Patent Publication Number: US-2022235048-A1

Title: Novel compounds and pharmaceutical compositions thereof for the treatment of diseases

Description:
FIELD OF THE INVENTION 
     The present invention relates to compounds, methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, uses and 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. In particular, the compounds of the invention may inhibit Salt-Inducible Kinases (“SIK” kinases). 
     BACKGROUND OF THE INVENTION 
     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. 
     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. 
     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. 
     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 Snf1-like Kinase (MSK)), SIK2 (SNF1LK2 or KIAA0781) and SIK3 (KIAA0999) (Katoh et al. 2004). 
     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). 
     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). 
     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. 
     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). 
     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). 
     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. 
     Furthermore, it is 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. 
     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. 
     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 is 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. 
     Despite great advances over the past two decades in the treatments of patients affected by auto-immune 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. 
     SUMMARY OF THE INVENTION 
     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 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. 
     Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I: 
     
       
         
         
             
             
         
       
     
     wherein, 
     W is N or CH; 
     one of X 1  and X 2  is N and the other one is C, with the proviso that when W is CH, X 2  is not N; 
     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.
 
           
         
       
    
     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. 
     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). 
     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. 
     Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used. 
     In a further aspect of the invention, this invention provides 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. 
     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. 
     In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein. 
     Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description. 
     It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Definitions 
     The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. 
     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. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. 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. 
     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. 
     ‘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. 
     ‘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 ) and the like. 
     ‘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 )— and the like. 
     ‘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—. 
     ‘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. 
     ‘Amino’ refers to the radical —NH 2 . 
     ‘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. 
     ‘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. 
     ‘Cyano’ refers to the radical —CN. 
     ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro. 
     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. 
     ‘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, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom. 
     ‘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. 
     Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups. 
     Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl. 
     Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl. 
     Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups. 
     Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to 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. 
     Examples of representative heteroaryls include the following: 
     
       
         
         
             
             
         
       
     
     wherein each Y is selected from &gt;C═O, NH, O and S. 
     ‘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, but are not limited to 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. 
     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. 
     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—. 
     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—. 
     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—. 
     Particular examples of spirocyclic rings are shown in the following illustrative examples: 
     
       
         
         
             
             
         
       
     
     wherein each Y is selected from —CH 2 —, —NH—, —O— and —S—. 
     ‘Hydroxyl’ refers to the radical —OH. 
     ‘Oxo’ refers to the radical ═O. 
     ‘Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). 
     ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as —SO 3 H. 
     ‘Thiol’ refers to the group —SH. 
     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. 
     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. 
     ‘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. 
     ‘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, and the like; 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, and the like; 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 and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; 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 and the like. 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, and the like. 
     ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. 
     ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. 
     ‘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 and the like. 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. 
     ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein. 
     ‘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, etc., of the subject to be treated. 
     ‘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. 
     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. 
     ‘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. 
     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&#39;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 
     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&#39;s disease. 
     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&#39;s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto&#39;s and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn&#39;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. 
     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 
     As used herein, the term ‘cancer’ refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, 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 but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, 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. 
     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). 
     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 but are not limited to 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&#39;s granulomatosis; Peyronie&#39;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. 
     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. 
     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. 
     As used herein the term ‘congenital cartilage malformation(s)’ includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders. 
     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&#39;s disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, hypophosphatasia. 
     As used herein the term ‘disease(s) associated with hypersecretion of IL-6’ includes conditions such as Castleman&#39;s disease, multiple myeloma, psoriasis, Kaposi&#39;s sarcoma and/or mesangial proliferative glomerulonephritis. 
     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&#39;s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn&#39;s disease. 
     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. 
     As used herein the term ‘endocrine and/or metabolic disease(s)’ refers to the group of conditions involving the body&#39;s over- or under-production of certain hormones, while metabolic disorders affect the body&#39;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&#39;s syndrome and Addison&#39;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. 
     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 (e.g., giant cell arteritis (GCA), retinal vasculitis, rheumatoid 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 or giant cell arteritis. 
     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. More particularly, the term dermatological disorders refers to vitiligo. 
     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. 
     ‘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. 
     When ranges are referred to herein, for example but without limitation, C 1-8  alkyl, the citation of a range should be considered a representation of each member of said range. 
     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). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the C 1-8  alkyl, C 2-8  alkenyl, C 6-10  optionally substituted aryl, and (C 6-10  aryl)-(C 1-4  alkyl) esters of the compounds of the invention. 
     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 &gt;20%, &gt;50%, &gt;75%, &gt;90%, &gt;95% or &gt;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. 
     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. 
     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 O and  13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. 
     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’. 
     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’. 
     ‘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. 
     Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. 
     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. 
     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. 
     It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites. 
     THE INVENTION 
     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. 
     The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and 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. 
     Accordingly, in a first aspect of the invention, the compounds of the invention are provided having Formula I: 
     
       
         
         
             
             
         
       
     
     wherein, 
     W is N or CH; 
     one of X 1  and X 2  is N and the other one is C, with the proviso that when W is CH, X 2  is not N; 
     Y is N or CR 2 b; 
     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.
 
           
         
       
    
     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. 
     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 . 
     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 . 
     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 . 
     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 . 
     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. 
     In one embodiment, the compound of the invention is according to Formula IIa, IIb, or IIc: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 3b , W, X 1 , X 2  and Y are as described above. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R 3b  is H. 
     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. 
     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 . 
     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 . 
     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. 
     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. 
     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. 
     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. 
     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 . 
     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 . 
     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. 
     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 
     
       
         
         
             
             
         
       
     
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein Y is N. 
     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. 
     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 . 
     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 . 
     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 2 , 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 . 
     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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein W is N, X 1  is N and X 2  is C. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein W is N, X 1  is C and X 2  is N. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein W is CH, X 1  is N and X 2  is C. 
     In one embodiment, the compound of the invention is according to Formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, or IIIh: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein R 1  is as described above. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIIh, wherein R 1  is C 1-3  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 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 . 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIIh, wherein R 1  is C 1-3  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 , —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 )CH 2 CH 3 , —CH 2 CH 2 CH 2 CH(C H 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(C H 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 )C H 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 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, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIIh, wherein R 1  is phenyl. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIIh, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIIh, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIIh, wherein R 1  is C 3-8  monocyclic or bridged polycyclic cycloalkyl substituted with one or more independently selected R 5  groups and 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIIh, wherein R 1  is C 3-8  monocyclic or bridged polycyclic cycloalkyl substituted with one or more independently selected R 5  groups, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIIh, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIIh, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IIIh, 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. 
     In one embodiment, the compound of the invention is according to Formula IVa, IVb, JVc, IVd, IVe, IVf, IVg, IVh, IVi, IVj, IVk, IVl, IVm, IVn, IVo, or IVp: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein R 4  is as described above. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, wherein R 4  is C 3-7  cycloalkyl. In a particular embodiment, R 4  is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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, —CH 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 14b , 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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. 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to any one of Formulae I-IVp, 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 . 
     In one embodiment, the compound of the invention is according to Formula I, wherein the compound is selected from:
     8-methoxy-6-[6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one,   2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[6-(2-hydroxy-1,1-dimethyl-ethoxy)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide,   2-(difluoromethoxy)-4-[6-(1,1-dimethyl-2-morpholino-ethoxy)pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,   8-methoxy-6-[6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, and   8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-b]pyridazin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, and   2-(difluoromethoxy)-4-[6-[1,1-dimethyl-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy]pyrazolo[1,5-a]pyridin-3-yl]-N-[(2S)-2-fluorocyclopropyl]-6-methoxy-benzamide.   

     In one embodiment, the compound of the invention is according to Formula I, wherein the compound is selected from:
     8-methoxy-6-[6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one,   2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-4-[6-(2-hydroxy-1,1-dimethyl-ethoxy)pyrazolo[1,5-a]pyridin-3-yl]-6-methoxy-benzamide,   2-(difluoromethoxy)-4-[6-(1,1-dimethyl-2-morpholino-ethoxy)pyrazolo[1,5-a]pyridin-3-yl]-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide,   8-methoxy-6-[6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one, and   8-methoxy-6-[7-(2-morpholinoethoxy)imidazo[1,2-b]pyridazin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one.   

     In one embodiment, the compound of the invention is according to Formula I, wherein the compound is 8-methoxy-6-[6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one. 
     In one embodiment, the compound of the invention is according to Formula I, wherein the compound is not 8-methoxy-6-[6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one. 
     In one embodiment a compound of the invention is not an isotopic variant. 
     In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base. 
     In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt. 
     In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound. 
     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. 
     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. Therefore, this invention is intended to include all combinations of such embodiments within its scope. 
     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. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope. 
     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. 
     In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. 
     Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the C1 to C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention. 
     PHARMACEUTICAL COMPOSITIONS 
     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&#39;s symptoms, and the like. 
     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. 
     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 or the like 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. 
     Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. 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. 
     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 and the like. 
     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. All such known transdermal formulations and ingredients are included within the scope of this invention. 
     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. 
     The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington&#39;s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference. 
     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&#39;s Pharmaceutical Sciences. (Remington 1985) 
     The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions. 
     Formulation 1—Tablets 
     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 
     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 
     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 
     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 
     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 
     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 
     In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. 
     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&#39;s disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn&#39;s disease, ulcerative colitis). 
     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&#39;s disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn&#39;s disease, ulcerative colitis). 
     In additional method of treatment aspects, this invention 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&#39;s disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn&#39;s disease, ulcerative colitis). 
     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&#39;s disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn&#39;s disease, ulcerative colitis). 
     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 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&#39;s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still&#39;s disease. 
     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&#39;s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still&#39;s disease. 
     In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with autoinflammatory 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 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&#39;s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still&#39;s disease. 
     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 autoinflammatory diseases treatment agent. 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&#39;s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still&#39;s disease. 
     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&#39;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&#39;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. 
     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&#39;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&#39;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. 
     In additional method of treatment aspects, this invention 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&#39;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&#39;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. 
     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&#39;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&#39;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. 
     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. 
     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. 
     In additional method of treatment aspects, this invention 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. 
     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. 
     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. 
     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. 
     In additional method of treatment aspects, this invention 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. 
     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. 
     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. 
     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. 
     In additional method of treatment aspects, this invention 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. 
     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. 
     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. 
     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. 
     In additional method of treatment aspects, this invention 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. 
     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. 
     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. 
     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. 
     In additional method of treatment aspects, this invention 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. 
     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. 
     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&#39;s disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis. 
     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&#39;s disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis. 
     In additional method of treatment aspects, this invention 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&#39;s disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis. 
     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&#39;s disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis. 
     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&#39;s disease, multiple myeloma, psoriasis, Kaposi&#39;s sarcoma and/or mesangial proliferative glomerulonephritis. 
     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&#39;s disease, multiple myeloma, psoriasis, Kaposi&#39;s sarcoma and/or mesangial proliferative glomerulonephritis. 
     In additional method of treatment aspects, this invention 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&#39;s disease, multiple myeloma, psoriasis, Kaposi&#39;s sarcoma and/or mesangial proliferative glomerulonephritis. 
     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&#39;s disease, multiple myeloma, psoriasis, Kaposi&#39;s sarcoma and/or mesangial proliferative glomerulonephritis. 
     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&#39;s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn&#39;s disease. More particularly, the term refers to Sjögren&#39;s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn&#39;s disease. 
     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&#39;s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn&#39;s disease. More particularly, the term refers to Sjögren&#39;s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn&#39;s disease. 
     In additional method of treatment aspects, this invention 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&#39;s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn&#39;s disease. More particularly, the term refers to Sjögren&#39;s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn&#39;s disease. 
     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&#39;s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn&#39;s disease. More particularly, the term refers to Sjögren&#39;s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and/or Crohn&#39;s disease. 
     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. 
     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. 
     In additional method of treatment aspects, this invention 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. 
     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. 
     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&#39;s syndrome and Addison&#39;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. 
     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&#39;s syndrome and Addison&#39;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. 
     In additional method of treatment aspects, this invention 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&#39;s syndrome and Addison&#39;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. 
     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&#39;s syndrome and Addison&#39;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. 
     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 or giant cell arteritis. 
     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 or giant cell arteritis. 
     In additional method of treatment aspects, this invention 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 or giant cell arteritis. 
     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 or giant cell arteritis. 
     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, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria. 
     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 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, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria. 
     In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with dermatological 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 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, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria. 
     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 dermatological diseases treatment agent. 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, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria. 
     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 abnormal angiogenesis associated diseases. In particular, the term abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy. 
     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 abnormal angiogenesis associated diseases. In particular, the term abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy. 
     In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with abnormal angiogenesis associated 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 abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy. 
     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 abnormal angiogenesis associated diseases treatment agent. In particular, the term abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy. 
     Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient. 
     For the prophylaxis and/or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days. 
     Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg. 
     Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses. 
     When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition. 
     A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen. 
     In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient. 
     In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of a disease involving inflammation, particular agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam. 
     In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of arthritis (e.g. rheumatoid arthritis), particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, etanercept, adalimumab, rituximab, and abatacept). 
     In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of proliferative disorders, particular agents include but are not limited to: methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. Herceptino), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. Iressa®, Tarceva®, Erbitux®), VEGF inhibitors (e.g. Avastin®), proteasome inhibitors (e.g. Velcade®), Glivec® and hsp90 inhibitors (e.g. 17-AAG). Additionally, the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery. In a specific embodiment the proliferative disorder is selected from cancer, myeloproliferative disease or leukemia. 
     In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of autoimmune diseases, particular agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g. anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-β), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fingolimod and myriocin. 
     In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of transplant rejection, particular agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), antibodies (e.g. monoclonal anti-IL-2Ra receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)). 
     In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of asthma and/or rhinitis and/or COPD, particular agents include but are not limited to: beta2-adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled), long-acting P2-agonists (e.g. salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. cetirizine, cinnarizine, fexofenadine) and vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline). 
     Additionally, a compound of the invention may be administered in combination with emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g. epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamiphylline), inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate. 
     In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of inflammatory bowel disease (JBD), particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and cyclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept). 
     In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of SLE, particular agents include but are not limited to: human monoclonal antibodies (belimumab (Benlysta)), Disease-modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine), immunosuppressants (e.g. methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressive drugs and analgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch. 
     In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of psoriasis, particular agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort®), fluocinonide, vitamin D3 analogues (for example, calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologics such as Amevive®, Enbrel®, Humira®, Remicade®, Raptiva® and ustekinumab (an IL-12 and IL-23 blocker). Additionally, a compound of the invention may be administered in combination with other therapies including, but not limited to phototherapy, or photochemotherapy (e.g. psoralen and ultraviolet A phototherapy (PUVA)). 
     In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of allergic reaction, particular agents include but are not limited to: antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g. prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or anti-leukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants. 
     By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times. 
     Chemical Synthetic Procedures 
     General 
     The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. 
     Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Wuts &amp; Greene 2006). 
     The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. 
     All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified. Column chromatography is performed on silica gel 60 (35-70 μm) or with Biotage® SNAP KP-NH, Biotage® SNAP Ultra, or Interchim© PuriFlash© Si HC flash chromatography cartridges. Thin layer chromatography is carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Biotage® ISOLUTE® phase separators (e.g., Cat #120-1907-E) are used for aqueous phase separation.  1 H NMR spectra are recorded on a Bruker DPX 400 NMR spectrometer (400 MHz) or a Bruker Avance 300 NMR spectrometer (300 MHz). Chemical shifts (δ) for  1 H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e. CHCl 3  (δ 7.27), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), multiplet (m) and broad (br). Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a UV PDA detector and to a Waters SQD or SQD2 mass spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×30/50 mm L; Waters Acquity UPLC CSH C18 1.7 μm, 2.1 mm ID×50/100 mm L; Waters Acquity UPLC CSH PhenylHexyl 1.7 Wm, 2.1 mm ID×100 mm L; Waters Acquity UPLC HSS PFP 1.8 μm, 2.1 mm ID×100 mm L. The methods are using ACN/H 2 O or MeGH/water gradients with either 0.1% formic acid in both mobile phases, 0.05% NH 3  in both mobile phases, or 10 mM NH 4 HCO 3  in H 2 O (adjusted to pH 10 with ammonia). Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XBRIDGE BEH C18 OBD 30 mm ID×100/150 mm L columns and ACN/H 2 O gradients with either 0.1% formic acid in both mobile phases, 0.1% diethylamine in both mobile phases, 0.1% formic acid in H 2 O, or 10 mM NH 4 HCO 3  in H 2 O (adjusted to pH 10 with ammonia). Microwave heating is performed with a Biotageo Initiator. 
     
