Novel compounds and pharmaceutical compositions thereof for the treatment of diseases

Abstract

The present invention relates to a compound of formula (I): [Formula 1] Disclose the compound TIFF2022534576000067.tif54170 (In the formula, R 1 , R 2a , W, X1, X2, Y, and Z are as defined herein). The present invention relates to compounds, methods for the preparation of the compounds, pharmaceutical compositions comprising the compounds, and methods of treatment using the compounds for the prevention and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, diseases associated with impaired bone turnover, diseases associated with excessive secretion of IL-6, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and / or diseases associated with abnormal angiogenesis by administering the compounds of the invention.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compounds, methods for preparing the compounds of the present invention, pharmaceutical compositions comprising the compounds of the present invention, and uses and methods for the prevention and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, diseases associated with impaired bone turnover, diseases associated with excessive secretion of IL-6, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and / or diseases associated with abnormal angiogenesis by administering the compounds of the present invention. In particular, the compounds of the present invention may inhibit salt-inducible kinase ("SIK" kinase). [Background technology]

[0002] BACKGROUND OF THE INVENTION Protein kinases belong to a large family of structurally related enzymes responsible for controlling diverse cellular signaling processes. In particular, they have been shown to be key regulators of cellular functions, including, for example, proliferation, metabolism, and apoptosis. Consequently, defective regulation of protein phosphorylation, leading to uncontrolled signal transduction, has been implicated in many diseases, including, for example, inflammation, allergy, cancer, autoimmune diseases, CNS disorders, and angiogenesis.

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

[0004] Indeed, in the normal process of inflammation in the body, an initial pro-inflammatory response is followed by a pro-resolving response that stops the inflammation after the injury is repaired, resulting in a decrease in pro-inflammatory cytokines such as TNFα and IL-12 combined with an increase in the levels of anti-inflammatory cytokines such as IL-10 and TGF-β, resulting in a so-called tolerogenic environment.

[0005] Adenosine monophosphate-activated protein kinase (AMPK) belongs to the protein kinase family, which includes salt-inducible kinases (SIKs), a family of serine / threonine kinases that are widely expressed in the body and are particularly involved in cellular energy homeostasis. Three SIK isoforms have been identified, named SIK1 (also called SNFI-like kinase (SNF1LK) or cardiac muscle Snfl-like kinase (MSK)), SIK2 (SNF1LK2 or KIAA0781), and SIK3 (KIAA0999) (Katoh et al., 2004).

[0006] SIK plays several roles in different cell types. SIK has been shown to phosphorylate several substrates, including CREB-responsive transcriptional coactivators (CRTC) and histone deacetylase (HDAC) proteins, thereby regulating the transcription of several different genes. One role of CRTC signaling is in controlling macrophage phenotype, specifically macrophage polarization through phosphorylation of CRTC3, as measured by a decrease in secretion of the pro-inflammatory cytokine IL-12 and a concomitant increase in secretion of the pro-resolution cytokine IL-10 (Clark et al., 2012; Ozanne et al., 2015).

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

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

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

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

[0011] Recently, small molecule SIK inhibitors such as PTH have also been shown to 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 disorders.

[0012] Furthermore, inhibition of SIK2 after oxygen-glucose deprivation has been shown to enhance neuronal survival (Sasaki et al., 2011) or promote melanogenesis in melanoma cells (Kumagai et al., 2011). In this context, the rapid activation or degradation of SIK proteins after multiple stresses makes them attractive targets in inflammatory, cardiac, or metabolic diseases, and neurodegenerative disorders, as therapeutic strategies are needed to modulate stress cellular responses, such as those during ischemia and after tissue reperfusion, in the chronic phase of cardiac remodeling, and in diabetes and neurodegenerative conditions. SIK inhibition may also be applied in cosmetic procedures or pigmentation-related diseases that induce melanogenesis.

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

[0014] In addition to their important functions in cellular energy homeostasis, SIK proteins are also involved in regulating the cell cycle. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancer (Ashour Ahmed et al., 2010). Furthermore, SIK3 expression was elevated in ovarian cancer, particularly in the serous subtype and later stages (Charoenfuprasert et al., 2011). Therefore, SIK inhibition may be useful in cancer treatment.

[0015] Despite significant advances in the treatment of patients suffering from autoimmune disorders over the past two decades, 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. Thus, a significant unmet medical need remains for the treatment of these diseases, and new drugs for the prevention and / or treatment of the above-mentioned diseases are needed. Summary of the Invention

[0016] (Summary of the Invention) The present invention is based on the identification of novel compounds and their use in the prevention and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, diseases associated with impaired bone turnover, diseases associated with excessive secretion of IL-6, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and / or diseases associated with abnormal angiogenesis. In particular, the compounds of the present invention may be SIK inhibitors, more particularly SIK1, SIK2, and / or SIK3 inhibitors. The present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, diseases associated with impaired bone turnover, diseases associated with excessive secretion of IL-6, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and / or diseases associated with abnormal angiogenesis by administering a compound of the invention.

[0017] Thus, in a first aspect of the present invention, there is provided a compound of the present invention having formula I: [ka] (In the formula, W is N or CH; One of X1 and X2 is N and the other is C (provided that if W is CH then X2 is not N); Y is N or CR 2b and; Z is - -NHR 3a , - further containing 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, and optionally one or more independently selected R 15an N-linked 4- to 7-membered heterocycloalkyl substituted with a group; or -NR 3b - (wherein N atom and R 2a together with the atom to which they are attached form a fused 5- to 6-membered heterocycloalkenyl containing 1 or 2 double bonds; R 1 teeth - one or more independently selected R 4 C optionally substituted with a group 1-8 Alkyl, - phenyl, - one or more independently selected R 5 C optionally substituted with a group 3-8 monocyclic or bridged polycyclic cycloalkyl, - a 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is one or more independently selected -CN or -C(=O)-C 1-4 one or more independently selected C optionally substituted with alkoxy 1-4 optionally substituted with alkyl, or - a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2a and R 2b teeth, - Hello, - C 1-4 Alkyl, - one or more independently selected halo or C 1-4 C optionally substituted with alkoxy 1-4 Alkoxy, and -NR 6a R 6b are independently selected from; R 3a teeth, - C optionally substituted with one or more independently selected halo or -CN 1-6 alkyl, or - C optionally substituted with one or more independently selected halo or -OH 3-7is cycloalkyl; R 3b is H, C 3-7 cycloalkyl, and C optionally substituted with one or more independently selected halo or -CN; 1-6 alkyl; Each R 4 teeth, - Hello, - -OH, - -CN, - phenyl, - -C(=O)OH, - -OC(=O)C 1-4 Alkyl, - -OS(=O)2-C 1-4 Alkyl, - one or more independently selected -OH, C 1-4 Alkoxy, 4-8 membered monocyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is selected from one or more independently selected C 1-4 optionally substituted with alkyl; or -NR 7a R 7b (In the formula, each R 7a and R 7b is H and C 1-4 C optionally substituted with alkyl 1-4 Alkoxy, one or more independently selected halo, -C(=O)-C 1-4 Alkoxy, -NR 8a R 8b or one or more independently selected -NR 9a R 9b C optionally substituted with 1-4 C optionally substituted with alkyl 3-7 cycloalkyl, - a 5-6 membered monocyclic heterocycloalkyl containing 1 or 2 N atoms fused to a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is fused to one or more independently selected C 1-4 optionally substituted with alkyl, - a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is selected from one or more independently selected C 1-4 Alkyl or C 3-7 optionally substituted with cycloalkyl; - 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is selected from one or more independently selected R 10 optionally replaced by -NR 11a R 11b , - -C(=O)C 1-4 Alkoxy, and - -C(=O)-NR 12a R 12b are independently selected from; Each R 5 teeth, - Hello, -CN, and -NR 13a R 13b Selected from; Each R 6a and R 6b is H and C 1-4 alkyl; Each R 10 teeth, - -OH, - phenyl, - =NH, - Hello, - oxo, - -CN, - -C(=O)H, - -C(=O)NH2, - -C(=O)OH, -NR 14a R 14b , one or more independently selected halo, —CN, —OH, —C(═O)—C 1-4 Alkoxy or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, - C 3-7 cycloalkyl, - a 4-6 membered monocyclic heterocycloalkyl containing 1, 2, or 3 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 selected from alkoxy; Each R 11a , R 11b teeth, -H - phenyl, one or more independently selected halo, —OH, —CN, or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, - C 3-7 cycloalkyl, - -C(=O)-C 1-4 Alkoxy, -C(=O)-C optionally substituted with one or more independently selected halo 1-4 Alkyl, and - independently selected from 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 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 H and C 1-4 independently selected from alkyl; Each R 14a and R 14b is H, C1-4 Alkyl, and -S(=O)2-C 1-4 alkyl; and Each R 15 is —OH, —CN, and C optionally substituted with one or more independently selected halo or —CN; 1-4 alkyl).

[0018] In certain embodiments, the compounds of the present invention are provided for use in the prevention and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, diseases associated with impaired bone turnover, diseases associated with excessive secretion of IL-6, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and / or diseases associated with abnormal angiogenesis.

[0019] Furthermore, unexpectedly, compounds of the present invention have also been shown to exhibit potency against SIK, particularly SIK1, SIK2, and / or SIK3, more particularly SIK2 and / or SIK3, which may result in immune tolerance induction therapy (i.e., a decrease in pro-inflammatory cytokines such as TNFα and IL-12 combined with an increase in the levels of anti-inflammatory cytokines such as IL-10 and TGF-β).

[0020] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutical carrier, excipient, or diluent. In certain embodiments, the pharmaceutical composition may further comprise an additional therapeutically active ingredient suitable for use in combination with the compound of the present invention. In more particular embodiments, the additional therapeutically active ingredient is an agent for the treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impaired cartilage turnover, congenital cartilage malformations, diseases associated with excessive secretion of IL-6, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and / or diseases associated with abnormal angiogenesis.

[0021] Furthermore, the compounds of the present invention useful in the pharmaceutical compositions and methods of treatment disclosed herein are pharmaceutically acceptable as prepared and used.

[0022] In a further aspect of the invention, the invention provides a method for treating a mammal, particularly a human, suffering from a disease selected from those enumerated herein, in particular inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, diseases associated with impaired bone turnover, diseases associated with excessive secretion of IL-6, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and / or diseases associated with abnormal angiogenesis, said method comprising administering an effective amount of a pharmaceutical composition or compound of the invention as described herein.

[0023] The present invention also provides a pharmaceutical composition comprising a compound of the present invention and a suitable pharmaceutical carrier, excipient, or diluent for use in medicine. In certain embodiments, the pharmaceutical composition is for use in the prevention and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, diseases associated with impaired bone turnover, diseases associated with excessive secretion of IL-6, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and / or diseases associated with abnormal angiogenesis.

[0024] In additional aspects, the present invention provides methods for synthesizing the compounds of the present invention using representative synthetic protocols and routes disclosed herein below.

[0025] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description.

[0026] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites. DETAILED DESCRIPTION OF THE INVENTION

[0027] (Detailed Description of the Invention) (definition) The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention.

[0028] In describing the present invention, which may include compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise specified. As described herein, it is also to be understood that any of the moieties defined below may be substituted with various substituents, and that each definition is intended to include such substituted moieties within its scope as set forth below. Unless otherwise specified, the term "substituted" shall be defined as set forth below. It should further be understood that the terms "group" and "radical" can be considered interchangeable when used herein.

[0029] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0030] "Alkyl" means a straight- or branched-chain 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, are attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH), ethyl (-CH-CH), n-propyl (-CH-CH-CH), isopropyl (-CH(CH)), n-butyl (-CH-CH-CH-CH), tert-butyl (-C(CH)), sec-butyl (-CH(CH)-CHCH), isobutyl (-CH-CH(CH)), n-pentyl (-CH-CH-CH-CH-CH), n-hexyl (-CH-CH-CH-CH-CH-CH-CH), and 1,2-dimethylbutyl (-CHCH)-C(CH)H-CH-CH). Particular alkyl groups have from 1 to 4 carbon atoms.

[0031] "Alkenyl" refers to a monovalent olefinically (unsaturated) hydrocarbon radical having the specified number of carbon atoms. Particular alkenyls have 2 to 8 carbon atoms, and more particularly 2 to 6 carbon atoms, which may be straight-chained or branched, and have at least 1, especially 1 to 2, olefinic unsaturations. Particular alkenyl groups include ethenyl (-CH=CH), n-propenyl (-CHCH=CH), isopropenyl (-C(CH)=CH), and the like.

[0032] "Alkylene" refers to a divalent alkene radical group which may be straight or branched and has the specified number of carbon atoms, specifically 1 to 6 carbon atoms, and more specifically 1 to 4 carbon atoms. This term is illustrated by groups such as methylene (-CH-), ethylene (-CH-CH-), or -CH(CH)-.

[0033] "Alkynylene" refers to a divalent alkyne radical group which may be straight-chained or branched and has the specified number of carbon atoms and the specified number of triple bonds, particularly 2 to 6 carbon atoms, more particularly 2 to 4 carbon atoms. This term is illustrated by groups such as -C≡C-, -CH-C≡C-, and -C(CH)HC≡CH-.

[0034] "Alkoxy" refers to the group -O-alkyl, where the alkyl group has the specified number of carbon atoms. In particular, the term refers to the group -OC 1-6 "Alkoxy" refers to 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., those having 1 to 6 carbon atoms. More particular alkoxy groups have 1 to 4 carbon atoms.

[0035] "Amino" refers to the radical -NH2.

[0036] "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. Specifically, aryl refers to a monocyclic or fused polycyclic aromatic ring structure having the specified number of ring atoms. In particular, the term encompasses groups containing 6 to 10 ring members. Particular aryl groups include phenyl and naphthyl.

[0037] "Cycloalkyl" refers to a monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic non-aromatic hydrocarbyl ring structure having the specified number of ring atoms. Cycloalkyls can have from 3 to 12 carbon atoms, particularly from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example only, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0038] "Cyano" refers to the radical -CN.

[0039] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). Particular halo groups are either fluoro or chloro.

[0040] As used herein, the term "polycyclic" refers to a chemical group characterized by several closed rings of atoms. In particular, it refers to groups characterized by rings of two, three, or four atoms, more particularly rings of two or three atoms, and most particularly rings of two atoms.

[0041] "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 are replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above-mentioned hydrocarbyl groups, such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocycloalkyl, aryl, e.g., heteroaryl, etc., having 1 to 4, especially 1 to 3, heteroatoms, more typically 1 or 2, heteroatoms, e.g., a single heteroatom.

[0042] "Heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring structure containing one or more heteroatoms independently selected from O, N, and S and the specified number of ring atoms. In particular, the aromatic ring structure can have 5 to 9 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring, or a fused bicyclic structure formed from a fused 5-membered and 6-membered ring, or from two fused 6-membered rings, or as a further example, from two fused 5-membered rings. Each ring can contain up to four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, the heteroaryl ring will contain up to four heteroatoms, more typically up to three heteroatoms, and more usually up to two, e.g., a single heteroatom. In particular, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in a heteroaryl ring 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. Generally, the number of basic nitrogen atoms present in a heteroaryl group will be fewer than five, including any amino group substituents on the ring.

[0043] Examples of 5-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.

[0044] Examples of 6-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0045] Illustrative examples of bicyclic heteroaryl groups containing a 5-membered ring fused to another 5-membered ring include, but are not limited to, imidazothiazolyl and imidazoimidazolyl.

[0046] Illustrative examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g., adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0047] Illustrative 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. Specific heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl, and pyrazinyl.

[0048] Representative examples of heteroaryls include: [ka] wherein each Y is selected from >C=O, NH, O, and S.

[0049] "Heterocycloalkyl" means a monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic non-aromatic fully saturated ring structure containing one or more heteroatoms independently selected from O, N, and S and the specified number of ring atoms. Heterocycloalkyl ring structures can have 4 to 12 ring members, particularly 4 to 10 ring members, and more particularly 4 to 7 ring members. Each ring can contain up to four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, heterocycloalkyl rings will contain up to four heteroatoms, more typically up to three heteroatoms, and more usually up to two, e.g., 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.

[0050] As used herein, the term "heterocycloalkenyl" refers to a "heterocycloalkyl" containing at least one double bond. Specific examples of heterocycloalkenyl groups are shown in the following examples: [ka] wherein each W is selected from CH, NH, O, and S; each Y is selected from NH, O, C(=O), SO, and S; and each Z is selected from N or CH.

[0051] Specific examples of monocyclic rings are shown in the examples below: [ka] wherein each W and Y is independently selected from —CH 2 —, —NH—, —O—, and —S—.

[0052] Specific examples of fused bicyclic rings are shown in the examples below: [ka] wherein each W and Y is independently selected from —CH 2 —, —NH—, —O—, and —S—.

[0053] Specific examples of bridged bicyclic rings are shown in the examples below: [ka] wherein each W and Y is independently selected from —CH 2 —, —NH—, —O—, and —S—.

[0054] Specific examples of spirocyclic rings are shown in the examples below: [ka] wherein each Y is selected from —CH 2 —, —NH—, —O—, and —S—.

[0055] "Hydroxyl" refers to the radical --OH.

[0056] "Oxo" refers to the radical =O.

[0057] "Substituted" refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0058] "Sulfo" or "sulfonic acid" refers to a radical such as -SO3H.

[0059] "Thiol" refers to the group --SH.

[0060] As used herein, the term "substituted with one or more" refers to one to four substituents. Particularly, the term refers to one to three substituents. More particularly, the term refers to one or two substituents. Most particularly, the term refers to one substituent.

[0061] Those skilled in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether aromatic or non-aromatic, is determined by the ring size, degree of unsaturation, and valence of the heteroatoms. Generally, a heterocyclic ring can have from 1 to 4 heteroatoms, so long as the aromatic heterocycle is chemically feasible and stable.

[0062] "Pharmaceutically acceptable" means approved or appropriable by a federal or state regulatory agency or the corresponding regulatory agency of a country other than the United States for use in animals, and more particularly in humans, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia.

[0063] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with 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-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbiphenylsulfonic acid, 4-methylbenzyl ... or (2) salts formed when an acidic proton present in the parent compound 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, etc. Salts further include, by way of example only, salts of non-toxic organic or inorganic acids such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, if the compound contains a basic functionality, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0064] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.

[0065] "Prodrug" refers to a compound containing derivatives of the compounds of the present invention that have cleavable groups and that, by solvolysis or under physiological conditions, become pharmaceutically active compounds of the present invention in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like.

[0066] "Solvate" refers to a form of a compound that is associated with a solvent, usually by solvolysis. This physical association includes hydrogen bonding. Common solvents include water, EtOH, acetic acid, and the like. The compounds of the present invention may be prepared, for example, in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0067] A "subject" includes a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0068] An "effective amount" means the amount of a compound of the present invention that, when administered to a subject for treating a disease, is sufficient to effect treatment for such 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.

[0069] "Preventing" or "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., preventing at least one clinical symptom of the disease from developing before the onset of the disease in a subject who may be exposed to a disease-causing agent or who may be predisposed to the disease).

[0070] The term "prophylaxis" is related to "prevention" and refers to a measure or treatment whose purpose is to prevent disease rather than to treat or cure it. Non-limiting examples of prophylactic measures include the administration of a vaccine; the administration of low molecular weight heparin to hospitalized patients who are at risk of thrombosis, for example, due to immobility; and the administration of an antimalarial agent, such as chloroquine, prior to visiting a geographic area where malaria is endemic or there is an increased risk of contracting malaria.

[0071] "Treating" or "treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (i.e., halting the disease or reducing the sign, extent, or severity of at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter that may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to physically modulating the disease or disorder (e.g., stabilizing discernible symptoms) or physiologically modulating the disease or disorder (e.g., stabilizing physical parameters), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

[0072] As used herein, the term "inflammatory disease" refers to a group of conditions including rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway diseases (e.g., asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), endotoxin-driven conditions (e.g., complications after bypass surgery or chronic endotoxin states contributing to, for example, chronic heart failure), and related diseases involving cartilage, such as joint diseases. In particular, the term refers to rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g., asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease. More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease.

[0073] As used herein, the term "autoinflammatory disease" refers to a group of diseases including cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), and tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

[0074] As used herein, the term "autoimmune disease" refers to obstructive airway diseases, including conditions such as COPD, asthma (e.g., intrinsic asthma, extrinsic asthma, dust-related asthma, childhood asthma), particularly chronic or refractory asthma (e.g., late-onset asthma and airway hyperresponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g., autoimmune liver disease), and the like. The term refers to a group of diseases including: psoriasis, dry eye disease, type 1 diabetes and its associated complications, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's thyroiditis and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis. In particular, the term refers to COPD, asthma, systemic lupus erythematosus, type 1 diabetes, and inflammatory bowel disease.

[0075] As used herein, the term "proliferative disease" refers to conditions such as cancer (e.g., uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g., polycythemia vera, essential thrombocythemia, 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.

[0076] As used herein, the term "cancer" refers to a malignant or benign proliferation of cells in the skin or in a body organ, such as, but not limited to, the breast, prostate, lung, kidney, pancreas, stomach, or intestine. Cancers tend to invade adjacent tissues and spread (metastasize) to distant organs, such as the bone, liver, lung, or brain. As used herein, the term cancer encompasses both metastatic tumor cell types (e.g., but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mast cell tumor) and tissue carcinoma types (e.g., but not limited to, colorectal cancer, prostate cancer, small cell and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, stomach cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma).In particular, the term "cancer" includes acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdomyosarcoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, and uterine cancer. Lung's sarcoma family 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 tumor (endocrine pancreas), Kaposi's 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's lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, oral cancer, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, 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, moderately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple This refers to primary myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing's sarcoma family of tumors, sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0077] 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, making the host highly susceptible to infection and bleeding. In particular, the term leukemia refers to acute myeloid leukemia (AML), as well as acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0078] As used herein, the term "fibrotic disease" refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment, and which 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 gastrointestinal tract. In particular, the term fibrotic disease includes idiopathic pulmonary fibrosis (IPF); other diffuse parenchymal lung diseases of various etiologies, including cystic fibrosis, iatrogenic drug-induced fibrosis, occupational- and / or environmental-induced fibrosis; granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis); collagen vascular diseases; pulmonary alveolar proteinosis; Langerhans cell granulomatosis; lymphangioleiomyomatosis; genetic 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); renal fibrosis; tubulointerstitial fibrosis; glomerular fibrosis. Nephritis; diabetic nephropathy, focal segmental glomerulosclerosis; IgA nephropathy; hypertension; Alport syndrome; intestinal fibrosis; hepatic fibrosis; cirrhosis; alcohol-induced liver fibrosis; toxic / drug-induced liver fibrosis; hemochromatosis; nonalcoholic steatohepatitis (NASH); bile duct injury; primary biliary cirrhosis; infection-induced liver fibrosis; viral-induced liver fibrosis; and autoimmune hepatitis; corneal scarring; hypertrophic scarring; Dupuytren's disease, keloids, skin fibrosis; cutaneous scleroderma; systemic sclerosis, spinal cord injury / fibrosis; myelofibrosis; Duchenne muscular dystrophy (DMD)-associated musculoskeletal fibrosis, vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease; or chronic lymphocytic fibrosis. More particularly, the term "fibrotic disease" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and dermal fibrosis.

[0079] As used herein, the term "transplant rejection" refers to acute or chronic rejection of an allogeneic or xenogeneic transplant of cells, tissues, or solid organs, e.g., pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, nervous tissue, heart, lung, combined heart-lung, kidney, liver, intestine, pancreas, trachea, or esophagus, or graft-versus-host disease.

[0080] As used herein, the term "diseases involving impaired cartilage turnover" includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful osteodystrophy, Tietze's syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis such as endemic osteoarthritis, Musereni's disease and Handigodu's disease; degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis.

[0081] As used herein, the term "congenital cartilage malformations" includes conditions such as hereditary chondrolysis, chondrodysplasia and pseudochondrodysplasia, particularly but not limited to microtia, anotia, metaphyseal chondrodysplasia, and related disorders.

[0082] As used herein, the term "diseases associated with impaired bone turnover" includes conditions such as osteoporosis (including postmenopausal osteoporosis, male osteoporosis, glucocorticosteroid-induced osteoporosis, and juvenile osteoporosis), osteoporosis caused by neoplastic bone marrow disorders, osteopenia, hormone deficiencies (vitamin D deficiency, male and female hypogonadism), hormone excesses (hyperprolactinemia, glucocorticoid excess, hyperthyroidism, hyperparathyroidism), Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia.

[0083] As used herein, the term "diseases associated with hypersecretion of IL-6" includes conditions such as Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma, and / or mesangial proliferative glomerulonephritis.

