general formula (Ibb) disclosed herein:

[0322] Each R d is independently -H or -C 1-4 alkyl

[0323] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0324] R 1B is independently selected from: -F, -Cl, -OH, -C 1-4 alkyl, -C 1-4 halogenated alkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 halogenated alkoxy

[0325] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba) or (Ibb) disclosed herein:

[0326] Each R 1C is independently selected from: -F, -Cl, -OH, -C 1-4 alkyl, -C 1-4 halogenated alkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 halogenated alkoxy

[0327] In some embodiments of the chemical entities of general formula (I) or (Ic) disclosed herein:

[0328] Each R 1D is independently selected from: L 6 or =O

[0329] In some embodiments of the chemical entities of general formula (I), (Ic), (Ica), (Icb) or (Icc) disclosed herein:

[0330] Each R 1E is independently selected from: -F, -Cl, -OH, -C 1-4 alkyl, -C 1-4 halogenated alkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 halogenated alkoxy

[0331] In some embodiments of the chemical entities of general formula (Iba) or (Ibb) disclosed herein:

[0332] Each R b is independently -H, -C 1-6 alkyl or -C 1-6 haloalkyl.

[0333] In some embodiments of the chemical entities of general formula (Iba) or (Ibb) disclosed herein:

[0334] m is 0.

[0335] In some embodiments of the chemical entities of general formula (Iba) or (Ibb) disclosed herein:

[0336] m is 1.

[0337] In some embodiments of the chemical entities of general formula (Iba) or (Ibb) disclosed herein:

[0338] m is 2.

[0339] In some embodiments of the chemical entities of general formula (Iba) or (Ibb) disclosed herein:

[0340] L 2 is -C 3-7 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl or 5- to 10-membered heteroaryl, said -C 3-7 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl and 5- to 10-membered heteroaryl are optionally substituted with one to three R 1B wherein each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy;

[0341] L 3 is -H, halogen, -C 1-6 alkyl or -C 1-4 alkoxy;

[0342] R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and

[0343] m is 0 or 1.

[0344] In some embodiments of the chemical entities of general formula (Iba) or (Ibb) disclosed herein:

[0345] L 2 is -C3-7 a cycloalkyl group, a 3- to 10-membered hetero cycloalkyl group, a phenyl group, or a 5- to 10-membered heteroaryl group, said -C 3-7 The cycloalkyl group, 3- to 10-membered hetero cycloalkyl group, phenyl group, and 5- to 10-membered heteroaryl group are optionally substituted by one to three R 1B wherein each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, and -C 1-4 haloalkoxy;

[0346] L 3 is -C 3-7 a cycloalkyl group, a 3- to 10-membered hetero cycloalkyl group, a phenyl group, a benzyl group, or a 5- to 10-membered heteroaryl group, said -C 3-7 The cycloalkyl group, 3- to 10-membered hetero cycloalkyl group, phenyl group, benzyl group, and 5- to 10-membered heteroaryl group are optionally substituted by one to three R 1C wherein each R 1C is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, and -C 1-4 haloalkoxy;

[0347] R b is -H, -C 1-3 alkyl, or -C 1-3 haloalkyl; and

[0348] m is 0 or 1.

[0349] In some embodiments of the chemical entities of the general formula (Iba) or (Ibb) disclosed herein:

[0350] L 2 is -C 3-7 a cycloalkyl group, said -C 3-7 The cycloalkyl group is optionally substituted by one to three R 1B wherein each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, and -C 1-4 haloalkyl;

[0351] L 3 is -H, a halogen, or -C 1-4 alkyl;

[0352] R bis -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and

[0353] m is 0 or 1.

[0354] In some embodiments of the chemical entities of general formula (Iba) or (Ibb) disclosed herein:

[0355] L 2 is phenyl or a 5-10 membered heteroaryl, said phenyl or 5-10 membered heteroaryl being optionally substituted by one to three R 1B where each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy;

[0356] L 3 is -C 3-7 cycloalkyl, a 3-10 membered heterocycloalkyl, phenyl or a 5-10 membered heteroaryl, said -C 3-7 cycloalkyl, 3-10 membered heterocycloalkyl, phenyl and 5-10 membered heteroaryl being optionally substituted by one to three R 1C where each R 1C is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy;

[0357] R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and

[0358] m is 0 or 1.

[0359] In some embodiments of the chemical entities of general formula (Iba) or (Ibb) disclosed herein:

[0360] L 2 is phenyl or a 5-10 membered heteroaryl, said phenyl or 5-10 membered heteroaryl being optionally substituted by one to three R 1B where each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C1-4 Alkyl-OH, -C 1-4 Alkoxy and -C 1-4 Halogenated alkoxy;

[0361] L 3 is -H, halogen, -C 1-6 alkyl or -C 1-4 alkoxy;

[0362] R b is -H, -C 1-3 alkyl or -C 1-3 halogenated alkyl; and

[0363] m is 1 or 2.

[0364] In some embodiments of the chemical entities of formula (Iba) or (Ibb) disclosed herein:

[0365] L 2 is phenyl or a 5- or 6-membered heteroaryl, the phenyl and 5- or 6-membered heteroaryl being optionally substituted by one to three R 1B where each R 1B is independently selected from: -F, -Cl, -Br, -C 1-3 alkyl, -C 1-3 halogenated alkyl, -C 1-3 alkoxy and -C 1-3 halogenated alkoxy;

[0366] L 3 is -H, -halogen, -C 1-6 alkyl or -C 1-4 alkoxy;

[0367] R b is -H or -CH 3 ; and

[0368] m is 1 or 2.

[0369] In some embodiments of the chemical entities of formula (Iba) or (Ibb) disclosed herein:

[0370] L 2 is pyridine, pyridazine, pyrazine or pyrimidine, each optionally substituted by one to three R 1B where each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 halogenated alkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 halogenated alkoxy;

[0371] L 3 is -H, halogen, -C 1-6 alkyl or -C 1-4 alkoxy;

[0372] R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and

[0373] m is 1.

[0374] In some embodiments of the chemical entities of general formula (Iba) or (Ibb) disclosed herein:

[0375] L 2 is pyrrole, pyrazole, imidazole, thiazole, oxazole or isoxazole, each optionally substituted by one to three R 1B wherein each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy;

[0376] L 3 is -H, halogen, -C 1-6 alkyl or -C 1-4 alkoxy;

[0377] R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and

[0378] m is 1.

[0379] In some embodiments of the chemical entities of general formula (Icaa), (Icab), (Icb) or (Icc) disclosed herein:

[0380] L 6 is selected from: -H, -OH, -CN, -NO 2 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy and -C 3-7 cycloalkyl.

[0381] In some embodiments of the chemical entities of general formula (Icaa), (Icab), (Icb) or (Icc) disclosed herein:

[0382] L6 is phenyl or a 5- or 6-membered heteroaryl, said phenyl and 5- or 6-membered heteroaryl being optionally substituted by one or more R 1E , where each R 1E is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy and -C 1-6 alkyl-O-C 1-4 alkyl.

[0383] In some embodiments of the chemical entities of general formula (Icc) disclosed herein:

[0384] r is 2, B 1 is N, E is N and D 1 and G are independently CH or C(R 1D ).

[0385] In some embodiments of the chemical entities of general formula (Icc) disclosed herein:

[0386] r is 2, D 1 is N, G is N and B 1 and E are independently CH or C(R 1D ).

[0387] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0388] L 1 is a monocyclic or bicyclic 5- to 10-membered C 4-9 heteroaryl containing one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen and sulfur.

[0389] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0390] L 1 is a monocyclic or bicyclic 5- to 9-membered C 4-8 heteroaryl containing one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen and sulfur.

[0391] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0392] L 1 is a monocyclic 5- to 6-membered C 3-5 heteroaryl containing one to three heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

[0393] In some embodiments of the chemical entities of general formula (I), (Ia), or (Ib) disclosed herein:

[0394] L 1 is a monocyclic 6-membered C 4-5 heteroaryl containing one to two heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

[0395] In some embodiments of the chemical entities of general formula (I), (Ia), or (Ib) disclosed herein:

[0396] L 1 is a monocyclic 5-membered C 3-4 heteroaryl containing one to two heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

[0397] In some embodiments of the chemical entities of general formula (I), (Ia), or (Ib) disclosed herein:

[0398] L 1 is a bicyclic or tricyclic 9- to 15-membered C 8-14 heterocyclic hydrocarbyl containing one to three heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

[0399] In some embodiments of the chemical entities of general formula (I), (Ia), or (Ib) disclosed herein:

[0400] L 1 is a monocyclic or bicyclic 3- to 10-membered C 2-9 heterocyclic hydrocarbyl containing one to four heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

[0401] In some embodiments of the chemical entities of general formula (I), (Ia), or (Ib) disclosed herein:

[0402] L 1 is a bicyclic 8- to 10-membered C 4-9 heterocyclic hydrocarbyl containing one to four heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

[0403] In some embodiments of the chemical entities of general formula (I), (Ia), or (Ib) disclosed herein:

[0404] L 1 is a bicyclic 8- to 10-membered C 5-9A heterocyclic hydrocarbyl group containing one to three nitrogen atoms.

[0405] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0406] L 1 is a monocyclic 4- to 7-membered C 3-6- heterocyclic hydrocarbyl group containing one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0407] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0408] L 1 is a monocyclic 5- to 6-membered C 3-5- heterocyclic hydrocarbyl group containing one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0409] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0410] L 1 is a monocyclic 4- to 7-membered C 3-6- heterocyclic hydrocarbyl group containing one to two nitrogen atoms.

[0411] In some embodiments of the chemical entities of general formula (I), (Ia) or (Ib) disclosed herein:

[0412] L 1 is a monocyclic 5- to 6-membered C 3-5- heterocyclic hydrocarbyl group containing one to two nitrogen atoms.

[0413] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba) or (Ibb) disclosed herein:

[0414] L 2 is a monocyclic or bicyclic 5- to 10-membered C 4-9 heteroaryl group containing one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0415] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba) or (Ibb) disclosed herein:

[0416] L 2 is a monocyclic or bicyclic 5- to 9-membered C 4-8 heteroaryl group containing one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0417] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba) or (Ibb) disclosed herein:

[0418] L 2 is a monocyclic 5-6 membered C 3-5 heteroaryl, which contains one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen and sulfur.

[0419] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba) or (Ibb) disclosed herein:

[0420] L 2 is a monocyclic 6 membered C 4-5 heteroaryl, which contains one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen and sulfur.

[0421] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba) or (Ibb) disclosed herein:

[0422] L 2 is a monocyclic 5 membered C 3-4 heteroaryl, which contains one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen and sulfur.

[0423] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba) or (Ibb) disclosed herein:

[0424] L 2 is a monocyclic or bicyclic 3-15 membered C 2-14 heterocyclic hydrocarbyl.

[0425] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba) or (Ibb) disclosed herein:

[0426] L 2 is a monocyclic or bicyclic 3-10 membered C 2-9 heterocyclic hydrocarbyl, which contains one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen and sulfur.

[0427] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba) or (Ibb) disclosed herein:

[0428] L 2 is a bicyclic 8-10 membered C 4-9 heterocyclic hydrocarbyl, which contains one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen and sulfur.

[0429] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba) or (Ibb) disclosed herein:

[0430] L 2 is a monocyclic 4- to 7-membered C 3-6- heterocyclic hydrocarbyl group containing one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0431] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba), or (Ibb) disclosed herein:

[0432] L 2 is a monocyclic 5- to 6-membered C 3-5- heterocyclic hydrocarbyl group containing one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0433] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba), or (Ibb) disclosed herein:

[0434] L 2 is a monocyclic 4- to 7-membered C 3-6- heterocyclic hydrocarbyl group containing one to two nitrogen atoms.

[0435] In some embodiments of the chemical entities of general formula (I), (Ib), (Iba), or (Ibb) disclosed herein:

[0436] L 2 is a monocyclic 5- to 6-membered C 3-5- heterocyclic hydrocarbyl group containing one to two nitrogen atoms.

[0437] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0438] L 3 is a monocyclic or bicyclic 5- to 10-membered C 4-9 heteroaryl group containing one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0439] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0440] L 3 is a monocyclic or bicyclic 5- to 9-membered C 4-8 heteroaryl group containing one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0441] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0442] L 3 is a monocyclic 5- to 6-membered C3-5 A heteroaryl group containing one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0443] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0444] L 3 is a monocyclic 6-membered C 4-5 heteroaryl group containing one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0445] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0446] L 3 is a monocyclic 5-membered C 2-4 heteroaryl group containing one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0447] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0448] L 3 is a monocyclic or bicyclic 3- to 15-membered C 2-14 heterocyclic hydrocarbyl group.

[0449] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0450] L 3 is a bicyclic 8- to 10-membered C 4-9 heterocyclic hydrocarbyl group containing one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0451] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0452] L 3 is a monocyclic 4- to 7-membered C 3-6- heterocyclic hydrocarbyl group containing one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0453] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0454] L 3 is a monocyclic 5- to 6-membered C 3-5-A heterocyclic hydrocarbyl group containing one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0455] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0456] L 3 is a monocyclic 4- to 7-membered C 3-6- heterocyclic hydrocarbyl group containing one to two nitrogen atoms.

[0457] In some embodiments of the chemical entities of general formula (I), (Ia), (Ib), (Iba), or (Ibb) disclosed herein:

[0458] L 3 is a monocyclic 5- to 6-membered C 3-5- heterocyclic hydrocarbyl group containing one to two nitrogen atoms.

[0459] In some embodiments of the chemical entities of general formula (I) or (Ic) disclosed herein:

[0460] L 4 and L 5 together with the nitrogen to which they are attached form a monocyclic 5-membered C 3-4 heteroaryl group containing one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0461] In some embodiments of the chemical entities of general formula (I) or (Ic) disclosed herein:

[0462] L 4 and L 5 together with the nitrogen to which they are attached form a bicyclic or tricyclic 9- to 15-membered C 8-14 heterocyclic hydrocarbyl group containing one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0463] In some embodiments of the chemical entities of general formula (I) or (Ic) disclosed herein:

[0464] L 4 and L 5 together with the nitrogen to which they are attached form a monocyclic or bicyclic 3- to 10-membered C 2-9 heterocyclic hydrocarbyl group containing one to four heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0465] In some embodiments of the chemical entities of general formula (I) or (Ic) disclosed herein:

[0466] L 4 and L 5together with the nitrogen to which they are attached form a bicyclic 8- to 10-membered C 4-9 heterocyclic hydrocarbyl group containing one to four heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

[0467] In some embodiments of the chemical entities of formula (I) or (Ic) disclosed herein:

[0468] L 4 and L 5 together with the nitrogen to which they are attached form a bicyclic 8- to 10-membered C 5-9 heterocyclic hydrocarbyl group containing one to three nitrogen atoms.

[0469] In some embodiments of the chemical entities of formula (I) or (Ic) disclosed herein:

[0470] L 4 and L 5 together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered C 3-6- heterocyclic hydrocarbyl group containing one to two heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

[0471] In some embodiments of the chemical entities of formula (I) or (Ic) disclosed herein:

[0472] L 4 and L 5 together with the nitrogen to which they are attached form a monocyclic 5- to 6-membered C 3-5- heterocyclic hydrocarbyl group containing one to two heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

[0473] In some embodiments of the chemical entities of formula (I) or (Ic) disclosed herein:

[0474] L 4 and L 5 together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered C 3-6- heterocyclic hydrocarbyl group containing one to two nitrogen atoms.

[0475] In some embodiments of the chemical entities of formula (I) or (Ic) disclosed herein:

[0476] L 4 and L 5 together with the nitrogen to which they are attached form a monocyclic 5- to 6-membered C 3-5- heterocyclic hydrocarbyl group containing one to two nitrogen atoms.

[0477] In some embodiments of the chemical entities of formula (I), (Ic), (Icaa), (Icab), (Icb), or (Icc) disclosed herein:

[0478] L 6 is a monocyclic 5- to 6-membered C 3-5 heteroaryl group that contains one to three heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0479] In some embodiments of the chemical entities of general formula (I), (Ic), (Icaa), (Icab), (Icb), or (Icc) disclosed herein:

[0480] L 6 is a monocyclic 6-membered C 4-5 heteroaryl group that contains one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0481] In some embodiments of the chemical entities of general formula (I), (Ic), (Icaa), (Icab), (Icb), or (Icc) disclosed herein:

[0482] L 6 is a monocyclic 5-membered C 3-4 heteroaryl group that contains one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0483] In some embodiments of the chemical entities of general formula (I), (Ic), (Icaa), (Icab), (Icb), or (Icc) disclosed herein:

[0484] L 6 is a monocyclic 5- to 6-membered C 3-5- heterocyclic hydrocarbyl group that contains one to two heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur.

[0485] In some embodiments of the chemical entities of general formula (I), (Ic), (Icaa), (Icab), (Icb), or (Icc) disclosed herein:

[0486] L 6 is a monocyclic 5- to 6-membered C 3-5- heterocyclic hydrocarbyl group that contains one to two nitrogen atoms.

[0487] In some embodiments, the chemical entity is selected from the compounds of Examples 1-814, and all of its pharmaceutically acceptable forms, including pharmaceutically acceptable chelates, solvates, conformational isomers, crystal forms / polymorphs, salts, prodrugs, and pharmacologically active metabolites. In other embodiments, the chemical entity is selected from the compounds of Examples 1-814 and their pharmaceutically acceptable salts. In other embodiments, the chemical entity is a compound selected from Examples 1-814.

[0488] Further embodiments provide pharmaceutically acceptable salts of the compounds of formula (I), tautomers of the compounds of formula (I), pharmaceutically acceptable prodrugs of the compounds of formula (I), and pharmaceutically active metabolites of the compounds of formula (I).

[0489] Isotope-Labeled Compounds

[0490] The compounds of formula (I) may contain any isotope in which one or more atoms are replaced by 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.

[0491] The compounds of the invention containing the above-mentioned isotopes or other isotopes of other atoms (and all forms of these compounds, such as pharmaceutically acceptable salts) are within the scope of the invention. The isotopically labeled compounds of this embodiment can be used in binding affinity studies and in drug and substrate tissue distribution and target occupancy analysis. For example, as further described herein, the isotopically labeled compounds can be used particularly in SPECT (single photon emission computed tomography) and PET (positron emission tomography). In addition, the 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.

[0492] Combinations

[0493] 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.

[0494] In some embodiments, the pharmaceutical composition may comprise: (a) an effective amount of at least one chemical entity of the present disclosure; (b) a pharmaceutically acceptable carrier.

[0495] In some embodiments, the pharmaceutical composition comprises a compound of any of the embodiments and examples disclosed herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In a specific embodiment, the pharmaceutical composition comprises a compound of any one of Examples 1-814; and a pharmaceutically acceptable carrier.

[0496] Formulations and Administration

[0497] Many standard references are available that describe procedures for preparing various formulations suitable for administration of the compounds according to the invention. 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.

[0498] Any suitable route of administration may be employed to provide an effective dose of the compound of the invention to an animal, particularly a human. For example, oral, rectal, topical, parenteral, ophthalmic, pulmonary, nasal, etc. may be employed. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc.

[0499] Suitable carriers, diluents, and excipients are 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 invention. Solvents are generally selected based on solvents recognized as generally regarded as safe (GRAS) for administration to animals. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. and mixtures thereof. The formulation may also contain one or more of buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide an aesthetic presentation of the medicament (i.e., the compound of the present invention or its pharmaceutical composition) or to assist in the manufacture of the pharmaceutical product (i.e., the medicament).

[0500] The formulation 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 compound of the present invention or a stable form of the compound (such as a complex with a cyclodextrin derivative or other known complexing agents)) is dissolved in a suitable solvent. The compounds of the present invention are generally formulated into pharmaceutical dosage forms to provide a medicament with easy control and appropriate dosage.

[0501] The pharmaceutical composition (or formulation) applied can be packaged in various ways depending on the method of administering the medicament. 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, materials such as bottles (plastic bottles and glass bottles), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include anti-tampering fittings to prevent inadvertent 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.

[0502] Dosage Forms

[0503] The chemical entity, and more particularly, the compound and its pharmaceutically acceptable salts can be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an absorbable edible carrier. They can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly 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, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. Such compositions and preparations should contain at least 0.1% of the active compound. Of course, the percentages of such compositions and preparations can vary and can suitably be from 1% to 65% or 2% to 60% of the weight of the 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.

[0504] Tablets, lozenges, pills, capsules, etc. can also contain the following: binders such as gum tragacanth, gum arabic, corn starch, or gelatin; excipients such as dibasic calcium phosphate; disintegrating agents 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 type, it can also contain a liquid carrier such as a vegetable oil or polyethylene glycol. A variety of other materials can 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 can be coated with gelatin, wax, shellac, or sugar, etc. Syrups or elixirs can 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 should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained-release preparations and devices.

[0505] The active compound can also be administered by intravenous or intraperitoneal infusion or injection. Solutions of the active compound or its 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 storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0506] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing an 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 glycol, 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 caused by microorganisms can be prevented by various antibacterial or antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, isotonic agents, such as sugars, buffers or sodium chloride, will preferably be included. The absorption of an injectable composition can be prolonged by using a composition of a reagent for delayed absorption, such as aluminum monostearate and gelatin.

[0507] Sterile injectable solutions are usually prepared by incorporating the required amount of the active compound into a suitable solvent, which has, according to need, any of the many other ingredients listed above, and then filtering to sterilize. In the case where sterile powders are used for the preparation of sterile injectable solutions, the commonly used preparation methods are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional required ingredients present in a previously sterile-filtered solution.

[0508] For topical administration, the compounds of the present invention can be applied in pure form, i.e., when it is a liquid. However, it is generally desirable to administer it to the skin in the form of a composition or formulation, which is combined with a dermatologically acceptable carrier, and the carrier can be solid or liquid. These compositions and formulations can be prepared according to the common general knowledge in the art.

[0509] 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 an absorbent pad used to impregnate bandages and other dressings, or can be sprayed onto the affected area using a pump or an aerosol sprayer.

[0510] Thickening agents can also be used with the liquid carrier to form spreadable pastes, gels, ointments, soaps, etc., for direct application to the skin of the user, and the thickening agents are, for example, synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified minerals.

[0511] Doses

[0512] The useful doses of the chemical entities and compounds (active agents) of the present disclosure can be determined by comparing their in vitro activity with their in vivo activity 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 compounds of Formula I can be determined by comparing their in vitro activity with their in vivo activity 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).

[0513] 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: e.g., 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 from 0.0001 mg of active agent per day to 200 mg of active agent per day, from 0.001 mg / day to 200 mg / day, from 0.05 mg / day to 100 mg / day, from 0.1 mg / day to 10 mg / day, from 1 mg / day to 200 mg / day, or from 5 mg / day to 50 mg / day.

[0514] In some embodiments, the desired dose can be presented in unit dosage forms; e.g., a composition containing from 0.01 mg to 1000 mg, from 0.1 mg to 200 mg, from 0.5 mg to 100 mg, or from 1 mg to 50 mg of active ingredient per unit dosage form.

[0515] In other embodiments, the desired dose can be presented in divided doses administered at appropriate intervals, e.g., 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, e.g., as used in the compositions and methods according to the present invention.

[0516] Methods and Uses

[0517] Uses of Isotope-Labeled Compounds

[0518] In some embodiments, the present disclosure provides methods for using isotopically labeled compounds of the present invention in: (i) metabolic studies (using, e.g., 14 C) and reaction kinetics studies (using, e.g., 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 matrix tissue distribution analysis; or (iii) radiotherapy of patients.

[0519] Isotopically labeled compounds of general formula (I) and related chemical entities can generally be prepared by carrying out the procedures disclosed in the protocols or examples and preparations described below, by replacing unlabeled reagents with readily available isotopically labeled reagents. With 18 F or 11 C labeled compounds 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.

[0520] Therapeutic Methods

[0521] General

[0522] 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. More specifically, the chemical entity is a compound of general formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb) or (Icc) or a pharmaceutically acceptable salt thereof.

[0523] 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.

[0524] In some embodiments, the chemical entities and compositions herein are used in a method for inhibiting PDE1 activity, which includes exposing PDE1 to an effective amount of a chemical entity or composition of any of the embodiments disclosed herein. In some embodiments, PDE1 is in an animal, more specifically in a human individual.

[0525] 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 PDE1 activity, including administering to the individual in need thereof an effective amount of a chemical entity or composition of any of the embodiments herein. In one aspect, the individual is diagnosed with a disorder mediated by PDE1 activity. In another aspect, the individual has a disorder mediated by PDE1 activity.

[0526] 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; Medina, 2011, Front. Neurosci. 5, 21). Thus, in some embodiments, the present disclosure provides methods for enhancing neuronal plasticity, which include administering to the individual in need thereof an effective amount of a chemical entity or composition of any of the embodiments 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 the individual in need thereof an effective amount of a chemical entity or composition of any of the embodiments disclosed herein.

[0527] In some embodiments, the chemical entities and compositions herein are used as neuroprotective agents, for example, as neuroprotectants by enhancing neuronal growth and survival. Thus, the present disclosure provides methods for conferring neuroprotection, which include administering to the individual in need thereof an effective amount of a chemical entity or composition described herein.

[0528] In some embodiments, the chemical entities and compositions herein are used as agents that promote neurogenesis, which can be applicable for treating neurological disorders as further described herein. PDE1B is highly expressed in the dentate gyrus and olfactory bulb, where neurogenesis occurs in the adult nervous system. Neurogenesis in the hippocampus is involved in memory formation in depression and cognitive deficits associated with neuropsychiatric disorders (including but not limited to PTSD and other anxiety disorders). See, e.g., Shors et al., 2001, Nature 410, 372-376; Shors et al., 2004, Trends Neurosci. 27, 250-256; Ming and Song, 2011, Neuron 70, 687-702; Hill et al., 2015, Neuropsychopharmacology 40, 2368-2378; Kheirbek et al., 2012, Nat. Neurosci. 15, 1613-1620.

[0529] In some embodiments, the chemical entities and compositions herein are used for treating disorders that include PDE1-mediated abnormal or dysregulated signaling pathways. These PDE1-related signaling pathways include but are not limited to those involving nitric oxide, natriuretic peptides (e.g., ANP, BNP, CNP), dopamine, norepinephrine, neurotensin, cholecystokinin (CCK), vasoactive intestinal peptide (VIP), serotonin, glutamate (e.g., NMDA receptor, AMPA receptor), GABA, acetylcholine, adenosine (e.g., A2A receptor), cannabinoids, natriuretic peptides (e.g., ANP, BNP, CNP), and endorphins.