       
         
           
               
             
               
                 TABLE I 
               
             
            
               
                   
               
               
                 List of abbreviations used in the experimental section: 
               
            
           
           
               
               
               
            
               
                   
                 Abbreviation 
                 Definition 
               
               
                   
                   
               
               
                   
                 ACN 
                 acetonitrile 
               
               
                   
                 ANOVA 
                 analysis of variance 
               
               
                   
                 aq. 
                 aqueous 
               
               
                   
                 ATP 
                 adenosine 5′-triphosphate 
               
               
                   
                 b.i.d. 
                 bis in die (twice a day) 
               
               
                   
                 B 2 pin 2   
                 4,4,5,5-tetramethyl-2- 
               
               
                   
                   
                 (4,4,5,5-tetramethyl-1,3,2- 
               
               
                   
                   
                 dioxaborolan-2-yl)-1,3,2- 
               
               
                   
                   
                 dioxaborolane 
               
               
                   
                 br s 
                 broad singlet 
               
               
                   
                 calcd 
                 calculated 
               
               
                   
                 d 
                 doublet 
               
               
                   
                 DCM 
                 dichloromethane 
               
               
                   
                 dd 
                 doublet of doublets 
               
               
                   
                 DMF 
                 N,N-dimethylformamide 
               
               
                   
                 DMSO 
                 dimethylsulfoxide 
               
               
                   
                 Et 3 N 
                 triethylamine 
               
               
                   
                 EtOAc 
                 ethyl acetate 
               
               
                   
                 EtOH 
                 ethanol 
               
               
                   
                 eq. 
                 equivalent 
               
               
                   
                 h 
                 hour 
               
               
                   
                 HPLC 
                 high-performance liquid 
               
               
                   
                   
                 chromatography 
               
               
                   
                 i.n. 
                 intranasal 
               
               
                   
                 i.p. 
                 intraperitoneal 
               
               
                   
                 i.v. 
                 intravenous 
               
               
                   
                 KOAc 
                 potassium acetate 
               
               
                   
                 LCMS 
                 liquid chromatography-mass 
               
               
                   
                   
                 spectrometry 
               
               
                   
                 LiHMDS 
                 lithium hexamethyldisilazane 
               
               
                   
                 m 
                 multiplet 
               
               
                   
                 MeOH 
                 methanol 
               
               
                   
                 MeONa 
                 sodium methoxide 
               
               
                   
                 mg 
                 milligram 
               
               
                   
                 min 
                 minute 
               
               
                   
                 mL 
                 milliliter 
               
               
                   
                 mmol 
                 millimole 
               
               
                   
                 MS 
                 mass spectrometry 
               
               
                   
                 MTBE 
                 methyl tert-butyl ether 
               
               
                   
                 MW 
                 molecular weight 
               
               
                   
                 MW (calc) 
                 molecular weight calculated 
               
               
                   
                 MW (obs) 
                 molecular weight observed 
               
               
                   
                 NA 
                 not available 
               
               
                   
                 obsd 
                 observed 
               
               
                   
                 Pd(dppf)Cl 2  ·  
                 1,1′-bis(diphenylphosphino) 
               
               
                   
                 DCM 
                 ferrocene]dichloropalladium 
               
               
                   
                   
                 (II), complex with 
               
               
                   
                   
                 dichloromethane 
               
               
                   
                 p.o. 
                 per os 
               
               
                   
                 ppm 
                 parts-per-million 
               
               
                   
                 q 
                 quadruplet 
               
               
                   
                 q.d. 
                 quaque die (once a day) 
               
               
                   
                 RockPhos 
                 di-tert-butyl(2′,4′,6′- 
               
               
                   
                   
                 triisopropyl-3-methoxy-6- 
               
               
                   
                   
                 methyl-[1,1′-biphenyl]-2- 
               
               
                   
                   
                 yl)phosphine 
               
               
                   
                 RT 
                 room temperature 
               
               
                   
                 s 
                 singlet 
               
               
                   
                 sat. 
                 saturated 
               
               
                   
                 sc 
                 subcutaneous 
               
               
                   
                 SEM 
                 standard error of the mean 
               
               
                   
                 SM 
                 starting material 
               
               
                   
                 t 
                 triplet 
               
               
                   
                 td 
                 triplet of doublets 
               
               
                   
                 TFA 
                 trifluoroacetic acid 
               
               
                   
                 THF 
                 tetrahydrofuran 
               
               
                   
                 tt 
                 triplet of triplets 
               
               
                   
                   
               
            
           
         
       
     
     SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION 
     Example 1. Preparation of the Compounds of the Invention 
     1.1 
     
       
         
         
             
             
         
       
     
     In a microwave vial, is added Cs 2 CO 3  (471 mg, 1.44 mmol, 1.5 eq), allylpalladium(II) chloride dimer (CAS #12012-95-2; 18 mg, 0.048 mmol, 0.05 eq.), RockPhos (CAS #1262046-34-3; 69 mg, 0.14 mmol, 0.15 eq.). Air is removed from the vial and the vial is filled with argon (×3). Toluene (2 mL) and 2-morpholinoethanol (CAS #622-40-2; 230 μL, 1.93 mmol, 2 eq.) are added to the mixture and stirred at 90° C. for 3 min. 6-Bromopyrazolo[1,5-a]pyridine (CAS #1264193-11-4; 200 mg, 0.96 mmol, 1 eq.) in toluene (1 mL) is added to the mixture and the reaction is stirred at 90° C. for 5 h. The mixture is filtered through a pad of Celite® eluting with EtOAc and concentrated in vacuo. The crude is purified by column chromatography on silica gel (eluting with 1 to 3% MeOH in DCM) to afford Int 1. 
     1.2 
     
       
         
         
             
             
         
       
     
     To a solution of Int 1 (62 mg, 0.25 mmol, 1.0 eq.) in ACN (0.4 mL) is added N-iodosuccinimide (CAS #516-12-1; 65.3 mg, 0.27 mmol, 1.1 eq.). The mixture is stirred at RT for 1 h, then quenched with water. The solid product is filtered, rinsed with water and dried in vacuo to afford Int 2. 
     1.3 
     
       
         
         
             
             
         
       
     
     Under N 2  atmosphere, to a solution of Int 14 (500 mg, 1.5 mmol, 1.0 eq.) in 1,4-dioxane (9 mL) degassed with N 2  are added B 2 pin 2  (CAS #73183-34-3; 460 mg, 1.8 mmol, 1.2 eq.), KOAc (430 mg, 4.4 mmol, 3 eq.) and Pd(dppf)Cl 2 .DCM (CAS #95464-05-4; 72 mg, 0.09 mmol, 0.06 eq.). The reaction mixture is stirred at 90° C. for 2 h, then filtered on Dicalite®, rinsed with EtOAc and concentrated. The crude product is purified by flash chromatography on silica gel (eluting with 0 to 2% MeOH in DCM). The residue obtained is solubilized in heptane, MTBE is added (few mL). The precipitate is filtered and the filtrate is concentrated in vacuo to provide Int 3 as a mixture of the expected boronate and the corresponding boronic acid. 
     1.4 
     
       
         
         
             
             
         
       
     
     Under N 2  atmosphere, to a solution of pyrazolo[1,5-a]pyridin-6-ol (CAS #184473-24-3; 200 mg, 1.49 mmol, 1.0 eq.) in ACN (8.7 mL) at 0° C. are added Cs 2 CO 3  (729 mg, 2.24 mmol, 1.5 eq.) and ethyl 2-bromoisobutyrate (CAS #600-00-0; 349 mg, 0.263 mL, 1.79 mmol, 1.2 eq.). The reaction mixture is stirred at RT overnight. The reaction mixture is concentrated and the crude is purified by flash chromatography (eluting with 0 to 100% EtOAc in heptane) to afford Int 4. 
     
       
         
         
             
             
         
       
     
     To a solution of Int 4 (0.18 g, 0.73 mmol, 1.0 eq.) in THF (7.3 mL) at 0° C. is added dropwise lithium aluminum hydride (1 M in THF; 1.11 mL, 1.11 mmol, 1.50 eq.). The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is quenched with water, filtered on Celite® and the filter cake is washed with EtOAc. The filtrate is washed with water, the layers are separated and the aqueous layer is extracted with EtOAc (×3). The combined organic layers are dried over MgSO 4 , filtered and concentrated in vacuo to afford Int 5 
     1.6 
     
       
         
         
             
             
         
       
     
     To a solution of Int 5 (50 mg, 0.23 mmol, 1.0 eq.) in DMF (0.5 mL) is added N-iodosuccinimide (CAS #516-12-1; 78 mg, 0.34 mmol, 1.5 eq.). The reaction mixture is stirred at RT for 30 min, then concentrated and diluted with water and extracted with DCM (×3). The combined organic layers are filtered on a phase separator and concentrated in vacuo to afford Int 6 
     1.7 
     
       
         
         
             
             
         
       
     
     1.7.1. Step i: N-[(1R,2S)-2-fluorocyclopropyl]-2-hydroxy-6-methoxy-benzamide 
     To a solution of 2-hydroxy-6-methoxy-benzoic acid (CAS #3147-64-6; 50 g, 297 mmol, 1 eq.) in DCM (300 mL) is added 1, 1′-carbonyldiimidazole (CAS #530-62-1; 49 g, 297 mmol, 1 eq.) portionwise causing release of CO 2 . Then (1R,2S)-2-fluorocyclopropanamine 4-methylbenzenesulfonate (CAS #143062-84-4; 80 g, 312 mmol, 1.05 eq.) and Et 3 N (50 mL, 359 mmol, 1.21 eq.) are added to the mixture. The resulting solution is stirred at RT for 2.5 h. Water is added and the pH is adjusted to 2 using a 12N HCl solution (60 mL). The organic layer is separated and the aqueous layer is extracted twice with DCM. The combined organic layers are washed three times with a sat. NaHCO 3  solution, and dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluting with DCM/EtOAc 100/0 to 90/10) to afford the desired intermediate. 
     1.7.2. Step ii: 2-(difluoromethoxy)-N-[(1R, 2S)-2-fluorocyclopropyl]-6-methoxy-benzamide 
     In a 3-necked round-bottom flask equipped with a temperature probe and a funnel, containing a solution of the above prepared N-[(1R, 2S)-2-fluorocyclopropyl]-2-hydroxy-6-methoxy-benzamide (29 g, 130 mmol, 1 eq.) in a mixture ACN/water (146 mL/146 mL) at 5° C. is added potassium hydroxide (73 g, 1298 mmol, 10 eq.) over 1 h. Then bromodifluoromethyl diethylphosphonate (CAS #65094-22-6; 46 mL, 260 mmol, 2 eq.) is added neat dropwise over 40 min while keeping the reaction temperature below 12° C. The reaction mixture is allowed to warm to RT and stirred at RT for 40 min. The reaction solution is then extracted twice with EtOAc. The combined organic layers are washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. The residue is re-slurried in MTBE (80 mL). The suspension is filtered, the solid washed with MTBE (20 mL) and dried to afford the desired intermediate. 
     1.7.3. Step iii: Int 7 
     To a solution of the above prepared 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide (22 g, 76 mmol, 1 eq.) in THF (217 mL) under inert atmosphere at RT is added B 2 pin 2  (CAS #73183-34-3; 25 g, 98 mmol, 1.3 eq.), 4,4′-di-tert-butyl-2,2′-bipyridine (CAS #72914-19-3; 829 mg, 3.0 mmol, 0.04 eq.) and [Ir(OCH 3 )(COD)] (CAS #12148-71-9; 1 g, 1.5 mmol, 0.02 eq.). The resulting mixture is heated to 70° C. for 2 h then concentrated in vacuo. This residue is purified by flash chromatography on silica gel (eluting with DCM/EtOAC 90/10). The collected fractions are concentrated and the obtained solid is then dissolved in a mixture DCM/heptane (100 mL/330 mL) and stirred for 15 min. The suspension is filtered; the solid is washed twice with heptane, dried in vacuo to afford Int 7. 
     1.8 
     
       
         
         
             
             
         
       
     
     In a round bottom flask under N 2  atmosphere, to a solution of Cpd 2 (50 mg, 0.099 mmol, 1.0 eq.) in dry DCM (5.0 mL) degassed at 0° C. with N 2 , is added Dess-Martin periodinane (CAS #87413-09-0; 51 mg, 0.12 mmol, 1.2 eq.). The reaction mixture is stirred at RT for 1 h. Dess-Martin periodinane (51 mg, 0.12 mmol, 1.2eq.) is added at 0° C. and the reaction mixture is stirred at RT for 1 h. The reaction mixture is quenched with NaHCO 3 , extracted with DCM (×2). The combined organic layers are separated with a phase separator and concentrated in vacuo to afford Int 8. This product is used as such in the next step. 
     1.9 
     
       
         
         
             
             
         
       
     
     In a vial, is added Cs 2 CO 3  (311.9 mg, 0.9572 mmol, 1.5 eq.), allylpalladium(II) chloride dimer (CAS #12012-95-2; 11.9 mg, 0.0317 mmol, 0.05 eq.), RockPhos (CAS #1262046-34-3, 0.15 eq., 0.095722 mmol, 0.045781 g). The tube is evacuated and backfill with argon (×3). Toluene (0.5 mL) and 2-morpholinoethanol (CAS #622-40-2; 156 μL, 1.27 mmol, 2 eq.) are added to the mixture and stirred at 90° C. for 3 min. 7-Chloroimidazo[1,2-b]pyridazine (CAS #1383481-11-5; 100 mg, 0.638 mmol, 1 eq.) and toluene (0.5 mL) are added to the mixture. The reaction mixture is heated at 100° C. for 2.5 h and then at 90° C. overnight. The mixture is filtered through a pad of Celite®, eluting with EtOAc, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluting with 1 to 4% MeOH in DCM) to afford Int 9. 
     1.10 
     
       
         
         
             
             
         
       
     
     In a vial, is added Cs 2 CO 3  (0.479 g, 0.116 mL, 1.47 mmol, 1.50eq.), allylpalladium(II) chloride dimer (CAS #12012-95-2; 18.3 mg, 0.0500 mmol, 0.05 eq.), RockPhos (CAS #1262046-34-3; 70.3 mg, 0.147 mmol, 0.15 eq.). The tube is evacuated and backfilled with argon (×3). Toluene (1 mL) and 2-morpholinoethanol (CAS #622-40-2; 240 μL, 1.96 mmol, 2 eq.) are added to the mixture and stirred at 90° C. for 5 min. 6-Bromopyrazolo[1,5-a]pyrimidine (CAS #705263-10-1; 0.200 g, 0.980 mmol, 1 eq.) in toluene (1 mL) is added to the mixture and the reaction is stirred at 90° C. for 7 h. The mixture is filtered through a pad of Celite® eluting with EtOAc and concentrated in vacuo. The residue is purified by flash chromatography (eluting with 5% MeOH in DCM) to afford Int 10. 
     1.11 
     
       
         
         
             
             
         
       
     
     To a solution of Int 9 (76 mg, 0.31 mmol, 1 eq.) in ACN (0.5 mL) is added N-iodosuccinimide (CAS #516-12-1; 159.5 mg, 0.6734 mmol, 2.2 eq.). The mixture is stirred at 60° C. for 4 h. N-iodosuccinimide (79.7 mg, 0.337 mmol, 1.1 eq.) is added and the reaction is stirred at 60° C. for 1 h. The reaction is stirred at 60° C. overnight. The mixture is quenched with water, extracted with EtOAc (×3). The organic layer is concentrated and the residue obtained is purified by flash chromatography on silica gel (eluting with 1 to 4% MeOH in DCM) to afford Int 11. 
     1.12 
     
       
         
         
             
             
         
       
     
     To a solution of Int 10 (0.110 g, 0.434 mmol, 1.00 eq.) in DMF (840 μL) is added N-iodosuccinimide (CAS #516-12-1; 151 mg, 0.651 mmol, 1.50 eq.). The reaction mixture is stirred at RT for 3 h. The reaction mixture is then concentrated in vacuo, diluted with water, and extracted with DCM (×3). The combined organic layers are filtered on a phase separator and concentrated in vacuo. The residue is purified by flash chromatography (eluting with 0 to 10% MeOH in DCM) to afford Int 12. 
     1.13 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 6-bromo-8-fluoro-3,4-dihydro-2H-isoquinolin-1-one (CAS #1242157-15-8; 3 g, 12.3 mmol, 1 eq.) in THF (30 mL) is added dropwise a solution of MeONa 25 w % in MeOH (3.35 mL, 14.75 mmol, 1.2 eq.). The reaction mixture is stirred at RT for 2 h, quenched with a sat. aq. NH 4 Cl solution and THF is evaporated. The solid obtained in the remaining aq. phase is filtered to afford the desired Int 13. 
     1.14 
     
       
         
         
             
             
         
       
     
     To a stirred solution of Int 13 (10 g, 39.1 mmol, 1 eq.) in THF (240 mL) at 0° C. is added dropwise a solution of LiHMDS (1 N in THF, 59 mL, 58.6 mmol, 1.5 eq.). The resulting mixture is stirred for 45 min at 0° C. and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS #6226-25-1; 8.44 mL, 58.6 mmol, 1.5 eq.) is added dropwise at 0° C. The reaction mixture is warmed slowly to RT and stirred at RT for 22 h. The reaction mixture is quenched with water and brine. THF is evaporated and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluting with 0 to 1% MeOH in DCM) to afford Int 14. 
     1.15 
     