[0084] As used herein, the term "diseases associated with hypersecretion of TNFα, interferon, IL-12, and / or IL-23" includes conditions such as systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0085] As used herein, the term "respiratory disease" refers to a disease affecting the organs involved in breathing, such as the nose, throat, larynx, Eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal muscles), 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 asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-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 pulmonary fibrosis and / or airway inflammation, cystic fibrosis, and hypoxia.

[0086] As used herein, the term "endocrine and / or metabolic disorders" refers to a group of conditions involving the overproduction or underproduction of certain hormones in the body, while metabolic disorders affect the body's ability to process certain nutrients and vitamins. In particular, endocrine disorders include hypothyroidism, congenital adrenal hyperplasia, parathyroid disease, diabetes, adrenal gland diseases (including Cushing's syndrome and Addison's disease), and ovarian dysfunction (including polycystic ovary syndrome). Some examples of metabolic disorders include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. A specific example of a metabolic disorder is obesity and / or type II diabetes.

[0087] As used herein, the term "cardiovascular disease" refers to diseases affecting the heart or blood vessels, or both. In particular, cardiovascular disease includes arrhythmias (atrial or ventricular, or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disorders; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis (e.g., giant cell arteritis (GCA), retinal vasculitis, rheumatoid vasculitis), stroke; peripheral occlusive arteriopathy of the limbs, organs, or tissues; post-ischemic reperfusion injury of the brain, heart, kidney, or other organ or tissue; endotoxin, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraine); vascular abnormalities, inflammation, and dysfunction limited to a single organ or tissue. More particularly, cardiovascular disease refers to atherosclerosis or giant cell arteritis.

[0088] As used herein, the term "skin disease" refers to a skin disorder. In particular, skin disorders include atopic dermatitis, bullous disorders, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria, and other proliferative or inflammatory disorders of the skin. More particularly, the term skin disorder refers to vitiligo.

[0089] As used herein, the term "abnormal angiogenesis-associated disease" refers to a disease caused by dysregulation of processes that mediate angiogenesis. In particular, abnormal angiogenesis-associated diseases refer to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy.

[0090] "Compound(s) of the invention" and equivalent expressions are meant to include compounds of the formula(s) described herein, and, where the context permits, the expression also includes pharmaceutically acceptable salts, and solvates, such as hydrates and solvates of pharmaceutically acceptable salts. Similarly, references to intermediates, whether or not they themselves are claimed, are meant to include their salts and solvates, where the context permits.

[0091] As used herein, for example, but not limited to, C 1-8 When a range is referred to, such as alkyl, the recitation of the range should be considered as a representation of each member of the range.

[0092] Other derivatives of the compounds of the present invention are active in both their acid and acid-derivative forms, although the acid-labile forms often offer advantages of mammalian solubility, tissue compatibility, or delayed release (Bundgaard, 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting 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 attached to the compounds of the present invention are particularly useful prodrugs. In some cases, it may be desirable to prepare double ester prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Certain such prodrugs are useful as prodrugs containing the C-terminal end of the compounds of the present invention. 1-8 Alkyl, C 2-8 Alkenyl, optionally substituted C6-10 Aryl, and (C 6-10 Aryl)-(C 1-4 alkyl) esters.

[0093] The present disclosure includes all isotopic forms of the compounds of the present invention provided herein, whether (i) in which all atoms of a given atomic number have the mass number (or a mixture of mass numbers) that is predominant in nature (referred to herein as "natural isotopic forms"), or (ii) in which one or more atoms are replaced by an atom having the same atomic number but a mass number different from the mass number of the atom that is predominant in nature (referred to herein as "non-natural variant isotopic forms"). It is understood that some atoms may naturally exist as a mixture of mass numbers. The term "non-natural variant isotopic form" also includes embodiments in which the proportion of atoms of a given atomic number having mass numbers less common in nature (referred to herein as "uncommon isotopes") is increased compared to that occurring in nature, e.g., to a level of >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (the latter embodiments are referred to as "isotopically enriched variant forms"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of uncommon isotopes is reduced compared to that occurring in nature. Isotopic forms can include radioactive forms (i.e., which incorporate a radioactive isotope) and non-radioactive forms. The radioactive form is usually an isotopically enriched variant form.

[0094] Thus, non-naturally occurring variant isotopic forms of a compound may contain one or more 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( 32P), sulfur-35( 35 S), chlorine-36( 36 Cl), chlorine-37( 37 Cl), fluorine-18( 18 F), iodine-123( 123 I), iodine-125( 125 It may contain artificial or uncommon isotopes, such as I), or may contain an increased proportion of the isotope at one or more atoms compared to the proportion predominant in nature.

[0095] Non-natural variant isotopic forms containing radioactive isotopes may be used, for example, in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. 2 Non-natural variant isotopic forms incorporating H or D may offer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in certain circumstances. 11 C. 18 F, 15 O, and 13 Non-natural variant isotopic forms may also be prepared, incorporating positron emitting isotopes such as N, which may be useful in Positron Emission Tissue Distribution (PET) studies to examine substrate receptor occupancy.

[0096] It should also 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."

[0097] Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and named as dextrorotatory or levorotatory (i.e., (+) or (-)-isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0098] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and differ in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting of π electrons and atoms (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, which are similarly formed by treatment with acid or base.

[0099] Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0100] The compounds of the present invention may possess one or more asymmetric centers; therefore, such compounds may be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.

[0101] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, whether racemic or not. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0102] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.

[0103] (The present invention) The present invention is based on the identification of novel compounds and their use in the prevention and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, diseases associated with impaired bone turnover, diseases associated with excessive secretion of IL-6, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and / or diseases associated with abnormal angiogenesis. In particular, the compounds of the present invention may be SIK inhibitors, more particularly SIK1, SIK2, and / or SIK3 inhibitors.

[0104] The present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, diseases associated with impaired bone turnover, diseases associated with excessive secretion of IL-6, diseases associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases, and / or diseases associated with abnormal angiogenesis by administering a compound of the invention.

[0105] Thus, in a first aspect of the present invention, there is provided a compound of the present invention having formula I: [ka] (In the formula, W is N or CH; One of X1 and X2 is N and the other is C (provided that if W is CH then X2 is not N); Y is N or CR 2b and; Z is - -NHR 3a , - further containing 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, and optionally one or more independently selected R 15 an N-linked 4- to 7-membered heterocycloalkyl substituted with a group; or -NR 3b - (wherein N atom and R 2a together with the atom to which they are attached form a fused 5- to 6-membered heterocycloalkenyl containing 1 or 2 double bonds; R 1 teeth - one or more independently selected R 4 C optionally substituted with a group 1-8 Alkyl, - phenyl, - one or more independently selected R 5 C optionally substituted with a group 3-8 monocyclic or bridged polycyclic cycloalkyl, - a 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is one or more independently selected -CN or -C(=O)-C 1-4 one or more independently selected C optionally substituted with alkoxy 1-4 optionally substituted with alkyl, or - a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; R 2a and R 2b teeth, - Hello, - C 1-4 Alkyl, - one or more independently selected halo or C 1-4 C optionally substituted with alkoxy 1-4 Alkoxy, and -NR 6a R 6b are independently selected from; R 3ateeth, - C optionally substituted with one or more independently selected halo or -CN 1-6 alkyl, or - C optionally substituted with one or more independently selected halo or -OH 3-7 is cycloalkyl; R 3b is H, C 3-7 cycloalkyl, and C optionally substituted with one or more independently selected halo or -CN; 1-6 alkyl; Each R 4 teeth, - Hello, - -OH, - -CN, - phenyl, - -C(=O)OH, - -OC(=O)C 1-4 Alkyl, - -OS(=O)2-C 1-4 Alkyl, - one or more independently selected -OH, C 1-4 Alkoxy, 4-8 membered monocyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is selected from one or more independently selected C 1-4 optionally substituted with alkyl; or -NR 7a R 7b (In the formula, each R 7a and R 7b is H and C 1-4 C optionally substituted with alkyl 1-4 Alkoxy, one or more independently selected halo, -C(=O)-C 1-4 Alkoxy, -NR 8a R 8b or one or more independently selected -NR 9a R 9b C optionally substituted with 1-4 C optionally substituted with alkyl 3-7cycloalkyl, - a 5-6 membered monocyclic heterocycloalkyl containing 1 or 2 N atoms fused to a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is fused to one or more independently selected C 1-4 optionally substituted with alkyl, - a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is selected from one or more independently selected C 1-4 Alkyl or C 3-7 optionally substituted with cycloalkyl; - 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is selected from one or more independently selected R 10 optionally replaced by -NR 11a R 11b , - -C(=O)C 1-4 Alkoxy, and - -C(=O)-NR 12a R 12b are independently selected from; Each R 5 teeth, - Hello, -CN, and -NR 13a R 13b Selected from; Each R 6a and R 6b is H and C 1-4 alkyl; Each R 10 teeth, - -OH, - phenyl, - =NH, - Hello, - Oxo, - -CN, - -C(=O)H, - -C(=O)NH2, - -C(=O)OH, -NR 14a R 14b , one or more independently selected halo, —CN, —OH, —C(═O)—C 1-4 Alkoxy or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, - C 3-7 cycloalkyl, - a 4-6 membered monocyclic heterocycloalkyl containing 1, 2, or 3 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 selected from alkoxy; Each R 11a , R 11b teeth, -H - phenyl, one or more independently selected halo, —OH, —CN, or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, - C 3-7 cycloalkyl, - -C(=O)-C 1-4 Alkoxy, -C(=O)-C optionally substituted with one or more independently selected halo 1-4 Alkyl, and - independently selected from 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 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 H and C 1-4 independently selected from alkyl; Each R 14aand R 14b is H, C 1-4 Alkyl, and -S(=O)2-C 1-4 alkyl; and Each R 15 is —OH, —CN, and C optionally substituted with one or more independently selected halo or —CN; 1-4 alkyl).

[0106] In one embodiment, the compounds of the present invention are 2a is halo. In certain embodiments, R 2a is F, Cl, or Br. In a more particular embodiment, R 2a is F.

[0107] In one embodiment, the compounds of the present invention are 2a But C 1-4 In certain embodiments, R 2a is -CH3, -CH2CH3, or -CH(CH3)2. In more particular embodiments, R 2a is -CH3.

[0108] In one embodiment, the compounds of the present invention are 2a But C 1-4 In certain embodiments, R 2a is —O—CH, —O—CHCH, or —O—CH(CH). In more particular embodiments, R 2a is —O—CH or —O—CH CH. In a most particular embodiment, R 2a is -O-CH3.

[0109] In one embodiment, the compounds of the present invention are 2a is one or more independently selected halo or C 1-4 Alkoxy-substituted C 1-4 In certain embodiments, R 2ais one or more independently selected halo or C 1-4 In another particular embodiment, R is -O-CH, -O-CHCH, or -O-CH(CH), each of which is substituted with alkoxy. 2a is one, two, or three independently selected halo or C 1-4 Alkoxy-substituted C 1-4 In yet another particular embodiment, R 2a is a C substituted with one or more independently selected F, Cl, Br, —O—CH3, —O—CH2CH3, or —O—CH(CH3)2; 1-4 In a more particular embodiment, R 2a is one, two, or three independently selected halo or C 1-4 In another more particular embodiment, R is -O-CH, -O-CHCH, or -O-CH(CH), each of which is substituted with alkoxy. 2a is C substituted with one, two, or three independently selected F, Cl, Br, —O—CH3, —O—CH2CH3, or —O—CH(CH3)2; 1-4 In further more particular embodiments, R 2a is —O—CH substituted with 1, 2, or 3 independently selected halo. 2a is one, two, or three independently selected halo or C 1-4 In a most particular embodiment, R 2a is —O—CHF2 or —O—CH2CH2—O—CH2CH3.

[0110] In one embodiment, the compounds of the present invention are 2a But, -NR 6a R 6b and R 6a and R 6b However, H and C 1-4 alkyl. In certain embodiments, R 6a and R 6band R are both H. In another particular embodiment, R 6a and R 6b One of the groups is H and the other is C 1-4 In yet another particular embodiment, R 6a and R 6b Both are C 1-4 In a more particular embodiment, R 6a and R 6b is H and the other is -CH, -CHCH, or -CH(CH). In another more particular embodiment, R 6a and R 6b is independently -CH3, -CH2CH3, or -CH(CH3)2. In a most particular embodiment, R 6a and R 6b One of is H and the other is -CH3.

[0111] In one embodiment, the compounds of the present invention are those in which Z is -NR 3b - (wherein the N atom and R 2a together with the atoms to which they are attached form a fused 5- to 6-membered heterocycloalkenyl containing one or two double bonds, and R 3b is as previously described. In certain embodiments, Z is -NR 3b - (wherein the N atom and R 2a together with the atoms to 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 to which they are attached form a fused 1,2,3,6-tetrahydropyridine).

[0112] In one embodiment, the compound of the invention is according to Formula IIa, Formula IIb, or Formula IIc: [ka] (In the formula, R 1 , R 3b , W, X1, X2, and Y are as described above).

[0113] In one embodiment, the compounds of the present invention are 3b is H.

[0114] In one embodiment, the compounds of the present invention are 3b But C 3-7 In certain embodiments, R is cycloalkyl. 3b is cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R 3b is cyclopropyl.

[0115] In one embodiment, the compounds of the present invention are 3b But C 1-6 In certain embodiments, R is an alkyl group. 3b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3. In more particular embodiments, R 3b is -CH2CH3.

[0116] In one embodiment, the compound of the invention is according to any one of Formulas I-IIc. 3b is C substituted with one or more independently selected halo or -CN; 1-6 In certain embodiments, R 3b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each substituted with one or more independently selected halo or -CN. 3b is C substituted with 1, 2, or 3 independently selected halo or -CN; 1-6 In yet another particular embodiment, R 3bis C substituted with one or more independently selected F, Cl, or —CN; 1-6 In a more particular embodiment, R 3b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each substituted with 1, 2, or 3 independently selected halo or -CN. 3b is C substituted with one, two, or three independently selected F, Cl, or -CN; 1-6 In yet another more particular embodiment, R 3b is —CH, —CHCH, —CHCHCH, —CH(CH), or —C(CH), each substituted with one or more independently selected F, Cl, or —CN. 3b is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each substituted with 1, 2, or 3 independently selected F, Cl, or -CN. 3b is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each substituted with one or more F or —CN. 3b is C substituted with 1, 2, or 3 independently selected F or -CN; 1-6 In a most particular embodiment, R 3b is —CH 2 CH 3 substituted with 1, 2, or 3 F. In another most particular embodiment, R 3b is —CH—CN. In a further most particular embodiment, R 3b is -CH2CF3.

[0117] In one embodiment, the compounds of the invention are according to formula I, where Z is an N-linked 4-7 membered heterocycloalkyl further containing 0, 1, or 2 additional heteroatoms independently selected from N, O, and S. In certain embodiments, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl. In more particular embodiments, Z is azetidinyl.

[0118] In one embodiment, compounds of the present invention are those in which Z is one or more independently selected R 15 In certain embodiments, Z is an N-linked 4-7 membered heterocycloalkyl further comprising 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R 15 In another particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each substituted with one, two, or three independently selected R 15 In a more particular embodiment, Z is an N-linked 4-7 membered heterocycloalkyl further containing 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, substituted with one or more independently selected R 15 In another more particular embodiment, Z is azetidinyl substituted with one, two, or three independently selected R 15 In yet another more particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each substituted with one or two independently selected R 15 In a further more particular embodiment, Z is an N-linked 4-7 membered heterocycloalkyl further containing 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, substituted with a group. In a further more particular embodiment, Z is substituted with 1, 2, or 3 independently selected R 15 In another further more particular embodiment, Z is azetidinyl substituted with one or two independently selected R15 In a most particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one or two independently selected R 15 and azetidinyl substituted with a group.

[0119] In one embodiment, compounds of the invention are those in which Z is one or more independently selected R 15 and R is an N-linked 4- to 7-membered heterocycloalkyl further containing 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, substituted with a group; and R 15 is -OH, -CN, or C 1-4 In certain embodiments, R 15 is -OH, -CN, -CH3, -CH2CH3, or -CH(CH3)2. In more particular embodiments, R 15 is —OH or —CN.

[0120] In one embodiment, compounds of the invention are those wherein Z further comprises 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, and one or more independently selected R 15 N-linked 4- to 7-membered heterocycloalkyl substituted with a group, and R 15 is substituted with one or more independently selected halo or -CN; 1-4 In certain embodiments, R 15 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 , each substituted with one or more independently selected halo or —CN. 15 is C substituted with 1, 2, or 3 independently selected halo or -CN; 1-4 In yet another particular embodiment, R 15 is C substituted with one or more F, Cl, Br, or -CN 1-4 In a more particular embodiment, R 15is -CH substituted with one or more independently selected halo or -CN. In another more particular embodiment, R 15 is -CH3, -CH2CH3, or -CH(CH3)2, each substituted with 1, 2, or 3 independently selected halo or -CN. 15 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 , each substituted with one or more independently selected F, Cl, Br, or —CN. 15 is C substituted with one, two, or three independently selected F, Cl, Br, or -CN; 1-4 In further more particular embodiments, R 15 is —CH substituted with 1, 2, or 3 independently selected halo or —CN. 15 is —CH 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 1, 2, or 3 independently selected F or —CN.

[0121] In one embodiment, compounds of the invention are those in which Z is -NHR 3a and R 3a But C 1-6 In certain embodiments, R 3a is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, or -CH(CH3)CH(CH3)2. In more particular embodiments, R 3a is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -CH2CH(CH3)2. In a most particular embodiment, R 3a is -CH2CH3.

[0122] In one embodiment, compounds of the invention are those in which Z is -NHR3a and R 3a is substituted with one or more independently selected halo or -CN; 1-6 In certain embodiments, R 3a is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each substituted with one or more independently selected halo or -CN. 3a is C substituted with 1, 2, or 3 independently selected halo or -CN; 1-6 In yet another particular embodiment, R 3a is C substituted with one or more independently selected F, Cl, or —CN; 1-6 In a more particular embodiment, R 3a is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each substituted with 1, 2, or 3 independently selected halo or -CN. 3a is C substituted with one, two, or three independently selected F, Cl, or -CN; 1-6 In yet another more particular embodiment, R 3a is —CH, —CHCH, —CHCHCH, —CH(CH), or —C(CH), each substituted with one or more independently selected F, Cl, or —CN. 3a is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each substituted with 1, 2, or 3 independently selected F, Cl, or -CN. 3a is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , or —C(CH 3 ) 3 , each substituted with one or more F or —CN. 3a is C substituted with 1, 2, or 3 independently selected F or -CN;1-6 In a most particular embodiment, R 3a is —CH 2 CH 3 substituted with 1, 2, or 3 F. In another most particular embodiment, R 3a is —CH—CN. In a further most particular embodiment, R 3a is -CH2CF3.

[0123] In one embodiment, compounds of the invention are those in which Z is -NHR 3a and R 3a But C 3-7 In certain embodiments, R 3a is cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R 3a is cyclopropyl.

[0124] In one embodiment, compounds of the invention are those in which Z is -NHR 3a and R 3a is substituted with one or more independently selected halo or —OH; 3-7 In certain embodiments, R 3a is cyclopropyl, cyclobutyl, or cyclopentyl, each substituted with one or more independently selected halo or —OH. 3a is a C substituted with one, two, or three independently selected halo or —OH; 3-7 In yet another particular embodiment, R 3a is C substituted with one or more independently selected F, Cl, or —OH; 3-7 In a more particular embodiment, R 3a is cyclopropyl, cyclobutyl, or cyclopentyl, each substituted with 1, 2, or 3 independently selected halo or —OH. 3a is C substituted with one, two, or three independently selected F, Cl, or —OH; 3-7In yet another more particular embodiment, R 3a is cyclopropyl, cyclobutyl, or cyclopentyl, each substituted with one or more independently selected F, Cl, or —OH. 3a is cyclopropyl, cyclobutyl, or cyclopentyl, each substituted with 1, 2, or 3 independently selected F, Cl, or —OH. 3a is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more F or —OH. 3a is a C substituted with one, two, or three independently selected F or —OH; 3-7 In a most particular embodiment, R 3a teeth, [ka] In a further most particular embodiment, R 3a teeth, [ka] is.

[0125] In one embodiment, the compound of the invention is according to any one of Formulas I-IIc, wherein Y is N.

[0126] In one embodiment, the compounds of the present invention are those in which Y is CR 2b and R 2b is halo. 2b is F, Cl, or Br. In a more particular embodiment, R 2b is F.

[0127] In one embodiment, the compounds of the present invention are those in which Y is CR 2b and R 2b But C1-4 In certain embodiments, R is an alkyl group. 2b is -CH3, -CH2CH3, or -CH(CH3)2. In more particular embodiments, R 2b is -CH3.

[0128] In one embodiment, the compounds of the present invention are those in which Y is CR 2b and R 2b But C 1-4 In certain embodiments, R is alkoxy. 2b is —O—CH, —O—CHCH, or —O—CH(CH). In more particular embodiments, R 2b is —O—CH or —O—CH CH. In a most particular embodiment, R 2b is -O-CH3.

[0129] In one embodiment, the compounds of the present invention are those in which Y is CR 2b and R 2b is one or more independently selected halo or C 1-4 Alkoxy-substituted C 1-4 In certain embodiments, R is alkoxy. 2b is one or more independently selected halo or C 1-4 In another particular embodiment, R is -O-CH, -O-CHCH, or -O-CH(CH), each of which is substituted with alkoxy. 2b is one, two, or three independently selected halo or C 1-4 Alkoxy-substituted C 1-4 In yet another particular embodiment, R 2b is a C substituted with one or more independently selected F, Cl, Br, —O—CH3, —O—CH2CH3, or —O—CH(CH3)2; 1-4 In a more particular embodiment, R 2b is one, two, or three independently selected halo or C1-4 In another more particular embodiment, R is -O-CH, -O-CHCH, or -O-CH(CH), each of which is substituted with alkoxy. 2b is C substituted with one, two, or three independently selected F, Cl, Br, —O—CH3, —O—CH2CH3, or —O—CH(CH3)2; 1-4 In further more particular embodiments, R 2b is —O—CH substituted with 1, 2, or 3 independently selected halo. 2b is one, two, or three independently selected halo or C 1-4 In a most particular embodiment, R 2b is —O—CHF2 or —O—CH2CH2—O—CH2CH3.

[0130] In one embodiment, the compounds of the present invention are those in which Y is CR 2b and R 2b But, -NR 6a R 6b and R 6a and R 6b However, H and C 1-4 alkyl. In certain embodiments, R 6a and R 6b and R are both H. In another particular embodiment, R 6a and R 6b One of the groups is H and the other is C 1-4 In yet another particular embodiment, R 6a and R 6b Both are C 1-4 In a more particular embodiment, R 6a and R 6b is H and the other is -CH, -CHCH, or -CH(CH). In another more particular embodiment, R 6a and R 6bis -CH3, -CH2CH3, or -CH(CH3)2. In a most particular embodiment, R 6a and R 6b One of is H and the other is -CH3.

[0131] In one embodiment, the compound of the invention is according to any one of Formulas I-IIc, wherein W is N, X 1 is N, and X 2 is C.

[0132] In one embodiment, the compound of the invention is according to any one of Formulas I-IIc, wherein W is N, X 1 is C, and X 2 is N.

[0133] In one embodiment, the compound of the invention is according to any one of Formulas I-IIc, wherein W is CH, X 1 is N, and X 2 is C.

[0134] In one embodiment, the compound of the invention is according to Formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, or IIIh: [ka] (In the formula, R 1 is as described above.)

[0135] In one embodiment, the compounds of the present invention are 1 But C 1-8 In certain embodiments, R is an alkyl group according to any one of Formulas I-IIIh. 1is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C H2CH2CH(CH3)2, -CH(CH2CH3)2, -CH(CH3)CH(CH3)2, -CH2C(CH3)3, -CH2CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)CH2CH2CH3, -CH2CH2CH(CH3)CH2CH3, -CH 2CH2CH2CH(CH3)2, -CH(CH2CH3)CH2CH2CH3, -CH2CH(CH2CH3)2, -CH(CH3)CH(CH3)CH2CH3, -CH(CH2CH3)CH(CH3)2, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH(CH3)2, -CH(CH3)CH2CH2CH(CH3)2, -CH2CH2CH(CH3)CH2CH(CH3)2, -CH2CH2CH(CH3)CH(CH3)2, -CH2CH2CH(CH3)CH(CH3)2CH2CH3, -CH2CH(CH3)CH(CH3)CH2CH3, or -CH(CH3)CH2CH(CH3)CH2CH(CH3)CH2CH3. In more particular embodiments, R 1 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH(CH3)2, -CH2C(CH3)3, or -CH2CH2CH2CH(CH3)2. In a most particular embodiment, R 1 is -CH3, -CH2CH3, or -CH2C(CH3)3.

