Compounds and pharmaceutical compositions derived therefrom for the treatment of diseases

Description

FIELD OF THE INVENTION

[0001] The present invention relates to compounds, methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, and compounds for use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases by administering the compounds of the invention. In particular, the compounds of the invention may inhibit Salt-Inducible Kinases ("SIK" kinases).BACKGROUND OF THE INVENTION

[0002] Protein kinases belong to a large family of structurally related enzymes which are responsible for the control of a wide variety of cellular signal transduction processes. In particular, they have been shown to be key regulators in cellular functions including for example proliferation, metabolism, and apoptosis. Consequently, defective control of protein phosphorylation which leads to uncontrolled signaling is involved in a number of diseases, including for example, inflammation, allergies, cancer, autoimmune diseases, CNS disorders, and angiogenesis.

[0003] In healthy individuals inflammation is self-limiting, and resolution is controlled by the release of anti-inflammatory mediators and cytokines, such as interleukin-10 (IL-10), produced by "suppressive" or "regulatory" cells, which are produced as part of a negative feedback loop.

[0004] Indeed, in the normal process of inflammation in the body, an initial pro-inflammatory response is followed by a pro-resolution response which turns the inflammation off after the insult has been resolved, leading to the reduction of pro-inflammatory cytokines such as TNFα and IL-12, coupled with increased levels of anti-inflammatory cytokines such as IL-10 and TGF-β, resulting in the generation of a so-called tolerogenic environment.

[0005] Adenosine Monophosphate-activated Protein Kinases (AMPK) belong to the protein kinase family, which comprises Salt-Inducible Kinases (SIKs), a family of serine / threonine kinases widely expressed in the body, and involved in particular in cellular energy homeostasis. Three SIK isoforms have been identified, named SIK1 (also referred as SNFI-Like Kinase (SNF1LK) or Myocardial Snfl-like Kinase (MSK)), SIK2 (SNF1LK2 or KIAA0781) and SIK3 (KIAA0999) (Katoh et al. 2004).

[0006] The SIKs play a number of roles in different cell types. They have been found to phosphorylate a number of substrates including CREB-responsive transcriptional co-activator (CRTC) proteins and Histone de-acetylase (HDAC) proteins, thereby regulating the transcription of a number of different genes. One of the roles of CRTC signalling relates to control the phenotype of macrophages, in particular polarisation of macrophages through phosphorylation of CRTC3 as measured by decreased proinflammatory cytokine IL-12 secretion and concomitant increased pro-resolution cytokine IL-10 secretion (Clark et al. 2012; Ozanne et al. 2015).

[0007] SIK1 has recently been shown to be involved in skeletal muscle sensitivity in obese mice, and may be an interesting target to prevent type II diabetes (Nixon et al. 2016), and diabetic nephropathy (Yu et al. 2013).

[0008] The regulation of ALK5 by SIK1 (Yu et al. 2013) and the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis (Liu et al. 2013) suggest a role for SIK proteins in fibrotic diseases.

[0009] SIK2 and SIK3 have recently been identified to play a role in inflammation through the secretion of high levels of anti-inflammatory cytokines, in particular Interleukin-10 (IL-10) and very low levels of pro-inflammatory cytokines such as TNFα (Darling et al. 2017).

[0010] A role for SIK2 in T helper (Th)1 cell differentiation has recently been described through the regulation of IFNγ and IL-12 signaling, suggesting SIK2 may be an interesting target for inflammatory diseases (Yao et al. 2013).

[0011] Recently, it has also been shown that like PTH, small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4 / 5 and CRTC2. Treatment with the small molecule SIK inhibitor YKL-05-099 increased bone formation and bone mass in mice (Wein et al. 2016), confirming the relevance of SIK inhibition in the treatment of bone turnover diseases.

[0012] Furthermore, it was shown that inhibition of SIK2 after oxygen-glucose deprivation enhances neuron survival (Sasaki et al. 2011) or promotes melanogenesis in melanoma cells (Kumagai et al. 2011). In this context, since therapeutic strategies are needed to modulate the stress cellular response, such as during ischaemia and post reperfusion of tissue, in the chronic phase of cardiac remodelling, in diabetes and neurodegenerative conditions, the rapid activation or degradation of the SIK proteins, following multiple kinds of stresses, makes them interesting targets in inflammatory, cardiac or metabolic diseases and neurodegenerative disorders. SIK inhibition might also have application in cosmetology or pigmentation-related diseases to induce melanogenesis.

[0013] The regulation of ALK5 by SIK1 (Yu et al. 2013) and the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis (Liu et al. 2013) suggest a role for SIK proteins in fibrotic diseases.

[0014] Besides the pivotal function in cellular energy homeostasis, the SIK proteins have also been involved in the regulation of the cell cycle. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers (Ashour Ahmed et al. 2010), moreover, expression of SIK3 was elevated in ovarian cancers, particularly in the serous subtype and at later stages (Charoenfuprasert et al. 2011). Therefore SIK inhibition may be useful in the treatment of cancer.

[0015] CN106496222 discloses an imidazo[1,2-a]pyridine compound, and a preparation method and applications thereof. The imidazo[1,2-a]pyridine compound can inhibit the activity of NEK2 kinases. CN106496222 also discloses effects of the imidazo[1,2-a]pyridine compound in inhibition of proliferation of tumor cells and inhibition of growth of the tumor cells in animal bodies through inducing cell cycle stopping and apoptosis.

[0016] Xi et al. (Composites: part A: applied science and manufacturing, vol. 126, 12 December 2016, pages 1083-1106) discloses imidazo[1,2a]pyridine derivatives useful for treating cancers.

[0017] Sekioka et al. (Bioorganic & Medicinal Chemistry, Elsevier, NL, vol 26, no 2, 14 December 2017, pages 435-442) discloses imidazo[1,2a]pyridine derivatives useful for treating CNS diseases, i.e. Alzheimer's disease.

[0018] He et al. (ACS Medicinal Chemistry Letters, vol 8, no 10, 4 October 2017, pages 1048-1053) discloses imidazo[1,2a]pyridine derivatives useful for the treatment of inflammatory diseases.

[0019] Despite great advances over the past two decades in the treatments of patients affected by autoimmune disorders, based on antibodies targeting pro-inflammatory cytokines such as anti-TNFα, a significant proportion of patients do not respond to these therapies or experience serious adverse events such as opportunistic infections. Therefore a large unmet medical need still exists for the treatment of these diseases, and new agents for the prophylaxis and / or treatment of the above mentioned diseases are required.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 refers to Example 4.2 and shows the evolution of the clinical score in the CIA mouse model for the vehicle (filled diamonds), Enbrel ®< (filled squares), Cpd 88 dosed at 10 mg / kg b.i.d. (crosses), Cpd 88 dosed at 30 mg / kg b.i.d. (triangles) and Cpd 88 dosed at 60 mg / kg b.i.d. (asterisks)SUMMARY OF THE INVENTION

[0021] The present invention is based on the identification of novel compounds, and their use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases. In particular, the compounds of the invention may be SIK inhibitors, and more particularly SIK1, SIK2 and / or SIK3 inhibitors. The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and compounds for use in methods for the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases by administering the compounds of the invention.

[0022] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I: wherein, X is N or CH; Y is N or CR 2b< ; Z is -NHR 3a< , N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R 15< groups, or -NR 3b< -, wherein the N atom and R 2a< together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds; R 1< is C 1-8 alkyl optionally substituted with one or more independently selected R 4< groups, phenyl, C 3-8 monocyclic or bridged polycyclic cycloalkyl optionally substituted with one or more independently selected R 5< groups, 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl optionally substituted with one or more independently selected -CN or -C(=O)-C 1-4 alkoxy, or 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S; R 2a< and R 2b< are independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy optionally substituted with one or more independently selected halo or C 1-4 alkoxy, and -NR 6a< R 6b< ; R 3a< is C 1-6 alkyl optionally substituted with one or more independently selected halo or -CN, or C 3-7 cycloalkyl optionally substituted with one or more independently selected halo or -OH; R 3b< is selected from H, C 3-7 cycloalkyl and C 1-6 alkyl optionally substituted with one or more independently selected halo or -CN; each R 4< is independently selected from halo, -OH, -CN, phenyl, -C(=O)OH, -O-C(=O)-C 1-4 alkyl, -O-S(=O) 2 -C 1-4 alkyl, C 1-4 alkoxy optionally substituted with one or more independently selected ∘ -OH, ∘ C 1-4 alkoxy, ∘ 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl, or ∘ -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl, C 3-7 cycloalkyl optionally substituted with one or more independently selected halo, -C(=O)-C 1-4 alkoxy, -NR 8a< R 8b< , or C 1-4 alkyl optionally substituted with one or more independently selected -NR 9a< R 9b< , 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl, 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl or C 3-7 cycloalkyl, 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R 10< , -NR 11a< R 11b< , -C(=O)-C 1-4 alkoxy, and -C(=O)-NR 12a< R 12b< ; each R 5< is selected from halo, -CN, and -NR 13a< R 13b< ; each R 6a< and R 6b< is independently selected from H and C 1-4 alkyl; each R 10< is selected from -OH, phenyl, =NH, halo, oxo, -CN, -C(=O)H, -C(=O)NH 2 , -C(=O)OH, -NR 14a< R 14b< , C 1-4 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, -C(=O)-C 1-4 alkoxy, or C 1-4 alkoxy, C 3-7 cycloalkyl, 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, -C(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl, and -C(=O)-C 1-6 alkoxy; each R 11a< , R 11b< is independently selected from H, phenyl, C 1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, or C 1-4 alkoxy, C 3-7 cycloalkyl, -C(=O)-C 1-4 alkoxy, -C(=O)-C 1-4 alkyl optionally substituted with one or more independently selected halo, and 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S; each R 8a< , R 8b< , R 9a< , R 9b< , R 12a< , R 12b< R 13a< , and R 13b< is independently selected from H and C 1-4 alkyl; each R 14a< and R 14b< is independently selected from H, C 1-4 alkyl, and -S(=O) 2 -C 1-4 alkyl; and each R 15< is independently selected from -OH, -CN, and C 1-4 alkyl optionally substituted with one or more independently selected halo or -CN.

[0023] In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases.

[0024] Furthermore, it has also been unexpectedly demonstrated that the compounds of the invention exhibit potency against SIK, particularly SIK1, SIK2 and / or SIK3, more particularly SIK2 and / or SIK3, which may result in a tolerogenic therapy (i.e. reduction of pro-inflammatory cytokines such as TNFα and IL-12, coupled with increased levels of anti-inflammatory cytokines such as IL-10 and TGF-β).

[0025] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases.

[0026] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0027] In a further aspect of the invention, this invention provides compounds for use in a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.

[0028] The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases.

[0029] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0030] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.DETAILED DESCRIPTION OF THE INVENTION Definitions

[0031] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description of the present invention.

[0032] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. Unless otherwise stated, the term "substituted" is to be defined as set out below. It should be further understood that the terms "groups" and "radicals" can be considered interchangeable when used herein.

[0033] The articles 'a' and 'an' may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example 'an analogue' means one analogue or more than one analogue.

[0034] 'Alkyl' means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH 3 ), ethyl (-CH 2 -CH 3 ), n-propyl (-CH 2 -CH 2 -CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n-butyl (-CH 2 -CH 2 -CH 2 -CH 3 ), tert-butyl (-C(CH 3 ) 3 ), sec-butyl (-CH(CH 3 )-CH 2 CH 3 ), isobutyl (-CH 2 -CH(CH 3 ) 2 ), n-pentyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), n-hexyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), and 1,2-dimethylbutyl (-CHCH 3 )-C(CH 3 )H 2 -CH 2 -CH 3 ). Particular alkyl groups have between 1 and 4 carbon atoms.

[0035] 'Alkenyl' refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH 2 ), n-propenyl (-CH 2 CH=CH 2 ), isopropenyl (-C(CH 3 )=CH 2 ).

[0036] 'Alkylene' refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), or -CH(CH 3 )-.

[0037] 'Alkynylene' refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -C=C-, -CH 2 -C=C-, and -C(CH 3 )H-C≡CH-.

[0038] 'Alkoxy' refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-C 1-6 alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0039] 'Amino' refers to the radical -NH 2 .

[0040] 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.

[0041] 'Cycloalkyl'refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0042] 'Cyano' refers to the radical -CN.

[0043] 'Halo' or 'halogen' refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0044] As used herein, term 'polycyclic' refers to chemical groups featuring several closed rings of atoms. In particular it refers to groups featuring two, three or four rings of atoms, more particularly two or three rings of atoms, most particularly two rings of atoms.

[0045] 'Hetero' when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.

[0046] 'Heteroaryl' means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have from 5 to 9 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In particular, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0047] Examples of five membered monocyclic heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0048] Examples of six membered monocyclic heteroaryl groups include pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0049] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include imidazothiazolyl and imidazoimidazolyl.

[0050] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0051] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0052] Examples of representative heteroaryls include the following: wherein each Y is selected from >C=O, NH, O and S.

[0053] 'Heterocycloalkyl' means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. Examples of heterocyclic rings include, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

[0054] As used herein, the term 'heterocycloalkenyl' means a 'heterocycloalkyl', which comprises at least one double bond. Particular examples of heterocycloalkenyl groups are shown in the following illustrative examples: wherein each W is selected from CH 2 , NH, O and S; each Y is selected from NH, O, C(=O), SO 2 , and S; and each Z is selected from N or CH.

[0055] Particular examples of monocyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH 2 -, -NH-, -O- and -S-.

[0056] Particular examples of fused bicyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH 2 -, -NH-, -O- and -S-.

[0057] Particular examples of bridged bicyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH 2 -, -NH-, -O- and -S-.

[0058] Particular examples of spirocyclic rings are shown in the following illustrative examples: wherein each Y is selected from -CH 2 -, -NH-, -O- and -S-.

[0059] 'Hydroxyl' refers to the radical -OH.

[0060] 'Oxo' refers to the radical =O.

[0061] 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0062] 'Sulfo' or 'sulfonic acid' refers to a radical such as -SO 3 H.

[0063] 'Thiol' refers to the group -SH.

[0064] As used herein, term 'substituted with one or more' refers to one to four substituents. In particular, it refers to one to three substituents. More particularly, it refers to one or two substituents. Most particularly, it refers to one substituent.

[0065] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0066] 'Pharmaceutically acceptable' means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0067] 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine. Salts further include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate. The term 'pharmaceutically acceptable cation' refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations.

[0068] 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0069] 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 'Solvate' encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0070] 'Subject' includes humans. The terms 'human', 'patient' and 'subject' are used interchangeably herein.

[0071] 'Effective amount' means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, of the subject to be treated.

[0072] 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

[0073] The term 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0074] 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

[0075] As used herein the term 'inflammatory disease(s)' refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints. Particularly the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases

[0076] As used herein the term 'autoinflammatory diseases(s)' refers to the group of diseases including Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease.

[0077] As used herein the term 'autoimmune disease(s)' refers to the group of diseases including obstructive airways disease, including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g. autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis), Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. Particularly the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.

[0078] As used herein the term 'proliferative disease(s)' refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular the term refers to cancer, leukemia, multiple myeloma and psoriasis

[0079] As used herein, the term 'cancer' refers to a malignant or benign growth of cells in skin or in body organs, for example breast, prostate, lung, kidney, pancreas, stomach or bowel. A cancer tends to infiltrate into adjacent tissue and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain. As used herein the term cancer includes both metastatic tumour cell types (such as melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). In particular, the term 'cancer' refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.