       
         
         
             
             
         
       
     
     In a round bottom flask under N 2  atmosphere, to a solution of Int 2 (57 mg, 0.15 mmol, 1 eq.) in a degassed 4/1 mixture of 1,4-dioxane and water (1 mL) are added Int 3 (70.6 mg, 0.183 mmol, 1.2 eq.), Cs 2 CO 3  (149.3 mg, 0.4582 mmol, 3.0 eq.) and Pd(dppf)Cl 2 .DCM (12.47 mg, 0.01527 mmol, 0.1 eq.). The mixture is stirred at 90° C. for 1 h. The reaction mixture is quenched with a sat. NaHCO 3  solution, extracted with EtOAc (×3). The combined organic layers are dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography on silica gel (eluting with 10 to 75% EtOAc in heptane). The product is triturated in MTBE and filtered. The product is purified again by flash chromatography on a 5 g Biotage® Sfär High Capacity Duo cartridge (eluting with 0 to 100% EtOAc in heptane, then 2 to 6% MeOH in DCM) to afford Cpd 1. 
     1.16 
     
       
         
         
             
             
         
       
     
     In a sealed vial, to a solution of Int 6 (0.075 g, 0.22 mmol, 1.0 eq.) in a 4/1 mixture of 1,4-dioxane and water (1.75 mL) degassed with N 2 , are added Int 7 (0.11 g, 0.26 mmol, 1.2 eq.), Cs 2 CO 3  (0.22 g, 0.65 mmol, 3.0 eq.), and Pd(dppf)Cl 2 .DCM (CAS #95464-05-4; 19 mg, 0.022 mmol, 0.10 eq.). The reaction mixture is stirred at 90° C. for 1 h and then cooled at RT, filtered on Dicalite® and rinsed with EtOAc. The filtrate is concentrated under reduced pressure. The crude product is purified by flash chromatography on silica gel (eluting with 0 to 100% EtOAc in heptane) to afford Cpd 2. 
     1.17 
     
       
         
         
             
             
         
       
     
     To a solution of Int 8 from Ex. 1.8 in 1,2-dichloroethane (0.5 mL) are added morpholine (CAS #110-91-8; 26 μL, 0.30 mmol, 3.0 eq.) and titanium(IV) isopropoxide (CAS #546-68-9; 45 μL, 0.15 mmol, 1.5 eq.). The reaction mixture is stirred at 65° C. for 5 h. NaBH(OAc) 3  (CAS #56553-60-7; 65 mg, 0.30 mmol, 3.0 eq.) is added and the reaction mixture is stirred at 65° C. overnight. The reaction mixture is quenched with a sat. NaHCO 3  solution, then poured into 10 mL of water, stirred for 1 h at RT, filtered through a Dicalite® pad and the filtrate is extracted with DCM (×3). The combined organic layers are dried over MgSO 4 , filtered and concentrated. The crude product is purified by flash chromatography on a Biotage® SNAP Ultra 10 g cartridge (eluting with heptane/EtOAc 100/0 to 0/100, then with EtOAc/MeOH 100/0 to 95/5) and purified again by flash chromatography on a Biotage® SNAP KP-NH 11 g cartridge (eluting with heptane/EtOAc 100/0 to 50/50) to afford Cpd 3. 
     1.18 
     
       
         
         
             
             
         
       
     
     In a round bottom flask under N 2  atmosphere, to a solution of Int 12 (0.105 g, 0.281 mmol, 1 eq.) in a 4/1 1,4-dioxane/water mixture degassed with N 2  (1.6 mL) are added Int 3 (0.130 g, 0.337 mmol, 1.20 eq.), Cs 2 CO 3  (0.277 g, 0.842 mmol, 3.0 eq.) and Pd(dppf)Cl 2 .DCM (0.0234 g, 0.0281 mmol, 0.100eq.). The reaction mixture is stirred at 90° C. for 1 h, then cooled at RT, filtered on Dicalite® and rinsed with EtOAc. The filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography twice (eluting first with 0 to 10% MeOH in DCM, then with 0 to 100% EtOAc in heptane) to afford Cpd 4. 
     1.19 
     
       
         
         
             
             
         
       
     
     In a round bottom flask under N 2  atmosphere, to a solution of Int 11 (31 mg, 0.083 mmol) in a degassed 4/1 mixture of 1,4-dioxane and water (0.6 mL) are added Int 3 (38.3 mg, 0.0994 mmol, 1.2 eq.), Cs 2 CO 3  (81.0 mg, 0.249 mmol, 3.0 eq.) and Pd(dppf)Cl 2 .DCM (6.8 mg, 0.0083 mmol, 0.1 eq.). The mixture is stirred at 90° C. for 1 h. The mixture is quenched with NaOH 2N, extracted with EtOAc (×3). The combined organic layers are dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography on silica gel (eluting with 10 to 75% EtOAc in heptane). The appropriate fractions are collected and the solvents are concentrated in vacuo. After trituration of the residue in MTBE and filtration, the product is purified by flash chromatography on a 5 g Biotage® Sfär High Capacity Duo cartridge (eluting with 0 to 100% EtOAc in heptane, then 2 to 6% MeOH in DCM) to afford Cpd 5. 
     1.20 
     
       
         
         
             
             
         
       
     
     To a solution of Int 8 from Ex. 1.8 in 1,2-dichloroethane (0.52 mL) are added 2-oxa-6-azaspiro[3.3]heptane (CAS #174-78-7; 31 mg, 0.31 mmol, 3 eq.) and titanium isopropoxide (CAS #546-68-9; 48 μL, 0.16 mmol, 1.5 eq.). The resulting mixture is stirred at 65° C. for 3.5 h. Then, NaBH(OAc) 3  (CAS #56553-60-7; 68 mg, 0.31 mmol, 3 eq.) is added. The reaction mixture is stirred at 65° C. overnight, quenched with a sat. NaHCO 3  solution, filtered through a Dicalite® pad and the filtrate is extracted with DCM (×3). The combined organic layers are dried over MgSO 4 , filtered and concentrated in vacuo. The crude is purified by flash chromatography on a Biotage® SNAP KP-NH column (eluting with heptane/EtOAc 100/0 to 15/85) to afford Cpd 6. 
     
       
         
           
               
             
               
                 TABLE II 
               
             
            
               
                   
               
               
                 Intermediates used towards the compounds of the invention. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 MS 
               
               
                 Int # 
                 Structure 
                 Name 
                 SM 
                 Mtd 
                 Mw 
                 Mes&#39;d 
               
               
                   
               
               
                  1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-(2-pyrazolo[1,5- a]pyridin-6- yloxyethyl) morpholine 
                 CAS # 622-40-2 + CAS # 1264193-11-4 
                 Ex. 1.1 
                 247.3 
                 248.3 
               
               
                   
               
               
                  2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-[2-(3- iodopyrazolo[1,5- a]pyridin-6- yl)oxyethyl] morpholine 
                 Int 1 
                 Ex. 1.2 
                 373.2 
                 374.1 
               
               
                   
               
               
                  3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 8-methoxy-6-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-2- (2,2,2-trifluoroethyl)- 3,4- dihydroisoquinolin-1- one/[8-methoxy-1- oxo-2-(2,2,2- trifluoroethyl)-3,4- dihydroisoquinolin-6- yl]boronic acid mixture 
                 Int 14 
                 Ex. 1.3 
                 385.2 + 303.0 
                 385.9 + 304.3 
               
               
                   
               
               
                   
                 + 
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
                   
                   
                   
               
               
                   
               
               
                  4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 ethyl 2-methyl-2- pyrazolo[1,5- a]pyridin-6-yloxy- propanoate 
                 CAS # 184473-24-3 + CAS # 600-00-0  
                 Ex. 1.4 
                 248.3 
                 249.3 
               
               
                   
               
               
                  5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-methyl-2- pyrazolo[1,5- a]pyridin-6-yloxy- propan-1-ol 
                 Int 4 
                 Ex. 1.5 
                 206.2 
                 207.3 
               
               
                   
               
               
                  6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-(3- iodopyrazolo[1,5- a]pyridin-6-yl)oxy-2- methyl-propan-1-ol 
                 Int 5 
                 Ex. 1.6 
                 332.1 
                 333.1 
               
               
                   
               
               
                  7 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-(difluoromethoxy)- N-[(1R,2S)-2- fluorocyclopropyl]-6- methoxy-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)benzamide 
                 CAS # 3147-64-6 
                 Ex. 1.7 
                 401.2 
                 402.2 
               
               
                   
               
               
                  8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-(difluoromethoxy)- 4-[6-(1,1-dimethyl-2- oxo- ethoxy)pyrazolo[1,5- a]pyridin-3-yl]-N- [(1R,2S)-2- fluorocyclopropyl]-6- methoxy-benzamide/ 2-(difluoromethoxy)- 4-[6-(2,2-dihydroxy- 1,1-dimethyl- ethoxy)pyrazolo[1,5- a]pyridin-3-yl]-N- [(1R,2S)-2- fluorocyclopropyl]-6- methoxy-benzamide mixture 
                 Cpd 2 
                 Ex. 1.8 
                 477.4 + 495.4 
                 478.2 + 496.3 
               
               
                   
               
               
                   
                 + 
                   
                   
                   
                   
                   
               
               
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
                   
                   
                   
               
               
                   
               
               
                  9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-(2-imidazo[1,2- b]pyridazin-7- yloxyethyl) morpholine 
                 CAS # 622-40-2 + CAS # 1383481-11-5 
                 Ex. 1.9 
                 248.3 
                 249.3 
               
               
                   
               
               
                 10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-(2-pyrazolo[1,5- a]pyrimidin-6- yloxyethyl) morpholine 
                 CAS # 622-40-2 + CAS # 705263-10-1 
                 Ex. 1.10 
                 248.3 
                 249.3 
               
               
                   
               
               
                 11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-[2-(3- iodoimidazo[1,2- b]pyridazin-7- yl)oxyethyl] morpholine 
                 Int 9 
                 Ex. 1.11 
                 374.2 
                 375.3 
               
               
                   
               
               
                 12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-[2-(3- iodopyrazolo[1,5- a]pyrimidin-6- yl)oxyethyl] morpholine 
                 Int 10 
                 Ex. 1.12 
                 374.2 
                 375.2 
               
               
                   
               
               
                 13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-bromo-8-methoxy- 3,4-dihydro-2H- isoquinolin-1-one 
                 CAS # 1242157-15-8 
                 Ex. 1.13 
                 256.1 
                 256.1 + 258.1 
               
               
                   
               
               
                 14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 6-bromo-8-methoxy- 2-(2,2,2- trifluoroethyl)-3,4- dihydroisoquinolin-1- one 
                 Int 13 
                 Ex. 1.14 
                 338.1 
                 338.1 + 340.1 
               
               
                   
               
               
                 SM = Starting Material, 
               
               
                 Mtd = Method, 
               
               
                 MS Mes&#39;d = Mesured mass, 
               
               
                 NA = not measured 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE III 
               
             
            
               
                   
               
               
                 Illustrative compounds of the invention. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 MS 
               
               
                 Cpd # 
                 Structure 
                 Name 
                 SM 
                 Mtd 
                 MW 
                 Mes&#39;d 
               
               
                   
               
               
                 1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 8-methoxy-6-[6-(2- morpholinoethoxy) pyrazolo[1,5-a]pyridin-3- yl]-2-(2,2,2- trifluoroethyl)-3,4- dihydroisoquinolin-1- one 
                 Int 2 + Int 3 
                 Ex. 1.15 
                 504.5 
                 505.3 
               
               
                   
               
               
                 2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-(difluoromethoxy)-N- [(1R,2S)-2- fluorocyclopropyl]-4- [6-(2-hydroxy-1,1- dimethyl- ethoxy)pyrazolo[1,5- a]pyridin-3-yl]-6- methoxy-benzamide 
                 Int 6 + Int 7 
                 Ex. 1.16 
                 479.4 
                 480.3 
               
               
                   
               
               
                 3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-(difluoromethoxy)-4- [6-(1,1-dimethyl-2- morpholino- ethoxy)pyrazolo[1,5- a]pyridin-3-yl]-N- [(1R,2S)-2- fluorocyclopropyl]-6- methoxy-benzamide 
                 Int 8 + CAS # 110-91-8 
                 Ex. 1.17 
                 548.6 
                 549.3 
               
               
                   
               
               
                 4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 8-methoxy-6-[6-(2- morpholinoethoxy) pyrazolo[1,5-a]pyrimidin-3- yl]-2-(2,2,2- trifluoroethyl)-3,4- dihydroisoquinolin-1- one 
                 Int 12 + Int 3 
                 Ex. 1.18 
                 505.5 
                 506.5 
               
               
                   
               
               
                 5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 8-methoxy-6-[7-(2- morpholinoethoxy) imidazo[1,2-b]pyridazin-3- yl]-2-(2,2,2- trifluoroethyl)-3,4- dihydroisoquinolin-1- one 
                 Int 11 + Int 3 
                 Ex. 1.19 
                 505.5 
                 506.4 
               
               
                   
               
               
                 6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-(difluoromethoxy)-4- [6-[1,1-dimethyl-2-(2- oxa-6- azaspiro[3.3]heptan-6- yl)ethoxy]pyrazolo[1,5- a]pyridin-3-yl]-N-[(2S)- 2-fluorocyclopropyl]-6- methoxy-benzamide 
                 Int 8 + CAS # 174-78-7 
                 Ex. 1.20 
                 560.6 
                 561.5 
               
               
                   
               
               
                 SM = Starting Material, 
               
               
                 Mtd = Method, 
               
               
                 MS Mes&#39;d = Mesured mass 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE IV 
               
             
            
               
                   
               
               
                 NMR data of illustrative compounds of the invention. 
               
            
           
           
               
               
            
               
                 Cpd# 
                 NMR data 
               
               
                   
               
               
                 1 
                   1 H NMR (400 MHz, CD 3 OD) δ 8.30 (dd, 1H), 8.25 (s, 1H), 7.93 (dd, 1H), 7.26-7.19 
               
               
                   
                 (m, 2H), 7.18-7.13 (m, 1H), 4.36 (d, 1H), 4.32 (d, 1H), 4.22 (t, 2H), 3.97 (s, 3H),  
               
               
                   
                 3.78-3.67 (m, 6H), 3.06 (t, 2H), 2.88 (t, 2H), 2.67-2.61 (m, 4H) 
               
               
                 2 
                   1 H NMR (400 MHz, CD 3 OD) δ 8.41 (dd, 1H), 8.25 (s, 1H), 7.83 (dd, 1H), 7.28 (dd, 
               
               
                   
                 1H), 7.16 (d, 1H), 7.07-6.66 (m, 2H), 4.72 (dd, 1H), 3.94 (s, 3H), 3.59 (s, 2H), 2.90 
               
               
                   
                 (dd, 1H), 1.34 (s, 6H), 1.14 (s, 1H), 1.02 (dd, 1H) 
               
               
                 3 
                   1 H NMR (400 MHz, CD 3 OD) 8.38 (dd, 1H), 8.25 (s, 1H), 7.83 (dd, 1H), 7.24 (dd, 
               
               
                   
                 1H), 7.16 (d, 1H), 7.07-6.67 (m, 2H), 4.81-4.62 (m, 1H), 3.94 (s, 3H), 3.73 (d, 4H), 
               
               
                   
                 2.89 (d, 1H), 2.68 (d, 4H), 2.60 (s, 2H), 1.37 (s, 6H), 1.19 (d, 1H), 1.08-0.97 (m, 1H) 
               
               
                 4 
                   1 H NMR (400 MHz, CD 3 OD) δ 8.67 (d, 1H), 8.57 (d, 1H), 8.55 (s, 1H), 7.86 (d, 1H), 
               
               
                   
                 7.58 (d, 1H), 4.32 (q, 2H), 4.26 (t, 2H), 3.96 (s, 3H), 3.75-3.72 (m, 4H), 3.69 (t, 2H), 
               
               
                   
                 3.04 (t, 2H), 2.88 (t, 2H), 2.63 (dd, 4H) 
               
               
                 5 
                   1 H NMR (400 MHz, CD 3 OD) δ 8.33 (d, 1H), 7.99 (s, 1H), 7.72 (d, 1H), 7.49 (d, 1H), 
               
               
                   
                 7.31 (d, 1H), 4.28-4.15 (m, 4H), 3.85 (s, 3H), 3.66-3.56 (m, 6H), 2.79 (t, 2H), 2.94 
               
               
                   
                 (t, 2H), 2.56-2.49 (m, 4H) 
               
               
                 6 
                   1 H NMR (400 MHz, CD 3 OD) δ 8.35 (dd, 1H), 8.26 (s, 1H), 7.83 (dd, 1H), 7.23 (dd, 
               