[0530] In a specific aspect, they can be used to modulate dopaminergic signaling or treat disorders characterized by altered dopamine signaling, particularly polyamine signaling mediated by dopamine receptor D1, which is encoded by the DRD1 gene in humans. See, e.g., Nishi and Snyder, 2010, J. Pharmacol. Sci. 114, 6-16.

[0531] In some embodiments, the chemical entities and compositions are used as "agents" (or "enhancers") to increase the efficiency of a training protocol that promotes functional reorganization in a targeted "region" (or "function") in the brain.

[0532] In some embodiments, the chemical entities and compositions are used in combination with other therapies or with other active agents, as further described herein.

[0533] Neurological Disorders

[0534] 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. In a specific aspect, the chemical entity is a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc) or a pharmaceutically acceptable salt thereof.

[0535] In some embodiments, the method targets nerve damage associated with a neurological disorder (“nerve dysfunction”), including cognitive impairment (“cognitive dysfunction”) or motor impairment (“motor dysfunction”) associated with the pathology of a neurological disorder.

[0536] 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 (e.g., declarative memory), such as episodic memory, semantic memory, and autobiographical memory, and implicit memory (e.g., procedural memory)); expressive language, including naming, word recall, fluency, grammar, and syntax; understanding 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 dysfunction is a memory deficit, more particularly a long-term memory deficit.

[0537] Motor impairment can manifest as, for example, weakness or paralysis, upper and lower limb dysfunction, balance or coordination problems, gross motor skill impairment, and fine motor skill deficits.

[0538] 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 affected site, 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).

[0539] Many CNS disorders may be amenable to treatment with chemical entities and compositions, including those discussed herein. As used 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", "somatic symptom disorders", "neurodegenerative disorders", "neurocognitive disorders", "delirium", "dementia", and "age-related cognitive decline" include the diagnoses and classifications of these CNS conditions and disorders (and related CNS conditions and disorders) as set forth 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.

[0540] Psychiatric disorders and mental conditions:

[0541] In certain embodiments, the chemical entities and compositions herein may be used to treat a psychiatric disorder or mental condition, particularly cognitive impairment associated with the pathology of such conditions. In a specific aspect, the chemical entity is a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc) or a pharmaceutically acceptable salt thereof.

[0542] Psychiatric disorders and mental conditions are well known in the art and include, but are not limited to, one or more of the following:

[0543] · Neurodevelopmental disorders (or "developmental" disorders), such as intellectual disability disorders (e.g., Rubinstein-Taybi syndrome, Down syndrome, and Fragile X 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;

[0544] · 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;

[0545] · Bipolar disorder and related conditions, such as bipolar I disorder and bipolar II disorder, cyclothymic disorder, and other bipolar disorders and related conditions;

[0546] · Depressive disorders, 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;

[0547] · Anxiety disorders, such as specific phobia, agoraphobia, social anxiety disorder (social phobia), panic attacks, panic disorder, acute stress disorder, generalized anxiety disorder, posttraumatic stress disorder (PTSD), and other anxiety disorders;

[0548] · Obsessive-compulsive disorder and related conditions, 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;

[0549] · Dissociative disorders, such as dissociative identity disorder, dissociative amnesia, depersonalization / derealization disorder, dissociative subtype (in combination with other conditions), and other dissociative disorders;

[0550] · Disruptive, impulse-control, and conduct disorders, such as conduct disorder, antisocial personality disorder, pyromania, kleptomania, and other disruptive, impulse-control, and conduct disorders;

[0551] · 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;

[0552] · 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;

[0553] · Sleep disorders, such as sleep-wake disorders, insomnia, hypersomnia, narcolepsy, sleep-related breathing 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;

[0554] · Sexual disorders, such as arousal disorders, desire disorders, functional disorders, substance- and medication-induced functional disorders, erectile dysfunction, and other sexual disorders;

[0555] · 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

[0556] · 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;

[0557] · 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.

[0558] Schizophrenia:

[0559] In a specific embodiment, 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 can 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 can 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. Intracellular signaling of dopamine D1 and various serotonin receptors that signal through cyclic nucleotides is known to be defective in schizophrenia as well as in depression and other cognitive disorders. More generally, PDEs, including PDE1, have been implicated in the interface between cognitive deficits and neuropsychiatric disorders. See, e.g., Wang et al., 2015, Curr. Pharm. Des. 21, 303-316.

[0560] Accordingly, the present disclosure provides methods for treating schizophrenia that include administering to an individual in need an effective amount of a chemical entity or composition of the present disclosure. In a specific aspect, the chemical entity is a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc) or a pharmaceutically acceptable salt thereof. 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 includes a cognitive training program.

[0561] Addictive disorders:

[0562] In a specific embodiment, the mental disorder or psychiatric condition is an addictive disorder. On the one hand, an 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, 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 hyperactivity or compulsive overwork.

[0563] Accordingly, the present disclosure provides methods for treating addictive disorders, which comprise administering to an individual in need thereof an effective amount of a chemical entity or composition herein. In a specific embodiment, the chemical entity is a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb) or (Icc) or a pharmaceutically acceptable salt thereof.

[0564] Cognitive disorders:

[0565] In a specific embodiment, the present disclosure provides methods for treating cognitive disorders, and more specifically, methods for treating nerve damage associated with the disorder, which comprise administering to an individual in need thereof an effective amount of a chemical entity or composition described herein. In a specific aspect, the chemical entity is a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb) or (Icc) or a pharmaceutically acceptable salt thereof.

[0566] "Cognitive disorder" (or "neurocognitive disorder") is a condition whose main clinical feature is impaired cognitive function, i.e., a disease in which there is no primary cognitive defect since birth or very early life, and thus represents a decline from a previously attained functional level. Such conditions include one or more of the following:

[0567] · Delirium, such as substance intoxication (or withdrawal) delirium, drug-induced delirium and other forms of delirium;

[0568] · 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 dementia"); autoimmune disorders; and other dementias and neurodegenerative diseases.

[0569] · 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);

[0570] · Trauma-dependent functional losses, including vascular diseases such as stroke (such as ischemic stroke or hemorrhagic stroke) or ischemia; infarcts, including cerebral infarcts and myocardial infarcts; microvascular or macrovascular diseases caused by diabetes or arteriosclerosis; 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

[0571] · Chemotherapy-induced cognitive impairment, such as post-chemotherapy cognitive impairment (PCCI); chemotherapy-induced cognitive dysfunction or impairment; chemo brain; or chemo fog.

[0572] 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 impairment of multiple neurological functions, such as impairment of motor function.

[0573] Age-related cognitive decline:

[0574] In a specific embodiment, the cognitive disorder is age-related cognitive decline.

[0575] 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 decrease in the 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 subjectively and objectively demonstrate memory loss 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).

[0576] 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 more often face memory problems than the average person of their age. Symptoms usually include misplacing items, forgetting events or appointments, and difficulty remembering the words needed (e.g., Arnáiz and Almkvist, 2003, Acta Neurol. Scand. Suppl. 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 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 considered to have MCI are at increased risk of developing Alzheimer's disease. However, some patients with MCI never progress to AD.

[0577] Accordingly, the present disclosure includes methods for treating age-related cognitive decline, more particularly methods for treating age-related memory impairment or mild cognitive impairment, comprising administering to an individual in need an effective amount of a chemical entity or composition disclosed herein. In a specific aspect, the chemical entity is a compound of general formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of general formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb) or (Icc) or a pharmaceutically acceptable salt thereof.

[0578] Trauma-dependent loss of function:

[0579] In a specific embodiment, the cognitive disorder is trauma-dependent loss of function, particularly stroke or TBI. Accordingly, the present disclosure includes methods for treating trauma-dependent loss of function, particularly stroke or TBI, comprising administering to an individual in need an effective amount of a chemical entity or composition disclosed herein.

[0580] Movement disorders:

[0581] In certain embodiments, the present disclosure provides methods for treating movement disorders and movement conditions, more specifically, treating movement impairment or movement injury associated with the pathology of such conditions, comprising administering to an individual in need an effective amount of a chemical entity or composition described herein. In a specific aspect, the chemical entity is a compound of general formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of general formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb) or (Icc) or a pharmaceutically acceptable salt thereof.

[0582] 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. PDE1 is highly expressed in the striatum, and there is increasing evidence that phosphodiesterases play a key role in regulating dopamine signaling in the brain (Ramirez and Smith, 2014, Cent. Nerv. Syst. Agents Med. Chem. 14, 72-82).

[0583] Movement disorders include, but are not limited to: basal ganglia disorders, Parkinson's disease, post-encephalitic Parkinson's disease, dopamine-responsive dystonia, Hallervorden-Spatz syndrome (HSS), restless legs syndrome, Wilson's disease, Shy-drager syndrome, periodic limb movement disorder (PLMD), periodic limb movements in sleep (PLMS), Tourette syndrome, restless legs syndrome (RLS); chorea, such as Huntington's chorea; myoclonus (including generalized myoclonus and focal myoclonus); convulsions (including simple convulsions, complex convulsions and symptomatic convulsions); attention deficit hyperactivity disorder, hypokinesia and dyskinesia disorders; drug-induced movement disorders, diseases associated with striatal hypofunction; and other movement disorders and movement diseases.

[0584] 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.

[0585] In certain embodiments, the movement disorder is a basal ganglia disorder.

[0586] 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.

[0587] In a specific embodiment, the movement disorder is Parkinson's disease or Huntington's disease, as further discussed herein.

[0588] In some embodiments, the method targets specific movement abnormalities associated with the pathology of a movement disorder or movement disease. Movement abnormalities include, but are not limited to, tremors, resting tremors, rigidity, bradykinesia and hypokinesia of postural reflexes.

[0589] Neurodegenerative diseases:

[0590] In specific embodiments, the present disclosure provides methods for treating neurodegenerative disorders, and more specifically, methods for treating nerve damage associated with the pathology of neurodegenerative disorders, including administering to an individual in need an effective amount of a chemical entity or composition described herein.

[0591] 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, PDE1 inhibition has shown neuroprotective and anti-inflammatory effects and is expected to be beneficial in treating neuroinflammation and other hallmarks of such disorders.

[0592] Thus, in some embodiments, the treatment methods are 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.

[0593] In other embodiments, the treatment methods are directed to neurodegenerative disorders caused by primary nervous system injuries. 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.

[0594] Parkinson's disease:

[0595] In specific embodiments, the present disclosure provides methods for treating Parkinson's disease, which include administering to an individual in need an effective amount of a chemical entity or composition described herein. Parkinson's disease (PD), also known as Parkinsonism, idiopathic Parkinsonism, or primary Parkinsonism, is a degenerative disorder of the CNS and is estimated to affect 5 million people worldwide. It is a slowly progressive neurological condition characterized by tremors, stiffness, slow movement (bradykinesia), and impaired balance. Altered cAMP / cGMP levels are associated with Parkinson's disease, and increased PDE1B activity has been observed in Parkinson's disease models (Sancesario et al., 2004, Eur. J. Neurosci. 20, 989-1000).

[0596] 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. See, e.g., Broeders et al., 2013, Neurology 81, 346-352. 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 (Litvan et al., 2012, Mov. Disord. 27, 349-356). 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).

[0597] Accordingly, in specific embodiments, the chemical entities and compositions herein can be used to treat motor deficits associated with PD, and in other embodiments can be used to treat cognitive impairment associated with PD, including PD-MCI individuals. In a specific aspect, the chemical entity is a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc) or a pharmaceutically acceptable salt thereof.

[0598] Alzheimer's disease:

[0599] In specific 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. In a specific aspect, the chemical entity is a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc) or a pharmaceutically acceptable salt thereof..

[0600] 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 related to the following: the presence of β-amyloid (or senile) plaques; lack of neurotransmission; neuronal loss, especially in the cortex and hippocampus; neurofibrillary tangles; and the hyperphosphorylation and intracellular deposition of the microtubule-associated protein tau in the form of filaments; the intracellular deposition of aggregated tau filaments. In Alzheimer's disease, the accumulation of β-amyloid protein can lead to a decrease in CREB phosphorylation, which may be related to the cognitive deficits seen in this condition. More generally, increasing the levels of cAMP or cGMP by PDE4 inhibition can restore neuronal plasticity in Alzheimer's disease models (Vitolo et al., 2002, Proc. Natl. Acad. Sci. U.S.A. 99, 13217–13221; Medina, 2011, Front. Neurosci. 5, 21).

[0601] Huntington's disease:

[0602] In certain embodiments, the present disclosure provides methods of treating Huntington's disease (or "Huntington's chorea"), comprising administering to an individual in need thereof an effective amount of a chemical entity or compound disclosed herein. In certain aspects, the chemical entity is a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc) or a pharmaceutically acceptable salt thereof

[0603] 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. The symptoms of Huntington's disease include behavioral changes, abnormal and involuntary movements, and dementia deterioration (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 the degeneration of striatal neurons in the basal ganglia responsible for movement and coordination. PDE1 is highly expressed in the striatum, and in experimental models of Huntington's disease, PDE1 inhibition has been shown to have a protective effect against behavioral and biochemical toxicity (Gupta and Sharma, 2014, Eur. J. Pharmacol. 732, 111-122). 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(American Psychiatric Association, 2013 ed.)

[0604] Enhanced Training

[0605] In some embodiments, the chemical entities and their compositions of the present disclosure are used as enhancers in methods to improve the efficiency of training programs for strengthening 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 programs 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.

[0606] Training (or "training program") typically requires multiple sessions to achieve the desired benefits, such as rehabilitating motor or language deficits after stroke. This can be costly and time-consuming, thereby preventing individuals from complying and achieving real-world benefits that persist over time. The efficiency of such training programs can be improved by co-administering certain agents (known as enhancers) in combination with the training program (see, for example, U.S. 7,868,015; U.S. 7,947,731; U.S. 2008-0188525). When co-administered with a training program (or "training"), the enhancer enhances functional reorganization in the targeted domain (or "function") in the brain.

[0607] Cognitive domains (or functions) that a training program can target include, but are not limited to, the following: attention (such as sustained attention, divided attention, selective attention, processing speed); executive function (such as planning, decision-making, and working memory); learning and memory (such as immediate memory; recent memory, including free recall, cued recall, and recognition memory; and long-term memory, which can be divided into explicit memory (such as declarative memory), such as episodic, semantic, and autobiographical memory, and implicit memory (such as procedural memory)); language (such as expressive language, including naming, word recall, fluency, grammar, and syntax; and receptive language); sensorimotor function (such as the abilities involved in visual perception, visual construction, sensorimotor practice, and intuition); and social cognition (such as emotion recognition, theory of mind). In a specific embodiment, the cognitive function is learning and memory, and more specifically, long-term memory.

[0608] The motor domains (or functions) that the training program 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; gross and fine motor skills; and eye-hand coordination.

[0609] Training program:

[0610] 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, e.g., Kim et al., 2014, J. Phys. Ther. Sci. 26, 1-6; Allen et al., 2012, Parkinson’s Dis. 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.

[0611] Process-specific training focuses on improving specific domains, such as attention, memory, language, executive function, or motor function. Here, the goal of training is to obtain an overall improvement, that is, to transfer from trained activities to untrained activities based on the same cognitive or motor function or domain.

[0612] 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 programs 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 specific to the domains involved in the memory process, such as the recognition and use of facts, and the acquisition and understanding of explicit knowledge rules.

[0613] 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 training alone.

[0614] In another aspect, the enhancer is a PDE1 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 potentiates 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 can include both 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.

[0615] In one aspect, the chemical entities or compositions of the present disclosure can be used as enhancers in combination with any psychotherapy method intended to modulate brain cognitive function, thereby strengthening the efficacy of such therapies by reducing the amount of training (e.g., number of sessions) necessary to obtain a benefit. In a specific aspect, the chemical entity is a compound of general formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of general formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb) or (Icc) or a pharmaceutically acceptable salt thereof.

[0616] Accordingly, in some embodiments, the present disclosure provides the use of the chemical entities or compositions herein in enhancing a method of 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 chemical entity or composition in combination with the training to the animal; (c) repeating the providing and administering steps one or more times; and (d) reducing the amount of training sufficient to produce the improvement in performance relative to the improvement in performance produced by the training alone. In a specific embodiment, the animal is a human individual. 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 a particular aspect, the neurological disorder is stroke or traumatic brain injury. In certain aspects, as further described herein, enhanced training is provided to a stroke patient during post-stroke rehabilitation. In a specific aspect, the chemical entity is a compound of general formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the training comprises spaced-apart training sessions. In other embodiments, the training comprises clustered training sessions.

[0617] Animal skill protocol:

[0618] 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 enhanced functions or cognitive abilities that exceed the levels that can be achieved by training alone in non-human animals.

[0619] In a specific embodiment, the animal is a non-human animal, and more specifically, a service animal, the categories including but 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.

[0620] 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 a service animal; thus, for a complex skill set, the training will include more than one task.

[0621] Accordingly, in some embodiments, the present invention provides a method of teaching one or more skills to a non-human animal, which includes (a) administering a PDE1 inhibitor to the 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, such that the amount of training sufficient to improve the performance is reduced compared to the performance produced by training alone.

[0622] Stroke:

[0623] In certain embodiments, the chemical entities and compositions of the present disclosure can be used in the treatment of trauma-dependent functional loss, particularly in methods for treating stroke. Stroke is the leading 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 a blood vessel in the brain ruptures. Stroke care is time-continuous, which includes medical interventions in the acute phase of stroke and subsequent rehabilitation therapies involving the restoration of function in the post-stroke phase of stroke.

[0624] Acute treatment:

[0625] The treatment after a stroke attack directly targets the initial injury caused by ischemic or hemorrhagic stroke. The acute treatment options for ischemic stroke include drug therapy 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.

[0626] Post-stroke rehabilitation:

[0627] After the acute phase of stroke (and usually 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 impairments (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 known as "stroke rehabilitation" or "post-stroke rehabilitation") targets post-stroke deficits that remain after the initial stroke injury, such as cognitive and motor deficits, with the aim of restoring and recovering neurological function as much as possible, such as physical, intellectual, psychological, and social function, to compensate for permanent tissue loss (e.g., 1995 Clinical Guideline by the Department of Health and Human Services on Post-Stroke Rehabilitation).

[0628] Stroke rehabilitation is typically a comprehensive program coordinated by a team of medical experts that may include occupational therapy, speech, and physical therapists. The team's physical therapists, for example, may work to maintain and restore the range of motion and strength of affected limbs, thus 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.

[0629] Neurological functions affected by stroke (and that can be targeted during rehabilitation) include impairments in cognitive and motor functions. Cognitive function impairments can manifest, for example, as deficits in speech comprehension or writing (aphasia); difficulty understanding appropriate speech but trouble articulating it clearly (dysarthria); and other cognitive function deficits, such as attention, reasoning, planning, execution, and learning and memory. Motor function impairments can manifest, for example, as weakness (hemiparesis) or paralysis (hemiplegia) on one side of the body that can affect the entire side or only the arm or leg; balance or coordination problems; deficits in gross motor skills, such as gait and walking speed; deficits in fine motor skills or manual dexterity; and upper and lower limb function deficits.

[0630] In the United States, more than 700,000 people suffer 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 paretic / paralyzed arm functionally (Gowland, 1982, Physiother. Can. 34, 77-84; Kwakkel et al., 1996, Age Ageing 25, 479-489), and despite extensive rehabilitation efforts, only about 5%-20% of patients achieve full functional recovery of the arm (Nakayama et al., 1994, Arch. Phys. Med. Rehabil. 75, 394-398).

[0631] 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 nerve damage, including damage caused by traumatic events such as stroke. Thus, in some embodiments, the present disclosure provides a method for treating neurological deficits during post-stroke rehabilitation, which comprises: (a) administering to an individual in need thereof a PDE1 inhibitor disclosed herein during the period of recovery of the individual from a stroke; (b) providing training to the individual under conditions sufficient to improve the performance of neurological function (the impairment 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 compared to the performance produced by training alone.

[0632] In some embodiments, administration can be initiated during the acute phase. In other embodiments, the PDE1 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 phase. In some embodiments, the PDE1 inhibitor is administered chronically, which means that the PDE1 inhibitor is suitable for long-term use after the end of the acute phase of stroke and the patient is medically stable.

[0633] In other embodiments, the individual is a post-stroke patient, and a PDE1 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 comprises 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.

[0634] 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.

[0635] Traumatic Brain Injury

[0636] 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.

[0637] 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.

[0638] Similar to stroke care, TBI cases are time-sequential, which includes acute (or subacute) treatment for the injury itself and subsequent rehabilitation for restoring function.

[0639] 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.

[0640] Some embodiments provide for the use of the disclosed PDE1 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 PDE1 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 compared to the performance produced by training alone.

[0641] In one aspect, the PDE1 inhibitor is a chemical entity of the present disclosure, and more specifically, is a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc) 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 cognitive and motor deficits. 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.

[0642] 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.

[0643] Peripheral Disorders

[0644] In some embodiments, the present disclosure provides methods of treating peripheral disorders (i.e., disorders other than primary neurological disorders), which include administering to an individual in need thereof an effective amount of a chemical entity or composition disclosed herein. In one embodiment of these methods, the chemical entity is a compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, the chemical entity is a compound of formula (Ia), (Ib), (Ic), (Iba), (Ibb), (Icaa), (Icab), (Icb), or (Icc) or a pharmaceutically acceptable salt thereof.

[0645] Peripheral disorders involving PDE1 include a variety of diseases, based on numerous biological studies and the expression of PDE1 isoforms in peripheral tissues such as the heart, lung, veins and arteries, smooth muscle, skeletal muscle, skin, adrenal gland, thyroid gland, pancreas, esophagus, stomach, small intestine, colon, liver, white blood cells, testis, ovary, bladder, and kidney. See, e.g., Bender and Beavo, 2006, Pharmacol. Rev. 58, 488–520. Thus, peripheral disorders that can be treated with the compounds and compositions of the present invention include, but are not limited to, cardiovascular disorders, kidney disorders, hematological disorders, gastrointestinal disorders, and liver disorders, cancer, fertility disorders, and metabolic disorders such as diabetes and obesity.

[0646] In certain embodiments, peripheral disorders also include diseases and conditions (except for primary neurological disorders) characterized by low levels of cAMP or cGMP in cells expressing PDE1, by inhibiting the cAMP or cGMP signaling pathway in cells expressing PDE1, and by reduced dopamine D1 receptor signaling activity.

[0647] Cardiovascular disorders

[0648] In certain embodiments, the peripheral disorder is a cardiovascular disorder. The PDE1 enzyme and cyclic nucleotides are emerging as key mediators of the pathological processes that underlie many vascular disorders, including hypertension and myocardial infarction. All three PDE1 isoforms are expressed in human pulmonary arteries, as well as in the aorta and mesenteric arteries (Schermuly et al., 2007, Circulation 115, 2331-2339; Murray et al., 2007, Am. J. Physiol. Lung Cell. Mol. Physiol., 292, L294-L303). In addition, selective PDE1 inhibition induces vasodilation and reduces blood pressure in rats (Laursen et al., 2017, Br. J. Pharmacol. 174, 2563-2575). In addition, the PDE1 enzyme constitutes most of the cAMP- and cGMP-hydrolyzing activity in the human myocardium, which means that they are involved in the regulation of the signaling pathways involved in heart failure.

[0649] Accordingly, the present invention includes the use of the compounds or compositions herein in a method of treating a cardiovascular disorder, which comprises administering to a patient in need thereof an effective amount of the chemical entity or composition.

[0650] Cardiovascular diseases within the scope of the present invention include, but are not limited to, angina pectoris, coronary artery disease, hypertension, congestive heart failure, myocardial infarction, ischemic diseases of the heart, atrial and ventricular arrhythmias, hypertensive vascular diseases, peripheral vascular diseases, pulmonary hypertension (PH) (or pulmonary arterial hypertension (PAH)), atherosclerosis and other pulmonary and respiratory conditions.

[0651] In some embodiments, a method of treating a cardiovascular disorder according to the present invention comprises increasing the concentration of cGMP, cAMP, or both, in any part of the myocardium of an individual, the method comprising administering to the individual a chemical entity or composition described herein.

[0652] In other embodiments, the chemical entities and compositions of the present invention can be used to reduce the heart rate or blood pressure of an animal.

[0653] Renal disorders

[0654] In certain embodiments, the peripheral disorder is a renal disease. PDE1 inhibitors are emerging therapeutic agents for progressive renal diseases. See, e.g., Cheng et al., 2007, Soc. Exp. Biol. Med. 232, 38 - 51. Consistent with these findings, recent studies have shown that cAMP and cGMP regulate multiple signaling pathways involved in the occurrence and development of renal diseases, including pathways regulating mitosis, inflammation, and extracellular matrix synthesis. See, e.g., Wang et al., 2010, Kidney Int. 77, 129 - 140; Wang et al., 2017, PLoS One 12, e0181087.

[0655] Accordingly, the present invention provides a chemical entity or composition for use in a method of treating a renal disorder, the method comprising administering to a patient in need thereof an effective amount of the chemical entity or composition. In a specific aspect, the renal disorder is selected from one or more of the following: including renal artery stenosis, pyelonephritis, glomerulonephritis, renal tumors, polycystic kidney disease, damage to the kidney, damage caused by radiation to the kidney, and autosomal dominant polycystic kidney disease (ADPKD).

[0656] Hematological disorders

[0657] In certain embodiments, the peripheral disorder is a hematological disorder. PDE1B is highly expressed in the hematopoietic system, including white blood cells (peripheral blood), bone marrow stromal cells, bone marrow CD33+ cells, cord blood CD34+ cells, neutrophil cord blood, neutrophil peripheral blood, spleen, cirrhotic spleen. Accordingly, the present invention includes methods of treating a hematological disorder, which include administering to a patient in need thereof a chemical entity or composition herein. Hematological diseases within the scope of the present invention include disorders of the blood and all of its components, including but not limited to anemia, myeloproliferative disorders, hemorrhagic disorders, leukopenia, eosinophilic disorders, leukemia, lymphoma, plasma cell dyscrasia, and spleen disorders.