[0080] As used herein the term 'leukemia' refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding. In particular the term leukemia refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0081] As used herein the term 'fibrotic disease(s)' refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and that are associated with the abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment and include fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and / or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidney fibrosis; tubulointerstitium fibrosis; glomerular nephritis; diabetic nephropathy, focal segmental glomerular sclerosis; IgA nephropathy; hypertension; Alport syndrome; gut fibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis; toxic / drug induced liver fibrosis; hemochromatosis; nonalcoholic steatohepatitis (NASH); biliary duct injury; primary biliary cirrhosis; infection induced liver fibrosis; viral induced liver fibrosis; and autoimmune hepatitis; corneal scarring; hypertrophic scarring; Dupuytren disease, keloids, cutaneous fibrosis; cutaneous scleroderma; systemic sclerosis, spinal cord injury / fibrosis; myelofibrosis; Duchenne muscular dystrophy (DMD) associated musculoskeletal fibrosis, vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, or chronic lymphocytic. More particularly, the term 'fibrotic diseases' refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.

[0082] As used herein the term 'transplantation rejection' refers to the acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases.

[0083] As used herein the term 'diseases involving impairment of cartilage turnover' includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0084] As used herein the term 'congenital cartilage malformation(s)' includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular microtia, anotia, metaphyseal chondrodysplasia, and related disorders.

[0085] As used herein the term 'diseases involving impairment of bone turnover' includes conditions such as osteoporosis (including postmenopausal osteoporosis, male osteoporosis, glucocorticosteroid induced osteoporosis and juvenile osteoporosis), osteoporosis caused through neoplastic bone marrow disorders, osteopenia, hormone deficiency (vitamin D deficiency, male and female hypogonadism), hormone excess (hyperprolactinaemia, excess glucocorticoid, hyperthyroidism , hyperparathyroidism), Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, hypophosphatasia.

[0086] As used herein the term 'disease(s) associated with hypersecretion of IL-6' includes conditions such as Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and / or mesangial proliferative glomerulonephritis.

[0087] As used herein the term 'disease(s) associated with hypersecretion of of TNFα, interferons, IL-12 and / or IL-23' includes conditions such as systemic and cutaneous lupus erythematosis, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0088] As used herein , the term 'respiratory disease(s)' refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphram and intercostals), and nerves. In particular, examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and / or airway inflammation, cystic fibrosis, and hypoxia.

[0089] As used herein the term 'endocrine and / or metabolic disease(s)' refers to the group of conditions involving the body's over- or under-production of certain hormones, while metabolic disorders affect the body's ability to process certain nutrients and vitamins. Endocrine disorders include hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing's syndrome and Addison's disease), and ovarian dysfunction (including polycystic ovary syndrome), among others. Some examples of metabolic disorders include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. A particular example of metabolic disorders is obesity and / or type II diabetes.

[0090] As used herein the term 'cardiovascular disease(s)' refers to diseases affecting the heart or blood vessels or both. In particular, cardiovascular disease includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, cardiovascular disease refers to atherosclerosis.

[0091] As used herein the term 'dermatological disease(s)' refers to a skin disorder. In particular, dermatological disorders include proliferative or inflammatory disorders of the skin such as atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria.

[0092] As used herein the term 'abnormal angiogenesis associated disease(s)' refers to diseases caused by the dysregulation of the processes mediating angiogenesis. In particular, abnormal angiogenesis associated disease refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy.

[0093] 'Compound(s) of the invention', and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[0094] When ranges are referred to herein, for example C 1 - 8 alkyl, the citation of a range should be considered a representation of each member of said range.

[0095] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985).

[0096] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the "natural isotopic form") or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an "unnatural variant isotopic form"). It is understood that an atom may naturally exists as a mixture of mass numbers. The term "unnatural variant isotopic form" also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an "uncommon isotope") has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term "unnatural variant isotopic form" also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0097] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium ( 2< H or D), carbon-11 ( 11< C), carbon-13 ( 13< C), carbon-14 ( 14< C), nitrogen-13 ( 13< N), nitrogen-15 ( 15< N), oxygen-15 ( 15< O), oxygen-17 ( 17< O), oxygen-18 ( 18< O), phosphorus-32 ( 32< P), sulphur-35 ( 35< S), chlorine-36 ( 36< Cl), chlorine-37 ( 37< Cl), fluorine-18 ( 18< F) iodine-123 ( 123< I), iodine-125 ( 125< I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0098] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3< H, and carbon-14, i.e. 14< C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e 2< H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as 11< C, 18< F, 15< 0 and 13< N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0099] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed 'isomers'. Isomers that differ in the arrangement of their atoms in space are termed 'stereoisomers'.

[0100] Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.

[0101] 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base.

[0102] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0103] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0104] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.THE INVENTION

[0105] The present invention is based on the identification of novel compounds, and their use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases. In particular, the compounds of the invention may be SIK inhibitors, more particularly SIK1, SIK2 and / or SIK3 inhibitors.

[0106] The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and compounds for use in methods for the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases by administering the compounds of the invention.

[0107] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having Formula I: wherein, X is N or CH; Y is N or CR 2b< ; Z is -NHR 3a< , N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R 15< groups, or -NR 3b< -, wherein the N atom and R 2a< together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds; R 1< is C 1-8 alkyl optionally substituted with one or more independently selected R 4< groups, phenyl, C 3-8 monocyclic or bridged polycyclic cycloalkyl optionally substituted with one or more independently selected R 5< groups, 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl optionally substituted with one or more independently selected -CN or -C(=O)-C 1-4 alkoxy, or 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S; R 2a< and R 2b< are independently selected from halo, C 1-4 alkyl, C 1-4 alkoxy optionally substituted with one or more independently selected halo or C 1-4 alkoxy, and -NR 6a< R 6b< ; R 3a< is C 1-6 alkyl optionally substituted with one or more independently selected halo or -CN, or C 3-7 cycloalkyl optionally substituted with one or more independently selected halo or -OH; R 3b< is selected from H, C 3-7 cycloalkyl and C 1-6 alkyl optionally substituted with one or more independently selected halo or -CN; each R 4< is independently selected from halo, -OH, -CN, phenyl, -C(=O)OH, -O-C(=O)-C 1-4 alkyl, -O-S(=O) 2 -C 1-4 alkyl, C 1-4 alkoxy optionally substituted with one or more independently selected ∘ -OH, ∘ C 1-4 alkoxy, ∘ 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl, or ∘ -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl, C 3-7 cycloalkyl optionally substituted with one or more independently selected halo, -C(=O)-C 1-4 alkoxy, -NR 8a< R 8b< , or C 1-4 alkyl optionally substituted with one or more independently selected -NR 9a< R 9b< , 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl, 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl or C 3-7 cycloalkyl, 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R 10< , -NR 11a< R 11b< , -C(=O)-C 1-4 alkoxy, and -C(=O)-NR 12a< R 12b< ; each R 5< is selected from halo, -CN, and -NR 13a< R 13b< ; each R 6a< and R 6b< is independently selected from H and C 1-4 alkyl; each R 10< is selected from -OH, phenyl, =NH, halo, oxo, -CN, -C(=O)H, -C(=O)NH 2 , -C(=O)OH, -NR 14a< R 14b< , C 1-4 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, -C(=O)-C 1-4 alkoxy, or C 1-4 alkoxy, C 3-7 cycloalkyl, 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, -C(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl, and -C(=O)-C 1-6 alkoxy; each R 11a< , R 11b< is independently selected from H, phenyl, C 1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, or C 1-4 alkoxy, C 3-7 cycloalkyl, -C(=O)-C 1-4 alkoxy, -C(=O)-C 1-4 alkyl optionally substituted with one or more independently selected halo, and 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S; each R 8a< , R 8b< , R 9a< , R 9b< , R 12a< , R 12b< R 13a< , and R 13b< is independently selected from H and C 1-4 alkyl; each R 14a< and R 14b< is independently selected from H, C 1-4 alkyl, and -S(=O) 2 -C 1-4 alkyl; and each R 15< is independently selected from -OH, -CN, and C 1-4 alkyl optionally substituted with one or more independently selected halo or -CN.

[0108] In one embodiment, the compound of the invention is according to Formula I, wherein Z is -NHR 3a< , or -NR 3b< -, wherein the N atom and R 2a< together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds; R 1< is C 1-8 alkyl optionally substituted with one or more independently selected R 4< groups, phenyl, C 3-8 monocyclic or bridged polycyclic cycloalkyl optionally substituted with one or more independently selected R 5< groups, 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl, or 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S; R 3a< is C 1-6 alkyl optionally substituted with one or more independently selected halo or -CN, or C 3-7 cycloalkyl; each R 4< is independently selected from: halo, -OH, -CN, phenyl, C 1-4 alkoxy optionally substituted with one or more independently selected -OH, C 1-4 alkoxy, or -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl, C 3-7 cycloalkyl optionally substituted with one or more independently selected halo, -C(=O)-C 1-4 alkoxy, -NR 8a< R 8b< , or C 1-4 alkyl optionally substituted with one or more independently selected -NR 9a< R 9b< , 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl or C 3-7 cycloalkyl, 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R 10< , -NR 11a< R 11b< , and -C(=O)-NR 12a< R 12b< ; each R 10< is selected from halo, oxo, -CN, -C(=O)H, -NR 14a< R 14b< , C 1-4 alkyl optionally substituted with one or more independently selected halo or C 1-4 alkoxy, C 3-7 cycloalkyl, -C(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl, and -C(=O)-C 1-6 alkoxy; each R 11a< , R 11b< is independently selected from H, phenyl, C 1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, or C 1-4 alkoxy, C 3-7 cycloalkyl, -C(=O)-C 1-4 alkyl, and 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S; and each R 14a< , and R 14b< is independently selected from H and C 1-4 alkyl.

[0109] In one embodiment, the compound of the invention is according to Formula I, wherein X is N.

[0110] In one embodiment, the compound of the invention is according to Formula I, wherein X is CH.

[0111] In one embodiment, the compound of the invention is according to Formula I, wherein R 2a< is halo. In a particular embodiment, R 2a< is F, Cl, or Br. In a more particular embodiment, R 2a< is F.

[0112] In one embodiment, the compound of the invention is according to Formula I, wherein R 2a< is C 1-4 alkyl. In a particular embodiment, R 2a< is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a more particular embodiment, R 2a< is -CH 3 .

[0113] In one embodiment, the compound of the invention is according to Formula I, wherein R 2a< is C 1-4 alkoxy. In a particular embodiment, R 2a< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In a more particular embodiment, R 2a< is -O-CH 3 or -O-CH 2 CH 3 . In a most particular embodiment, R 2a< is -O-CH 3 .

[0114] In one embodiment, the compound of the invention is according to Formula I, wherein R 2a< is C 1-4 alkoxy substituted with one or more independently selected halo or C 1-4 alkoxy. In a particular embodiment, R 2a< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo or C 1-4 alkoxy. In another particular embodiment, R 2a< is C 1-4 alkoxy substituted with one, two, or three independently selected halo or C 1-4 alkoxy. In yet another particular embodiment, R 2a< is C 1-4 alkoxy substituted with one or more independently selected F, Cl, Br, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In a more particular embodiment, R 2a< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected halo or C 1-4 alkoxy. In another more particular embodiment, R 2a< is C 1-4 alkoxy substituted with one, two, or three independently selected F, Cl, Br, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In a further more particular embodiment, R 2a< is -O-CH 3 , substituted with one, two, or three independently selected halo. In another further more particular embodiment, R 2a< is -O-CH 2 CH 3 , substituted with one, two, or three independently selected halo or C 1-4 alkoxy. In a most particular embodiment, R 2a< is -O-CHF 2 or -O-CH 2 CH 2 -O-CH 2 CH 3 .

[0115] In one embodiment, the compound of the invention is according to Formula I, wherein R 2a< is -NR 6a< R 6b< , and R 6a< and R 6b< are independently selected from H and C 1-4 alkyl. In a particular embodiment, R 6a< and R 6b< are both H. In another particular embodiment, one of R 6a< and R 6b< is H, and the other is C 1-4 alkyl. In yet another particular embodiment, R 6a< and R 6b< are both C 1-4 alkyl. In a more particular embodiment, one of R 6a< and R 6b< is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another more particular embodiment, R 6a< and R 6b< are independently -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a most particular embodiment, one of R 6a< and R 6b< is H, and the other is -CH 3 .

[0116] In one embodiment, the compound of the invention is according to Formula I, wherein Z is -NR 3b< -, wherein the N atom and R 2a< together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds, and R 3b< is as previously described. In a particular embodiment, Z is -NR 3b< -, wherein the N atom and R 2a< together with the atoms onto which they are attached form a fused 3-pyrroline, 1,2-dihydropyridine, or 1,2,3,6-tetrahydropyridine. In a more particular embodiment, Z is -NR 3b< -, wherein the N atom and R 2a< together with the atoms onto which they are attached form a fused 1,2,3,6-tetrahydropyridine.

[0117] In one embodiment, the compound of the invention is according to Formula IIa, IIb, or IIc: wherein R 1< , R 3b< , and Y are as described above.

[0118] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R 3b< is H.

[0119] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R 3b< is C 3-7 cycloalkyl. In a particular embodiment, R 3b< is cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R 3b< is cyclopropyl.

[0120] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R 3b< is C 1-6 alkyl. In a particular embodiment, R 3b< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 . In a more particular embodiment, R 3b< is -CH 2 CH 3 .

[0121] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R 3b< is C 1-6 alkyl substituted with one or more independently selected halo or -CN. In a particular embodiment, R 3b< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one or more independently selected halo or -CN. In another particular embodiment, R 3b< is C 1-6 alkyl substituted with one, two, or three independently selected halo or -CN. In yet another particular embodiment, R 3b< is C 1-6 alkyl substituted with one or more independently selected F, Cl, or -CN. In a more particular embodiment, R 3b< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one, two, or three independently selected halo or -CN. In another more particular embodiment, R 3b< is C 1-6 alkyl substituted with one, two, or three independently selected F, Cl, or -CN. In yet another more particular embodiment, R 3b< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one or more independently selected F, Cl, or -CN. In a further more particular embodiment, R 3b< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one, two, or three independently selected F, Cl, or -CN. In another further more particular embodiment, R 3b< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one or more F or -CN. In yet another further more particular embodiment, R 3b< is C 1-6 alkyl substituted with one, two, or three independently selected F or -CN. In a most particular embodiment, R 3b< is -CH 2 CH 3 substituted with one, two, or three F. In another most particular embodiment, R 3b< is -CH 2- CN. In a further most particular embodiment, R 3b< is -CH 2 CF 3 .

[0122] In one embodiment, the compound of the invention is according to Formula I, wherein Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S. In a particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl. In a more particular embodiment, Z is azetidinyl.

[0123] In one embodiment, the compound of the invention is according to Formula I, wherein Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R 15< groups. In a particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one or more independently selected R 15< groups. In another particular embodiment, Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one, two, or three independently selected R 15< groups. In a more particular embodiment, Z is azetidinyl substituted with one or more independently selected R 15< groups. In another more particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R 15< groups. In yet another more particular embodiment, Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or two independently selected R 15< group. In a further more particular embodiment, Z is azetidinyl substituted with one, two, or three independently selected R 15< groups. In another further more particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one or two independently selected R 15< groups. In a most particular embodiment, Z is azetidinyl substituted with one or two independently selected R 15< groups.

[0124] In one embodiment, the compound of the invention is according to Formula I, wherein Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R 15< groups, and R 15< is -OH, -CN, or C 1-4 alkyl. In a particular embodiment, R 15< is -OH, -CN, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a more particular embodiment, R 15< is -OH or -CN.