               
                   
                 1H), 7.16 (d, 1H), 7.07-6.67 (m, 2H), 4.80-4.64 (m, 1H), 4.76 (s, 4H), 3.94 (s, 3H), 
               
               
                   
                 3.57 (s, 4H), 2.90 (dd, 1H), 2.68 (s, 2H), 1.30 (s, 6H), 1.25-1.13 (m, 1H), 1.02 (dd, 
               
               
                   
                 1H) 
               
               
                   
               
            
           
         
       
     
     BIOLOGICAL EXAMPLES 
     Example 2. In Vitro Assays 
     2.1. Biochemical Assays 
     2.1.1. ADP-Glo™ Kinase Assay 
     2.1.1.1 Overview 
     The ADP-Glo™ kinase assay is a luminescent technology assay which measures the ADP formed from a kinase reaction. In this specific study, the kinase reactions consisted of the phosphorylation of the AMARA peptide substrate (SignalChem, Cat #A11-58) by SIK1 (Carma Biosciences, Cat #02-131), SIK2 (ThermoFisher Scientific, Cat #PV4792) or SIK3 (SignalChem, Cat #S12-11G-100). In a second step the kinase reactions are terminated and all the remaining ATP is depleted. In a final step the ADP is converted into ATP and this newly synthesized ATP is measured by using a luciferase/luciferin reaction. The generated light is measured using an Envision plate reader, wherein the luminescent signal obtained positively correlates with the kinase activity. 
     2.1.1.2. Protocol 
     The test compounds are prepared as a serial dilution of 10 point dose responses with 1/5 dilution steps in 100% DM5 starting from 2 mM highest concentration, diluted 1/20 in water and 1 mL is transferred to the assay plates (PerkinElmer Inc., Cat #6007290). 
     1% DMSO and 10 μM staurosporine final concentrations are used as negative and positive controls. 
     2 #L enzyme-substrate mixture is added to the assay plates. 
     The reaction is started by adding 2 μL diluted ATP on the assay plates. Plates are centrifuged for a few seconds at 1000 rpm and gently shaken for 2 min followed by an incubation at RT for 120 min. 
     The reactions are stopped and the unconsumed ATP is depleted by adding 5 μL ADP-Glo Reagent (Promega, Cat #V9121B) to the reaction. The plates are centrifuged for a few seconds at 1000 rpm and incubated at RT for 40 mT (ATP depletion). 
     The ADP is converted to ATP and luciferase and luciferin is introduced to detect ATP by adding 10 μL Kinase Detection Reagent (Promega, Cat #V913B+V914r) to the reaction. The plates are centrifuged for a few seconds at 1000 rpm and incubated at RT for 30 min (ADP detection). 
     Luminescence is measured on an Envision plate reader (PerkinElmer Inc.). 
     
       
         
           
               
             
               
                 TABLE V 
               
             
            
               
                   
               
               
                 Conditions for human SIK kinase ADP-Glo ™ assays 
               
            
           
           
               
               
               
               
               
            
               
                 Kinase, 
                 Substrate, 
                   
                   
                 Incubation 
               
               
                 [Kinase] 
                 [Substrate] 
                 ATP 
                 Assay buffer 
                 time 
               
               
                   
               
               
                 SIK1 (Carna 
                 AMARA 
                 5 μM ATP 
                 25 mM Tris pH 7.5 
                 120 min 
               
               
                 Biosciences, 
                 (SignalChem, 
                 (Promega, Cat# 
                 0.01% Triton X-100 
                   
               
               
                 Cat# 02-131), 
                 Cat# A11-58), 
                 V915B) 
                 0.5 mM EGTA 
                   
               
               
                 0.25 ng/μL 
                 45 μM 
                   
                 2.5 mM DTT 
                   
               
               
                   
                   
                   
                 5 mM MgCl 2   
                   
               
               
                 SIK2 (ThermoFisher 
                 AMARA 
                 5 μM ATP 
                 25 mM Tris pH 7.5 
                 120 min 
               
               
                 Scientific, 
                 (SignalChem, 
                 (Promega, Cat# 
                 0.01% Triton X-100 
                   
               
               
                 Cat# PV4792), 
                 Cat# A11-58), 
                 V915B) 
                 0.5 mM EGTA 
                   
               
               
                 0.0625 ng/μL 
                 45 μM 
                   
                 5 mM MgCl 2   
                   
               
               
                   
                   
                   
                 2.5 mM DTT 
                   
               
               
                 SIK3 (SignalChem, 
                 AMARA 
                 5 μM ATP 
                 25 mM Tris pH 7.5 
                 120 min 
               
               
                 Cat# S12-11G-100), 
                 (SignalChem, 
                 (Promega, Cat# 
                 0.01% Triton X-100 
                   
               
               
                 0.5 ng/μL 
                 Cat# A11-58), 
                 V915B) 
                 0.5 mM EGTA 
                   
               
               
                   
                 45 μM 
                   
                 5 mM MgCl 2   
                   
               
               
                   
                   
                   
                 2.5 mM DTT 
               
               
                   
               
            
           
         
       
     
     2.1.1.3. Data Analysis and Results 
     Raw data are generated following the read-out performed on the TopCount, plotted to generate dose response curves to calculate percentage inhibition (PIN) and average IC 50  for each SIK homologue which are reported in the table below. 
     
       
         
           
               
             
               
                 TABLE VI 
               
             
            
               
                   
               
               
                 ADP-Glo ™ SIK kinase assay IC 50  of  
               
               
                 illustrative compounds of the invention. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SIM1 
                 SIK2 
                 SIK3 
               
               
                   
                 Cpd # 
                 IC 50   
                 IC 50   
                 IC 50   
               
               
                   
                   
               
               
                   
                 1 
                 ** 
                 **** 
                 **** 
               
               
                   
                 2 
                 * 
                 ** 
                 **** 
               
               
                   
                 3 
                 * 
                 ** 
                 *** 
               
               
                   
                 4 
                 * 
                 *** 
                 *** 
               
               
                   
                 5 
                 * 
                 *** 
                 *** 
               
               
                   
                 6 
                 * 
                 *** 
                 *** 
               
               
                   
                   
               
               
                   
                 * &gt;500 nM 
               
               
                   
                 ** &gt;100-500 nM 
               
               
                   
                 *** &gt;10-100 nM 
               
               
                   
                 **** 0.01-10 nM 
               
               
                   
                 NA not measured 
               
            
           
         
       
     
     2.2. Cellular Assays 
     2.2.1. MdM Assay: LPS-Triggered TNFα/IL-10 (ELISA) 
     2.2.1.1. Overview 
     SIK inhibition inhibits TNFα and increases IL-10 release in LPS triggered monocyte-derived macrophages (MdM) and dendritic cells (MdDCs) (Clark et al. 2012; Sundberg et al. 2014; Ozanne et al. 2015). This assay evaluates illustrative compounds of the invention for their inhibition of LPS-induced TNFα and LPS triggered IL-10 secretion in monocyte-derived macrophages. 
     2.2.1.2. Protocols 
     PBMCs are isolated from human blood samples (buffycoats). The buffy coat is aseptically transferred into a 50 mL Falcon tube, and diluted 1/2 in PBS. Falcon tubes are filled with 20 mL Lymphoprep™, on top of which 25 mL of the buffy coat is carefully added, tubes are centrifuged for 35 min at 400 g in temperature controlled centrifuge, without brake, at 25° C. PBMCs are aspirated from the white interface layer between sample and Lymphoprep™. PBMCs are washed five times in PBS. Cells are resuspended in RPMI 1640 complete medium supplemented with 10% FBS, 1% P/S, and cell density is determined using a hematologic analyzer (Sysmex XS-500i). 
     PBMCs are centrifuged at 300×g for 10 min and resuspended at a density of 1.0*10 7  cells/80 μL Miltenyi buffer (PBS, pH 7.4, 1% FBS, 2 mM EDTA). 
     2.2.1.2.1 Positive Labelling of CD14+ Monocytes 
     Starting from this point of the protocol all steps are performed on ice. 20 μL of CD14+ micro-beads are added per 1.0*10 7  cells, the tube is mixed and incubated for 15 min in the fridge at 4° C. Cell suspension volume is adjusted to total volume of 100 mL using Miltenyi buffer, mixed gently and subsequently centrifuged for 10 min at 300×g. Supernantant is discarded and cell pellet is resuspended in 12 mL of Miltenyi buffer. 
     2.2.1.2.2 Magnetic Cell Sorting 
     Four LS columns are placed in the MACS Separator (magnet) from Miltenyi Biotec, and are prewet by rinsing with 3 mL of MACS buffer per column. Three mL of cell suspension is added onto the column (max 1*10 8  of labelled cells/column), and columns are subsequently washed 3 times with 3 mL of Miltenyi buffer. 
     The columns are removed from the magnets, and 5 mL of Miltenyi buffer are added to the column to flush out the CD14+ fraction by pushing the plunger into the column. The flushed fractions are collected in a fresh 50 mL Falcon and volume is adjusted to 30 mL using Miltenyi buffer, cells are centrifuged for 10 min at 300×g. The obtained cell pellet is resuspended in 10 mL RPMI w/o FBS, and cell density is determined using a hematologic analyser (Sysmex XS-500i). 100 000 cells are seeded per well of a 96-well plate for differentiation to MdM in RPMI 1640 medium supplemented with 10% FBS, 1% P/S and 100 ng/mL rhM-CSF. On day 5 the medium is refreshed with 100 μL RPMI 1640 medium supplemented with 10% FBS, 1% P/S and 100 ng/mL rhM-CSF. 
     On day 10, MdMs are triggered and compound is added. 
     A compound dilution plate is made in 100% DMSO by 3-fold dilution of 10 mM stock solution. An intermediate dilution plate (10× final concentration) is made by diluting the compound dilution plate 50-fold in RPMI medium. 
     Medium is carefully removed from cell plates using multichannel pipette, and replaced by 80 μL fresh medium. 10 μL of the 10× final concentration compound is added to the cells and incubated for 1 hour at 37° C. before addition of trigger. No trigger conditions/trigger conditions are spiked with equal final DMSO concentrations of 0.2% DMSO. 10 μL of 10×LPS (final conc. 200 ng/mL) solution are added to all wells except for the ‘no trigger wells’ where 10 μL medium is added. Supernatant is collected after 2 h (IL-10 determination) and after 20 h (TNFα determination) of LPS triggering. 
     2.2.1.2.3 TNFα ELISA 
     A Lumitrac 600 Greiner 384-well plate is coated with 40 μL of capture antibody (BD Pharmingen, Cat #551220) reaching a final concentration of 1 μg/mL in 1×PBS and stored overnight at 4° C. 
     The plate is then washed once with PBST (PBS+0.05% Tween20) and once with PBS followed by the addition of 100 μL of blocking buffer (1% Bovine Serum Albumin (BSA)-5% Sucrose) and plates are sealed and incubated for at least 4 h at RT. After washing the plate once with PBST and once with PBS, 40 μL of standard or sample are added (TNFα standard curve is prepared using a 1/2 serial dilution starting from 16000 μg/mL; dilutions are made in dilution buffer (PBS+1% BSA)). Plates are washed twice with PBST, and once with PBS, after which 35 μL of the detection antibody is added (final concentration 0.25 μg/mL diluted in dilution buffer) and plates are incubated for at least 2 h at RT. Plates are washed twice with PBST, and once with PBS, where after 35 μL of Strep-HRP conjugate (0.5 μg/mL final concentration diluted in dilution buffer) is added. Plates are incubated in the dark, at RT for at least 45 min but no longer than 1 hour. Plates are washed twice with PBST, and once with PBS. Thereafter, 50 μL of luminol substrate is added to each well (prepared according to manufacturer&#39;s instructions), and incubated for 5 min at RT protected from light. Chemiluminescence is measured on the Envision 2104. 
     2.2.1.2.1 IL-10 ELISA 
     An Immulon 2HB 96-well plate (Thermo Electron Co., Cat #3455) is coated with 40 μL of capture antibody (final concentration of 2 μg/mL diluted in Tris buffer (50 mM Tris; 150 mM NaCl; pH 9 (adjusted with HCl)) and stored overnight at 4° C. The next day the plate is washed three times with PBST, and subsequently 200 μL blocking buffer (1% BSA+5% sucrose in PBS-T) is added. After an incubation of 30 min at 37° C., the plate is washed three times with PBST, and 100 μL of standard or sample are added (IL-10 standard curve samples are prepared using a 1/2 serial dilution starting from 1000 μg/mL; dilutions are made in dilution buffer: PBS+1% BSA). After 1 hour incubation at 37° C., plates are washed three times with PBST, after which 100 μL of the detection antibody (BD Pharmingen, Cat #554499) is added (final concentration 0.25 μg/mL diluted in Tris buffer) and plates are incubated for at least 2 h at RT. Plates are washed three times with PBST, where after 100 μL of Strep-HRP conjugate (0.5 μg/mL final concentration diluted in dilution buffer) is added. Plates are incubated in the dark, at 37° C. for 30 min. Plates are washed three times with PBST. A substrate solution is made, for a total volume of 20 mL, 18 mL H 2 O; 2 mL citrate acetate buffer; 200 μL TMB mix (tetramethil benzidine (TMB) 101 mg, DMSO 10 mL stored at 4° C.); 2.5 μL 30% H 2 O 2  are mixed. 100 μL of substrate solution is added to each well and incubated until brilliant blue color develops. The reaction is stopped by adding 50 μL of 1 M H 2 SO 4 , after which absorbance is measured at 450 nm on the SpectraMax i3, Molecular Devices. 
     2.2.1.3. Data Analysis and Results 
     2.2.1.3.1 TNFα Inhibition Calculation 
     To measure the inhibition of LPS induced TNFα, percentage inhibition (PIN) values are calculated for all concentrations tested, compared to controls. Unstimulated samples (no trigger/vehicle (0.2% DMSO)) are used as negative control (100% inhibition). As a positive control (0% inhibition), the stimulated samples (trigger/vehicle)) are used. 
     
       
         
           
             PIN 
             = 
             
               
                 
                   ( 
                   
                     RLUp 
                     - 
                     
                       RLU 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       test 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       compound 
                     
                   
                   ) 
                 
                 
                   RLUp 
                   - 
                   RLUn 
                 
               
               × 
               1 
               ⁢ 
               0 
               ⁢ 
               0 
             
           
         
       
     
     wherein RLU=Relative Chemiluminescent Light Units (background subtracted) and p and n subscripts refer to the average of positive and negative controls, respectively. 
     PIN values are plotted in concentration-response and EC 50  values are derived using GraphPad Prism Software, applying 4-parameter nonlinear regression (sigmoidal) curve fitting. Because no clear bottom plateau is obtained, bottom of the curve is constrained to be equal to 0. 
     2.2.1.3.2 IL-10 Induction Calculation 
     IL-10 is induced upon SIK inhibition. To quantify these inductions fold changes (FC) compared to ‘LPS only’ are calculated for each concentration tested and the maximal FC is calculated (IL-OFCmax): 
     
       
         
           
             
               IL 
               - 
               
                 10 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 FC 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 max 
               
             
             = 
             
               
                 
                   max 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   ABS 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   test 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   compound 
                 
                 ⁢ 
                 
                     
                 
               
               
                 ABS 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 trigger 
               
             
           
         
       
     
     wherein ABS=Absorbance measured at 450 nm. 
     The median maximal FC for test compounds across two or more assays is reported (IL-10FCmax median). 
     2.2.1.3.3 Results &amp; Outcome 
     The data obtained when subjecting illustrative compounds of the invention are described in the table below. 
     
       
         
           
               
             
               
                 !TABLE VII 
               
             
            
               
                   
               
               
                 MdM TNFα inhibition and IL-10  
               
               
                 induction of illustrative compounds  
               
               
                 of the invention. 
               