[0658] Gastrointestinal and liver disorders

[0659] In certain embodiments, the peripheral disorder is a gastrointestinal or liver disease. PDE1B shows differential expression between diseased (e.g., cancerous) gastric tissue and healthy gastric tissue, diseased (e.g., cancerous) ileal tissue and healthy ileal tissue, diseased (cirrhotic) liver and healthy liver. Accordingly, the present invention includes methods of treating a gastrointestinal or liver disorder, which include administering to a patient in need thereof a compound or composition herein. Gastrointestinal diseases and liver diseases within the scope of the present invention include but are not limited to disorders of the esophagus, stomach, duodenum, pancreas, intestine, and liver.

[0660] Cancer

[0661] In certain embodiments, the peripheral disorder is cancer. PDE1B is highly expressed in many cancer tissues, including tumors of the stomach, ileum, ovary, breast, and kidney, and shows differential expression between cancerous and healthy stomach, ileum, lung, ovary, breast, and kidney. Accordingly, the present invention includes methods of treating cancer, which include administering to a patient in need thereof a compound or composition herein. Cancers within the scope of the present invention include but are not limited to neoplasms, dysplasias, hyperplasias, and tumors, including gastric cancer, ileal cancer, ovarian cancer, breast cancer, and renal cancer.

[0662] Fertility disorders

[0663] In certain embodiments, the peripheral disorder is a fertility disorder. For example, PDE1 inhibitors have been involved in enhancing progesterone signaling (e.g., WO 2008 / 070095). Accordingly, the present invention includes methods of treating a fertility disorder, which comprise administering a compound or composition herein to a patient in need thereof. Fertility disorders within the scope of the present invention include female sexual dysfunction and disorders involving progesterone signaling disorders, including but not limited to exercise-induced amenorrhea, anovulation, menopause, menopausal symptoms, hypothyroidism, premenstrual syndrome, premature birth, infertility, irregular menstrual cycle irregularities, abnormal uterine bleeding, osteoporosis, autoimmune diseases, multiple sclerosis, estrogen-induced endometrial hyperplasia, and estrogen-induced endometrial cancer.

[0664] Therapeutic Combinations

[0665] 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 one (e.g., one and only one) therapeutically effective chemical entity or a composition thereof.

[0666] In combination therapy, one or more chemical entities or compositions of the present invention can be co-administered or used in combination with one or more additional agents (or therapies) known in the art, such as additional agents (or therapies). Such administration can be simultaneous, sequential, or staggered. In certain embodiments, the additional agent (or therapy) is based on a different target or modality (e.g., not a PDE1 inhibitor).

[0667] 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.

[0668] 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. In some embodiments, the chemical entity or composition disclosed herein is administered as adjuvant therapy together with a dopamine precursor such as levodopa to treat Parkinson's disease or related disorders.

[0669] Exemplary agents for treating schizophrenia include but are not limited to: clozapine, aripiprazole, iloperidone, cariprazine, lurasidone, paliperidone, quetiapine, risperidone, olanzapine, ziprasidone, and iloperidone.

[0670] Exemplary agents for treating Parkinson's disease include but are not limited to dopamine preparations (including dopamine precursors such as levodopa), dopamine agonists, or COMT agents (drugs that inhibit catechol-O-methyltransferase activity).

[0671] Exemplary agents for the treatment of Alzheimer's disease include, but are not limited to, donepezil, rivastigmine, galantamine, cannabinomimetics, and memantine.

[0672] Exemplary agents for the treatment of Huntington's disease (or other movement disorders) may include, but are not limited to, tetrabenazine and antipsychotics such as haloperidol, chlorpromazine, risperidone, and quetiapine, as well as anti-seizure medications such as levetiracetam and clonazepam, which may be beneficial in treating chorea or related movement disorders.

[0673] Exemplary agents for the treatment of anxiety or depression include, but are not limited to, benzodiazepines and other anxiolytics, serotonin reuptake inhibitors (SSRIs) 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.

[0674] Exemplary agents for the treatment of 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).

[0675] The foregoing list of other active agents is meant to be illustrative rather than fully inclusive. Other active agents not included in the above list may be co-administered with the compounds of formula (I), such as those known for the treatment of 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 may be administered at less than the usually prescribed dose. Examples

[0676] The present disclosure will be further illustrated by the following non-limiting examples. These examples are understood to be merely illustrative and should not be construed as limiting the scope of one or more embodiments and the scope defined by the appended claims.

[0677] Preparation Examples

[0678] Exemplary compounds will now be described by reference to the exemplary synthetic schemes for their general preparation hereinbelow and the specific examples hereinafter.

[0679] Those skilled in the art will appreciate that, to obtain the numerous compounds herein, starting materials may be suitably selected such that the ultimately desired substituents are carried through the reaction scheme (with or without protection as needed) to produce the desired product. Alternatively, at the position of the ultimately desired substituent, it may be necessary or desirable to employ a suitable group which may be carried through the reaction scheme and replaced by the desired substituent as needed. Unless otherwise stated, 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. The reaction can also be carried out in a sealed pressure vessel above the normal reflux temperature of the solvent.

[0680] Abbreviations

[0681] This specification includes many abbreviations, the meanings of which are listed in the table below:

[0682] Table 1

[0683]

[0684]

[0685]

[0686] Synthesis Schemes

[0687] Scheme A

[0688]

[0689] Intermediate 2

[0690] According to Scheme A, 6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylic acid (Intermediate 1) can be synthesized from commercially available starting materials in 5 steps from ethyl 2-chloro-3-oxobutyrate. At a temperature from -78 °C to rt, sometimes at a temperature from -10 °C to 10 °C, in a solvent (such as ethanol, etc.), ethyl 2-chloro-3-oxobutyrate is treated with malononitrile and then treated with a base (such as sodium ethoxide, etc.) to give ethyl 5-amino-4-cyano-2-methylfuran-3-carboxylate. At a temperature from rt to 100 °C, ethyl 5-amino-4-cyano-2-methylfuran-3-carboxylate is treated with formic acid and then treated with acetic anhydride over a period of up to 48 hours to give ethyl 4-hydroxy-6-methylfuro[2,3-d]pyrimidine-5-carboxylate. Using conditions known to those skilled in the art, the subsequent chlorination reaction is carried out, for example, in the presence of a base (such as N,N-diisopropylethylamine, etc.), with or without a solvent, at a temperature from rt to 100 °C (sometimes 85 °C), treated with phosphorus oxychloride to give ethyl 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylate. Under conditions known to those skilled in the art, using 1-methylcyclopropylamine hydrochloride as the amine, a nucleophilic aromatic substitution reaction is carried out and then the ester is hydrolyzed to give 6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylic acid (Intermediate 1). For example, in the presence of a base such as triethylamine, in a solvent such as isopropanol, etc., at a temperature from rt to 80 °C (sometimes 45 °C), the aryl chloride is treated with 1-methylcyclopropylamine hydrochloride to give ethyl 6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylate. At room temperature, in a solvent mixture such as tetrahydrofuran and methanol, using a base such as lithium hydroxide, the subsequent base-catalyzed ester hydrolysis is carried out for several hours to give 6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylic acid (Intermediate 1).

[0691] In a similar manner, under conditions known to those skilled in the art, such as those described above, base-catalyzed hydrolysis of ethyl 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylate gives 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylic acid (Intermediate 2).

[0692] Scheme B

[0693]

[0694] According to Scheme B, the compounds of formula (VII) and (VIII) can be synthesized starting from the corresponding boronic acid pinacol esters.

[0695] Compound of general formula (IVa), wherein R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, can be synthesized by the nucleophilic aromatic substitution reaction of an amine with an aryl chloride of general formula (III), wherein R 2 is an optionally substituted aryl or heteroaryl, and X is Cl, Br or I. Under conditions known to those skilled in the art, the boronic acid pinacol ester of general formula (II) is subsequently subjected to Suzuki coupling with a commercially available or synthetically obtainable aryl halide or heteroaryl halide of general formula (IVa) or (IVb), providing a compound of general formula (V), wherein R 3 is an optionally substituted aryl or heteroaryl (with optional substitutions including -NHR 1 ). For example, in the presence of a base such as potassium carbonate, etc., in a solvent mixture such as ethanol and dioxane, etc., at a temperature of 80 °C to 150 °C, treating (II) with tetrakis(triphenylphosphine)palladium(0) provides a compound of general formula (V), wherein a is 1 or 2 and R 3 is an optionally substituted aryl or heteroaryl. Subsequently, using conditions known to those skilled in the art, the double bond is reduced in catalytic hydrogenation, and then the tert-butoxycarbonyl protecting group is removed under acidic conditions, providing a compound of general formula (VII). For example, in a hydrogen atmosphere, using a catalyst such as palladium on carbon, etc., provides a compound of general formula (VI). Subsequently, treating with a strong acid such as trifluoroacetic acid in a solvent such as dichloromethane, etc., or treating with hydrochloric acid in a solvent such as dioxane, etc., gives an amine of general formula (VII), wherein a is 1 or 2 and R 3 is an optionally substituted aryl or heteroaryl. Alternatively, as described above, treating a compound of general formula (V) with a strong acid under conditions known to those skilled in the art provides a dihydropyrrole or tetrahydropyridine compound of general formula (VIII), wherein a is 1 or 2, and R 3 is an optionally substituted aryl or heteroaryl.

[0696] Scheme C

[0697]

[0698] According to Scheme C, an aryl chloride can be converted to an aryl fluoride using conditions known to those skilled in the art. For example, in a solvent such as DMSO, etc., at a temperature of 40 °C to 100 °C, sometimes 70 °C, treating a compound of general formula (IX) with cesium fluoride gives an aryl fluoride of general formula (X). As described above, subsequently removing the tert-butoxycarbonyl protecting group gives an amine of compound (XI), wherein b is 0 or 1, c is 1 or 2, and B, D, E and G are C or N.

[0699] Under the conditions known to those skilled in the art, the synthesis of arylamines of general formula (XIII) from aryl chlorides of general formula (IX) was achieved by nucleophilic aromatic substitution, followed by removal of the tert-butoxycarbonyl protecting group. For example, in the presence of a base such as N,N-diisopropylethylamine, in a solvent such as DMA or DMF, heating to a temperature of 40 °C to 160 °C, sometimes 80 °C, treatment of the aryl chloride with an amine provided a compound of general formula (XII). As previously described, the amine was then deprotected using conditions known to those skilled in the art to give an amino compound of general formula (XIII), where b is 0 or 1; c is 1 or 2; B, D, E, and G are C or N; R 4 and R 5 are independently H or optionally substituted C 1-6 alkyl or C 3-7 cycloalkyl, or R 4 and R 5 together form an optionally substituted heterocycloalkyl.

[0700] Treatment of a compound of general formula (IX) with a strong acid such as HCl or TFA under the aforementioned conditions gave an amine compound of general formula (XIV), where b is 0 or 1, c is 1 or 2, and B, D, E, and G are C or N.

[0701] Scheme D

[0702]

[0703] The nucleophilic substitution reaction of a compound of general formula (XV), where X is Cl, Br, or I, with an amine provided a compound of general formula (XVI). For example, in the presence of a base such as potassium carbonate, in a solvent such as CAN, DMF, or DMA, treatment of the haloalkane with an amine for several hours at a temperature in the range of rt to 100 °C, sometimes 40 °C, gave a compound of general formula (XVI), where d is 0 or 1; B, D, E, and G are C or N; R 6 is -halogen, -OH, -CN, or optionally substituted amino, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, aryl, or heteroaryl; and R 7 is optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, or C 3-7 cycloalkyl.

[0704] Scheme E

[0705]

[0706] As shown in Scheme E, 3-cyclopropyl-1-ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine can be synthesized from commercially available or synthetically accessible 3-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine in five steps. At room temperature, in the presence of a base such as N,N-diisopropylethylamine, etc., in a solvent such as DCE, etc., 3-cyclopropyl-1-ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine is treated with di-tert-butyl dicarbonate to provide tert-butyl 3-cyclopropyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate. Using conditions known to those skilled in the art, for example, treatment with NIS, etc. in a solvent such as ACN, etc., iodination of the imidazole is carried out to obtain tert-butyl 3-cyclopropyl-1-iodo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate. In the presence of a base (such as potassium carbonate or sodium carbonate, etc.), in a solvent mixture (such as ACN and water), heated to a temperature of 60 °C to 110 °C, sometimes 90 °C, using palladium(0) as a catalyst, subsequently, the aryl iodide is subjected to Suzuki coupling with potassium vinyltrifluoroborate to obtain tert-butyl 3-cyclopropyl-1-vinyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate. Subsequently, hydrogenation is carried out to reduce the alkene, and then the tert-butoxycarbonyl protecting group is removed to provide the free amine compound. For example, catalytic hydrogenation is carried out under conditions known to those skilled in the art. For example, in a hydrogen atmosphere, in a solvent such as ethyl acetate, etc., 3-cyclopropyl-1-vinyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate is treated with palladium / carbon to obtain tert-butyl 3-cyclopropyl-1-ethyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate. In a solvent such as 2-methyltetrahydrofuran, the tert-butoxycarbonyl-protected compound is treated with trifluoroacetic acid to obtain 3-cyclopropyl-1-ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine.

[0707] Scheme F

[0708]

[0709] The 4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compound of general formula (XVIII) can be obtained by synthesis from commercially available 1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate in two steps. In the presence of a base such as sodium ethoxide, etc., in a solvent such as ethanol, at a temperature of 40 °C to 100 °C, sometimes 90 °C, 1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate is treated with a substituted amidine to provide the tetrahydropyridopyrimidinone of general formula (XVII), wherein R 8 is H or an optionally substituted C 1-6 alkyl, C1-6 Halogenoalkyl or C 3-7 cycloalkyl group. Chlorination is carried out using conditions known to those skilled in the art, for example, in the presence of triphenylphosphine, in a solvent such as dichloroethane, using carbon tetrachloride at a temperature of 70 °C to obtain a compound of general formula (XVIII). Several 4-substituted 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compounds can be synthesized from this intermediate.

[0710] In one example, under conditions known to those skilled in the art, the aryl chloride of general formula (XVIII) is subjected to Suzuki coupling with boric acid, pinacol borate or potassium trifluoroborate of general formula (XIX), where BL n is B(OH) 2 、B(O 2 C 2 (CH 3 ) 4 ) or BF 3 K, to provide a compound of general formula (XX). For example, using conditions similar to those described for the Suzuki coupling in Scheme E, using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as a catalyst and sodium carbonate as a base, provides a compound of general formula (XX), where R 8 is H or optionally substituted C 1-6 alkyl, C 1-6 halogenoalkyl or C 3-7 cycloalkyl group, and R 10 、R 11 and R 12 are independently H or C 1-6 alkyl, or R 9 and R 10 together form an optionally substituted unsaturated C 4-6 cycloalkyl group or an unsaturated C 4-6 heterocycloalkyl group. Removal of the tert-butoxycarbonyl protecting group provides a compound of general formula (XXI). Alternatively, as described in the previous Scheme B, the alkene of the compound of general formula (XX) is reduced in a catalytic hydrogenation reaction and then the tert-butoxycarbonyl protecting group is deprotected to obtain a compound of general formula (XXII), where R 8 is H or optionally substituted C 1-6 alkyl or C 3-7 cycloalkyl group, and R 10 、R 11 and R 12 are independently H or C 1-6 alkyl, or R 10 and R 11 together form an optionally substituted saturated C 3-6 cycloalkyl group or a saturated C 3-6A heterocyclic hydrocarbon group. Alternatively, under conditions known to those skilled in the art, the compound of general formula (XXIV) can be directly prepared from (XVIII) using the Suzuki reaction with cyclopropylboronic acid.

[0711] In another example, in a solvent such as THF, etc., at a temperature of 50 °C to 90 °C, sometimes 70 °C, the nucleophilic aromatic substitution reaction with an alkoxide such as sodium methoxide provides the compound of general formula (XXV), where R 8 is H or an optionally substituted C 1-6 alkyl, C 1-6 haloalkyl or C 3-7 cycloalkyl, and R 9 is an optionally substituted C 1-6 alkyl, C 1-6 haloalkyl or C 3-7 cycloalkyl. As described above, the amine is then deprotected to obtain the compound of general formula (XXVI).

[0712] In the metal-catalyzed cyanation reaction, under conditions known to those skilled in the art, in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium(0), etc., in a solvent (such as DMF or DMA, etc.), at a temperature of 90 °C, the aryl chloride of general formula (XVIII) is treated with zinc dicyanide for several hours, and then the tert-butoxycarbonyl group is removed as described above to obtain the amine of general formula (XXVII), where R 8 is H or an optionally substituted C 1-6 alkyl, C 1-6 haloalkyl or C 3-7 cycloalkyl.

[0713] Scheme G

[0714]

[0715] As shown in Scheme G, various amide analogs can be synthesized from Intermediate 1.

[0716] The compound of general formula (XXX), where R 3(which is an optionally substituted aryl or heteroaryl) can be synthesized from Intermediate 1 in one or two steps, either by amide coupling with a compound of formula (XXVIII), followed by a stepwise synthesis through Suzuki coupling, or by amide coupling with a bicyclic intermediate of formula (VIII) in one step. For example, under conditions known to those skilled in the art, in the presence of a base such as N,N-diisopropylethylamine, triethylamine, etc., in a solvent such as DMA or DMF, using a coupling agent such as HATU, Intermediate 1 is subjected to amide coupling with an amine of formula (XXVIII) (where a is 1 or 2) to obtain a compound of formula (XXIX), where a is 1 or 2. Subsequently, under the conditions previously described in Scheme B, pinacol boronic ester is subjected to Suzuki coupling with an aryl halide or heteroaryl halide of formula X-R 3 (where X is Cl, Br or I and R 3 is an optionally substituted aryl or heteroaryl) to provide a compound of formula (XXX). Alternatively, using the aforementioned conditions, in the amide coupling with a bicyclic of formula (VIII), a compound of formula (XXX) can be directly synthesized from Intermediate 1.

[0717] A compound of formula (XXXI) is synthesized, where a is 1 or 2 and R 3 is an optionally substituted aryl or heteroaryl, by catalytic hydrogenation of the olefin of formula (XXX) under the aforementioned conditions, or by amide coupling of Intermediate 1 with a compound of formula (VII).

[0718] Similar to the conditions described previously, in the presence of a base such as N,N-diisopropylethylamine, triethylamine, etc., in a solvent such as DMF or DMA, using a coupling agent (such as HATU or 2-chloro-1-methylpyridin-1-ium iodide, etc.), Intermediate 1 is subjected to amide coupling with an amine at room temperature for several hours to obtain a compound of formula (XXXII), where R 13 and R 14 are independently H or an optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylaryl or C 1-4 alkyl-heteroaryl; or R 13 and R 14 together form an optionally substituted N-containing heterocyclic hydrocarbon group or an optionally substituted N-containing heteroaryl.

[0719] Scheme H

[0720]

[0721] According to Scheme H, various amide analogs can be synthesized from Intermediate 1.

[0722] The formation of the fluoroalkoxy compound of general formula (XXXV) is achieved from Intermediate 1 in two steps. First, under the aforementioned conditions, Intermediate 1 undergoes amide coupling with the amine of (XXXIII) to obtain the hydroxy-substituted compound of general formula (XXXIV). Using a fluoroalkyl methylsulfonate compound, in the presence of a base such as cesium carbonate, etc., in a solvent such as DMF or DMA, etc., at a temperature of 40 °C to 130 °C, sometimes 70 °C, in a nucleophilic substitution reaction, the hydroxy group is then alkylated to provide the compound of general formula (XXXV), where b is 0 or 1; c is 1 or 2; e is 1, 2 or 3; B, D, E and G are C or N.

[0723] The aryl fluoride of general formula (XXXVII) can be synthesized in a similar manner, directly through the amide coupling of Intermediate 1 with the amine of general formula (XI), or the amide coupling of Intermediate 1 with the aryl chloride of general formula (XIV), followed by a fluorination reaction. For example, in the aforementioned manner, the amide coupling of Intermediate 1 with the amine of general formula (XI) provides the compound of general formula (XXXVII), where b is 0 or 1; c is 1 or 2; and B, D, E and G are C or N. Alternatively, under the aforementioned conditions, the amide coupling of Intermediate 1 with the amine of general formula (XIV) provides the aryl chloride of general formula (XXXVI), where b is 0 or 1; c is 1 or 2; and B, D, E and G are C or N. Under the conditions known to those skilled in the art, for example, in a solvent such as DMSO, etc., at a temperature of 100 °C to 200 °C, sometimes 170 °C, treated with potassium fluoride, the aryl chloride then undergoes a fluorination reaction to provide the compound of general formula (XXXVII).

[0724] The arylamine of general formula (XXXVIII) can be synthesized directly through amide coupling or in two steps through amide coupling followed by nucleophilic aromatic substitution of the resulting aryl chloride. For example, under the aforementioned conditions, treating Intermediate 1 with the amine of general formula (XIII) in an amide coupling reaction gives the amine of general formula (XXXVIII), where b is 0 or 1; c is 1 or 2; and B, D, E and G are C or N; and R 4 and R 5 are independently H or optionally substituted C 1-6 alkyl or C 3-7 cycloalkyl, or R 4 and R 5 together form an optionally substituted N-containing heterocycloalkyl. Alternatively, amide coupling with the aryl chloride of general formula (XIV), followed by a nucleophilic aromatic substitution reaction with a commercially available or synthetically obtainable amine in the presence of a base (such as potassium carbonate, etc.) in a solvent (such as ACN) at a temperature of 40 °C to 100 °C, sometimes 80 °C, also provides the compound of general formula (XXXVIII).

[0725] Scheme I

[0726]

[0727] As shown in Scheme I, various amide analogs can be synthesized from Intermediate 1.

[0728] By amide coupling of Intermediate 1 with an amine of general formula (XXVI) (the synthesis of which is described in Scheme F), or by initial amide coupling of Intermediate 1 with ethyl 3-oxopiperidine-4-carboxylate followed by a three-step transformation to the desired product, an oxygen-substituted compound of general formula (XLIII) is provided. For example, under the aforementioned conditions, amide coupling of Intermediate 1 with a commercially available or synthetically accessible amine of general formula (XXVI) provides a compound of general formula (XLIII) in which R 8 is H or optionally substituted C 1-6 alkyl, C 1-6 haloalkyl or C 3-7 cycloalkyl and R 9 is H or optionally substituted C 1-6 alkyl, C 1-6 haloalkyl or C 3-7 cycloalkyl. Alternatively, under the aforementioned conditions, Intermediate 1 is treated with ethyl 3-oxopiperidine-4-carboxylate in an amide coupling reaction to give ethyl 1-(6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carbonyl)-3-oxopiperidine-4-carboxylate. Subsequently, in the presence of a base (such as sodium ethoxide, etc.), in a solvent (such as ethanol), at a temperature of 40 °C to 100 °C, sometimes 90 °C, treatment with a substituted amidine gives a tetrahydropyridinopyrimidinone of general formula (XLI) in which R 8 is H or optionally substituted C 1-6 alkyl, C 1-6 haloalkyl or C 3-7 cycloalkyl. Chlorination is carried out using conditions known to those skilled in the art, for example, in the presence of triphenylphosphine, in a solvent such as dichloroethane, at a temperature of 70 °C, using carbon tetrachloride for chlorination to give an aryl chloride of general formula (XLII). Nucleophilic aromatic substitution with an alcoholate in a solvent such as THF at a temperature of 60 °C to 100 °C, sometimes 90 °C, also provides a compound of general formula (XLIII).

[0729] In another embodiment, Intermediate 1 is treated with an amine of general formula (XXVII) under the previously described conditions to provide a nitrile compound of general formula (XL) in which R 8 is H or optionally substituted C 1-6 alkyl, C 1-6 haloalkyl or C 3-7Cycloalkyl group. In a similar manner, under the aforementioned conditions, treating Intermediate 1 with an amine of the general formula (XXII) gives a compound of the general formula (XXXIX), where R 8 is H or optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, or C 3-7 cycloalkyl group, and R 10 , R 11 and R 12 are independently H or C 1-6 alkyl, or R 10 and R 11 together form an optionally substituted saturated C 3-6 cycloalkyl group or a saturated C 3-6 heterocycloalkyl group.

[0730] Scheme J

[0731]

[0732] According to Scheme J, under the aforementioned conditions, coupling of the compound of Intermediate 1 with an amide of 1,3-substituted 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine of the general formula (XLIV) provides a compound of the general formula (XLV), where R 15 and R 16 are optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl group.

[0733] Scheme K

[0734]

[0735] The amide of the general formula (XXXII) can be synthesized from Intermediate 2 in two steps, by amide coupling of Intermediate 2 with a commercially available or synthetically accessible amine, followed by a nucleophilic aromatic substitution reaction with 1-methylcyclopropan-1-amine hydrochloride. For example, under the aforementioned conditions, the amide coupling reaction of the carboxylic acid of Intermediate 2 with an amine provides an amide of the general formula (XLVI), where R 13 and R 14 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 alkylaryl, or C 1-4 alkyl-heteroaryl; or R 13 and R 14Together form an optionally substituted N-containing heterocyclic group or an optionally substituted N-containing heteroaryl group. Subsequently, in the presence of a base such as triethylamine, etc., in a solvent such as IPA, it is treated with 1-methylcyclopropan-1-amine hydrochloride to obtain an amide of general formula (XXXII).

[0736] Examples

[0737] Chemistry:

[0738] Unless otherwise specified, when obtaining the compounds and the corresponding analytical data described in the following examples, the following experimental and analytical protocols are followed.

[0739] Unless otherwise stated, the reaction mixture is magnetically stirred at room temperature (rt) under a nitrogen atmosphere. If the solution is "dry", it is usually dried over a drying agent (such as Na 2 SO 4 or MgSO 4 ). If the mixture, solution, and extract are "concentrated", they are usually concentrated under reduced pressure on a rotary evaporator.

[0740] Reactions under microwave irradiation conditions are carried out in a CEM Discover-SP equipped with an Activent microwave reaction device model 909150 or a Biotage initiator model 355302.

[0741] Normal-phase flash column chromatography (FCC) is carried out on silica (SiO 2 ) using a packed column or a pre-packed column and eluted with the specified solvent.