[0125] In one embodiment, the compound of the invention is according to Formula I, wherein Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R 15< groups, and R 15< is C 1-4 alkyl substituted with one or more independently selected halo or -CN. In a particular embodiment, R 15< is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo or -CN. In another particular embodiment, R 15< is C 1-4 alkyl substituted with one, two, or three independently selected halo or -CN. In yet another particular embodiment, R 15< is C 1-4 alkyl substituted with one or more F, Cl, Br, or -CN. In a more particular embodiment, R 15< is -CH 3 substituted with one or more independently selected halo or -CN. In another more particular embodiment, R 15< is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected halo or -CN. In yet another more particular embodiment, R 15< is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one or more independently selected F, Cl, Br, or -CN. In yet another more particular embodiment, R 15< is C 1-4 alkyl substituted with one, two, or three independently selected F, Cl, Br, or -CN. In a further more particular embodiment, R 15< is -CH 3 substituted with one, two, or three independently selected halo or -CN. In another further more particular embodiment, R 15< is -CH 3 substituted with one or more , two, or three independently selected F, Cl, Br, or -CN. In a most particular embodiment, R 15< is -CH 3 substituted with one, two, or three independently selected F or -CN.

[0126] In one embodiment, the compound of the invention is according to Formula I, wherein Z is -NHR 3a< , and R 3a< is C 1-6 alkyl. In a particular embodiment, R 3a< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )CH 2 CH 3 , or -CH(CH 3 )CH(CH 3 ) 2 . In a more particular embodiment, R 3a< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -CH 2 CH(CH 3 ) 2 . In a most particular embodiment, R 3a< is -CH 2 CH 3 .

[0127] In one embodiment, the compound of the invention is according to Formula I, wherein Z is -NHR 3a< , and R 3a< is C 1-6 alkyl substituted with one or more independently selected halo or -CN. In a particular embodiment, R 3a< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one or more independently selected halo or -CN. In another particular embodiment, R 3a< is C 1-6 alkyl substituted with one, two, or three independently selected halo or -CN. In yet another particular embodiment, R 3a< is C 1-6 alkyl substituted with one or more independently selected F, Cl, or -CN. In a more particular embodiment, R 3a< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one, two, or three independently selected halo or -CN. In another more particular embodiment, R 3a< is C 1-6 alkyl substituted with one, two, or three independently selected F, Cl, or -CN. In yet another more particular embodiment, R 3a< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one or more independently selected F, Cl, or -CN. In a further more particular embodiment, R 3a< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one, two, or three independently selected F, Cl, or -CN. In another further more particular embodiment, R 3a< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 , each of which is substituted with one or more F or -CN. In yet another further more particular embodiment, R 3a< is C 1-6 alkyl substituted with one, two, or three independently selected F or -CN. In a most particular embodiment, R 3a< is -CH 2 CH 3 substituted with one, two, or three F. In another most particular embodiment, R 3a< is -CH 2- CN. In a further most particular embodiment, R 3a< is -CH 2 CF 3 .

[0128] In one embodiment, the compound of the invention is according to Formula I, wherein Z is -NHR 3a< , and R 3a< is C 3-7 cycloalkyl. In a particular embodiment, R 3a< is cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R 3a< is cyclopropyl.

[0129] In one embodiment, the compound of the invention is according to Formula I, wherein Z is -NHR 3a< , and R 3a< is C 3-7 cycloalkyl substituted with one or more independently selected halo or -OH. In a particular embodiment, R 3a< is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more independently selected halo or -OH. In another particular embodiment, R 3a< is C 3-7 cycloalkyl substituted with one, two, or three independently selected halo or -OH. In yet another particular embodiment, R 3a< is C 3-7 cycloalkyl substituted with one or more independently selected F, Cl, or -OH. In a more particular embodiment, R 3a< is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected halo or -OH. In another more particular embodiment, R 3a< is C 3-7 cycloalkyl substituted with one, two, or three independently selected F, Cl, or -OH. In yet another more particular embodiment, R 3a< is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more independently selected F, Cl, or -OH. In a further more particular embodiment, R 3a< is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected F, Cl, or -OH. In another further more particular embodiment, R 3a< is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more F or -OH. In yet another further more particular embodiment, R 3a< is C 3-7 cycloalkyl substituted with one, two, or three independently selected F or -OH. In a most particular embodiment, R 3a< is In a further most particular embodiment, R 3a< is

[0130] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein Y is N.

[0131] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein Y is CR 2b< and R 2b< is halo. In a particular embodiment, R 2b< is F, Cl, or Br. In a more particular embodiment, R 2b< is F.

[0132] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein Y is CR 2b< and R 2b< is C 1-4 alkyl. In a particular embodiment, R 2b< is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a more particular embodiment, R 2b< is -CH 3 .

[0133] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein Y is CR 2b< and R 2b< is C 1-4 alkoxy. In a particular embodiment, R 2b< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In a more particular embodiment, R 2b< is -O-CH 3 or -O-CH 2 CH 3 . In a most particular embodiment, R 2b< is -O-CH 3 .

[0134] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein Y is CR 2b< and R 2b< is C 1-4 alkoxy substituted with one or more independently selected halo or C 1-4 alkoxy. In a particular embodiment, R 2b< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo or C 1-4 alkoxy. In another particular embodiment, R 2b< is C 1-4 alkoxy substituted with one, two, or three independently selected halo or C 1-4 alkoxy. In yet another particular embodiment, R 2b< is C 1-4 alkoxy substituted with one or more independently selected F, Cl, Br, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In a more particular embodiment, R 2b< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected halo or C 1-4 alkoxy. In another more particular embodiment, R 2b< is C 1-4 alkoxy substituted with one, two, or three independently selected F, Cl, Br, -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In a further more particular embodiment, R 2b< is -O-CH 3 , substituted with one, two, or three independently selected halo. In another further more particular embodiment, R 2b< is -O-CH 2 CH 3 , substituted with one, two, or three independently selected halo or C 1-4 alkoxy. In a most particular embodiment, R 2b< is -O-CHF 2 or -O-CH 2 CH 2 -O-CH 2 CH 3 .

[0135] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein Y is CR 2b< , R 2b< is -NR 6a< R 6b< , and R 6a< and R 6b< are independently selected from H and C 1-4 alkyl. In a particular embodiment, R 6a< and R 6b< are both H. In another particular embodiment, one of R 6a< and R 6b< is H, and the other is C 1-4 alkyl. In yet another particular embodiment, R 6a< and R 6b< are both C 1-4 alkyl. In a more particular embodiment, one of R 6a< and R 6b< is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another more particular embodiment, R 6a< and R 6b< are -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a most particular embodiment, one of R 6a< and R 6b< is H, and the other is -CH 3 .

[0136] In one embodiment, the compound of the invention is according to Formula IIIa, IIIb, or IIIc: wherein R 1< is as described above.

[0137] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1< is C 1-8 alkyl. In a particular embodiment, R 1< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 C H 2 CH 3 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 ) 2 , -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 2 CH 2 CH 3 , -CH 2 CH 2 CH(CH 3 )C H 2 CH 3 , -CH 2 CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 )CH 2 CH 2 CH 3 , -CH 2 CH(CH 2 CH 3 ) 2 , -CH(CH 3 )CH(CH 3 ) CH 2 CH 3 , -CH(CH 2 CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 CH 2 C H 3 , -CH 2 CH(CH 3 )CH(CH 3 )CH 2 CH 3 , or -CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 . In a more particular embodiment, R 1< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , or -CH 2 CH 2 CH 2 CH(CH 3 ) 2 . In a most particular embodiment, R 1< is -CH 3 , -CH 2 CH 3 , or -CH 2 C(CH 3 ) 3 .

[0138] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1< is C 1-8 alkyl substituted with one or more independently selected R 4< groups. In a particular embodiment, R 1< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 2 CH 3 , -C H 2 CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 ) 2 , -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(C H 3 )CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 2 CH 2 CH 3 , -CH 2 CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 )CH 2 CH 2 CH 3 , -CH 2 CH(CH 2 CH 3 ) 2 , -CH(CH 3 )CH(CH 3 )CH 2 CH 3 , -CH(CH 2 CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH(CH 3 )CH 2 CH 3 , or -CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 , each of which is substituted with one or more independently selected R 4< groups. In another particular embodiment, R 1< is C 1-8 alkyl substituted with one, two, or three independently selected R 4< groups. In a more particular embodiment, R 1< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C (CH 3 ) 3 , or -CH 2 CH 2 CH 2 CH(CH 3 ) 2 , each of which is substituted with one or more independently selected R 4< groups. In another more particular embodiment, R 1< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 C H 2 CH 3 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 ) 2 , -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 2 CH 2 CH 3 , -CH 2 CH 2 CH(CH 3 )C H 2 CH 3 , -CH 2 CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 )CH 2 CH 2 CH 3 , -CH 2 CH(CH 2 CH 3 ) 2 , -CH(CH 3 )CH(CH 3 )CH 2 CH 3 , -CH(CH 2 CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 3 )C H 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH(CH 3 )CH 2 CH 3 , or -CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 , each of which is substituted with one, two, or three independently selected R 4< groups. In yet another more particular embodiment, R 1< is C 1-8 alkyl substituted with one R 4< group. In a further more particular embodiment, R 1< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , or -CH 2 CH 2 CH 2 CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected R 4< groups. In another further more particular embodiment, R 1< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 ) 2 , -CH(CH 3 )CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 2 CH 2 C H 3 , -CH 2 CH(CH 3 )CH 2 CH 2 CH 3 , -CH 2 CH 2 CH(CH 3 )CH 2 CH 3 , -CH 2 CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 2 CH 3 )CH 2 CH 2 CH 3 , -CH 2 CH(CH 2 CH 3 ) 2 , -CH(CH 3 )CH(CH 3 )CH 2 CH 3 , -CH(CH 2 CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 2 C H 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )CH(CH 3 ) 2 , -CH 2 CH 2 C(CH 3 ) 2 CH 2 CH 3 , -CH 2 CH(CH 3 )CH(CH 3 )CH 2 CH 3 , or -CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 , each of which is substituted with one R 4< group. In a most particular embodiment, R 1< is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , or -CH 2 CH 2 CH 2 CH(CH 3 ) 2 , each of which is substituted with one R 4< group.

[0139] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1< is phenyl.

[0140] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1< is C 3-8 monocyclic or bridged polycyclic cycloalkyl. In a particular embodiment, R 1< is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl. In a more particular embodiment, R 1< is cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2.1]heptanyl.

[0141] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1< is C 3-8 monocyclic or bridged polycyclic cycloalkyl substituted with one or more independently selected R 5< groups. In a particular embodiment, R 1< is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl, each of which is substituted with one or more independently selected R 5< groups. In another particular embodiment, R 1< is C 3-8 monocyclic or bridged polycyclic cycloalkyl substituted with one, two, or three independently selected R 5< groups. In a more particular embodiment, R 1< is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected R 5< groups. In another more particular embodiment, R 1< is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl, each of which is substituted with one, two, or three independently selected R 5< groups. In yet another more particular embodiment, R 1< is C 3-8 monocyclic or bridged polycyclic cycloalkyl substituted with one R 5< group. In a further more particular embodiment, R 1< is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two, or three independently selected R 5< groups. In another further more particular embodiment, R 1< is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl, each of which is substituted with one R 5< group. In a most particular embodiment, R 1< is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one R 5< group.

[0142] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1< is 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R 1< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 1-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-thiaspiro[3.4]octanyl, 2-thiaspiro[3.4]octanyl, 5-thiaspiro[3.4]octanyl, 6-thiaspiro[3.4]octanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.2.1]heptanyl, 7-thiabicyclo[2.2.1]heptanyl, 2-thiabicyclo[2.2.1]heptanyl, quinuclidinyl, 1,4-diazabicyclo[2.2.2]octanyl, 2-azabicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, 2-thiabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3-thia-8-azabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, or 8-thiabicyclo[3.2.1]octanyl. In a more particular embodiment, R 1< is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxaspiro[3.3]heptanyl, or 8-azabicyclo[3.2.1]octanyl.

[0143] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1< is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R 1< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 1-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-thiaspiro[3.4]octanyl, 2-thiaspiro[3.4]octanyl, 5-thiaspiro[3.4]octanyl, or 6-thiaspiro[3.4]octanyl. In a more particular embodiment, R 1< is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 2-oxaspiro[3.3]heptanyl.

[0144] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1< is 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected C 1-4 alkyl optionally substituted with one or more independently selected -CN or -C(=O)-C 1-4 alkoxy. In a particular embodiment, R 1< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 1-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-thiaspiro[3.4]octanyl, 2-thiaspiro[3.4]octanyl, 5-thiaspiro[3.4]octanyl, 6-thiaspiro[3.4]octanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.2.1]heptanyl, 7-thiabicyclo[2.2.1]heptanyl, 2-thiabicyclo[2.2.1]heptanyl, quinuclidinyl, 1,4-diazabicyclo[2.2.2]octanyl, 2-azabicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, 2-thiabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3-thia-8-azabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, or 8-thiabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected C 1-4 alkyl optionally substituted with one or more independently selected-CN or -C(=O)-C 1-4 alkoxy. In a more particular embodiment, R 1< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 1-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-thiaspiro[3.4]octanyl, 2-thiaspiro[3.4]octanyl, 5-thiaspiro[3.4]octanyl, 6-thiaspiro[3.4]octanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.2.1]heptanyl, 7-thiabicyclo[2.2.1]heptanyl, 2-thiabicyclo[2.2.1]heptanyl, quinuclidinyl, 1,4-diazabicyclo[2.2.2]octanyl, 2-azabicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, 2-thiabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3-thia-8-azabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, or 8-thiabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is optionally substituted with one, two, or three independently selected -CN, -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , or -C(=O)-O-CH(CH 3 ) 2 . In another more particular embodiment, R 1< is azetidinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected C 1-4 alkyl optionally substituted with one or more independently selected -CN or -C(=O)-C 1-4 alkoxy. In a further more particular embodiment, R 1< is azetidinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is optionally substituted with one, two, or three independently selected -CN, -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , or - C(=O)-O-CH(CH 3 ) 2 . In another further more particular embodiment, R 1< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 1-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-thiaspiro[3.4]octanyl, 2-thiaspiro[3.4]octanyl, 5-thiaspiro[3.4]octanyl, 6-thiaspiro[3.4]octanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.2.1]heptanyl, 7-thiabicyclo[2.2.1]heptanyl, 2-thiabicyclo[2.2.1]heptanyl, quinuclidinyl, 1,4-diazabicyclo[2.2.2]octanyl, 2-azabicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, 2-thiabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3-thia-8-azabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, or 8-thiabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected -CH 3 , -CH 2 -CH 2 -CN, or -CH 2 -C(=O)-O-CH 2 CH 3 . In a most particular embodiment, R 1< is azetidinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, each of which is substituted with one -CH 3 , -CH 2 -CH 2 -CN, or -CH 2 -C(=O)-O-CH 2 CH 3 .

[0145] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1< is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected C 1-4 alkyl. In a particular embodiment, R 1< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 1-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-thiaspiro[3.4]octanyl, 2-thiaspiro[3.4]octanyl, 5-thiaspiro[3.4]octanyl, or 6-thiaspiro[3.4]octanyl, each of which is substituted with one, two, or three independently selected C 1-4 alkyl. In a more particular embodiment, R 1< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 1-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-thiaspiro[3.4]octanyl, 2-thiaspiro[3.4]octanyl, 5-thiaspiro[3.4]octanyl, or 6-thiaspiro[3.4]octanyl, each of which is substituted with one, two, or three independently selected -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another more particular embodiment, R 1< is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one, two, or three independently selected C 1-4 alkyl. In a further more particular embodiment, R 1< is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one, two, or three independently selected -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another further more particular embodiment, R 1< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 1-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-thiaspiro[3.4]octanyl, 2-thiaspiro[3.4]octanyl, 5-thiaspiro[3.4]octanyl, or 6-thiaspiro[3.4]octanyl, each of which is substituted with one, two, or three -CH 3 . In a most particular embodiment, R 1< is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one -CH 3 .

[0146] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 1< is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R 1< is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl. In a more particular embodiment, R 1< is pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl. In a most particular embodiment, R 1< is pyridinyl.