            
           
           
               
               
               
            
               
                   
                 TNFα 
                 IL-10 
               
               
                   
                 EC 50   
                 FCmax 
               
               
                 Cpd # 
                 (nM) 
                 median 
               
               
                   
               
               
                 1 
                 *** 
                 ++ 
               
               
                 2 
                 *** 
                 NA 
               
               
                 3 
                 *** 
                 NA 
               
               
                   
               
               
                 * &gt;5000 nM 
               
               
                 ** &gt;1000-5000 nM 
               
               
                 *** &gt;100-1000 nM 
               
               
                 **** 0.1-100 nM 
               
               
                 + ≤1.5 
               
               
                 ++ &gt;1.5-4.5 
               
               
                 +++ &gt;4.5 
               
               
                 NA not measured 
               
            
           
         
       
     
     2.2.2. Monocytes Assay: LPS-Triggered TNFα/IL-10 (ELISA) 
     2.2.2.1. Overview 
     SIK inhibition inhibits TNFα and increases IL-10 release in LPS triggered monocyte-derived macrophages (MdM) and dendritic cells (MdDCs) (Clark et al. 2012; Sundberg et al. 2014; Ozanne et al. 2015). This assay evaluates illustrative compounds of the invention for their inhibition of LPS-induced TNFα and LPS triggered IL-10 secretion in monocytes. 
     2.2.2.2. Protocols 
     PBMCs are isolated from human blood samples (buffycoats). The buffy coat is aseptically transferred into a 50 mL Falcon tube, and diluted 1/2 in PBS. Falcon tubes are filled with 20 mL Lymphoprep™, on top of which 25 mL of the buffy coat is carefully added, tubes are centrifuged for 35 min at 400 g in temperature controlled centrifuge, without brake, at 25° C. PBMCs are aspirated from the white interface layer between sample and Lymphoprep™. PBMCs are washed five times in PBS. Cells are resuspended in RPMI 1640 complete medium supplemented with 10% FBS, 1% P/S, and cell density is determined using a hematologic analyzer (Sysmex XS-500i). 
     PBMCs are centrifuged at 300×g for 10 min and resuspended at a density of 1.0*10 7  cells/80 μL Miltenyi buffer (PBS, pH 7.4, 1% FBS, 2 mM EDTA). 
     2.2.2.2.1 Positive Labelling of CD14+ Monocytes 
     Starting from this point of the protocol all steps are performed on ice. 20 μL of CD14+ micro-beads are added per 1.0*10 7  cells, the tube is mixed and incubated for 15 min in the fridge at 4° C. Cell suspension volume is adjusted to total volume of 100 mL using Miltenyi buffer, mixed gently and subsequently centrifuged for 10 min at 300×g. Supernantant is discarded and cell pellet is resuspended in 12 mL of Miltenyi buffer. 
     2.2.2.2.2 Magnetic Cell Sorting 
     Four LS columns are placed in the MACS Separator (magnet) from Miltenyi Biotec, and are prewet by rinsing with 3 mL of MACS buffer per column. Three mL of cell suspension is added onto the column (max 1*10 8  of labelled cells/column), and columns are subsequently washed 3 times with 3 mL of Miltenyi buffer. 
     The columns are removed from the magnets, and 5 mL of Miltenyi buffer are added to the column to flush out the CD14+ fraction by pushing the plunger into the column. The flushed fractions are collected in a fresh 50 mL Falcon and volume is adjusted to 30 mL using Miltenyi buffer, cells are centrifuged for 10 min at 300×g. The obtained cell pellet is resuspended in 10 mL RPMI w/o FBS, and cell density is determined using a hematologic analyser (Sysmex XS-500i). 100 000 cells are seeded in 80 μL per well of a 96-well plate in RPMI 1640 medium supplemented with 10% FBS, 1% P/S. 
     A compound dilution plate is made in 100% DMSO by 3-fold dilution of 10 mM stock solution. An intermediate dilution plate (10× final concentration) is made by diluting the compound dilution plate 50-fold in RPMI medium. 
     10 μL of the 10× final concentration compound is added to the cells and incubated for 1 h at 37° C. before addition of trigger. No trigger conditions/trigger conditions are spiked with equal final DMSO concentrations of 0.2% DMSO. 10 μL of 10×LPS (final conc. 200 ng/mL) solution are added to all wells except for the ‘no trigger wells’ where 10 μL medium is added. Supernatant is collected after 4 h of LPS triggering. 
     2.2.2.2.3 TNFα ELISA 
     A Lumitrac 600 Greiner 384-well plate is coated with 40 μL of capture antibody (BD Pharmingen, Cat #551220) reaching a final concentration of 1 μg/mL in 1×PBS and stored overnight at 4° C. 
     The plate is then washed once with PBST (PBS+0.05% Tween20) and once with PBS followed by the addition of 100 μL of blocking buffer (1% Bovine Serum Albumin (BSA)-5% Sucrose) and plates are sealed and incubated for at least 4 h at RT. After washing the plate once with PBST and once with PBS, 100 μL of of blocking buffer (1% BSA-5% Sucrose) is added and plates are sealed and incubated for at least 4 h at RT. Plates are washed twice with PBST, and once with PBS, after which 35 μL of the detection antibody is added (final concentration 0.25 μg/mL diluted in dilution buffer) and plates are incubated for at least 2 h at RT. Plates are washed twice with PBST, and once with PBS, whereafter 35 μL of Strep-HRP conjugate (0.5 μg/mL final concentration diluted in dilution buffer) is added. Plates are incubated in the dark, at RT for at least 45 min but no longer than 1 h. Plates are washed twice with PBST, and once with PBS. Thereafter, 50 μL of luminol substrate is added to each well (prepared according to manufacturer&#39;s instructions), and incubated for 5 min at RT protected from light. Chemiluminescence is measured on the Envision 2104. 
     2.2.2.2.4 IL-10 ELISA 
     A Lumitrac 600 Greiner 384-well plate is coated with 40 μL of capture antibody (final concentration of 1 μg/mL in 1×PBS) and stored overnight at 4° C. The next day the plate is washed three times with PBST (PBS+0.05% Tween20) and once with PBS followed by the addition of 100 μL of blocking buffer (1% BSA-5% Sucrose) and plates are sealed and incubated for at least 4 h at RT. After washing the plate once with PBST and once with PBS, 40 μL of standard or sample are added (IL-10 standard curve is prepared using a 1/2 serial dilution starting from 2000 μg/mL; dilutions are made in dilution buffer (PBS+1% BSA)). Plates are washed twice with PBST, and once with PBS, after which 35 μL of the detection antibody is added (final concentration 0.143 μg/mL diluted in dilution buffer) and plates are incubated for at least 2 h at RT. Plates are washed twice with PBST, and once with PBS, whereafter 35 μL of Strep-HRP conjugate (0.5 μg/mL final concentration diluted in dilution buffer) is added. Plates are incubated in the dark, at RT for at least 45 min but no longer than 1 h. Plates are washed twice with PBST, and once with PBS. Thereafter, 50 μL of luminol substrate is added to each well (prepared according to manufacturer&#39;s instructions), and incubated for 5 min at RT protected from light. Chemiluminescence is measured on the Envision 2104. 
     2.2.2.3. Data Analysis and Results 
     2.2.2.3.1 TNFα Inhibition Calculation 
     To measure the inhibition of LPS induced TNFα, percentage inhibition (PIN) values are calculated for all concentrations tested, compared to controls. Unstimulated samples (no trigger/vehicle (0.2% DMSO)) are used as negative control (100% inhibition). As a positive control (0% inhibition), the stimulated samples (trigger/vehicle)) are used. 
     
       
         
           
             PIN 
             = 
             
               
                 
                   ( 
                   
                     RLUp 
                     - 
                     
                       RLU 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       test 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       compound 
                     
                   
                   ) 
                 
                 
                   RLUp 
                   - 
                   RLUn 
                 
               
               × 
               100 
             
           
         
       
     
     wherein RLU=Relative Chemiluminescent Light Units (background subtracted) and p and n subscripts refer to the average of positive and negative controls, respectively. 
     PIN values are plotted in concentration-response and EC 50  values are derived using GraphPad Prism Software, applying 4-parameter nonlinear regression (sigmoidal) curve fitting. When no clear bottom plateau is obtained, bottom of the curve is constrained to be equal to 0. 
     2.2.2.3.2 IL-10 Induction Calculation 
     LPS-induced IL-10 is increased upon SIK inhibition. To quantify these increases, fold changes (FC) compared to ‘LPS only’ are calculated for each concentration tested and the maximal FC is calculated (IL-10 FCmax): 
     
       
         
           
             
               IL 
               ⁢ 
               
                 - 
               
               ⁢ 
               10 
               ⁢ 
               
                   
               
               ⁢ 
               FC 
               ⁢ 
               
                   
               
               ⁢ 
               max 
             
             = 
             
               max 
               ⁢ 
               
                 
                   ( 
                   
                     RLU 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     test 
                     ⁢ 
                     
                         
                     
                     ⁢ 
                     compound 
                   
                   ) 
                 
                 
                   RLU 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   trigger 
                 
               
             
           
         
       
     
     The median maximal FC for test compounds across two or more runs is reported (IL-10FCmax median). 
     2.2.2.3.3 Results &amp; Outcome 
     The data obtained when subjecting illustrative compounds of the invention are described in the table below. 
     
       
         
           
               
             
               
                 TABLE VIII 
               
             
            
               
                   
               
               
                 Monocytes TNFα inhibition and IL-10 induction of 
               
               
                 illustrative compounds of the invention. 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                 TNFα 
                 IL-10 
                   
                 TNFα 
                 IL-10 
               
               
                   
                   
                 EC 50   
                 FCmax 
                   
                 EC 50   
                 FCmax 
               
               
                   
                 Cpd# 
                 (nM) 
                 median 
                 Cpd# 
                 (nM) 
                 median 
               
               
                   
                   
               
               
                   
                 1 
                 *** 
                 +++ 
                 3 
                 *** 
                 NA 
               
               
                   
                 2 
                 *** 
                 + 
                 6 
                 *** 
                 NA 
               
               
                   
                   
               
               
                   
                 * &gt;5000 nM 
               
               
                   
                 ** &gt;1000-5000 nM 
               
               
                   
                 *** &gt;100-1000 nM 
               
               
                   
                 **** 0.1-100 nM 
               
               
                   
                 + ≤1.5 
               
               
                   
                 ++ &gt;1.5-4.5 
               
               
                   
                 +++ &gt;4.5 
               
               
                   
                 NA not measured 
               
            
           
         
       
     
     Example 3. In Vivo Assays 
     3.1. Inflammatory Bowel Disease 
     3.1.1. DSS Model (Mice) 
     The mouse chronic DSS-induced inflammatory bowel disease model (IBD) is a well validated disease model for inflammatory bowel disease (Wirtz et al. 2007; Sina et al. 2009). 
     To induce a chronic colitis, female BALB/c mice are fed with drinking water containing 4% dextran sodium sulfate (DSS) for 4 days, followed by 3 days of regular drinking water. This cycle is repeated until sacrifice on day 12 or 18. Animals are divided into several groups:
     a. intact water; vehicle alone, n=10),   b. diseased (DSS; vehicle alone, n=10),   c. sulfasalazine used as reference (DSS; 20 mg/kg/day, p.o., n=10) and   d. the tested compound (DSS; e.g., 1, 3, 10, 30 mg/kg/day, p.o., n=10).   

     Clinical parameters are measured every other day. The disease activity index (DAI) is a composite measure combining the individual scores for weight loss, stool consistency and blood presence in stools. Mice are sacrificed according to the protocol introduced by Sina et al. (2009) (Sina et al. 2009). At sacrifice time, the complete colon is removed and rinsed with sterile PBS. Segments of the distal colon are dissected for histological analysis, gene expression and protein level measurement. 
     3.2. CIA Model 
     3.2.1. Materials 
     Completed Freund&#39;s adjuvant (CFA) and incomplete Freund&#39;s adjuvant (IFA) are purchased from Difco. Bovine collagen type II (CII), lipopolysaccharide (LPS), and Enbrel® (etanercept) are obtained from Chondrex (L&#39;Isle d&#39;Abeau, France); Sigma (P4252, L&#39;Isle d&#39;Abeau, France), Whyet (25 mg injectable syringe, France), respectively. All other reagents used are of reagent grade and all solvents are of analytical grade. 
     3.2.2. Animals 
     DBA1/J mice (male, 7-8 weeks old) are obtained from Charles River Laboratories (Ecully, France). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22° C., and food and water are provided ad libitum. 
     3.2.3. Collagen Induced Arthritis (CIA) 
     One day before the experiment, CII solution (2 mg/mL) is prepared with 0.05 M acetic acid and stored at 4° C. Just before the immunization, equal volumes of adjuvant (IFA) and CII are mixed by a homogenizer in a pre-cooled glass bottle in an ice water bath. Extra adjuvant and prolonged homogenization may be required if an emulsion is not formed. 0.2 mL of the emulsion is injected intradermally at the base of the tail of each mouse on day 1, a second booster intradermal injection (CII solution at 2 mg/mL in CFA 0.1 mL saline) is performed on day 9. This immunization method is modified from published methods (Jou et al. 2005; Sims et al. 2004). 
     3.2.4. Study Design 
     The therapeutic effects of the compounds are tested in the mouse CIA model. Mice are randomly divided into equal groups and each group contained 10 mice. All mice are immunized on day 1 and boosted on day 21. The negative control group is treated with vehicle (MC 0.5%) and the positive control group with Enbrel® (10 mg/kg, 3× week., sc). A compound of interest is typically tested at 3 doses per os (p.o.). At day 32, randomization between groups is performed with respect with clinical score and animals are therapeutically treated regarding their group until day 47. Body weight and clinical score, are recorded at least twice a week. 
     3.2.5. Clinical Assessment of Arthritis 
     Arthritis is scored according to the method of Khachigian 2006, Lin et al 2007 and Nishida et al. 2004 (Khachigian 2006; Lin et al. 2007; Nishida et al. 2004). The swelling of each of the four paws is ranked with the arthritic score as follows: 0-no symptoms; 1-mild, but definite redness and swelling of one type of joint such as the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits; 2-moderate redness and swelling of two or more types of joints; 3-severe redness and swelling of the entire paw including digits; 4-maximally inflamed limb with involvement of multiple joints (maximum cumulative clinical arthritis score 16 per animal) (Nishida et al. 2004). 
     3.2.5.1. Change in Body Weight (%) after Onset of Arthritis 
     Clinically, body weight loss is associated with arthritis (Argilés &amp; López-Soriano 1998; Rall &amp; Roubenoff 2004; Shelton et al. 2005; Walsmith et al. 2004). Hence, changes in body weight after onset of arthritis can be used as a non-specific endpoint to evaluate the effect of therapeutics in the mouse model. The change in body weight (%) after onset of arthritis is calculated as follows: 
     
       
         
           
             
               
                 
                   Body 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   
                     Weight 
                     
                       ( 
                       
                         week 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         6 
                       
                       ) 
                     
                   
                 
                 - 
                 
                   Body 
                   ⁢ 
                   
                       
                   
                   ⁢ 
                   
                     Weight 
                     
                       ( 
                       
                         week 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         5 
                       
                       ) 
                     
                   
                 
               
               
                 Mice 
                 ⁢ 
                 
                   : 
                 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 Body 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 
                   Weight 
                   
                     ( 
                     
                       week 
                       ⁢ 
                       
                           
                       
                       ⁢ 
                       5 
                     
                     ) 
                   
                 
               
             
             × 
             100 
             ⁢ 
             % 
           
         
       