[0742] Analytical LC / MS is obtained on a Waters 2695 separation unit, 2487 dual absorbance detector, Micromass ZQ equipped with an ESI probe, or a Waters Acquity TM Ultra Performance LC (UPLC) with PDA eλ and SQ detectors. Alternatively, LC-MS is carried out 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: H 2 O solution of 0.1% HCOOH and solvent system B: ACN solution of 0.1% HCOOH. The column temperature is 45 °C. All compounds are 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.

[0743] On a Waters UPC 2Perform analytical SFC-MS on an -MS instrument equipped with an Acquity UPC 2 BEH 2 - ethylpyridine column (1.7 μm, 2.1×50 mm), solvent system A: CO 2 and solvent system B: MeOH solution of 0.1% NH 4 OH. The column temperature is 55 °C. All compounds are 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.

[0744] Perform preparative HPLC on a Shimadzu SIL - 10AP system using a Waters SunFire TM OBD (5 μm, 30×100 mm) C18 column, with a 15 - minute gradient of 10 - 100% aqueous acetonitrile, and 0.05% trifluoroacetic acid added as a modifier to both phases. Monitor the elution profile by UV at 254 nm and 220 nm.

[0745] Purify some compounds using a Waters Fractionlynx system equipped with an XBridge Prep C18 OBD column (5 μm, 19×50 mm), solvent system: H 2 O: AcCN and H 2 O solution of 2% TFA. The specific elution gradient is based on the retention time obtained using analytical UPLC - MS. However, generally, all elution gradients of H 2 O and ACN are run at a flow rate of 40 mL / min over a run time of 5.9 min. Use an automated mixing method to ensure a concentration of 0.1% TFA throughout each run.

[0746] Purify some compounds using a Waters Fractionlynx system equipped with an XBridge Prep C18 OBD column (5 μm, 30×100 mm), solvent system: H 2 O: AcCN and H 2 O solution of 2% TFA. The specific elution gradient is based on the retention time obtained using analytical UPLC - MS. However, generally, all elution gradients of H 2 O and ACN are run at a flow rate of 60 mL / min over a run time of 9 min. Use an automated mixing method to ensure a concentration of 0.1% TFA throughout each run.

[0747] Performing preparative SFC-MS on a Waters Prep100 SFC-MS system equipped with a Viridis 2-ethylpyridine OBD column (5μm, 30×100mm), solvent system: CO 2 : MeOH and a MeOH solution of 0.2% NH 4 OH as co-solvent. The specific elution gradient is based on the retention time obtained using analytical UPC 2 -MS. However, generally all elution gradients of CO 2 and MeOH are carried out at a flow rate of 100 mL / min within a running time of 3.6 minutes, and the column temperature is 55 °C. The automatic mixing method is used to ensure a concentration of 0.2% NH 4 OH throughout each run.

[0748] Obtaining nuclear magnetic resonance (NMR) spectra on an Agilent 300MHz VNMR (Varian 300MHz NMR) or Varian 400MHz or Bruker 400MHz NMR. Analyzing samples in deuterated acetone ((CD 3 ) 2 CO), deuterated chloroform (CDCl 3 ), MeOH-d 4 (CD 3 OD), N,N-dimethylformamide-d 7 (DMF-d 7 ), or dimethyl sulfoxide-d 6 (DMSO-d 6 ). For (CD 3 ) 2 CO samples, using the residual central resonance peak with 1 H at 2.05 for chemical shift assignment of 1 H NMR spectra. For CDCl 3 samples, using the residual central resonance peak with 1 H at 7.26 for chemical shift assignment of 1 H NMR spectra. For CD 3 OD, using the residual central resonance peak with 1 H at 3.31 for chemical shift assignment, and for DMF-d 7 , using the residual central resonance peak with 1 H at 2.92 or 2.75 for chemical shift assignment. For DMSO-d 6 , using the residual central resonance peak with 1 H at 2.50 ppm for chemical shift assignment. Below 1The format of the \(^{1}\)H NMR data is: chemical shift (ppm), low field, tetramethylsilane reference (multiplicity, coupling constant \(J\) (Hz), integration), and the following conventional abbreviations are used to specify the major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; p, pentuplet; m, multiplet; br, broad peak.

[0749] The chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoft Corp., Cambridge, MA), ChemDraw Professional 15.1 (CambridgeSoft Corp., Cambridge, MA), or ChemAxon.

[0750] Intermediate 1. 6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylic acid.

[0751]

[0752] Step 1. Ethyl 5-amino-4-cyano-2-methylfuran-3-carboxylate. Sodium ethoxide (2.49 L, 21% w / w, 6.68 mol) was diluted with ethanol (3.00 L). The jacket temperature was set at -10 °C. Separately, a solution of ethyl 2-chloro-3-oxobutyrate (840 mL, 6.08 mol) and malononitrile (401 g, 6.08 mol) in ethanol (2.00 L) was prepared. The substrate solution was added while maintaining the internal temperature below 10 °C. After complete addition, the jacket temperature was adjusted to 10 °C and the slurry was stirred overnight. A total of 2.90 L of solvent was removed by vacuum distillation. Then the temperature was raised to 45 °C and water (10 L) was added to the reactor. The slurry was stirred overnight and cooled to 11 °C. The solid was collected by vacuum filtration and then slurried / washed with additional water (10 L). The solid was air-dried to afford the title product (1.058 kg, 90%). 1 \(^{1}\)H NMR (400 MHz, DMSO-d 6 ) δ 7.42 (s, 2H), 4.21 (q, \(J = 7.1\) Hz, 2H), 2.37 (s, 3H), 1.26 (t, \(J = 7.2\) Hz, 3H). \([M + H]=195\).

[0753] Step 2. Ethyl 4-hydroxy-6-methylfuro[2,3-d]pyrimidine-5-carboxylate. Charge formic acid (700 mL) into a 5 L reactor, then add ethyl 5-amino-4-cyano-2-methylfuran-3-carboxylate (292 g, 1.50 mol) as a solid, and then add additional formic acid (1.46 L). Cool the mixture to 0 °C and add acetic anhydride (1,752 mL, 6.0 V) dropwise, maintaining the internal temperature below 10 °C (addition takes 2 hours). Allow the reaction to gradually warm up until the jacket temperature reaches 100 °C (the observed internal temperature is 97.5 °C). Hold the reaction at this temperature overnight. After 48 hours, cool the jacket temperature to 65 °C and remove 2.3 L of the solvent by vacuum distillation. Cool the reactor, and when the internal temperature is about 60 °C, add water (2.92 L) over 15 minutes and stir the reaction at this temperature for 2 hours until the solid becomes homogeneous. Then cool the slurry to 10 °C and hold overnight. Collect the solid by filtration and wash with water (5.84 L). After rinsing again with water (1.80 L), tamp the solid filter cake and then rinse with heptane (300 mL). Dry the solid filter cake on the funnel for 5 h and then in a vacuum oven to obtain the title compound as an off-white solid (285 g, 85%). 1 H NMR(400MHz,CDCl 3 )δ8.19(s,1H),4.42(q,J=8.0Hz,2H),2.71(s,3H),1.43(t,J=8.0Hz,3H).[M+H]=223.

[0754] Step 3. Ethyl 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylate. Add ethyl 4-hydroxy-6-methylfuro[2,3-d]pyrimidine-5-carboxylate (252 g, 1.13 mol) and ACN (2.52 L) to a 5 L vertical reactor. At room temperature, add phosphorus oxychloride (212 mL, 2.27 mol). Allow the internal reaction temperature to reach 0 °C, then slowly add DIEA (198 mL, 1.13 mol). After the addition is complete, raise the jacket temperature to 85 °C and stir the reaction at this temperature. After 4 hours, judge that the reaction is complete by UPLC analysis. Remove a portion of the ACN solvent (1.10 L) by vacuum distillation. Cool the internal reaction temperature to 0 °C, add cold water (2.52 L) to the reactor, and stir the mixture at 0 °C overnight. Filter the slurry, wash with cold water (5.04 L) to obtain a brown solid. Dry this material overnight to obtain the title compound (216 g, 79%). 1 H NMR(400MHz,CDCl 3)δ8.80(s,1H),4.43(q,J=8.0Hz,2H),2.80(s,3H),1.45(t,J=8.0Hz,3H).[M+H]=241.

[0755] Step 4. Ethyl 6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylate. Dissolve 1-methylcyclopropanamine hydrochloride (124 g, 1.09 mol) in IPA (800 mL). Add ethyl 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylate (203 g, 0.84 mol), and then add additional IPA (800 mL). Slowly add TEA (352 mL, 2.53 mol) at ambient temperature. Heat the reaction to 45 °C and stir overnight. Once the reaction is judged complete, add water (2.40 L) over 30 minutes, cool the temperature to 10 °C, and stir the reaction for 3 h. Filter the solid, wash with water (2.40 L) and dry to give the title compound (194 g, 84%). 1 H NMR(400MHz,CDCl 3 )δ8.62(br s,1H),8.45(s,1H),4.41(q,J=7.1Hz,2H),2.71(s,3H),1.56(s,3H),1.44(t,J=7.1Hz,3H),0.91 - 0.71(m,4H).[M+H]=276.

[0756] Step 5. 6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylic acid. Dissolve ethyl 6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxylate (128 g, 0.46 mol) in THF (1.24 L), slowly add lithium hydroxide (1.5 M, 1.24 L, 1.86 mol), and then add methanol (256 mL). Stir the reaction at ambient temperature for 1.5 h. After the reaction is complete, remove the methanol / THF (~1.4 L) mixture by vacuum distillation. Return the reactor temperature to 20 °C and add water (1.92 L) to the system. Fit a dropping funnel containing hydrochloric acid (12.1 M, 154 mL, 1.86 mol) to the reactor. Add the acid dropwise until pH < 4, during which a white precipitate starts to form. After addition, stir the slurry at ambient temperature for 1 h, then filter by vacuum. Wash the solid with water (1.92 L) and dry on the filter for an additional 2 h. Then slurry the solid in water (3.5 L) at 70 °C. Filter the solution and wash with ACN (4 × 1 L), then press / package and allow to dry to give the title compound as a white solid (104 g, 90%). 11H NMR (400 MHz, DMSO-d 6 ) δ 13.87 (br s, 1H), 8.33 (s, 1H), 2.68 (s, 3H), 1.46 (s, 3H), 0.73 (s, 4H). [M+H]=248.

[0757] Intermediate 2. 4-Chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylic acid.

[0758]

[0759] Aqueous lithium hydroxide (25 mL, 1.00 M, 25 mmol) was added to a solution of ethyl 4-chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylate (1.00 g, 4.16 mmol) in tetrahydrofuran (14 mL), and the mixture was stirred for 1 h. The mixture was acidified to pH 1 with concentrated hydrochloric acid (3 mL) and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO 4 ) and concentrated to give the product as a yellow solid, which was used without further purification. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 13.52 (br s, 1H), 8.81 (s, 1H), 2.70 - 2.77 (m, 3H). [M+H]=213.1.

[0760] Intermediate 3. 4-Fluoro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride.

[0761]

[0762] Step 1. tert-Butyl 4-fluoro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate. A mixture of tert-butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (200 mg, 0.74 mmol) and cesium fluoride (169 mg, 1.11 mmol) in DMSO (3.7 mL) was heated at 70 °C for 3 h. The reaction mixture was diluted with methanol and purified by preparative HPLC (eluting with an aqueous solution of 10 - 60% CAN containing 0.05% TFA). The fractions containing the product were combined, diluted with an aqueous NaHCO 3 solution and extracted with ethyl acetate. The combined organic matter was dried over MgSO 4 and concentrated to give the title compound (67 mg, 37%) as a yellow semi-solid. [M+H]=254.1.

[0763] Step 2. 4-Fluoro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride.

[0764] tert-Butyl 4-fluoro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (67 mg, 0.24 mmol) was dissolved in a dioxane solution of hydrogen chloride (4 M, 0.62 mL, 2.5 mmol). The mixture was stirred for 30 minutes and then concentrated in vacuo to give the title compound (46 mg, 100%) as a yellow solid.

[0765] Intermediate 4. 3-Fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)pyridine-2-carbonitrile

[0766]

[0767] tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.02 g, 3.30 mmol) and 5-bromo-3-fluoropyridine-2-carbonitrile (0.60 g, 3.0 mmol) were combined and dissolved in dioxane (7 mL) and ethanol (3 mL), and nitrogen was bubbled through the mixture. Water (2 mL), aqueous potassium carbonate solution (2.0 M, 4.5 mL, 9.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) were added, and the mixture was heated in a microwave reactor at 150 °C for 10 minutes. Most of the tert-butoxycarbonyl protecting group was also cleaved at this temperature. The mixture was poured into ethyl acetate (30 mL), the aqueous layer was removed, and the organic layer was washed with brine (20 mL). The solution was then dried (MgSO 4 ) and concentrated in vacuo to give a mixture of the title compound and the tert-butoxycarbonyl protected title compound (0.36 g). [M+H] = 204.1.

[0768] Intermediate 5. 5-Fluoro-6-methoxy-1',2',3',6'-tetrahydro-3,4'-bipyridine trifluoroacetate.

[0769]

[0770] Step 1. tert-Butyl 4-(5-fluoro-6-methoxypyridin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (1.02 g, 3.30 mmol) and 5-bromo-3-fluoro-2-methoxypyridine (0.62 g, 3.00 mmol) were combined and dissolved in dioxane (7 mL) and ethanol (3 mL), and nitrogen was bubbled through the mixture. Water (2 mL), aqueous potassium carbonate solution (2.0 M, 4.5 mL, 9.00 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) were added, and the mixture was heated by microwave at 150 °C for 10 min. The mixture was poured into ethyl acetate (30 mL), the aqueous layer was removed, and the organic layer was washed with brine (20 mL), dried (MgSO 4 ), and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 5-30% ethyl acetate / heptane) to afford the title compound (0.28 g, 30%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 2.0, 11.4 Hz, 1H), 6.00 (br s, 1H), 4.10 (d, J = 2.8 Hz, 2H), 4.05 (s, 3H), 3.66 (t, J = 5.7 Hz, 2H), 2.49 (br s, 2H), 1.51 (s, 10H). [M + H] = 309.0.

[0771] Step 2. 5-Fluoro-6-methoxy-1',2',3',6'-tetrahydro-3,4'-bipyridine trifluoroacetate. tert-Butyl 4-(5-fluoro-6-methoxypyridin-3-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (280 mg, 0.91 mmol) was stirred in a mixture of DCM (3 mL) and TFA (3 mL) for 1 h and then concentrated in vacuo to afford the title compound (574 mg, 100%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.94 (br s, 2H), 8.12 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 2.1, 12.2 Hz, 1H), 6.27 (br s, 1H), 3.96 (s, 3H), 3.82 - 3.72 (m, 2H), 3.34 (d, J = 5.6 Hz, 2H), 2.72 - 2.64 (m, 2H). [M + H] = 209.1.

[0772] Intermediate 6. 2-(2,5-Dihydro-1H-pyrrol-3-yl)-5-fluoropyrimidine trifluoroacetate.

[0773]

[0774] Step 1. tert-Butyl 3-(5-fluoropyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 5, Step 1, using appropriate starting materials in place thereof. 1 H NMR(400MHz,CDCl 3 )δ8.59(s,2H),6.96 - 6.75(m,1H),4.59(br s,2H),4.43(br s,2H),1.54(s,9H).[M + H]=266.1.

[0775] Step 2. 2-(2,5-Dihydro-1H-pyrrol-3-yl)-5-fluoropyrimidine trifluoroacetate. The title compound was prepared in a manner similar to that of Intermediate 5, Step 2, using appropriate starting materials in place thereof. [M + H] was not observed.

[0776] Intermediate 7. 2-(1,2,3,6-Tetrahydropyridin-4-yl)pyrimidine-4-carbonitrile trifluoroacetate.

[0777]

[0778] Step 1. tert-Butyl 4-(4-cyanopyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 5, Step 1, using appropriate starting materials in place thereof. 1 H NMR(400MHz,CDCl 3 )δ8.91(d,J=4.8Hz,1H),7.44(d,J=4.8Hz,1H),7.37(br s,1H),4.23(d,J=2.6Hz,2H),3.66(t,J=5.6Hz,2H),2.72(br s,2H),1.52(s,9H).[M + H - t-Bu]=231.1.

[0779] Step 2. 2-(1,2,3,6-Tetrahydropyridin-4-yl)pyrimidine-4-carbonitrile trifluoroacetate. The title compound was prepared in a manner similar to that of Intermediate 5, Step 2, using appropriate starting materials in place thereof. 1 H NMR(400MHz,CD 3OD) δ 9.09 - 8.97 (m, 1H), 8.38 - 8.35 (m, 1H), 7.94 (dd, J=5.0, 13.0 Hz, 1H), 7.50 - 7.34 (m, 1H), 4.06 - 3.96 (m, 3H), 3.79 - 3.57 (m, 1H), 3.14 - 2.95 (m, 2H). [M+H]=187.1.

[0780] Intermediate 8. (R)-4-(3-Fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride.

[0781]

[0782] Step 1. tert-Butyl (R)-4-(3-fluoropyrrolidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. 4-Chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate tert-butyl ester (226 mg, 0.84 mmol) in DMA (2.5 mL) was treated with (3R)-3-fluoropyrrolidine (1.58 g, 1.26 mmol) and DIEA (0.44 mL, 2.51 mmol), and the mixture was heated at 80 °C for 16 h. The mixture was cooled, concentrated in vacuo and the residue was purified by flash LC (eluting with 0 - 75% A / B, where A is 10% methanol / ethyl acetate and B is heptane) to give the title compound as a colorless semi-solid (212 mg, 78%). [M+H]=323.1.

[0783] Step 2. (R)-4-(3-Fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride. (R)-4-(3-Fluoropyrrolidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate tert-butyl ester (212 mg, 0.66 mmol) was dissolved in ethyl acetate (6 mL) and treated with a dioxane solution of hydrogen chloride (4 M, 1.97 mL, 7.89 mmol). The mixture was stirred for 24 h and then concentrated in vacuo to afford the title compound (192 mg, 99%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 8.65 (s, 1H), 5.58 - 5.33 (m, 1H), 4.47 (s, 2H), 4.40 - 4.04 (m, 4H), 3.76 - 3.69 (m, 1H), 3.56 - 3.35 (m, 3H), 2.54 - 2.12 (m, 2H). [M+H]=223.1.

[0784] Intermediate 9. (S)-4-(3-Fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride.

[0785]

[0786] Step 1. tert-Butyl (S)-4-(3-fluoropyrrolidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 8, Step 1, using appropriate starting materials in place. The LCMS data was the same as that of Intermediate 8.

[0787] Step 2. (S)-4-(3-fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride. The title compound was prepared in a manner similar to that of Intermediate 8, Step 2, using appropriate starting materials in place. The LCMS and 1 1H NMR data were the same as those of Intermediate 8.

[0788] Intermediate 10. 4-(5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)morpholine.

[0789]

[0790] Step 1. tert-Butyl 4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 8, Step 1, using appropriate starting materials in place. [M+H] = 321.1.

[0791] Step 2. 4-(5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)morpholine. The title compound was prepared in a manner similar to that of Intermediate 8, Step 2, using appropriate starting materials in place. 1 1H NMR (400 MHz, CD 3 OD) δ 8.69 (s, 1H), 4.50 (s, 2H), 4.13 - 4.01 (m, 4H), 3.89 - 3.80 (m, 4H), 3.52 (t, J = 5.7 Hz, 2H), 3.15 (t, J = 5.7 Hz, 2H). [M+H] = 221.1.

[0792] Intermediate 11. 4-(3-Fluoroazetidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.

[0793]

[0794] Step 1. tert-Butyl 4-(3-fluoroazetidin-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 8, Step 1, using appropriate starting materials in place. [M+H] = 309.0.

[0795] Step 2. 4-(3-Fluoroazetidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. The title compound was prepared in a manner similar to that of Intermediate 8, Step 2, using appropriate starting materials in place thereof. 1 H NMR(400MHz,CD 3 OD)δ8.64(s,1H),5.66-5.41(m,1H),4.99(br s,2H),4.73(br s,2H),4.43(s,2H),3.57(t,J=6.2Hz,2H),3.17(t,J=6.1Hz,2H).[M+H]=209.1.

[0796] Intermediate 12. 2-Fluoro-4-(pyrrolidin-3-yl)pyridine hydrochloride

[0797]

[0798] Step 1. tert-Butyl 3-(2-fluoropyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate. tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (434 mg, 1.47 mmol), 4-bromo-2-fluoropyridine (311 mg, 1.76 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (54 mg, 0.07 mmol) and dioxane (23 mL) were combined. Aqueous sodium bicarbonate solution (1.2 M, 7.7 ml, 8.8 mmol) was added and the mixture was heated at 100 °C for 24 h. The mixture was cooled and diluted with ethyl acetate (75 mL) and brine (25 mL) and the layers were separated. The organic layer was dried (Na 2 SO 4 ) and concentrated. The residue was purified by flash chromatography (eluting with 0-75% ethyl acetate / heptane) to afford the title compound (341 mg, 88%) as an off-white solid. 1 H NMR(400MHz,CDCl 3 )δ8.41(d,J=5.3Hz,1H),8.22(d,J=5.0Hz,1H),7.23-7.13(m,1H),6.86(br s,1H),6.53-6.40(m,1H),4.50(dd,J=3.6,19.3Hz,2H),4.38(d,J=18.5Hz,2H),1.55-1.52(m,9H).[M+H]=265.1.

[0799] Step 2. 2-Fluoro-4-(pyrrolidin-3-yl)pyridine hydrochloride. A solution of tert-butyl 3-(2-fluoropyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (251 mg, 0.95 mmol) in methanol (7.5 mL) and ethyl acetate (7.5 mL) was flushed with nitrogen and palladium on activated carbon (81 mg, 0.38 mmol) was added. The mixture was stirred rapidly under a hydrogen balloon for 3 h. The mixture was flushed with nitrogen, filtered through a pad and concentrated in vacuo. The residue was suspended in ethyl acetate (5 mL) and a solution of hydrochloric acid in dioxane (4 M, 5.0 mL, 5.0 mmol) was added. The mixture was stirred for 1 h and concentrated in vacuo. The residue was dissolved in a 1:1 mixture of dioxane-water and lyophilized to give the title compound (294 mg, 90%), as a brown semi-solid. 1 H NMR (400 MHz, CD 3 OD) δ 8.21 (d, J = 5.3 Hz, 1H), 7.37 - 7.30 (m, 1H), 7.13 (s, 1H), 3.91 - 3.54 (m, 5H), 3.54 - 3.39 (m, 2H), 2.24 - 2.10 (m, 1H). [M + H] = 167.2.

[0800] Intermediate 13. 2-Fluoro-4-methyl-6-(pyrrolidin-3-yl)pyridine hydrochloride

[0801]

[0802] Step 1. tert-Butyl 4-(6-fluoro-4-methylpyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate. The title compound was prepared in a manner analogous to Intermediate 12, Step 1, using appropriate starting materials in place. 1 H NMR (400 MHz, CDCl 3 ) δ 7.11 - 6.84 (m, 1H), 6.67 (s, 1H), 6.65 - 6.51 (m, 1H), 4.53 (br s, 2H), 4.42 - 4.29 (m, 2H), 2.42 (d, J = 4.9 Hz, 3H), 1.56 - 1.51 (m, 9H). [M + H] not observed.

[0803] Step 2. 2-Fluoro-4-methyl-6-(pyrrolidin-3-yl)pyridine hydrochloride. The title compound was prepared in a manner analogous to Intermediate 12, Step 2, using appropriate starting materials in place. 1 H NMR (400 MHz, CD 3OD) δ 7.16 (s, 1H), 6.82 (s, 1H), 3.81 - 3.48 (m, 4H), 3.48 - 3.36 (m, 1H), 2.56 - 2.38 (m, 4H), 2.26 - 2.11 (m, 1H). [M + H] = 181.1.

[0804] Intermediate 14. 3-Fluoro-2-methyl-6-(pyrrolidin-3-yl)pyridine hydrochloride

[0805]

[0806] Step 1. tert-Butyl 4-(5-fluoro-6-methylpyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 12, Step 1, using appropriate starting materials in place. [M + H - tert-butyl] = 223.1.

[0807] Step 2. 3-Fluoro-2-methyl-6-(pyrrolidin-3-yl)pyridine hydrochloride. The title compound was prepared in a manner similar to that of Intermediate 12, Step 2, using appropriate starting materials in place. 1 H NMR(400MHz, CD 3 OD) δ 8.09 (t, J = 8.7 Hz, 1H), 7.78 (dd, J = 4.0, 8.8 Hz, 1H), 3.97 (quin, J = 8.2 Hz, 1H), 3.81 (dd, J = 8.3, 11.8 Hz, 1H), 3.73 - 3.54 (m, 2H), 3.48 (td, J = 8.1, 11.5 Hz, 1H), 2.71 (d, J = 2.6 Hz, 3H), 2.68 - 2.54 (m, 1H), 2.31 (qd, J = 8.7, 13.2 Hz, 1H). [M + H] = 181.1.

[0808] Intermediate 15. 5-Fluoro-4-methyl-2-(pyrrolidin-3-yl)pyrimidine hydrochloride

[0809]

[0810] Step 1. tert-Butyl 4-(5-fluoro-4-methylpyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 12, Step 1, using appropriate starting materials in place. 1 H NMR(400MHz, CDCl 3)δ8.41(s,1H),6.91 - 6.74(m,1H),4.67 - 4.47(m,2H),4.47 - 4.30(m,2H),2.60 - 2.48(m,3H),1.59 - 1.47(m,9H).[M + H - tert - butyl]=224.1.

[0811] Step 2. 3 - fluoro - 2 - methyl - 6 - (pyrrolidin - 3 - yl)pyridine hydrochloride. The title compound was prepared in a manner similar to that of Intermediate 12, Step 2, using appropriate starting materials as substitutes. 1 H NMR(400MHz,CD 3 OD)δ8.60(d,J = 1.8Hz,1H),3.97 - 3.84(m,1H),3.80 - 3.74(m,1H),3.72 - 3.64(m,1H),3.54 - 3.41(m,2H),2.61 - 2.47(m,4H),2.33(qd,J = 6.7,13.8Hz,1H).[M + H]=182.1.