[0147] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 5< is halo or -CN. In a particular embodiment, R 5< is F, Cl, Br, or -CN. In a more particular embodiment, R 5< is F or -CN.

[0148] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein R 5< is -NR 13a< R 13b< , and each R 13a< and R 13b< are as previously described. In a particular embodiment, R 13a< and R 13b< are both H. In another particular embodiment, one of R 13a< and R 13b< is H, and the other is C 1-4 alkyl. In yet another particular embodiment, R 13a< and R 13b< are both C 1-4 alkyl. In a more particular embodiment, one of R 13a< and R 13b< is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another more particular embodiment, each R 13a< and R 13b< is independently -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a most particular embodiment, R 5< is -NH-CH 3 .

[0149] In one embodiment, the compound of the invention is according to Formula IVa, IVb, IVc, IVd, IVe, or IVf: wherein R 4< is as described above.

[0150] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is halo, -OH, -CN, phenyl, or -C(=O)OH. In a particular embodiment, R 4< is F, Cl, Br, -OH, -CN, phenyl, or -C(=O)OH. In a more particular embodiment, R 4< is F, -OH, -CN, phenyl, or -C(=O)OH.

[0151] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is halo, -OH, -CN, or phenyl. In a particular embodiment, R 4< is F, Cl, Br, -OH, -CN, or phenyl. In a more particular embodiment, R 4< is F, -OH, -CN, or phenyl.

[0152] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -O-C(=O)-C 1-4 alkyl. In a particular embodiment, R 4< is -O-C(=O)-CH 3 , -O-C(=O)-CH 2 CH 3 , or -O-C(=O)-CH(CH 3 ) 2 . In a more particular embodiment, R 4< is -O-C(=O)-CH 3 .

[0153] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -O-S(=O) 2 -C 1-4 alkyl. In a particular embodiment, R 4< is -O-S(=O) 2 -CH 3 , -O-S(=O) 2 -CH 2 CH 3 , or -O-S(=O) 2 -CH(CH 3 ) 2 . In a more particular embodiment, R 4< is -O-S(=O) 2 -CH 3 .

[0154] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is C 1-4 alkoxy. In a particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In a more particular embodiment, R 4< is -O-CH 3 or -O-CH 2 CH 3 .

[0155] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is C 1-4 alkoxy substituted with one or more independently selected 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl. In a particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one or more independently selected 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl. In another particular embodiment, R 4< is C 1-4 alkoxy substituted with one 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl. In yet another particular embodiment, R 4< is C 1-4 alkoxy substituted with one or more independently selected azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one or more independently selected 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl. In another more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl. In yet another more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one or more independently selected azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In yet another more particular embodiment, R 4< is C 1-4 alkoxy substituted with one azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In yet another more particular embodiment, R 4< is C 1-4 alkoxy substituted with one or more independently selected piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one -CH(CH 3 ) 2 . In a further more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C 1-4 alkyl. In another further more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one or more independently selected azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In yet another further more particular embodiment, R 4< is C 1-4 alkoxy substituted with one piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one -CH(CH 3 ) 2 . In yet another further more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or - O-CH(CH 3 ) 2 , each of which is substituted with one azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In yet another further more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one or more independently selected piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one -CH(CH 3 ) 2 . In an even further more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted with one, two, or three -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another even further more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one or more independently selected piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one -CH(CH 3 ) 2 . In yet another even further more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one -CH(CH 3 ) 2 . In a most particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one piperidinyl, morpholinyl, or piperazinyl, each of which is optionally substituted with one -CH(CH 3 ) 2 .

[0156] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is C 1-4 alkoxy substituted with one or more independently selected -OH, C 1-4 alkoxy, or -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl. In a particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one or more independently selected -OH, C 1-4 alkoxy, or -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl. In another particular embodiment, R 4< is C 1-4 alkoxy substituted with one, two or three independently selected -OH, C 1-4 alkoxy, or -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl. In yet another particular embodiment, R 4< is C 1-4 alkoxy substituted with one or more independently selected -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 )-CH(CH 3 ) 2 , or -N(CH(CH 3 ) 2 ) 2 . In a more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one or more independently selected -OH, C 1-4 alkoxy, or -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl. In another more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one, two or three independently selected -OH, C 1-4 alkoxy, or -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl. In yet another more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one or more independently selected -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 )-CH(CH 3 ) 2 , or -N(CH(CH 3 ) 2 ) 2 . In yet another more particular embodiment, R 4< is C 1-4 alkoxy substituted with one -OH, C 1-4 alkoxy, or -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl. In yet another more particular embodiment, R 4< is C 1-4 alkoxy substituted with one, two or three independently selected -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 )-CH(CH 3 ) 2 , or -N(CH(CH 3 ) 2 ) 2 . In yet another more particular embodiment, R 4< is C 1-4 alkoxy substituted with one or more independently selected -OH, -O-CH 3 , or -N(CH 3 ) 2 . In a further more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one, two, or three independently selected -OH, C 1-4 alkoxy, or -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl. In another further more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one or more independently selected -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 )-CH(CH 3 ) 2 , or -N(CH(CH 3 ) 2 ) 2 . In another further more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one -OH, C 1-4 alkoxy, or -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl. In another further more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 )-CH(CH 3 ) 2 , or -N(CH(CH 3 ) 2 ) 2 . In another further more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one or more -OH, -O-CH 3 , or -N(CH 3 ) 2 . In another further more particular embodiment, R 4< is C 1-4 alkoxy substituted with one -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 )-CH(CH 3 ) 2 , or -N(CH(CH 3 ) 2 ) 2 . In another further more particular embodiment, R 4< is C 1-4 alkoxy substituted with one, two, or three -OH, -O-CH 3 , or -N(CH 3 ) 2 . In an even further more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one -OH, C 1-4 alkoxy, or -NR 7a< R 7b< , wherein each R 7a< and R 7b< is independently selected from H and C 1-4 alkyl. In another even further more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one, two, or three -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 )-CH(CH 3 ) 2 , or -N(CH(CH 3 ) 2 ) 2 . In yet another even further more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one or more -OH, -O-CH 3 , or -N(CH 3 ) 2 . In yet another even further more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 )-CH(CH 3 ) 2 , or -N(CH(CH 3 ) 2 ) 2 . In yet another even further more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one, two, or three -OH, -O-CH 3 , or -N(CH 3 ) 2 . In a furthest more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one -OH, -O-CH 3 , -O-CH 2 CH 3 , -O-CH(CH 3 ) 2 , -NH 2 , -NH-CH 3 , -NH-CH 2 CH 3 , -NH-CH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )-CH 2 CH 3 , -N(CH 3 )-CH(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 3 )-CH(CH 3 ) 2 , or -N(CH(CH 3 ) 2 ) 2 . In another furthest more particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one, two, or three -OH, -O-CH 3 , or -N(CH 3 ) 2 . In yet another furthest more particular embodiment, R 4< is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one -OH, -O-CH 3 , or -N(CH 3 ) 2 . In a most particular embodiment, R 4< is -O-CH 2 CH 3 substituted with one -OH, -O-CH 3 , or -N(CH 3 ) 2 .

[0157] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is C 3-7 cycloalkyl. In a particular embodiment, R 4< is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0158] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is C 3-7 cycloalkyl substituted with one or more independently selected halo, -C(=O)-C 1-4 alkoxy, -NR 8a< R 8b< , or C 1-4 alkyl optionally substituted with one or more independently selected -NR 9a< R 9b< . In a particular embodiment, R 4< is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected halo, -C(=O)-C 1-4 alkoxy, -NR 8a< R 8b< , or C 1-4 alkyl optionally substituted with one or more independently selected -NR 9a< R 9b< . In another particular embodiment, R 4< is C 3-7 cycloalkyl substituted with one, two, or three independently selected halo, -C(=O)-C 1-4 alkoxy, -NR 8a< R 8b< , or C 1-4 alkyl optionally substituted with one or more independently selected -NR 9a< R 9b< . In yet another particular embodiment, R 4< is C 3-7 cycloalkyl substituted with one or more independently selected F, Cl, Br, -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , -C(=O)-O-CH(CH 3 ) 2 , -NR 8a< R 8b< , -CH 3 optionally substituted with one -NR 9a< R 9b< , -CH 2 CH 3 optionally substituted with one -NR 9a< R 9b< , or -CH(CH 3 ) 2 optionally substituted with one -NR 9a< R 9b< . In a more particular embodiment, R 4< is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two, or three independently selected halo, -C(=O)-C 1-4 alkoxy, -NR 8a< R 8b< , or C 1-4 alkyl optionally substituted with one or more independently selected -NR 9a< R 9b< . In another more particular embodiment, R 4< is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected F, Cl, Br, -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , -C(=O)-O-CH(CH 3 ) 2 , -NR 8a< R 8b< , -CH 3 optionally substituted with one -NR 9a< R 9b< , -CH 2 CH 3 optionally substituted with one -NR 9a< R 9b< , or -CH(CH 3 ) 2 optionally substituted with one -NR 9a< R 9b< . In yet another more particular embodiment, R 4< is C 3-7 cycloalkyl substituted with one, two, or three independently selected F, Cl, Br, -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , -C(=O)-O-CH(CH 3 ) 2 , -NR 8a< R 8b< , -CH 3 optionally substituted with one -NR 9a< R 9b< , -CH 2 CH 3 optionally substituted with one -NR 9a< R 9b< , or -CH(CH 3 ) 2 optionally substituted with one -NR 9a< R 9b< . In yet another more particular embodiment, R 4< is C 3-7 cycloalkyl substituted with one or more independently selected F, -C(=O)-O-CH 3 , -NR 8a< R 8b< , -CH 3 , or -CH 2 -NR 9a< R 9b< . In a further more particular embodiment, R 4< is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two, or three independently selected F, Cl, Br, -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , -C(=O)-O-CH(CH 3 ) 2 , -NR 8a< R 8b< , -CH 3 optionally substituted with one -NR 9a< R 9b< , -CH 2 CH 3 optionally substituted with one -NR 9a< R 9b< , or -CH(CH 3 ) 2 optionally substituted with one -NR 9a< R 9b< . In yet another further more particular embodiment, R 4< is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected F, -C(=O)-O-CH 3 , -NR 8a< R 8b< , -CH 3 , or -CH 2 -NR 9a< R 9b< . In yet another further more particular embodiment, R 4< is C 3-7 cycloalkyl substituted with one, two, or three independently selected F, -C(=O)-O-CH 3 , -NR 8a< R 8b< , -CH 3 , or -CH 2 -NR 9a< R 9b< . In an even further more particular embodiment, R 4< is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two, or three independently selected F, -C(=O)-O-CH 3 , -NR 8a< R 8b< , -CH 3 , or -CH 2 -NR 9a< R 9b< . In a most particular embodiment, R 4< is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three F. In another most particular embodiment, R 4< is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one -C(=O)-O-CH 3 , -NR 8a< R 8b< , -CH 3 , or -CH 2 -NR 9a< R 9b< .

[0159] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is C 3-7 cycloalkyl substituted with -NR 8a< R 8b< , and R 8a< and R 8b< are as previously described. In a particular embodiment, R 8a< and R 8b< are both H. In another particular embodiment, one of R 8a< and R 8b< is H, and the other is C 1-4 alkyl. In yet another particular embodiment, R 8a< and R 8b< are both C 1-4 alkyl. In a more particular embodiment, one of R 8a< and R 8b< is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another more particular embodiment, R 8a< and R 8b< are independently -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .

[0160] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is C 3-7 cycloalkyl substituted with one or more independently selected C 1-4 alkyl substituted with one or more independently selected -NR 9a< R 9b< , and R 9a< and R 9b< are as previously described. In a particular embodiment, R 9a< and R 9b< are both H. In another particular embodiment, one of R 9a< and R 9b< is H, and the other is C 1-4 alkyl. In yet another particular embodiment, R 9a< and R 9b< are both C 1-4 alkyl. In a more particular embodiment, one of R 9a< and R 9b< is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another more particular embodiment, R 9a< and R 9b< are independently -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .

[0161] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R 4< is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S. In another particular embodiment, R 4< is 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a pyrrole, furane, thiophene, imidazole, furazane, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine. In a more particular embodiment, R 4< is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is fused to a pyrrole, furane, thiophene, imidazole, furazane, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine. In a most particular embodiment, R 4< is 1H,2H,3H,4H-pyrrolo[1,2-a]pyrazinyl, 5H,6H,7H,8H-imidazo[1,2-a]pyrazinyl, 5H,6H,7H,8H-[1,2,4]triazolo[1,5-a]pyrazinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl, or 5H,6H,7H,8H-pyrido[4,3-d]pyrimidinyl.

[0162] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected C 1-4 alkyl. In a particular embodiment, R 4< is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected C 1-4 alkyl. In another particular embodiment, R 4< is 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a pyrrole, furane, thiophene, imidazole, furazane, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with one, two, or three independently selected -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a more particular embodiment, R 4< is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is fused to a pyrrole, furane, thiophene, imidazole, furazane, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with one, two, or three independently selected -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a most particular embodiment, R 4< is piperidinyl fused to an imidazole substituted with one -CH 3 .

[0163] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R 4< is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In a more particular embodiment, R 4< is thiazolyl, oxazolyl, pyridinyl, pyridazinyl, or pyrimidinyl.

[0164] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected C 1-4 alkyl or C 3-7 cycloalkyl. In a particular embodiment, R 4< is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one or more independently selected C 1-4 alkyl or C 3-7 cycloalkyl. In another particular embodiment, R 4< is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one, two, or three independently selected C 1-4 alkyl or C 3-7 cycloalkyl. In yet another particular embodiment, R 4< is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more particular embodiment, R 4< is imidazolyl, pyrazolyl, triazolyl, thiazolyl, or oxadiazolyl, each of which is substituted with one or more independently selected C 1-4 alkyl or C 3-7 cycloalkyl. In another more particular embodiment, R 4< is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one, two, or three independently selected C 1-4 alkyl or C 3-7 cycloalkyl. In an even more particular embodiment, R 4< is imidazolyl, pyrazolyl, triazolyl, thiazolyl, or oxadiazolyl, each of which is substituted with one, two, or three independently selected C 1-4 alkyl or C 3-7 cycloalkyl. In another even more particular embodiment, R 4< is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one, two, or three independently selected -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a most particular embodiment, R 4< is imidazolyl, pyrazolyl, triazolyl, thiazolyl, or oxadiazolyl, each of which is substituted with one or two independently selected - CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or cyclopropyl.