[0136] In one embodiment, the compounds of the present invention are 1 is one or more independently selected R 4 C substituted with a group 1-8 In certain embodiments, R is an alkyl group according to any one of Formulas I-IIIh. 1 is one or more independently selected R4 -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)C, each substituted with a group H2CH3, -CH2CH2CH(CH3)2, -CH(CH2CH3)2, -CH(CH3)CH(CH3)2, -CH2C(CH3)3, -CH2CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)CH2CH2CH3, -CH2CH2CH(CH3)CH2CH 3, -CH2CH2CH2CH(CH3)2, -CH(CH2CH3)CH2CH2CH3, -CH2CH(CH2CH3)2, -CH(CH3)CH(CH3)CH2CH3, -CH(CH2CH3)CH(CH3)2, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH(CH3)2, -CH(CH3)CH2CH2CH(CH3)2, -CH2CH2CH(CH3)CH2CH(CH3)2, -CH2CH2CH(CH3)CH2CH(CH3)2, -CH2CH2CH(CH3)CH(CH3)2, -CH2CH2C(CH3)2CH2CH3, -CH2CH(CH3)CH(CH3)CH2CH3, or -CH(CH3)CH2CH(CH3)CH2CH(CH3)CH2CH3. In another particular embodiment, R 1 is one, two, or three independently selected R 4 C substituted with a group 1-8 In a more particular embodiment, R 1 is one or more independently selected R 4 In another more particular embodiment, R is -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CH(CH), -CH(CH)CHCH, -C(CH), -CHCHCH(CH), -CHC(CH), or -CHCHCHCHCH(CH). 1 is one, two, or three independently selected R 4-CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)C, each substituted with a group H2CH3, -CH2CH2CH(CH3)2, -CH(CH2CH3)2, -CH(CH3)CH(CH3)2, -CH2C(CH3)3, -CH2CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)CH2CH2CH3, -CH2CH2CH(CH3)CH2CH 3, -CH2CH2CH2CH(CH3)2, -CH(CH2CH3)CH2CH2CH3, -CH2CH(CH2CH3)2, -CH(CH3)CH(CH3)CH2CH3, -CH(CH2CH3)CH(CH3)2, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH(CH3)2, -CH(CH3)CH2CH2CH(CH3)2, -CH2CH2CH(CH3)CH2CH(CH3)2, -CH2CH2CH(CH3)CH2CH(CH3)2, -CH2CH2CH(CH3)CH(CH3)2, -CH2CH2C(CH3)2CH2CH3, -CH2CH(CH3)CH(CH3)CH2CH3, or -CH(CH3)CH2CH(CH3)CH2CH(CH3)CH2CH3. In yet another more particular embodiment, R 1 is one R 4 C substituted with a group 1-8 In further more particular embodiments, R 1 is one, two, or three independently selected R 4 In another further more particular embodiment, R is -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCHCH, -CH(CH), -CH(CH)CHCH, -C(CH), -CHCHCH(CH), -CHC(CH), or -CHCHCHCHCH(CH). 1 is one R 4-CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH3, -CH2CH(CH3)C, each substituted with a group H2CH3, -CH2CH2CH(CH3)2, -CH(CH2CH3)2, -CH(CH3)CH(CH3)2, -CH2C(CH3)3, -CH2CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH2CH(CH3)CH2CH2CH3, -CH2CH2CH(CH3)CH2CH 3, -CH2CH2CH2CH(CH3)2, -CH(CH2CH3)CH2CH2CH3, -CH2CH(CH2CH3)2, -CH(CH3)CH(CH3)CH2CH3, -CH(CH2CH3)CH(CH3)2, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH(CH3)2, -CH(CH3)CH2CH2CH(CH3)2, -CH2CH2CH(CH3)CH2CH(CH3)2, -CH2CH2CH(CH3)CH(CH3)2, -CH2CH2CH(CH3)CH(CH3)2, -CH2CH2C(CH3)2CH2CH3, -CH2CH(CH3)CH(CH3)CH2CH3, or -CH(CH3)CH2CH(CH3)CH2CH(CH3)CH2CH3. In a most particular embodiment, R 1 is one R 4 and -CH(CH)2, -CHCH2CH2CH3, -CH(CH)2, -CH2CH2CH2CH3, -CH2CH(CH)2, -CH(CH)CH2CH3, -C(CH)3, -CH2CH2CH(CH)2, -CH2C(CH)3, or -CH2CH2CH2CH(CH)2, each substituted with a group.

[0137] In one embodiment, the compounds of the present invention are 1 is phenyl.

[0138] In one embodiment, the compounds of the present invention are 1 But C 3-8In certain embodiments, R is a monocyclic or bridged polycyclic cycloalkyl according to any one of Formulas I-IIIh. 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl. In more particular embodiments, R 1 is cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2.1]heptanyl.

[0139] In one embodiment, the compounds of the present invention are 1 is one or more independently selected R 5 C substituted with a group 3-8 In certain embodiments, R is a monocyclic or bridged polycyclic cycloalkyl according to any one of Formulas I-IIIh. 1 is one or more independently selected R 5 In another particular embodiment, R 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 a group. 1 is one, two, or three independently selected R 5 substituted with a C group 3-8 In a more particular embodiment, R 1 is one or more independently selected R 5 In another more particular embodiment, R is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with a group. 1 is one, two, or three independently selected R 5 In yet another more particular embodiment, R 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 a group. 1 is one R 5 substituted with a C group 3-8In further more particular embodiments, R 1 is one, two, or three independently selected R 5 In another further more particular embodiment, R is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with a group. 1 is one R 5 In a most particular embodiment, R 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 a group. 1 is one R 5 and cyclobutyl, cyclopentyl, or cyclohexyl, each substituted with a group.

[0140] In one embodiment, the compounds of the present invention are 1 is one or more independently selected R 5 C substituted with a group 3-8 is a monocyclic or bridged polycyclic cycloalkyl; R 5 is halo or —CN. 5 is F, Cl, Br, or —CN. In more particular embodiments, R 5 is F or -CN.

[0141] In one embodiment, the compounds of the present invention are 1 is one or more independently selected R 5 C substituted with a group 3-8 is a monocyclic or bridged polycyclic cycloalkyl; R 5 But, -NR 13a R 13b and each R 13a and R 13b is according to any one of Formulas I-IIIh, wherein R 13a and R 13b and R are both H. In another particular embodiment, R 13a and R13b One of the groups is H and the other is C 1-4 In yet another particular embodiment, R 13a and R 13b Both are C 1-4 In a more particular embodiment, R 13a and R 13b is H and the other is -CH, -CHCH, or -CH(CH). In another more particular embodiment, each R 13a and R 13b is independently -CH3, -CH2CH3, or -CH(CH3)2. In a most particular embodiment, R 5 is -NH-CH3.

[0142] In one embodiment, the compounds of the present invention are 1 is a 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In certain embodiments, R 1are 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 nyl, 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 In a more specific embodiment, R is cyclo[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. 1 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxaspiro[3.3]heptanyl, or 8-azabicyclo[3.2.1]octanyl.

[0143] In one embodiment, the compounds of the present invention are 1is a 4-8 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected -CN or -C(=O)-C 1-4 one or more independently selected C optionally substituted with alkoxy 1-4 In certain embodiments, R is a heterocycloalkyl substituted with alkyl, according to any one of Formulas I-IIIh. 1 represents one or more independently selected -CN or -C(=O)-C 1-4 1, 2, or 3 independently selected C optionally substituted with alkoxy 1-4Azetidinyl, 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-thiazolin ... Pyro[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[2.2.1]heptanyl In a more specific embodiment, R is 8-azabicyclo[3.2.1]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. 1is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, each substituted with one, two, or three independently selected -CH, -CHCH, or -CH(CH) each optionally substituted with one, two, or three independently selected -CN, -C(=O)-O-CH, -C(=O)-O-CHCH, or -C(=O)-O-CH(CH) 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, quinucin In another more particular embodiment, R is lysinyl, 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. 1represents one or more independently selected -CN or -C(=O)-C 1-4 1, 2, or 3 independently selected C optionally substituted with alkoxy 1-4 In further more particular embodiments, R is azetidinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, each of which is substituted with alkyl. 1 is azetidinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, each substituted with one, two, or three independently selected -CH, -CHCH, or -CH(CH), each optionally substituted with one, two, or three independently selected -CN, -C(=O)-O-CH, -C(=O)-O-CHCH, or -C(=O)-O-CH(CH). 1represents azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 1-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, each of which is substituted by one, two, or three independently selected -CH, -CH-CH-CN, or -CH-C(=O)-O-CHCH. , 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 most particular embodiment, R 1is azetidinyl, pyrrolidinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, each substituted with one -CH3, -CH2-CH2-CN, or -CH2-C(=O)-O-CH2CH3.

[0144] In one embodiment, the compounds of the present invention are 1 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In certain embodiments, R 1 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl. 1 is pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl. In a most particular embodiment, R 1 is pyridinyl.

[0145] In one embodiment, the compound of the invention is according to formula IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVi, IVj, IVk, IVl, IVm, IVn, IVo, or IVp: [ka] (In the formula, R 4 is as described above.)

[0146] In one embodiment, the compounds of the present invention are 4 is according to any one of formulas I-IVp, wherein R is halo, —OH, —CN, phenyl, or —C(═O)OH. 4 is F, Cl, Br, —OH, —CN, phenyl, or —C(═O)OH. 4 is F, —OH, —CN, phenyl, or —C(═O)OH.

[0147] In one embodiment, the compounds of the present invention are 4 But -OC(=O)-C 1-4 In certain embodiments, R is an alkyl group according to any one of Formulas I-IVp. 4 is -OC(=O)-CH, -OC(=O)-CHCH, or -OC(=O)-CH(CH). In more particular embodiments, R 4 is -OC(=O)-CH3.

[0148] In one embodiment, the compounds of the present invention are 4 But -OS(=O)2-C 1-4 In certain embodiments, R is an alkyl group according to any one of Formulas I-IVp. 4 is —OS(═O)—CH, —OS(═O)—CHCH, or —OS(═O)—CH(CH). In more particular embodiments, R 4 is -OS(=O)2-CH3.

[0149] In one embodiment, the compounds of the present invention are 4 But C 1-4 In certain embodiments, R is alkoxy. 4 is —O—CH, —O—CHCH, or —O—CH(CH). In more particular embodiments, R 4 is —O—CH3 or —O—CH2CH3.

[0150] In one embodiment, the compounds of the present invention are 4 is one or more independently selected 4-8 membered monocyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected C 1-4 C substituted with said heterocycloalkyl, optionally substituted with alkyl 1-4In certain embodiments, R is alkoxy. 4 is one or more independently selected 4-8 membered monocyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected C 1-4 In another particular embodiment, R is -O-CH, -O-CHCH, or -O-CH(CH), each of which is substituted with said heterocycloalkyl, optionally substituted with alkyl. 4 is a 4-8 membered monocyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected C 1-4 C substituted with said heterocycloalkyl, optionally substituted with alkyl 1-4 In yet another particular embodiment, R 4 is C substituted by 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 by one, two, or three -CH3, -CH2CH3, or -CH(CH3)2; 1-4 In a more particular embodiment, R 4 is one or more independently selected 4-8 membered monocyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected C 1-4 In another more particular embodiment, R 4 is a 4-8 membered monocyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected C 1-4In yet another more particular embodiment, R is -O-CH, -O-CHCH, or -O-CH(CH), each of which is substituted with said heterocycloalkyl, optionally substituted with alkyl. 4 is -O-CH, -O-CHCH, or -O-CH(CH), each substituted with one or more independently selected azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each optionally substituted with one, two, or three -CH, -CHCH, or -CH(CH). 4 is substituted by one azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is optionally substituted by one, two, or three -CH3, -CH2CH3, or -CH(CH3)2; 1-4 In yet another more particular embodiment, R 4 is C substituted with one or more independently selected piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one —CH(CH3)2; 1-4 In further more particular embodiments, R 4 is a 4-8 membered monocyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected C 1-4 In another further more particular embodiment, R 4is —O—CHCH substituted by one or more independently selected azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each optionally substituted with 1, 2, or 3 —CH, —CHCH, or —CH(CH) . 4 is a C substituted with one piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one -CH(CH3)2; 1-4 In yet another further more particular embodiment, R 4 is -O-CH, -O-CHCH, or -O-CH(CH), each substituted with one azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each optionally substituted with one, two, or three -CH, -CHCH, or -CH(CH). 4 is —O—CH, —O—CHCH, or —O—CH(CH), each substituted with one or more independently selected piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one —CH(CH). In an even more particular embodiment, R 4 is -O-CHCH substituted by one azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each optionally substituted by one, two, or three -CH, -CHCH, or -CH(CH) . 4is -O-CHCH substituted with one or more independently selected piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one -CH(CH) . In yet another even more particular embodiment, R 4 is —O—CH, —O—CHCH, or —O—CH(CH), each substituted with one piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one —CH(CH). In a most particular embodiment, R 4 is —O—CH2CH3 substituted with one piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one —CH(CH3)2.

[0151] In one embodiment, the compounds of the present invention are 4 is one or more independently selected —OH, C 1-4 Alkoxy or -NR 7a R 7b (In the formula, each R 7a and R 7b are independently H and C 1-4 C substituted with alkyl 1-4 In certain embodiments, R is alkoxy. 4 represents one or more independently selected —OH, C 1-4 Alkoxy or -NR 7a R 7b (In the formula, each R 7a and R 7b are independently H and C 1-4 In another particular embodiment, R is —O—CH, —O—CHCH, or —O—CH(CH), each of which is substituted with an alkyl group selected from the group consisting of aryl, ... 4 is one, two, or three independently selected —OH, C 1-4 Alkoxy or -NR 7a R 7b (In the formula, each R 7a and R 7b are independently H and C 1-4 C substituted with alkyl 1-4In yet another particular embodiment, R 4 is a C substituted by one or more independently selected -OH, -O-CH3, -O-CH2CH3, -O-CH(CH3)2, -NH2, -NH-CH3, -NH-CH2CH3, -NH-CH(CH3)2, -N(CH3)2, -N(CH3)-CH2CH3, -N(CH3)-CH(CH3)2, -N(CH2CH3)-CH(CH3)2, or -N(CH(CH3)2)2; 1-4 In a more particular embodiment, R 4 represents one or more independently selected —OH, C 1-4 Alkoxy or -NR 7a R 7b (In the formula, each R 7a and R 7b are independently H and C 1-4 In another more particular embodiment, R 4 is one, two, or three independently selected —OH, C 1-4 Alkoxy or -NR 7a R 7b (In the formula, each R 7a and R 7b are independently H and C 1-4 In yet another more particular embodiment, R is —O—CH, —O—CHCH, or —O—CH(CH), each of which is substituted with an alkyl group selected from the group consisting of aryl, ... 4 is -O-CH, -O-CHCH, or -O-CH(CH), each substituted with one or more independently selected -OH, -O-CH, -O-CHCH, -O-CH(CH), -NH, -NH-CH, -NH-CHCH, -NH-CH(CH), -N(CH), -N(CH)-CHCH, -N(CH)-CH(CH), -N(CHCH), -N(CHCH)-CH(CH), or -N(CH(CH)). 4 is one -OH, C 1-4 Alkoxy or -NR 7a R 7b(In the formula, each R 7a and R 7b are independently H and C 1-4 C substituted with alkyl 1-4 In yet another more particular embodiment, R 4 is a C substituted by one, two, or three independently selected -OH, -O-CH3, -O-CH2CH3, -O-CH(CH3)2, -NH2, -NH-CH3, -NH-CH2CH3, -NH-CH(CH3)2, -N(CH3)2, -N(CH3)-CH2CH3, -N(CH3)-CH(CH3)2, -N(CH2CH3)-CH(CH3)2, or -N(CH(CH3)2)2; 1-4 In yet another more particular embodiment, R 4 is a C substituted with one or more independently selected -OH, -O-CH3, or -N(CH3)2. 1-4 In further more particular embodiments, R 4 is one, two, or three independently selected —OH, C 1-4 Alkoxy or -NR 7a R 7b (In the formula, each R 7a and R 7b are independently H and C 1-4 In another further more particular embodiment, R 4 is -O-CH2CH3 substituted with one or more independently selected -OH, -O-CH3, -O-CH2CH3, -O-CH(CH3)2, -NH2, -NH-CH3, -NH-CH2CH3, -NH-CH(CH3)2, -N(CH3)2, -N(CH3)-CH2CH3, -N(CH3)-CH(CH3)2, -N(CH2CH3)-CH(CH3)2, or -N(CH(CH3)2). In another further more particular embodiment, R 4 is one -OH, C 1-4 Alkoxy or -NR 7a R 7b (In the formula, each R 7a and R 7b are independently H and C1-4 In another further more particular embodiment, R is —O—CH 3 , —O—CH 2 CH 3 , or —O—CH(CH 3 ) 2 , each of which is substituted with an alkyl group selected from alkyl. 4 is -O-CH, -O-CHCH, or -O-CH(CH), each substituted with one, two, or three independently selected -OH, -O-CH, -O-CHCH, -O-CH(CH), -NH, -NH-CH, -NH-CHCH, -NH-CH(CH), -NH-CH(CH), -N(CH), -N(CH)-CHCH, -N(CH)-CH(CH), -N(CHCH), -N(CHCH)-CH(CH), or -N(CH(CH)). 4 is —O—CH, —O—CHCH, or —O—CH(CH), each substituted with one or more —OH, —O—CH, or —N(CH). 4 is a C substituted by one -OH, -O-CH3, -O-CH2CH3, -O-CH(CH3)2, -NH2, -NH-CH3, -NH-CH2CH3, -NH-CH(CH3)2, -N(CH3)2, -N(CH3)-CH2CH3, -N(CH3)-CH(CH3)2, -N(CH2CH3)2, -N(CH2CH3)-CH(CH3)2, or -N(CH(CH3)2)2. 1-4 In another further more particular embodiment, R 4 is a C substituted with one, two, or three -OH, -O-CH3, or -N(CH3)2. 1-4 In an even more particular embodiment, R 4 is one -OH, C 1-4 Alkoxy or -NR 7a R 7b (In the formula, each R 7a and R 7b are independently H and C 1-4 In another even more particular embodiment, R 4is -O-CHCH substituted by one, two, or three -OH, -O-CH, -O-CHCH, -O-CH(CH), -NH, -NH-CH, -NH-CHCH, -NH-CH(CH), -N(CH), -N(CH)-CHCH, -N(CH)-CH(CH), -N(CHCH), -N(CHCH)-CH(CH), or -N(CH(CH)). 4 is —O—CH2CH3 substituted with one or more —OH, —O—CH3, or —N(CH3)2. In yet another even more particular embodiment, R 4 is -O-CH, -O-CHCH, -O-CH(CH), -NH, -NH-CH, -NH-CH, -NH-CHCH, -NH-CH(CH), -N(CH), -N(CH)-CHCH, -N(CH)-CH(CH), -N(CH)-CH(CH), -N(CHCH), -N(CHCH)-CH(CH), or -N(CH(CH)). 4 is —O—CH, —O—CHCH, or —O—CH(CH), each substituted with 1, 2, or 3 —OH, —O—CH, or —N(CH). 4 is -O-CHCH substituted with one -OH, -O-CH, -O-CHCH, -O-CH(CH), -NH, -NH-CH, -NH-CHCH, -NH-CH(CH), -N(CH), -N(CH)-CHCH, -N(CH)-CH(CH), -N(CHCH), -N(CHCH)-CH(CH), or -N(CH(CH)). 4 is —O—CH2CH3 substituted with 1, 2, or 3 —OH, —O—CH3, or —N(CH3)2. In yet another most particular embodiment, R 4is —O—CH, —O—CHCH, or —O—CH(CH), each substituted with one —OH, —O—CH, or —N(CH). In a most particular embodiment, R 4 is —O—CH2CH3 substituted with one —OH, —O—CH3, or —N(CH3)2.

[0152] In one embodiment, the compounds of the present invention are 4 But C 3-7 In certain embodiments, R is cycloalkyl. 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0153] In one embodiment, the compounds of the present invention are 4 is one or more independently selected halo, -C(=O)-C 1-4 Alkoxy, -NR 8a R 8b or one or more independently selected —NR 9a R 9b C optionally substituted with 1-4 Alkyl-substituted C 3-7 In certain embodiments, R is cycloalkyl. 4 is one or more independently selected halo, -C(=O)-C 1-4 Alkoxy, -NR 8a R 8b or one or more independently selected —NR 9a R 9b C optionally substituted with 1-4 In another particular embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each substituted with alkyl. 4 is one, two, or three independently selected halo, -C(=O)-C 1-4 Alkoxy, -NR 8a R 8b or one or more independently selected —NR 9a R 9b C optionally substituted with1-4 Alkyl-substituted C 3-7 In yet another particular embodiment, R 4 represents one or more independently selected from F, Cl, Br, —C(═O)—O—CH3, —C(═O)—O—CH2CH3, —C(═O)—O—CH(CH3)2, and —NR 8a R 8b , 1 -NR 9a R 9b -CH3 optionally substituted with one -NR 9a R 9b or one -NR 9a R 9b C optionally substituted with -CH(CH3)2 3-7 In a more particular embodiment, R 4 is one, two, or three independently selected halo, -C(=O)-C 1-4 Alkoxy, -NR 8a R 8b or one or more independently selected —NR 9a R 9b C optionally substituted with 1-4 In another more particular embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each substituted with alkyl. 4 represents one or more independently selected from F, Cl, Br, —C(═O)—O—CH3, —C(═O)—O—CH2CH3, —C(═O)—O—CH(CH3)2, and —NR 8a R 8b , 1 -NR 9a R 9b -CH3 optionally substituted with one -NR 9a R 9b or one -NR 9a R 9b In yet another more particular embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with —CH(CH) optionally substituted with 4represents one, two, or three independently selected from F, Cl, Br, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, -NR 8a R 8b , 1 -NR 9a R 9b -CH3 optionally substituted with one -NR 9a R 9b or one -NR 9a R 9b C optionally substituted with -CH(CH3)2 3-7 In yet another more particular embodiment, R 4 represents one or more independently selected F, —C(═O)—O—CH3, —NR 8a R 8b , -CH3, or -CH2-NR 9a R 9b C replaced with 3-7 In further more particular embodiments, R 4 represents one, two, or three independently selected from F, Cl, Br, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, -NR 8a R 8b , 1 -NR 9a R 9b -CH3 optionally substituted with one -NR 9a R 9b or one -NR 9a R 9b In yet another further more particular embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with —CH(CH) optionally substituted with 4 represents one or more independently selected F, —C(═O)—O—CH3, —NR 8a R 8b , -CH3, or -CH2-NR 9a R 9bIn yet another further more particular embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with 4 represents one, two, or three independently selected F, -C(=O)-O-CH3, -NR 8a R 8b , -CH3, or -CH2-NR 9a R 9b C replaced with 3-7 In an even more particular embodiment, R 4 represents one, two, or three independently selected F, -C(=O)-O-CH3, -NR 8a R 8b , -CH3, or -CH2-NR 9a R 9b In a most particular embodiment, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each substituted with 1, 2, or 3 F. In another most particular embodiment, R 4 is one -C(=O)-O-CH3, -NR 8a R 8b , -CH3, or -CH2-NR 9a R 9b and cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with

[0154] In one embodiment, the compounds of the present invention are 4 But, -NR 8a R 8b C replaced with 3-7 cycloalkyl, and R 8a and R 8b is according to any one of Formulas I-IVp, wherein R 8a and R 8b and R are both H. In another particular embodiment, R 8a and R 8b One of the groups is H and the other is C 1-4In yet another particular embodiment, R 8a and R 8b Both are C 1-4 In a more particular embodiment, R 8a and R 8b is H and the other is -CH, -CHCH, or -CH(CH). In another more particular embodiment, R 8a and R 8b are independently -CH3, -CH2CH3, or -CH(CH3)2.

[0155] In one embodiment, the compounds of the present invention are 4 is one or more independently selected -NR 9a R 9b one or more independently selected C substituted with 1-4 Alkyl-substituted C 3-7 cycloalkyl, and R 9a and R 9b is according to any one of Formulas I-IVp, wherein R 9a and R 9b and R are both H. In another particular embodiment, R 9a and R 9b One of the groups is H and the other is C 1-4 In yet another particular embodiment, R 9a and R 9b Both are C 1-4 In a more particular embodiment, R 9a and R 9b is H and the other is -CH, -CHCH, or -CH(CH). In another more particular embodiment, R 9a and R 9b are independently -CH3, -CH2CH3, or -CH(CH3)2.