[0812] Intermediate 16. 2-(Pyrrolidin-3-yl)-6-(trifluoromethyl)pyridine hydrochloride

[0813]

[0814] Step 1. tert - butyl 4 - (6 - (trifluoromethyl)pyridin - 2 - yl)-2,5 - dihydro - 1H - pyrrole - 1 - carboxylate. The title compound was prepared in a manner similar to that of Intermediate 12, Step 1, using appropriate starting materials as substitutes. 1 H NMR(400MHz,CDCl 3 )δ7.86(t,J = 7.9Hz,1H),7.63 - 7.40(m,2H),6.68(d,J = 18.0Hz,1H),4.61(d,J = 15.3Hz,2H),4.51 - 4.29(m,2H),1.54(d,J = 7.1Hz,9H).[M + H - tert - butyl]=259.1.

[0815] Step 2. 2 - (pyrrolidin - 3 - yl)-6 - (trifluoromethyl)pyridine hydrochloride. The title compound was prepared in a manner similar to that of Intermediate 12, Step 2, using appropriate starting materials as substitutes. 1 H NMR(400MHz,CD 3OD) δ 8.05 (t, J = 7.9 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 3.91 (quin, J = 7.7 Hz, 1H), 3.80 - 3.63 (m, 2H), 3.63 - 3.53 (m, 1H), 3.46 (td, J = 7.8, 11.5 Hz, 1H), 2.62 - 2.47 (m, 1H), 2.32 - 2.18 (m, 1H). [M+H] = 217.2.

[0816] Intermediate 17. 2-(Pyrrolidin-3-yl)-4-(trifluoromethyl)pyridine hydrochloride

[0817]

[0818] Step 1. tert-Butyl 4-(4-(trifluoromethyl)pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 12, Step 1, using appropriate starting materials in place. 1 1H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 5.0 Hz, 1H), 7.69 - 7.48 (m, 1H), 7.48 - 7.38 (m, 1H), 6.66 (br s, 1H), 4.68 - 4.56 (m, 2H), 4.49 - 4.34 (m, 2H), 1.56 - 1.52 (m, 9H), 1.56 - 1.52 (m, 9H). [M+H - tert-butyl] = 259.3.

[0819] Step 2. 2-(Pyrrolidin-3-yl)-4-(trifluoromethyl)pyridine hydrochloride. The title compound was prepared in a manner similar to that of Intermediate 12, Step 2, using appropriate starting materials in place. 1 1H NMR (400 MHz, CD 3 OD) δ 8.86 (d, J = 5.3 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 5.1 Hz, 1H), 3.97 (quin, J = 7.2 Hz, 1H), 3.72 - 3.66 (m, 2H), 3.64 - 3.53 (m, 1H), 3.47 (td, J = 7.6, 11.6 Hz, 1H), 2.58 (dtd, J = 6.1, 7.6, 13.4 Hz, 1H), 2.31 - 2.19 (m, 1H). [M+H] = 217.2.

[0820] Intermediate 18. 4-Ethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride.

[0821]

[0822] Step 1. tert-Butyl 4-vinyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. A mixture of tert-butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (500 mg, 1.85 mmol), potassium vinyltrifluoroborate (372 mg, 2.78 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (76 mg, 0.09 mmol), ACN (7.4 mL) and aqueous sodium bicarbonate solution (1 M, 3.3 mL, 3.3 mmol) was degassed with nitrogen for 1 minute and then heated to 90 °C for 2 h. The mixture was passed through filtration, diluted with ethyl acetate, washed with brine, dried (MgSO 4 ) and concentrated to a red oil. The material was adsorbed onto silica using DCM and subjected to flash chromatography (eluting with 0 - 25% ethyl acetate / heptane) to afford the title compound (300 mg, 62%) as an oil. 1 1H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 6.91 (dd, J = 10.64, 16.87 Hz, 1H), 6.68 (dd, J = 1.83, 16.99 Hz, 1H), 5.77 (dd, J = 1.83, 10.64 Hz, 1H), 4.65 (s, 2H), 3.75 (t, J = 5.87 Hz, 2H), 2.89 (t, J = 5.75 Hz, 2H), 1.51 (s, 9H). [M + H] = 262.2.

[0823] Step 2. tert-Butyl 4-ethyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. tert-Butyl 4-vinyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (293 mg, 1.12 mmol) and 10% palladium / carbon (60 mg, 0.056 mol) in ethyl acetate (3.7 mL) and methanol (3.7 mL) were stirred under hydrogen at 180 psi for 16 h. The catalyst was filtered off and the filtrate was concentrated to afford the title compound (269 mg, 91%) as a solid. 1 1H NMR (400 MHz, CDCl 3 ) δ 8.93 (s, 1H), 4.63 (s, 2H), 3.74 (t, J = 5.8 Hz, 2H), 2.86 - 2.72 (m, 4H), 1.51 (s, 9H), 1.31 (t, J = 7.5 Hz, 3H). [M + H] = 264.2.

[0824] Step 3. 4-Ethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride. To a stirred solution of tert-butyl 4-ethyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (269 mg, 1.0 mmol) in dioxane (5.1 mL) was added a solution of hydrogen chloride in dioxane (4 M, 1.28 mL, 5.1 mmol), and the solution was stirred for 18 h. The mixture was concentrated, and the residue was dissolved in methanol and concentrated twice, dissolved in DCM and concentrated twice to afford the title compound (222 mg, 100%) as a solid.

[0825] Intermediate 19. 4-(Tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride.

[0826]

[0827] Step 1. tert-Butyl 4-(3,6-dihydro-2H-pyran-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to Intermediate 18, Step 1, using appropriate starting materials in place. 1 HNMR(400MHz,CDCl 3 )δ9.01(s,1H),8.99(s,1H),6.10(br s,1H),5.96(s,1H),5.66(d,J=2.20Hz,1H),4.68(s,3H),4.37(q,J=2.69Hz,2H),3.96(t,J=5.32Hz,2H),3.67(t,J=5.56Hz,2H),2.92(t,J=5.32Hz,2H),2.59(dd,J=2.57,4.40Hz,2H),1.52(s,13H),1.29(s,2H),1.26(s,1H.[M+H]=318.2.

[0828] Step 2. tert-Butyl 4-(tetrahydro-2H-pyran-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to Intermediate 18, Step 2, using appropriate starting materials in place. 1 H NMR(400MHz,CDCl 3) δ 8.97 (s, 1H), 4.64 (s, 2H), 4.12 (dd, J = 3.6, 11.2 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.62 - 3.50 (m, 2H), 3.06 (tt, J = 3.5, 11.6 Hz, 1H), 2.86 (t, J = 5.7 Hz, 2H), 2.18 - 2.02 (m, 2H), 1.63 (dd, J = 1.6, 13.2 Hz, 2H), 1.51 (s, 9H). [M + H - tert - butyl] = 320.3.

[0829] Step 3. 4-(Tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride. The title compound was prepared in a manner similar to that of Intermediate 18, Step 3, using appropriate starting materials in place. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.86 (br s, 2H), 8.99 (s, 1H), 4.26 (t, J = 4.59 Hz, 2H), 3.96 (dd, J = 3.42, 11.25 Hz, 2H), 3.47 - 3.55 (m, 2H), 3.43 (d, J = 6.97 Hz, 2H), 3.17 (tt, J = 3.59, 11.51 Hz, 1H), 3.10 (t, J = 6.05 Hz, 2H), 1.83 (dq, J = 4.34, 12.41 Hz, 2H), 1.60 (d, J = 11.25 Hz, 2H). [M + H] = 220.2.

[0830] Intermediate 20. 4-(Prop-1-en-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine trifluoroacetate.

[0831]

[0832] Step 1. tert-Butyl 4-(prop-1-en-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 18, Step 1, using potassium trifluoro(prop-1-en-2-yl)borate and any appropriate starting materials in place. [M + H] = 276.3.

[0833] Step 2. 4-(Prop-1-en-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine trifluoroacetate. The title compound was prepared in a manner similar to that of Intermediate 18, Step 3, using any appropriate starting materials in place. [M + H] = 176.1.

[0834] Intermediate 21. 4-Cyclopropyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine trifluoroacetate.

[0835]

[0836] Step 1. tert-Butyl 4-cyclopropyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 18, Step 1, using cyclopropylboronic acid and any suitable starting material in place. [M+H] = 276.3.

[0837] Step 2. 4-Cyclopropyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine trifluoroacetate. The title compound was prepared in a manner similar to that of Intermediate 18, Step 3, using any suitable starting material in place. [M+H] = 176.1.

[0838] Intermediate 22. 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidine-4-carbonitrile.

[0839]

[0840] Step 1. tert-Butyl 4-cyano-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. A mixture of tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (500 mg, 1.85 mmol), DMF (10 mL), zinc dicyanide (272 mg, 2.32 mmol), and tetrakis(triphenylphosphine)palladium(0) (214 mg, 0.19 mmol) was degassed by bubbling nitrogen through the mixture for 1 minute, and then the mixture was heated at 90 °C for 2 hours. The mixture was diluted with ethyl acetate, filtered, washed with water and brine, dried (MgSO ) and concentrated. The residue was adsorbed onto silica and purified by flash chromatography (eluting with 0 - 25% ethyl acetate / heptane) to afford the title compound (374 mg, 78%). 4 ) and concentrated. The residue was adsorbed onto silica and purified by flash chromatography (eluting with 0 - 25% ethyl acetate / heptane) to afford the title compound (374 mg, 78%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.14 (s, 1H), 4.74 (s, 2H), 3.81 (t, J = 5.87 Hz, 2H), 3.08 (t, J = 5.75 Hz, 2H), 1.52 (s, 9H).

[0841] Step 2. 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidine-4-carbonitrile. tert-Butyl 4-cyano-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (20 mg, 0.08 mmol) was dissolved in DCM (0.20 mL) and TFA (0.20 mL), and the mixture was stirred for 1 h. It was diluted with DCM and washed with 1 M Na 2 CO 3 washing. The aqueous layer was extracted with a DCM solution of 10% methanol, and the combined organics were dried (MgSO4 ) and concentrated to afford the title compound (4.0 mg, 33%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.08 (s, 1H), 4.15 (s, 2H), 3.26 (t, J = 5.87 Hz, 2H), 3.04 (t, J = 5.69 Hz, 2H), 2.07 (br s, 2H). [M+H] = 161.3.

[0842] Intermediate 23. 4-Ethoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.

[0843]

[0844] Step 1. tert-Butyl 4-ethoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. 4-Chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (700 mg, 2.60 mmol) was dissolved in tetrahydrofuran (7 mL). Sodium ethoxide (25% w / w, 1.12 mL, 3.9 mmol) was added and stirring was continued for 15 minutes. The reaction was quenched with aqueous ammonium chloride solution (3.5 mL) and water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried (MgSO 4 ), concentrated and the residue was purified by flash chromatography (eluting with 0 - 60% ethyl acetate / heptane) to afford the title compound (729 mg, 100%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (s, 1H), 5.32 (s, 1H), 4.56 (s, 2H), 4.47 (q, J = 7.05 Hz, 2H), 3.69 (t, J = 5.81 Hz, 2H), 2.70 (t, J = 5.38 Hz, 2H), 1.51 (s, 9H), 1.42 (s, 3H). [M+H] = 280.0.

[0845] Step 2. 4-Ethoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. The title compound was prepared in a manner analogous to Intermediate 22, Step 2, using appropriate starting materials in place. 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (s, 1H), 4.46 (q, J = 7.05 Hz, 2H), 3.99 (s, 2H), 3.16 (t, J = 5.93 Hz, 2H), 2.64 (t, J = 5.81 Hz, 2H), 1.42 (t, J = 7.03 Hz, 3H). [M+H] = 180.0.

[0846] Intermediate 24. 4-Propoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.

[0847]

[0848] Step 1. tert-Butyl 4-propoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to Intermediate 23, Step 1, using appropriate starting materials in place thereof. 1 H NMR(400MHz,CDCl 3 ) δ 8.58(s,1H), 5.32(s,1H), 4.56(s,2H), 4.36(t, J = 6.66Hz,2H), 3.70(t, J = 5.75Hz,2H), 2.70(t, J = 5.32Hz,2H), 1.78 - 1.87(m,2H), 1.61 - 1.66(m,2H), 1.51(s,9H), 1.04(s,3H). [M+H] = 294.3.

[0849] Step 2. 4-Propoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. This material was prepared using the procedure described for Intermediate 23, Step 2. 1 H NMR(400MHz,CDCl 3 ) δ 8.54(s,1H), 5.32 - 5.33(m,1H), 4.35(t, J = 6.60Hz,2H), 3.99(s,2H), 3.16(t, J = 5.93Hz,2H), 2.65(t, J = 5.81Hz,2H), 1.82(sxt, J = 7.12Hz,2H), 1.04(t, J = 7.40Hz,3H). [M+H] = 194.2.

[0850] Intermediate 25. 4-Isobutoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.

[0851]

[0852] Step 1. tert-Butyl 4-isobutoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to Intermediate 23, Step 1, using appropriate starting materials in place thereof. 1 H NMR(400MHz,CDCl 3) δ 8.58 (s, 1H), 4.57 (s, 2H), 4.17 (d, J = 6.60 Hz, 2H), 3.70 (t, J = 5.75 Hz, 2H), 2.72 (t, J = 5.44 Hz, 2H), 2.08 - 2.18 (m, 1H), 1.51 (s, 9H), 1.04 (d, J = 6.72 Hz, 6H). [M+H] = 308.3.

[0853] Step 2. 4-Isobutoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. The title compound was prepared in a manner similar to that of Intermediate 23, Step 2, using appropriate starting materials in place. 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (s, 1H), 5.32 (s, 1H), 4.16 (d, J = 6.60 Hz, 2H), 4.00 (s, 2H), 3.18 (t, J = 5.93 Hz, 2H), 2.67 (t, J = 5.81 Hz, 2H), 2.12 (dt, J = 13.36, 6.71 Hz, 1H), 1.04 (d, J = 6.72 Hz, 6H). [M+H] = 208.2.

[0854] Intermediate 26. 4-(Cyclopropylmethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.

[0855]

[0856] Step 1. tert-Butyl 4-(cyclopropylmethoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 23, Step 1, using appropriate starting materials in place. [M+H] = 306.3.

[0857] Step 2. 4-(Cyclopropylmethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. The title compound was prepared in a manner similar to that of Intermediate 23, Step 2, using appropriate starting materials in place. 1 H NMR (400 MHz, CDCl 3 ) δ 8.51 (s, 1H), 4.23 (d, J = 7.09 Hz, 2H), 3.97 (s, 2H), 3.12 - 3.18 (m, 2H), 2.61 - 2.69 (m, 2H), 1.24 - 1.34 (m, 1H), 0.57 - 0.65 (m, 2H), 0.37 (q, J = 4.89 Hz, 2H). [M+H] = 206.2.

[0858] Intermediate 27. 4-(2-Methoxyethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.

[0859]

[0860] Step 1. tert-Butyl 4-(2-methoxyethoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 23, Step 1, using appropriate starting materials in place. [M+H] = 310.0.

[0861] Step 2. 4-(2-Methoxyethoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. The title compound was prepared in a manner similar to that of Intermediate 23, Step 2, using appropriate starting materials in place. 1 H NMR(400MHz,CDCl 3 ) δ 8.54 (s, 1H), 4.54 - 4.61 (m, 2H), 4.02 (s, 1H), 3.98 - 4.01 (m, 2H), 3.74 - 3.82 (m, 2H), 3.45 (s, 3H), 3.26 - 3.28 (m, 1H), 3.16 (t, J = 5.93 Hz, 2H), 2.68 (t, J = 5.81 Hz, 2H), 2.46 (s, 1H), 2.29 (s, 1H), 2.23 (s, 1H), 2.19 (s, 1H), 1.46 (s, 1H), 1.28 (s, 1H), 0.04 - 0.21 (m, 1H). [M+H] = 210.2.

[0862] Intermediate 28. 4-Cyclobutoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.

[0863]

[0864] Step 1. tert-Butyl 4-cyclobutoxy-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 23, Step 1, using appropriate starting materials in place. [M+H] = 306.1.

[0865] Step 2. 4-Cyclobutoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. The title compound was prepared in a manner similar to that of Intermediate 23, Step 2, using appropriate starting materials in place. 1 H NMR(400MHz,CDCl 3 ) δ 8.51 (s, 1H), 5.25 - 5.33 (m, 1H), 3.97 (s, 2H), 3.15 (t, J = 5.87 Hz, 2H), 2.63 (t, J = 5.81 Hz, 2H), 2.48 (brs, 2H), 2.10 - 2.21 (m, 2H), 1.80 - 1.94 (m, 1H), 1.75 (s, 4H). [M+H] = 206.1.

[0866] Intermediate 29. 4-Cyclopropoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.

[0867]

[0868] Step 1. tert-Butyl 4-cyclopropoxy-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate. The title compound was prepared in a manner similar to that of Intermediate 23, Step 1, using appropriate starting materials in place. [M+H] = 292.0.

[0869] Step 2. 4-Cyclopropoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. The title compound was prepared in a manner similar to that of Intermediate 23, Step 2, using appropriate starting materials in place. 1 H NMR(400MHz,CDCl 3 )δ8.61(s,1H),5.32(s,1H),4.39(tt,J=6.22,3.13Hz,1H),3.98(s,2H),3.13(t,J=5.93Hz,2H),2.56(t,J=5.75Hz,2H),0.75 - 0.89(m,5H).[M+H] = 192.1.

[0870] Intermediate 30. N-(2-Fluoroethyl)-2-(piperidin-4-yl)pyrimidin-4-amine hydrochloride

[0871]

[0872] Step 1. 2-Chloro-N-(2-fluoroethyl)pyrimidin-4-amine. 2-Fluoroethylamine hydrochloride (3.6 g, 36.5 mmol) and K 2 CO 3 (13.8 g, 101 mmol) were added to a stirred solution of 2,4-dichloropyrimidine (5.0 g, 33.6 mmol) in ACN (250 mL) and stirring was continued for 6 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was evaporated under reduced pressure and the residue was purified by flash chromatography to give the title compound (3.9 g, 66%), as a pale yellow solid. 1 H NMR(500MHz,DMSO-d 6 )δ8.24 - 7.88(m,2H),6.52(d,J=5.9Hz,1H),4.59(t,J=4.9Hz,1H),4.49(t,J=4.9Hz,1H),3.67 - 3.51(m,2H).[M+H] = 176.0.

[0873] Step 2. tert-Butyl 4-(4-(2-fluoroethylamino)pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate. A solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.0 g, 9.7 mmol) in dioxane (15 mL) and sodium carbonate (5.42 g, 29 mmol) in water (20 mL) were combined and degassed with argon. PdCl 2 (dppf)·DCM (0.695 g, 0.85 mmol) and 2-chloro-N-(2-fluoroethyl)pyrimidin-4-amine (3.5 g, 11.6 mmol) were added and the resulting mixture was heated at 90 °C for 4 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography to afford the title compound (1.8 g, 58%) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (d, J = 9.6 Hz, 1H), 7.05 - 6.99 (m 1H), 6.22 (d, J = 9.6 Hz 1H), 5.02 (br s, 1H), 4.69 - 4.65 (dd, J = 9.6, 4.8 Hz), 4.54 - 4.57 (dd, J = 9.6, 4.8 Hz), 4.41 (t, J = 7.2 Hz, 2H), 3.68 - 3.81 (m, 2H), 3.68 (br s, 2H), 2.66 (m, 2H), 1.48 (s, 9H). [M+H] = 323.1.

[0874] Step 3. tert-Butyl 4-(4-(2-fluoroethylamino)pyrimidin-2-yl)piperidine-1-carboxylate. A stirred suspension of tert-butyl 4-(4-(2-fluoroethylamino)pyrimidin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.8 g, 5.6 mmol) and 10% palladium / carbon (700 mg) in ethanol (20 mL) was stirred under hydrogen for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (1.3 g, 72%) as a pale yellow liquid. H NMR (400 MHz, CDCl 1 H NMR (400 MHz, CDCl 3)δ 8.18 (d, J = 5.9 Hz, 1H), 7.05 (s, 1H), 6.22 (d, J = 5.9 Hz, 1H), 5.02 (d, J = 17.6 Hz, 1H), 4.68 (t, J = 4.8 Hz, 1H), 4.55 (q, J = 4.4, 3.9 Hz, 1H), 4.21 - 4.05 (m, 2H), 3.77 (dd, J = 27.1, 5.2 Hz, 2H), 3.60 (s, 2H), 2.66 (s, 2H), 1.48 (s, 9H), 1.25 (d, J = 4.6 Hz, 4H). [M+H] = 325.1.

[0875] Step 4. N-(2-Fluoroethyl)-2-(piperidin-4-yl)pyrimidin-4-amine hydrochloride. The title compound was prepared by treating tert-butyl 4-(4-(2-fluoroethylamino)pyrimidin-2-yl)piperidine-1-carboxylate with HCl in a manner similar to Step 2 of Intermediate 12. 1 H NMR (400 MHz, CDCl 3 )δ 14.76 (s, 1H), 9.89 (d, J = 7.5 Hz, 1H), 9.37 - 9.09 (m, 2H), 8.13 (d, J = 7.1 Hz, 1H), 6.81 (d, J = 7.0 Hz, 1H), 4.69 (t, J = 4.9 Hz, 1H), 4.58 (t, J = 4.9 Hz, 1H), 3.80 (dq, J = 27.5, 5.2 Hz, 2H), 3.35 (d, J = 12.9 Hz, 2H), 3.22 (ddt, J = 11.1, 8.0, 3.9 Hz, 1H), 3.05 - 2.90 (m, 2H), 2.16 - 1.97 (m, 4H).

[0876] Intermediate 31. 2-Isopropyl-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine trifluoroacetate

[0877]

[0878] Step 1. tert-Butyl 2-isopropyl-4-oxo-3,4,5,6-tetrahydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. 2-Methylpropanamidine hydrochloride (153 mg, 1.24 mmol) and sodium ethoxide (21% w / w, 0.62 mL, 1.66 mmol) were added to a stirred solution of 1-(tert-butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (225 mg, 0.83 mmol) in ethanol (8.3 mL), and the reaction was refluxed for 20 h. The reaction was cooled to room temperature, diluted with DCM and washed with brine. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried over MgSO 4Dry and concentrate under vacuum. Purify the residue by column chromatography (eluting with 0 - 100% ethyl acetate and / heptane) to give the title compound (189 mg, 78%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 4.34 (s, 2H), 3.68 - 3.54 (m, 2H), 2.84 (spt, J = 6.9 Hz, 1H), 2.51 (t, J = 5.7 Hz, 2H), 1.49 (s, 9H), 1.28 (d, J = 7.0 Hz, 6H). [M + H] = 294.3.

[0879] Step 2. tert - Butyl 4 - chloro - 2 - isopropyl - 5,6 - dihydropyrido[3,4 - d]pyrimidine - 7(8H) - carboxylate. A mixture of tert - butyl 2 - isopropyl - 4 - oxo - 3,4,5,6 - tetrahydropyrido[3,4 - d]pyrimidine - 7(8H) - carboxylate (180 mg, 0.61 mmol) and triphenylphosphine (320 mg, 1.23 mmol) in 1,2 - dichloroethane (7.2 mL) was stirred for 15 min. Carbon tetrachloride (0.18 mL) was added and the reaction mixture was heated at 70 °C for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography (eluting with 0 - 25% ethyl acetate / heptane) to give the title compound (125 mg, 65%) as a colorless oil. [M + H] = 312.3.

[0880] Step 3. tert - Butyl 2 - isopropyl - 4 - methoxy - 5,6 - dihydropyrido[3,4 - d]pyrimidine - 7(8H) - carboxylate. Dissolve tert - butyl 4 - chloro - 2 - isopropyl - 5,6 - dihydropyrido[3,4 - d]pyrimidine - 7(8H) - carboxylate (125 mg, 0.38 mmol) in methanol (2.35 mL) and add sodium methoxide (25% w / w, 0.34 mL, 1.51 mmol). Heat the mixture to 70 °C and hold for 1 h, cool and evaporate the solvent. Extract the residue with ethyl acetate and wash with saturated ammonium chloride. Dry the organic matter (MgSO 4 ) and evaporate the solvent to give the title compound (116 mg, 96%) as a colorless oil. [M + H] = 308.4.

[0881] Step 4. 2-Isopropyl-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine trifluoroacetate. tert-Butyl 2-isopropyl-4-methoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (111 mg, 0.22 mmol) was dissolved in DCM (1.3 mL), and TFA (0.67 mL) was added. The reaction mixture was stirred for 1 h and concentrated in vacuo to afford the title compound (70 mg, 89%) as a yellow oil. [M+H] = 208.2.

[0882] Intermediate 32. 2-Cyclopropyl-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine trifluoroacetate

[0883]

[0884] Step 1. tert-Butyl 2-cyclopropyl-4-oxo-3,4,5,6-tetrahydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to Intermediate 31, Step 1, using appropriate starting materials in place. 1 H NMR (400 MHz, CD 3 OD) δ 4.24 (s, 2H), 3.66 - 3.54 (m, 2H), 2.49 (t, J = 5.8 Hz, 2H), 1.90 - 1.80 (m, 1H), 1.48 (s, 9H), 1.16 - 1.01 (m, 4H). [M+H] = 292.3.

[0885] Step 2. tert-Butyl 4-chloro-2-cyclopropyl-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to Intermediate 31, Step 2, using appropriate starting materials in place. [M+H] = 310.3.

[0886] Step 3. tert-Butyl 2-cyclopropyl-4-methoxy-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate. The title compound was prepared in a manner similar to Intermediate 31, Step 3, using appropriate starting materials in place. [M+H] = 306.3.

[0887] Step 4. 2-Cyclopropyl-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine trifluoroacetate. The title compound was prepared in a manner similar to Intermediate 31, Step 4, using appropriate starting materials in place. [M+H] = 206.3.

[0888] Intermediate 33. N-((6-Methoxypyrimidin-4-yl)methyl)cyclopropylamine.

[0889]

[0890] Cyclopropylamine (0.048 mL, 0.69 mmol) was added to a mixture of 4-(chloromethyl)-6-methoxypyrimidine (100 mg, 0.63 mmol) and potassium carbonate (131 mg, 0.95 mmol) in DMF (3.2 mL). The mixture was heated at 40 °C for 15 h. The reaction was filtered and the solvent was removed in vacuo to give a mixture of the title product and N,N-bis((6-methoxypyrimidin-4-yl)methyl)cyclopropylamine (113 mg). [M+H] was not observed.