[0165] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R 4< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 1-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-thia-6-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-thia-1-azaspiro[3.3]heptanyl, 1-oxaspiro[3.4]octanyl, 2-oxaspiro[3.4]octanyl, 5-oxaspiro[3.4]octanyl, 6-oxaspiro[3.4]octanyl, 1-thiaspiro[3.4]octanyl, 2-thiaspiro[3.4]octanyl, 5-thiaspiro[3.4]octanyl, 6-thiaspiro[3.4]octanyl, 1-azaspiro[3.4]octanyl, 1-oxa-6-azaspiro[3.4]octanyl, 1-thia-6-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 2-oxa-5-azaspiro[3.4] octanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-thia-5-azaspiro[3.4]octanyl, 2-thia-6-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-oxa-6-azaspiro[3.5]nonanyl, 1-thia-6-azaspiro[3.5]nonanyl, 2,8-dioxa-5-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-8-thia-5-azaspiro[3.5]nonanyl, 2-thia-6-azaspiro[3.5]nonanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 5-thia-8-azaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, 8-thia-5-azaspiro[3.5]nonanyl, 1-azaspiro[4.5]decanyl, 1-oxa-7-azaspiro[4.5]decanyl, 1-oxa-8-azaspiro[4.5]decanyl, 1-thia-7-azaspiro[4.5]decanyl, 1-thia-8-azaspiro[4.5]decanyl, 2-azaspiro[4.5]decanyl, 2-oxa-6-azaspiro[4.5]decanyl, 2-oxa-7-azaspiro[4.5]decanyl, 2-oxa-8-azaspiro[4.5]decanyl, 2-thia-6-azaspiro[4.5]decanyl, 2-thia-7-azaspiro[4.5]decanyl, 2-thia-8-azaspiro[4.5]decanyl, 6-azaspiro[4.5]decanyl, 6-oxa-2-azaspiro[4.5]decanyl, 6-oxa-9-azaspiro[4.5]decanyl, 6-thia-2-azaspiro[4.5]decanyl, 6-thia-9-azaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 7-oxa-1-azaspiro[4.5]decanyl, 7-oxa-2-azaspiro[4.5]decanyl, 7-thia-1-azaspiro[4.5]decanyl, 7-thia-2-azaspiro[4.5]decanyl, 8-azaspiro[4.5]decanyl, 8-oxa-1-azaspiro[4.5]decanyl, 8-oxa-2-azaspiro[4.5]decanyl, 8-thia-1-azaspiro[4.5]decanyl, 8-thia-2-azaspiro[4.5]decanyl, 9-oxa-6-azaspiro[4.5]decanyl, 9-thia-6-azaspiro[4.5]decanyl, 2-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 2-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 2-oxabicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[3.1.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 2-thiabicyclo[2.2.1]heptanyl, 7-thiabicyclo[2.2.1]heptanyl, 2-thiabicyclo[3.1.1]heptanyl, 3-thiabicyclo[3.1.1]heptanyl, 6-thiabicyclo[3.1.1]heptanyl, 2-oxabicyclo[3.2.1]octanyl, 3-oxabicyclo[3.2.1]octanyl, 6-oxabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, 2-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 6-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-thiabicyclo[3.2.1]octanyl, 3-thiabicyclo[3.2.1]octanyl, 6-thiabicyclo[3.2.1]octanyl, 8-thiabicyclo[3.2.1]octanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-2-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-6-azabicyclo[3.2.1]octanyl, 2-thia-5-azabicyclo[2.2.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-thia-3-azabicyclo[3.1.1]heptanyl, 2-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-8-azabicyclo[3.2.1]octanyl, 8-thia-2-azabicyclo[3.2.1]octanyl, 8-thia-3-azabicyclo[3.2.1]octanyl, or 8-thia-6-azabicyclo[3.2.1]octanyl. In a more particular embodiment, R 4< is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2,8-dioxa-5-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl.

[0166] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R 4< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 2-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 2-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 2-oxabicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[3.1.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 2-thiabicyclo[2.2.1]heptanyl, 7-thiabicyclo[2.2.1]heptanyl, 2-thiabicyclo[3.1.1]heptanyl, 3-thiabicyclo[3.1.1]heptanyl, 6-thiabicyclo[3.1.1]heptanyl, 2-oxabicyclo[3.2.1]octanyl, 3-oxabicyclo[3.2.1]octanyl, 6-oxabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, 2-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 6-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-thiabicyclo[3.2.1]octanyl, 3-thiabicyclo[3.2.1]octanyl, 6-thiabicyclo[3.2.1]octanyl, 8-thiabicyclo[3.2.1]octanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-2-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-6-azabicyclo[3.2.1]octanyl, 2-thia-5-azabicyclo[2.2.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-thia-3-azabicyclo[3.1.1]heptanyl, 2-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-8-azabicyclo[3.2.1]octanyl, 8-thia-2-azabicyclo[3.2.1]octanyl, 8-thia-3-azabicyclo[3.2.1]octanyl, or 8-thia-6-azabicyclo[3.2.1]octanyl. In a more particular embodiment, R 4< is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl.

[0167] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10< . In a particular embodiment, R 4< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-azaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-thia-6-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-thia-1-azaspiro[3.3]heptanyl, 1-azaspiro[3.4]octanyl, 1-oxa-6-azaspiro[3.4]octanyl, 1-thia-6-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 2-oxa-5-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-thia-5-azaspiro[3.4]octanyl, 2-thia-6-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-oxa-6-azaspiro[3.5]nonanyl, 1-thia-6-azaspiro[3.5]nonanyl, 2,8-dioxa-5-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-8-thia-5-azaspiro[3.5]nonanyl, 2-thia-6-azaspiro[3.5]nonanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 5-thia-8-azaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, 8-thia-5-azaspiro[3.5]nonanyl, 1-azaspiro[4.5]decanyl, 1-oxa-3,8-diazaspiro[4.5]decanyl, 1-oxa-7-azaspiro[4.5]decanyl, 1-oxa-8-azaspiro[4.5]decanyl, 1-thia-3,8-diazaspiro[4.5]decanyl, 1-thia-7-azaspiro[4.5]decanyl, 1-thia-8-azaspiro[4.5]decanyl, 2-azaspiro[4.5]decanyl, 2-oxa-6-azaspiro[4.5]decanyl, 2-oxa-7-azaspiro[4.5]decanyl, 2-oxa-8-azaspiro[4.5]decanyl, 2-thia-6-azaspiro[4.5]decanyl, 2-thia-7-azaspiro[4.5]decanyl, 2-thia-8-azaspiro[4.5]decanyl, 6-azaspiro[4.5]decanyl, 6-oxa-2-azaspiro[4.5]decanyl, 6-oxa-9-azaspiro[4.5]decanyl, 6-thia-2-azaspiro[4.5]decanyl, 6-thia-9-azaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 7-oxa-1-azaspiro[4.5]decanyl, 7-oxa-2-azaspiro[4.5]decanyl, 7-thia-1-azaspiro[4.5]decanyl, 7-thia-2-azaspiro[4.5]decanyl, 8-azaspiro[4.5]decanyl, 8-oxa-1-azaspiro[4.5]decanyl, 8-oxa-2-azaspiro[4.5]decanyl, 8-thia-1-azaspiro[4.5]decanyl, 8-thia-2-azaspiro[4.5]decanyl, 9-oxa-6-azaspiro[4.5]decanyl, 9-thia-6-azaspiro[4.5]decanyl, 2-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 2-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 2-oxabicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[3.1.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 2-thiabicyclo[2.2.1]heptanyl, 7-thiabicyclo[2.2.1]heptanyl, 2-thiabicyclo[3.1.1]heptanyl, 3-thiabicyclo[3.1.1]heptanyl, 6-thiabicyclo[3.1.1]heptanyl, 2-oxabicyclo[3.2.1]octanyl, 3-oxabicyclo[3.2.1]octanyl, 6-oxabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, 2-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 6-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-thiabicyclo[3.2.1]octanyl, 3-thiabicyclo[3.2.1]octanyl, 6-thiabicyclo[3.2.1]octanyl, 8-thiabicyclo[3.2.1]octanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-2-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-6-azabicyclo[3.2.1]octanyl, 2-thia-5-azabicyclo[2.2.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-thia-3-azabicyclo[3.1.1]heptanyl, 2-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-8-azabicyclo[3.2.1]octanyl, 8-thia-2-azabicyclo[3.2.1]octanyl, 8-thia-3-azabicyclo[3.2.1]octanyl, or 8-thia-6-azabicyclo[3.2.1]octanyl, each of which is substituted with one or more independently selected R 10< . In another particular embodiment, R 4< is 4-11 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected R 10< . In a more particular embodiment, R 4< is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1-thia-6-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, or 1-oxa-3,8-diazaspiro[4.5]decanyl, each of which is substituted with one or more independently selected R 10< . In another more particular embodiment, R 4< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-azaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 1-thia-6-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-thia-6-azaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 6-thia-1-azaspiro[3.3]heptanyl, 1-azaspiro[3.4]octanyl, 1-oxa-6-azaspiro[3.4]octanyl, 1-thia-6-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 2-oxa-5-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-thia-5-azaspiro[3.4]octanyl, 2-thia-6-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-oxa-6-azaspiro[3.5]nonanyl, 1-thia-6-azaspiro[3.5]nonanyl, 2,8-dioxa-5-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-8-thia-5-azaspiro[3.5]nonanyl, 2-thia-6-azaspiro[3.5]nonanyl, 5-oxa-8-azaspiro[3.5]nonanyl, 5-thia-8-azaspiro[3.5]nonanyl, 8-oxa-5-azaspiro[3.5]nonanyl, 8-thia-5-azaspiro[3.5]nonanyl, 1-azaspiro[4.5]decanyl, 1-oxa-3,8-diazaspiro[4.5]decanyl, 1-oxa-7-azaspiro[4.5]decanyl, 1-oxa-8-azaspiro[4.5]decanyl, 1-thia-3,8-diazaspiro[4.5]decanyl, 1-thia-7-azaspiro[4.5]decanyl, 1-thia-8-azaspiro[4.5]decanyl, 2-azaspiro[4.5]decanyl, 2-oxa-6-azaspiro[4.5]decanyl, 2-oxa-7-azaspiro[4.5]decanyl, 2-oxa-8-azaspiro[4.5]decanyl, 2-thia-6-azaspiro[4.5]decanyl, 2-thia-7-azaspiro[4.5]decanyl, 2-thia-8-azaspiro[4.5]decanyl, 6-azaspiro[4.5]decanyl, 6-oxa-2-azaspiro[4.5]decanyl, 6-oxa-9-azaspiro[4.5]decanyl, 6-thia-2-azaspiro[4.5]decanyl, 6-thia-9-azaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 7-oxa-1-azaspiro[4.5]decanyl, 7-oxa-2-azaspiro[4.5]decanyl, 7-thia-1-azaspiro[4.5]decanyl, 7-thia-2-azaspiro[4.5]decanyl, 8-azaspiro[4.5]decanyl, 8-oxa-1-azaspiro[4.5]decanyl, 8-oxa-2-azaspiro[4.5]decanyl, 8-thia-1-azaspiro[4.5]decanyl, 8-thia-2-azaspiro[4.5]decanyl, 9-oxa-6-azaspiro[4.5]decanyl, 9-thia-6-azaspiro[4.5]decanyl, 2-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 2-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 2-oxabicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[3.1.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 2-thiabicyclo[2.2.1]heptanyl, 7-thiabicyclo[2.2.1]heptanyl, 2-thiabicyclo[3.1.1]heptanyl, 3-thiabicyclo[3.1.1]heptanyl, 6-thiabicyclo[3.1.1]heptanyl, 2-oxabicyclo[3.2.1]octanyl, 3-oxabicyclo[3.2.1]octanyl, 6-oxabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, 2-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 6-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-thiabicyclo[3.2.1]octanyl, 3-thiabicyclo[3.2.1]octanyl, 6-thiabicyclo[3.2.1]octanyl, 8-thiabicyclo[3.2.1]octanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-2-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-6-azabicyclo[3.2.1]octanyl, 2-thia-5-azabicyclo[2.2.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-thia-3-azabicyclo[3.1.1]heptanyl, 2-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-8-azabicyclo[3.2.1]octanyl, 8-thia-2-azabicyclo[3.2.1]octanyl, 8-thia-3-azabicyclo[3.2.1]octanyl, or 8-thia-6-azabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected R 10< . In a most particular embodiment, R 4< is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1-thia-6-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, or 1-oxa-3,8-diazaspiro[4.5]decanyl, each of which is substituted with one, two, or three independently selected R 10< .

[0168] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10< . In a particular embodiment, R 4< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 2-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 2-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 2-oxabicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[3.1.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 2-thiabicyclo[2.2.1]heptanyl, 7-thiabicyclo[2.2.1]heptanyl, 2-thiabicyclo[3.1.1]heptanyl, 3-thiabicyclo[3.1.1]heptanyl, 6-thiabicyclo[3.1.1]heptanyl, 2-oxabicyclo[3.2.1]octanyl, 3-oxabicyclo[3.2.1]octanyl, 6-oxabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, 2-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 6-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-thiabicyclo[3.2.1]octanyl, 3-thiabicyclo[3.2.1]octanyl, 6-thiabicyclo[3.2.1]octanyl, 8-thiabicyclo[3.2.1]octanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-2-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-6-azabicyclo[3.2.1]octanyl, 2-thia-5-azabicyclo[2.2.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-thia-3-azabicyclo[3.1.1]heptanyl, 2-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-8-azabicyclo[3.2.1]octanyl, 8-thia-2-azabicyclo[3.2.1]octanyl, 8-thia-3-azabicyclo[3.2.1]octanyl, or 8-thia-6-azabicyclo[3.2.1]octanyl, each of which is substituted with one or more independently selected R 10< . In another particular embodiment, R 4< is 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected R 10< . In a more particular embodiment, R 4< is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, each of which is substituted with one or more independently selected R 10< . In another more particular embodiment, R 4< is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 2-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 2-thiabicyclo[2.1.1]hexanyl, 5-thiabicyclo[2.1.1]hexanyl, 2-oxabicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[3.1.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 2-thiabicyclo[2.2.1]heptanyl, 7-thiabicyclo[2.2.1]heptanyl, 2-thiabicyclo[3.1.1]heptanyl, 3-thiabicyclo[3.1.1]heptanyl, 6-thiabicyclo[3.1.1]heptanyl, 2-oxabicyclo[3.2.1]octanyl, 3-oxabicyclo[3.2.1]octanyl, 6-oxabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, 2-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 6-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-thiabicyclo[3.2.1]octanyl, 3-thiabicyclo[3.2.1]octanyl, 6-thiabicyclo[3.2.1]octanyl, 8-thiabicyclo[3.2.1]octanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-2-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-6-azabicyclo[3.2.1]octanyl, 2-thia-5-azabicyclo[2.2.1]heptanyl, 3-thia-6-azabicyclo[3.1.1]heptanyl, 6-thia-3-azabicyclo[3.1.1]heptanyl, 2-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-6-azabicyclo[3.2.1]octanyl, 3-thia-8-azabicyclo[3.2.1]octanyl, 8-thia-2-azabicyclo[3.2.1]octanyl, 8-thia-3-azabicyclo[3.2.1]octanyl, or 8-thia-6-azabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected R 10< . In a most particular embodiment, R 4< is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R 10< .

[0169] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10< , and R 10< is as previously described. In a particular embodiment, R 10< is -OH, phenyl, =NH, halo, oxo, -CN, -C(=O)H, -C(=O)NH 2 , -C(=O)OH, -NR 14a< R 14b< , C 1-4 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, -C(=O)-C 1-4 alkoxy, or C 1-4 alkoxy, C 3-7 cycloalkyl, 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, -C(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl, or -C(=O)-C 1-6 alkoxy. In a more particular embodiment, R 10< is -OH, phenyl, =NH, F, Cl, Br, oxo, -CN, - C(=O)H, -C(=O)NH 2 , -C(=O)OH, -NR 14a< R 14b< , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CN, -CH 2 -CH 2 -CN, -CH(CH 3 )-CN, -C(CH 3 ) 2 -CN, -CH(CH 3 )-CH 2 -CN, -CH 2 -C(CH 3 ) 2 -CN, -CH 2 -OH, -CH 2 -CH 2 -OH, -CH(CH 3 )-OH, -C(CH 3 ) 2 -OH, -CH(CH 3 )-CH 2 -OH, -CH 2 -C(CH 3 ) 2 -OH, -CH 2 -C(=O)-O-CH 3 , -CH 2 -C(=O)-O-CH 2 -CH 3 , -CH 2 -CH 2 -C(=O)-O-CH 3 , -CH 2 -CH 2 -C(=O)-O-CH 2 -CH 3 , -CH(CH 3 )-C(=O)-O-CH 3 , -CH(CH 3 )-C(=O)-O-CH 2 -CH 3 , -C(CH 3 ) 2 -C(=O)-O-CH 3 , -C(CH 3 ) 2 -C(=O)-O-CH 2 -CH 3 , -CH(CH 3 )-CH 2 -C(=O)-O-CH 3 , -CH(C H 3 )-CH 2 -C(=O)-O-CH 2 -CH 3 , -CH 2 -CH(CH 3 )-C(=O)-O-CH 3 , -CH 2 -CH(CH 3 )-C(=O)-O-CH 2 -CH 3 , -CH 2 -C (CH 3 ) 2 -C(=O)-O-CH 3 , -CH 2 -C(CH 3 ) 2 -C(=O)-O-CH 2 -CH 3 , -CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , -C(=O)-CH(CH 3 ) 2 , -S(=O) 2 -CH 3 , -S(=O) 2 -CH 2 CH 3 , -S(=O) 2 -CH(CH 3 ) 2 , -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , -C(=O)-O-CH( CH 3 ) 2 , or -C(=O)-O-C(CH 3 ) 3 . In a most particular embodiment, R 10< is -OH, phenyl, =NH, F, oxo, -CN, -C(=O)H, -NR 14a< R 14b< , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CN, -C H 2 -CH 2 -CN, -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -C(CH 3 ) 2 -OH, -CH 2 -C(=O)-O-CH 2 -CH 3 , -CH 2 -O-CH 3 , cyclopropyl, oxetanyl, -C(=O)-CH 3 , -S(=O) 2 -CH 3 , -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , or -C(=O)-O-C(CH 3 ) 3 .