[0156] In one embodiment, the compounds of the present invention are 4is a 5-6 membered monocyclic heterocycloalkyl containing 1 or 2 N atoms fused to a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In certain embodiments, R 4 is pyrrolidinyl, piperidinyl, or piperazinyl, each fused to a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In another particular embodiment, R 4 is a 5-6 membered monocyclic heterocycloalkyl containing 1 or 2 N atoms fused to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine. 4 is pyrrolidinyl, piperidinyl, or piperazinyl, each fused to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine. 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.

[0157] In one embodiment, the compounds of the present invention are 4 is a 5-6 membered monocyclic heterocycloalkyl containing 1 or 2 N atoms fused to a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is selected from one or more independently selected C 1-4In certain embodiments, R is a heterocycloalkyl substituted with alkyl. 4 is pyrrolidinyl, piperidinyl, or piperazinyl, each fused to a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is selected from one or more independently selected C 1-4 In another particular embodiment, R 4 is a 5-6 membered monocyclic heterocycloalkyl containing 1 or 2 N atoms fused to a pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine, each of which is substituted with 1, 2, or 3 independently selected -CH, -CHCH, or -CH(CH). 4 is pyrrolidinyl, piperidinyl, or piperazinyl, each fused to a pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, pyridine, pyrazine, pyridazine, or pyrimidine, each substituted with one, two, or three independently selected -CH, -CHCH, or -CH(CH). 4 is a piperidinyl fused to an imidazole substituted with one -CH3.

[0158] In one embodiment, the compounds of the present invention are 4 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In certain embodiments, R 4is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. 4 is thiazolyl, oxazolyl, pyridinyl, pyridazinyl, or pyrimidinyl.

[0159] In one embodiment, the compounds of the present invention are 4 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected C 1-4 Alkyl or C 3-7 According to any one of Formulas I-IVp, said heteroaryl is substituted with cycloalkyl. 4 is one or more independently selected C 1-4 Alkyl or C 3-7 In another particular embodiment, R is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with cycloalkyl. 4 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 1, 2, or 3 independently selected C 1-4 Alkyl or C 3-7 In yet another particular embodiment, R 4 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, substituted with one or more independently selected -CH, -CHCH, -CH(CH), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 4 is one or more independently selected C 1-4Alkyl or C 3-7 In another more particular embodiment, R is imidazolyl, pyrazolyl, triazolyl, thiazolyl, or oxadiazolyl, each of which is substituted with cycloalkyl. 4 is one, two, or three independently selected C 1-4 Alkyl or C 3-7 In an even more particular embodiment, R is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with cycloalkyl. 4 is one, two, or three independently selected C 1-4 Alkyl or C 3-7 In another even more particular embodiment, R is imidazolyl, pyrazolyl, triazolyl, thiazolyl, or oxadiazolyl, each substituted with cycloalkyl. 4 is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each substituted with one, two, or three independently selected -CH, -CHCH, -CH(CH), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 4 is imidazolyl, pyrazolyl, triazolyl, thiazolyl, or oxadiazolyl, each substituted with one or two independently selected -CH3, -CH2CH3, -CH(CH3)2, or cyclopropyl.

[0160] In one embodiment, the compounds of the present invention are 4 is a 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In certain embodiments, R 4is 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 nyl, 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 thia-5-azabicyclo[2.2.1]heptanyl, 3-thia-6-azabicyclo[3.2.1]octanyl, 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[3.2.1]octanyl cyclo[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 more particular embodiments, R. 4are 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.

[0161] In one embodiment, the compounds of the present invention are 4 is a 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected R 10 In certain embodiments, R 4 is one or more independently selected R 10Azetidinyl, 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- A-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 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 Zaspiro[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.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-oxo 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 another particular embodiment, R. 4 is a 4-11 membered monocyclic or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and 1, 2, or 3 independently selected R 10 In a more particular embodiment, R 4 is one or more independently selected R 10In another more particular embodiment, R 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 4 is one, two, or three independently selected R 10Azetidinyl, 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- A-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 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 Zaspiro[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.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-oxo 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 most particular embodiment, R. 4 is one, two, or three independently selected R 10 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

[0162] In one embodiment, the compounds of the present invention are 4is a 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected R 10 and R 10 is according to any one of Formulas I-IVp, wherein R 10 is -OH, phenyl, =NH, halo, oxo, -CN, -C(=O)H, -C(=O)NH2, -C(=O)OH, -NR 14a R 14b , one or more independently selected halo, —CN, —OH, —C(═O)—C 1-4 Alkoxy or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, C 3-7 cycloalkyl, 4-6 membered monocyclic heterocycloalkyl containing 1, 2, or 3 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 In a more particular embodiment, R 10 are -OH, phenyl, =NH, F, Cl, Br, oxo, -CN, -C(=O)H, -C(=O)NH2, -C(=O)OH, -NR 14a R 14b, -CH3, -CH2CH3, -CH(CH3)2, -CHF2, -CF3, -CH2-CHF2, -CH2-CF3, -CH2-CN, -CH2-CH2-CN, -CH(CH3)-CN, -C(CH3)2-CN, -CH(CH3)-C H2-CN, -CH2-C(CH3)2-CN, -CH2-OH, -CH2-CH2-OH, -CH(CH3)-OH, -C(CH3)2-OH, -CH(CH3)-CH2-OH, -CH2-C(CH3)2-OH, -CH2-C(=O) -O-CH3, -CH2-C(=O)-O-CH2-CH3, -CH2-CH2-C(=O)-O-CH3, -CH2-CH2-C(=O)-O-CH2-CH3, -CH(CH3)-C(=O)-O-CH3, -CH(CH3)-C(=O )-O-CH2-CH3, -C(CH3)2-C(=O)-O-CH3, -C(CH3)2-C(=O)-O-CH2-CH3, -CH(CH3)-CH2-C(=O)-O-CH3, -CH(CH3)-CH2-C(=O)-O-CH2- CH3, -CH2-CH(CH3)-C(=O)-O-CH3, -CH2-CH(CH3)-C(=O)-O-CH2-CH3, -CH2-C(CH3)2-C(=O)-O-CH3, -CH2-C(CH3)2-C(=O)-O-CH2-CH3, -CH2-O-CH3, -CH2CH2-O-CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene nyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH(CH3), -S(=O)2-CH3, -S(=O)2-CH2CH3, -S(=O)2-CH(CH3), -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3), or -C(=O)-OC(CH3). In a most particular embodiment, R 10 -OH, phenyl, =NH, F, oxo, -CN, -C(=O)H, -NR 14a R 14b, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2-CHF2, -CH2-CF3, -CH2-CN, -CH2-CH2-CN, -CH2-OH, -CH2-CH2-OH, -CH2-C(CH3)2-OH, -CH2-C(=O)-O-CH2-CH3, -CH2-O-CH3, cyclopropyl, oxetanyl, -C(=O)-CH3, -S(=O)2-CH3, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, or -C(=O)-OC(CH3)3.

[0163] In one embodiment, the compounds of the present invention are 4 is a 4-11 membered monocyclic, spirocyclic, or bridged polycyclic heterocycloalkyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and one or more independently selected R 10 and R 10 But, -NR 14a R 14b and R 14a and R 14b is according to any one of Formulas I-IVp, wherein R 14a and R 14b and R are both H. In another particular embodiment, R 14a and R 14b One of the groups is H and the other is C 1-4 Alkyl or -S(=O)2-C 1-4 In yet another particular embodiment, R 14a and R 14b are independent, C 1-4 Alkyl or -S(=O)2-C 1-4 In a more particular embodiment, R 14a and R 14b is H and the other is -CH, -CHCH, -CH(CH), or -S(=O)-CH. 14a and R 14b are independently -CH3, -CH2CH3, -CH(CH3)2, or -S(=O)2-CH3.

[0164] In one embodiment, the compounds of the present invention are 4 But, -NR 11a R 11b and R 11a and R 11b is according to any one of Formulas I-IVp, wherein R 11a is H. In another particular embodiment, R 11a is one or more independently selected halo, —OH, —CN, or C 1-4 C optionally substituted with alkoxy 1-4 In a more particular embodiment, R 11a is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CHF2. In a most particular embodiment, R 11a is -CH3.

[0165] In one embodiment, the compounds of the present invention are 4 But, -NR 11a R 11b and R 11a is as already mentioned, and R 11b is H or phenyl. In a most particular embodiment, R 4 is -NH2.

[0166] In one embodiment, the compounds of the present invention are 4 But, -NR 11a R 11b and R 11a is as already mentioned, and R 11b But C 1-4 In certain embodiments, R is an alkyl group according to any one of Formulas I-IVp. 11b is -CH3, -CH2CH3, or -CH(CH3)2. In more particular embodiments, R 4is -NH-CH3, -N(CH3)2, -NH-CH2CH3, -N(CH2CH3)2, -N(CH(CH3)2)2, or -N(CH3)-CH2CHF2.

[0167] In one embodiment, the compounds of the present invention are 4 But, -NR 11a R 11b and R 11a is as already mentioned, and R 11b is one or more independently selected halo, —OH, —CN, or C 1-4 Alkoxy-substituted C 1-4 In certain embodiments, R is an alkyl group according to any one of Formulas I-IVp. 11b is one or more independently selected halo, —OH, —CN, or C 1-4 In another particular embodiment, R is -CH, -CHCH, or -CH(CH), each of which is substituted with alkoxy. 11b is one, two, or three independently selected halo, -OH, -CN, or C 1-4 Alkoxy-substituted C 1-4 In yet another particular embodiment, R 11b is a C substituted with one or more independently selected halo, —OH, —CN, —O—CH, —O—CHCH, or —O—CH(CH) 1-4 In a more particular embodiment, R 11b is —CH or —CHCH, each substituted with one F, —OH, —CN, or —O—CH. In a most particular embodiment, R 11b is -CH2-CN, -CH2CH2-OH, or -CH2CH2-O-CH3.

[0168] In one embodiment, the compounds of the present invention are 4 But, -NR 11a R 11b and R 11a is as already mentioned, and R 11b But C 3-7In certain embodiments, R is cycloalkyl. 11b is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a more particular embodiment, R 11b is cyclopropyl.

[0169] In one embodiment, the compounds of the present invention are 4 But, -NR 11a R 11b and R 11a is as already mentioned, and R 11b But -C(=O)-C 1-4 In certain embodiments, R is alkoxy. 11b is —C(═O)—O—CH, —C(═O)—O—CHCH, or —C(═O)—O—CH(CH). In more particular embodiments, R 11b is -C(=O)-O-CH3.

[0170] In one embodiment, the compounds of the present invention are 4 But, -NR 11a R 11b and R 11a is as already mentioned, and R 11b But -C(=O)-C 1-4 In certain embodiments, R is an alkyl group according to any one of Formulas I-IVp. 11b is —C(═O)—CH, —C(═O)—CHCH, or —C(═O)—CH(CH). In more particular embodiments, R 11b is -C(=O)-CH3.

[0171] In one embodiment, the compounds of the present invention are 4 But, -NR 11a R 11b and R 11a is as already mentioned, and R 11b is substituted with one or more independently selected halo; 1-4In certain embodiments, R is an alkyl group according to any one of Formulas I-IVp. 11b is —C(═O)—CH, —C(═O)—CHCH, or —C(═O)—CH(CH), each substituted with 1, 2, or 3 F, Cl, or Br. 11b is —C(═O)—CH 3 substituted with 1, 2, or 3 F. In a most particular embodiment, R 11b is -C(=O)-CHF2.

[0172] In one embodiment, the compounds of the present invention are 4 But, -NR 11a R 11b and R 11a is as already mentioned, and R 11b is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In certain embodiments, R 11b is pyrrolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, furazanyl, thiadiazolyl, oxadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl. 11b is pyridinyl, pyridazinyl, or pyrimidinyl.

[0173] In one embodiment, the compounds of the present invention are 4 But -C(=O)-C 1-4 In certain embodiments, R is alkoxy. 4 is —C(═O)—O—CH, —C(═O)—O—CHCH, or —C(═O)—O—CH(CH). In more particular embodiments, R 4 is -C(=O)-O-CH2CH3.

[0174] In one embodiment, the compounds of the present invention are 4 -C(=O)-NR 12a R 12b and each R 12a and R 12b is according to any one of Formulas I-IVp, wherein R 12a and R 12b and R are both H. In another particular embodiment, R 12a and R 12b One of the groups is H and the other is C 1-4 In yet another particular embodiment, R 12a and R 12b Both are C 1-4 In a more particular embodiment, R 12a and R 12b is H and the other is -CH, -CHCH, or -CH(CH). In another more particular embodiment, each R 12a and R 12b is independently -CH3, -CH2CH3, or -CH(CH3)2. In a most particular embodiment, R 12a and R 12b is -CH3.

[0175] In one embodiment, the compounds of the invention are: 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 according to formula I.

[0176] In one embodiment, the compounds of the invention are: 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 according to formula I.

[0177] 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.

[0178] 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.

[0179] In one embodiment, the compounds of the invention are not isotopic variations.

[0180] In one aspect, the compound of the invention according to any one of the embodiments described herein is present as the free base.

[0181] In one aspect, the compounds of the invention according to any one of the embodiments described herein are pharmaceutically acceptable salts.

[0182] In one aspect, a compound of the invention according to any one of the embodiments described herein is a solvate of said compound.

[0183] In one aspect, a compound of the invention according to any one of the embodiments described herein is a solvate of a pharmaceutically acceptable salt of the compound.

[0184] Although the specified groups for each embodiment have generally been listed individually above, the compounds of the present invention include compounds in which any or each embodiment in the above formula, and other formulas presented herein, is selected from one or more of the particular members or groups respectively specified for each variable. Thus, the present invention is intended to include within its scope all combinations of such embodiments.

[0185] Although the specified groups for each embodiment have generally been listed individually above, compounds of the invention can have one or more variables (e.g., R groups) selected from one or more embodiments according to any of the formula(s) listed above. Thus, the invention is intended to include within its scope all combinations of variables from any of the disclosed embodiments.

[0186] Alternatively, the elimination of one or more of the specified variables from any group or any embodiment, or combinations thereof, is also contemplated by the present invention.

[0187] In some embodiments, the present invention provides prodrugs and derivatives of the compounds according to the formula above. Prodrugs are derivatives of the compounds of the present invention that have metabolically cleavable groups and that, by solvolysis or under physiological conditions, become pharmaceutically active compounds of the present invention in vivo. Examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like.

[0188] Although other derivatives of the compounds of the present invention are active in both their acid and acid-derivative forms, the acid-labile forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard, 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid with a substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups on the compounds of the present invention are preferred prodrugs. In some cases, it may be desirable to prepare double ester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly useful are C1-C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the present invention.

[0189] (Pharmaceutical composition) When used as a medicine, the compound of the present invention is usually administered in the form of a pharmaceutical composition.Such a composition can be prepared in a manner well known in the pharmaceutical field and can comprise at least one active compound of the present invention according to formula I.Usually, the compound of the present invention is administered in a pharmaceutically effective amount.The amount of the compound of the present invention that is actually administered is usually determined by a physician, taking into account the relevant circumstances, including the condition to be treated, the selected administration route, the actual compound of the present invention that is administered, the age, weight and response of each individual patient, the severity of the patient's symptoms, etc.

[0190] The pharmaceutical compositions of the present invention can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intraarticular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds of the present invention are preferably formulated either as injectable or oral compositions, or as ointments, lotions, or patches, all for transdermal administration.

[0191] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle, or carrier. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like for solid compositions. In such compositions, the compound of the present invention according to Formula I is usually the minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids useful for forming the desired dosage form.

[0192] Liquid forms suitable for oral administration can include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms can include, for example, any of the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrant such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint or orange flavoring, or a compound of the invention of a similar nature.

[0193] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As noted above, the active compound of the invention according to Formula I in such compositions is typically the minor component, often about 0.05-10% by weight, with the remainder being the injectable carrier and the like.

[0194] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient in an amount generally 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 ingredient is typically combined with either a paraffinic ointment base or a water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include additional ingredients that enhance skin permeability or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are within the scope of the present invention.

[0195] The compounds of this 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.

[0196] The above ingredients for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are described in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0197] The compounds of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences (Remington, 1985).

[0198] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared according to the present invention, but the present invention is not limited to the following pharmaceutical compositions.

[0199] (Formulation 1 - Tablets) A compound of the invention according to Formula I can be mixed as a dry powder with a dry gelatin binder in about a 1:2 weight ratio. A trace amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 240-270 mg tablets (80-90 mg of an active compound of the invention according to Formula I per tablet) in a tablet press.

[0200] (Formulation 2 - Capsules) A compound of the invention according to Formula I can be mixed as a dry powder with a starch diluent in about a 1:1 weight ratio, and the mixture can be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).

[0201] (Formulation 3 - Liquid) A compound of the invention according to Formula I (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended and passed through a No. 10 mesh US sieve, then mixed with a pre-prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color can be diluted with water and added with stirring. Sufficient water can then be added with stirring. Sufficient water can then be added to produce a total volume of 5 mL.

[0202] (Formulation 4 - Tablets) A compound of the invention according to Formula I can be mixed as a dry powder with a dry gelatin binder in about a 1:2 weight ratio. A trace amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 450-900 mg tablets (150-300 mg of the active compound of the invention according to Formula I) in a tablet press.

[0203] (Formulation 5 - Injection) The compounds of the invention according to Formula I can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg / mL.

[0204] (Formulation 6 - Topical) Stearyl alcohol (250 g) and white petrolatum (250 g) can be melted at about 75° C., after which 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) can be added, and the resulting mixture can be stirred until solidified.

[0205] (Treatment Methods) In one embodiment, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in medicine.

[0206] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of inflammatory diseases.In particular, the term inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g., asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis).More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis).

[0207] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of an inflammatory disease. In particular, the term inflammatory disease refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g., asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).

[0208] In a further method of therapeutic aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from an inflammatory disease, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term inflammatory disease refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g., asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).

[0209] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for inflammatory diseases. In particular, the term inflammatory disease refers to rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g., asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis). More particularly, the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis).

[0210] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of an autoinflammatory disease. In particular, the term autoinflammatory disease refers to cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS, and Still's disease.

[0211] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of an autoinflammatory disease. In particular, the term autoinflammatory disease refers to cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS, and Still's disease.

[0212] In a further method of treatment aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from an autoinflammatory disease, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term autoinflammatory disease refers to cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS, and Still's disease.

[0213] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for an autoinflammatory disease. In particular, the term autoinflammatory disease refers to cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndromes (TRAPS), Behcet's disease, systemic juvenile idiopathic arthritis (SJIA), or Still's disease. More particularly, the term refers to CAPS, FMF, TRAPS, and Still's disease.

[0214] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of autoimmune disease.In particular, the term autoimmune disease refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis.More particularly, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease.

[0215] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a drug for the prevention and / or treatment of autoimmune diseases. In particular, the term autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease.

[0216] In a further method of therapeutic application, the present invention provides a method for the prevention and / or treatment of a mammal suffering from an autoimmune disease, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term autoimmune disease refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjögren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease.

[0217] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for an autoimmune disease. In particular, the term autoimmune disease refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease.

[0218] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of a proliferative disease.In particular, the term proliferative disease refers to cancer, myeloproliferative disorder, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis.More particularly, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0219] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of a proliferative disease. In particular, the term proliferative disease refers to cancer, myeloproliferative disorder, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0220] In a further method of therapeutic aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a proliferative disease, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term proliferative disease refers to cancer, myeloproliferative disorder, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0221] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for a proliferative disease. In particular, the term proliferative disease refers to cancer, myeloproliferative disorder, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma, and psoriasis.

[0222] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of a fibrotic disease. In particular, the term fibrotic disease refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and skin fibrosis.

[0223] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of a fibrotic disease. In particular, the term fibrotic disease refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and skin fibrosis.

[0224] In a further method of treatment aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a fibrotic disease, comprising administering an effective amount of a compound of the present invention or one or more of the pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term fibrotic disease refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and dermal fibrosis.

[0225] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for a fibrotic disease. In particular, the term fibrotic disease refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and skin fibrosis.

[0226] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of transplant rejection. In particular, the term transplant rejection refers to acute or chronic rejection of allogeneic or xenogeneic transplants of cells, tissues, or solid organs, such as pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, nervous tissue, heart, lung, combined heart-lung, kidney, liver, intestine, pancreas, trachea, or esophagus, or graft-versus-host disease. More particularly, the term refers to graft-versus-host disease.

[0227] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the production of a medicament for the prevention and / or treatment of transplant rejection. In particular, the term transplant rejection refers to acute or chronic rejection of an allogeneic or xenogeneic transplant of cells, tissues, or solid organs, such as pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, nervous tissue, heart, lung, combined heart-lung, kidney, liver, intestine, pancreas, trachea, or esophagus, or graft-versus-host disease. More particularly, the term refers to graft-versus-host disease.

[0228] In a further method of therapeutic aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from transplant rejection, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term transplant rejection refers to acute or chronic rejection of allogeneic or xenogeneic transplants of cells, tissues, or solid organs, such as pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, nervous tissue, heart, lung, combined heart-lung, kidney, liver, intestine, pancreas, trachea, or esophagus, or graft-versus-host disease. More particularly, the term refers to graft-versus-host disease.

[0229] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for transplant rejection. In particular, the term transplant rejection refers to acute or chronic rejection of allogeneic or xenogeneic transplants of cells, tissues, or solid organs, such as pancreatic islets, stem cells, bone marrow, skin, muscle, corneal tissue, nervous tissue, heart, lung, combined cardiopulmonary, kidney, liver, intestine, pancreas, trachea, or esophagus, or graft-versus-host disease. More particularly, the term refers to graft-versus-host disease.

[0230] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of diseases associated with impaired cartilage turnover.In particular, the term "diseases associated with impaired cartilage turnover" refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful osteodystrophy, Tietze's syndrome or costochondritis, fibromyalgia, osteochondritis, neuropathic or neuropathic arthritis, arthropathy, endemic forms of arthritis such as endemic osteoarthritis, Musereni's disease and Handigodu's disease; degeneration caused by 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.

[0231] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the production of a drug for the prevention and / or treatment of a disease associated with impaired cartilage turnover. In particular, the term disease associated with impaired cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful osteodystrophy, Tietze's syndrome or costochondritis, fibromyalgia, osteochondritis, neurological or neuropathic arthritis, arthropathy, endemic forms of arthritis such as endemic osteoarthritis, Musereni's disease and Handigodu's disease; degeneration caused by 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.

[0232] In a further method of treatment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a disease associated with impaired cartilage turnover, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term disease associated with impaired cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful osteodystrophy, Tietze's syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis such as endemic osteoarthritis, Musereni's disease and Handigodu's disease; degeneration caused by 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.

[0233] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for diseases associated with impaired cartilage turnover. In particular, the term diseases associated with impaired cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, painful osteodystrophy, Tietze's syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis such as endemic osteoarthritis, Musereni's disease and Handigodu's disease; degeneration caused by 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.

[0234] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of congenital cartilage malformations. In particular, the term congenital cartilage malformations refers to hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia, microtia, anotia, and metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, and metaphyseal chondrodysplasia.

[0235] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of congenital cartilage malformations. In particular, the term congenital cartilage malformations refers to hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia, microtia, anotia, and metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, and metaphyseal chondrodysplasia.

[0236] In a further method of treatment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a congenital cartilage malformation, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia, microtia, anotia, and metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, and metaphyseal chondrodysplasia.

[0237] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for congenital cartilage malformation. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasia, and pseudochondrodysplasia, microtia, anotia, and metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, and metaphyseal chondrodysplasia.

[0238] In one embodiment, the present invention provides the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in the prevention and / or treatment of diseases associated with bone turnover disorder.In particular, the term disease associated with bone turnover disorder refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta and hypophosphatasia.More particularly, the term refers to osteoporosis.

[0239] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a drug for the prevention and / or treatment of a disease associated with a bone turnover disorder. In particular, the term disease associated with a bone turnover disorder refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0240] In a further method of therapeutic aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a disease associated with impaired bone turnover, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term disease associated with impaired bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0241] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for diseases associated with bone turnover disorders. In particular, the term diseases associated with bone turnover disorders refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0242] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of a disease associated with hypersecretion of IL-6. In particular, the term disease associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma, and / or mesangial proliferative glomerulonephritis.

[0243] In another embodiment, the present invention provides use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the production of a medicament for the prevention and / or treatment of a disease associated with hypersecretion of IL-6. In particular, the term disease associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma, and / or mesangial proliferative glomerulonephritis.

[0244] In a further method of therapeutic aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a disease associated with hypersecretion of IL-6, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term disease associated with hypersecretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma, and / or mesangial proliferative glomerulonephritis.

[0245] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for a disease associated with excessive secretion of IL-6. In particular, the term disease associated with excessive secretion of IL-6 refers to Castleman's disease, multiple myeloma, psoriasis, Kaposi's sarcoma, and / or mesangial proliferative glomerulonephritis.