     
     3.2.5.2. Radiology 
     X-ray photos are taken of the hind paws of each individual animal. A random blind identity number is assigned to each of the photos, and the severity of bone erosion is ranked by two independent scorers with the radiological Larsen&#39;s score system as follows: 0—normal with intact bony outlines and normal joint space; 1—slight abnormality with any one or two of the exterior metatarsal bones showing slight bone erosion; 2—definite early abnormality with any three to five of the exterior metatarsal bones showing bone erosion; 3—medium destructive abnormality with all the exterior metatarsal bones as well as any one or two of the interior metatarsal bones showing definite bone erosions; 4—severe destructive abnormality with all the metatarsal bones showing definite bone erosion and at least one of the inner metatarsal joints completely eroded leaving some bony joint outlines partly preserved; 5—mutilating abnormality without bony outlines. This scoring system is a modification from Salvemini et al., 2001; Bush et al., 2002; Sims et al., 2004; Jou et al., 2005 (Bush et al. 2002; Jou et al. 2005; Salvemini et al. 2001; Sims et al. 2004). 
     3.2.5.3. Steady State PK 
     At day 7, blood samples are collected at the retro-orbital sinus with lithium heparin as anti-coagulant at the following time points: predose, 1, 3 and 6 hrs. Whole blood samples are centrifuged and the resulting plasma samples are stored at −20° C. pending analysis. Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive electrospray mode. 
     3.3. Murine Model of Psoriatic-Like Epidermal Hyperplasia Induced by Topical Applications of Imiquimod, a TLR7/8 Agonist 
     3.3.1. Materials 
     Aldara® 5% imiquimod cream is obtained from MEDA. 
     Anti mouse IL 12/IL 23 p40 purified antibody (C17.8) (Cat #16 7123 85) is obtained from eBioscience (Frankfurt, Germany). 
     3.3.2. Animals 
     Balb/cJ mice (female, 18-20 g body weight) are obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22±2° C., food and water are provided ad libitum. 
     3.3.3. Study Design 
     The design of the study is adapted from Van der Fits L. et al. (van der Fits et al. 2009). 
     On the first day, the mice are shaved around the two ears under light anaesthesia. 
     30 mg of commercially available imiquimod cream (Aldara® 5% cream) are applied on both internal and external surfaces of each ear for 4 consecutive days, corresponding to a daily dose of 1.5 mg of the active compound. Control animals received the same quantity of vaseline. 
     From day 1 to day 5, mice are dosed with test compound, 10 or 30 mg/kg, p.o., b.i.d. in methyl cellulose 0.5%, before application of imiquimod (on day 5, the mice are dosed only once, 2 h before euthanasia). 
     In a positive reference group, the animals receive two intraperitoneal injections of anti mouse IL-12/IL-23 p40 antibody, 10 mg/kg, on day 1 and 3 days before day 1. 
     3.3.4. Assessment of Disease 
     The thickness of both ears is measured daily with a thickness gage (Mitutoyo, Absolute Digimatic, 547 321). Body weight is assessed at initiation of the experiment and at sacrifice. At day 5, 2 h after the last dosing, the mice are sacrificed. The pinnae of the ear are cut, excluding cartilage. The pinnae are weighed and then immersed in a vial containing 1 mL of RNAlater® solution to assess gene expression. 
     The results are expressed as mean±SEM and statistical analysis is performed using one way ANOVA followed by Dunnett&#39;s post hoc test versus imiquimod vehicle group. 
     3.3.5. Gene Expression Analysis 
     Ears are removed from the RNAlater® solution and put in Trizol® after disruption with 1.4 mm ceramic beads in a Precellys® device. Total RNA is then purified using NucleoSpin® RNA kit. cDNA is prepared and quantitative PCR is performed with gene-specific primers from Qiagen using SYBR Green technology in a ViiA7 real-time PCR system (Applied Biosystems). Expression levels of each gene (are calculated relative to the cyclophilin A housekeeping gene expression level. Data are expressed as mean±SEM of the relative quantity. The statistical test used is ANOVA analysis of variance with Dunnett&#39;s post-hoc test versus imiquimod vehicle group. 
     3.4. Murine Model of Psoriatic-Like Epidermal Hyperplasia Induced by Intradermal Injections of IL-23 
     3.4.1. Materials 
     Mouse recombinant IL-23, carrier free (Cat #14-8231) is provided by e-Bioscience (Frankfurt, Germany). 
     3.4.2. Animals 
     Balb/c mice (female, 18-20 g body weight) are obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22° C., food and water are provided ad libitum. 
     3.4.3. Study Design 
     The design of the study is adapted from Rizzo H L. et al. (Rizzo et al. 2011). 
     On the first day (D1), the mice are shaved around the two ears. For 4 consecutive days (D1 to D4), the mice received a daily intradermal dose of mouse recombinant IL-23 (1 μg/20 μL in PBS/0.1% BSA) in the right pinna ear and 20 μL of PBS/0.1% BSA in the left pinna ear under anesthesia. 
     From D1 to D5, mice are dosed with test-compound or with vehicle, 1 h prior IL-23 injection. 
     3.4.4. Assessment of Disease 
     The thickness of both ears is measured daily with an automatic caliper. Body weight is assessed at initiation and at sacrifice. On fifth day, 2 h after the last dosing, the mice are sacrificed. The pinnae of the ear are cut, excluding cartilage. The pinnae, placed in a vial containing 1 mL of RNAlater® solution. 
     At D4, blood samples are also collected from the retro-orbital sinus for PK profiling just before dosing (T0) and 1 h, 3 h, 6 h post-dosing. 
     There are 8 mice per group. The results are expressed as mean±SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett&#39;s post-hoc test versus IL-23 vehicle groups. 
     3.4.5. Gene Expression Analysis 
     Half ears are removed from RNAlater® solution and put in Trizol® after disruption with 1.4 mm ceramic beads in a Precellys® device. Total RNA is then purified using NucleoSpin® RNA kit. cDNA is prepared and quantitative PCR is performed with gene-specific primers from Qiagen using SYBR Green technology in a ViiA7 real-time PCR system (Applied Biosystems). Expression levels of each gene are calculated relative to the cyclophilin A housekeeping gene expression level. Data are expressed as mean±SEM of the relative quantity. The statistical test used is ANOVA analysis of variance with Dunnett&#39;s post-hoc test versus the IL-23 vehicle group. 
     3.5. Murine Model of Systemic Lupus Erythematosus Induced by Epicutaneous Applications of Imiquimod 
     3.5.1. Materials 
     Aldara® 5% imiquimod cream is obtained from MEDA. 
     Mouse anti-double-stranded DNA antibodies ELISA kits are obtained from Alpha Diagnostic International (Cat #5120). Mouse urinary albumin ELISA kits are obtained from Abcam (Cat #ab108792). Urine creatinine assay kits are obtained from Abnova (Cat #KA4344). 
     3.52. Animals 
     BALB/cJ mice (female, 18-20 g body weight) are obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22±2° C., food and water are provided ad libitum. 
     3.5.3. Study Design 
     The design of the study is adapted from Yokogawa M. et al. (Yokogawa et al. 2014). 
     On the first day (D1), the mice are shaved around the right ears. 
     The mice receive an epicutaneous application of 1.25 mg of imiquimod 3 times per week on the right pinna ear for 12 consecutive weeks (D1 to D86). The control group receives the same quantity of vaseline. 
     From D1 to D86, mice are dosed with test compound (30 mg/kg, p.o., q.d. in methylcellulose 0.5%) or with vehicle (10 mL/kg). 
     3.5.4. Assessment of Disease 
     The thickness of the ears is measured once a week with an automatic gage (Mitutoyo, Absolute Digimatic, 547-321). 
     Body weight is assessed at initiation and once a week until sacrifice. At necropsy, the spleen weight is also measured. The mice are sacrificed 2 h after the last dosing. 
     At different time points (e.g., on days D28, D56 and D84), the mice are individually placed in a metabolic cage to perform urinalysis and assess proteinuria (albumin to creatinine ratio). 
     Serums are collected at different time points (e.g., on D28, D56 and D86) to assess anti-double stranded-DNA IgG levels. 
     At D13, blood samples are also collected from the retro-orbital sinus for PK profiling just before dosing (T0) and 1 h, 3 h, and 6 h post-dosing. 
     There are 8-19 mice per group. The results are expressed as mean±SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett&#39;s post-hoc test versus imiquimod vehicle groups. 
     3.5.5. Quantification of Compound Levels in Plasma 
     Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive or negative electrospray mode. 
     3.5.5.1. Histopathology 
     In each glomerulus, 4 different readouts including mesangioproliferation, endocapillary proliferation, mesangial matrix expansion and segmental sclerosis are graded on a scale of 0 to 2 and then summed. For each kidney, about 50 glomeruli are scored and then averaged giving one glomerular lesion score (Yokogawa et al. 2014). Data are expressed as mean±SEM and statistical analysis is performed using the Kruskal-Wallis test followed by Dunn&#39;s post-hoc test versus imiquimod vehicle group. 
     3.5.5.2. Cellular Quantifications 
     For each cell type, immunohistochemical analysis is performed using image analysis (CaloPix software, TRIBVN Healthcare) on the whole tissue section at a magnification of ×20. Data are expressed as mean±SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett&#39;s post-hoc test versus imiquimod vehicle group. 
     3.5.5.3. Gene Expression Analysis 
     At sacrifice, the second part of the left kidneys is placed in tubes containing 1.4 mm ceramic beads and disrupted in 1% DTT RLT lysis buffer (Qiagen, Cat #79216) with a Bertin Instruments Precellys® homogenizer. Total RNA is then purified with a QIAcube using an RNeasy® 96 QIAcube® HT Kit (Qiagen, Cat #74171). cDNA is prepared and quantitative PCR performed with gene-specific primers from Qiagen using SYBR Green technology in a ViiA 7 real-time PCR system (Applied Biosystems). Expression levels of each gene of interest (GOI=CD3, CD68, CD20, OAS1, Mx1, IFIT1, CXCL11 and Usp18) are calculated relative to the cyclophilin, GAPDH and $3-actin housekeeping gene expression levels. 
     At sacrifice, one-third of the spleen is placed into tubes containing 1.4 mm ceramic beads and disrupted in Trizol® with a Bertin Instruments Precellys® homogenizer. Total RNA is extracted using a phenol/chloroform process and then purified with a QIAcube using an RNeasy® 96 QIAcube® HT Kit (Qiagen, Cat #74171). cDNA is prepared and quantitative PCR performed with gene-specific primers from Qiagen using SYBR Green technology in a ViiA 7 real-time PCR system (Applied Biosystems). Expression levels of each gene of interest are calculated relative to the cyclophilin, GAPDH and $3-actin housekeeping gene expression levels. 
     3.6. Murine Model of Psoriatic Arthritis Induced by Overexpression of IL-23 
     3.6.1. Materials 
     Mouse IL-23 enhanced episomal expression vector (EEV) is obtained from System Biosciences (Cat #EEV651A-1). Mouse IL-23 Quantikine ELISA Kits are obtained from R&amp;D Systems (Cat #M2300). ProSense® 680 and OsteoSense® 750EX are obtained from PerkinElmer (Cat #NEV10003 and NEV10053EX). RNAlater® is obtained from Ambion (Cat #AM7021). Imalgene® 1000 (Merial) and Rompun® 2% (Bayer) are obtained from Centravet (Cat #IMA004-6827812 and ROM001-6835444). 
     3.62. Animals 
     B10.RIII mice (male, 8-week old) are obtained from Charles River (Ecully, France). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22±2° C., food and water are provided ad libitum. 
     3.6.3. Study Design 
     The design of the study is adapted from Sherlock J P. et al. (Sherlock et al. 2012). 
     On the first day (D1), the mice undergo a hydrodynamic injection of Ringer or IL-23 EEV in Ringer into the tail vein. 
     As of D5, twice a week, the mice are scored for clinical symptoms until the end of the experiment. 
     On D5, blood is collected by puncture in the submandibular vein to assess the serum IL-23 concentration. 
     On D9, mice from all groups receive ProSense® 680 probe (0.8 nmol/10 g, i.p.). On D10, the mice are anesthetized. Granulocyte infiltration is then measured using in vivo molecular imaging (Bruker In-Vivo Xtreme imaging system). 
     On D11, randomization is performed according to ProSense® 680 molecular imaging and scoring. 
     As of D12, mice are dosed with test compound or with vehicle. 
     On D19, blood is sampled at time T0, T1h, T3h and T6h after last dosing. Plasma is separated and kept at 20° C. until bioanalysis. 
     On D36, mice from all groups are sacrificed 2 h after last administration of compound. 
     Total blood is collected in a serum blood tube and mixed by gentle inversion 8-10 times. After clotting, blood samples are centrifuged 10 min at 1800×g. After centrifugation, serum is stored at −80° C. 
     3.6.4. Assessment of Disease 
     Body weight is assessed at initiation of the study, then twice a week and at sacrifice. 
     Twice weekly, clinical signs of inflammation are scored: 0 for normal paw; 1 if swelling of one digit; 2 if swelling of two or more digits; 3 if swelling of the entire paw. The scores of all limbs are summed up to produce a global score. 
     On D32, mice from all groups receive ProSense® 680 probe (0.8 nmol/10 g, i.p.) and OsteoSense® 750EX probe (0.8 nmol/10 g, i.p.). On D33, the mice are anesthetized and granulocyte infiltration and bone remodelling are measured using in vivo molecular imaging (Bruker In-Vivo Xtreme imaging system). 
     There are 10 mice per group. The results are expressed as mean±SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett&#39;s post-hoc test versus diseased vehicle group for scoring and imaging analysis, versus sham vehicle group for body weight. 
     3.7. Murine Collagen-Antibody Induced Arthritis Model (CAIA) 
     3.7.1. Materials 
     ArthritoMab™ antibody cocktail for inducing arthritis and lipopolysaccharide (LPS) from  Escherichia Coli  serotype 055:B5 are purchased from MD Biosciences (Oakdale, Minn., USA, Cat #CIA-MAB-50); PBS 1× (GIBCO, Cat #140190-086) is obtained from ThermoFisher Scientific, and Enbrel® (etanercept) is purchased from Chondrex (L&#39;Isle d&#39;Abeau, France, Cat #3771910). 
     3.7.2. Animals 
     Five to seven week old BALBc female mice are obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22° C., food and water are provided ad libitum. 
     3.7.3. Study Design 
     The therapeutic effects of the compounds of the invention are tested in the mouse CAIA model (MD Biosciences 2008; Nandakumar et al. 2003). At day 1 (D1), mice are randomly divided into equal groups containing 10 mice. All mice including vehicle, except the non-treated group, are immunized with ArthritoMab™ cocktail (100 mg/kg, i.v., 200 μL/mouse) and treatment with compound or vehicle started. Bodyweight and clinical score of each mouse is assessed every day except the weekend until the end of the study. At D4, all mice, except the non-treated group, received a challenge of LPS (2.5 mg/kg, i.p.). At D11, all mice are sacrificed and blood is sampled on serum tube. After centrifugation, serum is collected and frozen at −80° C. pending analysis (e.g., cytokine levels, gene expression, compound levels). For histology readouts, right and left hind paws are individually collected in vials (25 mL minimum) filled with 4% buffered formaldehyde for a minimum of 24 h to a maximum of 4 days at RT. 
     3.7.4. Clinical Assessment of Arthritis 
     Arthritis is scored according to the method of Khachigian 2006; Lin et al 2007 and Nishida et al. 2004 (Khachigian 2006; Lin et al. 2007; Nishida et al. 2004). The swelling of each of the four paws is ranked with the arthritic score as follows: 
     
       
         
           
               
               
             
               
                   
               
               
                 Score 
                 Definition 
               
               
                   
               
             
            
               
                 0 
                 no symptoms 
               
               
                 1 
                 mild, but definite redness and swelling of one type  
               
               
                   
                 of joint such as the ankle or wrist, or apparent  
               
               
                   
                 redness and swelling limited to individual digits,  
               
               
                   
                 regardless of the number of affected digits 
               
               
                 2 
                 moderate redness and swelling of two or more types of joints 
               
               
                 3 
                 severe redness and swelling of the entire paw including digits 
               
               
                 4 
                 maximally inflamed limb with involvement of multiple joints 
               
               
                   
               
            
           
         
       
     
     The final clinical score is the cumulative score of the four paws (maximum cumulative clinical arthritis score 16 per animal)(Nishida et al. 2004). A curve of cumulative clinical score is drawn for each group, and the area under the curve is calculated. The results are expressed as mean±SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett&#39;s post-hoc test versus vehicle groups. 
     3.8. Murine Therapeutic Model of Atopic Dermatitis Induced by Topical Application of MC903 
     3.8.1. Materials 
     Methylcellulose 0.5% (Cat #AX021233) is obtained from VWR. MC903 (calcipotriol, Cat #2700/50) is obtained from Tocris Bioscience (Bristol, UK). ProSense® 680 (Cat #NEV10003) is obtained from PerkinElmer (Massachusetts, USA). RNAlater® (Cat #AM7021) is obtained from Ambion (California, USA). 
     3.8.2. Animals 
     BALB/cN mice (female, 18-20 g body weight) or CD1/Swiss mice (female, 24-26 g body weight) are obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice are kept on a 12 h light/dark cycle. 
     Temperature is maintained at 22±2° C., food and water are provided ad libitum. 
     3.8.3. Study Design 
     The design of the study is adapted from Li M. et al. (Li et al. 2006). On the first day (D1), the mice are anesthetized and shaved around the two ears. As of D1, either 20 μL EtOH or 2 nmol of MC903 (in 20 μL EtOH) are topically applied on each ear of the mice up to D9, D11 or D15 (except during the weekend). 
     From D5, the mice are dosed with test compound (15 or 30 mg/kg, p.o., b.i.d. in methylcellulose 0.5%) or dexamethasone (5 mg/kg, p.o., q.d. in methylcellulose 0.5%), or with vehicle, until D10, D12, or D16. 
     3.8.4. Quantification of Compound Levels in Plasma 
     Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive or negative electrospray mode. 
     3.8.5. Determination of Pharmacokinetic Parameters 
     Pharmacokinetic parameters are calculated using Phoenix® WinNonlin® (Pharsight®, USA). 
     3.8.6. Assessment of Disease 
     The thickness of each ear is measured immediately before first application of MC903 (baseline), three times a week, and at sacrifice using a thickness gauge (Mitutoyo, Absolute Digimatic, Cat #547-321). 
     Body weight is assessed at immediately before first application of EtOH (baseline), three times a week and at sacrifice. 
     On D8, D10 or D11, mice from all groups receive ProSense® 680 probe (0.8 nmol/10 g, i.p.). On the next day (D9, D11 or D12), the mice are anesthetized. Granulocyte infiltration is then measured using in vivo molecular imaging (Bruker In-Vivo Xtreme imaging system, excitation wavelength: 630 nm, emission wavelength: 700 nm, acquisition time: 5 seconds). 
     On D10, D12, or D16, 2 h after the last dosing, the mice are sacrificed, total blood is collected in EDTA-coated tubes and plasma is frozen for further measurements (including circulating compound). 
     The pinnae of the ears are collected. One ear is cut longitudinally into 2 halves. One half is fixed in formaldehyde buffer 3.7% for histology; the other one is immersed in RNAlater® to assess gene expression. 
     There are 8 mice per group. The results are expressed as mean±SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett&#39;s post-hoc test versus MC903 vehicle groups (MC903 treated mice dosed with vehicle alone) for ear thickness and weight, and/or versus EtOH vehicle group (EtOH treated mice dosed with vehicle alone) for body weight. 
     3.8.7. Histology 
     After sacrifice, half ears are collected and fixed in 3.7% formaldehyde before embedding in paraffin. 4 μm thick sections are immunostained by immunohistochemistry with anti-CD3 antibody. The immunostained cell areas from a whole section per mouse are measured by image analysis (CaloPix software, TRIBVN Healthcare, France). Data are expressed as mean±SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett&#39;s post-hoc test versus MC903 vehicle group. 
     3.8.8. Gene Expression Analysis 
     Ears are removed from RNAlater® solution and placed in Trizol® after disruption with 1.4 mm ceramic beads in a Bertin Instruments Precellys® homogenizer. Total RNA is then extracted using a phenol/chloroform protocol and purified with a QIAcube using an RNeasy® 96 QIAcube® HT Kit (Qiagen, Cat #74171). cDNA is prepared and quantitative PCR performed with gene-specific primers from Qiagen using SYBR Green technology in a ViiA 7 real-time PCR system (Applied Biosystems). Expression levels of each gene of interest (GOI=IL4, IL5, IL13, TSLP, IL33, ST2, IL25, IL31, IFNγ, IL6, IL10, LCN2, S100A8, and S100A9) are calculated relative to the housekeeping gene expression levels (HPRT, GAPDH and β-actin). 
     All qPCR data are expressed as mean±SEM of the normalized relative quantity (NRQ) calculated according to the following steps: 
     1—Calculate the geometric mean of NRQ for each group of animals 
     