[0170] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10< , and R 10< is as previously described. In a particular embodiment, R 10< is halo, oxo, -CN, -C(=O)H, -NR 14a< R 14b< , C 1-4 alkyl optionally substituted with one or more independently selected halo or C 1-4 alkoxy, C 3-7 cycloalkyl, -C(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl, or-C(=O)-C 1-6 alkoxy. In a more particular embodiment, R 10< is F, Cl, Br, oxo, -CN, -C(=O)H, -NR 14a< R 14< , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -O-CH 3 , -CH 2 CH 2 -O-CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , -C(=O)-CH(CH 3 ) 2 , -S(=O) 2 -CH 3 , -S(=O) 2 -CH 2 CH 3 , -S(=O) 2 -CH(CH 3 ) 2 , -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , -C(=O)-O-CH(CH 3 ) 2 , or -C(=O)-O-C(CH 3 ) 3 . In a most particular embodiment, R 10< is F, oxo, -CN, -C(=O)H, -NR 14a< R 14< , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -O-CH 3 , cyclopropyl, -C(=O)-CH 3 , -S(=O) 2 -CH 3 , -C(=O)-O-CH 3 , or -C(=O)-O-C(CH 3 ) 3 .

[0171] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10< , R 10< is -NR 14a< R 14< , and R 14a< and R 14b< are as previously described. In a particular embodiment, R 14a< and R 14b< are both H. In another particular embodiment, one of R 14a< and R 14b< is H, and the other is C 1-4 alkyl or -S(=O) 2 -C 1-4 alkyl. In yet another particular embodiment, R 14a< and R 14b< are independently C 1-4 alkyl or -S(=O) 2 -C 1-4 alkyl. In a more particular embodiment, one of R 14a< and R 14b< is H, and the other is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -S(=O) 2 -CH 3 . In another more particular embodiment, R 14a< and R 14b< are independently -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -S(=O) 2 -CH 3 .

[0172] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 10< , R 10< is -NR 14a< R 14< , and R 14a< and R 14b< are as previously described. In a particular embodiment, R 14a< and R 14b< are both H. In another particular embodiment, one of R 14a< and R 14b< is H, and the other is C 1-4 alkyl. In yet another particular embodiment, R 14a< and R 14b< are both C 1-4 alkyl. In a more particular embodiment, one of R 14a< and R 14b< is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another more particular embodiment, R 14a< and R 14b< are independently -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .

[0173] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -NR 11a< R 11b< , and R 11a< and R 11b< are as previously described. In a particular embodiment, R 11a< is H. In another particular embodiment, R 11a< is C 1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, or C 1-4 alkoxy. In a more particular embodiment, R 11a< is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -CH 2 CHF 2 . In a most particular embodiment, R 11a< is -CH 3 .

[0174] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -NR 11a< R 11b< , R 11a< is as previously described, and R 11b< is H or phenyl. In a most particular embodiment, R 4< is -NH 2 .

[0175] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -NR 11a< R 11b< , R 11a< is as previously described, and R 11b< is C 1-4 alkyl. In a particular embodiment, R 11b< is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a more particular embodiment, R 4< is -NH-CH 3 , -N(CH 3 ) 2 , -NH-CH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -N(CH(CH 3 ) 2 ) 2 , or -N(CH 3 )-CH 2 CHF 2 .

[0176] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -NR 11a< R 11b< , R 11a< is as previously described, and R 11b< is C 1-4 alkyl substituted with one or more independently selected halo, -OH, -CN, or C 1-4 alkoxy. In a particular embodiment, R 11b< is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo, -OH, -CN, or C 1-4 alkoxy. In another particular embodiment, R 11b< is C 1-4 alkyl substituted with one, two, or three independently selected halo, -OH, -CN, or C 1-4 alkoxy. In yet another particular embodiment, R 11b< is C 1-4 alkyl substituted with one or more independently selected halo, -OH, -CN, -O-CH 3 , -O-CH 2 CH 3 , or-O-CH(CH 3 ) 2 . In a more particular embodiment, R 11b< is -CH 3 , or -CH 2 CH 3 , each of which is substituted with one F, -OH, -CN, or -O-CH 3 . In a most particular embodiment, R 11b< is -CH 2 -CN, -CH 2 CH 2 -OH, or -CH 2 CH 2 -O-CH 3 .

[0177] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -NR 11a< R 11b< , R 11a< is as previously described, and R 11b< is C 3-7 cycloalkyl. In a particular embodiment, R 11b< is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more particular embodiment, R 11b< is cyclopropyl.

[0178] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -NR 11a< R 11b< , R 11a< is as previously described, and R 11b< is -C(=O)-C 1-4 alkoxy. In a particular embodiment, R 11b< is -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , or -C(=O)-O-CH(CH 3 ) 2 . In a more particular embodiment, R 11b< is -C(=O)-O-CH 3 .

[0179] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -NR 11a< R 11b< , R 11a< is as previously described, and R 11b< is -C(=O)-C 1-4 alkyl. In a particular embodiment, R 11b< is -C(=O)-CH 3 , -C(=O)-CH 2 CH 3 , or -C(=O)-CH(CH 3 ) 2 . In a more particular embodiment, R 11b< is -C(=O)-CH 3 .

[0180] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -NR 11a< R 11b< , R 11a< is as previously described, and R 11b< is -C(=O)-C 1-4 alkyl substituted with one or more independently selected halo. In a particular embodiment, R 11b< is -C(=O)-CH 3 ,-C(=O)-CH 2 CH 3 , or -C(=O)-CH(CH 3 ) 2 , each of which is substituted with one, two, or three F, Cl, or Br. In a more particular embodiment, R 11b< is -C(=O)-CH 3 substituted with one, two, or three F. In a most particular embodiment, R 11b< is -C(=O)-CHF 2 .

[0181] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -NR 11a< R 11b< , R 11a< is as previously described, and R 11b< is 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R 11b< is pyrrolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, furazanyl, thiadiazolyl, oxadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl. In a more particular embodiment, R 11b< is pyridinyl, pyridazinyl, or pyrimidinyl.

[0182] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -C(=O)-C 1-4 alkoxy. In a particular embodiment, R 4< is -C(=O)-O-CH 3 , -C(=O)-O-CH 2 CH 3 , or -C(=O)-O-CH(CH 3 ) 2 . In a more particular embodiment, R 4< is -C(=O)-O-CH 2 CH 3 .

[0183] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf, wherein R 4< is -C(=O)-NR 12a< R 12b< , and each R 12a< and R 12b< are as previously described. In a particular embodiment, R 12a< and R 12b< are both H. In another particular embodiment, one of R 12a< and R 12b< is H, and the other is C 1-4 alkyl. In yet another particular embodiment, R 12a< and R 12b< are both C 1-4 alkyl. In a more particular embodiment, one of R 12a< and R 12b< is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another more particular embodiment, each R 12a< and R 12b< is independently -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a most particular embodiment, R 12a< and R 12b< are -CH 3 .