[0246] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of a disease associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23. In particular, the term disease associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease. More particularly, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0247] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the production of a medicament for the prevention and / or treatment of a disease associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23. In particular, the term disease associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease. More particularly, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0248] In a further method of therapeutic aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a disease associated with hypersecretion of TNFα, interferon, IL-12, and / or IL-23, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term disease associated with hypersecretion of TNFα, interferon, IL-12, and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease. More particularly, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0249] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for a disease associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23. In particular, the term disease associated with excessive secretion of TNFα, interferon, IL-12, and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease. More particularly, the term refers to Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, and / or Crohn's disease.

[0250] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention 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 pulmonary fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial pulmonary fibrosis.

[0251] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of a respiratory disease. In particular, the term respiratory disease 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 pulmonary fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial pulmonary fibrosis.

[0252] In a further method of therapeutic application, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a respiratory disease, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term respiratory disease 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 pulmonary fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial pulmonary fibrosis.

[0253] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for a respiratory disease. In particular, the term respiratory disease 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 pulmonary fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial pulmonary fibrosis.

[0254] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of endocrine and / or metabolic disorders.In particular, the term endocrine and / or metabolic disorders refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid disorders, diabetes, adrenal disorders, Cushing's syndrome and Addison's disease, ovarian dysfunction, and polycystic ovarian syndrome, as well as cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.More particularly, the term refers to obesity and / or type II diabetes.

[0255] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the production of a medicament for the prevention and / or treatment of an endocrine and / or metabolic disorder. In particular, the term endocrine and / or metabolic disorder refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid diseases, diabetes, adrenal gland diseases, Cushing's syndrome and Addison's disease, ovarian dysfunction, and polycystic ovary syndrome, as well as cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. More particularly, the term refers to obesity and / or type II diabetes.

[0256] In a further method of therapeutic application, the present invention provides a method for the prevention and / or treatment of a mammal suffering from an endocrine and / or metabolic disorder, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term endocrine and / or metabolic disorder refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid disorders, diabetes, adrenal gland disorders, Cushing's syndrome and Addison's disease, 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.

[0257] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for an endocrine and / or metabolic disorder. In particular, the term endocrine and / or metabolic disorder refers to hypothyroidism, congenital adrenal hyperplasia, parathyroid diseases, diabetes, adrenal gland diseases, Cushing's syndrome and Addison's disease, 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.

[0258] In one embodiment, the present invention provides the compound of the present invention or the pharmaceutical composition comprising the compound of the present invention for use in the prevention and / or treatment of cardiovascular disease.In particular, the term cardiovascular disease refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disorders; myocardial ischemia; myocardial infarction; heart or vascular aneurysm; vasculitis, stroke; peripheral occlusive arteriopathy of limbs, organs, tissues; post-ischemic reperfusion injury of the brain, heart, kidney, or other organs or tissues; endotoxin, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including those related to migraine); vascular abnormalities, inflammation, or dysfunction limited to a single organ or tissue.More particularly, the term refers to atherosclerosis or giant cell arteritis.

[0259] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a drug for the prevention and / or treatment of cardiovascular disease.In particular, the term cardiovascular disease refers to arrhythmia (atrial or ventricular, or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disorders; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral occlusive arteriopathy of the limbs, organs, or tissues; post-ischemic reperfusion injury of the brain, heart, kidney, or other organs or tissues; endotoxin, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraine); vascular abnormalities, inflammation, or dysfunction limited to a single organ or tissue.More particularly, the term refers to atherosclerosis or giant cell arteritis.

[0260] In a further method of therapeutic aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from cardiovascular disease, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term cardiovascular disease refers to arrhythmias (atrial or ventricular, or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disorders; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral occlusive arteriopathy of the limbs, organs, or tissues; post-ischemic reperfusion injury of the brain, heart, kidney, or other organs or tissues; endotoxin, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraine); vascular abnormalities, inflammation, or dysfunction limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.

[0261] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for cardiovascular disease. In particular, the term cardiovascular disease refers to arrhythmia (atrial or ventricular, or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disorders; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral occlusive arteriopathy of the limbs, organs, or tissues; post-ischemic reperfusion injury of the brain, heart, kidney, or other organs or tissues; endotoxin, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraine); vascular abnormalities, inflammation, or dysfunction limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.

[0262] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of skin diseases. In particular, the term skin disease refers to atopic dermatitis, bullous disorders, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria.

[0263] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of a skin disease. In particular, the term skin disease refers to atopic dermatitis, bullous disorders, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria.

[0264] In a further method of treatment, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a skin disease, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term skin disease refers to atopic dermatitis, bullous disorders, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria.

[0265] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for a skin disease. In particular, the term "skin disease" refers to atopic dermatitis, bullous disorders, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome, or urticaria. More particularly, the term refers to atopic dermatitis, scleroderma, Sjögren-Larsson syndrome, vitiligo, or urticaria.

[0266] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of abnormal angiogenesis-related diseases. In particular, the term abnormal angiogenesis-related diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0267] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of a disease associated with abnormal angiogenesis. In particular, the term disease associated with abnormal angiogenesis refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0268] In a further method of treatment aspect, the present invention provides a method for the prevention and / or treatment of a mammal suffering from a disease associated with abnormal angiogenesis, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of the disease. In particular, the term disease associated with abnormal angiogenesis refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0269] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for a disease associated with abnormal angiogenesis. In particular, the term disease associated with abnormal angiogenesis refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0270] Injection dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all for about 1 to about 120 hours, and particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve adequate steady-state levels. The maximum total dose is expected to not exceed about 1 g / day for a 40-80 kg human patient.

[0271] Treatment regimens for the prevention and / or treatment of long-term conditions, such as degenerative conditions, typically span several months or years, and therefore oral administration is preferred for patient convenience and tolerability. For oral administration, typical regimens include one to four (1-4) doses per day, particularly one to three (1-3) doses per day, typically one to two (1-2) doses per day, and most typically one (1) dose per day. Alternatively, for long-acting drugs, typical oral regimens include once every two weeks, once a week, and once a day. Specifically, the dosing regimen can be every 1 to 14 days, more specifically every 1 to 10 days, even more specifically every 1 to 7 days, and most specifically every 1 to 3 days.

[0272] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with specific doses each providing from about 10 to about 500 mg, and more particularly from about 30 to about 250 mg.

[0273] Transdermal doses are typically selected to provide blood levels similar to or lower than those achieved with injection doses.

[0274] When used to prevent the onset of a condition, the compounds of the invention would be administered at the dosage levels described above to patients at risk of developing the condition, typically under the advice and supervision of a physician. Patients at risk of developing a particular condition usually include those who have a family history of the condition or who have been identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0275] The compounds of the invention can be administered as the sole active agent, or they can be administered in combination with another therapeutic agent, including other compounds of the invention that exhibit the same or similar therapeutic activity and that have been shown to be safe and effective for such combined administration. In specific embodiments, coadministration of two (or more) agents allows for the use of significantly lower doses of each, thereby reducing observed side effects.

[0276] In one embodiment, the compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament, hi a specific embodiment, the pharmaceutical composition further comprises an additional active ingredient.

[0277] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of a disease involving inflammation, including, but not limited to, immunomodulators such as azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g., Orthoclone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0278] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of arthritis (e.g., rheumatoid arthritis), including, but not limited to, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, synthetic DMARDs (e.g., but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, gold sodium thiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporine), and biologic DMARDs (e.g., but not limited to, infliximab, etanercept, adalimumab, rituximab, and abatacept).

[0279] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of a proliferative disorder, specific 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 antibodies (e.g., Herceptin®), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g., Iressa®, Tarceva®, Erbitux®), VEGF inhibitors (e.g., Avastin®), proteasome inhibitors (e.g., Velcade®), Gleevec®, and hsp90 inhibitors (e.g., 17-AAG). Additionally, the compounds of the invention according to Formula I can be administered in combination with other therapies, including, but not limited to, radiation therapy or surgery. In specific embodiments, the proliferative disorder is selected from cancer, a myeloproliferative disorder, or leukemia.

[0280] In one embodiment, the compounds of the invention are co-administered with other therapeutic agents for the treatment and / or prevention of autoimmune diseases, including, but not limited to, glucocorticoids, cytostatic agents (e.g., purine analogs), alkylating agents (e.g., nitrogen mustard (cyclophosphamide), nitrosoureas, platinum compounds of the invention, and others), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., dactinomycin, azathioprine, and mercaptopurine), and the like. anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobulin®), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (e.g., IFN-β), TNF-binding proteins (e.g., infliximab, etanercept, or adalimumab), mycophenolate, fingolimod, and myriocin.

[0281] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of transplant rejection, including, but not limited to, calcineurin inhibitors (e.g., cyclosporine or tacrolimus (FK506)), mTOR inhibitors (e.g., sirolimus, everolimus), antiproliferative agents (e.g., azathioprine, mycophenolic acid), corticosteroids (e.g., prednisolone, hydrocortisone), antibodies (e.g., monoclonal anti-IL-2Rα receptor antibodies, basiliximab, daclizumab), polyclonal anti-T cell antibodies (e.g., antithymocyte globulin (ATG), antilymphocyte globulin (ALG)).

[0282] In one embodiment, the compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of asthma and / or rhinitis and / or COPD, including, but not limited to, β2-adrenergic receptor agonists (e.g., salbutamol, levalbuterol, terbutaline, and bitolterol), epinephrine (inhaled or tablet), anticholinergics (e.g., ipratropium bromide), glucocorticoids (oral or inhaled), long-acting β2-agonists (e.g., salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), and / or other therapeutic agents for the treatment and / or prevention of asthma and / or rhinitis and / or COPD. These include inhaled steroids and long-acting bronchodilator combinations (e.g., fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists and synthesis inhibitors (e.g., montelukast, zafirlukast, and zileuton), mediator release inhibitors (e.g., cromoglycate and ketotifen), biomodulators of IgE responses (e.g., omalizumab), antihistamines (e.g., cetirizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g., oxymetazoline, xylometazoline, naphazoline, and tramazoline).

[0283] Furthermore, the compounds of the invention may be administered in combination with acute treatments for asthma and / or COPD, including oxygen or heliox administration, nebulized salbutamol or terbutaline, optionally combined with an anticholinergic, such as ipratropium, systemic steroids (oral or intravenous, e.g., prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, nonspecific β-agonists, injected or inhaled (e.g., epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (injected or nebulized, e.g., glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, amifylline), inhaled anesthetics with bronchodilatory effects (e.g., isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

[0284] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of inflammatory bowel disease (IBD), including, but not limited to, glucocorticoids (e.g., prednisone, budesonide), synthetic disease-modifying immunomodulators (e.g., methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine, and cyclosporine), and biologic disease-modifying immunomodulators (infliximab, adalimumab, rituximab, and abatacept).

[0285] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of SLE, including, but 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, immunosuppressants 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 fentanyl-Duragesic transdermal patches.

[0286] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of psoriasis, including, but not limited to, topical treatments such as coal tar, dithranol (anthralin), corticosteroid-like desoximetasone (Topicort®), fluocinonide, vitamin D3 analogs (e.g., calcipotriol), argan oil, and baths, moisturizers, medicated creams and ointments containing retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, thioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumarates, or biologics such as Amebiv®, Enbrel®, Humira®, Remicade®, Raptiva®, and ustekinumab (an IL-12 and IL-23 blocker). Additionally, the compounds of the present invention may be administered in combination with other therapies, including, but not limited to, phototherapy or photochemotherapy (eg, psoralen and ultraviolet A therapy (PUVA)).

[0287] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of an allergic reaction, including, but not limited to, an antihistamine (e.g., cetirizine, diphenhydramine, fexofenadine, levocetirizine), a glucocorticoid (e.g., prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or antileukotriene (e.g., montelukast or zafirlukast), an anticholinergic agent, and a decongestant.

[0288] As will be apparent to one of skill in the art, co-administration encompasses any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen. The two or more agents can be administered simultaneously in a single formulation, i.e., in a single pharmaceutical composition, but this is not required. The agents can also be administered in different formulations and at different times.

[0289] (chemical synthesis method) (General) The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0290] 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 selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, is well known in the art (Wuts and Greene, 2006).

[0291] The following methods are presented in detail for the preparation of the compounds of the invention as defined hereinabove and comparative examples. The compounds of the invention can be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0292] All reagents are commercial grade and used as received without further purification unless otherwise noted. Commercially available anhydrous solvents are used for reactions conducted under an inert atmosphere. Unless otherwise specified, reagent grade solvents are used in all other cases. Column chromatography is performed on silica gel 60 (35-70 μm) or using Biotage® SNAP KP-NH, Biotage® SNAP Ultra, or Interchim® PuriFlash® Si HC flash chromatography cartridges. Thin-layer chromatography is performed using precoated silica gel F-254 plates (0.25 mm thick). Biotage® ISOLUTE® Phase Separators (e.g., catalog number 120-1907-E) are used for aqueous phase separation. 1 1 H NMR spectra are recorded on a Bruker DPX 400 NMR spectrometer (400 MHz) or a Bruker Avance 300 NMR spectrometer (300 MHz). 1Chemical shifts (δ) for H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) as an internal reference or to the appropriate residual solvent peak, i.e., CHCl (δ 7.27). Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), multiplet (m), and broad (br). Electrospray MS spectra were obtained on a Waters Acquity H-class UPLC system coupled to a UV PDA detector and a Waters SQD or SQD2 mass spectrometer. The columns used are: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID x 30 / 50 mm L; Waters Acquity UPLC CSH C18 1.7 μm, 2.1 mm ID x 50 / 100 mm L; Waters Acquity UPLC CSH PhenylHexyl 1.7 μm, 2.1 mm ID x 100 mm L; Waters Acquity UPLC HSS PFP 1.8 μm, 2.1 mm ID x 100 mm L. The method uses gradients of ACN / HO or MeOH / water with 0.1% formic acid in both mobile phases, 0.05% NH in both mobile phases, or 10 mM NHHCO in HO (adjusted to pH 10 with ammonia). Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using a Waters XBRIDGE BEH C18 OBD 30 mm ID x 100 / 150 mm L column and an ACN / HO gradient with 0.1% formic acid in both mobile phases, 0.1% diethylamine in both mobile phases, 0.1% formic acid in HO, or 10 mM NH4HCO3 in HO (adjusted to pH 10 with ammonia). Microwave heating is performed using a Biotage® Initiator. (Table I. List of abbreviations used in the experimental section:) [Table 1] TIFF0007621277000015.tif100170

[0293] (Synthetic Preparation of Compounds of the Invention) Example 1. Preparation of compounds of the present invention (1.1. Intermediate 1) [ka] In a microwave vial, add CsCO (471 mg, 1.44 mmol, 1.5 eq), allylpalladium(II) chloride dimer (CAS# 12012-95-2; 18 mg, 0.048 mmol, 0.05 eq), and RockPhos (CAS# 1262046-34-3; 69 mg, 0.14 mmol, 0.15 eq). Remove air from the vial and fill it with argon (x3). Add toluene (2 mL) and 2-morpholinoethanol (CAS# 622-40-2; 230 μL, 1.93 mmol, 2 eq) to the mixture and stir at 90 °C for 3 min. 6-Bromopyrazolo[1,5-a]pyridine (CAS# 1264193-11-4; 200 mg, 0.96 mmol, 1 equiv.) 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 material is purified by column chromatography on silica gel (eluting with 1-3% MeOH in DCM) to give Intermediate 1.

[0294] (1.2. Intermediate 2) [ka] To a solution of Intermediate 1 (62 mg, 0.25 mmol, 1.0 equiv.) in ACN (0.4 mL) was added N-iodosuccinimide (CAS# 516-12-1; 65.3 mg, 0.27 mmol, 1.1 equiv.). The mixture was stirred at RT for 1 h and then quenched with water. The solid product was filtered, rinsed with water, and dried in vacuo to give Intermediate 2.

[0295] (1.3. Intermediate 3) [ka] To a solution of intermediate 14 (500 mg, 1.5 mmol, 1.0 equiv.) in 1,4-dioxane (9 mL) degassed with N2 under N2 atmosphere, B2pin2 (CAS# 73183-34-3; 460 mg, 1.8 mmol, 1.2 equiv.), KOAc (430 mg, 4.4 mmol, 3 equiv.), and Pd(dppf)Cl2·DCM (CAS# 95464-05-4; 72 mg, 0.09 mmol, 0.06 equiv.) were added. The reaction mixture was stirred at 90 °C for 2 h, then filtered over Dicalite®, rinsed with EtOAc, and concentrated. The crude product was purified by flash chromatography on silica gel (eluting with 0–2% MeOH in DCM). The resulting residue was solubilized in heptane and MTBE was added (several mL). The precipitate is filtered and the filtrate is concentrated in vacuo to provide intermediate 3 as a mixture of the expected boronate and the corresponding boronic acid.

[0296] (1.4. Intermediate 4) [ka] To a solution of pyrazolo[1,5-a]pyridin-6-ol (CAS#184473-24-3; 200 mg, 1.49 mmol, 1.0 equiv.) in ACN (8.7 mL) at 0 °C under N atmosphere, add CsCO (729 mg, 2.24 mmol, 1.5 equiv.) and ethyl 2-bromoisobutyrate (CAS#600-00-0; 349 mg, 0.263 mL, 1.79 mmol, 1.2 equiv.). The reaction mixture is stirred at RT overnight. The reaction mixture is concentrated, and the crude material is purified by flash chromatography (eluting with 0–100% EtOAc in heptane) to give Intermediate 4.

[0297] (1.5. Intermediate 5) [ka] To a solution of intermediate 4 (0.18 g, 0.73 mmol, 1.0 equiv) in THF (7.3 mL) at 0 °C is added lithium aluminum hydride (1 M in THF; 1.11 mL, 1.11 mmol, 1.50 equiv). The reaction mixture is stirred at 0 °C for 30 min. The reaction mixture is quenched with water, filtered over 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 (x3). The combined organic layers are dried over MgSO4, filtered, and concentrated in vacuo to give intermediate 5.

[0298] (1.6. Intermediate 6) [ka] To a solution of intermediate 5 (50 mg, 0.23 mmol, 1.0 equiv.) in DMF (0.5 mL) is added N-iodosuccinimide (CAS# 516-12-1; 78 mg, 0.34 mmol, 1.5 equiv.). The reaction mixture is stirred at RT for 30 min, then concentrated, diluted with water, and extracted with DCM (×3). The combined organic layers are filtered over a phase separator and concentrated in vacuo to give intermediate 6.

[0299] (1.7. Intermediate 7) [ka] 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 equiv.) in DCM (300 mL), 1,1'-carbonyldiimidazole (CAS# 530-62-1; 49 g, 297 mmol, 1 equiv.) was added portionwise to release CO. Subsequently, (1R,2S)-2-fluorocyclopropanamine 4-methylbenzenesulfonate (CAS# 143062-84-4; 80 g, 312 mmol, 1.05 equiv.) and EtN (50 mL, 359 mmol, 1.21 equiv.) were added to the mixture. The resulting solution was stirred at RT for 2.5 h. Water was added and the pH was adjusted to 2 with 12 N HCl solution (60 mL). The organic layer was separated, and the aqueous layer was extracted twice with DCM. The combined organic layers are washed three times with saturated NaHCO3 solution, dried over Na2SO4, 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 give the desired intermediate.

[0300] 1.7.2. Step ii: 2-(Difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide To a three-necked round-bottom flask equipped with a temperature probe and addition funnel containing the above-prepared N-[(1R,2S)-2-fluorocyclopropyl]-2-hydroxy-6-methoxy-benzamide (29 g, 130 mmol, 1 equiv.) solution in a 5°C mixture of ACN / water (146 mL / 146 mL), potassium hydroxide (73 g, 1298 mmol, 10 equiv.) was added and allowed to stand for 1 h. Subsequently, neat bromodifluoromethyl diethylphosphonate (CAS# 65094-22-6; 46 mL, 260 mmol, 2 equiv.) was added dropwise over 40 min, maintaining the reaction temperature below 12°C. The reaction mixture was allowed to warm to RT and stirred at RT for 40 min. The reaction solution was then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was reslurried in MTBE (80 mL). The suspension is filtered and the solid is washed with MTBE (20 mL) and dried to give the desired intermediate.

[0301] (1.7.3. Step iii: Intermediate 7) To a solution of the above-prepared 2-(difluoromethoxy)-N-[(1R,2S)-2-fluorocyclopropyl]-6-methoxy-benzamide (22 g, 76 mmol, 1 equiv.) in THF (217 mL) was added B2pin2 (CAS# 73183-34-3; 25 g, 98 mmol, 1.3 equiv.), 4,4'-di-tert-butyl-2,2'-bipyridine (CAS# 72914-19-3; 829 mg, 3.0 mmol, 0.04 equiv.), and [Ir(OCH3)(COD)] (CAS# 12148-71-9; 1 g, 1.5 mmol, 0.02 equiv.) at room temperature under an inert atmosphere. The resulting mixture was heated at 70 °C for 2 h and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM / EtOAc 90 / 10). The collected fractions are concentrated to give a solid, which is then dissolved in a mixture of DCM / heptane (100 mL / 330 mL) and stirred for 15 minutes. The suspension is filtered; the solid is washed twice with heptane and dried in vacuo to give intermediate 7.

[0302] (1.8. Intermediate 8) [ka] To a solution of compound 2 (50 mg, 0.099 mmol, 1.0 equiv.) in dry DCM (5.0 mL) degassed with N2 at 0 °C in a round-bottom flask under N2 atmosphere, Dess-Martin periodinane (CAS# 87413-09-0; 51 mg, 0.12 mmol, 1.2 equiv.) is added. The reaction mixture is stirred at RT for 1 h. Dess-Martin periodinane (51 mg, 0.12 mmol, 1.2 equiv.) is added at 0 °C, and the reaction mixture is stirred at RT for 1 h. The reaction mixture is quenched with NaHCO3 and extracted with DCM (x2). The combined organic layers are separated using a phase separator and concentrated in vacuo to give intermediate 8. This product is used directly in the next step.

[0303] (1.9. Intermediate 9) [ka] In a vial, add Cs2CO3 (311.9 mg, 0.9572 mmol, 1.5 equiv.), allylpalladium(II) chloride dimer (CAS# 12012-95-2; 11.9 mg, 0.0317 mmol, 0.05 equiv.), and RockPhos (CAS# 1262046-34-3; 0.15 equiv., 0.095722 mmol, 0.045781 g). Evacuate the tube and backfill with argon (×3). Add toluene (0.5 mL) and 2-morpholinoethanol (CAS# 622-40-2; 156 μL, 1.27 mmol, 2 equiv.) to the mixture and stir at 90 °C for 3 min. 7-Chlorimidazo[1,2-b]pyridazine (CAS# 1383481-11-5; 100 mg, 0.638 mmol, 1 equiv.) and toluene (0.5 mL) are added to the mixture. The reaction mixture is heated at 100° C. for 2.5 hours, followed by heating 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 1-4% MeOH in DCM) to give intermediate 9.

[0304] (1.10. Intermediate 10) [ka] In a vial, add CsCO (0.479 g, 0.116 mL, 1.47 mmol, 1.50 equiv.), allylpalladium(II) chloride dimer (CAS# 12012-95-2; 18.3 mg, 0.0500 mmol, 0.05 equiv.), and RockPhos (CAS# 1262046-34-3; 70.3 mg, 0.147 mmol, 0.15 equiv.). 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 equiv.) are added to the mixture, which is then 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 hours. 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 give intermediate 10.

[0305] (1.11. Intermediate 11) [ka] To a solution of intermediate 9 (76 mg, 0.31 mmol, 1 equiv) in ACN (0.5 mL) is added N-iodosuccinimide (CAS# 516-12-1; 159.5 mg, 0.6734 mmol, 2.2 equiv). The mixture is stirred at 60 °C for 4 h. N-iodosuccinimide (79.7 mg, 0.337 mmol, 1.1 equiv) 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 and extracted with EtOAc (×3). The organic layer is concentrated, and the residue is purified by flash chromatography on silica gel (eluting with 1–4% MeOH in DCM) to give intermediate 11.

[0306] (1.12. Intermediate 12) [ka] To a solution of intermediate 10 (0.110 g, 0.434 mmol, 1.00 equiv.) in DMF (840 μL) is added N-iodosuccinimide (CAS# 516-12-1; 151 mg, 0.651 mmol, 1.50 equiv.). 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 over a phase separator and concentrated in vacuo. The residue is purified by flash chromatography (eluting with 0–10% MeOH in DCM) to give intermediate 12.