       
         
           
             
               NRQ 
               sample 
             
             = 
             
               
                 2 
                 
                   - 
                   CqGOI 
                 
               
               
                 Geometric 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 
                   mean 
                   ⁡ 
                   
                     ( 
                     
                       
                         2 
                         
                           - 
                           CqhPRT 
                         
                       
                       , 
                       
                         2 
                         
                           - 
                           CqGADPH 
                         
                       
                       , 
                       
                         2 
                         
                           
                             
                               - 
                               Cq 
                             
                             ⁢ 
                             
                                 
                             
                             ⁢ 
                             β 
                           
                           - 
                           actin 
                         
                       
                     
                     ) 
                   
                 
               
             
           
         
       
     
     2—Calculate NRQ-scaled compared to the MC903 vehicle group 
     
       
         
           
             NRQscaled 
             = 
             
               
                 NRQ 
                 sample 
               
               
                 Geometric 
                 ⁢ 
                 
                     
                 
                 ⁢ 
                 
                   mean 
                   ⁡ 
                   
                     ( 
                     
                       NRQ 
                       
                         samples 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         MC903 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         vehicle 
                         ⁢ 
                         
                             
                         
                         ⁢ 
                         group 
                       
                     
                     ) 
                   
                 
               
             
           
         
       
     
     The statistical test used is ANOVA analysis of variance with Dunnett&#39;s post-hoc test versus the EtOH vehicle group and/or MC903 vehicle group. 
     3.9. Mouse LPS-Induced Endotoxic Shock 
     Injection of lipopolysaccharide (LPS) induces a rapid release of soluble tumour necrosis factor (TNFα) into the periphery. This model is used to assess prospective blockers of TNFα release in vivo. 
     3.9.1. Materials 
     Lipopolysaccharide (LPS) from  Escherichia Coli  serotype O111:B4 is obtained from Sigma Aldrich (Cat #L2630). 
     3.9.2. Animals 
     BALB/cAnNCrl mice (female, 18-20 g body weight) are obtained from Charles River (Calco, Italy). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22±2° C., food and water are provided ad libitum. 
     3.9.3. Study Design 
     Mice are dosed once by oral (p.o.) or subcutaneous (sc) route with the tested compound in the appropriate vehicle. 
     At the Tmax of compound, 100 μg of LPS (in H 2 O) is injected intraperitoneally to mice. A control group is included which comprises administering the vehicle without an LPS challenge. 
     Mice are sacrificed 90 min after LPS challenge and blood is collected in heparinised tubes. Plasma is obtained by centrifugation for 15 min, 2000×g at +4° C. and frozen at −80° C. before cytokine analysis. 
     3.9.4. Assessment of Disease 
     TNFα and IL-10 are quantified in plasma by AlphaLISA detection kits obtained from PerkinElmer (Massachusetts, USA), Cat #AL505C and AL502C, respectively. 
     Statistics are performed with Prism 5.03 software (GraphPad) using an ANOVA analysis of variance with Dunnett&#39;s post-hoc test versus LPS group. 
     Active compounds are defined as showing a statistically significant decrease in TNFα with or without a statistically significant induction of IL-10. 
     3.10. MultiDrug Resistance-1a-Ablated (MDRa1) Model (Mice) 
     3.10.1. Principle of Assay 
     Mice deficient in Abcb1a (MDRa1) develop spontaneous colitis that can be accelerated by infection with  Helicobacter bilis . This model is used to evaluate the ability of a compound to treat or prevent colitis (Maxwell et al. 2015). 
     3.10.2. Materials 
     Sterile PBS (Gibco, Cat #20012027) is obtained from ThermoFisher Scientific (Massachusetts, USA); Brucella Agar (Cat #211086) is obtained from Becton Dickinson (New Jersy, USA); Brucella Broth Base (Cat #B3051-500g) is obtained from Sigma Aldrich (Missouri, USA). Defibrinated sheep blood (Cat #SR0051) and Campygen (Cat #CN0025) are obtained from ThermoFisher Scientific (Massachusetts, USA).  H. bilis  ATCC 51360 is obtained from LGC Standards (Molsheim, France) and Combur testE (Cat #11896857) is obtained from Roche Diagnostics (Basel, Switzerland). 
     3.10.3. Animals 
     Seven to nine week old MDR1a (FVB.129P2—Abcblatm1Bor N7) female mice are obtained from Taconic (Rensselaer, N.Y., USA) and seven to nine week old FVB female mice are obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22° C., food and water are provided ad libitum. 
     3.10.4.  H. bilis  Inoculum Preparation 
     Frozen vial of  H. bilis  is thawed, put in Brucella Broth and incubated in Brucella Agar slant containing 5% of defibrinated sheep blood under microaerophily at 37° C. for 4 to 5 days. At D1, just before administration, a part of  H. bilis  culture is diluted in PBS in order to obtain 10 7  cfu/mouse and a second part is put in fresh Brucella Broth and incubated as previously for 7 days. At D8, just before administration,  H. bilis  culture is diluted in PBS in order to obtain 10 7  cfu/mouse. 
     3.10.5. Study Design 
     After a 10 days acclimatization period, the disease activity index of each MDR1a mouse is determined in order to constitue homogene groups regarding the DAI score between groups. All mice (10 mice per group), except for the SHAM group (n=10), are then administered by oral route with an inoculum of  H. bilis  (10 7  cfu/mouse) and treatment started accordingly to the protocol for six weeks. Seven days after the start of treatment, a second administration of  H. bilis  is performed. During the whole treatment period, disease activity index is determined twice a week. Six weeks after the start of treatment, mice are sacrificed, blood is sampled and the complete colon is collected and rinsed with sterile PBS. Collected colons are measured and weighed in order to determine colon weight/length ratio, and histological analysis, gene expression, protein level measurement and/or FACs immunophenotyping analysis are performed on the samples. The results are expressed as mean±SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett&#39;s post-hoc test versus vehicle groups. 
     3.10.6. Disease Activity Index (DAI) Determination 
     The DAI score of each mouse (sum of scores for weight loss, stool consistency and rectal bleeding) is monitored during the entire treatment period and a DAI score progression curve is obtained. 
     
       
         
           
               
               
               
               
               
             
               
                   
                   
               
               
                   
                   
                 Weight  
                   
                 Rectal  
               
               
                   
                 DAI 
                 evolution 
                 Stool consistency 
                 bleeding* 
               
               
                   
                   
               
             
            
               
                   
                 0 Point 
                 No weight 
                 Well molded stools 
                   
               
               
                   
                   
                 loss (vs D1) 
                   
                   
               
               
                   
                 1 point 
                 1 to 5% 
                 Semi-soft stools 
                   
               
               
                   
                 2 points 
                  5 to 10% 
                 Soft stools that do not  
                   
               
               
                   
                   
                   
                 stick to the anus 
                   
               
               
                   
                 3 points 
                 10 to 20% 
                 Semi-liquid stools not  
                   
               
               
                   
                   
                   
                 sticking to the anus 
                   
               
               
                   
                 4 Points 
                 &gt;20% 
                 Liquid stools remaining  
                   
               
               
                   
                   
                   
                 stuck to the anus 
               
               
                   
                   
               
               
                   
                 *A little piece of stool is deposited on a vial containing 1 mL of D-PBS and homogeneized, deposited on a test strip (Combur TestE), a color appears according to the blood intensity in the stool, a score is given according to this intensity, from 0 to 4 points. 
               
            
           
         
       
     
     3.11. Radiation Induced Fibrosis Mouse Model 
     3.11.1. Study Overview 
     Pneumonitis and lung fibrosis are the major radiation-induced complications following thoracic radiotherapy, which is one of the major treatment of lung and breast cancers, lymphomas and hematopoietic transplant conditioning. The objective of this model is to evaluate the effect of a compound of the invention in lung fibrosis induced by radiation in mice (Favaudon et al. 2014), in particular on lung functionality (Flexivent) and fibrosis marker (Collagen I). 
     3.11.2. Animals 
     7 weeks old (18-22 gr) female C57BL/6J mice from Charles River (Ecully, France), batch number S1672) are maintained on 12 h light/dark cycle at 22° C. with ad libitum access to tap water and food. 
     3.11.3. Materials 
     The test compounds are dissolved/suspended in appropriate vehicle prior to using and kept light-free, under agitation at RT. 
     An aliquot of the formulation (˜200 μL) is frozen at T0 (day of preparation) and all the formulations are checked (daily) for any change in aspect. 
     The dose volume administered is 10 mL/kg and the volume is adapted following mean (body weight (BW) of the group as follows: 200 μL if mean BW&lt;22.5 g, 250 μL if mean BW≥22.5 g; 300 μL if mean BW&gt;27.5 g. 
     3.11.4. In Vivo Experimental Procedure 
     On day 1 of week 1, the animals are exposed at the thorax to a 17 Gray irradiation dose, under isoflurane anesthesia. 
     At the beginning of week 18 post radiation (D1), animals are randomized into 6 study groups (15 subjects per group): 1) sham (vehicle: methylcellulose (MC) 0.5%), 2) diseased (vehicle: methylcellulose (MC) 0.5%), 3) positive control (nintedanib dosed 60 mg/kg in 0.1% Natrosol™), and 4) 3 groups test compound (60 mg/kg in 0.5% Methylcellulose (MC)), and dosed p.o. b.i.d. until D23 (week 21). 
     Body weight is recorded once a week, and on D23, lung function measurement under anesthesia is realized by Flexivent (Devos et al. 2017) for all groups (6 successful measurement per group) before sacrifice. 
     Lungs are collected and fixed in 4% formaldehyde for 24 h before embedding in paraffin. 4 μm thick sections are immunostained with anti-collagen I antibody (LSBio, 2401 Fourth Avenue Suite 900, Seattle Wash. 98121, USA, Cat #LS-343921). The sections are deparaffinized and processed by heat antigen retrieval before incubation for one hour with the primary antibody. The anti-collagen I antibody is detected and amplified by ImmPress kit (Vector Laboratories, 3, Accent Park, Bakewell Road, Orton Southgate, Peterborough, PE2 6XS, United Kingdom, Cat #MP-7401). The immunostained sections are then scanned (Nanozoomer, Hamamatsu) before quantification by image analysis (CaloPix software, TRIBVN Healthcare). Data are expressed as percentage collagen I area per area of lung tissue. 
     Values of all mice from the same group are averaged. Data are expressed as mean±sem and are compared with a a one-way ANOVA on Log-transformed data and Dunnett&#39;s post-hoc test. Significance levels are defined as * (p&lt;0.05), ** (p&lt;0.01), or *** (p&lt;0.0) versus irradiated control group. 
     3.12. Bleomycin Induced Pulmonary Fibrosis in Mice 
     3.12.1. Study Overview 
     The aim of the study is to test the efficacy of a test compound at three different doses in a 14-day model of bleomycin induced pulmonary fibrosis in mice. 
     3.122. Animals 
     This study is carried out on C527BL/6N male mice, supplied by Charles River (Calco, Italy), which are acclimatized for at least 5 days in an environment maintained at 22° C., at 55% relative humidity, with 15-20 air changes per h under light cycles of 12 h. Mice pelleted food and water are provided ad libitum. 
     At least one day prior to start of experiment, all animals are allocated randomly into groups as indicated in the table below. 
     
       
         
           
               
             
               
                 TABLE IX 
               
             
            
               
                   
               
               
                 Study groups 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Treatment  
                   
                   
               
               
                   
                   
                   
                   
                 schedule  
                   
                   
               
               
                   
                   
                   
                   
                 Days  
                   
                   
               
               
                 Groups 
                 Purpose 
                 n 
                 Dose 
                 (Frequency) 
                 Route 
                 Vehicle 
               
               
                   
               
               
                 1 
                 control 
                 15 
                 — 
                 D0-D14 
                 NA 
                 NA 
               
               
                 PBS + vehicle 
                   
                   
                   
                 (b.i.d.) 
                   
                   
               
               
                 2 
                 control 
                 15 
                 — 
                 D0-D14 
                 p.o. 
                 PEG400/ 
               
               
                 BLM + vehicle 
                   
                   
                   
                 (b.i.d.) 
                   
                 MC 0.5% 
               
               
                   
                   
                   
                   
                   
                   
                 20/80 (v/v) 
               
               
                 3 
                 control 
                 15 
                 50 
                 D0-D14 
                 p.o. 
                 0.1%  
               
               
                 BLM +  
                   
                   
                 mg/kg 
                 (b.i.d.) 
                   
                 Natrosol ™ 
               
               
                 pirfenidone 
                   
                   
                   
                   
                   
                   
               
               
                 4 
                 active 
                 15 
                  1 
                 D0-D14 
                 p.o. 
                 PEG400/ 
               
               
                 BLM + test  
                   
                   
                 mg/kg 
                 (b.i.d.) 
                   
                 MC 0.5% 
               
               
                 compound 
                   
                   
                   
                   
                   
                 20/80 (v/v) 
               
               
                 5 
                 active 
                 15 
                  3 
                 D0-D14 
                 p.o. 
                 PEG400/ 
               
               
                 BLM + test  
                   
                   
                 mg/kg 
                 (b.i.d.) 
                   
                 MC 0.5% 
               
               
                 compound 
                   
                   
                   
                   
                   
                 20/80 (v/v) 
               
               
                 6 
                 active 
                 15 
                 10 
                 D0-D14 
                 p.o. 
                 PEG400/ 
               
               
                 BLM + test  
                   
                   
                 mg/kg 
                 (b.i.d.) 
                   
                 MC 0.5% 
               
               
                 compound 
                   
                   
                   
                   
                   
                 20/80 (v/v) 
               
               
                 7 
                 active 
                 10 
                 10 
                 D0-D14 
                 p.o. 
                 PEG400/ 
               
               
                 BLM + test  
                   
                   
                 mg/kg 
                 (b.i.d.) 
                   