[0184] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is selected from: N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-tetrahydropyran-4-yloxyimidazo[1,2-a]pyridin-3-yl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methyl-3-piperidyl)oxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-methoxy-2-methyl-propoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 2,6-dimethoxy-4-(7-tetrahydropyran-4-yloxyimidazo[1,2-a]pyridin-3-yl)-N-(2,2,2-trifluoroethyl)benzamide, 2,6-dimethoxy-4-[7-[(1-methyl-3-piperidyl)oxy]imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methyl-4-piperidyl)oxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(4-methylpiperazin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-methyl-2-morpholino-propoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methyl-2-morpholino-ethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(dimethylamino)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methylpyrrolidin-3-yl)oxyimidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(1-methylpyrrolidin-2-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(3-methylimidazol-4-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-pyrrolidin-1-ylethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-morpholinopropoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(1-methyl-2-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methyl-4-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methyl-5-oxo-pyrrolidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(2-acetamidoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylpyrrolidin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methylazetidin-3-yl)oxyimidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, 4-[7-(2-cyanoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxazol-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxazol-5-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(2-cyano-2-methyl-propoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxetan-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-fluoroethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(ethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(2-methoxyethoxy)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 8-methoxy-6-[7-[(1-methylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[2-(1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-4-[7-[(2,2-difluorocyclopropyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-pyridylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(2-methylpyrazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2,2,2-trifluoro-1-methyl-ethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(thiazol-4-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(thiazol-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(tetrahydropyran-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(tetrahydropyran-4-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-fluoro-6-methoxybenzamide, N-cyclopropyl-4-[7-[(3,3-difluorocyclobutyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, 6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-ethyl-8-methoxy-3,4-dihydroisoquinolin-1-one, 2-(2,2-difluoroethyl)-6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-(3-morpholinopropoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2-ethoxyethoxy)-6-methoxy-benzamide, methyl 1-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]cyclopropanecarboxylate, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-norboman-2-yloxyimidazo[1,2-a]pyridin-3-yl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(tetrahydropyran-3-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxazol-4-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(cyclopentylmethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-4-[7-(3,3-difluorocyclopentoxy)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(2-oxopyrrolidin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-tetrahydropyran-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-[2-(dimethylamino)ethoxy]ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2,2-dimethylpropoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, 2-[6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-1-oxo-3,4-dihydroisoquinolin-2-yl]acetonitrile, 4-(7-benzyloxyimidazo[1,2-a]pyridin-3-yl)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(cyclohexylmethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(cyclobutylmethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-ethoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(2-hydroxyethoxy)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(3-hydroxy-2,2-dimethyl-propoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[(3,3-difluorocyclopentyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-(3,3-difluorocyclobutyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-4-[7-(4,4-difluorocyclohexoxy)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(diisopropylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-[[(2R)-1-(2,2-difluoroethyl)pyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(4-methylmorpholin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-ethyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 8-methoxy-6-[7-[(2-methylpyrazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[(3-methylimidazol-4-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, tert-butyl 2-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl] oxymethyl] azetidine-1-carboxylate, 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(3-methyloxetan-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-(2,2-difluoroethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(tetrahydrofuran-3-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(tetrahydrofuran-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(pyrimidin-2-ylmethoxy)imidazo[1,2-a]pyiidin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(thiazol-5-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-(cyclopropylmethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylcyclopropyl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1,4-dioxan-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(5-oxopyrrolidin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)-2-oxo-ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylimidazol-4-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(5-oxopyrrolidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(4-pyridylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(2-amino-2-methyl-propoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-pyridylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)-2-methyl-propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-(diethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[(3-aminocyclobutyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(azetidin-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylimidazol-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(2R)-1-methyl-2-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-[2-(azetidin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(morpholin-3-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(2-hydroxyethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(3-aminopropoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, 4-[7-[[1-(aminomethyl)cyclobutyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(methylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(2-aminoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-piperidylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(2S)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(2-amino-3-methyl-butoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 8-methoxy-6-[7-[2-(1-methylpyrrolidin-2-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-(2-pyrrolidin-1-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-(oxetan-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-(oxazol-5-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[(4-methylmorpholin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-[2-(diethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylsulfonyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, methyl 2-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]piperidine-1-carboxylate, 4-[7-(2-aminobutoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, 4-[7-[(2S)-2-amino-4-methyl-pentoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[(2S)-2-amino-2-cyclohexyl-ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-amino-2-tetrahydrofuran-3-yl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-amino-2-tetrahydropyran-4-yl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-amino-2-tetrahydrofuran-2-yl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-amino-2-cyclopropyl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-aminopropoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(2S)-1-methyl-2-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-ethoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 4-[7-[(1-acetyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-formyl-3-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-piperidylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylpyrrolidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-pyridyloxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-fluoro-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-(methylamino)benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-isopropyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[[1-(2,2-difluoroethyl)-2-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, 2-(2,2-difluoroethyl)-8-(difluoromethoxy)-6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one, 4-[7-(cyclobutoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxetan-3-yloxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-methyl-2-(methylamino)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(pyrrolidin-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-fluoro-N-(2,2,2-trifluoroethyl)benzamide, N-cyclopropyl-2,6-bis(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-phenoxyimidazo[1,2-a]pyridin-3-yl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[2-(methoxymethyl)morpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-(7-benzyloxyimidazo[1,2-c]pyrimidin-3-yl)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-[(3S)-3-fluoropyrrolidin-l-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(methylamino)cyclobutoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-oxaspiro[3.3]heptan-6-yloxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-tetrahydrofuran-3-yloxyimidazo[1,2-a]pyridin-3-yl)benzamide, 4-[7-(3-cyanocyclobutoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, 2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-(methylamino)-N-(2,2,2-trifluoroethyl)benzamide, 2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-N-(2,2,2-trifluoroethyl)benzamide, 6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-(methylamino)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(2-methylpyrrolidin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-[(1-aminocyclohexyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[(3-aminooxetan-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[(1-aminocyclopropyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(2-methyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-ethylimidazol-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[(1-aminocyclobutyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-isopropylimidazol-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[(3-aminotetrahydrofuran-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(2,6-dimethylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[2-(3-cyanomorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[2-(trifluoromethyl)morpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(4,4-difluoro-1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[1-(2,2,2-trifluoroethyl)-2-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[methyl(2-pyridyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(N-methylanilino)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 8-methoxy-6-[7-[2-(methylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-4-[7-[2-(3,3-difluoroazetidin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, tert-butyl 3-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]-3-fluoro-azetidine-1-carboxylate, tert-butyl 3-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]-3-methyl-azetidine-1 -carboxylate, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 8-methoxy-6-[7-[[(2R)-4-methylmorpholin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[[(2S)-4-methylmorpholin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(3,3-dimethylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(2,2-dimethylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-[2-(2-cyclopropylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, 2-cyclopropyl-8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(2,5-dimethylpyrazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylpyrazol-4-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylpyrazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(4-methylmorpholin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)butoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(1-methylpyrazol-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(3-fluoroazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(3-methylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-1,1-dimethyl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-2H-isoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(3,3-difluoro-1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(3-fluoro-1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[2-(2-cyanomorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(2-methylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-[2-[cyanomethyl(methyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[2-(3-cyano-1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, 2-(2,2-difluoroethyl)-8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one, 2-(2,2-difluoroethyl)-6-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1,3-dimethylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)isoquinolin-1-one, N-cyclopropyl-2-methoxy-6-methyl-4-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[methyl(4-pyridyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 2-cyclopropyl-8-(difluoromethoxy)-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one, 6-[7-[[(2S)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(pyridazin-3-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(4-methyl-1,2,4-triazol-3-yl)methoxy]imidazo1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(3-methyl-2-oxo-oxazolidin-5-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 2-(difluoromethoxy)-6-methoxy-4-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(3-methylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[(3S)-3-methylmorpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[(3R)-3-methylmorpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-[2-[cyclopropyl(2,2-difluoroethyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-[2,2-difluoroethyl(methyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-[2,2-difluoroethyl(2-methoxyethyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[methyl(pyrimidin-2-yl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[methyl(pyrimidin-4-yl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[methyl(pyridazin-4-yl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methyl-4-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 6-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-3,4-dihydro-2H-isoquinolin-1-one, 2-(difluoromethoxy)-6-methyl-4-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide, 6-[7-[2-(3,3-difluoroazetidin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 2-(2,2-difluoroethyl)-8-(difluoromethoxy)-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one, tert-butyl 3-fluoro-3-[[3-[8-methoxy-1-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-6-yl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]azetidine-1-carboxylate, tert-butyl 3-[[3-[8-methoxy-1-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-6-yl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]-3-methyl-azetidine-1-carboxylate, 6-[7-[(3-fluoroazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[(3-methylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-[(3-fluoro-1-methyl-azetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-[(1,3-dimethylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-3-methoxy-5-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]pyridine-2-carboxamide, 4-[7-(1-cyanocyclopentoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, 8-methoxy-6-(7-methoxyimidazo[1,2-a]pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[2-[(3S)-3-methylmorpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[2-[(3R)-3-methylmorpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-methoxy-1,1-dimethyl-ethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 3-methoxy-5-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide, 3-methoxy-5-[7-[(2-methylpyrazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide, 4-[7-(1-cyano-1-methyl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 6-(7-ethoxyimidazo[1,2-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 5-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-3-methoxy-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide, 3-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-6-(2,2,2-trifluoroethyl)-5H-pyrrolo[3,4-b]pyridin-7-one, N-cyclopropyl-3-(difluoromethoxy)-5-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]pyridine-2-carboxamide, ethyl 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxyacetate, 4-[7-[[1-(cyanomethyl)-2-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[[(1R,5S)-8-azabicyclo[3.2.1]octan-3-yl]oxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[[(1S,5R)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl]oxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, ethyl 2-[(1R,5S)-3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxy-8-azabicyclo[3.2.1]octan-8-yl]acetate, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-[3-(azetidin-1-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-pyrrolidin-1-ylpropoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(4-isopropylpiperazin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(4-hydroxy-1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-piperazin-1-ylpropoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(4-isopropylpiperazin-1-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-isopropyl-3-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(8-oxa-5-azaspiro[3.5]nonan-5-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl acetate, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(4-isopropylmorpholin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(2-oxa-7-azaspiro[3.4]octan-7-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(3-hydroxyazetidin-1-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-isopropylpyrrolidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[1-(oxetan-3-yl)pyrrolidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[1-(oxetan-3-yl)pyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(2,6-dimethyl-1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-[3-(2-azaspiro[3.3]heptan-2-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(2,6-dimethyl-1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-isopropylpyrrolidin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(2,8-dioxa-5-azaspiro[3.5]nonan-5-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-[2-(4-isopropylpiperazin-1-yl)ethoxy]ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[1-(oxetan-3-yl)pyrrolidin-2-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(6-oxa-1-azaspiro[3.3]heptan-1-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(1-isopropylpyrrolidin-2-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[3-(1-azaspiro[3.3]heptan-1-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(2-oxa-8-azaspiro[3.5]nonan-8-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[2-(1-piperidyl)ethoxy]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(2-morpholinoethoxy)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-[2-[2-(diethylamino)ethoxy]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-[4-(2-hydroxyethyl)piperazin-1-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(1-methyl-6,7-dihydro-4H-imidazo[4,5-c]pyridin-5-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(3S)-pyrrolidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(3S)-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(3S)-1-isopropylpyrrolidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(3S)-1-(oxetan-3-yl)pyrrolidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(3S)-1-(oxetan-3-yl)-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(3-hydroxypyrrolidin-1-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-hydroxy-3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[[1-(cyanomethyl)azetidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[[1-(2-cyanoethyl)azetidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-[4-[methyl(methylsulfonyl)amino]-1-piperidyl]propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(1-imino-1-oxo-1,4-thiazinan-4-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(3-hydroxy-1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(3S)-1-isopropyl-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-3-morpholino-propoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(1,1-dioxo-1,4-thiazinan-4-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(1,1-dioxo-«Â»^{6}-thia-6-azaspiro[3.3]heptan-6-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl methanesulfonate, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(3R)-pyrrolidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(3R)-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(3R)-1-isopropylpyrrolidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(3R)-1-isopropyl-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(3R)-1-(oxetan-3-yl)-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(3S)-1-(2-hydroxyethyl)-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(3S)-1-(2-hydroxyethyl)pyrrolidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[1-(2-hydroxy-2-methyl-propyl)azetidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[1-(2-hydroxyethyl)azetidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[3-(4,4-difluoro-3-hydroxy-1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-4-[7-[3-(3,3-difluoro-4-hydroxy-pyrrolidin-1-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[3-(3-cyano-1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(4-methylsulfonyl-1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(3R)-1-(2-hydroxyethyl)pyrrolidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[[(3S)-1-(2-cyanoethyl)pyrrolidin-3-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[[(3S)-1-(2-cyanoethyl)-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-[(2R,6S)-2,6-dimethyl-1-piperidyl]propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 2-(difluoromethoxy)-N-[(1S,2R)-2-hydroxycyclobutyl]-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 2-(difluoromethoxy)-N-[(1R,2S)-2-hydroxycyclobutyl]-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, [2-(difluoromethoxy)-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]phenyl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone, 2-[1-[2-(difluoromethoxy)-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzoyl]-3-hydroxy-azetidin-3-yl]acetonitrile, N-(cyanomethyl)-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 1-[2-(difluoromethoxy)-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzoyl]azetidine-3-carbonitrile, [2-(difluoromethoxy)-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]phenyl]-[3-(difluoromethyl)-3-hydroxy-azetidin-1-yl]methanone, 2-(difluoromethoxy)-N-[(1R,2R)-2-hydroxycyclobutyl]-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 2-(difluoromethoxy)-N-[(1S,2S)-2-hydroxycyclobutyl]-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl]-4-fluoro-piperidine-4-carboxamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(3-hydroxy-3-methyl-azetidin-1-yl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, ethyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl]-4-fluoro-piperidine-4-carboxylate, 4-[7-(3-amino-2,2-difluoro-propoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, methylN-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxy-2,2-difluoro-propyl]carbamate, 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl]-4-fluoro-piperidine-4-carboxylic acid, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(2-pyridylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(pyrimidin-2-ylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(pyrimidin-4-ylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-[(2,2-difluoroacetyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(3-hydroxy-1-isopropyl-pyrrolidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(3R,4S)-4-hydroxy-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(3S,4R)-4-hydroxy-3-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(1,1-dioxo-1,4-thiazinan-4-yl)-2-hydroxy-propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-hydroxy-3-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-hydroxy-3-[(3R)-3-hydroxypyrrolidin-1-yl]propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, ethyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl]piperidine-4-carboxylate, ethyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl]-4-phenyl-piperidine-4-carboxylate, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-hydroxy-3-(4-hydroxy-1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, ethyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl]-4-methyl-piperidine-4-carboxylate, ethyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl]-4-hydroxy-piperidine-4-carboxylate, ethyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxy-2-hydroxy-propyl]-4-methyl-piperidine-4-carboxylate, ethyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxy-2-hydroxy-propyl]-4-hydroxy-piperidine-4-carboxylate, ethyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxy-2-hydroxy-propyl]-4-fluoro-piperidine-4-carboxylate, ethyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl]-3-methyl-azetidine-3-carboxylate, methyl (2S)-4-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxy-2-hydroxy-propyl]morpholine-2-carboxylate, methyl (2S)-4-[2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxyethyl]morpholine-2-carboxylate, ethyl 1-[2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxyethyl]-4-fluoro-piperidine-4-carboxylate, tert-butyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl]azetidine-3-carboxylate, ethyl 1-[2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxyethyl]piperidine-3-carboxylate, methyl 1-[2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxyethyl]azetidine-3-carboxylate, tert-butyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxy-2-hydroxy-propyl]azetidine-3-carboxylate, ethyl 1-[3-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxypropyl]piperidine-3-carboxylate, 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxyacetic acid, and ethyl 2-[2-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]-1-piperidyl]acetate.

[0185] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is selected from: N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-tetrahydropyran-4-yloxyimidazo[1,2-a]pyridin-3-yl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methyl-3-piperidyl)oxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-methoxy-2-methyl-propoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 2,6-dimethoxy-4-(7-tetrahydropyran-4-yloxyimidazo[1,2-a]pyridin-3-yl)-N-(2,2,2-trifluoroethyl)benzamide, 2,6-dimethoxy-4-[7-[(1-methyl-3-piperidyl)oxy]imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methyl-4-piperidyl)oxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(4-methylpiperazin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-methyl-2-morpholino-propoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methyl-2-morpholino-ethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[3-(dimethylamino)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methylpyrrolidin-3-yl)oxyimidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(1-piperidyl)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(1-methylpyrrolidin-2-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(3-methylimidazol-4-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-pyrrolidin-1-ylethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-morpholinopropoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(1-methyl-2-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methyl-4-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methyl-5-oxo-pyrrolidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(2-acetamidoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylpyrrolidin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methylazetidin-3-yl)oxyimidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, 4-[7-(2-cyanoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxazol-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxazol-5-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(2-cyano-2-methyl-propoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxetan-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-fluoroethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(ethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(2-methoxyethoxy)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 8-methoxy-6-[7-[(1-methylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[2-(1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-4-[7-[(2,2-difluorocyclopropyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-pyridylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(2-methylpyrazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2,2,2-trifluoro-1-methyl-ethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(thiazol-4-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(thiazol-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(tetrahydropyran-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(tetrahydropyran-4-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-fluoro-6-methoxy-benzamide, N-cyclopropyl-4-[7-[(3,3-difluorocyclobutyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, 6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-ethyl-8-methoxy-3,4-dihydroisoquinolin-1-one, 2-(2,2-difluoroethyl)-6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-(3-morpholinopropoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2-ethoxyethoxy)-6-methoxy-benzamide, methyl 1-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]cyclopropanecarboxylate, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-norboman-2-yloxyimidazo[1,2-a]pyridin-3-yl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(tetrahydropyran-3-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxazol-4-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(cyclopentylmethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-4-[7-(3,3-difluorocyclopentoxy)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(2-oxopyrrolidin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-tetrahydropyran-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-[2-(dimethylamino)ethoxy]ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2,2-dimethylpropoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, 2-[6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-1-oxo-3,4-dihydroisoquinolin-2-yl]acetonitrile, 4-(7-benzyloxyimidazo[1,2-a]pyridin-3-yl)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(cyclohexylmethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(cyclobutylmethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-ethoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(2-hydroxyethoxy)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(3-hydroxy-2,2-dimethyl-propoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[(3,3-difluorocyclopentyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-(3,3-difluorocyclobutyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-4-[7-(4,4-difluorocyclohexoxy)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(diisopropylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-yclopropyl-4-[7-[[(2R)-1-(2,2-difluoroethyl)pyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(4-methylmorpholin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-ethyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 8-methoxy-6-[7-[(2-methylpyrazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[(3-methylimidazol-4-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, tert-butyl 2-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl] oxymethyl] azetidine-1-carboxylate, 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(3-methyloxetan-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-(2,2-difluoroethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(tetrahydrofuran-3-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(tetrahydrofuran-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(pyrimidin-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(thiazol-5-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-(cyclopropylmethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylcyclopropyl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(1,4-dioxan-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(5-oxopyrrolidin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)-2-oxo-ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylimidazol-4-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(5-oxopyrrolidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(4-pyridylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(2-amino-2-methyl-propoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-pyridylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)-2-methyl-propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-(diethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[(3-aminocyclobutyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(azetidin-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylimidazol-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(2R)-1-methyl-2-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-[2-(azetidin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(morpholin-3-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(2-hydroxyethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(3-aminopropoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, 4-[7-[[1-(aminomethyl)cyclobutyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(methylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-(2-aminoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-piperidylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(2S)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-(2-amino-3-methyl-butoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 8-methoxy-6-[7-[2-(1-methylpyrrolidin-2-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-(2-pyrrolidin-1-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[[(2R)-1-methylpyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-(oxetan-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-(oxazol-5-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[(4-methylmorpholin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-[2-(diethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylsulfonyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, methyl 2-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]piperidine-1-carboxylate, 4-[7-(2-aminobutoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, 4-[7-[(2S)-2-amino-4-methyl-pentoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[(2S)-2-amino-2-cyclohexyl-ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-amino-2-tetrahydrofuran-3-yl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-amino-2-tetrahydropyran-4-yl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-amino-2-tetrahydrofuran-2-yl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-amino-2-cyclopropyl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-(2-aminopropoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[(2S)-1-methyl-2-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-ethoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 4-[7-[(1-acetyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-formyl-3-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(3-piperidylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylpyrrolidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-pyridyloxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-fluoro-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-(methylamino)benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-isopropyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-4-[7-[[1-(2,2-difluoroethyl)-2-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, 2-(2,2-difluoroethyl)-8-(difluoromethoxy)-6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one, 4-[7-(cyclobutoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(oxetan-3-yloxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-methyl-2-(methylamino)propoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(pyrrolidin-2-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-fluoro-N-(2,2,2-trifluoroethyl)benzamide, N-cyclopropyl-2,6-bis(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-phenoxyimidazo[1,2-a]pyridin-3-yl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[2-(methoxymethyl)morpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-(7-benzyloxyimidazo[1,2-c]pyrimidin-3-yl)-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-[(3S)-3-fluoropyrrolidin-l-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[3-(methylamino)cyclobutoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-oxaspiro[3.3]heptan-6-yloxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-(7-tetrahydrofuran-3-yloxyimidazo[1,2-a]pyridin-3-yl)benzamide, 4-[7-(3-cyanocyclobutoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, 2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-(methylamino)-N-(2,2,2-trifluoroethyl)benzamide, 2-(difluoromethoxy)-4-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-N-(2,2,2-trifluoroethyl)benzamide, 6-[7-[2-(dimethylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-(methylamino)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(2-methylpyrrolidin-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-[(1-aminocyclohexyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[(3-aminooxetan-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[(1-aminocyclopropyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(2-methyl-2-piperidyl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1-ethylimidazol-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[(1-aminocyclobutyl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-yclopropyl-2-(difluoromethoxy)-4-[7-[(1-isopropylimidazol-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[(3-aminotetrahydrofuran-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(2,6-dimethylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[2-(3-cyanomorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[2-(trifluoromethyl)morpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(4,4-difluoro-1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[[1-(2,2,2-trifluoroethyl)-2-piperidyl]methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[methyl(2-pyridyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(N-methylanilino)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 8-methoxy-6-[7-[2-(methylamino)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-4-[7-[2-(3,3-difluoroazetidin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, tert-butyl 3-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]-3-fluoro-azetidine-1-carboxylate, tert-butyl 3-[[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl] oxymethyl]-3-methyl-azetidine-1-carboxylate, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 8-methoxy-6-[7-[[(2R)-4-methylmorpholin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[[(2S)-4-methylmorpholin-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(3,3-dimethylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(2,2-dimethylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-[2-(2-cyclopropylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, 2-cyclopropyl-8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(2,5-dimethylpyrazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylpyrazol-4-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(1-methylpyrazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(4-methylmorpholin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)propoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(dimethylamino)butoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(1-methylpyrazol-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(3-fluoroazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(3-methylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2-hydroxy-1,1-dimethyl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-2H-isoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(3,3-difluoro-1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[2-(3-fluoro-1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 4-[7-[2-(2-cyanomorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(2-methylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 4-[7-[2-[cyanomethyl(methyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 4-[7-[2-(3-cyano-1-piperidyl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydro-2H-isoquinolin-1-one, 2-(2,2-difluoroethyl)-8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one, 2-(2,2-difluoroethyl)-6-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-4-[7-[(1,3-dimethylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-6-methoxy-benzamide, 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)isoquinolin-1-one, N-cyclopropyl-2-methoxy-6-methyl-4-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[methyl(4-pyridyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 2-cyclopropyl-8-(difluoromethoxy)-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one, 6-[7-[[(2S)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(pyridazin-3-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(4-methyl-1,2,4-triazol-3-yl)methoxy]imidazo1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(3-methyl-2-oxo-oxazolidin-5-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, 2-(difluoromethoxy)-6-methoxy-4-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-(3-methylmorpholin-4-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[(3S)-3-methylmorpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[(3R)-3-methylmorpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-4-[7-[2-[cyclopropyl(2,2-difluoroethyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-[2,2-difluoroethyl(methyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-4-[7-[2-[2,2-difluoroethyl(2-methoxyethyl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(difluoromethoxy)-6-methoxy-benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[methyl(pyrimidin-2-yl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[methyl(pyrimidin-4-yl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-[2-[methyl(pyridazin-4-yl)amino]ethoxy]imidazo[1,2-a]pyridin-3-yl]benzamide, N-cyclopropyl-2-(difluoromethoxy)-6-methyl-4-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 6-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-3,4-dihydro-2H-isoquinolin-1-one, 2-(difluoromethoxy)-6-methyl-4-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)benzamide, 6-[7-[2-(3,3-difluoroazetidin-1-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 2-(2,2-difluoroethyl)-8-(difluoromethoxy)-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one, tert-butyl 3-fluoro-3-[[3-[8-methoxy-1-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-6-yl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]azetidine-1-carboxylate, tert-butyl 3-[[3-[8-methoxy-l-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-6-yl]imidazo[1,2-a]pyridin-7-yl]oxymethyl]-3-methyl-azetidine-1-carboxylate, 6-[7-[(3-fluoroazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[(3-methylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-[(3-fluoro-1-methyl-azetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-[(1,3-dimethylazetidin-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-3-methoxy-5-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]pyridine-2-carboxamide, 4-[7-(1-cyanocyclopentoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, 8-methoxy-6-(7-methoxyimidazo[1,2-a]pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[2-[(3S)-3-methylmorpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 6-[7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 8-methoxy-6-[7-[2-[(3R)-3-methylmorpholin-4-yl]ethoxy]imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-methoxy-1,1-dimethyl-ethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, 3-methoxy-5-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide, 3-methoxy-5-[7-[(2-methylpyrazol-3-yl)methoxy]imidazo[1,2-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide, 4-[7-(1-cyano-1-methyl-ethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-benzamide, 6-(7-ethoxyimidazo[1,2-a]pyridin-3-yl)-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, 5-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-3-methoxy-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide, 3-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-6-(2,2,2-trifluoroethyl)-5H-pyrrolo[3,4-b]pyridin-7-one, and N-cyclopropyl-3-(difluoromethoxy)-5-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]pyridine-2-carboxamide.