[0891] Intermediate 34. N-((6-Methoxypyrimidin-4-yl)methyl)ethylamine.

[0892]

[0893] The title compound was prepared in a manner similar to Intermediate 33, using appropriate starting materials in place. [M+H] = 168.1.

[0894] Intermediate 35. 3-Cyclopropyl-1-ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine.

[0895]

[0896] Step 1. tert-Butyl 3-cyclopropyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate.

[0897] Di-tert-butyl dicarbonate (12.2 g, 55.8 mmol) was added portionwise to a stirred solution of 3-cyclopropyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (7.0 g, 43 mmol) and DIEA (145 mL, 86 mmol) in 1,2-dichloroethane (70 mL). The mixture was stirred for 5 h, then diluted with DCM, washed with water and brine, dried (MgSO 4 ) and concentrated to give an oily residue. The material was purified by flash chromatography (eluting with 10 - 100% ethyl acetate / heptane) to afford the title compound (4.13 g, 37%). 1 1H NMR (400 MHz, CDCl 3 ) δ 6.68 (s, 1H), 4.62 (s, 2H), 3.98 - 4.06 (m, 2H), 3.83 (t, J = 5.44 Hz, 2H), 1.69 - 1.81 (m, 1H), 1.51 (s, 9H), 0.97 - 1.03 (m, 2H), 0.90 - 0.97 (m, 2H). [M+H] = 264.3.

[0898] Step 2. tert-Butyl 3-cyclopropyl-1-iodo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate. 3-Cyclopropyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (1.12 g, 4.25 mmol) and 1-iodopyrrolidine-2,5-dione (1.15 g, 5.10 mmol) were combined and diluted with ACN (11.2 mL). The mixture was stirred for 22 h, then diluted with ethyl acetate and washed successively with 1 M Na 2 SO 3 aqueous solution and 1 M Na 2 CO 3 aqueous solution, then dried (MgSO 4 ) and concentrated. The residue was purified by flash chromatography (eluting with 10 - 50% ethyl acetate / heptane) to afford the title compound (1.16 g, 71%) as a gum. 1 1H NMR (400 MHz, CDCl 3 ) δ 4.46 (s, 2H), 3.95 - 4.05 (m, 2H), 3.82 (t, J = 5.32 Hz, 2H), 1.68 - 1.78 (m, 1H), 1.53 (s, 9H), 1.01 - 1.07 (m, 2H), 0.91 - 1.00 (m, 2H). [M + H] = 390.2.

[0899] Step 3. tert-Butyl 3-cyclopropyl-1-vinyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate. A mixture of tert-butyl 3-cyclopropyl-1-iodo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (277 mg, 0.71 mmol), (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine dichloropalladium(II) (26 mg, 0.04 mmol), potassium fluoride / vinyltrifluoroborate potassium (1:1) (286 mg, 2.13 mmol), ACN (3.6 mL), and aqueous sodium bicarbonate solution (1 M, 1.8 mL, 1.8 mmol) was combined in a 20 mL vial and degassed with nitrogen for 1 min. The mixture was heated to 90 °C for 8 h. Some starting material persisted, so additional potassium fluoride / vinyltrifluoroborate potassium (1:1) (286 mg, 2.13 mmol), palladium catalyst (26 mg, 0.04 mmol), ACN (3.6 mL), and sodium bicarbonate (1 M, 1.8 mL, 1.8 mmol) were added. The mixture was degassed again and heated at 90 °C for 16 h. The mixture was shaken with ethyl acetate and Na 2 CO 3 aqueous solution, and the resulting aqueous layer was extracted with ethyl acetate. The combined organics were dried (MgSO4 ) and concentrated, and the residue was purified by flash chromatography (eluting with 10 - 75% ethyl acetate / heptane) to afford the title compound (76 mg, 37%). 1 1H NMR (400 MHz, CDCl 3 ) δ 6.55 (dd, J = 11.1, 17.5 Hz, 1H), 5.56 (dd, J = 1.5, 17.6 Hz, 1H), 5.12 (dd, J = 1.3, 11.1 Hz, 1H), 4.66 (s, 2H), 4.07 - 3.95 (m, 2H), 3.83 (t, J = 5.3 Hz, 2H), 1.73 (tt, J = 5.2, 8.2 Hz, 1H), 1.52 (s, 9H), 1.07 - 0.99 (m, 2H), 0.98 - 0.88 (m, 2H). [M + H] = 290.3.

[0900] Step 4. tert-Butyl 3-cyclopropyl-1-ethyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate. A mixture of tert-butyl 3-cyclopropyl-1-vinyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (73 mg, 0.25 mmol) and palladium on carbon (27 mg, 0.03 mmol) in ethyl acetate (1.5 mL) was stirred under hydrogen at 180 psi for 16 h. The mixture was passed through filtration and concentrated in vacuo to afford the title compound (90 mg, 100%). 1 1H NMR (400 MHz, CDCl 3 ) δ 4.55 (s, 2H), 3.98 (t, J = 6.1 Hz, 2H), 3.81 (t, J = 5.4 Hz, 2H), 2.48 (q, J = 7.6 Hz, 2H), 1.75 - 1.66 (m, 1H), 1.51 (s, 9H), 1.18 (t, J = 7.6 Hz, 3H), 1.01 - 0.95 (m, 2H), 0.95 - 0.89 (m, 2H). [M + H] = 292.3.

[0901] Step 5. 3-Cyclopropyl-1-ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine. tert-Butyl 3-cyclopropyl-1-ethyl-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (90 mg, 0.31 mmol) was stirred in 2-methyltetrahydrofuran (0.45 mL) and TFA (0.45 mL) for 3 h. The solvent was evaporated and the residue was diluted with 1 M Na 2 2CO 3 3. The solution was extracted with a 5:1 DCM-methanol solution (3 × 25 mL), and the combined extracts were dried (MgSO4 ) And concentrated to give the title compound (54 mg, 91%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 3.99 (s, 2H), 3.93 (t, J = 5.6 Hz, 2H), 3.23 (t, J = 5.6 Hz, 2H), 2.51 - 2.43 (m, 2H), 1.72 (tt, J = 5.1, 8.2 Hz, 1H), 1.16 (t, J = 7.6 Hz, 3H), 1.03 - 0.98 (m, 2H), 0.94 - 0.87 (m, 2H). [M+H] = 192.2.

[0902] Example 1. (6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidin-5-yl)(4-phenyl piperazin-1-yl)methanone (or 6-Methyl-N-(1-methylcyclopropyl)-5-(4-phenylpiperazine-1-carbonyl)furo[2,3-d]pyrimidin-4-amine). Example 2. (2-Cyclopropyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(6-methyl-4-((1-methyl

[0903]

[0904] Step 1. (4-Chloro-6-methylfuro[2,3-d]pyrimidin-5-yl)(4-phenylpiperazin-1-yl)methanone. 4-Chloro-6-methylfuro[2,3-d]pyrimidine-5-carboxylic acid (Intermediate 2, 500 mg, 1.65 mmol) and DIEA (0.57 ml, 3.3 mmol) were combined in DMA (8.2 mL) and treated with HATU (810 mg, 2.14 mmol) and 1-phenylpiperazine (0.26 mL, 1.73 mmol). The mixture was stirred for 1 h, diluted with water and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine and dried over MgSO 4 Dried. The solvent was evaporated and the residue was purified by column chromatography (eluting with 0 - 80% ethyl acetate / heptane) to give the title compound (320 mg, 54%) as a white solid. [M+H] = 357.0.

[0905] Step 2. (6-Methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidin-5-yl)(4-phenylpiperazin-1-yl)methanone. (4-Chloro-6-methylfuro[2,3-d]pyrimidin-5-yl)(4-phenylpiperazin-1-yl)methanone (25 mg, 0.07 mmol) was dissolved in DMA (0.70 mL) and treated with DIEA (0.050 mL, 0.28 mmol) and 1-methylcyclopropanamine hydrochloride (0.01 g, 0.09 mmol). The mixture was stirred at 85 °C for 16 h and cooled. It was filtered and purified by preparative HPLC (using 20 - 80% ACN containing 0.05% TFA). The fractions containing the product were combined and lyophilized to give the title compound (26 mg, 74%) as a white powder. 11H NMR (400 MHz, CD 3 OD) δ 8.41 (s, 1H), 7.33 - 7.26 (m, 2H), 7.04 (d, J = 7.8 Hz, 2H), 6.92 (t, J = 7.3 Hz, 1H), 4.09 - 3.74 (m, 4H), 3.30 - 3.16 (m, 4H), 2.62 - 2.56 (m, 3H), 1.58 - 1.49 (m, 3H), 1.00 - 0.82 (m, 4H). [M+H] = 392.3.

[0906] cyclopropyl)amino)furo[2,3-d]pyrimidin-5-yl)methanone (or 5-{2-cyclopropyl-5H,6H,7H,8H-pyrido[4, 3-d]pyrimidin-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine). Example 3. N-(1-(Fluoromethyl)cyclopropyl)-6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-

[0907]

[0908] DIEA (0.063 mL, 0.36 mmol) and 6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxy...

Claims

1. Compounds of general formula (I): or a pharmaceutically acceptable salt thereof, wherein R a is -L 1 -L 3 、-L 1 -L 2 -L 3 or -N(L 4 )-L 5 ; L 1 Selected from: -N(R b )-, -N(R b )-(C(R b ) 2 ) m -, -N(R b )(CH 2 ) m O-, -NHNH-, a 3- to 15-membered heterocyclic hydrocarbon group, and a 5- to 10-membered heteroaryl group, wherein the 3- to 15-membered heterocyclic hydrocarbon group or 5- to 10-membered heteroaryl group is optionally substituted by one to four R 1A groups, and each R 1A is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl; each m is independently 0, 1, 2 or 3; Each R b is independently -H, -OH, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -C 3-7 cycloalkyl, -C 2-6 alkenyl or -C 2-6 alkynyl; L 2 Selected from: -N(R c )-, -N(R c )(CH 2 ) m -, -O-, -S-, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -CHR c -, -(CH 2 ) m NH-, -(CH 2 ) m O-, -(CH 2 ) m S-, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl and 5- to 10-membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl and 5- to 10-membered heteroaryl are optionally substituted by one to four R 1B , wherein each R 1B is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 , -C 3-7 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl and 5- to 10-membered heteroaryl; Each R c is independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -C 3-7 cycloalkyl, -C 2-6 alkenyl or -C 2-6 alkynyl; L 3 Selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -N(R 1DD ) 2 , -N=S(=O)(CH 3 ) 2 , -NO 2 , -SO 2 CH 3 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C 1-6 alkyl-O-C 1-4 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl, and 5- to 10-membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl, and 5- to 10-membered heteroaryl are optionally substituted with one to four R 1C , where each R 1C is independently selected from: halogen, -OH, ═O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 , -C 3-7 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl; Each R 1DD is independently selected from: -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C 3-7 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl; L 4 and L 5 together with the nitrogen atom to which they are attached form a 3- to 15-membered heterocyclic hydrocarbon group or a 5- to 10-membered heteroaryl ring, optionally substituted by one to four R 1D wherein each R 1D is independently selected from: L 6 , =O, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl and -COOC 1-6 alkyl; and L 6 Selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -N═S(═O)(CH 3 ) 2 , -NO 2 , -SO 2 CH 3 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C 3-10 cycloalkyl, -C 1-6 alkyl - O - C 1-4 alkyl, a 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and a 5 - 10 - membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, a 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and a 5 - 10 - membered heteroaryl are optionally substituted by one to four R 1E , wherein each R 1E is independently selected from: halogen, -OH, ═O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl - OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl - O - C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 , -C 3-7 cycloalkyl, a 3 - 15 - membered heterocycloalkyl, phenyl and a 5 - 10 - membered heteroaryl.

2. The compound according to claim 1, which has the structure of general formula (Ia): or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, which has the structure of general formula (Ib): or a pharmaceutically acceptable salt thereof.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 3, wherein L 1 Selected from: -N(R b )-, -N(R b )-(C(R b ) 2 ) m -, -N(R b )(CH 2 ) m O- and -NHNH-; each m is independently 0, 1, 2 or 3; and Each R b is independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -C 3-7 cycloalkyl, -C 2-6 alkenyl or -C 2-6 alkynyl.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 is -N(R b )- or -N(R b )-(C(R b ) 2 ) m -; each m is independently 0, 1, 2 or 3; and Each R b is independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl or -C 3-7 cycloalkyl.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 is -NH- or -NHCH 2 -.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 is a 3- to 15-membered heterocyclic hydrocarbon group or a 5- to 10-membered heteroaryl group, and the 3- to 15-membered heterocyclic hydrocarbon group or the 5- to 10-membered heteroaryl group is optionally substituted with one to four R 1A substituents.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 Selected from: azetidine, pyrrolidine, 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, imidazolidine, piperidine, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, piperazine, morpholine, 3-azabicyclo[3.1.0]hexane, octahydrocyclopenta[c]pyrrole, octahydrocyclopenta[b]pyrrole, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 5,6,7,8-tetrahydro-1,6-naphthyridine, 5,6,7,8-tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,6-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, isoindoline, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, 5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[1,2-c]pyrimidine, hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole, hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole, decahydroisoquinoline, decahydroquinoline, azepane, diazepane, 8-oxa-3-azabicyclo[3.2.1] Octane, 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine, 3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine, spiro[indoline-3,3'-piperidine]-2-one, spiro[indoline-3,3'-pyrrolidine]-2-one, 2,3-dihydrospiro[indene-1,2'-morpholine], 3H-spiro[isobenzofuran-1,3'-piperidine], 3H-spiro[isobenzofuran-1,3'-pyrrolidine], spiro[benzo[d][1,3]oxazine-4,4'-piperidine]-2(1H)-one, spiro[indene-1,4'-piperidine], 3H-spiro[benzo[c]thiophene-1,4'-piperidine] and 2,3,4,5-tetrahydro-1H-1,5-methanobenzodiazepine, wherein the 3- to 15-membered heterocyclic hydrocarbon group is substituted with one to three R. 1A Optionally substituted.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 is selected from: azetidine, pyrrolidine, piperidine, azepane, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, and 2,3-dihydro-1H-pyrrole.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from: imidazolidine, piperazine, diazepane and morpholine.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from: 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 5,6,7,8-tetrahydro-1,6-naphthyridine, 5,6,7,8-tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,6-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine and isoindoline.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 is selected from: 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, octahydropyrrolo[1,2-a]pyrazine, and octahydropyrrolo[1,2-c]pyrimidine.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 is selected from: 3-azabicyclo[3.1.0]hexane, octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole, hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole, decahydroisoquinoline, decahydroquinoline, 8-oxa-3-azabicyclo[3.2.1]octane, 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine, 3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocin, spiro[indoline-3,3'-piperidine]-2-one, spiro[indoline-3,3'-pyrrolidine]-2-one, 2,3-dihydrospiro[indene-1,2'-morpholine], 3H-spiro[isobenzofuran-1,3'-piperidine], 3H-spiro[isobenzofuran-1,3'-pyrrolidine], spiro[benzo[d][1,3]oxazine-4,4'-piperidine]-2(1H)-one, spiro[indene-1,4'-piperidine], 3H-spiro[benzo[c]thiophene-1,4'-piperidine], and 2,3,4,5-tetrahydro-1H-1,5-methanobenzodiazepine.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 is a 5- to 10-membered heteroaryl selected from pyrazole, imidazole, pyrrole, oxazole, thiazole, indole and indazole, and the 5- to 10-membered heteroaryl is optionally substituted with one to three R 1A substituents.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 1 is pyrazole, which is optionally substituted with one to three R 1A groups.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R a is -L 1 -L 3 or -L 1 -L 2 -L 3 , and R 1A is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl.

17. The compound according to claim 3, which has the structure of general formula (Iba): or a pharmaceutically acceptable salt thereof, wherein L 2 is -C 3-10 a cycloalkyl group, a 3- to 15-membered heterocycloalkyl group, a phenyl group or a 5- to 10-membered heteroaryl group, and the -C 3-10 cycloalkyl group, 3- to 15-membered heterocycloalkyl group, phenyl group and 5- to 10-membered heteroaryl group are optionally substituted by one to four R 1B groups, where each R 1B is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy and -C 1-6 alkyl-O-C 1-4 alkyl; R b is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 3-6 cycloalkyl, -C 2-6 alkenyl or -C 2-6 alkynyl; L 3 is -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkyl -O -C 1-4 alkyl, -C 3-10 cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl or 5 - 10 - membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl are optionally substituted by one to four R 1C , where each R 1C is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl -OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl -O -C 1-4 alkyl; and m is 0, 1 or 2.

18. The compound according to claim 3, which has the structure of general formula (Ibb): or a pharmaceutically acceptable salt thereof, wherein L 2 is -C 3-10 a cycloalkyl group, a 3- to 15-membered heterocycloalkyl group, a phenyl group or a 5- to 10-membered heteroaryl group, wherein said -C 3-10 cycloalkyl group, 3- to 15-membered heterocycloalkyl group, phenyl group and 5- to 10-membered heteroaryl group are optionally substituted by one to four R 1B groups, where each R 1B is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy and -C 1-6 alkyl-O-C 1-4 alkyl; L 3 is -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkyl -O -C 1-4 alkyl, -C 3-10 cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl or 5 - 10 - membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl are optionally substituted by one to four R 1C , wherein each R 1C is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl -OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl -O -C 1-4 alkyl; R b is -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 3-6 cycloalkyl, -C 2-6 alkenyl or -C 2-6 alkynyl; Each R d is independently selected from: -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH and -C 3-6 cycloalkyl; and m is 0, 1 or 2.

19. The compound according to claim 1, which has the structure of general formula (Ic): or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19, which has the structure of general formula (Icaa) or (Icab): or a pharmaceutically acceptable salt thereof, wherein L 6 Selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C 3-10 cycloalkyl, -C 1-6 alkyl - O - C 1-4 alkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl are optionally substituted by one to four R 1E , where each R 1E is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl - OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl - O - C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl; B 1 is CH or C(R 1D )); B 2 is CH 2 or CH(R 1D )); R 1D is L 6 , =O, -C 1-6 alkyl-OH or -C 1-6 alkyl-O-C 1-4 alkyl; and p is 0, 1, 2 or 3.

21. The compound according to claim 19, which has the structure of general formula (Icb): or a pharmaceutically acceptable salt thereof, wherein L 6 Selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C 3-10 cycloalkyl, -C 1-6 alkyl - O - C 1-4 alkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl, wherein the -C 1-6 alkyl, -C 3-10 cycloalkyl, 3 - 15 - membered heterocycloalkyl, phenyl, benzyl and 5 - 10 - membered heteroaryl are optionally substituted by one to four R 1E , wherein each R 1E is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl - OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl - O - C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl; B 2 is CH 2 or CH(R 1D ); R 1D is L 6 、=O、-C 1-6 alkyl-OH or -C 1-6 alkyl-O-C 1-4 alkyl; Q is NH, N(R 1D ) or O; and q is 1, 2 or 3.

22. The compound or a pharmaceutically acceptable salt thereof according to claim 21, wherein Q is NH or N(R 1D ); and q is 1.

23. The compound according to claim 19, which has the structure of general formula (Icc): or a pharmaceutically acceptable salt thereof, wherein L 6 Selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -N=S(=O)(CH 3 ) 2 , -NO 2 , -SO 2 CH 3 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C 3-10 cycloalkyl, -C 1-6 alkyl-O-C 1-4 alkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl and 5- to 10-membered heteroaryl, wherein said -C 1-6 alkyl, -C 3-10 cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, benzyl and 5- to 10-membered heteroaryl are optionally substituted by one to four R 1E , wherein each R 1E is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl; Each B 1 , D 1 , E and G are CH, C(R 1D ), or N, provided that no more than two of B 1 , D 1 , E and G are simultaneously N; Each R 1D is independently selected from: L 6 , =O, -C 1-6 alkyl-OH and -C 1-6 alkyl-O-C 1-4 alkyl; and r is 1 or 2.

24. The compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein L 6 Selected from: -H, halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy and -C 1-6 haloalkoxy; B 1 and E are N; D 1 and G are independently CH or C(R 1D ); and r is 2.

25. The compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein L 6 Selected from: -H, halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy and -C 1-6 haloalkoxy; D 1 and G are N; B 1 and E are independently CH or C(R 1D ); and r is 2.

26. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 2 is -N(R c )-, -NR c (CH 2 ) m -, -O-, -S-, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 2-5 alkenyl, -C 2-5 alkynyl, -C(O)C 1-4 alkyl, -CHR c -, -(CH 2 ) m NH-, -(CH 2 ) m O- or -(CH 2 ) m S-, and the -C 1-4 alkyl is optionally substituted by one to three R 1B , wherein each R 1B is independently selected from: -F, -Br, -Cl, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-6 cycloalkyl.

27. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 2 is selected from: -C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl, wherein the -C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl are optionally substituted with one to three R 1B substituents.

28. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentan-1-yl, adamantyl or 2,3-dihydro-1H-inden-5-yl, each optionally substituted with one to three R 1B substituents.

29. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 2 is selected from: azetidine, pyrrolidine, piperidine, azepane, dihydropyrrole, tetrahydropyridine, imidazoline, piperazine, diazepane, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, benzo[d][1,3]dioxole, 2,3-dihydrobenzo[b][1,4]dioxin, tetrahydroquinoline, tetrahydroisoquinoline, quinolin-2(1H)-one, decahydroisoquinoline, decahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3-dihydrobenzo[b][1,4]dioxin, pyrimidinone, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 8-oxa-3-azabicyclo[3.2.1]octane, pyrimidin-4(3H)-one, octahydrocyclopenta[c]pyrrole, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, tetrahydronaphthyridine, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine and isoindoline, each optionally substituted with one to three R 1B wherein each R 1B is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-6 cycloalkyl.

30. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is selected from: azetidine, pyrrolidine, piperidine, azepane, imidazoline, piperazine, diazepane, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, benzo[d][1,3]dioxolene, 2,3-dihydrobenzo[b][1,4]dioxin, tetrahydroquinoline, tetrahydroisoquinoline, quinolin-2(1H)-one, decahydroisoquinoline, decahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3-dihydrobenzo[b][1,4]dioxin, pyrimidinone, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 8-oxa-3-azabicyclo[3.2.1]octane and pyrimidin-4(3H)-one, each optionally substituted with one to three R 1B wherein each R 1B is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-6 cycloalkyl.

31. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is phenyl, which is optionally substituted with one to three R 1B groups.

32. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 2 is a 5- to 10-membered heteroaryl selected from: pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole, indole, indazole, benzimidazole, benzoxazole, benzothiazole, [1,2,4]triazolo[4,3-a]pyridine and imidazo[1,2-a]pyrazine, each optionally substituted by one to three R 1B , where each R 1B is independently selected from: halogen, -OH, ═O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-6 cycloalkyl.

33. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 2 is pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazole, thiazole, oxazole and isoxazole, each optionally substituted with one to three R 1B wherein each R 1B is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl, -C(O)C 1-4 alkyl, -COOC 1-4 alkyl, -C(O)NH 2 and -C 3-6 cycloalkyl.

34. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -N═S(═O)(CH 3 ) 2 , -NO 2 , -SO 2 CH 3 , -F, -Cl, -Br, -I, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 2-5 alkenyl, -C 2-5 alkynyl, -C 1-4 alkyl-O-C 1-4 alkyl, -C(O)C 1-4 alkyl and -C(O)NH 2 , wherein the -C 1-4 alkyl is optionally substituted with one to three R 1C .

35. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 3 is selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -F, -Cl, -Br, -I, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkoxy, -C 1-4 haloalkoxy, wherein the -C 1-4 alkyl is optionally substituted with one to three R 1C .

36. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from: -C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl, wherein the -C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl are optionally substituted with one to three R 1C substituents.

37. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentan-1-yl, adamantyl or 2,3-dihydro-1H-inden-5-yl, each optionally substituted with one to three R 1C substituents.

38. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from: azetidine, pyrrolidine, piperidine, azepane, dihydropyrrole, tetrahydropyridine, imidazoline, piperazine, diazepane, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, benzo[d][1,3]dioxolene, 2,3-dihydrobenzo[b][1,4]dioxin, tetrahydroquinoline, tetrahydroisoquinoline, quinolin-2(1H)-one, decahydroisoquinoline, decahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3-dihydrobenzo[b][1,4]dioxin, pyrimidinone, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 8-oxa-3-azabicyclo[3.2.1]octane, pyrimidin-4(3H)-one, octahydrocyclopenta[c]pyrrole, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, tetrahydronaphthyridine, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine and isoindoline, each optionally substituted by one to three R 1C wherein each R 1C is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -SO 2 CH 3 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl.

39. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from: azetidine, pyrrolidine, piperidine, azepane, imidazoline, piperazine, diazepane, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, benzo[d][1,3]dioxolene, 2,3-dihydrobenzo[b][1,4]dioxin, tetrahydroquinoline, tetrahydroisoquinoline, quinolin-2(1H)-one, decahydroisoquinoline, decahydroquinoline, 6,7-dihydro-5H-cyclopenta[b]pyridine, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, 2,3-dihydrobenzo[b][1,4]dioxin, pyrimidinone, 3-oxabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexane, 8-oxa-3-azabicyclo[3.2.1]octane and pyrimidin-4(3H)-one, each optionally substituted by one to three R 1C wherein each R 1C is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl-O-C 1-4 alkyl and -C 3-6 cycloalkyl.

40. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 3 is phenyl, which is optionally substituted with one to three R 1C groups.

41. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from: pyridine, pyridazine, pyrazine, pyrimidine, pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole, tetrazole, indole, indazole, benzimidazole, benzoxazole, benzothiazole, [1,2,4]triazolo[4,3-a]pyridine and imidazo[1,2-a]pyrazine, each of which is optionally substituted by one to three R 1C wherein each R 1C is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 alkyl-O-C 1-4 alkyl, -C(O)C 1-6 alkyl, -COOC 1-6 alkyl, -C(O)NH 2 and -C 3-7 cycloalkyl.

42. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 3 is selected from: pyridine, pyridazine, pyrazine and pyrimidine, each being optionally substituted by one to three R 1C groups, where each R 1C is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy and -C 3-6 cycloalkyl.

43. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L 3 is selected from: pyrrole, pyrazole, imidazole, thiazole, oxazole and isoxazole, each optionally substituted by one to three R 1C wherein each R 1C is independently selected from: -F, -Cl, -Br, -I, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy and -C 3-6 cycloalkyl.

44. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 19, wherein L 4 and L 5 Together with the nitrogen atoms to which they are attached, form azetidine, pyrrolidine, 2,5-dihydro-1H-pyrrole, 2,3-dihydro-1H-pyrrole, imidazolidine, piperidine, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, piperazine, morpholine, 3-azabicyclo[3.1.0]hexane, octahydrocyclopenta[c]pyrrole, octahydrocyclopenta[b]pyrrole, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 5,6,7,8-tetrahydro-1,6-naphthyridine, 5,6,7,8-tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,6-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine, isoindoline, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, 5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[1,2-c]pyrimidine, hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole, hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole, decahydroisoquinoline, decahydroquinoline, azepane, diazepane, 8-oxa-3-azabicyclo[3.2.1] Octane, 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine, 3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocin, spiro[indoline-3,3'-piperidine]-2-one, spiro[indoline-3,3'-pyrrolidine]-2-one, 2,3-dihydrospiro[indene-1,2'-morpholine], 3H-spiro[isobenzofuran-1,3'-piperidine], 3H-spiro[isobenzofuran-1,3'-pyrrolidine], spiro[benzo[d][1,3]oxazine-4,4'-piperidine]-2(1H)-one, spiro[indene-1,4'-piperidine], 3H-spiro[benzo[c]thiophene-1,4'-piperidine] or 2,3,4,5-tetrahydro-1H-1,5-methano-1,5-benzodiazepine, each of which is substituted with one to three R. 1D Optionally substituted.

45. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 19, wherein L 4 and L 5 together with the nitrogen to which they are attached form azetidine, pyrrolidine, piperidine, azepane, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine or 2,3-dihydro-1H-pyrrole, each optionally substituted by one to three R 1D substituents.

46. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 19, wherein L 4 and L 5 together with the nitrogen to which they are attached form imidazolidine, piperazine, diazepane or morpholine, each optionally substituted with one to three R 1D substituents.

47. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 19, wherein L 4 and L 5 together with the nitrogen atom to which they are attached form 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,4-c]pyridazine, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazine, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, 5,6,7,8-tetrahydro-1,6-naphthyridine, 5,6,7,8-tetrahydro-1,7-naphthyridine, 1,2,3,4-tetrahydro-2,6-naphthyridine, 1,2,3,4-tetrahydro-2,7-naphthyridine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine or isoindoline, each of which is optionally substituted by one to three R 1D substituents.

48. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 19, wherein L 4 and L 5 together with the nitrogen to which they are attached form 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, octahydropyrrolo[1,2-a]pyrazine or octahydropyrrolo[1,2-c]pyrimidine, each optionally substituted by one to three R 1D substituents.

49. The compound according to claim 1 or 19, or a pharmaceutically acceptable salt thereof, wherein L 4 and L 5 together with the nitrogen to which they are attached form 3-azabicyclo[3.1.0]hexane, octahydrocyclopenta[b]pyrrole, octahydrocyclopenta[c]pyrrole, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, hexahydro-2H-furo[3,2-b]pyrrole, hexahydro-2H-furo[2,3-c]pyrrole, hexahydro-1H-furo[3,4-c]pyrrole, hexahydro-1H-furo[3,4-b]pyrrole, decahydroisoquinoline, decahydroquinoline, 8-oxa-3-azabicyclo[3.2.1]octane, 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine, 3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocine, spiro[indoline-3,3'-piperidine]-2-one, spiro[indoline-3,3'-pyrrolidine]-2-one, 2,3-dihydrospiro[indene-1,2'-morpholine], 3H-spiro[isobenzofuran-1,3'-piperidine], 3H-spiro[isobenzofuran-1,3'-pyrrolidine], spiro[benzo[d][1,3]oxazine-4,4'-piperidine]-2(1H)-one, spiro[indene-1,4'-piperidine], 3H-spiro[benzo[c]thiophene-1,4'-piperidine] or 2,3,4,5-tetrahydro-1H-1,5-methanobenzo[d]azepine, each optionally substituted by one to three R 1D substituents.

50. The compound according to claim 1 or 19, or a pharmaceutically acceptable salt thereof, wherein L 4 and L 5 together with the nitrogen to which they are attached form pyrazole, imidazole, pyrrole, oxazole, thiazole, indole or indazole, each optionally substituted by one to three R 1D substituents.

51. The compound according to claim 1 or 19, or a pharmaceutically acceptable salt thereof, wherein L 4 and L 5 together with the nitrogen to which they are attached form a pyrazole, which is optionally substituted with one to three R 1D substituents.

52. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R b is independently -H, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 alkyl-OH, -C 1-3 alkyl-O-C 1-3 alkyl or -C 3-5 cycloalkyl.

53. The compound according to claim 1 or 19, or a pharmaceutically acceptable salt thereof, wherein L 6 is selected from: -H, -OH, -CN, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -F, -Cl, -Br, -I, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C(O)C 1-4 alkyl, -C(O)NH 2 , -C 3-10 cycloalkyl, -C 1-4 alkyl - O - C 1-4 alkyl, a 3 - 10 - membered heterocycloalkyl, phenyl, benzyl, and a 5 - 10 - membered heteroaryl, wherein the -C 1-4 alkyl, -C 3-10 cycloalkyl, -C 3-7 cycloalkoxy, a 3 - 10 - membered heterocycloalkyl, phenyl, benzyl, and a 5 - 10 - membered heteroaryl are optionally substituted by one or more R 1E , where each R 1E is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl - OH, -C 1-4 alkoxy, -C 1-4 haloalkoxy, -C 1-4 alkyl - O - C 1-4 alkyl, and -C 3-6 cycloalkyl.

54. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R c is -H, -C 1-4 alkyl or -C 1-4 haloalkyl.

55. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 18, 26 to 43 and 54, wherein each R d is independently -H or -C 1-4 alkyl.

56. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1B is independently selected from: -F, -Cl, -OH, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy.

57. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1C is independently selected from: -F, -Cl, -OH, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy.

58. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 1D is L 6 or =O.

59. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 1E is independently selected from: -F, -Cl, -OH, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy.

60. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein each R b is independently -H, -C 1-4 alkyl or -C 1-4 haloalkyl.

61. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein m is 0.

62. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein m is 1.

63. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein m is 2.

64. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein L 2 is -C 3-7 a cycloalkyl group, a 3- to 10-membered heterocycloalkyl group, a phenyl group or a 5- to 10-membered heteroaryl group, wherein the -C 3-7 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, phenyl group and 5- to 10-membered heteroaryl group are optionally substituted by one to three R 1B groups, where each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy; L 3 is -H, halogen, -C 1-6 alkyl or -C 1-4 alkoxy; R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and m is 0 or 1.

65. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein L 2 is -C 3-7 a cycloalkyl group, a 3- to 10-membered heterocycloalkyl group, a phenyl group or a 5- to 10-membered heteroaryl group, wherein the -C 3-7 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, phenyl group and 5- to 10-membered heteroaryl group are optionally substituted by one to three R 1B groups, where each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy; L 3 is -C 3-7 a cycloalkyl group, a 3- to 10-membered heterocycloalkyl group, a phenyl group, a benzyl group or a 5- to 10-membered heteroaryl group, wherein the -C 3-7 cycloalkyl group, 3- to 10-membered heterocycloalkyl group, phenyl group, benzyl group and 5- to 10-membered heteroaryl group are optionally substituted by one to three R 1C groups, where each R 1C is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy; R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and m is 0 or 1.

66. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein L 2 is -C 3-7 cycloalkyl, said -C 3-7 cycloalkyl is optionally substituted by one to three R 1B groups, where each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl and -C 1-4 haloalkyl; L 3 is -H, halogen, or -C 1-4 alkyl; R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and m is 0 or 1.

67. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein L 2 is phenyl or a 5- to 10-membered heteroaryl group, which phenyl or 5- to 10-membered heteroaryl group is optionally substituted by one to three R 1B groups, where each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy; L 3 is -C 3-7 a cycloalkyl group, a 3- to 10-membered hetero cycloalkyl group, a phenyl group or a 5- to 10-membered heteroaryl group, and the -C 3-7 cycloalkyl group, 3- to 10-membered hetero cycloalkyl group, phenyl group and 5- to 10-membered heteroaryl group are optionally substituted by one to three R 1C groups, where each R 1C is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy; R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and m is 0 or 1.

68. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein L 2 is phenyl or a 5- to 10-membered heteroaryl, said phenyl or 5- to 10-membered heteroaryl being optionally substituted by one to three R 1B wherein each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy; L 3 is -H, halogen, -C 1-6 alkyl or -C 1-4 alkoxy; R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and m is 1 or 2.

69. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein L 2 is phenyl or a 5- or 6-membered heteroaryl group, said phenyl and 5- or 6-membered heteroaryl group being optionally substituted by one to three R 1B groups, where each R 1B is independently selected from: -F, -Cl, -Br, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 alkoxy and -C 1-3 haloalkoxy; L 3 is -H, halogen, -C 1-6 alkyl or -C 1-4 alkoxy; R b is -H or -CH 3 ; and m is 1 or 2.

70. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein L 2 is pyridine, pyridazine, pyrazine or pyrimidine, each being optionally substituted by one to three R 1B groups, where each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy; L 3 is -H, halogen, -C 1-6 alkyl or -C 1-4 alkoxy; R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and m is 1.

71. The compound or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein L 2 is pyrrole, pyrazole, imidazole, thiazole, oxazole or isoxazole, each being substituted by one to three R 1B optionally, wherein each R 1B is independently selected from: -F, -Cl, -Br, -CN, -C 1-4 alkyl, -C 1-4 haloalkyl, -C 1-4 alkyl-OH, -C 1-4 alkoxy and -C 1-4 haloalkoxy; L 3 is -H, halogen, -C 1-6 alkyl or -C 1-4 alkoxy; R b is -H, -C 1-3 alkyl or -C 1-3 haloalkyl; and m is 1.

72. The compound according to any one of claims 20 to 22 or a pharmaceutically acceptable salt thereof, wherein L 6 is selected from: -H, -OH, -CN, -NO 2 , halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy and -C 3-7 cycloalkyl.

73. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 22, wherein L 6 is phenyl or a 5- or 6-membered heteroaryl, said phenyl and 5- or 6-membered heteroaryl being optionally substituted by one or more R 1E , where each R 1E is independently selected from: halogen, -OH, =O, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -NO 2 , -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkyl-OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy and -C 1-6 alkyl-O-C 1-4 alkyl.

74. The compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein r is 2, B 1 is N, E is N and D 1 and G are independently CH or C(R 1D ).

75. The compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein r is 2, D 1 is N, G is N and B 1 and E are independently CH or C(R 1D ).

76. A compound selected from: N-[6-(Furan-3-yl)pyridin-3-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[5-(morpholin-4-yl)pyridin-2-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(oxetan-3-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-(5-Fluoropyridin-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(1-Cyanocyclobutyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pyridin-4-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pyridin-3-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(1-methyl-1H-pyrazol-5-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(5,6,7,8-tetrahydroquinolin-8-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(1-methyl-1H-pyrazol-3-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(1,5-Dimethyl-1H-pyrazol-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(trimethyl-1H-pyrazol-4-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-2-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(2-Methoxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl}furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(6-methylpyridin-2-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(4-methylpyridin-2-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3-methylpyridin-2-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(2-Methoxyethyl)-1H-pyrazol-4-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(1,4-Dimethyl-1H-pyrazol-3-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(Dimethyl-1,3-thiazol-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(6-methylpyridazin-3-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(1-methyl-1H-imidazol-4-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(5-Fluoro-6-methylpyridin-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(6-methylpyrazin-2-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(5-methylpyridin-2-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-(1,5-Dimethyl-1H-pyrazol-3-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(2-Methoxyethyl)-1H-pyrazol-3-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(5,6-Dimethylpyrazin-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(Dimethyl-1,3-oxazol-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(4-methyl-1,3-thiazol-2-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(propan-2-yl)-1H-pyrazol-3-yl]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(3-Fluoropyridin-2-yl)-1H-pyrazol-3-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(3-Fluoropyridin-2-yl)-1H-pyrazol-4-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(4-methyl-1,3-oxazol-2-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(2-methyl-1,3-thiazol-4-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(3-methyl-1,2,4-thiadiazol-5-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(oxan-4-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-[1-(propan-2-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-2-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-3-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-4-yl)-1H-pyrazol-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; N-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-2-yl)piperidin-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(2-methyl-1,3-benzoxazol-5-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[4-(morpholin-4-yl)phenyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[6-(morpholin-4-yl)pyridazin-3-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(morpholin-4-yl)pyrimidin-5-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[5-(morpholin-4-yl)pyrazin-2-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrazin-2-yl)piperidin-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-2-yl)piperidin-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-2-yl)pyrrolidin-3-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(2-methylpyrimidin-4-yl)piperidin-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(6-methylpyrimidin-4-yl)piperidin-4-yl]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(2,6-Dimethylpyrimidin-4-yl)piperidin-4-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-4-yl)azetidin-3-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[4-(oxan-4-yl)phenyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[5-(oxan-4-yl)pyridin-2-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[6-(oxan-4-yl)pyridin-3-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[5-(oxan-4-yl)pyrazin-2-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[6-(morpholin-4-yl)pyridin-3-yl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-{8-oxa-3-azabicyclo[3.2.1]oct-3-yl}pyrimidin-5-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(3,3-Dimethylmorpholin-4-yl)pyrimidin-5-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{2-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]pyrimidin-5-yl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3-methyloxetan-3-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(tetrahydrofuran-3-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3-methyltetrahydrofuran-3-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(oxan-4-yl)furo[2,3-d]pyrimidine-5-carboxamide 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(4-methyloxan-4-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-(2,2-Dimethyloxan-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(1R,5S,6R)-3-oxabicyclo[3.1.0]hex-6-yl]furo[2,3-d]pyrimidine-5-carboxamide; N-(4-Cyclopropyloxan-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3-phenyloxetan-3-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-(4-Ethyloxan-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(1-methyl-1H-pyrazol-4-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(5-methyl-1,2-oxazol-3-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-thiazol-2-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-(5-Methoxypyridin-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-methylphenyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(4-methylphenyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3-methylphenyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-methylpyridin-3-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-(3-Fluorophenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Fluorophenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1-methylpiperidin-4-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-(2,5-Dimethylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-phenylfuro[2,3-d]pyrimidine-5-carboxamide N-(3-Methoxyphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(3-Fluoro-4-methylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(3,4-Difluorophenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(3,5-Difluorophenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2,3-Dihydro-1H-inden-5-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2,3-Dihydro-1H-inden-1-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2,3-Dihydro-1H-inden-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2,3-Dihydro-1H-inden-4-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[4-(propan-2-yl)phenyl]furo[2,3-d]pyrimidine-5-carboxamide; N-(2H-1,3-Benzodioxol-5-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(4-Methoxy-2-methylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(3-Methoxy-2-methylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(5-Fluoro-2-methoxyphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(4-Fluoro-3-methoxyphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Chloro-4-methylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Chloro-5-methylphenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(4-Chloro-2-fluorophenyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(1-methyl-1H-indazol-5-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(1,3-Benzothiazol-5-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(1,3-Benzothiazol-6-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2,2-Dimethyloxan-4-yl)-N-ethyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[3-Methoxy-5-(trifluoromethyl)phenyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(Adamantan-1-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(6-methylpyridin-3-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-(Adamantan-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{5H,6H,7H-Cyclopenta[b]pyridin-7-yl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(Fluoromethyl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(4-Fluorophenyl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-2-yl)cyclopropyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(trifluoromethyl)cyclopropyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(1-methylcyclopropyl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(1-methylcyclobutyl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Cyclopropyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(1R,3R)-3-fluorocyclobutyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(1S,3S)-3-fluorocyclobutyl]furo[2,3-d]pyrimidine-5-carboxamide; N-(3,3-Difluorocyclobutyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(1-Ethylcyclopropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(Hydroxymethyl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(propan-2-yl)cyclopropyl]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(Methoxymethyl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(1-Cyclopropylcyclopropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(1-Cyclobutylcyclopropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[3-(4-Fluorophenyl)cyclobutyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Cyclopentyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Cyclobutyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(5-Fluoropyridin-2-yl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(2-Hydroxyethyl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(3-Fluoro-4-methoxyphenyl)cyclopropyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(oxan-4-yl)cyclopropyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrazin-2-yl)cyclopropyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-2-yl)cyclopropyl]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(Hydroxymethyl)cyclobutyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{Bicyclo[1.1.1]pent-1-yl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{1-[(4-Methoxyphenyl)methyl]cyclopropyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; and pharmaceutically acceptable salts thereof.

77. A compound selected from: N-[(5-Chloropyrazin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Fluoropyrazin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Hydroxypyridin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[5-(Fluoromethoxy)pyridin-2-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Cyclopropyl-N-[(6-methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Fluoropyridin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Cyanophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Methoxypyridin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Methoxypyridin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Methoxypyridin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[5-(Difluoromethoxy)pyridin-2-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Cyanophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-thiazol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-thiazol-5-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-thiazol-4-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-Ethyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Cyano-3-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Cyano-4-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(oxetan-3-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1,2-oxazol-3-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(3-methyloxetan-3-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Fluorooxetan-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(2-methyl-1,3-thiazol-4-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1H-pyrrol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-oxazol-4-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(1-methyl-1H-pyrrol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(Dimethyl-1,3-oxazol-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(1-methyl-1H-imidazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(oxan-4-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Fluoropyridin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Fluoropyridin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(tetrahydrofuran-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-Benzyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[4-(morpholin-4-yl)phenyl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; N-[(2,3-Difluoro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(thiophen-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(thiophen-3-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-(Cyclohexylmethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(4-methylphenyl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(3-methylphenyl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Methoxyphenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(pyridin-3-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(thiophen-3-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(thiophen-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-[(3,4-Dimethylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2,3-Dimethylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Benzyl-N-ethyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Fluorophenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Fluorophenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Fluorophenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Ethyl-1,2-oxazol-5-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Chlorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Cyclopropyl-1H-pyrazol-3-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[4-(Difluoromethoxy)phenyl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Fluoropyridin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Fluoropyridin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Fluoropyrimidin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Fluoropyridin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Chloropyridin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Chloropyrimidin-5-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Bromo-1,2-oxazol-5-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(3-methyl-1,2-oxazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Ethyl-1,2-oxazol-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Cyclopropyl-1,2-oxazol-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(propan-2-yl)-1,2-oxazol-3-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; N-{[5-(4-Fluorophenyl)-1,2-oxazol-3-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[5-(4-Methoxyphenyl)-1,2-oxazol-3-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 3-[({6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidin-5-yl}formylamino)methyl]-1,2-oxazole-5-carboxamide; N-[(4-Fluoro-3-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Fluoro-3-nitrophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Cyano-2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-{[5-(1-methyl-1H-pyrazol-4-yl)-1,2-oxazol-3-yl]methyl}-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(5-methyl-1,3-oxazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(trifluoromethyl)pyridin-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(4-methylpyrimidin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4,6-Dimethylpyrimidin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(5-methylpyrazin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(4-methylpyridin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Fluorophenyl)methyl]-N-(3-methoxypropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Fluoro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Hydroxy-3-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Chloro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Ethyl-N-[(4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[3-(4-Fluorophenyl)-1,2-oxazol-5-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(7-Methoxy-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[3-(2-Fluorophenyl)-1,2-oxazol-5-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3,5-Dimethoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Methoxy-3,5-dimethylpyridin-2-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Fluoro-6-methylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Chloro-3-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2,6-Difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2,4-Difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3,4-Difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Chloro-4-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]-N-(prop-2-en-1-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Ethoxy-3-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(5-Fluoro-2-methyl-1H-indol-3-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Chloro-2-fluoro-3-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Methoxy-2-methylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Fluoro-2-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Chloro-5-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Methoxyphenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Cyano-2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Chloro-2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(3-Ethoxy-4-methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(3,5-Difluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(5-Chloro-2-fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(2,5-Dimethoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(2,3-Dimethoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(3-Chloro-4-fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(3,4-Dimethoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Fluoro-6-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Chloro-2,4-difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Fluoro-3-methylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Chloro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Ethoxy-6-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Fluoro-3-methylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Fluoro-2-methylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Chloro-2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Fluoro-4-methylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(3,4,5-trifluorophenyl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Chloro-2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[3-(5-Fluoro-1H-1,3-benzodiazol-2-yl)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Fluoro-1H-indol-2-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Methoxy-1H-indol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[1-(4-Fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[1-(3-Fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(3-Hydroxypropyl)-N-[(4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Fluorophenyl)methyl]-N-(3-hydroxypropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Fluoro-1H-1,3-benzodiazol-2-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Hydroxyethyl)-N-[(2-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Methoxyethyl)-N-[(2-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Methoxyethyl)-N-[(3-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(5-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(7-Fluoro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[1-(4-Fluorophenyl)pyrrolidin-3-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Ethyl-N-[(2-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[3-Methoxy-4-(propan-2-yloxy)phenyl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[3-(3-Fluorophenyl)-1,2-oxazol-5-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(3-Hydroxy-4-methoxyphenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]-N-(prop-2-yn-1-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]-N-(prop-2-yn-1-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Chloro-2-methoxyphenyl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Ethyl-N-[(4-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Chloro-4,5-difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Fluoro-5-methylphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Chloro-2,6-difluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Fluoro-5-nitrophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Ethyl-N-[(3-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(3,4-Dimethoxyphenyl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide N-[2-(4-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(2-methylpyrimidin-4-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; N-{[5-(Chlorodifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[2-(propan-2-yl)pyrimidin-4-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pyrimidin-5-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-{5H,6H,7H-Cyclopenta[d]pyrimidin-2-ylmethyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-{[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]methyl}-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pyrimidin-4-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pyrimidin-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(6-methylpyrimidin-4-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(4-methylpyrimidin-5-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(6-oxo-1,6-dihydropyrimidin-4-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(2-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(propan-2-yl)-1,3-oxazol-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Methoxy-2-methylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[2-(1H-Imidazol-1-yl)pyridin-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[2-(morpholin-4-yl)pyridin-4-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; N-[(4-Methoxy-2-methylpyrimidin-5-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Chloropyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Fluoro-5-methoxypyridin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(2-methylpyrimidin-5-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[4-(trifluoromethyl)pyrimidin-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Methoxypyrimidin-4-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Cyclopropylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Cyclopropylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-tert-Butyl-1,3-oxazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-oxazol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(2-Cyclopropylpyrimidin-5-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(trifluoromethyl)pyrimidin-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(6-methylpyridin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Methoxypyrimidin-5-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-thiazol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(4-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(5-methylpyrimidin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; N-{[5-(Difluoromethyl)pyrimidin-2-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[4-(Difluoromethyl)pyrimidin-2-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Cyclopropylpyrimidin-5-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Methoxypyridazin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-oxazol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Methoxy-1,3-benzoxazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(1-methyl-1H-imidazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Chloropyrimidin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(6-methylpyridazin-3-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; N-{Imidazo[1,2-a]pyrazin-6-ylmethyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[4-(trifluoromethoxy)phenyl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; N-{[2-Fluoro-4-(trifluoromethoxy)phenyl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(5-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-Fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-Ethylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(Dimethyl-1,3-oxazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Fluoro-1H-1,3-benzodiazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(5-Fluoro-1,3-benzoxazol-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Methoxypyrazin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Cyclopropylpyrazin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(5-Fluoro-1-methyl-1H-1,3-benzodiazol-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[6-(morpholin-4-yl)pyridin-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(2-methyl-2H-1,2,3,4-tetrazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(2-methyl-2H-1,2,3-triazol-4-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(2-methyl-1,3-thiazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(2-methyl-1,3-oxazol-5-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[6-(morpholin-4-yl)pyridazin-3-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(2-methyl-1,3-oxazol-4-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-Fluoro-1,3-benzoxazol-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[3-(pyrrolidin-1-yl)propyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(4-methyl-1,3-oxazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Ethyl-N-[(6-methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(4-Fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(morpholin-4-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(1H-pyrrol-1-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(Furan-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(1H-Imidazol-1-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-phenylethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(3-Chlorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(4-Methoxyphenyl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(5-Fluoro-1H-indol-3-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[3-(1H-Imidazol-1-yl)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(thiophen-2-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(4-methylphenyl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(2-methylphenyl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Cyclohexylethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-(2-phenylethyl)furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]-N-[2-(pyridin-2-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[3-(morpholin-4-yl)propyl]furo[2,3-d]pyrimidine-5-carboxamide; N-{[1-(Ethoxymethyl)cyclopropyl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[1-(3-Fluorophenyl)cyclopentyl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[1-(2-Fluorophenyl)cyclopentyl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Ethyl-N-[(3-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Cyclopropyl-N-[(2-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(Cyclopropylmethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(2,2-Difluorocyclopropyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; and pharmaceutically acceptable salts thereof.

78. A compound selected from: N-[1-(5-Fluoropyridin-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(4-Fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyridin-2-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(pyridin-2-yl)propan-2-yl]furo[2,3-d]pyrimidine-5-carboxamide; N,6-Dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N,N,6-Trimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Methoxyethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Fluoroethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Hydroxyethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(4-Hydroxy-2-methylbutan-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(propan-2-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-methylpropyl)furo[2,3-d]pyrimidine-5-carboxamide; N-tert-Butyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-pentylfuro[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(3-methylbutyl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(pentan-3-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(3-methylbutan-2-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(2-Ethoxyethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[2-(propan-2-yloxy)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1-phenylethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(prop-2-yn-1-yl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-propylfuro[2,3-d]pyrimidine-5-carboxamide; N-Butyl-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(2-phenylpropan-2-yl)furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(5-Fluoropyrimidin-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(3-Fluoro-4-methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1S)-1-(2-Fluoro-4-methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1R)-1-(2-Fluoro-4-methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrazin-2-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-4-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[1-(5-methyl-1,2-oxazol-3-yl)ethyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N'-(5-Fluoropyrimidin-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbohydrazide; N-(1-Fluoro-2-methylpropan-2-yl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(1-Cyclopropylethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-(1-Cyclopropylpropyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(1-methylcyclopropyl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(1-methylcyclopropyl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(4-Methoxyphenyl)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(3-Methoxyphenyl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1S)-1-(3-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1R)-1-(3-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1S)-1-(4-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1S)-1-(2-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1R)-1-(4-Fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1S)-1-(4-Fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(2,5-Difluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(3-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-Hydroxy-3-(4-methoxyphenoxy)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(4-Methoxy-3-methylphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(3-Fluoro-4-methoxyphenyl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(4-Fluorophenyl)-2-hydroxyethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1R)-1-(2,4-Difluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1S)-1-(5-Fluoropyrimidin-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-(2-methylbut-3-yn-2-yl)-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(4-Fluorophenyl)propan-2-yl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(3,5-Difluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(4-Fluorophenyl)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(3,5-Dimethoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1R)-1-(3,4-Dimethoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(2-Methoxyphenoxy)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(2-Methoxyphenoxy)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(2-Fluorophenoxy)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1R)-1-(4-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(2-Methoxyphenyl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-(4-Fluorophenoxy)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{2-[(4-Methoxyphenyl)thio]ethyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(4-Ethoxy-3-fluorophenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(3,4-Dimethoxyphenyl)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(4-Methoxy-3,5-dimethylphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[2-Hydroxy-3-(3-methoxyphenoxy)propyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Ethyl-N-[2-(4-methoxyphenoxy)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[3-(4-Methoxyphenoxy)propyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(2-Methoxyphenyl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(1R)-1-(5-Fluoropyrimidin-2-yl)ethyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[1-(4-Fluorophenyl)ethyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-Methoxy-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(pyrimidin-5-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(1,3-oxazol-2-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[1-(1,2-oxazol-3-yl)ethyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(3,3,3-trifluoropropyl)furo[2,3-d]pyrimidine-5-carboxamide; N-(2-{[Dimethyl(oxo)-λ 6 -sulfanylidene]amino}ethyl)-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; and pharmaceutically acceptable salts thereof.

79. A compound selected from: 3-Fluoro-5-(1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)pyridine-2-carbonitrile; 5-[4-(5-Fluoro-6-methoxypyridin-3-yl)-1,2,3,6-tetrahydropyridin-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Fluoro-6-methoxypyridin-3-yl)piperidin-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Fluoropyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(2-Fluoropyridin-4-yl)pyrrolidin-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; N-(2-Fluoroethyl)-2-(1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidin-4-yl)pyrimidin-4-amine; 5-[3-(5-Fluoropyridin-2-yl)azetidin-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 4-(1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}azetidin-3-yl)benzonitrile; 6-Methyl-N-(1-methylcyclopropyl)-5-[3-(1,3-thiazol-2-yl)azetidin-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-{3-[3-Fluoro-5-(trifluoromethyl)pyridin-2-yl]azetidin-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(4-Fluorophenyl)azetidin-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(4-Fluorophenyl)pyrrolidin-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Fluorophenyl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-Fluoro-4-(pyridin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 4-(4-Fluorophenyl)-1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidin-4-ol; 3-(4-Fluorophenyl)-1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}pyrrolidin-3-ol; 6-Methyl-N-(1-methylcyclopropyl)-5-[3-(pyridin-2-yl)pyrrolidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[3-(pyridin-3-yl)pyrrolidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[3-(pyridin-4-yl)pyrrolidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[3-(4-Fluorophenyl)-3-methylpyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 3-(4-Fluorophenyl)-1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}azetidin-3-ol; 5-(3-Methoxy-3-phenylazetidine-1-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-(morpholine-4-carbonyl)furo[2,3-d]pyrimidin-4-amine; 5-{3-[4-(Difluoromethyl)phenyl]pyrrolidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-(3-Fluoro-3-phenylpyrrolidine-1-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-Fluoro-3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}pyrrolidin-3-ol; N,N-Dimethyl-1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidin-4-amine; 5-[2-(Furan-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-4-phenylpiperidine-4-carbonitrile; 5-[3-(4-Fluorophenyl)azepane-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Fluorophenyl)azepane-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(pyridin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(pyrimidin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-(3-Fluoro-3-phenylazetidine-1-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-[3-(1-methyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-[3-(1-methyl-1H-pyrazol-4-yl)pyrrolidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(3-Chloro-5-fluoropyridin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(5-Chloropyrimidin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(5-Fluoropyridin-3-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Chloropyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Methoxypyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 4-(1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}pyrrolidin-3-yl)phenol; 1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-3-phenylpyrrolidin-3-ol; 5-[3-(5-Chloropyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Chloro-5-fluoropyrimidin-4-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(6-Fluoropyridin-2-yl)azetidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 2-(1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidin-4-yl)pyrimidin-5-ol; 5-[4-(5-Fluoropyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(5-methylpyrimidin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[3-(3-Methoxyphenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(6-Methoxypyridazin-3-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Methoxypyrazin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Methoxypyridin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(6-Methoxypyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Cyclopropylpyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(4-propylpyrimidin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Methoxypyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(6-Bromopyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(5-Bromopyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 4-(1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidin-4-yl)benzamide; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(6-methylpyridin-3-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(4-methylphenyl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 4-(1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidin-4-yl)benzonitrile; 5-[3-(3-Fluorophenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(4-methylpyrimidin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[4-(4,5-Dimethylpyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(5-methylpyrazin-2-yl)piperidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Methoxypyrimidin-5-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[3-(3-methylphenyl)pyrrolidine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{3-[3-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl}furo[2,3-d]pyrimidin-4-amine; 5-[3-(3,5-Dimethylphenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(3-Fluorophenoxy)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(4-Fluorophenoxy)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{3-[(4-Fluorophenyl)methyl]pyrrolidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(6-Methoxypyridin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Methoxy-4-methylpyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{4-[5-(trifluoromethyl)pyrimidin-2-yl]piperidine-1-carbonyl}furo[2,3-d]pyrimidin-4-amine; 4-(6-Fluoropyridin-2-yl)-1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidine-4-carbonitrile; Methyl 2-(1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}azetidin-3-yl)pyrimidine-5-carboxylate; 5-{3-[(2-Fluorophenyl)methoxy]azetidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{3-[(3-Fluorophenyl)methoxy]azetidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[2-(3-Fluorophenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(4-Fluorophenoxy)azetidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(3-Methoxyphenyl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4,6-Dimethoxypyrimidin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(3-Fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(6-Fluoro-5-methoxypyridin-2-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-Fluoro-2-(1-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperidin-4-yl)-N-(propan-2-yl)pyrimidin-4-amine; 5-[3-(6-Fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[2-(4-Fluorophenyl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[2-(3-Methoxyphenyl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[2-(3-Methoxyphenyl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Fluorophenoxy)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Fluorophenoxy)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[2-(3-Fluorophenyl)azepane-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(2-Methoxyphenoxy)azetidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(3-Methoxyphenoxy)azetidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-[5-(Fluoromethoxy)pyrimidin-2-yl]piperidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{3-[4-(Fluoromethoxy)phenyl]pyrrolidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(5-Fluoropyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 2-(1-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-4-carbonitrile; 6-Methyl-5-[4-(1-methyl-1H-pyrazol-3-yl)piperidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-[4-(1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-[4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(1,5-Dimethyl-1H-pyrazol-3-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2,4-Dimethyl-1H-imidazol-5-yl)piperidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{4-[1-(propan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carbonyl}furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-[4-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Fluoro-1,3-thiazol-5-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Methoxypyrazin-2-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Methoxypyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{3-[4-(2-Fluoroethoxy)phenyl]pyrrolidine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(6-Fluoro-4-methylpyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(5-Fluoro-6-methylpyridin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(5-Fluoro-4-methylpyrimidin-2-yl)pyrrolidine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{3-[6-(trifluoromethyl)pyridin-2-yl]pyrrolidine-1-carbonyl}furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{3-[4-(trifluoromethyl)pyridin-2-yl]pyrrolidine-1-carbonyl}furo[2,3-d]pyrimidin-4-amine.

80. A compound selected from 6-Methyl-N-(1-methylcyclopropyl)-5-(4-phenylpiperazine-1-carbonyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(1,3-thiazol-2-yl)piperazine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(pyridin-2-yl)piperazine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Fluoropyridin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(5-methylpyridin-2-yl)piperazine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 4-(4-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperazin-1-yl)benzonitrile; 5-[4-(4-Fluorophenyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 1-(3,4-Difluorophenyl)-4-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}piperazin-2-one; 6-Methyl-N-(1-methylcyclopropyl)-5-[2-(pyridin-2-yl)morpholine-4-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[2-(pyridin-4-yl)morpholine-4-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[2-(pyridin-3-yl)morpholine-4-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-[2-(1-methyl-1H-pyrazol-4-yl)morpholine-4-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[2-(4-Fluorophenyl)morpholine-4-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[2-(4-Methoxyphenyl)morpholine-4-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(3-Fluoropyridin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Fluoropyrimidin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(6-Fluoropyridin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Fluorophenyl)-1,4-diazepane-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-(4-phenyl-1,4-diazepane-1-carbonyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(pyridin-2-yl)-1,4-diazepane-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Methoxyphenyl)-1,4-diazepane-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Fluoropyridin-4-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(6-Fluoropyrimidin-4-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Fluoropyrimidin-4-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Methoxyphenyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-(4-methyl-1,4-diazepane-1-carbonyl)-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 1-(4-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidin-5-carbonyl}piperazin-1-yl)ethan-1-one; 1-(4-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidin-5-carbonyl}-1,4-diazepan-1-yl)ethan-1-one; 5-(4-tert-Butylpiperazine-1-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Methoxyethyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(6-Fluoropyridin-3-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(tetrachloropyridin-2-yl)piperazine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Methoxypyrimidin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Fluoropyrimidin-2-yl)-2-methylpiperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(5-Fluoropyrimidin-2-yl)-3-methylpiperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Fluoro-4-methylsulfonylphenyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Chloro-5-fluoropyrimidin-4-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(pyrimidin-5-yl)piperazine-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-{4-[(4-Fluorophenyl)methyl]piperazine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Methoxypyrimidin-2-yl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Fluoro-2-methylsulfonylphenyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Fluoro-4-methylsulfonylphenyl)-2-methylpiperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Fluoro-4-nitrophenyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2,4-Difluorophenyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(4-Fluorophenyl)piperazine-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-[(3-Fluorophenyl)methyl]piperazine-1-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; and its pharmaceutically acceptable salts.

81. A compound selected from: 5-{2-Cyclopropyl-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-Methoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-Fluoro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-Chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-[(2-Fluoroethyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 3-(Fluoromethyl)-7-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-3H,4H,5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-one; 5-[4-(Fluoromethoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-[(3R)-3-Fluoropyrrolidin-1-yl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 7-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-5,6,7,8-tetrahydro-1,7-naphthyridin-4-ol; 5-[4-(2-Fluoroethoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 7-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-2-(propan-2-yl)-3H,4H,5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-one; 5-{4-Ethyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 7-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-4-carbonitrile; 5-{4-Ethoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-Methoxy-2-(propan-2-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[2-(trifluoromethyl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[2-(4-Fluorophenyl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-{2-methyl-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbonyl}-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-(5-Methoxy-1,2,3,4-tetrahydro-2,6-naphthyridin-2-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{2-Tert-butyl-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{2-Methoxy-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 2-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile; 6-Methyl-N-(1-methylcyclopropyl)-5-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carbonyl}furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-(7-methyl-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carbonyl)-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-(2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-(5-Chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-(2-Chloro-5,6,7,8-tetrahydro-1,7-naphthyridine-7-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-(2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{3-Chloro-5H,6H,7H,8H-pyrido[4,3-c]pyridazine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{2-Chloro-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[2-(oxan-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[2-(propan-2-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-{2-Cyclopropyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{2-Fluoro-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{2-Fluoro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 2-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-5-ol; 2-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-ol; 2-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-8-ol; 2-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-7-ol; 6-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-5,6,7,8-tetrahydro-1,6-naphthyridin-3-ol; 6-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,5,6,7,8-hexahydro-2,6-naphthyridin-1-one; 1-Methyl-2-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-7-ol; 5-[4-(Cyclopropylamino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-[(Cyclopropylmethyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 2-(4-Fluorophenyl)-7-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-3H,4H,5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-one; 2-(Methoxymethyl)-7-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-3H,4H,5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-one; 6-Methyl-5-{4-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(propan-2-yloxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}furo[2,3-d]pyrimidin-4-amine; 7-Methoxy-1-methyl-2-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2,3,4-tetrahydroisoquinolin-6-ol; 5-(7-Fluoro-1,2,3,4-tetrahydroisoquinolin-2-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-Methoxy-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(propan-2-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-(5,6,7,8-tetrahydro-1,7-naphthyridine-7-carbonyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)furo[2,3-d]pyrimidin-4-amine; 5-(6-Methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-(2-Methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-(1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)furo[2,3-d]pyrimidin-4-amine; 5-(6-Chloro-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-Methoxy-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-(1,2,3,4-tetrahydro-2,6-naphthyridine-2-carbonyl)furo[2,3-d]pyrimidin-4-amine; 2-Cyclopropyl-6-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-3H,4H,5H,6H,7H-pyrrolo[3,4-d]pyrimidin-4-one; 6-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-2-(propan-2-yl)-3H,4H,5H,6H,7H-pyrrolo[3,4-d]pyrimidin-4-one; 5-{2-Cyclopropyl-4-methoxy-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-Methoxy-2-(propan-2-yl)-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{2-Chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{2-Methoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-Methoxy-2-methyl-5H,6H,7H-pyrrolo[3,4-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-Methoxy-2-methyl-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{3-Bromo-5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[3-(oxan-4-yl)-5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{4-[(propan-2-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}furo[2,3-d]pyrimidin-4-amine; 5-[4-(Fluoromethoxy)-5,6,7,8-tetrahydro-1,7-naphthyridine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[5-(Fluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[6-(Fluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[8-(Fluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[7-(Fluoromethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3-(Fluoromethoxy)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[5-(Fluoromethoxy)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[7-(Fluoromethoxy)-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(Fluoromethoxy)-2-(methoxymethyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-[(3S)-3-Fluoropyrrolidin-1-yl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(morpholin-4-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[4-(3-Fluoroazetidin-1-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{2-Chloro-4-[(propan-2-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-[Cyclopropyl(methyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(Dimethylamino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-[4-(methylamino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-{4-[methyl(oxan-4-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{4-[(oxan-4-yl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}furo[2,3-d]pyrimidin-4-amine; 5-(4-{[1-(methoxymethyl)cyclopropyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{4-[(1-methylcyclopropyl)amino]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(oxan-4-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(prop-1-en-2-yl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-{4-Cyclopropyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{4-propoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(2-methylpropoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[4-(Cyclopropylmethoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(2-Methoxyethoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-Cyclobutoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-Cyclopropoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{2-Cyclopropyl-4-methoxy-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; and its pharmaceutically acceptable salts.

82. A compound selected from: 6-Methyl-N-(1-methylcyclopropyl)-5-[4-(propan-2-yl)-1H-pyrazole-1-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-(4-phenyl-1H-pyrazole-1-carbonyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Methoxyphenyl)-1H-pyrazole-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(4-Fluorophenyl)-1H-pyrazole-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-(4-methyl-1H-pyrazole-1-carbonyl)-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-(trimethyl-1H-pyrazole-1-carbonyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-(1H-pyrazole-1-carbonyl)furo[2,3-d]pyrimidin-4-amine; 5-(3,5-Dimethyl-1H-pyrazole-1-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[4-(3-Methoxyphenyl)-1H-pyrazole-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[3,5-Dimethyl-4-(morpholin-4-ylmethyl)-1H-pyrazole-1-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; and its pharmaceutically acceptable salts.

83. A compound selected from: 5-{3-Cyclopropyl-1-ethyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[(8aS)-Octahydropyrrolo[1,2-a]piperazine-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[2-(trifluoromethyl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-{3-Bromo-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-{2-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-5-carbonyl}-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-{2-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-7-carbonyl}-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidin-5-carbonyl}-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-2-carbonitrile; 6-Methyl-N-(1-methylcyclopropyl)-5-[1-(oxan-4-yl)-3-(trifluoromethyl)-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-Methyl-5-[3-methyl-1-(oxan-4-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl]-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{3-Bromo-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-5-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-{4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-5-carbonyl}furo[2,3-d]pyrimidin-4-amine; 5-{3-Cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{1-Chloro-3-cyclopropyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{3-Cyclopropyl-1-iodo-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{1,3-dimethyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; and its pharmaceutically acceptable salts.

84. A compound selected from: 6-methyl-N-(1-methylcyclopropyl)-5-[(1R,5S,6S)-6-(pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl]furo[2,3-d]pyrimidin-4-amine; 6-methyl-N-(1-methylcyclopropyl)-5-[(1R,5S,6S)-6-[5-(trifluoromethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[(3aS,6aS)-hexahydro-2H-furo[3,2-b]pyrrole-4-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[(1R,5S)-3-azabicyclo[3.1.0]hexane-3-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[(3aR,6aS)-octahydrocyclopenta[c]pyrrole-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-methyl-N-(1-methylcyclopropyl)-5-[(1R,5S,6S)-6-phenyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-[(1R,5S,6S)-6-(2-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[(4aS,8aR)-decahydroisoquinoline-2-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-methyl-N-(1-methylcyclopropyl)-5-{4H,5H,6H,7H-thieno[3,2-c]pyridine-5-carbonyl}furo[2,3-d]pyrimidin-4-amine; 5-{6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-[(1R,5S,6S)-6-(4-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 1'-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2-dihydrospiro[indole-3,3'-piperidine]-2-one; 1-Methyl-1'-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2-dihydrospiro[indole-3,3'-piperidine]-2-one; 1'-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-4'-carbonitrile; 5-({2,3-Dihydrospiro[indene-1,2'-morpholine]-4'-yl}carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-({3H-spiro[2-benzofuran-1,3'-piperidine]-1'-yl}carbonyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-({3H-spiro[2-benzofuran-1,3'-pyrrolidine]-1'-yl}carbonyl)furo[2,3-d]pyrimidin-4-amine; 6-Fluoro-1'-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2-dihydrospiro[3,1-benzoxazine-4,4'-piperidine]-2-one; 6-Methyl-N-(1-methylcyclopropyl)-5-({spiro[indene-1,4'-piperidine]-1'-yl}carbonyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-({3H-spiro[2-benzothiophene-1,4'-piperidine]-1'-yl}carbonyl)furo[2,3-d]pyrimidin-4-amine; 1'-{6-Methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-2-one; 5-{10-Azatricyclo[6.3.1.02,7]dodeca-2,4,6-triene-10-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 6-Methyl-N-(1-methylcyclopropyl)-5-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl]furo[2,3-d]pyrimidin-4-amine; 5-(10-Methoxy-3,4,5,6-tetrahydro-2H-1,5-benzoxazocin-5-carbonyl)-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; 5-{4-Methoxy-5H,6H,7H,8H,9H-pyrimido[4,5-d]azepine-7-carbonyl}-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine; and pharmaceutically acceptable salts thereof.

85. A compound selected from 6-Methyl-N-{[5-(1-methyl-1H-pyrazol-4-yl)-1,2-oxazol-3-yl]methyl}-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(5-methyl-1,3-oxazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-[(5-methylpyrazin-2-yl)methyl]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-N-[(5-methyl-1,3-thiazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-{[5-(propan-2-yl)-1,3-oxazol-2-yl]methyl}furo[2,3-d]pyrimidine-5-carboxamide; and its pharmaceutically acceptable salts.

86. A compound selected from 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1,3-thiazol-4-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; 6-Methyl-4-[(1-methylcyclopropyl)amino]-N-(1H-pyrrol-2-ylmethyl)furo[2,3-d]pyrimidine-5-carboxamide; N-[(2-fluorophenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(5-cyclopropyl-1H-pyrazol-3-yl)methyl]-N,6-dimethyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-chloropyridin-3-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; and its pharmaceutically acceptable salts.

87. A compound selected from N-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[1-(4-fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-{[1-(3-fluorophenyl)-1H-pyrazol-4-yl]methyl}-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; N-[(6-methoxy-2-methylpyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide; and its pharmaceutically acceptable salts.

88. A compound which is 6-methyl-N-[(5-methyl-1,3-oxazol-2-yl)methyl]-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt thereof.

89. A compound which is N-[(6-methoxypyrimidin-4-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt thereof.

90. A pharmaceutical composition comprising the compound according to any one of claims 1-89 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

91. Use of the compound according to any one of claims 1-89 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 90 in the manufacture of a medicament for treating a neurological disorder associated with the modulation of PDE1B in an individual.

92. Use according to claim 91, wherein the neurological disorder is a central nervous system (CNS) disorder.

93. Use according to claim 92, wherein the CNS disorder is selected from mental disorders and psychiatric conditions, cognitive disorders, movement disorders, and neurodegenerative disorders.

94. Use according to claim 93, wherein the CNS disorder is a mental disorder and psychiatric condition, which is selected from schizophrenia spectrum disorders, psychotic disorders, schizophrenia, and cognitive impairment associated with schizophrenia (CIAS).

95. Use according to claim 93, wherein the CNS disorder is a cognitive disorder, which is selected from age-related cognitive decline and trauma-dependent loss of function.

96. Use according to claim 95, wherein the cognitive disorder is trauma-dependent loss of function.

97. Use according to claim 96, wherein the trauma-dependent loss of function is stroke.

98. Use according to claim 97, wherein the stroke is ischemic stroke or hemorrhagic stroke.

99. Use according to claim 97, wherein the individual is a patient with acute or subacute stroke.

100. Use according to claim 97, wherein the individual is a post-stroke patient.

101. Use according to claim 97, wherein the individual is undergoing post-stroke rehabilitation.

102. Use according to claim 95, wherein the cognitive disorder is age-related cognitive decline.

103. Use according to claim 102, wherein the age-related cognitive decline is age-related memory impairment (AAMI) or mild cognitive impairment (MCI).

104. Use according to claim 93, wherein the CNS disorder is a movement disorder, which is selected from basal ganglia disorders, Parkinson's disease, Huntington's disease, attention deficit hyperactivity disorder, hypokinesia, and movement disordering conditions.

105. Use according to claim 104, wherein the movement disorder is Parkinson's disease.

106. Use according to claim 93, wherein the CNS disorder is a neurodegenerative disorder, which is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and spinal cord injury.

107. The use according to claim 106, wherein the neurodegenerative disorder is Parkinson's disease.

108. The use according to claim 107, wherein the neurodegenerative disorder includes motor deficits associated with Parkinson's disease.

109. The use according to claim 107, wherein the neurodegenerative disorder includes cognitive deficits associated with Parkinson's disease.

110. The use according to claim 107, wherein the neurodegenerative disorder is Parkinson's disease with mild cognitive impairment (PD-MCI).

111. Use of a compound according to any one of claims 1-89 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 90 in the manufacture of a medicament for enhancing training in a method for treating a neurological disorder associated with the modulation of PDE1B, wherein the method comprises: (a) providing training to an animal in need of treatment for a neurological deficit associated with the neurological disorder, the neurological deficit of the animal being associated with the neurological disorder, under conditions sufficient to produce an improvement in the manifestation of the neurological function of the animal; (b) administering the compound or the pharmaceutical composition to the animal in combination 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 improvement in manifestation relative to the improvement in manifestation produced by training alone.

112. The use according to claim 111, wherein the enhanced training is enhanced cognitive training and the neurological deficit is a cognitive deficit.

113. The use according to claim 111, wherein the enhanced training is enhanced motor training and the neurological deficit is a motor deficit.

114. The use according to claim 111, wherein the neurological disorder is stroke or traumatic brain injury (TBI).

115. The use according to claim 111, wherein the neurological disorder is stroke and enhanced training is provided during post-stroke rehabilitation.

116. Use of a compound according to any one of claims 1-89 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 90 in the manufacture of a medicament for treating a peripheral disorder associated with the modulation of PDE1B.

117. The use according to claim 116, wherein the peripheral disorder is a cardiovascular disorder, a renal disorder, a hematological disorder, a gastrointestinal disorder, a hepatic disorder, cancer, a fertility disorder or a metabolic disorder.

118. The use according to claim 116, wherein the peripheral disorder is a cardiovascular disorder selected from angina pectoris, coronary artery disease, hypertension, congestive heart failure, myocardial infarction, ischemic diseases of the heart, atrial and ventricular arrhythmias, hypertensive vascular diseases, peripheral vascular diseases, pulmonary hypertension and atherosclerosis.

119. The use according to claim 116, wherein the peripheral disorder is a renal disorder selected from renal artery stenosis, pyelonephritis, glomerulonephritis, renal tumors, polycystic kidney disease, kidney damage, damage caused by renal radiation, and autosomal dominant polycystic kidney disease (ADPKD).

120. The use according to claim 116, wherein the peripheral disorder is a hematological disorder selected from anemia, myeloproliferative disorders, hemorrhagic disorders, leukopenia, eosinophilic disorders, leukemia, lymphoma, plasma cell dyscrasia, and splenic disorders.

121. The use according to claim 116, wherein the peripheral disorder is a gastrointestinal disorder selected from disorders of the esophagus, stomach, duodenum, pancreas, and intestine.

122. The use according to claim 116, wherein the peripheral disorder is cancer selected from tumors, dysplasia, and hyperplasia.

123. The use according to claim 122, wherein the cancer is selected from gastric cancer, ileal cancer, ovarian cancer, breast cancer, and renal cancer.

124. Use of a compound according to any one of claims 1 - 89 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 90 for the manufacture of a medicament for the treatment of a disorder involving an abnormal or dysregulated signal transduction pathway mediated by PDE1B.

125. The use according to claim 124, wherein the PDE1B-mediated signal transduction pathway comprises nitric oxide, natriuretic peptides, dopamine, norepinephrine, neurotensin, cholecystokinin (CCK), vasoactive intestinal peptide (VIP), serotonin, glutamate, GABA, acetylcholine, adenosine, cannabinoids, natriuretic peptides, or endorphins.

126. Use of a compound according to any one of claims 1 - 89 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 90 for the manufacture of a medicament for the treatment of a disorder involving an abnormal or dysregulated dopaminergic signal transduction pathway mediated by PDE1B.

127. The use according to claim 126, wherein the abnormal or dysregulated dopaminergic signal transduction pathway is mediated by dopamine receptor D1.

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