                 MC 0.5% 
               
               
                 compound 
                   
                   
                   
                   
                   
                 20/80 (v/v) 
               
               
                 satellite for PK 
               
               
                   
               
            
           
         
       
     
     3.12.3. Materials 
     The solvent for the test solutions is prepared by adding 0.5 g of hydroxyethylcellulose (Natrosol™) into 500 mL aqua distillate (0.1%) under continuous stirring without heating for 5 h on a magnetic stirrer. 
     To prepare a solution for intranasal (i.n.) challenge, 0.8 mg/mL stock solutions of bleomycin (Cat #BML-AP302-0010, Enzo Life Sciences, Inc., USA) are thawed and diluted in 330 μL of saline. 
     Prior to i.n. administration, mice are anesthetized i.p. 
     Fresh pirfenidone formulation is prepared daily in 0.1% Natrosol™ formulations to a final concentration of 5 mg/mL. Before dosing, animals are weighed and the pirfenidone amount administered is adjusted accordingly to individual weights corresponding to 10 mL/kg body weight, twice daily p.o., with 7.5 h intervals between two administrations. 
     Finally, test compound solutions are prepared by dissolving the suitable amount of said test compound in PEG 400 (20% of the final volume) then MC 0.5% (80% of the final volume) to reach final concentrations of 1 mg/mL, 0.3 mg/mL and 0.1 mg/mL, thus yielding compound for a doses of 10 mg/kg, 3 mg/kg and 1 mg/kg. Prior to dosing, animals are weighed and the amount administered adjusted accordingly to individual weights. 
     The application volume of the test doses corresponds to 10 mL/kg body weight, and the test compounds are administered p.o. twice daily, with 7.5 h interval between two administrations. 
     3.12.4. Study 
     Animals are examined clinically twice daily, and clinical signs and parameters are recorded. Animals are weighed daily starting from D0. 
     On day 14, 2 h post dosing with vehicle, pirfenidone or test compound, mice are sacrificed. 
     The lungs are excised and weighed individually. For all groups: the whole superior right lung lobe is placed into a Precellys® tube containing silica beads and immediately snap frozen in liquid nitrogen and subjected to gene expression analysis. 
     All remaining lungs are placed into marked bottles containing 10% buffered formalin for further histopathological evaluation. 
     3.13. Therapeutic Bleomycin Induced Pulmonary Fibrosis 21-Day Mice Model 
     The aim of the study is to test the efficacy of a test compound at three different doses in a 21-day model of bleomycin induced pulmonary fibrosis in mice. 
     3.13.1. Animals 
     This study is carried out on C57BL/6N male mice, supplied by Charles River (Calco, Italy), which are acclimatized for at least 5 days in an environment maintained at 22° C., at 55% relative humidity, with 15-20 air changes per hour under light cycles of 12 h. Mice pelleted food and water are provided ad libitum. 
     At least one day prior to start of experiment, all animals are allocated randomly into groups as indicated in the table below. 
     
       
         
           
               
             
               
                 TABLE X 
               
             
            
               
                   
               
               
                 Study groups 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Treatment  
                   
                   
               
               
                   
                   
                   
                   
                 schedule 
                   
                   
               
               
                   
                   
                   
                   
                 Days  
                   
                   
               
               
                 Groups 
                 Purpose 
                 n 
                 Dose 
                 (Frequency) 
                 Route 
                 Vehicle 
               
               
                   
               
               
                 1 
                 control 
                 15 
                 — 
                 D7-D21  
                 NA 
                 NA 
               
               
                 PBS +  
                   
                   
                   
                 (b.i.d.) 
                   
                   
               
               
                 Vehicle 
                   
                   
                   
                   
                   
                   
               
               
                 2 
                 control 
                 15 
                 — 
                 D7-D21  
                 p.o. 
                 PEG400/MC 
               
               
                 BLM +  
                   
                   
                   
                 (b.i.d.) 
                   
                 0.5%  
               
               
                 Vehicle 
                   
                   
                   
                   
                   
                 20/80 (v/v) 
               
               
                 3 
                 control 
                 15 
                 60 
                 D7-D21 
                 p.o. 
                 0.1%  
               
               
                 BLM +  
                   
                   
                 mg/kg 
                 (q.d.) 
                   
                 Natrosol ™ 
               
               
                 Nintedanib 
                   
                   
                   
                   
                   
                   
               
               
                 4 
                 active 
                 15 
                  1 
                 D7-D21  
                 p.o. 
                 PEG400/MC 
               
               
                 BLM + test  
                   
                   
                 mg/kg 
                 (b.i.d.) 
                   
                 0.5%  
               
               
                 compound 
                   
                   
                   
                   
                   
                 20/80 (v/v) 
               
               
                 5 
                 active 
                 15 
                  3 
                 D7-D21  
                 p.o. 
                 PEG400/MC 
               
               
                 BLM + test  
                   
                   
                 mg/kg 
                 (b.i.d.) 
                   
                 0.5%  
               
               
                 compound 
                   
                   
                   
                   
                   
                 20/80 (v/v) 
               
               
                 6 
                 active 
                 15 
                 10 
                 D7-D21  
                 p.o. 
                 PEG400/MC 
               
               
                 BLM + test  
                   
                   
                 mg/kg 
                 (b.i.d.) 
                   
                 0.5%  
               
               
                 compound 
                   
                   
                   
                   
                   
                 20/80 (v/v) 
               
               
                 7 
                 active 
                 10 
                 10 
                 D7-D21  
                 p.o. 
                 PEG400/MC 
               
               
                 BLM + test  
                   
                   
                 mg/kg 
                 (b.i.d.) 
                   
                 0.5%  
               
               
                 compound 
                   
                   
                   
                   
                   
                 20/80 (v/v) 
               
               
                 satellite  
                   
                   
                   
                   
                   
                   
               
               
                 for PK 
               
               
                   
               
            
           
         
       
     
     3.13.2. Materials 
     The solvent for the test solutions is prepared by adding 0.5 g of hydroxyethylcellulose (Natrosol™) into 500 mL aqua distillate (0.1%) under continuous stirring without heating for 5 h on a magnetic stirrer. 
     To prepare a solution for intranasal (i.n.) challenge, 0.8 mg/mL stock solutions of bleomycin (Cat #BML-AP302-0010, Enzo Life Sciences, Inc., USA) are thawed and diluted in 330 μL of saline. Prior to i.n. administration, mice are anesthetized i.p. 
     Fresh nintedanib formulation is prepared daily in 0.1% Natrosol™ formulations to a final concentration of 5 mg/mL. Before dosing, animals are weighed and the nintedanib amount administered is adjusted accordingly to individual weights corresponding to 10 mL/kg body weight, once daily p.o. 
     Finally, test compound solutions are prepared by dissolving the suitable amount of said test compound in PEG 400 (20% of the final volume) then MC 0.5% (80% of the final volume) to reach final concentrations of 1 mg/mL, 0.3 mg/mL and 0.1 mg/mL, thus yielding compound for a doses of 10 mg/kg, 3 mg/kg and 1 mg/kg. Prior to dosing, animals are weighed and the amount administered adjusted accordingly to individual weights. 
     The application volume of the test doses corresponds to 10 mL/kg body weight, and is the test compounds are administered p.o. twice daily, with 7.5 h interval between two administrations. 
     3.13.3. Study 
     Animals are examined clinically twice daily. List of clinical signs and parameters are indicated in human endpoints table. Animals are weighed daily starting from D0. 
     On day 21, 2 h post dosing with vehicle, nintedanib or test compound, mice are sacrificed. 
     The lungs are excised and weighed individually. For all groups: the whole superior right lung lobe is placed into a Precellys® tube containing silica beads and immediately snap frozen in liquid nitrogen and subjected to gene expression analysis. 
     All remaining lungs are placed into marked bottles containing 10% buffered formalin for further histopathological evaluation. 
     3.13.4. Sample Analysis, Data Processing and Statistical Evaluation 
     Body weight data and lung weight data are processed using MS Excel. Statistical analysis and graphical presentation are performed using GraphPad Prism software. One-way ANOVA or Mann-Whitney test are employed for lung weights. Two-way ANOVA are employed for body weight changes. 
     Differences between groups are considered statistically significant when p&lt;0.05. 
     For histopathological evaluation, whole lungs (except sampled superior right lung) are embedded in paraffin and stained with Mallory&#39;s trichrome. 
     Pulmonary histological changes are assessed using Matsuse modification of Ashcroft score (Ashcroft et al. 1988; Matsuse et al. 1999). Statistical analysis and graphical presentation is performed using GraphPad Prism software. A Mann-Whitney test is employed. 
     Differences between groups are considered statistically significant when p&lt;0.05. 
     
       
         
           
               
               
             
               
                   
               
               
                 Ashcroft  
                   
               
               
                 Score 
                 Definition 
               
               
                   
               
             
            
               
                 1 
                 Normal lungs (no fibrosis) 
               
               
                 2 
                 Minimal fibrotic thickening of alveolar or bronchial  
               
               
                   
                 walls (network of fine collagen fibrils) 
               
               
                 3 
                 Moderate fibrotic thickening of walls without  
               
               
                   
                 obvious damage to lung architecture 
               
               
                 4 
                 Fibrosis with damage of pulmonary structure (coarse  
               
               
                   
                 fibrous bands or small fibrous masses, intra-alveolar  
               
               
                   
                 collagen fibrils) 
               
               
                 5 
                 Large fibrous area with severe distortion of lung  
               
               
                   
                 structure 
               
               
                   
               
            
           
         
       
     
     3.13.5. PK Analysis—Group 7 
     3.13.5.1. Protocol 
     Animals in group 7 (n=10) are included for PK study only and are not subjected to clinical sign scoring. 
     These animals are induced with the disease at the start of treatment at day 0 (D0) and are sequentially sacrificed on D7 at 1 h, 3 h, 6 h, 8 h, 24 h after the first administration of test compound. 
     A blood sample (50 μL) is collected from the tail vein into Li-heparin anticoagulant tubes for each time point and kept on ice until separation. Within maximum 30 min after collection, blood samples are centrifuged at 2000×g for 10 min at 4° C. and the resulting plasma samples are aliquoted into polypropylene tubes (1×25 μL). The samples are stored frozen at −20° C. until analysis. 
     The lung tissue is collected at sacrifice after blood sampling for each animal, then weighed and placed into polypropylene tubes prior to freezing. The samples are stored frozen at −80° C. until analysis. 
     3.13.5.2. Plasma Concentration and Pharmacokinetic Analysis 
     Plasma and lung concentrations are measured via LC-MS/MS. Samples are prepared for LC-MS/MS analysis via protein precipitation. The plasma concentrations measured below the lower limit of quantification (LLOQ) are reported as below the limit of quantification (BLQ). The test compound concentrations in plasma are expressed in ng/mL. Mean plasma concentrations are calculated. For mean calculation, the concentrations below the LLOQ are set to zero. Therefore, mean values may be BLQ. Standard deviation (SD), standard error of the mean (SE) and coefficient of variation (CV, %) are tabulated when at least three plasma concentration values are above the LLOQ. 
     Non-compartmental analysis on individual plasma concentrations is performed using Phoenix™ WinNonlin® 6.3 (Pharsight Corporation) to determine at least, the following pharmacokinetic parameters:
         Maximum plasma concentration, Cmax (μg/mL) with the corresponding time, tmax (h),   Area under the plasma concentration versus time curve up to the last quantifiable concentration AUC 0-t  or up to 24 h AUC 0-24  h (μg·h/mL) (if compound is quantifiable up to 24 h postdose), and/or up to infinity AUC 0-∞ , (μg·h/mL) is calculated according to the linear up/log down trapezoidal rule. Partial AUC may be calculated if deemed necessary. Concentrations below the limit of quantification (BLQ) are set to zero. No AUC is calculated if there are less than three quantifiable time points. AUC 0-∞  is considered if %AUCextra&lt;20%,   Apparent terminal elimination half-life, t½ (h) is only reported if three or more time points, excluding tmax is used for linear regression, and if the adjusted R 2 &gt;0.80.   Normalized AUC and Cmax dose.   Mean pharmacokinetic parameters are calculated. Standard deviation (SD) and coefficient of variation (CV, %) are tabulated if at least three values are available.       

     3.14. T Cell Transfer Model (Mice) 
     3.14.1. Materials 
     DynaMag (Cat #12321D and 123203D) are obtained from Life Technologies Invitrogen (California, USA); DynabeadsFlowComp Mouse CD4+CD25-treg cells (Cat #11463D) are obtained from Life Technologies Invitrogen (California, USA), Fetal Bovine Serum (GIBCO), Cat #10270-106; RPMI (Gibco) Cat #32404-014 and D-PBS 1× without CaCl 2  without MgCl 2  (GIBCO), Cat #14190-086 are obtained ThermoFisher Scientific (Massachusetts, USA). Red Blood Cell (RBC) lysis buffer 10×, Cat #BLE420301 obtained from Ozyme (Montigny-le-Bretonneux, France). Cell strainer (70 μm grid), Cat #352350, obtained from Corning (New York, USA). Bovine Serum Albumin (BSA), Cat #A9647-50g and EDTA, Cat #EDS-100g obtained from Sigma Aldrich (Missouri, USA) and Combur testE, Cat #11896857, obtained from Roche Diagnostics (Basel, Switzerland). 
     3.14.2. Animals 
     Five to seven week old BALBc/N female mice and five to seven week old SCID female mice are obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22° C., food and water are provided ad libitum. 
     3.14.3. Study Design 
     The therapeutic effects of the compounds are tested in the mouse T cell transfer model model (Lindebo Holm et al. 2012). After a 7-day acclimatization period, BALBc/N mice are sacrificed, spleens are removed, homogenized, rinsed with D-PBS and centrifuged. Cell pellets are resuspended in RBC lysis isolation buffer (D-PBS, EDTA, BSA, 1/1/1) and centrifuged, then resuspended in isolation buffer and processed following DynabeadsFlowComp Mouse CD4+CD25-treg cells Dynabeads kit protocol. The obtained cells are resuspended in RPMI and 0.2 mL are injected to SCID mice by intra-peritoneal injection. Sham group of mice received RPMI alone. 
     Fourteen days after cell injection, 100 μL of blood is sampled on each mouse under anesthesic conditions in order to determine CD4 level. Treatment starts on the next day, with groups homogenized by level of disease activity index (DAI). Disease activity index is determined twice a week. Four to six weeks after the start of treatment, mice are sacrificed, blood is sampled and the complete colon is removed and rinsed with sterile PBS, it is measured and weighed in order to determine colon weight/length ratio. Segments of colon are dissected for histological analysis, gene expression, protein level measurement and/or totally sampled for immunophetntyping by FACs. 
     There are 12 mice per group. The results are expressed as mean±SEM and statistical analysis is performed using non parametric test Kruskal-Wallis with Dunn&#39;s Multiple comparison test versus vehicle groups. 
     3.14.4. Disease Activity Index (DAI) Determination 
     The DAI score of each mouse (sum of scores for weight loss, stool consistency and rectal bleeding) is monitored during the entire treatment period and a DAI score progression curve is obtained. 
     
       
         
           
               
               
               
               
               
             
               
                   
                   
               
               
                   
                   
                 Weight  
                   
                 Rectal  
               
               
                   
                 DAI 
                 evolution 
                 Stool consistency 
                 bleeding* 
               
               
                   
                   
               
             
            
               
                   
                 0 Point 
                 No weight  
                 Well molded stools 
                   
               
               
                   
                   
                 loss (vs D1) 
                   
                   
               
               
                   
                 1 point 
                 1 to 5% 
                 Semi-soft stools 
                   
               
               
                   
                 2 points 
                  5 to 10% 
                 Soft stools that do not  
                   
               
               
                   
                   
                   
                 stick to the anus 
                   
               
               
                   
                 3 points 
                 10 to 20% 
                 Semi-liquid stools not  
                   
               
               
                   
                   
                   
                 sticking to the anus 
                   
               
               
                   
                 4 Points 
                 &gt;20% 
                 Liquid stools remaining  
                   
               
               
                   
                   
                   
                 stuck to the anus 
               
               
                   
                   
               
               
                   
                 *A little piece of stool is deposited on a vial containing 1 mL of D-PBS and homogeneized, deposited on a test strip (Combur TestE), a color appears according to the blood intensity in the stool, a score is given according to this intensity, from 0 to 4 points. 
               
            
           
         
       
     
     3.15. Surgical Destabilization of the Medial Meniscus (DMM) Mouse Model of Osteoarthritis 
     The experiment assesses disease-modifying osteoarthritis drug (DMOAD) effect by prophylactic treatment of compounds that inhibits the structural disease progression of OA and ideally also improves symptoms and/or function. 
     DMM surgery is performed in the right knees of 10-week old male C57BL/6 mice. For the prophylactic study, systemic (p.o.) treatment starts at the time of surgery. Mice are sacrificed 8 weeks after surgery, and another group are sacrificed 12 weeks after surgery. Knees are harvested for detailed histopathological assessment (Glasson et al. 2007). Thus, the DMM model uniquely captures the chronic progressive nature of OA and associated sensitization and pain-related behaviours. Knees are collected for histology, following standard methods (Miller et al. 2016). 
     3.16. Ovariectomized (OVX) Mouse Model 
     The OVX model is used widely for investigating problems related to postmenopausal bone loss, a primary risk factor for osteoporosis 
     A cohort of C57Bl6 female mice of 12 weeks of age are subjected to sham surgery, or to OVX. Animals are kept for a period of 8 weeks, during which time hypogonadal bone loss is established. Then, at 20 weeks of age (8 weeks after sham or OVX surgery), the OVX mice are treated once daily over the course of 4 weeks (Dempster et al. 2013). 
     The following skeletal-directed endpoints are used at the completion of the 4 weeks treatment period: μ-CT of the femur and L5 vertebrae to assess bone mass and micro-architecture. 
     FINAL REMARKS 
     It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary and explanatory in nature, and intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents. 
     All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication are specifically and individually indicated to be incorporated by reference herein as though fully set forth. 
     It should be understood that factors such as the differential cell penetration capacity of the various compounds can contribute to discrepancies between the activity of the compounds in the in vitro biochemical and cellular assays. 
     At least some of the chemical names of compound of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by OpenEye Scientific Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control. 
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