[0307] (1.13. Intermediate 13) [ka] To 6-bromo-8-fluoro-3,4-dihydro-2H-isoquinolin-1-one (CAS# 1242157-15-8; 3 g, 12.3 mmol, 1 equiv.) stirred in THF (30 mL) was added dropwise a solution of 25 wt.% MeONa in MeOH (3.35 mL, 14.75 mmol, 1.2 equiv.). The reaction mixture was stirred at RT for 2 h, quenched with saturated aqueous NH4Cl, and the THF was evaporated. The resulting solid in the remaining aqueous phase was filtered to give the desired intermediate 13.

[0308] (1.14. Intermediate 14) [ka] To a solution of intermediate 13 (10 g, 39.1 mmol, 1 equiv.) stirred in THF (240 mL) at 0 °C is added LiHMDS (1 N in THF, 59 mL, 58.6 mmol, 1.5 equiv.). The resulting mixture is stirred at 0 °C for 45 min, and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS# 6226-25-1; 8.44 mL, 58.6 mmol, 1.5 equiv.) is added dropwise at 0 °C. The reaction mixture is slowly warmed to RT and stirred at RT for 22 h. The reaction mixture is quenched with water and brine. The THF is evaporated, and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluting with 0-1% MeOH in DCM) to give intermediate 14.

[0309] (1.15. Compound 1) [ka] To a solution of intermediate 2 (57 mg, 0.15 mmol, 1 equiv.) in a 4 / 1 mixture of degassed 1,4-dioxane and water (1 mL) in a round-bottom flask under N2 atmosphere, intermediate 3 (70.6 mg, 0.183 mmol, 1.2 equiv.), Cs2CO3 (149.3 mg, 0.4582 mmol, 3.0 equiv.), and Pd(dppf)Cl2·DCM (12.47 mg, 0.01527 mmol, 0.1 equiv.) were added. The mixture was stirred at 90 °C for 1 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with 10–75% EtOAc in heptane). The product was triturated in MTBE and filtered. The product is re-purified by flash chromatography on a 5 g Biotage® Sfar High Capacity Duo cartridge (eluting with 0-100% EtOAc in heptane followed by 2-6% MeOH in DCM) to give compound 1.

[0310] (1.16. Compound 2) [ka] To a solution of intermediate 6 (0.075 g, 0.22 mmol, 1.0 equiv.) in a 4 / 1 mixture of 1,4-dioxane and water (1.75 mL) degassed with N in a sealed vial, intermediate 7 (0.11 g, 0.26 mmol, 1.2 equiv.), CsCO (0.22 g, 0.65 mmol, 3.0 equiv.), and Pd(dppf)Cl·DCM (CAS# 95464-05-4; 19 mg, 0.022 mmol, 0.10 equiv.) were added. The reaction mixture was stirred at 90 °C for 1 h, then cooled to RT and filtered over Dicalite®, rinsing with EtOAc. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with 0–100% EtOAc in heptane) to give compound 2.

[0311] (1.17. Compound 3) [ka] To a solution of Intermediate 8 from Example 1.8 in 1,2-dichloroethane (0.5 mL) was added morpholine (CAS# 110-91-8; 26 μL, 0.30 mmol, 3.0 equiv.) and titanium(IV) isopropoxide (CAS# 546-68-9; 45 μL, 0.15 mmol, 1.5 equiv.). The reaction mixture was stirred at 65° C. for 5 h. NaBH(OAc) (CAS# 56553-60-7; 65 mg, 0.30 mmol, 3.0 equiv.) was added, and the reaction mixture was stirred at 65° C. overnight. The reaction mixture was quenched with saturated NaHCO solution, then poured into 10 mL of water, stirred at RT for 1 h, filtered through a Dicalite® pad, and the filtrate was extracted with DCM (×3). The combined organic layers were dried over MgSO, 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, followed by elution 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 give compound 3.

[0312] (1.18. Compound 4) [ka] To a solution of intermediate 12 (0.105 g, 0.281 mmol, 1 equiv.) in a N2-degassed 4 / 1 1,4-dioxane / water mixture (1.6 mL) in a round-bottom flask under N2 atmosphere, intermediate 3 (0.130 g, 0.337 mmol, 1.20 equiv.), Cs2CO3 (0.277 g, 0.842 mmol, 3.0 equiv.), and Pd(dppf)Cl2·DCM (0.0234 g, 0.0281 mmol, 0.100 equiv.) were added. The reaction mixture was stirred at 90 °C for 1 h, then cooled to RT and filtered over Dicalite®, rinsing with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified twice by flash chromatography (eluting first with 0–10% MeOH in DCM, followed by 0–100% EtOAc in heptane) to give compound 4.

[0313] (1.19. Compound 5) [ka] To a solution of intermediate 11 (31 mg, 0.083 mmol) in a 4 / 1 mixture of degassed 1,4-dioxane and water (0.6 mL) in a round-bottom flask under N2 atmosphere, intermediate 3 (38.3 mg, 0.0994 mmol, 1.2 equiv.), Cs2CO3 (81.0 mg, 0.249 mmol, 3.0 equiv.), and Pd(dppf)Cl2·DCM (6.8 mg, 0.0083 mmol, 0.1 equiv.) were added. The mixture was stirred at 90 °C for 1 h. The mixture was quenched with 2 N NaOH and extracted with EtOAc (×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with 10–75% EtOAc in heptane). The appropriate fractions were collected and the solvent was concentrated in vacuo. After trituration of the residue in MTBE and filtration, the product is purified by flash chromatography on a 5 g Biotage® Sfar High Capacity Duo cartridge (eluting with 0-100% EtOAc in heptane followed by 2-6% MeOH in DCM) to give compound 5.

[0314] (1.20. Compound 6) [ka] To a solution of Intermediate 8 from Example 1.8 in 1,2-dichloroethane (0.52 mL) was added 2-oxa-6-azaspiro[3.3]heptane (CAS# 174-78-7; 31 mg, 0.31 mmol, 3 equiv.) and titanium isopropoxide (CAS# 546-68-9; 48 μL, 0.16 mmol, 1.5 equiv.). The resulting mixture was stirred at 65° C. for 3.5 hours. NaBH(OAc) (CAS# 56553-60-7; 68 mg, 0.31 mmol, 3 equiv.) was then added. The reaction mixture was stirred overnight at 65° C., quenched with saturated NaHCO solution, filtered through a Dicalite® pad, and the filtrate was extracted with DCM (×3). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude material is purified by flash chromatography on a Biotage® SNAP KP-NH column (eluting with heptane / EtOAc 100 / 0 to 15 / 85) to give compound 6. Table II. Intermediates used in compounds of the present invention. SM = Starting Material, Mtd = Method, MS Mes'd = Measured Mass, NA = Not Determined [Table 2] TIFF0007621277000037.tif241170TIFF0007621277000038.tif195170Table III. Exemplary compounds of the present invention SM = Starting Material, Mtd = Method, MS Mes'd = Measured Mass [Table 3] TIFF0007621277000040.tif132170Table IV. NMR data for exemplary compounds of the present invention. [Table 4]

[0315] Biological Examples Example 2. In vitro assay 2.1. Biochemical Assays 2.1.1. ADP-Glo™ Kinase Assay (2.1.1.1. Overview) The ADP-Glo™ Kinase Assay is a luminescence technology assay that measures ADP formed from a kinase reaction. In this particular study, the kinase reaction consisted of phosphorylation of the AMARA peptide substrate (SignalChem, Catalog No. A11-58) by SIK1 (Carna Biosciences, Catalog No. 02-131), SIK2 (ThermoFisher Scientific, Catalog No. PV4792), or SIK3 (SignalChem, Catalog No. S12-11G-100). In a second step, the kinase reaction is terminated and all remaining ATP is depleted. In the final step, ADP is converted to ATP, and this newly synthesized ATP is measured using a luciferase / luciferin reaction. The light generated is measured using an Envision plate reader, where the resulting luminescence signal positively correlates with kinase activity.

[0316] (2.1.1.2. Protocol) Test compounds are prepared as 10-point dose-response serial dilutions in 1 / 5 dilution steps in 100% DMSO starting from a top concentration of 2 mM, diluted 1 / 20 in water, and 1 μL transferred to an assay plate (PerkinElmer, Cat. No. 6007290).

[0317] 1% DMSO and 10 μM staurosporine final concentrations are used as negative and positive controls.

[0318] 2 μL of the enzyme substrate mix is ​​added to the assay plate.

[0319] The reaction is initiated by adding 2 μL of diluted ATP onto the assay plate, which is centrifuged at 1000 rpm for a few seconds and gently shaken for 2 minutes, followed by incubation at room temperature for 120 minutes.

[0320] The reaction is stopped and unconsumed ATP is depleted by adding 5 μL of ADP-Glo ​​reagent (Promega, Cat. No. V912B) to the reaction. The plate is centrifuged at 1000 rpm for a few seconds and incubated at room temperature for 40 minutes (ATP depletion).

[0321] ADP is converted to ATP, and ATP is detected by introducing luciferase and luciferin by adding 10 μL of kinase detection reagent (Promega, catalog no. V913B+V914B) to the reaction. The plate is centrifuged at 1000 rpm for a few seconds and incubated at room temperature for 30 minutes (ADP detection).

[0322] Luminescence is measured on an Envision plate reader (PerkinElmer). Table V. Human SIK Kinase ADP-Glo™ Assay Conditions [Table 5]

[0323] (2.1.1.3. Data Analysis and Results) After readout performed in TopCount, raw data was generated and plotted to generate dose-response curves and provide percentage inhibition (PIN) and mean IC for each SIK homolog. 50 This is reported in the table below. Table VI. ADP-Glo™ SIK Kinase Assay IC of exemplary compounds of the present invention 50 ) [Table 6]

[0324] 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 (MdDC) (Clark et al., 2012; Sundberg et al., 2014; Ozanne et al., 2015). In this assay, exemplary compounds of the invention are evaluated for inhibition of LPS-induced TNFα secretion and LPS-triggered IL-10 secretion in monocyte-derived macrophages.

[0325] (2.2.1.2. Protocol) PBMCs are isolated from human blood samples (buffy coats). The buffy coats are aseptically transferred into 50 mL Falcon tubes and diluted 1 / 2 in PBS. The Falcon tubes are filled with 20 mL of Lymphoprep™, 25 mL of buffy coat is carefully added on top, and the tubes are centrifuged at 400 g for 35 minutes at 25°C in a temperature-controlled centrifuge without the brake. PBMCs are aspirated from the white interface layer between the sample and Lymphoprep™. The PBMCs are washed five times in PBS. The cells are resuspended in RPMI 1640 complete medium supplemented with 10% FBS, 1% P / S, and the cell density is determined using a hematology analyzer (Sysmex XS-500i).

[0326] PBMCs were centrifuged at 300 × g for 10 min and collected at a concentration of 1.0 × 10 cells per 80 μL of Miltenyi buffer (PBS, pH 7.4, 1% FBS, 2 mM EDTA). 7 Resuspend at a density of 100 μg.

[0327] 2.2.1.2.1 Positive Labeling of CD14+ Monocytes From this point on in the protocol, all steps are performed on ice. 7Add 20 μL of CD14+ microbeads per cell, mix the tube, and incubate for 15 minutes in a 4°C refrigerator. Adjust the volume of the cell suspension to 100 mL total volume with Miltenyi buffer, mix gently, and then centrifuge at 300 × g for 10 minutes. Discard the supernatant, and resuspend the cell pellet in 12 mL of Miltenyi buffer.

[0328] 2.2.1.2.2 Magnetic Cell Sorting Four LS columns are placed in the Miltenyi Biotec MACS separator (magnet) and pre-wetted by rinsing with 3 mL of MACS buffer per column. 3 mL of cell suspension is added to the top of the columns (maximum 1 x 10 cells per column). 8 labeled cells), followed by washing the column three times with 3 mL of Miltenyi buffer.

[0329] The column was removed from the magnet, and 5 mL of Miltenyi buffer was added to the column by pushing the plunger into the column to flush out the CD14+ fraction. The flushed fraction was collected in a new 50 mL Falcon tube, the volume adjusted to 30 mL with Miltenyi buffer, and the cells were centrifuged at 300 × g for 10 minutes. The resulting cell pellet was resuspended in 10 mL of RPMI (without FBS), and the cell density was determined using a hematology analyzer (Sysmex XS-500i). 100,000 cells were seeded per well of a 96-well plate in RPMI 1640 medium supplemented with 10% FBS, 1% P / S, and 100 ng / mL rhM-CSF for differentiation into MdM. On day 5, the medium is refreshed with 100 μL of RPMI 1640 medium supplemented with 10% FBS, 1% P / S, and 100 ng / mL rhM-CSF.

[0330] On day 10, MdM is triggered and compounds are added.

[0331] Compound dilution plates are made by 3-fold dilutions of 10 mM stock solutions in 100% DMSO. Intermediate dilution plates (10x final concentration) are made by 50-fold dilution of compound dilution plates in RPMI medium.

[0332] The medium is carefully removed from the cell plate using a multichannel pipette and replaced with 80 μL of fresh medium. 10 μL of 10× final concentration compound is added to the cells and incubated at 37°C for 1 hour before adding the trigger. The non-triggered / triggered conditions are spiked with equal final DMSO concentrations of 0.2% DMSO. 10 μL of 10× LPS (final concentration 200 ng / mL) solution is added to all wells except the "non-triggered wells," to which 10 μL of medium is added. After 2 hours (IL-10 determination) and 20 hours (TNFα determination) of LPS triggering, the supernatants are collected.

[0333] 2.2.1.2.3 TNFα ELISA Lumitrac 600 Greiner 384-well plates are coated with 40 μL of capture antibody (BD Pharmingen, Cat. No. 551220) at a final concentration of 1 μg / mL in 1×PBS and stored at 4° C. overnight.

[0334] The plate is then washed once with PBST (PBS + 0.05% Tween 20) and once with PBS, followed by the addition of 100 μL of blocking buffer (1% bovine serum albumin (BSA) - 5% sucrose), sealing the plate, and incubating at room temperature for at least 4 hours. After washing the plate once with PBST and once with PBS, 40 μL of standard or sample is added (a TNFα standard curve is prepared using 1 / 2 serial dilutions starting from 16,000 pg / mL; dilutions are prepared in dilution buffer (PBS + 1% BSA)). The plate is washed twice with PBST and once with PBS, followed by the addition of 35 μL of detection antibody (final concentration 0.25 μg / mL, diluted in dilution buffer), and the plate is incubated at room temperature for at least 2 hours. The plate is washed twice with PBST and once with PBS, after which 35 μL of Strep-HRP conjugate (0.5 μg / mL final concentration, diluted in dilution buffer) is added. The plate is incubated in the dark at room temperature for at least 45 minutes, but not longer than 1 hour. The plate is washed twice with PBST and once with PBS. 50 μL of luminol substrate (prepared according to the manufacturer's instructions) is then added to each well and incubated for 5 minutes at room temperature in the dark. Chemiluminescence is measured using an Envision 2104.

[0335] (2.2.1.2. 4 IL-10 ELISA Immulon 2HB 96-well plates (Thermo Electron, Cat. No. 3455) are 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 at 4°C overnight. The next day, the plates are washed three times with PBST, followed by the addition of 200 μL of blocking buffer (1% BSA + 5% sucrose in PBS-T). After a 30-minute incubation at 37°C, the plates are washed three times with PBST and 100 μL of standards or samples are added (IL-10 standard curve samples are prepared using 1 / 2 serial dilutions starting at 1000 pg / mL; dilutions are made in dilution buffer: PBS + 1% BSA). After 1 hour of incubation at 37°C, wash the plate three times with PBST, then add 100 μL of detection antibody (BD Pharmingen, Cat. No. 554499) (final concentration 0.25 μg / mL, diluted in Tris buffer) and incubate the plate for at least 2 hours at room temperature. Wash the plate three times with PBST, then add 100 μL of Strep-HRP conjugate (final concentration 0.5 μg / mL, diluted in dilution buffer). Incubate the plate for 30 minutes in the dark at 37°C. Wash the plate three times with PBST. Prepare substrate solution: for a total volume of 20 mL, add 18 mL of HO; 2 mL of citrate acetate buffer; 200 μL of TMB mix (101 mg of tetramethil benzidine (TMB), 10 mL of DMSO, stored at 4°C); 2.5 μL of 30% Mix H2O2. Add 100 μL of substrate solution to each well and incubate until a bright blue color develops. Stop the reaction by adding 50 μL of 1 M H2SO4, then measure absorbance at 450 nm on a SpectraMax i3, Molecular Devices.

[0336] (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 ​​compared to the control are calculated for all concentrations tested. An unstimulated sample (no trigger / vehicle (0.2% DMSO)) is used as a negative control (100% inhibition). A stimulated sample (trigger / vehicle) is used as a positive control (0% inhibition).

number

[0337] PIN values ​​were plotted as a concentration-response and EC 50 Values ​​are derived using GraphPad Prism Software by applying a 4-parameter nonlinear regression (sigmoidal) curve fit. Because no clear bottom plateau is obtained, the constraint that the underside of the curve is equal to 0 is added.

[0338] (2.2.1.3.2 IL-10 guidance calculation) IL-10 is induced immediately after SIK inhibition. To quantify this induction, the fold change (FC) compared to "LPS only" is calculated for each concentration tested and the maximum FC is calculated (IL-10 FCmax):

number

[0339] The median maximum FC for test compounds across two or more assays is reported (median IL-10FCmax).

[0340] (2.2.1.3.3 Results and Outcomes) The data obtained when carried out with exemplary compounds of the invention are set forth in the table below. Table VII. MdM TNFα Inhibition and IL-10 Induction of Exemplary Compounds of the Invention [Table 7]

[0341] 2.2.2. Monocyte 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 (MdDC) (Clark et al., 2012; Sundberg et al., 2014; Ozanne et al., 2015). In this assay, exemplary compounds of the invention are evaluated for inhibition of LPS-induced TNFα and LPS-triggered IL-10 secretion in monocytes.

[0342] (2.2.2.2. Protocol) PBMCs are isolated from human blood samples (buffy coats). The buffy coats are aseptically transferred into 50 mL Falcon tubes and diluted 1 / 2 in PBS. The Falcon tubes are filled with 20 mL of Lymphoprep™, 25 mL of buffy coat is carefully added on top, and the tubes are centrifuged at 400 g for 35 minutes at 25°C in a temperature-controlled centrifuge without the brake. PBMCs are aspirated from the white interface layer between the sample and Lymphoprep™. The PBMCs are washed five times in PBS. The cells are resuspended in RPMI 1640 complete medium supplemented with 10% FBS, 1% P / S, and the cell density is determined using a hematology analyzer (Sysmex XS-500i).

[0343] PBMCs were centrifuged at 300 × g for 10 min and collected at a concentration of 1.0 × 10 cells per 80 μL of Miltenyi buffer (PBS, pH 7.4, 1% FBS, 2 mM EDTA). 7 Resuspend at a density of 100 μg.

[0344] 2.2.2.2.1 Positive Labeling of CD14+ Monocytes From this point on in the protocol, all steps are performed on ice. 7 Add 20 μL of CD14+ microbeads per cell, mix the tube, and incubate for 15 minutes in a 4°C refrigerator. Adjust the volume of the cell suspension to 100 mL total volume with Miltenyi buffer, mix gently, and then centrifuge at 300 × g for 10 minutes. Discard the supernatant, and resuspend the cell pellet in 12 mL of Miltenyi buffer.

[0345] 2.2.2.2.2 Magnetic Cell Sorting Four LS columns are placed in the Miltenyi Biotec MACS separator (magnet) and pre-wetted by rinsing with 3 mL of MACS buffer per column. 3 mL of cell suspension is added to the top of the columns (maximum 1 x 10 cells per column). 8 labeled cells), followed by washing the column three times with 3 mL of Miltenyi buffer.

[0346] The column is removed from the magnet, and 5 mL of Miltenyi buffer is added to the column by pushing the plunger into the column to flush out the CD14+ fraction. The flushed fraction is collected in a new 50 mL Falcon tube, the volume adjusted to 30 mL with Miltenyi buffer, and the cells are centrifuged at 300 × g for 10 minutes. The resulting cell pellet is resuspended in 10 mL of RPMI (without FBS), and the cell density is determined using a hematology analyzer (Sysmex XS-500i). 100,000 cells are seeded per well of a 96-well plate in 80 μL of RPMI 1640 medium supplemented with 10% FBS and 1% P / S.

[0347] Compound dilution plates are made by 3-fold dilutions of 10 mM stock solutions in 100% DMSO. Intermediate dilution plates (10x final concentration) are made by 50-fold dilution of compound dilution plates in RPMI medium.

[0348] 10 μL of 10x final concentration compound is added to the cells and incubated at 37°C for 1 hour before adding the trigger. The non-trigger / trigger conditions are spiked with equal final DMSO concentrations of 0.2% DMSO. 10 μL of 10x LPS (final concentration 200 ng / mL) solution is added to all wells except the "non-trigger wells," to which 10 μL of medium is added. After 4 hours of LPS triggering, the supernatant is collected.

[0349] 2.2.2.2.3 TNFα ELISA Lumitrac 600 Greiner 384-well plates are coated with 40 μL of capture antibody (BD Pharmingen, Cat. No. 551220) at a final concentration of 1 μg / mL in 1×PBS and stored at 4° C. overnight.

[0350] The plate is then washed once with PBST (PBS + 0.05% Tween 20) and once with PBS, followed by the addition of 100 μL of blocking buffer (1% bovine serum albumin (BSA) - 5% sucrose), sealing the plate, and incubating at room temperature for at least 4 hours. The plate is washed once with PBST and once with PBS, followed by the addition of 100 μL of blocking buffer (1% BSA - 5% sucrose), sealing the plate, and incubating at room temperature for at least 4 hours. The plate is washed twice with PBST and once with PBS, followed by the addition of 35 μL of detection antibody (final concentration 0.25 μg / mL, diluted in dilution buffer), and the plate is incubated at room temperature for at least 2 hours. The plate is washed twice with PBST and once with PBS, followed by the addition of 35 μL of Strep-HRP conjugate (final concentration 0.5 μg / mL, diluted in dilution buffer). The plate is incubated in the dark at room temperature for at least 45 minutes, but not more than 1 hour. The plate is washed twice with PBST and once with PBS. 50 μL of luminol substrate (prepared according to the manufacturer's instructions) is then added to each well and incubated for 5 minutes at room temperature in the dark. Chemiluminescence is measured in an Envision 2104.

[0351] 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 at 4°C overnight. The next day, the plate is washed three times with PBST (PBS + 0.05% Tween 20) and once with PBS, followed by the addition of 100 μL of blocking buffer (1% BSA-5% sucrose), sealing the plate, and incubating at room temperature for at least 4 hours. After washing the plate once with PBST and once with PBS, 40 μL of standards or samples are added (IL-10 standard curve is prepared using 1 / 2 serial dilutions starting at 2000 pg / mL; dilutions are prepared in dilution buffer (PBS + 1% BSA)). The plate is washed twice with PBST and once with PBS, after which 35 μL of detection antibody is added (final concentration 0.143 μg / mL, diluted in dilution buffer), and the plate is incubated at room temperature for at least 2 hours. The plate is washed twice with PBST and once with PBS, after which 35 μL of Strep-HRP conjugate (final concentration 0.5 μg / mL, diluted in dilution buffer) is added. The plate is incubated in the dark at room temperature for at least 45 minutes, but not longer than 1 hour. The plate is washed twice with PBST and once with PBS. 50 μL of luminol substrate (prepared according to the manufacturer's instructions) is then added to each well, and the plate is incubated in the dark for 5 minutes at room temperature. Chemiluminescence is measured using an Envision 2104.

[0352] 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 ​​compared to the control are calculated for all concentrations tested. An unstimulated sample (no trigger / vehicle (0.2% DMSO)) is used as a negative control (100% inhibition). A stimulated sample (trigger / vehicle) is used as a positive control (0% inhibition).

number

[0353] PIN values ​​were plotted as a concentration-response and EC 50 Values ​​are derived using GraphPad Prism Software by applying a 4-parameter nonlinear regression (sigmoidal) curve fit. If no clear lower plateau is obtained, the underside of the curve is constrained to be equal to 0.

[0354] (2.2.2.3.2 IL-10 guidance calculation) Immediately following SIK inhibition, LPS-induced IL-10 increases. To quantify these increases, the fold change (FC) compared to "LPS alone" is calculated for each concentration tested, and the maximum FC is calculated (IL-10 FCmax):

number

[0355] The median maximum FC for test compounds across two or more trials is reported (median IL-10FCmax).

[0356] (2.2.2.3.3 Results and Outcomes) The data obtained when carried out with exemplary compounds of the invention are set forth in the table below. Table VIII. Monocyte TNFα Inhibition and IL-10 Induction of Exemplary Compounds of the Invention [Table 8]

[0357] Example 3. In vivo assay (3.1. Inflammatory bowel disease) (3.1.1. DSS model (mouse)) The mouse chronic DSS-induced inflammatory bowel disease (IBD) model is a well-validated disease model of inflammatory bowel disease (Wirtz et al., 2007; Sina et al., 2009).

[0358] To induce chronic colitis, female BALB / c mice are given 4% dextran sulfate sodium (DSS) in drinking water for 4 days, followed by 3 days of regular drinking water. This cycle is repeated until sacrifice on day 12 or 18. The animals are divided into groups: a. Intact water; vehicle alone, n=10), b. Disease (DSS; vehicle alone, n=10); c. Sulfasalazine (DSS; 20 mg / kg / day, orally, n=10), used as a reference, and d. Test compound (DSS; e.g., 1, 3, 10, 30 mg / kg / day, orally, n=10).

[0359] Clinical parameters are measured every other day. The Disease Activity Index (DAI) is a composite measure that combines the individual scores of weight loss, stool consistency, and the presence of blood in the stool. Mice are sacrificed according to the protocol introduced by Sina et al. (2009) (Sina et al., 2009). At the time of sacrifice, the entire colon is removed and rinsed with sterile PBS. A segment of the distal colon is excised for histological analysis, gene expression, and protein level measurements.

[0360] (3.2. CIA Model) (3.2.1. Materials) Complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA) were purchased from Difco. Bovine type II collagen (CII), lipopolysaccharide (LPS), and Enbrel® (etanercept) were obtained from Chondrex (L'Isle d'Abeau, France); Sigma (P4252, L'Isle d'Abeau, France), and Whyet (25 mg injection syringe, France), respectively. All other reagents used were of reagent grade, and all solvents were of analytical grade.

[0361] (3.2.2. Animals) DBA1 / J mice (male, 7-8 weeks old) were obtained from Charles River Laboratories (Ecully, France). Mice were housed under a 12-hour light / dark cycle. The temperature was maintained at 22°C, and food and water were provided ad libitum.

[0362] 3.2.3. Collagen-induced Arthritis (CIA) One day before the experiment, a CII solution (2 mg / mL) was prepared using 0.05 M acetic acid and stored at 4°C. Immediately before immunization, equal volumes of adjuvant (IFA) and CII were mixed using a homogenizer in a glass bottle pre-cooled in an ice-water bath. If an emulsion does not form, extra adjuvant and longer homogenization may be required. 0.2 mL of the emulsion was injected intradermally at the base of the tail of each mouse on day 1, and a second booster intradermal injection (2 mg / mL CII solution in CFA, 0.1 mL saline) was administered on day 9. This immunization method was modified from published methods (Jou et al., 2005; Sims et al., 2004).

[0363] (3.2.4. Test Design) The therapeutic effect of compounds was tested in a mouse CIA model. Mice were randomly divided into equal groups, each containing 10 mice. All mice were immunized on day 1 and boosted on day 21. The negative control group was treated with vehicle (MC 0.5%), and the positive control group was treated with Enbrel® (10 mg / kg, 3 times weekly, subcutaneously). The target compounds were usually tested orally (po) at three doses. On day 32, randomization between groups was performed based on clinical scores, and animals were treated according to their groups until day 47. Body weight and clinical scores were recorded at least twice a week.

[0364] 3.2.5. Clinical Assessment of Arthritis Arthritis was scored according to the methods of Khachigian, 2006, Lin et al., 2007, and Nishida et al., 2004 (Khachigian, 2006; Lin et al., 2007; Nishida et al., 2004). Swelling in each of the four paws was ranked using the following arthritis score: 0—no symptoms; 1—mild but localized redness and swelling of one joint, such as the ankle or wrist, or obvious redness and swelling limited to individual digits, regardless of how many digits were affected; 2—moderate redness and swelling of two or more joints; 3—severe redness and swelling of the entire paw, including the digits; and 4—mostly inflamed paw with involvement of multiple joints (maximum cumulative clinical arthritis score of 16 per animal) (Nishida et al., 2004).

[0365] 3.2.5.1. Change in Body Weight (%) After the Onset of Arthritis Clinically, weight loss is associated with arthritis (Argiles and Lopez-Soriano, 1998; Rall and Roubenoff, 2004; Shelton et al., 2005; Walsmith et al., 2004). Therefore, the change in body weight after the onset of arthritis can be used as a non-specific endpoint to evaluate the efficacy of treatment in mouse models. The change in body weight (%) after the onset of arthritis was calculated as follows:

number

[0366] (3.2.5.2. Radiology) Radiographs of each animal's hind paws are taken. A random, blinded identification number is assigned to each photograph, and the severity of bone erosion is ranked by two independent raters using the following radiological Larsen scoring system: 0 - normal, with intact bone contours and normal joint spaces; 1 - slight abnormality, with slight erosion of any one or two of the lateral metatarsals; 2 - focal early abnormality, with erosion of any three to five of the lateral metatarsals; 3 - moderate destructive abnormality, with focal erosion of all of the lateral metatarsals and any one or two of the medial metatarsals; 4 - severe destructive abnormality, with focal erosion of all of the metatarsals and complete erosion of at least one medial metatarsal joint, leaving some bone joint contours partially preserved; and 5 - whiplash abnormality, with loss of bone contour. This scoring system is adapted 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).

[0367] (3.2.5.3. Steady-state PK) On Day 7, blood samples were collected from the retro-orbital sinus using lithium heparin as an anticoagulant at the following times: pre-dose, 1, 3, and 6 hours. Whole blood samples were centrifuged, and the resulting plasma samples were stored at -20°C until analysis. Plasma concentrations of each test compound were determined by an LC-MS / MS method, with the mass spectrometer operating in positive electrospray mode.

[0368] 3.3. A mouse model of psoriasis-like epidermal hyperplasia induced by topical administration of the TLR7 / 8 agonist imiquimod. (3.3.1. Materials) Aldara® 5% imiquimod cream is obtained from MEDA.

[0369] Anti-mouse IL12 / IL23 p40 purified antibody (C17.8) (catalog number 16 7123 85) is obtained from eBioscience (Frankfurt, Germany).

[0370] (3.3.2. Animals) Balb / cJ mice (female, weighing 18-20 g) are obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice are housed under a 12-hour light / dark cycle. Temperature is maintained at 22±2°C, and food and water are provided ad libitum.

[0371] (3.3.3. Test Design) The study design is adapted from Van der Fits L. et al. (van der Fits et al., 2009).

[0372] On day 1, under light anesthesia, mice are shaved around both ears.

[0373] 30 mg of commercially available imiquimod cream (Aldara® 5% cream) was applied to both the inner and outer surfaces of each ear for four consecutive days, corresponding to a daily dose of 1.5 mg of the active compound. Control animals received an equal amount of petrolatum.

[0374] From days 1 to 5, mice received test compound at 10 or 30 mg / kg orally twice daily in 0.5% methylcellulose, followed by topical application of imiquimod (on day 5, mice received only one dose, 2 hours before euthanasia).

[0375] In the positive reference group, 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.

[0376] 3.3.4. Disease Assessment The thickness of both ears is measured daily using a pachymeter (Mitutoyo, Absolute Digimatic, 547 321). Body weight is assessed at the start of the experiment and at the time of sacrifice. On day 5, 2 hours after the last dose, the mice are sacrificed. The ear pinna (minus the cartilage) is excised. The pinna is weighed and then immersed in a vial containing 1 mL of RNAlater® solution to assess gene expression.

[0377] Results are expressed as mean±SEM and statistical analysis is performed using one-way analysis of variance followed by Dunnett's post-hoc test versus the imiquimod vehicle group.

[0378] (3.3.5. Gene Expression Analysis) The ears were removed from the RNAlater® solution and placed in Trizol® after disruption with 1.4 mm ceramic beads in a Precellys® device. Total RNA was then purified using the NucleoSpin® RNA kit. cDNA was prepared, and quantitative PCR was performed using Qiagen gene-specific primers in a ViiA7 real-time PCR system (Applied Biosystems) using SYBR Green technology. The expression level of each gene was calculated relative to that of the cyclophilin A housekeeping gene. Data were expressed as the mean ± SEM of relative amounts. The statistical test used was ANOVA analysis of variance with Dunnett's post-hoc test against the imiquimod vehicle group.

[0379] 3.4. Mouse model of psoriasis-like epidermal hyperplasia induced by intradermal injection of IL-23 (3.4.1. Materials) Mouse recombinant IL-23, carrier-free (cat. no. 14-8231) is provided by e-Bioscience (Frankfurt, Germany).

[0380] (3.4.2. Animals) Balb / c mice (female, weighing 18-20 g) were obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice were housed under a 12-hour light / dark cycle. Temperature was maintained at 22°C. Food and water were provided ad libitum.

[0381] (3.4.3. Test Design) The study design was adapted from Rizzo HL et al. (Rizzo et al., 2011). On day 1 (D1), the hair around both ears of the mice is shaved. For four consecutive days (D1-D4), the mice receive, under anesthesia, a daily intradermal dose of murine recombinant IL-23 (1 μg / 20 μL in PBS / 0.1% BSA) in the right ear and 20 μL of PBS / 0.1% BSA in the left ear.

[0382] From D1 to D5, mice receive test compound or vehicle 1 hour before IL-23 injection.

[0383] 3.4.4. Disease Assessment The thickness of both ears is measured daily using an automatic caliper. Body weight is assessed at baseline and at sacrifice. On day 5, 2 hours after the final dose, mice were sacrificed. The ear pinna (minus cartilage) is excised. The pinna is placed in a vial containing 1 mL of RNAlater® solution.

[0384] Additionally, on D4, blood samples were collected from the retro-orbital sinus immediately before dosing (T0) and 1, 3, and 6 hours after dosing for PK profiling.

[0385] There are 8 mice per group. Results are expressed as mean±SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett's post-hoc test versus the IL-23 vehicle group.

[0386] (3.4.5. Gene Expression Analysis) Half the ears were removed from the RNAlater solution and placed in Trizol® after disruption with 1.4 mm ceramic beads in a Precellys® device. Total RNA was then purified using the NucleoSpin® RNA kit. cDNA was prepared, and quantitative PCR was performed using Qiagen gene-specific primers in a ViiA7 real-time PCR system (Applied Biosystems) using SYBR Green technology. The expression level of each gene was calculated relative to that of the cyclophilin A housekeeping gene. Data were expressed as the mean ± SEM of relative amounts. The statistical test used was ANOVA analysis of variance with Dunnett's post-hoc test versus the IL-23 vehicle group.

[0387] 3.5. A mouse model of systemic lupus erythematosus induced by epicutaneous application of imiquimod (3.5.1. Materials) Aldara® 5% imiquimod cream is obtained from MEDA.

[0388] Mouse anti-double stranded DNA antibody ELISA kit is obtained from Alpha Diagnostic International (Cat. No. 5120). Mouse urinary albumin ELISA kit is obtained from Abcam (Cat. No. ab108792). Urine creatinine assay kit is obtained from Abnova (Cat. No. KA4344).

[0389] (3.5.2. Animals) BALB / cJ mice (female, weighing 18-20 g) are obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice are housed under a 12-hour light / dark cycle. Temperature is maintained at 22±2°C, and food and water are provided ad libitum.

[0390] (3.5.3. Test Design) The design of this study was adapted from Yokogawa M et al. (Yokogawa et al., 2014).

[0391] On day 1 (D1), the hair around the right ear of the mice is shaved.

[0392] Mice received 1.25 mg of imiquimod applied epicutaneously to the right ear pinna three times per week for 12 consecutive weeks (D1 to D86). The control group received the same amount of petrolatum.

[0393] From D1 to D86, mice are administered the test compound (30 mg / kg, orally, once daily, 0.5% in methylcellulose) or vehicle (10 mL / kg).

[0394] 3.5.4. Disease Assessment Ear thickness is measured weekly using an automated measuring device (Mitutoyo, Absolute Digimatic, 547-321).

[0395] Body weights are assessed at baseline and weekly until sacrifice. Spleen weights are also measured at necropsy. Mice are sacrificed 2 hours after the final dose.

[0396] At various time points (eg, on days D28, D56, and D84), mice are individually placed in metabolic cages and urinalysis is performed to assess proteinuria (albumin / creatinine ratio).

[0397] Serum is collected at various time points (eg, D28, D56, and D86) to assess anti-double-stranded DNA IgG levels.

[0398] Additionally, on D13, blood samples were collected from the retro-orbital sinus immediately before dosing (T0) and 1, 3, and 6 hours after dosing for PK profiling.

[0399] There are 8 to 19 mice per group. Results are expressed as mean ± SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett's post-hoc test versus the imiquimod vehicle group.

[0400] 3.5.5. Quantitation of Compound Levels in Plasma The plasma concentration of each test compound is determined by an LC-MS / MS method, with the mass spectrometer operating in either positive or negative electrospray mode.

[0401] (3.5.5.1. Histopathological Diagnosis) Four different readings for each glomerulus, including mesangial proliferation, endoluminal proliferation, mesangial matrix expansion, and segmental sclerosis, are scored on a scale of 0 to 2 and then summed. Approximately 50 glomeruli are scored for each kidney and then averaged to obtain a single glomerular lesion score (Yokogawa et al., 2014). Data are presented as mean ± SEM, and statistical analysis is performed using the Kruskal-Wallis test followed by Dunn's post-hoc test versus the imiquimod vehicle group.

[0402] 3.5.5.2. Cell Quantification For each cell type, immunohistochemical analysis was performed on whole tissue sections at 20x magnification using image analysis (CaloPix software, TRIBVN Healthcare). Data are presented as mean ± SEM, and statistical analysis was performed using one-way ANOVA followed by Dunnett's post-hoc test versus the imiquimod vehicle group.

[0403] (3.5.5.3. Gene Expression Analysis) At the time of sacrifice, the second portion of the left kidney was placed in a tube containing 1.4 mm ceramic beads and disrupted using a Bertin Instruments Precellys® homogenizer in 1% DTT RLT lysis buffer (Qiagen, Cat. No. 79216). Total RNA was then purified on a QIAcube using an RNeasy® 96 QIAcube® HT Kit (Qiagen, Cat. No. 74171). cDNA was prepared, and quantitative PCR was performed using Qiagen gene-specific primers on a ViiA 7 real-time PCR system (Applied Biosystems) using SYBR Green technology. The expression levels of each gene of interest (GOI = CD3, CD68, CD20, OAS1, Mx1, IFIT1, CXCL11, and Usp18) were calculated relative to the expression levels of cyclophilin, GAPDH, and β-actin housekeeping genes.

[0404] At the time of sacrifice, one-third of the spleen was placed in a tube containing 1.4 mm ceramic beads and disrupted in Trizol® using a Bertin Instruments Precellys® homogenizer. Total RNA was extracted using a phenol / chloroform process and then purified on a QIAcube using an RNeasy® 96 QIAcube® HT Kit (Qiagen, catalog number 74171). cDNA was prepared, and quantitative PCR was performed using Qiagen's gene-specific primers on a ViiA 7 real-time PCR system (Applied Biosystems) using SYBR Green technology. The expression level of each gene of interest was calculated relative to that of the housekeeping genes cyclophilin, GAPDH, and β-actin.

[0405] 3.6. Mouse model of psoriatic arthritis induced by IL-23 overexpression (3.6.1. Materials) Mouse IL-23 Enhanced Episomal Expression Vector (EEV) is obtained from System Biosciences (catalog number EEV651A-1). Mouse IL-23 Quantikine ELISA Kit is obtained from R&D Systems (catalog number M2300). ProSense® 680 and OsteoSense® 750EX are obtained from PerkinElmer (catalog numbers NEV10003 and NEV10053EX). RNAlater® is obtained from Ambion (catalog number AM7021). Imalgene® 1000 (Merial) and Rompun® 2% (Bayer) are obtained from Centravet (catalog numbers IMA004-6827812 and ROM001-6835444).

[0406] (3.6.2. Animals) B10.RIII mice (male, 8 weeks old) are obtained from Charles River (Ecully, France). Mice are housed on a 12-hour light / dark cycle. Temperature is maintained at 22±2° C., and food and water are provided ad libitum.

[0407] (3.6.3. Test Design) The study design was adapted from Sherlock JP et al. (Sherlock et al., 2012).

[0408] On day 1 (D1), mice receive a hydrodynamic injection of Ringer's solution or IL-23 EEV in Ringer's solution into the tail vein.

[0409] From D5 onwards, mice are scored for clinical symptoms twice weekly until the end of the experiment.

[0410] On D5, blood is collected by submandibular vein puncture to assess serum IL-23 concentrations.

[0411] On D9, mice in all groups receive ProSense® 680 probe (0.8 nmol / 10 g, ip). On D10, mice are anesthetized. Granulocyte infiltration is then measured using in vivo molecular imaging (Bruker In-Vivo Xtreme Imaging System).

[0412] On D11, randomization will be performed according to ProSense® 680 molecular imaging and scoring.

[0413] From D12 onwards, mice are administered the test compound or vehicle.

[0414] Blood is collected on D19 at time points TO, T1h, T3h, and T6h after the last dose. Plasma is separated and kept at 20°C until bioanalysis.

[0415] On D36, mice from all groups are sacrificed 2 hours after the last administration of compound.

[0416] Whole blood is collected into serum blood tubes and mixed by gently inverting 8-10 times. After clotting, the blood samples are centrifuged at 1800 x g for 10 minutes. After centrifugation, the serum is stored at -80°C.

[0417] 3.6.4. Disease Assessment Body weights are assessed at the start of the study, then twice weekly, and at sacrifice.

[0418] Clinical signs of inflammation are scored twice weekly: 0 normal paw; 1 if swelling of one toe; 2 if swelling of two or more toes; 3 if swelling of the entire paw. Scores for all paws are summed to give an overall score.

[0419] On D32, mice in all groups received ProSense® 680 probes (0.8 nmol / 10 g, ip) and OsteoSense® 750EX probes (0.8 nmol / 10 g, ip). On D33, mice were anesthetized and granulocyte infiltration and bone remodeling were measured in vivo using molecular imaging (Bruker In-Vivo Xtreme Imaging System).

[0420] There are 10 mice per group. Results are expressed as mean ± SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett's post-hoc test for scoring and imaging analysis versus disease vehicle group and for body weight versus sham vehicle group.

[0421] 3.7. Collagen Antibody-Induced Arthritis Model (CAIA) in Mice (3.7.1. Materials) ArthritoMab™ antibody cocktail for inducing arthritis and lipopolysaccharide (LPS) from Escherichia coli serotype O55:B5 were purchased from MD Biosciences (Oakdale, MN, USA, catalog number CIA-MAB-50); PBS 1X (GIBCO, catalog number 140190-086) was obtained from ThermoFisher Scientific, and Enbrel® (etanercept) was purchased from Chondrex (L'Isle d'Abeau, France, catalog number 3771910).

[0422] (3.7.2. Animals) Five- to seven-week-old BALBc female mice were obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice were housed under a 12-hour light / dark cycle. Temperature was maintained at 22°C. Food and water were provided ad libitum.

[0423] (3.7.3. Test Design) The therapeutic effects of the compounds of the present invention were tested in a mouse CAIA model (MD Biosciences 2008; Nandakumar et al. 2003). On day 1 (D1), mice were randomly divided into equal groups of 10 mice. All mice, including the vehicle group (except the untreated group), were immunized with ArthritoMab™ cocktail (100 mg / kg, iv, 200 μL / mouse) and then treatment with the compound or vehicle was initiated. The body weight and clinical score of each mouse were evaluated daily except on weekends until the end of the study. On D4, all mice, except the untreated group, were challenged with LPS (2.5 mg / kg, ip). On D11, all mice were sacrificed, and blood was collected into serum tubes. After centrifugation, serum was collected and frozen at -80°C until analysis (e.g., cytokine levels, gene expression, compound levels). For histological readout, the right and left hind paws were collected individually into vials (minimum 25 mL) filled with 4% buffered formaldehyde at room temperature for a minimum of 24 hours and a maximum of 4 days.

[0424] 3.7.4. Clinical Assessment of Arthritis Arthritis was scored according to the methods of Khachigian, 2006; Lin et al., 2007, and Nishida et al., 2004 (Khachigian, 2006; Lin et al., 2007; Nishida et al., 2004). Swelling in each of the four paws was ranked using the following arthritis score: [Table 9]

[0425] The final clinical score was the cumulative score of the four paws (maximum cumulative clinical arthritis score of 16 per animal) (Nishida et al., 2004). A cumulative clinical score curve was drawn for each group, and the area under the curve was calculated. Results were expressed as mean ± SEM, and statistical analysis was performed using one-way analysis of variance followed by Dunnett's post-hoc test versus the vehicle group.

[0426] 3.8. Mouse therapeutic model of atopic dermatitis induced by topical administration of MC903 (3.8.1. Materials) Methylcellulose 0.5% (catalog number AX021233) is obtained from VWR. MC903 (calcipotriol, catalog number 2700 / 50) is obtained from Tocris Bioscience (Bristol, UK). ProSense® 680 (catalog number NEV10003) is obtained from PerkinElmer (Massachusetts, USA). RNAlater® (catalog number AM7021) is obtained from Ambion (California, USA).

[0427] (3.8.2. Animals) BALB / cN mice (female, weighing 18-20 g) or CD1 / Swiss mice (female, weighing 24-26 g) were obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice were housed under a 12-hour light / dark cycle. Temperature was maintained at 22 ± 2°C, and food and water were provided ad libitum.

[0428] (3.8.3. Test Design) The study design was adapted from Li M. et al. (Li et al., 2006). On day 1 (D1), mice were anesthetized and the hair around both ears was shaved. From D1, either 20 μL of EtOH or 2 nmol of MC903 (in 20 μL of EtOH) was administered topically to each ear of the mice until D9, D11, or D15 (weekends excluded).

[0429] From D5 to D10, D12, or D16, mice are administered test compound (15 or 30 mg / kg, orally, twice daily, in 0.5% methylcellulose) or dexamethasone (5 mg / kg, orally, once daily, in 0.5% methylcellulose), or vehicle.

[0430] 3.8.4. Quantitation of Compound Levels in Plasma The plasma concentration of each test compound is determined by an LC-MS / MS method, with the mass spectrometer operating in either positive or negative electrospray mode.

[0431] 3.8.5. Determination of Pharmacokinetic Parameters Pharmacokinetic parameters are calculated using Phoenix® WinNonlin® (Pharsight®, USA).

[0432] 3.8.6. Disease Assessment The thickness of each ear is measured using a pachymeter (Mitutoyo, Absolute Digimatic, Cat. No. 547-321) immediately prior to the first administration of MC903 (baseline), three times weekly, and at the time of sacrifice.

[0433] Body weights are assessed immediately prior to the first EtOH administration (baseline), three times weekly, and at sacrifice.

[0434] On D8, D10, or D11, mice in all groups were administered ProSense® 680 probe (0.8 nmol / 10 g, ip). On the following day (D9, D11, or D12), mice were anesthetized. Granulocyte infiltration was 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).

[0435] Two hours after the final dose on D10, D12, or D16, mice are sacrificed, whole blood is collected in EDTA-coated tubes, and plasma is frozen (containing circulating compounds) for further measurements.

[0436] The ear pinna is collected. One ear is cut in half lengthwise. One half is fixed in 3.7% formaldehyde buffer for histological examination; the other half is immersed in RNAlater® to assess gene expression.

[0437] There were 8 mice per group. Results were expressed as mean ± SEM and statistical analysis was performed using one-way analysis of variance followed by Dunnett's post-hoc test for ear thickness and body weight versus the MC903 vehicle group (mice that received vehicle alone and were treated with MC903) and / or body weight versus the EtOH vehicle group (mice that received vehicle alone and were treated with EtOH).

[0438] (3.8.7. Histological Examination) After sacrifice, half ears were collected and fixed in 3.7% formaldehyde before being embedded in paraffin. 4 μm thick sections were immunostained by immunohistochemistry using anti-CD3 antibody. The immunostained cell area of ​​all sections per mouse was measured by image analysis (CaloPix software, TRIBVN Healthcare, France). Data were expressed as mean ± SEM, and statistical analysis was performed using one-way ANOVA followed by Dunnett's post-hoc test against the MC903 vehicle group.

[0439] 3.8.8. Gene Expression Analysis The ears were removed from the RNAlater® solution and placed in Trizol® after disruption with 1.4 mm ceramic beads in a Bertin Instruments Precellys® homogenizer. Total RNA was then extracted using a phenol / chloroform protocol and purified on a QIAcube using an RNeasy® 96 QIAcube® HT kit (Qiagen, catalog no. 74171). cDNA was prepared, and quantitative PCR was performed using Qiagen gene-specific primers on a ViiA 7 real-time PCR system (Applied Biosystems) using SYBR Green technology. The expression levels of each gene of interest (GOI = IL4, IL5, IL13, TSLP, IL33, ST2, IL25, IL31, IFNγ, IL6, IL10, LCN2, S100A8, and S100A9) were calculated relative to the expression levels of housekeeping genes (HPRT, GAPDH, and β-actin). All qPCR data are expressed as the mean ± SEM of normalized relative quantities (NRQ) calculated by the following steps: 1- Calculate the geometric mean of the NRQ for each group of animals

number

number

[0440] The statistical test used is ANOVA analysis of variance with Dunnett's post-hoc test versus the EtOH vehicle group and / or the MC903 vehicle group.

[0441] 3.9. LPS-induced endotoxic shock in mice Injection of lipopolysaccharide (LPS) induces a rapid release of soluble tumor necrosis factor (TNFα) into the periphery. This model is used to evaluate blockers of TNFα release in vivo.

[0442] (3.9.1. Materials) Lipopolysaccharide (LPS) from Escherichia coli serotype O111:B4 is obtained from Sigma Aldrich (catalog number L2630).

[0443] (3.9.2. Animals) BALB / cAnNCrl mice (female, weighing 18-20 g) are obtained from Charles River (Calco, Italy). Mice are housed under a 12-hour light / dark cycle. Temperature is maintained at 22±2°C, and food and water are provided ad libitum.

[0444] (3.9.3. Test Design) Mice are dosed once with the test compound in an appropriate vehicle by the oral (po) or subcutaneous (sc) route.

[0445] At the Tmax of the compound, mice are injected intraperitoneally with 100 μg of LPS (in H 2 O). A control group is included that receives vehicle without LPS challenge.

[0446] Mice are sacrificed 90 minutes after LPS challenge, and blood is collected in heparinized tubes. Plasma is obtained by centrifugation for 15 minutes at 2000×g at +4° C. and frozen at −80° C. prior to cytokine analysis.

[0447] 3.9.4. Disease Assessment TNFα and IL-10 in plasma are quantified by alpha LISA detection kits obtained from PerkinElmer (Massachusetts, USA, catalog numbers AL505C and AL502C, respectively).

[0448] Statistics are performed using ANOVA analysis of variance with Dunnett's post-hoc test versus LPS group using Prism 5.03 software (GraphPad).

[0449] Active compounds are defined as those that show a statistically significant reduction in TNFα, with or without a statistically significant induction of IL-10.

[0450] 3.10. Multidrug resistance 1a erasure (MDRa1) model (mouse) 3.10.1. Assay Principle Abcb1a (MDRa1)-deficient mice spontaneously develop colitis, which can be accelerated by infection with Helicobacter bilis. This model is used to evaluate the ability of compounds to treat or prevent colitis (Maxwell et al., 2015).

[0451] (3.10.2. Materials) Sterile PBS (Gibco, catalog number 20012027) was obtained from ThermoFisher Scientific (Massachusetts, USA); Brucella agar (catalog number 211086) was obtained from Becton Dickinson (New Jersey, USA); Brucella broth base (catalog number B3051-500g) was obtained from Sigma-Aldrich (Missouri, USA). Defiberized sheep blood (catalog number SR0051) and Campygen (catalog number CN0025) were obtained from ThermoFisher Scientific (Massachusetts, USA). H. bilis ATCC 51360 was obtained from LGC Standards (Molsheim, France), and Combur test E (catalog number 11896857) was obtained from Roche Diagnostics (Basel, Switzerland).

[0452] (3.10.3. Animals) Seven- to nine-week-old MDR1a (FVB.129P2- Abcb1atm1Bor N7) female mice were obtained from Taconic (Rensselaer, NY, USA), and seven- to nine-week-old FVB female mice were obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice were housed under a 12-hour light / dark cycle. Temperature was maintained at 22°C. Food and water were provided ad libitum.

[0453] (3.10.4. H. bilis inoculum preparation) A frozen vial of H. bilis is thawed, placed in Brucella broth, and incubated on Brucella agar slants containing 5% defibrinated sheep blood at 37°C under microaerophilic conditions for 4-5 days. On Day 1, immediately before administration, a portion of the H. bilis culture is diluted in PBS and diluted to 10 7 cfu / mouse, and a second portion is placed in fresh Brucella broth and incubated for 7 days as described above. Immediately prior to administration on D8, H. bilis cultures are diluted in PBS and incubated at 10 7 Obtain cfu / mouse.

[0454] (3.10.5. Test Design) After a 10-day acclimation period, the disease activity index of each MDR1a mouse was determined to constitute homogeneous groups in terms of DAI score between groups. Then, all mice (10 mice per group) except for the sham group (n=10) were inoculated with H. bilis (10 7cfu / mouse) is administered orally to initiate 6 weeks of treatment according to the protocol. Seven days after the start of treatment, a second dose of H. bilis is administered. Disease activity indexes are determined twice weekly throughout the entire treatment period. Six weeks after the start of treatment, mice are sacrificed, blood is collected, and the entire colon is collected and rinsed with sterile PBS. Collected colons are measured and weighed to determine colon weight / length ratio, and histological analysis, gene expression, protein level measurement, and / or FACs immunophenotyping analysis are performed on samples. Results are expressed as mean ± SEM, and statistical analysis is performed using one-way analysis of variance followed by Dunnett's post-hoc test versus the vehicle group.

[0455] 3.10.6. Determination of Disease Activity Index (DAI) The DAI score (sum of scores for weight loss, stool consistency, and rectal bleeding) of each mouse is monitored throughout the treatment period to obtain a DAI score progression curve. [Table 10] *A small piece of stool was placed in a vial containing 1 mL of D-PBS, homogenized, and placed on a test strip (Combur Test E). A color appeared depending on the blood strength in the stool. A score of 0 to 4 was assigned according to this strength.

[0456] 3.11. Mouse model of radiation-induced fibrosis (3.11.1. Test Overview) Interstitial pneumonia and pulmonary fibrosis are major radiation-induced complications after thoracic radiotherapy, which is one of the main treatments for lung and breast cancer, lymphoma, and hematopoietic transplant preparative treatments. The purpose of this model is to evaluate the effects of compounds of the present invention on radiation-induced pulmonary fibrosis in mice (Favaudon et al., 2014), particularly on lung function (Flexivent) and fibrosis markers (Collagen I).

[0457] (3.11.2. Animals) Seven-week-old (18-22 grams) female C57BL / 6J mice Charles River (Ecully, France, batch number S1672) are maintained at 22° C. with a 12-hour light / dark cycle and tap water and food available ad libitum.

[0458] (3.11.3. Materials) Prior to use, the test compound is dissolved / suspended in a suitable vehicle and stored at room temperature with stirring and away from light.

[0459] Aliquots of the formulation (approximately 200 μL) are frozen on TO (the day of preparation) and all formulations are checked (daily) for any changes in appearance.

[0460] The administered dose was 10 mL / kg, which was modified according to the mean body weight (BW) of the group as follows: 200 μL if mean BW<22.5 g, 250 μL if mean BW≧22.5 g, and 300 μL if mean BW>27.5 g.

[0461] 3.11.4. In Vivo Experimental Procedures On day 1 of week 1, animals are exposed to a radiation dose of 17 Gray in the chest under isoflurane anesthesia.

[0462] Beginning at week 18 post-radiation (D1), animals are randomized into six test groups (15 subjects per group): 1) Sham (vehicle: methylcellulose (MC) 0.5%), 2) Disease (vehicle: methylcellulose (MC) 0.5%), 3) Positive Control (nintedanib administered at 60 mg / kg in 0.1% Natrosol™), and 4) three groups of test compound (60 mg / kg in 0.5% methylcellulose (MC)) administered orally twice daily until D23 (week 21).

[0463] Body weights will be recorded weekly and on D23, and pulmonary function measurements under anesthesia will be performed on all groups (six successful measurements per group) by Flexivent (Devos et al., 2017) before sacrifice.

[0464] Lungs were harvested and fixed in 4% formaldehyde for 24 hours before being embedded in paraffin. 4-μm-thick sections were immunostained with anti-collagen I antibody (LSBio, 2401 Fourth Avenue Suite 900, Seattle, WA 98121, USA, Catalog No. LS-343921). The sections were deparaffinized, treated with heat-induced antigen retrieval, and then incubated with primary antibody for 1 hour. Anti-collagen I antibody was detected and amplified using an ImmPress kit (Vector Laboratories, 3 Accent Park, Bakewell Road, Orton Southgate, Peterborough, PE2 6XS, UK, Catalog No. MP-7401). Immunostained sections were then scanned (Nanozoomer, Hamamatsu) and quantified by image analysis (CaloPix software, TRIBVN Healthcare). Data are expressed as the percentage of collagen I area per area of ​​lung tissue.

[0465] Values ​​for all mice in the same group are averaged. Data are expressed as mean ± sem and compared using one-way analysis of variance and Dunnett's post-hoc test on log-transformed data. Significance levels are defined as follows: * (p < 0.05), ** (p < 0.01), or *** (p < 0.001) (vs. non-irradiated control group).

[0466] 3.12. Bleomycin-induced pulmonary fibrosis in mice (3.12.1. Test Overview) The purpose of this study is to test the efficacy of the test compound at three different doses in a 14-day model of bleomycin-induced pulmonary fibrosis in mice.

[0467] (3.12.2. Animals) The study was performed on C527BL / 6N male mice provided by Charles River (Calco, Italy). Mice were acclimated for at least 5 days in an environment maintained at 22°C and 55% relative humidity with a 12-hour light cycle and 15-20 air changes per hour. Pelleted food and water were provided ad libitum to the mice.

[0468] At least one day before the start of the experiment, all animals are randomly assigned to groups as shown in the table below. Table IX. Study Groups [Table 11]

[0469] (3.12.3. Materials) A solvent for the test solution is prepared by adding 0.5 g of hydroxyethyl cellulose (Natrosol™) to 500 mL of aqua distillate (0.1%) with continuous magnetic stirring without heating for 5 hours.

[0470] To prepare a solution for intranasal (in) challenge, a 0.8 mg / mL stock solution of bleomycin (Cat. No. BML-AP302-0010, Enzo Life Sciences, USA) is thawed and diluted in 330 μL of saline.

[0471] Prior to intranasal administration, mice are anesthetized intraperitoneally (ip).

[0472] Fresh pirfenidone formulation is prepared daily in 0.1% Natrosol™ formulation to a final concentration of 5 mg / mL. Before dosing, animals are weighed, and the amount of pirfenidone administered is adjusted to the individual body weight, equivalent to 10 mL / kg body weight, twice daily, orally. There is a 7.5-hour interval between two doses.

[0473] Finally, test compound solution is prepared by dissolving the appropriate amount of test compound in PEG 400 (20% of final volume), then in MC 0.5% (80% of final volume), to obtain final concentrations of 1 mg / mL, 0.3 mg / mL, and 0.1 mg / mL, thus obtaining compound for doses of 10 mg / kg, 3 mg / kg, and 1 mg / kg.Before dosing, animals are weighed, and the amount administered is adjusted according to individual body weight.

[0474] The test dose application volume corresponds to 10 mL / kg body weight and the test compound is administered orally twice daily with an interval of 7.5 hours between the two doses.

[0475] 3.12.4 Testing The animals are clinically examined twice daily and clinical symptoms and parameters are recorded. The animals are weighed daily starting from D0.

[0476] On day 14, mice are sacrificed 2 hours after dosing with vehicle, pirfenidone, or test compound.

[0477] Lungs are excised and weighed individually. For all groups: The entire right upper lobe of the lung is placed into a Precellys® tube containing silica beads and immediately snap-frozen in liquid nitrogen for gene expression analysis.

[0478] All remaining lungs are placed in marked jars containing 10% buffered formalin for further histopathological evaluation.

[0479] 3.13. Therapeutic Bleomycin-Induced Pulmonary Fibrosis 21-Day Mouse Model The purpose of this study is to test the efficacy of the test compound at three different doses in a 21-day model of bleomycin-induced pulmonary fibrosis in mice.

[0480] (3.13.1. Animals) The study was performed on C57BL / 6N male mice provided by Charles River (Calco, Italy). Mice were acclimated for at least 5 days in an environment maintained at 22°C and 55% relative humidity with a 12-hour light cycle and 15-20 air changes per hour. Pelleted mouse food and water were provided ad libitum.

[0481] At least one day before the start of the experiment, all animals are randomly assigned to groups as shown in the table below. (Table X. Study Groups) [Table 12]

[0482] (3.13.2. Materials) A solvent for the test solution is prepared by adding 0.5 g of hydroxyethyl cellulose (Natrosol™) to 500 mL of aqua distillate (0.1%) with continuous magnetic stirring without heating for 5 hours.

[0483] To prepare a solution for intranasal (in) challenge, a 0.8 mg / mL stock solution of bleomycin (catalog number BML-AP302-0010, Enzo Life Sciences, USA) is thawed and diluted in 330 μL of saline. Prior to intranasal administration, mice are anesthetized intraperitoneally (i.p.).

[0484] Fresh nintedanib formulation is prepared daily to a final concentration of 5 mg / mL in a 0.1% Natrosol™ formulation. Prior to dosing, animals are weighed and the amount of nintedanib administered is adjusted to individual body weight, equivalent to 10 mL / kg body weight, once daily, orally.

[0485] Finally, test compound solution is prepared by dissolving the appropriate amount of test compound in PEG 400 (20% of final volume), then in MC 0.5% (80% of final volume), to obtain final concentrations of 1 mg / mL, 0.3 mg / mL, and 0.1 mg / mL, thus obtaining compound for doses of 10 mg / kg, 3 mg / kg, and 1 mg / kg.Before dosing, animals are weighed, and the amount administered is adjusted according to individual body weight.

[0486] The test dose application volume corresponds to 10 mL / kg body weight and the test compound is administered orally twice daily with an interval of 7.5 hours between the two doses.

[0487] 3.13.3 Testing Animals are clinically examined twice daily. A list of clinical symptoms and parameters is given in the Human Endpoint Table. Animals are weighed daily starting from DO.

[0488] On day 21, mice are sacrificed 2 hours after dosing with vehicle, nintedanib, or test compound.

[0489] Lungs are excised and weighed individually. For all groups: The entire right upper lobe of the lung is placed into a Precellys® tube containing silica beads and immediately snap-frozen in liquid nitrogen for gene expression analysis.

[0490] All remaining lungs are placed in marked jars containing 10% buffered formalin for further histopathological evaluation.

[0491] 3.13.4. Sample Analysis, Data Processing, and Statistical Evaluation Body weight and lung weight data are processed using MS Excel. Statistical analysis and plotting are performed using GraphPad Prism software. One-way analysis of variance or Mann-Whitney test is used for lung weight. Two-way analysis of variance is used for body weight change.

[0492] Differences between groups are considered statistically significant when p<0.05.

[0493] For histopathological evaluation, the entire lung (except the right upper lobe, which is harvested) is embedded in paraffin and stained with Mallory's trichrome.

[0494] Lung histological changes are assessed using the Matsuse modification of the Ashcroft score (Ashcroft et al., 1988; Matsuse et al., 1999). Statistical analysis and visualization are performed using GraphPad Prism software. The Mann-Whitney test is used.

[0495] Differences between groups are considered statistically significant when p<0.05. [Table 13]

[0496] (3.13.5. PK analysis - Group 7) (3.13.5.1. Protocol) Group 7 animals (n=10) are included for PK studies only and are not subject to clinical symptom scoring.

[0497] The animals will have the disease induced at the start of treatment on day 0 (D0) and will be sacrificed sequentially 1, 3, 6, 8 and 24 hours after the first administration of the test compound on D7.

[0498] For each time point, blood samples (50 μL) are collected from the tail vein into Li heparin anticoagulant tubes and kept on ice until separation. Within a maximum of 30 minutes after collection, blood samples are centrifuged at 2000 × g for 10 minutes at 4 ° C, and the resulting plasma samples are aliquoted into polypropylene tubes (1 × 25 μL). Samples are stored frozen at −20 ° C until analysis.

[0499] Lung tissue is collected from each animal at sacrifice after blood collection, then weighed, placed in polypropylene tubes, and frozen. Samples are stored frozen at -80°C until analysis. 3.13.5.2 Plasma Concentrations and Pharmacokinetic Analysis Plasma and lung concentrations are measured by LC-MS / MS. Samples are prepared for LC-MS / MS analysis by protein precipitation. Plasma concentrations measured below the lower limit of quantitation (LLOQ) are reported as below the limit of quantitation (BLQ). Test compound concentrations in plasma are expressed in ng / mL. The mean plasma concentration is calculated. For the mean calculation, concentrations below the LLOQ are set to zero. Thus, the mean value may also be the BLQ. When at least three plasma concentration values ​​are above the LLOQ, the standard deviation (SD), standard error of the mean (SE), and coefficient of variation (CV, %) are reported in the table.

[0500] Non-compartmental analysis of individual plasma concentrations will be performed using Phoenix™ WinNonlin® 6.3 (Pharsight) to determine at least the following pharmacokinetic parameters: - maximum plasma concentration, Cmax (μg / mL) (together with the corresponding time, tmax (h)), - AUC to final quantifiable concentration 0-t or 24-hour AUC 0-24h (μg.h / mL) (if the compound is quantifiable up to 24 hours after administration), and / or AUC to infinity 0-∞ The area under the plasma concentration versus time curve (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. If there are fewer than three quantifiable time points, AUC is not calculated. If %AUCextra<20%, AUC0-∞ is considered. - Apparent terminal elimination half-life, t1 / 2 (h), is calculated when ≥3 time points, excluding tmax, are used in the linear regression and the adjusted R 2 Reported only if >0.80. - Normalized AUC and Cmax dose. - Calculate the mean pharmacokinetic parameters. If at least three values ​​are available, the standard deviation (SD) and coefficient of variation (CV, %) are tabulated.

[0501] 3.14. T cell transplantation model (mouse) (3.14.1. Materials) DynaMag (catalog numbers 12321D and 123203D) are obtained from Life Technologies Invitrogen (California, USA); Dynabeads FlowComp Mouse CD4+CD25- Regulatory T Cells (catalog number 11463D) are obtained from Life Technologies Invitrogen (California, USA); fetal bovine serum (GIBCO), catalog number 10270-106; RPMI (Gibco), catalog number 32404-014, and D-PBS 1X, CaCl2-free, MgCl2-free (GIBCO), catalog number 14190-086 are obtained from ThermoFisher Scientific (Massachusetts, USA). Red blood cell (RBC) lysis buffer 10X, catalog number BLE420301, is obtained from Ozyme (Montigny-le-Bretonneux, France). Cell strainers (70 μm grid), catalog number 352350, are obtained from Corning (New York, USA). Bovine serum albumin (BSA), catalog number A9647-50g, and EDTA, catalog number EDS-100g, are obtained from Sigma Aldrich (Missouri, USA), and Combur test E, catalog number 11896857, is obtained from Roche Diagnostics (Basel, Switzerland).

[0502] (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 housed under a 12-hour light / dark cycle. Temperature is maintained at 22°C. Food and water are provided ad libitum.

[0503] ...

Claims

1. Compounds of Formula I: 【Chemistry 1】 (In the formula, W is N or CH; X 1 and X 2 One of them is N and the other is C (provided that if W is CH, then X 2 (assuming that is not N); Y is N or CR 2b and Z is - -NHR 3a 、 - further comprising 0, 1, or 2 additional heteroatoms independently selected from N, O, and S, and optionally one or more independently selected R 15 an N-linked 4- to 7-membered heterocycloalkyl substituted with a group; or - -NR 3b - (wherein N atom and R 2a together with the atom to which they are attached form a fused 5-6 membered heterocycloalkenyl containing 1 or 2 double bonds; R 1 teeth - one or more independently selected R 4 C optionally substituted with a group 1-8 Alkyl, - Phenyl, - one or more independently selected R 5 C optionally substituted with a group 3-8 monocyclic or bridged polycyclic cycloalkyl; - a 4-8 membered monocyclic, spirocyclic or bridged polycyclic heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocycloalkyl is one or more independently selected -CN or -C(=O)-C 1-4 one or more independently selected C optionally substituted with alkoxy 1-4 optionally substituted with alkyl; or - a 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S; R 2a and R 2b teeth, - Hello, - C 1-4 Alkyl, - one or more independently selected halo or C 1-4 C optionally substituted with alkoxy 1-4 Alkoxy, and - -NR 6a R 6b are independently selected from R 3a teeth, - C optionally substituted with one or more independently selected halo or -CN; 1-6 Alkyl, or - C optionally substituted with one or more independently selected halo or -OH 3-7 is cycloalkyl; R 3b , H, C 3-7 Cycloalkyl, and C optionally substituted with one or more independently selected halo or -CN 1-6 alkyl; Each R 4 teeth, - Hello, -OH, - -CN, - Phenyl, - -C(=O)OH, - -OC(=O)C 1-4 Alkyl, - -OS(=O) 2 -C 1-4 Alkyl, - 1 or more independently selected -OH, ・C 1-4 Alkoxy, - 4-8 membered monocyclic heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, said heterocycloalkyl being one or more independently selected C 1-4 optionally substituted with alkyl; or -NR 7a R 7b (In the formula, each R 7a and R 7b H and C 1-4 C optionally substituted with alkyl 1-4 Alkoxy, - one or more independently selected halo, -C(=O)-C 1-4 Alkoxy, -NR 8a R 8b or one or more independently selected -NR 9a R 9b C optionally substituted with 1-4 C optionally substituted with alkyl 3-7 Cycloalkyl, - a 5-6 membered monocyclic heterocycloalkyl containing 1 or 2 N atoms fused to a 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, said heteroaryl being fused to one or more independently selected C 1-4 optionally substituted with alkyl; - a 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, said heteroaryl being selected from one or more independently selected C 1-4 Alkyl or C 3-7 optionally substituted with cycloalkyl; - 4-11 membered monocyclic, spirocyclic or bridged polycyclic heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, said heterocycloalkyl being selected from one or more independently selected R 10 , optionally replaced by - -NO 11a R 11b 、 - -C(=O)C 1-4 Alkoxy, and - -C(=O)-NR 12a R 12b are independently selected from Each R 5 teeth, - Hello, -CN, and - -NR 13a R 13b Selected from: Each R 6a and R 6b H and C 1-4 independently selected from alkyl, Each R 10 teeth, -OH, - Phenyl, - =NH, - Hello, - Oxo, - -CN, - -C(=O)H, - -C(=O)NH 2 、 - -C(=O)OH, - -NO 14a R 14b 、 - one or more independently selected halo, -CN, -OH, -C(=O)-C 1-4 Alkoxy or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, - C 3-7 Cycloalkyl, - a 4-6 membered monocyclic heterocycloalkyl containing 1, 2 or 3 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 teeth, - H - Phenyl, - one or more independently selected halo, -OH, -CN, or C 1-4 C optionally substituted with alkoxy 1-4 Alkyl, - C 3-7 Cycloalkyl, - -C(=O)-C 1-4 Alkoxy, - -C(=O)-C optionally substituted with one or more independently selected halo 1-4 Alkyl, and - independently selected from 5-6 membered monocyclic heteroaryl containing 1, 2 or 3 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 H and C 1-4 independently selected from alkyl; Each R 14a and R 14b , H, C 1-4 Alkyl, and -S(=O) 2 -C 1-4 alkyl; and Each R 15 is -OH, -CN, and C optionally substituted with one or more independently selected halo or -CN; 1-4 alkyl.

2. Y is CR 2b and R 2b But, C 1-4 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is alkoxy.

3. R 2a is substituted with 1, 2, or 3 independently selected halo; 3 3. The compound according to claim 1 or 2, wherein:

4. Z is -NR 3b -, wherein N atom and R 2a 3. The compound according to claim 1 or 2, wherein: together with the atom to which they are attached form a fused 1,2,3,6-tetrahydropyridine, or a pharma- ceutically acceptable salt thereof.

5. Formulae IIIa-IIIh: 【Chemistry 2】 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, according to any one of the following:

6. R 1 But -CH 3 or -CH 2 CH 3 and each of them is an R 4 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, which is substituted with a group.

7. Formulas IVa to IVp: 【Chemistry 3】 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, according to any one of the following:

8. R 4 But -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 8. The compound according to any one of claims 1 to 7, or a pharma- ceutical acceptable salt thereof,

9. R 4 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl, or a pharma- ceutical acceptable salt thereof.

10. R 4 The compound according to any one of claims 1 to 7 or 9, or a pharma- ceutically acceptable salt thereof, wherein is morpholinyl.

11. R 4 The compound according to any one of claims 1 to 7 or 9, or a pharma- ceutically acceptable salt thereof, wherein is dioxanyl.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharma- ceutical acceptable salt thereof.

13. 13. The pharmaceutical composition according to claim 12 for use in the prevention and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases associated with disorders of cartilage turnover, congenital cartilage malformations, diseases associated with disorders of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferon, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, skin diseases and / or diseases associated with abnormal angiogenesis.

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