[0186] In one embodiment, the compound of the invention according to Formula I is selected from N-cyclopropyl-2-(difluoromethoxy)-4-[7-(2,2-dimethoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-6-methoxybenzamide, 6-[7-(2,2-dimethoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one ethyl 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxy-2-methyl-propanoate, 4-[7-(azetidin-3-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]-N-cyclopropyl-2-(difluoromethoxy)-6-methoxybenzamide, 2-[3-[4-(cyclopropylcarbamoyl)-3-(difluoromethoxy)-5-methoxy-phenyl]imidazo[1,2-a]pyridin-7-yl]oxyethyl methanesulfonate, N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(pyrrolidin-3-ylmethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide, and N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(2-pyrrolidin-2-ylethoxy)imidazo[1,2-a]pyridin-3-yl]benzamide

[0187] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one.

[0188] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is not 8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one.

[0189] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is 6-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one.

[0190] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is not 6-[7-[[(2R)-1,4-dioxan-2-yl]methoxy]imidazo[1,2-a]pyridin-3-yl]-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one.

[0191] In one embodiment a compound of the invention is not an isotopic variant.

[0192] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0193] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.

[0194] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0195] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.

[0196] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable.

[0197] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above.

[0198] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.PHARMACEUTICAL COMPOSITIONS

[0199] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms.

[0200] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0201] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term 'unit dosage forms' refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules in the case of solid compositions. In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0202] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors. Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.

[0203] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier.

[0204] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability of the active ingredients or the formulation.

[0205] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0206] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania.

[0207] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences. (Remington 1985)

[0208] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention.Formulation 1 - Tablets

[0209] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.Formulation 2 - Capsules

[0210] A compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).Formulation 3 - Liquid

[0211] A compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.Formulation 4 - Tablets

[0212] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.Formulation 5 - Injection

[0213] A compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL.Formulation 6 - Topical

[0214] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.METHODS OF TREATMENT

[0215] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.

[0216] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of inflammatory diseases. In particular, the term inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis).

[0217] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of inflammatory diseases. In particular, the term inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis).

[0218] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with inflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis).

[0219] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a inflammatory diseases treatment agent. In particular, the term inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis).

[0220] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of autoinflammatory diseases. In particular, the term auto inflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.

[0221] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of autoinflammatory diseases. In particular, the term autoinflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.

[0222] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with auto inflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term auto inflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.

[0223] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a auto inflammatory diseases treatment agent. In particular, the term auto inflammatory diseases refers to Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behçets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still's disease.

[0224] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of autoimmune diseases. In particular, the term autoimmune diseases refers to COPD, asthma , bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.

[0225] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of autoimmune diseases. In particular, the term autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.

[0226] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with autoimmune diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term autoimmune diseases refers to COPD, asthma , bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.

[0227] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is an autoimmune diseases treatment agent. In particular, the term autoimmune diseases refers to COPD, asthma , bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.

[0228] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.

[0229] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.

[0230] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.

[0231] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a proliferative diseases treatment agent. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis.

[0232] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of fibrotic diseases. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.

[0233] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of fibrotic diseases. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.

[0234] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with fibrotic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.

[0235] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a fibrotic diseases treatment agent. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.

[0236] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of transplantation rejection. In particular, the term transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to agraft-versus-host disease.

[0237] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of transplantation rejection. In particular, the term transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to agraft-versus-host disease.

[0238] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with transplantation rejection, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to agraft-versus-host disease.

[0239] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a transplantation rejection treatment agent. In particular, the term transplantation rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases. More particularly, the term refers to agraft-versus-host disease.

[0240] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of diseases involving impairment of cartilage turnover. In particular, the term diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0241] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of diseases involving impairment of cartilage turnover. In particular, the term diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0242] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with diseases involving impairment of cartilage turnover, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0243] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a diseases involving impairment of cartilage turnover treatment agent. In particular, the term diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0244] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of congenital cartilage malformation. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0245] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of congenital cartilage malformation. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0246] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with congenital cartilage malformation, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0247] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a congenital cartilage malformation treatment agent. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0248] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of diseases involving impairment of bone turnover. In particular, the term diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0249] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of diseases involving impairment of bone turnover. In particular, the term diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0250] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with diseases involving impairment of bone turnover, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0251] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a diseases involving impairment of bone turnover treatment agent. In particular, the term diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0252] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of diseases associated with hypersecretion of IL-6. In particular, the term diseases associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and / or mesangial proliferative glomerulonephritis.

[0253] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of diseases associated with hypersecretion of IL-6. In particular, the term diseases associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and / or mesangial proliferative glomerulonephritis.

[0254] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with diseases associated with hypersecretion of IL-6, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term diseases associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and / or mesangial proliferative glomerulonephritis.

[0255] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a diseases associated with hypersecretion of IL-6 treatment agent. In particular, the term diseases associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma and / or mesangial proliferative glomerulonephritis.

[0256] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23. In particular, the term diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease. More particularly, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0257] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23. In particular, the term diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease. More particularly, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0258] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease. More particularly, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0259] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23 treatment agent. In particular, the term diseases associated with hypersecretion of TNFα, interferons, IL-12 and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease. More particularly, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0260] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of respiratory diseases. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.

[0261] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of respiratory diseases. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.

[0262] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with respiratory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.

[0263] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a respiratory diseases treatment agent. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.

[0264] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of endocrine and / or metabolic diseases. In particular, the term endocrine and / or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing's syndrome and Addison's disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and / or type II diabetes.

[0265] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of endocrine and / or metabolic diseases. In particular, the term endocrine and / or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing's syndrome and Addison's disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and / or type II diabetes.

[0266] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with endocrine and / or metabolic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term endocrine and / or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing's syndrome and Addison's disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and / or type II diabetes.

[0267] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a endocrine and / or metabolic diseases treatment agent. In particular, the term endocrine and / or metabolic diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing's syndrome and Addison's disease, and ovarian dysfunction polycystic ovary syndrome, cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and / or type II diabetes.

[0268] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of cardiovascular diseases. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis.

[0269] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of cardiovascular diseases. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis.

[0270] In additional method of treatment aspects, this disclosure provides methods of prophylaxis and / or treatment of a mammal afflicted with cardiovascular diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis.

[0271] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a cardiovascular diseases treatment agent. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis.

[0272] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of dermatological diseases. In particular, the term dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kaw...

Claims

1. A compound according to Formula I: wherein, X is N or CH; Y is N or CR2b; Z is - -NHR3a, - N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R15 groups, or - -NR3b-, wherein the N atom and R2a together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds; R1 is - C1-8 alkyl optionally substituted with one or more independently selected R4 groups, - phenyl, - C3-8 monocyclic or bridged polycyclic cycloalkyl optionally substituted with one or more independently selected R5 groups, - 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C1-4 alkyl optionally substituted with one or more independently selected -CN or -C(=O)-C1-4 alkoxy, or - 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S; R2a and R2b are independently selected from - halo, - C1-4 alkyl, - C1-4 alkoxy optionally substituted with one or more independently selected halo or C1-4 alkoxy, and - -NR6aR6b; R3a is - C1-6 alkyl optionally substituted with one or more independently selected halo or -CN, or - C3-7 cycloalkyl optionally substituted with one or more independently selected halo or -OH; R3b is selected from H, C3-7 cycloalkyl and C1-6 alkyl optionally substituted with one or more independently selected halo or -CN; each R4 is independently selected from - halo, - -OH, - -CN, - phenyl, - -C(=O)OH, - -O-C(=O)-C1-4 alkyl, - -O-S(=O)2-C1-4 alkyl, - C1-4 alkoxy optionally substituted with one or more independently selected ∘ -OH, ∘ C1-4 alkoxy, ∘ 4-8 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C1-4 alkyl, or ∘ -NR7aR7b, wherein each R7a and R7b is independently selected from H and C1-4 alkyl, - C3-7 cycloalkyl optionally substituted with one or more independently selected halo, -C(=O)-C1-4 alkoxy, -NR8aR8b, or C1-4 alkyl optionally substituted with one or more independently selected -NR9aR9b, - 5-6 membered monocyclic heterocycloalkyl comprising one or two N atoms fused to a 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C1-4 alkyl, - 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C1-4 alkyl or C3-7 cycloalkyl, - 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R10, - -NR11aR11b, - -C(=O)-C1-4 alkoxy, and - -C(=O)-NR12aR12b; - each R5 is selected from - halo, - -CN, and - -NR13aR13b; each R6a and R6b is independently selected from H and C1-4 alkyl; each R10 is selected from - -OH, - phenyl, - =NH, - halo, - oxo, - -CN, - -C(=O)H, - -C(=O)NH2, - -C(=O)OH, - -NR14aR14b, - C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, -C(=O)-C1-4 alkoxy, or C1-4 alkoxy, - C3-7 cycloalkyl, - 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, - -C(=O)-C1-4 alkyl, - -S(=O)2-C1-4 alkyl, and - -C(=O)-C1-6 alkoxy; each R11a, R11b is independently selected from - H, - phenyl, - C1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, or C1-4 alkoxy, - C3-7 cycloalkyl, - -C(=O)-C1-4 alkoxy, - -C(=O)-C1-4 alkyl optionally substituted with one or more independently selected halo, and - 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S; each R8a, R8b, R9a, R9b, R12a, R12b, R13a, and R13b is independently selected from H and C1-4 alkyl; each R14a and R14b is independently selected from H, C1-4 alkyl, and -S(=O)2-C1-4 alkyl; and each R15 is independently selected from -OH, -CN, and C1-4 alkyl optionally substituted with one or more independently selected halo or -CN.

2. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein Z is - -NHR3a, or - -NR3b-, wherein the N atom and R2a together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds; R' is - C1-8 alkyl optionally substituted with one or more independently selected R4 groups, - phenyl, - C3-8 monocyclic or bridged polycyclic cycloalkyl optionally substituted with one or more independently selected R5 groups, - 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected C1-4 alkyl, or - 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S; R3a is - C1-6 alkyl optionally substituted with one or more independently selected halo or -CN, or - C3-7 cycloalkyl; each R4 is independently selected from - halo, - -OH, - -CN, - phenyl, - C1-4 alkoxy optionally substituted with one or more independently selected -OH, C1-4 alkoxy, or -NR7aR7b, wherein each R7a and R7b is independently selected from H and C1-4 alkyl, - C3-7 cycloalkyl optionally substituted with one or more independently selected halo, -C(=O)-C1-4 alkoxy, -NR8aR8b, or C1-4 alkyl optionally substituted with one or more independently selected -NR9aR9b, - 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C1-4 alkyl or C3-7 cycloalkyl, - 4-8 membered monocyclic or bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R10, - -NR11aR11b, and - -C(=O)-NR12aR12b; each R10 is selected from - halo, - oxo, - -CN, - -C(=O)H, - -NR14aR14b, - C1-4 alkyl optionally substituted with one or more independently selected halo or C1-4 alkoxy, - C3-7 cycloalkyl, - -C(=O)-C1-4 alkyl, - -S(=O)2-C1-4 alkyl, and - -C(=O)-C1-6 alkoxy; each R11a, R11b is independently selected from - H, - phenyl, - C1-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, or C1-4 alkoxy, - C3-7 cycloalkyl, - -C(=O)-C1-4 alkyl, and - 5-6 membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S; and each R14a, and R14b is independently selected from H and C1-4 alkyl.

3. A compound or pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein X is CH.

4. A compound or pharmaceutically acceptable salt thereof, according to claim 1, 2, or 3, wherein Y is CR2b and R2b is C1-4 alkoxy.

5. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-4, wherein R2a is -O-CH3, substituted with one, two, or three independently selected halo.

6. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-4, wherein Z is -NR3b-, wherein the N atom and R2a together with the atoms onto which they are attached form a fused 1,2,3,6-tetrahydropyridine.

7. A compound or pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein the compound is according to any one of Formulae IIIa-IIIc:

8. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein R' is -CH3 or -CH2CH3, each of which is substituted with one R4 group.

9. A compound or pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein the compound is according to any one of Formulae IVa-IVf:

10. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-9, wherein R4 is -NH-CH3, -N(CH3)2, -NH-CH2CH3, -N(CH2CH3)2, -N(CH(CH3)2)2, or -N(CH3)-CH2CHF2.

11. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-9, wherein R4 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl.

12. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-9 and 11, wherein R4 is morpholinyl.

13. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-9 and 11, wherein R4 is dioxanyl.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-13.

15. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-13, or a pharmaceutical composition according to claim 14 for use in medicine.

16. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-13, or a pharmaceutical composition according to claim 14 for use in the prophylaxis and / or treatment of inflammatory diseases, auto inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma, mesangial proliferative glomerulonephritis, systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, Crohn's disease, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases.